THE

DUCTLESS GLANDULAR
DISEASES

FALTA

THE

i

DUCTLESS GLANDULAR
DISEASES

BY

WILHELM FALTA

TRANSLATED AND EDITED BY

MILTON K. MEYERS, M. D.

NEUROLOGIST TO THE LEBANON HOSPITAL, AND TO THE DISPENSARIES OF THE
JEWISH AND ST. AGNES HOSPITALS, PHILADELPHIA, ETC., ETC.

WITH A FOREWORD BY

ARCHIBALD E. GARROD, M. D. (Oxon.)
F. R. C. P. (London), F. R. S.

PHYSICIAN TO ST. BARTHOLOMEW'S HOSPITAL, LONDON

SECOND EDITION

^ / Of\

WITH 101 ILLUSTRATIONS IN THE TEXT

PHILADELPHIA

P. BLAKISTON'S SON & CO.

1012 WALNUT STREET

COPYRIGHT, 1916, BY P. BLAKISTON'S SON & Co.

THE M v I'l.l. PRESS YORK PA

DEDICATED

TO MY

CLINICAL MASTERS
W. HIS, FR. V. MULLER

AND

C. V. NOORDEN

PREFACE

The considerable impetus that has been given to the study of the internal
secretion in the last two decades quite justifies the experiment of publishing
the diseases of the ductless glands connectedly. The experimental physiol-
ogy and pathology has been dealt with in exhaustive fashion in the excellent
work of A . Biedl.

The present volume is concerned with the clinical aspects of the diseases
of the ductless glands. Of the results of experimental pathology I have set
forth only as much as seemed to me necessary for the explanation of the clin-
ical manifestations. For the rest of these results the reader is referred to
the work of Biedl.

In most of the chapters I have tried to describe the clinical symptomatol-
ogy on the basis of my own observations, such as I had occasion to make,
for the most part, at the first medical clinic in Vienna.

Prof. Dr. L. von Frankl-Hockwart and Privat-Docent Dr. R. Stern I thank
cordially for the revision of the neurological part, Prof. Dr. Stoerck for the
revision of the pathologico-anatomical part, and the latter also for numerous
microscopical preparations. The X-ray examinations, when not especially
credited, were by Dr. G. Schwarz, director of the Roentgen division of the
first medical clinic. I thank Assistant Dr. S. Bernheim for aid in the work-
ing-through of numerous experimental questions. Finally I am indebted to
my publishers, the firm of Julius Springer, for their assistance in the fitting-
out of the book. N

W. FALTA.

VIENNA.

EDITOR'S PREFACE

The aim and effort of the American editor has been to furnish, not merely
a faithful rendering of the German text, but also a rounding out of the sub-
ject by the consideration of recent American and English views. To this
end he has consulted a wealth of material, comprising some hundreds of
references and numerous original articles, from which it is quite apparent
that many of the investigators have been concerned with the purely scien-
tific or abstruse, rather than with the clinical aspects of the subject. While
consulting the literature, the editor could not help but feel that when it
has been properly digested and classified, a considerable advance will have
been made toward raising the status of the ductless glandular diseases to the
level of an exact science.

The American and English views mentioned will be found in the adden-
dum that is at the end of nearly every chapter. If some of these addenda
bear a too subjective tinge it is because the editor in his choice of the litera-
ture was guided more or less by his personal experience, in which case he may
not have done full justice to certain chapters. Care has been taken, in add-
ing the new matter, not to confuse the clear-cut scheme of Falta, who so
admirably separates the various groups of ductless glandular diseases by
well-defined lines. This delimitation of the various groups of ductless glandu-
lar diseases at the present time is a most desirable generalization which will
enable us to appreciate not only the various parts which the different duct-
less glands play in the make-up of an individual disease picture, but also
to individualize in our diagnosis, even as we are now justified in individualiz-
ing, to a certain extent, in the types of Basedow's disease. Granted that we
are not as yet prepared for this along the whole line of the ductless glandular
diseases, it then becomes our obvious duty to ascertain what symptoms the
individual ductless glandular diseases, as expressed or evidenced in different
patients, have in common, so that the patients may be classed in their re-
spective groups. Only later will the emphasis of differences between indi-
viduals of the same group add pleasure and refinement to the diagnosis, and
efficiency to the treatment. This is said with a knowledge of the prevailing
tendency of certain foreign schools, chiefly the French, to regard each indi-
vidual patient's condition as a disease picture sui generis; which in truth in
one sense it really is, but which, for purposes of analysis and ultimate
progress, we are not as yet justified in regarding as such.

\ EDITOR'S PREFACE TO SECOND EDITION

As to the text proper, but very little difficulty has been found. Occa-
sionally when the editor could think of no corresponding English expression,
an approximate meaning is given, with the German word in brackets.
"Die Erkrankungen der Blutdrusen" has been translated "The Ductless
Glandular Diseases," as forming a sufficiently comprehensive and universally
intelligible title. It is especially, however, to the ductless glands with
more or less well-defined internal secretions (endocrine organs) that our
author directs his attention, consequently such bodies as the spleen, the
diseases of which are well described in relation with those of the hemato-
poietic system, and Luschka's gland, and the carotid body are not here
considered.

"Ausfallerschienungen" has been variously translated "phenomena" or
"manifestations" or "symptoms" due to "lack," "deficiency," "loss,"
"withdrawal," "absence" and in some cases "falling out." "Uberlange"
has been translated "upper length;" "Unterlange" "lower length." The
first mentioned of these anthropological measurements is taken from the
vertex to the symphysis pubis, the second from the symphysis to the heels
(according to A. Saenger, Ueber Eunuchoidismus, Deutsche Zeitschrift fur
Nervenheilkunde, Bd. 51, Heft. 5-6, 1914, p. 192).

The author's list of references has been corrected to some extent, and the
abbreviations of journals have been changed to correspond to the standard
abbreviations of the U. S. Surgeon General's Catalogue. The index has
been revised and enlarged.

The editor's thanks are hereby accorded to Messrs. P. Blakiston's Son
&• Co. for the uniform kindness and courtesy shown him in the preparation of
this volume.

MILTON KAYTON MEYERS.
PHILADELPHIA.

EDITOR'S PREFACE TO SECOND EDITION

Advantage has been taken, on the issue of a new edition, to revise
the text thoroughly and to add a few abstracts of recent literature to the
addenda.

MILTON KAYTON MEYERS.

PHILADELPHIA.

FOREWORD

BY

ARCHIBALD E. GARROD, M. D. OXON., F. R. C. P. LOND., F. R. S.
PHYSICIAN TO ST. BARTHOLOMEW'S HOSPITAL, LONDON

When Addison first described the syndrome which has ever since borne
his name, and proved its dependence upon destructive lesions of the adrenal
glands, he broke ground in a new field of medical enquiry of the extent of
which neither he nor his contemporaries can have formed any conception.

The ductless glands had long been known to anatomists as structures of
wholly obscure functions, and only in quite recent times has any wide
knowledge been gained of the important parts which they play in the animal
economy.

Indeed some thirty years elapsed after Addison's discovery before the next
step in advance was achieved by the recognition of the dependence of cretin-
ism and myxedema upon disease of the thyroid gland. Since then facts
have accumulated rapidly, yet hardly so rapidly as to keep pace with the
hypotheses built upon them.

Nowadays the influences of the glands of internal secretion, in which
category are included other organs besides the glands which are classed as
ductless, hold a very prominent place in medical thought and investigation.
As witness the many discussions which took place in various sections of the
1 7th International Medical Congress, which met in London in 1913, and
in many informal gatherings of its members from all parts of the civilized
world.

Pathological investigations have come to the aid of physiological research
in the elucidation of the functions of these glands in health, and of clinical
medicine in the study of the diseases to which they are liable, and of the
symptoms by which these diseases are revealed. There is indeed no de-
partment of physiology in which more has been learned from the experiments
which Nature herself has carried out.

By the removal of individual glands, and by observation of cases in which
they have been destroyed by disease, we have learned what results accrue
from withdrawal of their influence, and have even been enabled to discrimi-
nate between the individual functions of the parts of such of these organs as
are compound structures. For it is a remarkable example of the economy of
Nature that in some instances two or more structures yielding internal secre-

zi

xii FOREWORD

tions have been welded together into a single compact organ. Thus the
i hromaffin medulla of the adrenals is clothed with the functionally distinct
cortex; and the pituitary body, small as it is, appears to be even more
complex.

That certain morbid states result from loss of function of particular glands
of internal secretion is a fact so clearly established as to admit of no two opin-
ions. As regards the thyroid gland, if the effects of its removal left any room
for doubt, the striking results of the administration of the gland substance in
cases of myxedema and cretinism would remove that doubt. Nor is evi-
dence lacking that such cases of athyroidism are but the extreme examples of
series of cases of gradations of thyroid defect which bridge over the gap
which separates myxedema from normality. To describe such conditions,
of impaired but not abolished function, there have come into use such terms
as hypothyroidism and hypopituitarism.

Concerning diseases of another kind, of which exophthalmic goiter may
be selected as the type, there is no such unanimity. It is widely held that
such conditions present the reverse of the picture, and that they result from
overactivity of the gland involved, and excessive production of its secretory
products.

Many facts may be adduced in support of this theory, such as the effects
of partial removal of the thyroid gland in exophthalmic goiter, and of liga-
ture of its arteries, and the results of administration of thyroid extract in
excess. Moreover, there are certain less obvious symptoms which suggest
a converse to myxedema. For example the exalted tolerance of carbohy-
drates, which is a feature of myxedema, as contrasted with the so frequent
lowering of tolerance in exophthalmic goiter. Such evidence is fully set
forth by Professor Folia in this work, for he is a staunch upholder of the view
that all the morbid symptoms which result from diseases of the glands of
internal secretion, so far as they can be ascribed to their secretory functions,
are attributable either to depression or exaltation of the function of the gland
concerned.

However, there are some, who are entitled to speak with authority, who
are unable to accept this interpretation, and who hold that the maladies so
often ascribed to excessive functional activity are rather due to perversion
of function, and the production by the gland concerned of an abnormal secre-
tion. Such terms as dysthyroidism and dyspituitarism are used to express
this conception.

The arguments adduced in its favor are of several kinds. It must be
acknowledged that the administration in excess of the active principle of the
thyroid gland, although it brings about exaltation of the metabolic processes
in strict contrast to the depression of those processes observed in myxedema,
and produces some of the symptoms of exophthalmic goiter, does not repro-
duce the picture of that disease so exactly as to place its origin in excessive

FOREWORD Xlll

functional activity of the gland beyond all question. Again it is urged that
it is difficult to conceive of overfunction as resulting from disease, which
might rather be expected to impair the activities to a greater or less extent.

As against this it may be urged that it is equally hard to imagine a per-
version of the metabolic changes into new lines, other than those in which the
several protein fractions, and even the several carbohydrates, are normally
dealt with, stage by stage, by specialized enzymes.

The more the internal secretions are studied the more clearly it is being
realized how wide is the field of their activities. We are learning that, in
addition to the control of metabolism, or rather in virtue of that control, the
endocrine glands exert immense influence upon growth and development;
and their their hormonic functions are exercised now in the direction of stimu-
lation, and now in that of restraint. Indeed it is not possible to conceive
of a control which is wholly one-sided; the controlling agent must be able to
curb as well as to urge on. So we are led to think of inhibiting as well as
exciting hormones, if that term may be so perverted from its literal meaning.

In addition to our more exact knowledge, so encouraging in its progress,
although as yet so incomplete, of the work of the individual glands, we begin
to see evidences of an interaction of the organs of internal secretion, as mem-
bers of a group of immense influence, a hormonpoietic system. Here we are
stepping on to far less firm ground than we have hitherto trodden, and we
need to move with caution lest our hypotheses carry us further than our facts
warrant. Yet the evidence is at the least highly suggestive. We see how
removal of a single gland, by operation or disease, is followed by changes in
other glands of the group — changes which are best explained by removal
of a wonted stimulus or withdrawal of a regulating control.

Moreover there is evidence, as Claude and Gougerot were the first to
point out, that the various glands of internal secretion may be attacked simul-
taneously by a morbid process which is described as pluriglandular sclerosis.
Where this is the case the clinical picture presents elements of the several
syndromes which result from depression of function of the individual glands
of the group. Thus there are suggestions of hyperthyroidism, of pituitary
defect, of genital hypoplasia, and of Addison's disease, side by side in the
same patient.

The interrelation of the endocrine glands and the nervous system is yet
another subject full of interest, and which receives full consideration in Pro-
fessor Falta's pages. How close is the control exerted by the vegetative
nervous system over the organs of internal secretion is brought home to us
when we consider such phenomena as puncture glycosuria. It may now be
taken as proven that the impulse conveyed to the adrenals by the splanchnic
nerves excites a temporary excess of secretion of these glands, and to this the
excretion of sugar is due. Thus it is suggested that not a few phenomena,
attributable to nervous impulses, are produced through the instrumentality

xiv FOREWORD

of the endocrine glands, and the symptoms referable to disturbances of their
functions are not necessarily due to actual disease of these organs. It may be
that such is the explanation of much which is still obscure as to the part
played by the pancreas in diabetes.

The literature of internal secretions is already a very large one, and in
the monumental work of Biedl we have set before us all that is known of the
subject from the standpoints of physiology and experimental pathology.

The present work has a different scope and aim. In it the maladies of
the hormonopoietic system are for the first time discussed in a single volume,
and from the clinical standpoint. It will be welcomed by members of the
medical profession in all lands, for in it will be found accurate and detailed
descriptions of the symptom groups which have their origin in lesions of the
glands of internal secretion, and also of some diseases for which such an origin
has been suggested.

It is all the more valuable because it is the work of a physician who com-
bines bedside observation with experimental research in the laboratory.
Professor Falta's important contributions to our knowledge of pathological
chemistry are widely known, and he has been led on to the study of the regu-
lators of metabolism by his interest in the chemical processes which it is
their function to control.

CONTENTS

CHAPTER I

PAGE

General Part 1-52

Historical Development and Definition i

Reciprocal Action of the Ductless Glands 3

Question of Dysfunction 10

Influence of the Ductless Glands on the Growth 13

Influence of the Ductless Glands on the Regulation of Metabolism 16

Embryology of the Ductless Glandular System 20

Grouping of the Ductless Glands 22

Relationship between the Ductless Glandular System and the Nervous System . 23

A. Influence of the Ductless Glandular System on the Nervous System ... 24

B. Influence of the Nervous System on the Function of the Ductless Glandu-

lar System 32

Influence of the Ductless Glands on the Hematopoietic Apparatus 33

Pathogenesis and Etiology of the Ductless Glandular Diseases 35

Relation between Diseases of the Central Nervous System and the Ductless Glandu-
lar System 37

Pluriglandular Disturbances 42

The Ductless Glands and Constitution '. 45

Addendum 49

CHAPTER II

The Diseases of the Thyroid Gland 53-153

Anatomy and Embryology 53

Tumors of the Thyroid Gland 54

Inflammations of the Thyroid Gland 55

(a) Morbus Basedowi—Hyperthyrosis 57

Historical and Definition 57

Occurrence and Symptomatology 57

Pathogenesis 84

Etiology 93

Forms of Basedow's Disease 94

Diagnosis '98

Prognosis and Treatment 98

(6) Athyrosis or Hypothyrosis 103

Historical 103

1. Myxcedema Adultorum or Cachexia Thyreopriva Adultorum 104

Definition 104

Occurrence and Symptomatology 104

Etiology and Course 117

Differential Diagnosis 118

2. Sporadic Cretinism 120

Definition 120

Symptomatology 123

Differential Diagnosis 138

Treatment of Athyrosis or Hypothyrosis 139

Addendum • 144

xv

xvi CONTENTS

CHAPTER III

PAGE

The Cretinic Degeneration I54~J73

1. Goiter 155

2. Goiter-Jieart 156

3. Endemic Cretinism 158

Symptomatology . 158

Endemic Mutism 161

Treatment 165

Pathogenesis 169

Differential Diagnosis 171

Addendum 172

Diseases of the Parathyroid Glands 1 74-222

Anatomy 174

Embryology 175

Historical 176

(a) Aparathyrosis or Hypoparathyrosis, Tetany 177

Definition 177

Symptomatology 177

Pathogenesis of Tetany 200

Forms of Tetany and Pathological Anatomy 207

1. The Para thy roprivic or Traumatic Tetany 207

2. Tetany in Diseases of the Thyroid Gland 209

3. Tetany in Infectious Diseases and Intoxications 209

4. Idiopathic Tetany (Occupation Tetany) 210

5. The Tetany of Children 212

6. The Tetany of Maternity 213

7. Tetany in Gastrointestinal Diseases 214

Differential Diagnosis 216

Prognosis and Treatment 218

(b) Condition of Hyperfunction of the Parathyroid Glands 220

Addendum 221

CHAPTER V

Diseases of the Thymus Gland 223-230

Anatomy and Embryology 223

Physiology 223

Pathology and Semiology 225

•Addendum 229

CHAPTER VI

Diseases of the Hypophysis 231-328

Anatomy and Embryology . 231

(a) Acromegaly 235

Definition 235

Occurrence and Symptomatology 235

Pathological Anatomy 267

Pathogenesis 269

Early Acromegaly " 277

Differential Diagnosis 280

Treatment •. .... 281

(b) Hypophysial Dystrophy . 282

Historical 282

CONTENTS XV11

PAGE

Definition 283

Symptomatology 283

The Metabolism 280

Pathogenesis 315

Differential Diagnosis 324

Treatment 325

Therapeutic Use of the Hypophysis Extracts 326

Addendum 327

CHAPTER VII

Diseases of the Epiphysis 329-333

Anatomy and Embryology 329

Pathological Anatomy and Symptomatology 330

Diagnosis and Treatment 332

Addendum 333

CHAPTER VIII

Diseases of the Suprarenal Apparatus 334-364

Anatomy and Embryology 334

(a) Condition of Hypo/unction of the Suprarenal Apparatus 336

1. Addison's Disease 336

Definition 336

Symptomatology 336

Course 338

Pathological Anatomy 338

Pathological Physiology of the Suprarenals 342

Pathogenesis of Addison's Disease 346

Differential Diagnosis 347

Prognosis and Treatment 348

2. Isolated Phenomena due to Failure of Function of the Suprarenal Cortex . .351

(b) Conditions of Hyperf unction of the Suprarenal Apparatus 352

1. Tumors that Proceed from Chromaffin Tissue 352

2. Tumors that Proceed from the Cortex 356

Treatment • 363

3. Tumors of the Suprarenal Gland that Apparently Consist in Cortex and Medulla. 363
Addendum 363

CHAPTER IX

Status Lymphaticus and Status Hypoplasticus 365-368

A. Status Lymphaticus 365

B. Status Hypoplasticus 367

CHAPTER X

Diseases of the Sexual Glands 369-439

Embryology, Anatomical and Physiological Preliminary Remarks 370

A. The Interstitial Glands 370

B. The Generative Apparatus 374

Pregnancy 377

I. The Malformations 385

1. Aplasia of the Sexual Glands 385

2. Hermaphroditism 386

II. Agenitalism, or Hypogenitalism 391

i. Eunuchs . : 391

Occurrence and Symptomatology 391

xviii CONTENTS

PAGE

2. Late Castrates 394

3. Eunuchoidism 397

Definition 397

.Historical and Case Histories 397

Symptomatology . 4°5

Occurrence and Pathogenesis 410

Differential Diagnosis 410

Prognosis and Treatment 412

4. Late Eunuchoidism . 413

Historical 413

Definition 414

Case Reports _ 414

Symptomatology 418

Differential Diagnosis 421

Treatment 422

5. Treatment of Genital Glandular Insufficiency 422

III. Hypergenitalism 424

Definition 424

Pathologico-anatomical Findings 424

Symptomatology . 424

Treatment •- • 427

IV. Chlorosis ........,.".... 426

Historical 426

Symptomatology 428

Pathogenesis 431

Appendix, Osteomalacia 435

Addendum 438

CHAPTER XI

Pluriglandular Diseases 440-463

Multiple Ductless Glandular Sclerosis .;...•. 440

Historical ' 441

Definition 442

Case Reports , 442

Symptomatology 445

Differential Diagnosis 453

Treatment 453

Giganlism 454

Historical ......••.." 454

Symptomatology 455

Pathogenesis 461

CHAPTER XII

Vegetative Disturbances that do not depend Directly on Diseases of the Ductless

Glands 464-498

I. Infantilism 465

Historical 465

Definition 468

Symptomatology 472

Forms and Etiology . 474

Differential Diagnosis 475

Pathogenesis \ 470

Prognosis and Treatment 479

II. True Dwarfism 480

CONTENTS xix

PAGE

Historical 480

Primordial Nanosomia 480

Paltauf's Dwarf 481

III. The Rachitic Dwarf 384

IV. Chondrodystrophy 484

Historical 484

Definition 485

Symptomatology 485

Occurrence 491

Etiology 493

Differential Diagnosis . 493

V. Mongolism 494

Symptomatology 494

Pathogenesis and Treatment 497

Addendum 497

CHAPTER XIII

Diseases of the Insular Apparatus of the Pancreas and Their Relation to Diabetes

Mellitus 499-569

Historical Development 499

Anatomy and Embryology 501

I. Experimental Part 503

A. Diabetes after Extirpation of the Pancreas 503

B. Experimental Nervous Diabetes . 515

II. Clinical Part 518

A. Gross Anatomical Disturbances 518

B. Genuine Diabetes Mellitus 526

The Carbohydrate Metabolism 527

The Protein Metabolism 529

The Water Equilibrium 530

The Respiratory Metabolism 531

Vegetative Nervous System 540

Pathological Anatomy of Diabetes Mellitus 546

Theoretical 561

Differential Diagnosis 566

Addendum 568

CHAPTER XIV

The Different Forms. A Obesity and Adipositas Dolorosa 570

A. The Different Forms of Obesity 570

1. Pancreatogenic Obesity 572

2. Thyrogenic Obesity 573

3. Dystrophia Adiposo-genitalis 574

4. Epiphysial Obesity 575

B. Adipositas Dolorosa 575

Historical 575

Symptomatology 581

Pathological Anatomy 583

Pathogenesis 584

Differential Diagnosis 587

Treatment 587

Addendum 587

Literature 590

Index 659

THE DUCTLESS GLANDULAR DISEASES

CHAPTER I

GENERAL PART

Historical Development and Definition

The clinical delimitation of a group of the disease pictures which to-day
are known as diseases of the ductless glands is to a certain extent very much
older than the conception of the idea of internal secretion as elaborated by
experimental pathology. The profound alterations in the bevelopment of
the human organism after removal of the sexual glands in early life are too
remarkable not to have awakened the interest of physicians and the laity
as early as the days of antiquity. The breeders of animals had made use of
empirical knowledge long before the question was discussed as to in which
way the sexual glands influence the formation of the body and its dis-
tribution of fat. A material progress, however, in the development of
the clinical aspects of the diseases of the ductless glands began only about
the middle of the igth century. It is associated indissolubly with the name
of Thomas Addison. Addison in 1855, on the ground of pathologico-anat-
omical findings, referred the sickness that bears his name to a destruction
of both suprarenal glands. Then after Gull, Ord, and Charcot had described
myxedema clinically, Theodore Kocher and Reverdin, in 1882 and 1883,
demonstrated that this disease picture is due to the absence of the functional
activities of the thyroid gland. We must regard the year 1886 as a further
landmark in the history of the diseases of the ductless glands. In this
year Mb'bius first expressed the idea that a disease picture — Basedow's
disease — depends on an abnormally increased activity of a ductless gland.
First in the year 1889 Brown-Sequard reported to the Biological Society of
Paris concerning experiments that made it seem as though the ductless
glands furnished to the blood substances that, when carried by the blood
to distant-lying organs, influenced these extensively. Brown-Sequard in-
jected juice of the testicle subcutaneously into his own body and observed
an increase in corporeal and mental powers that he attributed to the in-
fluence of these injections. It is true that Johannes Muller, Ruysch, and
other authors preceded Brown-Sequard; it was, however, Brown-Sequard who
first clearly formulated these thoughts, based them on experiments, and
thus attracted the general interest of the medical world to them. With
the extension of experimental pathology, disease pictures that had formerly
been regarded as nervous diseases or constitutional diseases were added to

2 GENERAL PART

the new disease group in rapid succession. The discovery of pancreatic
diabetes by von Mering and Minkowski placed the pancreas as the central
figure in the pathogenesis of diabetes mellitus. Then later came the studies
of Schulze and Ssobolew as to the physiological and pathological independence
of the insular apparatus, and of Opie, Saltykoiv, W eichselbaum and others as
to the histological alterations in the insular apparatus in diabetes mellitus.
The very much later discovery by Blum of the glycosuric action of the
suprarenal extract and the knowledge that "sugar puncture" produces
discharge [of the secretion] of the suprarenal through conduction to the
chromaffin tissue by way of the sympathetic paths have again brought about
partial recognition of neurogenic origin of diabetes as first advocated by
Claude Bernard. For clinical purposes the chromaffin tissues won recog-
nition through the teaching of Wiesel, that hyper tonia in contracted kidney
originates through hyperplasia of the chromaffin tissue, and through the
recognition that in status lymphaticus the chromaffin tissue is ordinarily
found to be hypoplastic (Wiesel, Hedinger). "Thyroid tetany" was dis-
covered experimentally by Schiff and clinically by N. Wein. The discovery
of parathyroprivic tetany by Gley, Vassale, andGenerali dissociated, however,
the symptoms of tetany from those of absence of the thyroid gland and
ascribed to the parathyroid gland the decisive role in pathogenesis of the
individual forms of tetany (Jeandel-ize, Pineles, Erdheim, Chvoslek). After
Pierre Marie had already brought the disease acromegaly, which had been
described by him, into relation with the hypophysis, the fact became gen-
erally recognized that not, as was originally thought, a diminution but an
increase in function of the hypophysis brought about this disease; while in
1901 A. Frb'hlich and after him especially v. Frankl-Hochwart distinguished a
disease type, in many respects the anti-type of acromegaly, that through
the newer investigations of experimental pathology can be regarded as the
sequel of a diminution of function of this organ. The pathological anatomy
of the hypophysis was especially advanced by Benda, who established the
adenomatous character of the hyperplasia of the hypophysis in acromegaly,
and by the studies of Erdheim on squamous epithelioma in hypophysial
dystrophy. The histology of the struma of Basedow's disease was thor-
oughly studied earlier. The pathogenetic place of the thyroid then won
further significance through the operative treatment of Basedow's disease
(Rehn, Kocher, and others), and through the study of its relationship to
sporadic cretinism (" thyreoaplasie " of Pineles), to endemic cretinism
(V. Wagner, H. &• E. Bircher, Ewald, Scholz) and to goiter heart (Fr. Kraus).
Also the significance of the sexual glands for many disease pictures was
more exactly studied. Eunuchoidism was sharply delineated by Tandler
and Grosz, and the clinical symptomatology of pmareture development of
the sexual glands was more widely developed. Then were added new
investigations as to the relation of the epiphysis [pineal gland] (Marburg,

HISTORICAL DEVELOPMENT AND DEFINITION 3

v. Frankl-Hochwart] and the suprarenal cortex to premature development.
Only the thymus gland has not as yet found a secure position in the sympto-
matology of the disease of the ductless glands. Finally, the symptomatol-
ogy of multiple ductless glandular sclerosis has been more sharply delimited
under the multiform syndrome of " insuffisance pluriglandulaire " described
by Claude and Gougerot, and from it has been separated the disease picture
of isolated late eunuchoidism.

These few examples may suffice to furnish an idea of the impetus that the
clinical aspects of the disease of the ductless glands have assumed in the last
decade. The advance in experimental pathology and especially in physio-
logical chemistry has really not kept pace with this development of clinical
pathology and the extension of pathological anatomy. I do not mean to
belittle the significance of what has been brought to recognition through
experimental pathology; this alone has made possible the rapid advance of
the clinical side; I only wish to say that the deficient knowledge of the
chemical nature of the active substances given off by the ductless glands
constitutes the weak point in the knowledge of the internal secretions and
explains why even to-day we are very often compelled to work with hazy
ideas. But even in this direction significant accretions [to our knowledge]
are present; we can say that through the isolation and chemical definition
of adrenalin (Takamine) and through the knowledge that this body of re-
latively simple chemical structure and eminent physiological activity is the
specific secretion of the chromaffin system, the foundation stone has been
laid for the physiological chemistry of the internal secretions. Experi-
mental pathology entered here most opportunely, and acted prominently
in the discovery of the manifold actions of this substance and its points of
attack on the organs affected by the sympathetic nerves. The isolation
of adrenalin, it is known, followed from that of iodthyroglobulin (Baumann,
Oswald). In this case, however, slight doubts are still present as to whether
we have in iodthyroglobulin the specific internal secretion of the thyroid
in purest form. Then, too, we are very much less exactly informed as to
its way of action and points of attack. The knowledge of the specific
secretion of the other ductless glands is as yet extremely faulty. Of the
suprarenal cortex we only know that it contains cholin, a body of con-
siderable physiologic activity that is distributed otherwise in the organism.
That, however, we have in cholin a specific secretion of the suprarenal cortex
is improbable. It has been possible recently to obtain from the lobes of
the hypophysis extracts of great physiologic importance that have already
secured for themselves a place in therapeutics; but there are wanting the
chemical definition and the demonstration that these bodies are given off
to the blood. All postulates that we must ascribe to a substance in order
that we may regard it as the specific secretion of the ductless gland in question
have not as yet been fulfilled by any of the hormones. We must ascertain:

4 GENERAL PART

1. That the substance in question be found in the efferent blood-path or
lymph-path*

2. That after experimental extirpation of the ductless gland in question
the' symptoms due to the removal are combated by peroral or sub-
cutaneous administration.

3. That through the long-continued administration of this substance
manifestations are elicited that are similar to those which clinical
evidence leads us to regard as the symptoms following upon increased
function, a conception that, as the results of the surgical therapy of
these conditions, has in recent years been -made certain.

All these postulates are not fulfilled in the case of adrenalin. Adrenalin
has been demonstrated in the blood of the suprarenal vein, but the relation-
ship to clinical medicine is still lacking in clearness. In the case of iodthy-
roglo^ulin, the demonstration in the blood or the lymph is as yet lacking.
Hypophysis extract has as yet not been studied enough, so that we can-
not say that it fulfills any of these postulates. As far as the other ductless
glands are concerned (for example, the insular apparatus of the pancreas, or
the parathyroid glands), the significance of which in experimental or clinical
pathology is extraordinarily imperfect, we have not as yet succeeded in
obtaining active extracts, or we are not at all certain that the observed
actions of the extracts are specific. The physiological chemistry of the
internal secretions is still in its childhood. From it alone, however, is a
sharp definition of the disease picture to be expected; the chemical demon-
stration of the specific substances in the blood even in combined form, the
possibility of the demonstration that these substances in lessened, normal, or
increased quantities circulate in the blood, would be of great importance for
clinical medicine. The biological method in this direction has up to the pres-
ent failed. The chemical definition and isolation in pure form of these spe-
cific substances will also furnish an important advance in the therapy of the
diseases due to lack of these glandular substances in the organism. The
domain of the internal secretions constitutes for physiological chemistry an
inexhaustible field for labor that theoretically and practically represents a
rich reward.

The backwardness of the physiologico-chemical knowledge in this
territory explains why it has not been possible up to the present to obtain a
clear definition of the idea of internal secretion. According to the original
assumption, we understand by internal secretion the giving off of physio-
logically active substances into the circulation, of substances that through
their action on distantly-lying organs act in a regulatory manner on the
complex processes sustaining life. According to this general definition, how-
ever, every tissue in the animal body really yields an internal secretion, as
von Krehl has already pointed out. The point of emphasis in this defini-
tion lies in the assumption of a chemical correlation of the individual organs

HISTORICAL DEVELOPMENT AND DEFINITION 5

of the body in contradistinction to the assumption of a nervous correlation,
which formerly was almost all-sufficient. This distinction is indeed not to be
maintained so rigidly for, as we shall see later on, it must be assumed that
to many specific ductless glandular secretions must be ascribed an important
and, after its fashion, a quite definite influence on the condition of excita-
tion of the nervous system. We cannot indeed exclude the question as to
whether the action of the ductless glandular secretions does not come about
through alterations in the metabolic processes in the various parts of the
somatic and vegetative neurones (ganglion-cells, myoneural junctions, etc.).
A. Biedl happily expresses these changes in our views by the dictum: "For-
merly every correlation of organs was regarded as nervous; to-day, however,
even nervous actions are regarded as brought about chemically." Bayliss
and Starling have found that under the influence of the acid gastric juice
upon the epithelial cells of the intestinal mucosa a substance is secreted by
the latter that brings about through the circulation the secretion of pan-
creatic juice. They call such chemical messengers hormones (from 6^/iaw =
I call), a designation that now has found almost general use also as applied
to the specific secretions of the ductless glands. With such a general
application of the meaning of the internal secretions, not much is to be
gained for clinical purposes, as may readily be seen. Nor is a morphological
definition of the ductless glands possible, as Biedl has pointed out. The histo-
logical structure of the individual ductless glands varies according to their
genesis from the different germinal layers. Whether the specific secretions
of the ductless glands are to be separated from the other hormones through
their chemical characteristics cannot be answered at all at the present day.
Anatomy, morphology, embryology, experimental physiology, and patholog-
ical chemistry do not furnish to-day a satisfactory characterization of the
ductless glandular system. Up to the present, the demonstration that an
individual ductless gland belongs to a system is furnished most distinctly
by clinical observation, particularly by the intimate reciprocal relations of
the ductless glands under physiological and pathological conditions.

It appears to me, therefore, that first and foremost it is more important for
the clinical point of view not to associate the meaning of internal secretion
exclusively with the ductless glands. I might formulate this standpoint in
the following way: probably very many cell-complexes of the animal organ-
ism possess an internal secretion. We may designate the totality of all cell-
complexes provided with an internal secretion a hormonopoietic system. There
are, however, a series of organs the proper function of which we must regard as the
production of especially important hormones, which are provided with powerful
physiological characteristics. It is a common property of these organs that they
separate out their specific secretion directly into the blood-path. We therefore
call them ductless glands, and their collective total the ductless glandular system.

The recognition that the ductless glands form a system was of great sig-

6 GENERAL PART

n ilk a nee for the clinical aspects of the diseases of the ductless glands. This
recognition, that was especially furnished by the serviceable work olPineles,
(IrjK'nds not only upon the observations of intimate physiological reciprocal
relations., but also upon numerous clinical experiences and pathological-
anatomical findings that show that diseases very frequently affect several
ductless glands simultaneously, and lead not only to simultaneous increase of
function, but also to simultaneous diminution in function, or to a combination
of increase of function in some of these organs and to diminution of func-
tion in others.

Reciprocal Action of the Ductless Glands

I would like here to enter a little more fully into the question of the re-
ciprocal action of the ductless glands; the phrase has become, as Novak says,
a catchword. An immense amount of work in recent years has been de-
voted to the study of this reciprocal action, and hypotheses and speculations
have grown luxuriantly upon this soil. It is true that up to the present
we really know nothing exactly concerning the intimate process in these
reciprocal actions, but in a clinical relation such correlations force themselves
unmistakably upon the observer; the knowledge of them makes easier the
analysis of the often complicated disease picture. Finally, the expressions
"reciprocal reinforcement" or "reciprocal inhibition" are in the first place
nothing other than circumlocutions for [clinical] observations. If we view
the thing from this standpoint it seems to me that the study of these corre-
lations is productive.

For the understanding of these often very complicated processes it seems
to me that a separation of physiological and pathological correlations becomes
absolutely necessary. Among physiological correlations I mean to include
the action that the alteration of function of a ductless gland — diminution
or increase of function — exercises upon the function of another otherwise
normal ductless gland. These conditions are fulfilled in an ideal manner,
when the ductless gland has been extirpated, for example. This can occur in
human pathology. I have reference to the total extirpation of the thyroid
gland which, formerly, before we knew about the incurable results of the
operation, was also undertaken in human beings; or to parathyroprivic
tetany after operations on the thyroid gland; or to castration. Further,
an inflammatory process may become established in an isolated ductless
gland and cause its destruction. In such cases we must by all means be
very careful as to the assumption of a pure physiological correlation, as,
according to experience, inflammatory processes affect very commonly other
members of the ductless glandular system. Here we often find, therefore,
as we shall see later, transitions to pathological correlations. Also the
increase in function may be produced experimentally in the pure form as, for
example, after feeding with thyroid-gland substance. Again, in many cases

RECIPROCAL ACTION OF THE DUCTLESS GLANDS 7

of Basedow's disease and of acromegaly there are no grounds for doubting
an increase in function of the ductless gland affected, though even here the
transition to pathological correlations is extraordinarily common.

I will now quote some examples of the physiological correlations, con-
fining myself chiefly to the investigations I carried out in collaboration
with Eppinger and Rudinger.

The total extirpation of the thyroid gland with careful avoidance of the
parathyroid glands — the electric excitability must show no increase in con-
sequence of the procedure — calls forth a diminution of the total processes
of metabolism. Let us examine a little more in detail the carbohydrate
metabolism in a thyroidless animal. The power of assimilation for carbo-
hydrates is increased. Now, as it has been known that the capacity of as-
similation depends upon the functional breadth of the insular apparatus of
the pancreas, we may draw the conclusion that there must be a relative or
an absolute increase of the function of the insular apparatus of the pancreas.
But the extirpation of the thyroid gland also diminishes the excitability

X

C. T.

FIG. i.— P, Insular apparatus of the pancreas; T, thyroid; C.T., chromaffin tissue;
— , inhibition; +, reinforcement.

of the vegetative nerves. For example, the glycosuric action of adrenalin —
in addition to other actions, such as the production of a hyperglobulia — is
diminished. As it is known that the excitability of the myoneural junction
of the sympathetic nerves depends upon the activity of the chromafrin tissue,
we may readily infer that the activity of this ductless gland (i.e., the
chromafrin tissue) is diminished, whether it be that the production of adren-
alin is diminished, or that the working of this hormone in the organs affected
is slighter because of the fact that an otherwise present sensitivization of the
organs fails to occur (Asher and Flack). A sensitivization for adrenalin has
also been assumed as due to the extract from the posterior lobe of the hypo-
physis (Kepinow).

After the total extirpation of the pancreas there occurs an increase of all
metabolic processes with a high-grade diminution of the assimilation limits
for carbohydrates. In addition there are indications of an increased ex-

S GENERAL PART

citability of the sympathetic nerves (Loui's reaction, increased glycosuric
action of adrenalin). Therefore we conclude that there is an increased
function of the chromaffin tissue or at least there is an increased action of the
circulating adrenalin. Again, in Addison's disease, in which the function
of the chromaffin tissue is primarily diminished, we find a heightening of
the assimilation limits for carbohydrates. We explain this as due to with-
drawal of the inhibition exercised by the chromaffin tissue on the insular
apparatus and to a secondarily increased function of the latter.

Newburgh, Nobel and 7 have contributed a further observation. Peroral
administration of thyroidin occasions in human diabetes a long-continued
hypertonia. We interpret this as the functional increase of the chromaffin
tissue in consequence of a heightened sensibility of this tissue or of its central
projection fields.

Through this and similar experimental findings and clinical observations
the conclusion was drawn as to a reciprocal action between thyroid, insular
apparatus of the pancreas, and chromaffin tissue. This is .well shown in the
accompanying diagram (see Fig. i).

As before stated, we are not as yet clear as to the intimate process of such
physiological correlations. This applies not only to the reinforcement
[Forderung] but also to inhibition. We have indeed assumed that increased
activity of the insular apparatus inhibits the function of the chromaffin
tissue or of the thyroid, and the converse. Another possibility consists in
the fact that adrenalin and the pancreas hormone act antagonistically to-
ward each other in the liver; the one in an acceleratory manner, the other
in a retarding manner, upon the diastatic processes; or the one acts for the
building up of glycogen, the other for its splitting up. Increased activity of the
one would therefore disturb the balance between the two ductless glands.1

As I have expressed in a recent communication, the relations between
thyroid and pancreas seem to me better based and explained in the following
way: Increased activity of the thyroid makes greater demand on the func-
tion of the insular apparatus. If the insular apparatus does not come up to
these demands, the balance between both becomes disturbed. This point
of view is supported by a series of clinical observations.

It is futile to raise ideas as to physiological correlation which deal with
the question whether one ductless gland can act compensatorily for another.
Such an assumption depends upon entirely superficial observation. Every
ductless gland has its specific function, although similar features may enter
into the sum total of activity. As this point is of important significance, I
will quote some examples. The extirpation of the hypophysis, just as that
of the thyroid gland, brings about a condition in which the vegetative func-
tions are diminished (Aschner). Nevertheless, a dog deprived of its hypo-
physis looks otherwise than one deprived of its thyroid, as R. Paltauf lays

1 Experiments of Zultizer and of Von Bdlint and Molnar point in this direction.

RECIPROCAL ACTION OF THE DUCTLESS GLANDS 9

stress on. Naturally this is also true in a clinical sense. Practically nobody
confuses a typical myxedema with typical hypophysial dystrophy. The
extirpation of the parathyroid glands increases the excitability of the vegeta-
tive nerves, extirpation of the thyroid diminishes it; the mechanism, however,
as I shall show later, is different. It is true that the tetany of the parathyro-
privic animal runs a milder course (after associated or subsequent thyroidec-
tomy), because on account of the absence of the secretion of the thyroid
gland the excitability of the vegetative nervous system is diminished, but
nevertheless the tetany is not thereby prevented.

Now, as to the pathological correlations! These are furnished by the
ductless glands' membership in the same system. Diseases which affect one
gland often attack very commonly other ductless glands, or a disease process
may affect simultaneously several ductless glands, or the entire ductless
glandular system. By pathological correlations I understand the conceal-
ment, intensification, or modification of symptoms due to the alteration of
function of one kind of ductless gland through the presence of disease in an-
other. This may also be shown experimentally. I have already mentioned
that extirpation of the thyroid gland diminishes the excitability of the vege-
tative nerves, while that of the parathyroids increases it. We observe that
the glycosuric action of adrenalin, which is diminished after extirpation of
the thyroid gland, is not diminished on simultaneous extirpation of the para-
thyroid gland and may even be somewhat intensified. Another example:
Extirpation of the thyroid gland raises the assimilation limits for carbohy-
drates and reduces the protein exchange during fasting. Extirpation of the
pancreas reduces the assimilation limits very strongly and increases the pro-
tein exchange during fasting. Simultaneous extirpation of the thyroid gland
and pancreas produces indeed a diabetes; this, however, pursues a milder
course to the extent that the increase of the protein destruction is not so high
and the diminution in weight does not progress so rapidly. Therefore,
there has occurred a diminution of an otherwise increased metabolism.

Now some examples from human pathology.

Thyroid gland and the anterior lobe of the hypophysis show in many
respects much similarity; as, for example, in a phylogenetic respect both were
formerly glands with external secretion. They show similarity in morpho-
logical structure, and in many respects also in their physiological activity.
For example, young animals deprived of their thyroid gland or of their
hypophysis remain backward in growth, show diminution of the vegetative
processes, etc. Often both glands become diseased simultaneously. In-
deed, in acromegaly the development of a Basedow's struma is not unusual,
and in the later stages of acromegaly the thyroid may degenerate, with
attendant myxedema symptoms, as Pineles has described. In the cretinic
degeneration there is found not uncommonly both a goitrous degeneration
of the thyroid gland and degeneration of the glandular hypophysis. A

10 GENERAL PART

simultaneous affection of thyroid gland and glandular hypophysis is found
also in multiple ductless glandular sclerosis.

Another example concerns the insular apparatus of the pancreas and the
thyroid. - In typical myxedema the assimilation limit for carbohydrates is
raised. Now there are individual cases of myxedema described in the litera-
ture in which alimentary glycosuria may be obtained, and even indeed a
spontaneous glycosuria may be present on ingestion of diet somewhat richer
in carbohydrates than ordinarily. Such cases have been held up to me as
irreconcilable with our theory as to the reciprocal actions of the thyroid gland
and pancreas, but incorrectly. In such cases it may be assumed that
there is a simultaneous affection of the insular apparatus. I have already
mentioned that after simultaneous extirpation of the thyroid gland and the
pancreas the oppositely directed effect of the absence of the thyroid on the
carbohydrate metabolism compensates for the effect of the absence of the
pancreas. It is therefore fully comprehensible that in an affection of the
insular apparatus disturbances in the carbohydrate metabolism may occur
in spite of the myxedema that is present.

Finally, further example is afforded by the pancreas and the suprarenal
glands. In the cases of cirrhose bronzee dependent upon severe alcoholism
there are found extensive sclerotic processes in the liver, the spleen, and
eventually in different other organs, with simultaneous deposition of a pig-
ment that is at first rich in iron and later free of iron (hemosiderosis). With
involvement of the pancreas in the sclerotic process, diabetes mellitus
not unusually occurs (diabete bronzee). Now, observations have shown
that in such cases the diabetes later disappears, as not rarely the cirrhose
bronzee involves also the suprarenal glands in the sclerotic processes and may
finally even bring about the condition of symptoms resembling Addison's
disease; so that we may readily draw the conclusion that the retrogression of
the diabetic disturbances of metabolism stands in connection with a more
intense sclerosing of the suprarenal glands that occurs later [in the course
of the disease].

Question of Dysfunction

The -study of the pathological correlations seems to me to throw light on
the question as to whether we are justified in postulating, in addition to an
increase in function and a diminution in function of the ductless glands, also
ajdysfunction. I shall in this book try to explain the individual ductless
glandular diseases exclusively as due to quantitative alterations in the duct-
less glands. I know well full that to-day this opinion is not throughout
the generally prevailing one, and I expect to meet with opposition. I believe,
however, that I can at least adduce so much evidence for my standpoint
that a certain justification for it will not be denied.

As has been previously stated, the physiologico-chemical basis of the

QUESTION OF DYSFUNCTION II

hormone teaching is still insufficient. Up to the present only a single hor-
mone, adrenalin, has been denned chemically. A dysfunction of the chrom-
affin tissue would then signify that a qualitatively altered, faulty, adrenalin
is obtained from the chromaffin tissue and given off into the blood-path.
But every ground for this opinion has, up to the present, been lacking. As
a principal argument for dysfunction is adduced the variability of the clinical
pictures that may be expressed by the disease of a definite ductless gland.
The study of the pathologic correlations teaches us, however, that often the
pure picture of a functional increase or deficiency may be set aside and
concealed if other ductless glands become affected at the same time.
Thus it not rarely happens that trophoneuroses accompany the diseases of
the ductless glands, the combination seeming to me only a loose one. For in-
stance, special stress has been laid on the observation that in the later stages
of Basedow's disease sometimes signs of myxedema occur, while the signs of
hyperthyrosis are still present. In the description of Basedow's disease
I shall dwell at length on these cases, and I believe that in no case is the evi-
dence for the existence of a myxedema absolutely convincing. In common
with Newburgh and Nobel, I have further shown, in connection with this
question, that the great multiplicity of syndromes in conditions of func-
tional increase of a definite ductless gland are for the most part to be explained
through diversities of constitution. We have attempted to justify this
experimentally. The individual hormones or ductless glandular extracts
have very different kinds of action throughout. As I shall come to speak of
adrenalin in this connection later, I shall choose as example at this place
the thyroid-gland substance. By peroral administration of large amounts
of thyroid-gland substance, we can see the following symptoms make their
appearance:

1. Tachycardia.

2. Great depression in the blood pressure from center to the periphery.

3. Increase of the fundamental exchange.

4. Increase of the protein exchange.

5. Increase of the elimination of salts.

6. Lowering of the assimilation for carbohydrates, and finally spon-

taneous glycosuria.

7. Sweats.

8. Mononucleosis.

9. Tremor.
10. Diarrheas.

n. Psychic agitation, etc., etc.

Thus there are produced almost all the symptoms of a Basedow's disease.
We almost never, however, succeed in obtaining all these symptoms in a
single individual, but do note the regular appearance of tachycardia as the
cardinal symptom. To this other symptoms group themselves to form definite

12 GENERAL PART

syndromes; for example, tachycardia, sweats, mononucleosis, or tachycardia,
mononucleosis, tremor, etc. We can therefore obtain in miniature almost
all the syndromes that we find in cases of Basedow's disease. As thyroidin
is always the same, the cause of this dissociation must be ascribed only to the
various constitutions of the persons tested. The question as to why this is
so in the individual case is naturally hard to answer, as the sum of the partial
constitutions (to use an expression of Marlins's) that go to make the total
constitution is enormous. In many respects it seems most reasonable in
experimental hyperthyroidism to seek the explanation in the different reac-
tion activities of the ductless glandular system.- When, for example, we see
that administration of thyroid substance produces glycosuria in one in-
dividual and in another does not alter the carbohydrate metabolism, we
may readily infer that, on account of the known physiological correlation
between thyroid and pancreas, in the first case the insular apparatus has not
kept pace with the demands that the hyperthyroidism has made upon it,
while in the other case the functional capacity of the pancreas is sufficient.
In other cases entirely different constitutional factors appear more strongly in
the foreground. For example, in neuropathic predisposition, the symptoms
on the part of the nervous system and the mind occur more markedly and
have other features. This, ceteris paribus, holds just as good for the [diseases
due to] functional increases as [for those due to] deficiencies.

Our standpoint as to dysfunction is important not only theoretically but
practically. If we discard dysfunction, the therapeutic indications are much
clearer. The results of substitution therapy are thus readily made intelli-
gible, and the operative treatment of conditions due to hyperfunction
properly receives its justification only in this way. It appears to me that
the study of the pathologic correlations is important for the explanation of
many a therapeutic failure. In symptoms due to lack of a gland, a complete
result as the consequence of substitution therapy is not to be expected when
other parts of the ductless glandular system are involved at the same time.
Perhaps in such cases more can be achieved through combined organotherapy.
Pertinent contributions in the French literature appear to me to be in part
very optimistic. A similar consideration of the pathological correlations is
perhaps due in the position of the indications for the operative treatment of
the hyperfunctional disease. One would perhaps take exception to a resec-
tion of the thyroid when at the same time other manifestations are present
that point to exhaustion of another ductless gland, for instance, the chrom-
affin tissue. In this connection still another factor is important, namely, the
relations between the ductless glandular system and the central nervous
system. I shall speak about this subject later.

Only a few words yet as to the intoxication theory that plays so great a
role in the study of the internal secretions. The expression "poisoning" is,
according to my opinion, well adapted in many diseases due to hyperfunction;

INFLUENCE OF THE DUCTLESS GLANDS ON THE GROWTH 13

for example, in Basedow's disease. On this account we do not need to as-
sume a dysfunction, as a normal secretion, too, given in excess to the body,
may poison it. A fitting example is furnished by adrenalin poisoning. On
the contrary, I must assume that no sufficient experimental evidence is at
hand for the detoxication theory of the disease due to lack of secretions; that
is, for the assumption that poisons normally formed in the1 organism are
rendered nonpoisonous in the ductless glands, and that they poison the body
when the ductless glands are insufficient. Even the pathogenesis of tetany
may be explained without the aid of detoxication theory, as we shall see in
the chapter on the subject.

The great number of works as to the physiology and pathology of the
ductless glandular system that have appeared in the last decade show the
growing interest that physiologists and clinicians take in this subject. What
makes the subject so fascinating is the fact that it allows us to have what up
to the present was a scarcely anticipated look into the complicated regulatory
mechanism of the animal organism. In many respects this influence is espe-
cially true for the influencing of the growth and of the metabolic processes.
But also the development and the activity of the hematopoietic apparatus
stand under the control "f this ductless glandular system; finally, the most
intimate relations exi<- between the ductless glandular system and the
nervous system, whereby practically all the somatic and vegetative functions,
yes even the mind itself, are brought within the zone of influence. To de-
scribe in detail this invasive activity of the ductless glandular system into
all the vital processes does not lie within the limits of the task I have set for
myself. I shall only sketch a few points in gross.

Influence of the Ductless Glands on the Growth

I begin with the influence of the ductless glands upon the growth and the
configuration of the body. This influence is apparent and has long been
known in eunuchs and through the experience of breeders of animals, al-
though exact experimental work in this direction dates only from recent
years. It seems to me most suitable for our purposes to select certain better
studied types and to sketch them.

i. Loss or high-grade hypoplasia of the sexual glands at an early age
leads to tall growth; the skeleton is built slenderly and shows charac
teristic proportions (large lower length, large span width, small head).
There is found herewith a characteristic distribution of fat and faulty de-
velopment of the secondary sexual characters. The closure of the epiphy-
sial junctures, and especially of those which under physiological conditions
close the latest, are markedly delayed. This is the foundation of the char-
acteristic proportions and the cause of the tall growth. (The assumption of
secondary increase in function of the hypophysis, as I shall treat in Chapter

14 GENERAL PART

X, I do not regard as warranted.) We may therefore assume that there is
exercised by the sexual glands, especially at the time of puberty, an influence
upon the zone of ossification in the sense of a definite bone formation. This
influence is exercised on the part of the interstitial glands.

2. Absence or high-grade diminution of the function of the thyroid gland
at an early age leads to dwarf growth; that is, to inhibition of growth. The
skeleton retains in general the childish dimensions. The epiphysial closure
is to a marked degree delayed. The fontanelles remain open for a long time,
the root of the nose is drawn in, the development of the bone-nuclei is very
much retarded. The bones already formed show a slight degree of sclerosis.
The bones are thick. In youthful individuals with Graves' disease there is
found on the contrary a slightly accelerated growth in the length, and a
somewhat premature closure of the epiphyses. The eunuchoid distribution
of fat is absent. The genitals remain backward in development, but not so
markedly as in eunuchoidism. Under the influence of the insufficiency of the
thyroid gland the endochondral and periosteal ossifications are to a slight
degree retarded.

3. Absence of the hypophysis in early years also leads, as clinical and
recently, also, experimental observations show, to an inhibition of growth.
Closure of epiphysial junctures and development of the bone-nuclei are like-
wise delayed, perhaps not so markedly as in the thyrogenic inhibition of
growth; this, however, is hard to decide, at least in the clinical observations,
as the observations on the disturbances do not seem to deal with cases at
such an early age. The hypoplasia of the genitalia and especially of the
interstitial glands is very much more marked, also when the disturbance sets
in later. Correspondingly there is found a eunuchoidal distribution of fat
and even a (secondary) influencing of the body proportions which approxi-
mate more or less closely the eunuchoid type.

In cases of youthful acromegaly the relations are very much more com-
plex. The typical cases appear to me, as I shall treat of in greater length in
Chapter VI, to be those with a marked accentuation of the functions of the
interstitial glands. We find then premature closure of the epiphysial junc-
tures, more emphatic pronunciation of the secondary sexual characters,
and premature thickening of the bones with exostosis formation and thicken-
ing of the soft parts. In other cases we find, however, inhibition of develop-
ment in the genital sphere, together with a marked eunuchoidal tendency
in the proportioning, with tall growth.

4. In disorders of hyperfunction of the sexual glands, of the suprarenal
cortex, or of the epiphysis in youthful life, we find premature development of the
whole body, accelerated growth with potentized childish dimensions, prema-
ture development of the genitalia, and then later premature epiphysial closure ;
in short, a transitory gigantism. Whether these vegetative disturbances can
be the direct outcome of those of the organs mentioned, or whether they are

INFLUENCE OF THE DUCTLESS GLANDS ON THE GROWTH 15

always dependent on a primary or secondary increase in function of the
suprarenal cortex, is as yet uncertain.

As to the influence of the other ductless glands on the growth and confor-
mation of the body as yet little that is reliable is known. I shall only men-
tion that extirpation of the thymus glands leads to an inhibition of growth
that is later compensated. I shall treat of this further in the appropriate
chapter.

The manner and means in which the ductless glands affect the growth is
only partly known. It may be said with certainty that the closure of the
epiphyses and hence a definite cessation in the normal growth occurs under
the influence of the sexual glands and indeed the interstitial glands; further,
that the development of the bone-nuclei and the growth in length of the bones
is strongly influenced by the thyroid gland and the hypophysis. I would
ascribe to the thyroid in this connection an influence at least as great as that of
the hypophysis. The influence of the latter seems to be very much over-
estimated, to the extent that it has been regarded as the dominating growth
center. The disturbances in growth produced by the thyroid differ im-
portantly from those produced by the hypophysis; I would especially at-
tach importance to the fact that in the thyroidal growth disturbances the
bones are thick [German word "plump" = coarse, thick, awkward]; in the
hypophysoprivic they are slender; the contrary may be seen in the increase of
function of these glands in early youth. In youthful Basedow's patients the
bones are slender; in youthful acromegalics they are thick and provided with
exostoses, and, so far as the disease is not complicated with associated eu-
nuchoidism, the bony processes are thickened. For the overestimation of
the significance of the hypophysis for the growth in length the Brissaud-
Meige's formula for gigantism should be held responsible. According to this
formula, gigantism is nothing other than an acromegaly of youth. It seems
to me, however, that in gigantism, at least in the earlier stages, there is found
mostly a hyperplasia also of other ductless glands, perhaps of the whole duct-
less glandular system; and especially the suprarenal cortex is often hyper-
plastic and, according to recent investigations, may influence in many ways
the clinical picture of gigantism as well as of acromegaly. I have pre-
viously mentioned that also premature development can be associated with
an increase of function in this organ, perhaps is regularly associated with it.

Although here, too, very little is as yet known and explained in a satis-
factory manner as to the influence on the growth and bodily conformation
through the ductless glands, yet this influence is so striking that we may
conclude that a harmonious development of the body is not possible without
orderly functioning of the ductless glandular system. We as yet know
nothing as to the intimate processes in this kind of hormone action. Trophic
influencing of the nervous system may come into play in many of these
actions,' as the symmetry in such formative influences seems^to signify.

1 6 GENERAL PART

Further, a specific influencing of the metabolic processes, for example in an
athyrosis, is to be thought of; further, a modeling influence on the skeleton
through alteration of the muscle tonus, etc., etc. It would, however, be
a mistake to bring into relationship with the ductless glandular system
all variations and diminutions or increases in the growth energy of the
protoplasm.

Influence of the Ductless Glands on the Regulation of Metabolism.

The ductless glands assume a still more considerable influence in the regu-
lation of metabolism. I shall here choose only a few of the most marked
examples. First let us consider the carbohydrate metabolism. The pan-
creatic insular apparatus governs the carbohydrate assimilation, for after
extirpation of the pancreas the glycogen formation in the liver and also
otherwise in the tissues, especially the muscles, is markedly disturbed. That,
this consists chiefly in a disturbance of glycogenesis seems to arise from the
fact that on low-grade insufficiency of the pancreas the disturbances first
become manifest only on alimentary overloading, while otherwise the regu-
lation of the carbohydrate metabolism is proceeding normally. Then an
increased sugar production occurs first in the high grades of the disturbance,
for now there occurs also on fasting — hence, with full exclusion of the ali-
mentary influence — hyperglycemia and glycosuria.

On the other hand, the mobilization of glycogen seems to stand chiefly
under the influence of the chromafiin tissue, for artificially induced hyper-
adrenalinemia (through subcutaneous injection of adrenalin or through
sugar puncture) brings about a rapid melting down of the glycogen present
in the liver and muscles, and perhaps also an increased combustion of sugar
(for after injection of adrenalin we saw a rise of the respiratory quotient).
Thereby occurs hyperglycemia and eventually glycosuria; after extirpation
of the suprarenals or in Addison's disease there exists, on the contrary,
a hypoglycemia.

Both the pancreatic insular apparatus and the chromaffin tissue are to be
regarded as most important regulators of the carbohydrate metabolism,
and we must add to them as a regulator the thyroid gland; for, as previously
mentioned, in typical myxedema the assimilation limits are raised, and in
Basedow's disease or in artificial thyroidism they are not rarely reduced, in
some cases to such an extent that spontaneous glycosuria occurs. As I here
again emphasize, the thyroid gland seems to influence especially the pan-
creatic insular apparatus or the hormone produced by it, as here the ali-
mentary factor is so prominent. A similar regulatory influence, although
probably not such a strong one, seems to proceed from the hypophysis; I
shall speak of this in the appropriate chapter.

So far as the protein metabolism is concerned, we have known for some

INFLUENCE OF THE DUCTLESS GLANDS ON THE REGULATION OF METABOLISM I 7

time that the thyroid gland influences it enormously. In Basedow's disease
the protein requirements are increased; the patient must ingest more protein
if he does not wish to use up the protein constituents of his body. In
myxedema the protein requirements are abnormally low. In hypophysial
and suprarenal diseases these disturbances in the protein economy are not so
distinctly prominent. Also the severe diabetic ordinarily has no heightened
protein requirements.1

From these examples it will be seen that the regulatory influence of indi-
vidual ductless glands on the different metabolic processes is to a great extent
specific. While pancreas and chromaffin tissue govern the carbohydrate
metabolism, the thyroid gland is especially important for the protein meta-
bolism. For the calcium metabolism the function of the parathyroid would
seem to be of especial importance, as in tetany the assimilation of calcium in
the nervous system seems to be disturbed, although also other ductless glands
would seem to take a part in the regulation of calcium metabolism. Thus
the thymus gland seems to be of importance for the assimilation of calcium
in young bones. Administration of thyroid-gland substance or of extracts
of the posterior lobe of the hypophysis increases chiefly the elimination of
calcium ; adrenalin increases that of potassium and sodium, while the elimina-
tion of calcium is restricted. The significance of these experiments for
clinical medicine is not as yet clear.

The influence of ductless glands on the purin metabolism has as yet been
investigated but little. The observations that in acromegaly the endogenous
factor of the uric-acid elimination is raised, that in hypophysial dystrophy it
may lie strikingly low, and that also the exogenous factor may show oppo-
sitely directed alterations, and that, further, alterations of purin metabolism
also occur in the thyroid-gland diseases, as I shall show in Chapter II, make
probable the regulatory influences of the ductless glands on the purin met-
abolism. I must not off-hand make any statement as to whether the
problem of gout will be elucidated by such investigation.

The study of the respiratory gaseous exchange has furnished a deep insight
into the regulation of metabolism in the ductless glandular diseases. Here,
too, I will limit myself to certain important facts. In Basedow's disease the
fundamental exchange is increased. In thyroprivic or spontaneous myxe-
dema the fundamental exchange and the caloric requirements are reduced.
In acromegaly a distinct rise of the fundamental exchange is present only
when symptoms of Basedow's disease are present at the same time. In
hypophysial dystrophy the fundamental exchange is reduced only in espe-
cially severe cases. In failure of the sexual glands the reduction of the
fundamental exchange is still a moot question and if present is but slight.

1 Also qualitative alterations of the protein metabolism are observed in ductless glandular
diseases; in tetany, for example, there is a heightening of the ammonia, amino-acid, and polypeptid
fractions.

1 8 GENERAL PART

Investigations of the metabolism in premature development as the result
of suprarenal cortical, sexual glandular, and epiphysial tumors have not as
yet been made. In severe diabetes mellitus, as will be told about in detail in
Chapter XIII, the caloric production in the rest-fasting experiments is not
essentially increased; the caloric and oxygen requirements are increased,
correspondingly to the loss of sugar and of ketone bodies. According to
the investigations up to the present, a considerable influence on the funda-
mental exchange is to be attributed only to the thyroid gland. It seems
to me, however, that for a correct appreciation of the influence that the duct-
less glands exercise on the metabolic processes and nutritional conditions,
it is just as important that we consider the endogenous factors as well as the
exogenous factors. By fundamental exchange we mean, as is known, the
amount of the carbonic-acid production and of the oxygen requirements, or
of the heat production, on ruling out of digestion and muscular work. If
we calculate the fundamental exchange per kilogram of body weight, we
find in (grown) small and thin individuals higher values than in (grown)
large and fat individuals. In youthful individuals the fundamental exchange
is relatively larger than in adults. In the small individuals the variations to
which it is subject are ordinarily only very slight. The fundamental ex-
change is a measure for the work that in a resting fasting organism is per-
formed by the heart, the glands, the nervous system, etc., including that
which is furnished by a certain muscular tonus that cannot be excluded.
That the thyroid enormously influences the fundamental exchange may be
readily understood when we consider that in Basedow's disease the organs
are in a condition of marked excitement, while in myxedema the vegetative
functions are markedly reduced. A certain influencing of the fundamental
exchange is to be expected also on the part of the other ductless glands as
they too influence the vegetative nervous system in manifold ways, so far
as its condition of irritability is concerned, even if their influence does not
cause such distinct effects. But also the exogenous factor of the exchange
is influenced by the ductless glands more or less pronouncedly. I have
reference to the unrest and mental irritability of Basedow's disease and to the
apathy and lack of interest of the myxedemic. In tetany we find in addition
to the increase in the vegetative functions also an extraordinary influencing
of the exogenous factors through the fibrillary twitchings and through the
spasms. Also as far as the sexual glands are concerned does an exogenous
factor come into play; for instance, in eunuchs there are absent the stimulus
to motion and the animation of the normal man. All these are factors that
are of great importance for the regulation of the total exchange and for the
condition of nutrition.

Even more significant appears to me the following circumstance : That a
normal grown man retains the same bodily weight for years depends on a
correct relation between assimilation and dissimilation assured by such

INFLUENCE OF THE DUCTLESS GLANDS ON THE REGULATION OF METABOLISM IQ

different factors as appetite, impulse for movements, etc. On these processes
the ductless glands have a considerable influence. We can with great prob-
ability, as we shall see later, divide the hormones into anabolic and catabolic
(retarding and acceleratory, or assimilatory and dissimilatory) . An im-
portant anabolic hormone is, for example, the pancreas hormone, as it is very
important for the carbohydrate assimilation and, as I am inclined to assume,
also for the fat assimilation. This fact also makes comprehensible an in-
fluence of the ductless glandular system upon the regulation of the total ex-
change (not the caloric production alone). A fattening,1 that is, a significant
increase in the assimilatory processes, would only then be possible when the
ability for it, that is, a certain breadth of function of the ductless glands in
question, is present, otherwise the organism would protect itself against the
increased supply of food. This seems to throw some light on the obesity
associated so commonly with certain ductless glandular diseases. The con-
sideration of the fundamental exchange alone would not carry us to the goal,
for it is very well conceivable that the fine mechanism of regulation between
assimilation and dissimilation is disturbed without an alteration of the
activity of the vegetative organs to such an extent as to influence the funda-
mental exchange. Only in diseases in which the diminution of the funda-
mental exchange is quite clear, for instance in myxedema, must there be
added, if obesity is to develop, a disturbance in the relation between assimi-
lation and dissimilation, as otherwise the ingestion of nutrition would simply
diminish with the lessened need.

Also in those ductless glandular diseases that according to experience are
associated with emaciation must there be present a similar disturbance of
the mechanism of regulation, although in the opposite direction. The increase
in the fundamental exchange in Basedow's disease can otherwise be vitiated
by corresponding increased ingestion of food. Here indeed the relations are
very much more complicated, as the ingestion of much food may be made
difficult through vomiting or through diarrhea. It seems to me, however,
that this explanation is not sufficient for all cases. We sometimes see indeed
in this very Basedow's disease a paradoxical relation; in spite of the per-
sistence of Basedow's disease, an obesity can develop after initial wasting, and
some have seen in this obesity evidence for a dysfunction of the thyroid gland.

•It seems to me very likely that in such cases, in spite of persistence of an
increased dissimilation, the assimilatory processes on account of a gradual
developing hyperfunction of the pancreas, win the upper hand. On the
other hand, emaciation may enter in on account of primary disturbance of
assimilation, as is the case in severe diabetes mellitus ; here the gross exchange
is increased, the production of calories not however increasing.

Finally there must be ascribed to the ductless glandular system an influ-
ence on the heat-regulation of the animal organism. These disturbances of

1 Increase in weight due to feeding [Mastung]. — Editor.'

20 GENERAL PART

the heat regulation occur most commonly and most pronouncedly in diseases
of the thyroid gland. In myxedema the bodily warmth often sinks far below
the normal; in Basedow's disease hyperthermia is not rare. In the one the
vegetative functions are diminished, in the other increased; the diminished or
increased heat production cannot, however, alone be the cause. There must
occur in addition other sorts of disturbances, especially in the mode of action
of the vessels of the skin or in the vegetative nervous system, changes that
I shall not go into here on account of their complexity. On the ground last
mentioned, it is well also to ascribe to the chromaffin tissue an important
role in the regulation of heat, for adrenalin, as may readily be demonstrated
experimentally, through contraction of the vessels of the skin and prevention
of the perspiration may lead transitorily to a significant hyperthermia, even
with shivering. Also the hypophysis seems to enter into the regulation of
temperature on account of its influencing the vegetative nervous system ; to
this statement points the fact that in hypophysial dystrophy the temperature
always is instituted at an abnormally low level. I content myself with these
few examples; the intimate relation of the ductless glands to the vegetative
nervous system, which I shall speak about later, furnishes obvious explana-
tion. The same holds true for the influencing of the water economy; retention
of water in myxedema, with throwing off of water in this condition by the use
of thyroidin, polyuria in the "hypertonic diathesis/' diabetes insipidus in
individuals with disease of the hypophysis, diabetes decipiens or high-grade
polyuria in diabetes mellitus, are all questions which have as yet been very
little investigated and the study of which represents many results.

Embryology of the Ductless Glandular System

Before I attempt to group the blood-glands according to their functions, I
should like to say a few words as to the embryology of the ductless glandular
system. It is a shame that this subject has to the present been somewhat
neglected by the embryologists. All three germinal layers contribute to the
structure of the ductless glandular system. According to the contributions
that I have found in the literature, it seems to me that the following grouping
is possible:

The chromaffin tissue is of neuroectodermal origin.

The posterior lobe of the hypophysis is also of neuroectodermal origin.
The pars intermedia is also of ectodermal origin. It is questionable,
however, whether the pars intermedia develops from the anterior or
the posterior lobe. In the latter case it would be of neuroectodermal
origin.

The anterior lobe of the hypophysis develops from an extrusion of the
dorsal wall of the ectodermal primary mouth cavity where it passes
over into the entodermal head-gut.

EMBRYOLOGY OF THE DUCTLESS GLANDULAR SYSTEM 21

The middle lobe of the thyroid gland develops from the ventral wall of the
entodermal head-gut, the lateral lobes apparently in part from the
ventral wall of the fourth pharyngeal pouch. The anterior lobe of
the hypophysis and the thyroid gland are phylogenetically older struc-
tures and were formerly glands with external secretion that poured
their secretions into the intestines.
The parathyroid glands are of entodermal origin and develop from the

dorsal wall of the third and fourth pharyngeal pouches.
The thymus gland is also of entodermal origin and develops from the

ventral wall of the third pharyngeal pouch.

The pancreatic insular apparatus develops from an extrusion from the
pancreatic excretory ducts and according to W ' eichselbaum is of
entodermal origin.
The suprarenal cortex comes from the epithelium of the body cavity

and is of mesodermic origin.

The sexual glands develop from a neighdoring site of the celomic epithe-
lium and are therefore also of mesodermal origin; this is generally
assumed to be true of the interstitial cells, while the glands of genera-
tion, according to the views of many authors, develop directly from
the primordial cells. The cells of the suprarenal cortex and the cells
of the interstitial glands show a certain morphological similarity.
The epiphysis develops from an extrusion of the roof of the third ventricle ;
it is therefore in part of neuroectodermal origin; in a clinical respect
it shows a certain relationship with the interstitial glands and the
suprarenal cortex, so that we can believe that it is in part of meso-
dermic origin.

Hence we may group the ductless glands, according to their origin from
the germinal layers, into those of neuroectodermal origin (chromaffin tissue,
posterior lobe of the hypophysis), those of ectodermal origin (anterior lobe
of the hypophysis), endodermal origin (a) from the head-gut (thyroid), (b)
from the branchial derivatives (parathyroid glands, thymus gland), and
finally those of mesodermal origin (suprarenal cortex, interstitial glands,
pancreatic insular apparatus). The glands of generation seem, on account of
their development from the original primordial cells, to take a special place.
Although this grouping is incomplete, still it seems to me that important
analogies may be derived from it. It is striking that the posterior lobe of the
hypophysis (and pars intermedia?) and chromaffin tissue, the active prin-
ciples of which, adrenalin and pituitrinum infundibulare, show a certain
similarity in their action, are both of neuroectodermic origin, and that the
anterior lobe of the hypophysis and the thyroid gland, whose relationship
in a physiological and pathological sense has been many times referred to,
show phylogenetically a certain relationship in that formerly they were both
glands with an external secretion. Finally, it is striking that the interstitial

22 GENERAL PART

glands and the suprarenal cortex, which are both of such importance for the
development of the secondary sexual characters and stand in immediate
relation to premature development, both develop from the celomic epithelium.
From this standpoint it would be interesting to see whether in eunuchs the
suprarenal cortex is not hypoplastic. I am well aware that this grouping of
the ductless glands is associated with much that is speculative, but never-
theless it seems to me that their study in this direction is of practical value.

Grouping of the Ductless Glands

Let us now attempt a classification of the ductless glands according to
their physiological actions. I first attempted such a classification four years
ago, in which I differentiated acceleratory and retarding hormones. This
differentiation was founded on observations as to the in many respects an-
tagonistic influencing of the metabolic processes through the hormones or
ductless glandular extracts. Biedl later used the terms dissimilatory and
assimilatory for them. We can also say catabolic and anabolic. This
division cannot be carried out for the totality of the ductless glands, yet it
seems to me one well adapted for its purpose. I quote the following examples :

The hormone of the thyroid gland we may regard with full right as ac-
celeratory or dissimilatory or catabolic. As far as we know its actions,
it quickens metabolism and increases excitability. That in absence of the
thyroid in early youth growth and assimilation remain behind does not seem
to me to speak against this assumption, for the arrest in growth is to be re-
garded only as the effect of serious inhibition of all metabolic processes.

Also the hormone of the chromaffin tissue is of pronounced acceleratory
or catabolic action. It increases the excitability of the sympathetic nerves —
decomposes glycogen, increases the respiratory metabolism, etc. (the more
intense formation of glycogen in the course of a chronic adrenalinizing I
regard as only a secondary one, through compensatorily increased activity
of the pancreatic insular apparatus) .

Again, the posterior lobe of the hypophysis belongs to this group of duct-
less glands, at least we must regard the actions of the pituitrinum infundi-
bulare as pronouncedly catabolic or dissimilatory.

To this group we may oppose the glands with retardative or anabolic
or assimilatory hormones. To the latter belong the pancreatic insular
apparatus, that controls the building up of glycogen and also the assimilation
of fat, and diminishes the excitability of the sympathetic nerves (Lowi)\
further the parathyroid glands, that probably assist the assimilation of cal-
cium in the ganglion-cells and at the same time reduce their excitability.
Both work assimilatory and excitability-diminishing, each however in a
specific way; cataract formation may accompany deficiency of either.

Probably to this group belongs also the anterior lobe of the hypophysis,

DUCTLESS GLANDS AND NERVOUS SYSTEM

the extract from which reduces the fundamental exchange and the func-
tional increase of which brings about, as is known, an abnormal growth
energy in the bones and soft parts. Further I might here include the inter-
stitial glands, as they influence the ossification of the epiphysial junctures,
the growth of the larynx,1 etc.

I might express the opinion that the generative glands on the contrary
belong to the catabolic group, as in the inhibitions of growth that occur after
removal of the interstitial glands as, for example, by X-ray, only the genera-
tive glands are damaged; furthermore, we shall see in the chapter on the
sexual glands that in the premenstrual period in women all life processes are
increased when the follicle ripens; it is probable that in man, too, tonic ex-
citability-increasing influences proceed from the generative apparatus.

Thymus gland and epiphysis probably belong to the anabolic group.

If this classification, which I regard as speculative, is confirmed by further
investigation, it would lead to a result that appears to me to be very sig-
nificant. As is known, the ductless glands are for the most part arranged in
the organs in pairs. It would then be seen that the pairs regularly belong to
different groups. This is well shown in the accompanying diagram.

Acceleratory group
(catabolic-dissimilatory)

Retardative group
(anabolic-assi milatory)

Germinal layer

Ductless gland

Ductless gland

Germinal layer

Foje-gut
Neuroectodermal

Neuroectodermal
Primordial cell

Thyroid gland
Posterior lobe of
hypophysis
Chromaffin tissue
Glands of generation

Parathyroid
Anterior lobe of
hypophysis
Suprarenal cortex
Interstitial glands

Pharyngeal pouch
Ectodermal

Mesodermal
Mesodermal

Relation between the Ductless Glandular System and the Nervous System

I finally consider the relations between the ductless glandular system and the
central nervous system. The most recent years have furnished an abundance
of observations and ideas just in this direction, but these observations and
ideas are still very unclear and contradictory; so that a concise consideration
of this subject is hardly possible without strong subjective coloring.

I shall not consider more intimately here the manifold reciprocal influ-
ences that are already furnished by the spatial relationship between many of
the ductless glands and the nervous system (for example pressure action on

1 Novak has quoted just the sexual glands as an example to show that we are not yet prepared
for a division into an acceleratory and retardative group. He says: If after the removal of a
sexual gland we cause an increase in growth and at the same time find a decrease in beard forma-
tion and inhibition in the growth of the larynx, is then the gland growth-inhibiting or growth-
increasing?

If, however, we regard the increased growth only as a result of the delayed epiphysial closure,
we find that all effects of the removal of the interstitial glands in youth are growth-inhibiting.

24 GENERAL PART

the mid-brain by hypophysial and epiphysial tumors, and of brain tumors on
the hypophysis and epiphysis).

A. Influence of the Ductless Glandular System on the Nervous System

Very significant is the influence of the ductless glandular system on the
psychical and mental functions. This subject has been dealt with very often
in recent years, for instance, by Laignel-Lavastine, Bauer, Marburg, Munzer,
and others; and recently a considerable study has been published on the
subject by v. Frankl-Hochwart.

I refer to the alteration in character that is almost always associated with
the development of Basedow's disease; to the psychical irritability, the incli-
nation to irascibility, the manic-euphoristic attitude of patients with Base-
dow's disease; to the apathy and the lack of interest of the myxedematous;
to the characteristic quiet mental attitude in hypophysial dystrophy, and the
feeling of mental want of strength in those suffering with Addison's disease;
to the depressive attitude of the tetany patient, and finally to the profound
influence that the ripening of the sexual glands at the time of puberty or
the loss of function of the sexual glands in castrates exercises on the psyche.

The relations of the ductless glandular system to the vegetative nervous
system, as we shall see later, are not only important for the pathogenesis of
the ductless glandular diseases, but they possess also a great practical
interest through the fact that in many ductless glandular diseases they
simplify the solution of the individual symptom-complexes in many respects.
These relations are of two kinds:

1. The ductless glands themselves are vegetative organs. They are sup-
plied by vegetative nerves and possess, therefore, central projection
fields. Thus the function of the ductless glands is in great measure
regulated by the nervous system.

2. The ductless glandular system influences the excitability of the vege-
tative nervous system by the hormones that it gives off to the circula-
tion. At least this has been ascertained with certainty with regard
to adrenalin, and is in probability true of the other ductless glandular
hormones. I shall take up this point first. But before this I wish to
say something as to the anatomy and physiology of the vegetative
nervous system.

As is known, the vegetative nervous system supplies chiefly the organs
with smooth muscle fibers. In its function it is partially independent, in
great degree, of the central nervous system. While the somatic or animal
nerves pass uninterruptedly from the central nervous system to their organs
of supply, the vegetative nerves are always interrupted in the vegetative
ganglia. We hence distinguish preganglionic and postganglionic vegetative
neurons. Langley divides the vegetative nervous system into two groups,

DUCTLESS GLANDS AND NERVOUS SYSTEM 25

according to anatomical relations, into the cranio-sacral and the sym-
pathetic groups. He terms the whole vegetative nervous system autono-
mous, the group of the cranio-sacral autonomous nerves parasympathetic,
the other group sympathetic. The Viennese authors, who have busied
themselves much with this question, call the cranio-sacral autonomous nerves
without further ado autonomous, hence distinguishing between autonomous
and sympathetic nerves. This terminology has secured a large foothold in
the German literature. The disturbance in these two groups depends upon
an extensive difference not only in their anatomical relations, but also in
their physiological behavior. The action of both groups on the organs
they affect is in great part an antagonistic action. While, for example, the
sympathetic accelerator nerve accelerates heart action, heart action is
slowed by the autonomous vagus nerve. While the sympathetic splanchnic
nerves inhibit the peristalsis of the intestine, this is reinforced through irrita-
tion of the autonomous vagus. The following scheme, which is taken from
the experimental pharmacology of H. H. Meyer and R. Gottlieb, shows these
relations in a manner that may be readily understood (p. 26).

The two groups also are different in a most noteworthy manner in their
behavior toward certain pharmacological agents. Indeed there has been
based on this difference a pharmacologic test of function that should furnish
evidence as to the condition of excitability of the vegetative nerves. As it is
also used in affections of the ductless glands I shall here briefly detail the most
important facts.

Nicotine shows a specific affinity for all vegetative nerves, but only for the
preganglionic fibers interrupting conduction in these fibers.

Adrenalin acts as a stimulant to the myoneural junction of the sympa-
thetic nerves in all their organs of supply, and indeed is furthering or inhibi-
tory according as the activity of the organ of supply, is furthered [fordern] or
inhibited by electrical stimulations. Only the sweat-glands are not, when
the doses are not too large, influenced by adrenalin. On the contrary, ergotin
shows a specific affinity for the furthering sympathetic fibers, while the in-
hibitory fibers remain unaffected.

On the contrary, pilocarpine, muscarine, physostigmine, and cholin act
as stimulants on all the autonomous nerves, but only the sweat-glands in-
nervated by the sympathetic are energetically stimulated by these agents.
Picrotoxin acts similarly, but with a central point of attack. On the con-
trary, atropine acts as a paralyzant on the autonomous nerves and also in-
hibits the activity of the sympathetically innervated sweat-glands.

The fact that among the substances mentioned there is a true hormone,
adrenalin, leads us to expect that this direction of investigation is very im-
portant for the internal secretions. In addition, specific affinities for the
vegetative nervous system are shown by certain ductless glandular extracts
not well defined chemically.

26

DUCTLESS GLANDS AND NERVOUS SYSTEM 2J

Let us examine more closely the action of these hormones or ductless
glandular extracts in this direction.

Of adrenalin, the internal secretion of the chromamn tissue, we have al-
ready mentioned that it is of great significance for the excitability of the
myoneural junctions. As in a genetic relationship the chromamn tissue be-
longs to the sympathetic system, this system possesses within itself a regu-
lator of its excitability (Bayliss and Starling). As for the physiological
significance of the chromaffin tissue, it must furthermore be considered that
by the lasting function of this tissue there is maintained a certain dis-
tribution of blood. The sympathetic innervation of the different vascular
districts is of different richness; for example, the vessels of the muscles and
skin are very abundantly supplied, while the vessels of the lungs, of the
coronary arteries, and of the brain possess a weak sympathetic supply.
Priestley and 7 have pointed out that the venous blood emanating from the
organs with a rich sympathetic innervation are adrenalin-free or are es-
sentially poorer in adrenalin than the arterial blood flowing to them. The
liver is supplied with blood rich in adrenalin only by the hepatic arteries,
while the very much larger amount of blood that flows to it through the portal
vein is adrenalin-free or at least poor in adrenalin, as this blood has already
passed through the capillary system of the intestine. Hence in a quiet
fasting organism there occurs a definite blood distribution, a distribution
that may be regarded as purposeful. Thus the resting organs (muscle,
skin, intestine, etc.) contain very little blood, while those organs whose
activity is necessary for the maintenance of life (heart, central nervous
system, lungs, liver, etc.) are relatively rich in blood. The former become
supplied with more abundant blood, through the regulatory activity of the
sympathetic simultaneously with increased cardiac activity, only when they
are functionally more in demand.

The chromaffin system plays an important role in the regulation of the
blood's plasma contents. After the injection of large amounts of adrenalin,
Bertelli, Schweeger and 7 saw an appreciable increase in the count of the red
cells of the circulating blood. As this hyperglobulia survives the vaso-con-
traction for a long time, the cause of this is to be sought not only in the press-
ing-out of the plasma, but also in an alteration of the permeability of the ves-
sel wall on account of which the return flow of plasma is delayed for a long
time. Now it is known that in individuals who are brought relatively rapidly
into an atmosphere poor in oxygen (mountains, balloon trips, etc.) the num-
ber of red blood cells increases very rapidly. The hyperglobulia brings about
greater respiratory surface, this counterbalancing the slighter partial pressure
of the oxygen. To-day it is generally assumed that at least in rapid transi-
tions it is not the result of the increased production of erythrocytes. We
believe rather that it is due chiefly to a regulatory exudation of plasma into
the tissues, and that in this regulation is involved the chromaffin tissue.

28 GENERAL PART

Finally, our investigations have shown that injection of adrenalin pro-
duces neutrophilic hyperleucocytosis and induces a disappearance of the
eosinophiles from the circulating blood. Whether this is due directly to
excitation of the sympathetic nerves or indirectly to alteration in the dis-
tribution of blood is hard to decide. I would only point out that the curves
of the white and red cells are not parallel throughout, and that we can show
that drugs such as pilocarpine and cholin lead always in the first stage of
their action to an appreciable relative and absolute increase of the mono-
nuclear cells, eventually, too, to a changed distribution of the neutrophilic
cells in the vascular tree. These accumulate in the organs less well in-
nervated by the sympathetic, such as the lungs and the liver, while there are
fewer of them in the vessels of the skin and muscles. Hence the chromafrin
tissue seems to exercise a regulatory influence on the activity of the blood-
forming apparatus, chiefly through excitation of the medullary system
[of the bones].

The actions of thyroidin on the nervous system are far more manifold
than those of adrenalin. We must, however, refer most of the various symp-
toms of hyperthyroidism to alterations of tonus in the organs supplied by the
vegetative nerves, for example, the tachycardia to excitations of the sympa-
thetic accelerator nerve, the marked fall in blood-pressure to diminution of
the vascular tonus in the muscles, skin, and intestinal vessels, the irregularity
of the breathing to a heightening of the vagal tonus, the sweats to an excita-
tion of the nerves of the sweat-glands, etc., etc. Probably the excitability
throughout the entire vegetative nervous system is increased, although an elec-
tive affinity for definite sympathetic or autonomous nerves is unmistakable.
The same holds true for extracts of the hypophysis. The pituitrinum
infundibulare, obtained from the posterior lobe, works as an increaser of blood
pressure and as a strong diuretic ; it also acts as a slower of the pulse through
excitation of the vagus, and as an increaser of excitability of the autonomous
nervus pelvicus, moreover as an increaser of the excitability of the uterus,
etc. ; here also there are elective affinities for certain vegetative organs sup-
plied by the sympathetic or autonomous nerves.

Pituitrinum glandulare, according to our investigations, changes the dis-
tribution of the blood in the opposed sense. It reduces blood-pressure and
lessens the volume of the liver.

Let us now consider the alterations of the excitability on the tonus of
the vegetative organs in the ductless glandular diseases.

In Basedow's disease there is an abundance of symptoms that depend on
an increased tonus of both the autonomous and the sympathetic vegetative
organs, for example, the tachycardia, the eye symptoms, the sweats, the in-
creased falls of blood-pressure, etc., etc. As these symptoms are fSuhd In
more or less pronounced manner in artificial thyroidism, the conclusion is
justified that they are produced also in Basedow's disease by an increased

DUCTLESS GLANDS AND NERVOUS SYSTEM 2Q

production of the secretion of the thyroid gland. Reversely, in typical
myxedema the vegetative functions are found to be delayed, slow; the excita-
bility of the organs supplied by the sympathetic and autonomous nerves is
reduced (slower pulse, sluggishness of the intestine, etc., or reduction of the
glycosuric action of adrenalin, absent or deficient hyperglobulia after the in-
jection of adrenalin, reduced action of pilocarpine, etc.).

Then again the parathyroid bodies influence the excitement or excitability
of the vegetative nerves. In the acute stage of tetany are found hyper-
globulia, spasmodic conditions of the stomach and intestines, the bladder,
ciliary muscles, the heart, etc. The different actions of sympathicotropic or
automonotropic agents, such as adrenalin and pilocarpine, are essentially
strengthened. The circumstance that in tetany the manifestations on the
part of the vegetative organs are essentially different from those of Basedow's
disease shows that the affinities for the vegetative organs displayed by the
hormone of the parathyroids and the hormone of the thyroid are electively
different; and also the point of attack in the neuron is different, as in the one
case the hyperirritability [or hyperexcitability, Uberregbarkeit], the other
the hyperexcitement [Uberregung], is more prominent.

In Addison's disease, as is to be expected, there is a reduction of the
excitability and a slighter tonus of the organs innervated by the sympathetic,
and especially prominent are the reduction of the blood-pressure and the
lessened action of adrenalin. Here the picture is complicated by a number of
symptoms depending on a strong excitement of the vegetative organs, symp-
toms the genesis of which is as yet doubtful.

In the rest of the ductless glandular affections these relations are still less
apparent. I shall report the appropriate investigations and observations in
the respective chapters, and here shall only indicate the following: In hypo-
physial dystrophy and in eunuchoidism the excitability of some of the vege-
tative nerves seems to be somewhat decreased. Probably there exists a
certain sluggishness of the vegetative functions, which however does not
attain the degree of sluggishness of those in myxedema. Diabetes insipidus,
which not rarely is associated continuously or temporarily with diseases of the
hypophysis, seems to depend on an irritation of the posterior lobe of the hypo-
physis or on a specific increase of the function of the kidneys. In acromegaly
are found, not rarely, profuse sweats, even when no other manifestations
of complicating hyperthyroidism are present. In some cases of diabetes
mellitus, Lowi has shown an increased excitability of the dilator pupillae,
which is innervated by the sympathetic; we found in a definite category of
cases which perhaps are similar to Lowi's cases a strikingly strong glycosuric
action of adrenalin; in such cases, in which also the neurogenous factor of the
glycosuria markedly predominates, there is sometimes found an increase of
blood-pressure (hypertonic diabetes).

Also the glands of generation seem to exercise an important influence on

•jO GENERAL PART

the tonus of the vegetative organs. This is expressed in the female sex
especially, in the form of the known wave-movement. With maturation of
the follicles (especially of the fertilized ovum in pregnancy) there occurs an
increased vitality of the whole organism, an increase of the vegetative func-
tions which is in part indirectly due to the higher activity of the whole ductless
glandular system. At the climacteric, when the generative glands dis-
continue their function, there occurs in woman lability of the vegetative
nervous system, especially of the vasomotors, a sort of vasomotor ataxia
which first disappears again with the complete loss of ovulation. In men
too, these climacteric disorders occur, although they are rare.

At the time of puberty there very decidedly sets in an increase of vegeta- -
tive functions; it is attended with the enormous development of the glands
of generation, again rather stronger in woman than in man; it often takes
place in an incoordinated manner, giving occasion to various disturbances.
In specially predisposed female individuals the revolutions in the organism
at this time lead to an exhaustion which seems to stand in relation with the
development of chlorosis.

In the other ductless glandular diseases the behavior of the vegetative
nervous sytem is still less clear. In premature development due to pineal,
suprarenal cortical, or sexual glandular tumors this pubertal increase of the
vegetative functions is probably anticipated. As to the influence of the
thymus glands on the vegetative nervous system, we can state nothing certain .

This condensed survey suffices well to show to what extent the activity of
the vegetative organs and the excitability of the vegetative nervous system is
influenced by the ductless glands. This direction of investigation has just
been determined on. As to its further development, especially when physio-
logical chemistry has established still more hormones, there is to be expected
a deepening of our knowledge as to the symptomatology of the ductless
glandular diseases. From the observations up to the present, however, it
may be stated, although with insufficient surety, that the affinity of the
hormones for the vegetative nerves is an elective affinity ; not even adrenalin
itself influences the entire sympathetic group, for it leaves the sweat-glands
unaffected. The other ductless glandular extracts, as we know, always show
especial elective affinities for certain organs, whether these are supplied by
sympathetic or autonomous nerves; clinical observations furnish still more
evidence to this effect. Hence it seems to me improper to draw too extensive
conclusions from the pharmacological tests of function. Certainly they have
furnished us with very valuable inferences, and have provided a deep view
into the functions of the organ innervated by the vegetative nervous system.
For example, Lowi's reaction is practically constant on the dog without a
pancreas. Another example is the reduction of the excitability of the sym-
pathetic nerves after extirpation of the thyroid; this is evidenced not only
by the diminished glycosuric action of adrenalin, but also by the remaining

DUCTLESS GLANDS AND NERVOUS SYSTEM 31

absent of a marked hyperglobulia. This also occurs in typical myxedema
so far as it remains uncomplicated by pathological correlations, for ex-
ample by a tetany. I believe, however, that we would not be just to the
complex relationships if we were to draw from the result of such functional
tests a conclusion as to the condition of excitability of the whole sympathetic
or the whole autonomous group. In this respect I would not subscribe to the
views of Eppinger and Hess so far as these views are concerned with diseases
of the ductless glands. These are based chiefly on the observations that in
individuals in whom adrenalin work's diuretically, the action of pilocarpine
remains absent, and reversely that in individuals who show a strong pilocar-
pine reaction, adrenalin does not produce glycosuria. The absence of a
glycosuric action of adrenalin does not show that the entire sympathetic
group is hyposensitive. Adrenalin acts as a raiser of blood-pressure, accel-
erates cardiac action, acts as a diuretic, produces aneosinophilic hyperleu-
cocytosis, etc., etc. The glycosuric action is only a partial manifestation of a
very manifold action-complex. Besides this, hyperglycemia and consider-
able increase of the respiratory quotient can occur without glycosuria,
if diuresis does not come in the way; and besides, perhaps glycosuria may
remain absent in cases where the consumption of sugar is high. We saw, for
instance, in the acute stage of tetany, absence of glycosuria in spite of enormous
vascular action. In other cases we may observe marked glycosuria, while
the vascular and cardiac action remain almost entirely absent. In bronchial
asthma I never saw glycosuria after the injection of adrenalin; the hyper-
eosinophilia which was often present was, however, diminished markedly.
Also the other active ductless glandular extracts, as for example thyroidin,
show such a dissociation of their action.

The relations are rendered still more complex by the fact that individual
organs are innervated by furthering (fordern] as well as inhibitory fibers of
the same group. As Elliot has shown, adrenalin in minimal doses produces
vascular dilatation, and only in large doses vascular contraction. Pitui-
trinum infundibulare increases the peristaltic wave-movement of the gravid
rabbit uterus. The same extract acts for the most part inhibitory on the
virginal rabbit uterus. I can therefore agree with Eppinger and Hess
when they assume a relative preponderance of the autonomous innervation
in an insufficiency of the chromaffin tissue. -But even in Addison's disease
(perhaps through failure of the cortex, perhaps through other as yet obscure
factors) there may occur acute, highly complex conditions of excitement in
the vegetative nervous system.

In many later works there is found the tendency to distinguish between
vagotonic and sympathicotonic conditions in ductless glandular diseases.
For instance, Adler supposes after the failure of the sexual glands a sympa-
theticotonic condition, on account of the fact that he found glycosuria in cer-
tain castrated individuals after the injection of relatively small doses of adrena-

32 GENERAL PART

lin, while pilocarpine for the most part did not cause sweating; and he regards
the complicated process in the vegetative nervous system in dysmenorrhea
as vagotonic. I do not believe that these things allow of such a grouping.

B. Influence of the Nervous System on the Function of the Ductless

Glandular System

I now come to the consideration of those relations between the ductless
glandular system and the nervous system which are characterized by the fact
that the ductless glandular system is itself vegetative, that it is made up of
organs supplied by vegetative nerves that possess central projection-fields.
We shall have investigated in what measure activity of the ductless glandular
system is regulated by the nervous system. Our knowledge as to this kind
of relationship is as yet very deficient. We may scarcely put aside the sup-
position that in this respect the ductless glands behave very differently. The
impulses emanating from the central nervous system are very important
for the activity of the chromaffin tissue; for example, perhaps a regulated
activity is not possible even for a short time if the central innervation is want-
ing. Centers for these ductless glands lie on the floor of the fourth ventricle
and according to the later investigations of Aschner also in the subthalamic
region. Stimulation of these centers leads, just as the stimulation of the
nervous paths proceeding from them to the chromaffin tissue, to the dis-
semination of adrenalin. Priestley and / have shown that after interruption
of these paths by transection of the lowest cervical cord the amount of sugar
in the blood rapidly decreases; apparently, therefore, the activity of the
chromaffin tissue is discontinued if its connection with central projection-
fields is interrupted. The number of experiments is not at all great, as the
operative attack is difficult. It seems to me, however, noteworthy that
indications are wanting that after this attack, which also deprives the insular
apparatus of its central innervation, disturbances in the insular apparatus
occur during the short time that the animals survive the attack. I would
not at all state that the activity of the insular apparatus is not regulated by
the central nervous system; it seems, however, as though this influence were
very much slighter than is true in the case of the chromaffin system ; the in-
sular apparatus seems better able to continue its activity for some time even
after interruption of its connecting paths. That the production of the assimi-
latory hormone is accessible to few nerve influences seems purposeful; such
ductless glands always seem to work with a certain surplus; while the giving
off of the dissimilatory hormone must be very finely graduated in order to do
justice to the rapidly changing demands; this is only possible, however, if
the central nervous system governs the function of the ductless gland furnish-
ing them.

That the activity of the thyroid gland is dependent on the central nervous
system may be concluded from the older literature. How otherwise can

DUCTLESS GLANDS AND HEMATOPOIETIC APPARATUS 33

we explain that existence of an acute Basedow's disease with the rapidly
developing thyroid swelling that comes over night? Newer investigations
of AsJier and Flack make it very probable that the nerves regulating the thy-
roid glandular activity run in the nervi recurrentes. These investigations
also make it seem possible that rapid variations in the function of the thyroid
gland are governed by nervous influence.

Practically nothing as yet is known in this connection with respect to
other ductless glands. I must discuss a little more thoroughly only the
sexual glands. The sexual glands seem to assume an individual position
by virtue of their independence of the central nervous system. At least
the results of transplantation experiments up to the present would seem to
indicate this. With the thyroid gland only autotransplantation is success-
ful, that is, the transplantation of the thyroid gland to another place in
the same individual. Homiotransplantation (transplantation to another
individual of the same kind) fails. But up to the present it has not been
possible to maintain autotransplants capable of retaining their function,
even when their vessels are united directly with the vessels of the part by
means of suture. This shows, provided of course that the efforts of the
surgeons are not crowned with success at some time in the future, that the
function of the thyroid gland is not possible for a length of time without
connection with a central projection-field. It is different with the sexual
glands. Here in many cases not only autotransplantation but also homio-
transplantation succeeds. Indeed here even the results of heterotransplanta-
tion far surpass all that has been seen on the transplantation of the other
ductless glands. This separate position of the sexual glands was really to
have been expected. According to the noteworthy views of many authors
the generative glands originate from the primordial cells, which through
division of same kind of preceding cells, the ovum and the spermatozoon,
are organisms in themselves and lead an independent life. That the sexual
glands are also accessible to influences on the part of the central nervous
system and have central projection-fields in no way contradicts this idea.
According to Aschner such a projection-field lies in the subthalmic region.
On its long-continued excitation degeneration of the sexual glands occurs.
Indeed it may be supposed that the hypophysis furnishes trophic influences
to the sexual glands by way of the blood.

If we summarize the little we know concerning this important subject
we find that the ductless glandular system shows a certain degree of autonomy
which, however, is developed in very different ways on the part of the individual
ductless glands. The sexual glands are provided with the greatest degree of
autonomy, the chromajfin tissue with the least.

Influence of the Ductless Glands on the Hematopoietic Apparatus

Before I speak of the significance of the influences just described on the
pathogenesis and etiology of the ductless glandular affections, I would like

34

GENERAL PART

to make a few remarks on the influence that the ductless glandular system
exercises on the activity and development of the hematopoietic apparatus.
I should like to emphasize the fact that the thyroid secretion is necessary
for a normal development and activity of the hematopoietic apparatus. In
myxedema and still more in thyroid glandular insufficiency in youthful years
do disturbances in the formation of blood occur. Especially in infantile
myxedema does there come about a degree of anemia which is often not
inconsiderable, and a reduction of the erythrocyte count and the amount of
hemoglobin ; the involution of the lymphatic apparatus is insufficient ; in the
blood picture the neutrophilic leucocytes retrogress, and the mononuclear
and eosinophilic predominate. On the administration of thyroid extract
these disturbances disappear wholly or at least in great part. Similar, but
less pronounced, manifestations occur in other ductless glandular diseases
due to absence of secretion, as, for example, hypophysial dystrophy and
eunuchoidisin. The production of neutrophilic granulocytes hence seems to
require a furthering influence on the part of the thyroid gland and chrom-
affin tissue. From this fact are elicited relations of the ductless glands to the
so-called status lymphaticus. The significance of a hypoplasia of the
chromaffin system for this condition has been mentioned, especially by
Wiedel, Hedinger, and Eppinger and Hess.

A noteworthy influence on the hematopoietic apparatus is exercised by
the increase of function of the thyroid gland. The finding of Kocher, that
the count of mononuclear cells in the blood considerably predominates, is
one of the most constant features of Basedow's disease. In addition to this
relative and (to a great extent) absolute increase of the mononuclears (and
sometimes of the eosinophiles), there is found, just as frequently, an absolute
diminution of the neutrophilic cells in the circulating blood. Often the
relative increase of the former is only the sequel of the absolute diminution of
the latter. It seems to me that in this connection should be mentioned the
fact that Bertelli and / after the administration of thyroidin to dogs found an
accumulation of neutrophilic cells in the blood of the liver. It seems there-
fore that thyroidin influences the distribution of blood in the vascular tree.
The alterations in the blood picture in Basedow's disease are therefore not
analogous throughout to those of myxedema; which is best explained by
the fact that on administration of thyroidin in myxedema the blood picture
approaches the normal, while in Basedow's disease it diverges from the
normal (Falta, Newburgh, and Nobel). We are dealing in the first case with
symptoms of absence, in the latter case with irritative manifestations.

Same as has already been described, sympathicotropic and autonomo-
tropic substances influence the blood picture and the distribution of the
leucocytes in the vascular tree in a definite way, we can comprehend the
fact that symptoms of irritation in ductless glandular affections and in part
also the symptoms of absence are the result of an altered condition of ex-
citability in the vegetative nervous system.

PATHOGENESIS AND ETIOLOGY OF DUCTLESS GLANDULAR DISEASES 35

With this agrees the fact that in many nervous diseases that have in-
volved especially or partially the vegetative nervous system, as especially
in the vagal neurosis, there have been found mononucleosis and eventually
hypereosinophilia, while in the initial stage of the hypertonic diathesis, for
example, the count of neutrophilic cells lies at the upper boundary of the
normal or even exceeds this.

On long continuance, however, there are found in many ductless glandular
diseases morphological alterations in the hematopoietic apparatus. The
alterations in the blood pictures that are observed are at first hand very hard
to interpret. It may be stated that in acromegaly there is very frequently
found mononucleosis and eventually slight eosinophilia. We have seen
mononucleosis in chronic tetany (in this disease under the influence of acute
exacerbation there may occur rapid reversals of the blood picture). Mono-
nucleosis (without status lymphaticus) may be observed even in severe
diabetes. I agree with Borchardt, who has likewise studied these relations,
that in general in most of the ductless glandular diseases there is observed
a tendency to mononucleosis and neutropenia, and in many a slighter or
severer grade of status lymphaticus.

Pathogenesis and Etiology of the Ductless Glandular Diseases

On turning our attention to the consideration of the pathogenesis and
etiology of the ductless glandular diseases, we find that the idea we have de-
veloped as to the influencing of the function of these glands by the nervous
system is not without significance. However, the etiology of a great number
of ductless glandular diseases is to be sought in an entirely different direction.
Let us first consider the diseases due to absence or deficiency. Here we meet
with congenital aplasia or marked hypoplasia, as, for instance, in thyro-
aplasia. A defective development [of a "rudiment" or "Anlage"] often
seems to be a favorable soil for a later infection. Wiesel, for instance, assumes
that a tuberculosis infection very frequently becomes established in the
suprarenals on hypoplasias of the chromaffin tissue. But on such a defective
mapping out, an insufficiency may become manifest, temporary, or perma-
nent, even without the addition of an infectious process, if larger demands
are made on the ductless gland in question; for example, glycosuria may occur
on marked alimentary overloading with carbohydrates if a (often heredi-
tary) weak mapping out of the insular apparatus is present. In addition,
we should mention trauma. This, for example, may affect the testicles
and lead to eunuchoidism or late eunuchoidism; in operation on goiter too
much of the functionating thyroid glandular tissue may be extirpated, or the
parathyroid glands may be injured. A very great role in the pathogenesis
of the disease due to absence is played by infection. Tuberculous, luetic, or
other bacteriological processes, most as yet not investigated, may temporarily
damage the ductless glands or lead to permanent destruction or sclerosis.

36 GENERAL PART

These infectious processes may spread to the ductless gland from the neigh-
borhood, they may affect the acini of the pancreas through the ducts and
involve the insular apparatus by contiguity; in most cases, however, the
infection follows by the hematogenous route. In many cases in which the
infectious process involves many ductless glands at a time and causes de-
struction (multiple ductless glandular sclerosis), a congenital or acquired
predisposition of the ductless glandular system is perhaps present. Also
chronic intoxications, as alcoholism, poisoning by the toxin of goiter, etc.,
may damage single or several ductless glands. Furthermore, tumors that
proceed from parts in the neighborhood or from the ductless gland itself may
destroy the functionating tissue. Again, in many ductless glands, purely
functional disturbances on a nervous basis are possible, analogous to those
hyposecretions that occur in glands with external secretion. The possi-
bility of a functional Addison's disease was long ago discussed by v. Neusser.
A like supposition seems to me debatable for the chromaffin tissue or for
the pancreatic insular apparatus. Nor would trophic degenerations of the
ductless glands be impossible.

A greater importance should be ascribed to nervous influences in the
pathogenesis of the diseases of hyperfunction. The pathologico-anatomical
correlate of hyperfunction is hyperplasia, or in ductless glands of definite
morphological structure, of adenoma formation. The latter is found in
the disease of hyperfunction of the glandular hypophysis, of the thyroid
gland, and the suprarenal cortex; while in the sexual glands sarcoma toid
tumors are more often found. Hyperplasia of the chromaffin tissue is found
in the hypertonic diathesis. Even where, however, the adenoma formation is
most common, indeed constant, can a nervous cause of the hyperfunction not
always be precluded. In peracute Basedow's disease, the entire symptom-
complex and the swelling of the thyroid gland can develop in a few hours; here
we cannot well blame the adenoma formation, as it is very much more likely
that in such cases the adenoma formation sets in at some later stage of
the disease. Such cases and the fact that many symptoms of Basedow's
disease, for instance the marked exophthalmos, can hardly be produced by
hyperthyroidization have led certain authors back to the conception of the
older French authors, according to which Basedow's disease was regarded
as a vegetative neurosis and in which many of the symptoms of the Basedow's
were considered as coordinated with the hyperthyroidism. According to
this we might distinguish Basedow's disease as a hyperthyrosis from the
symptom-complex of hyperthyroidism. Whether such views are to be ap-
plied to the adenomata of the hypophysis and suprarenal cortex can hardly
be decided at the present time. As far as severe diabetes is concerned, we
can hardly get away from the assumption of a hyperfunction, whether it be
secondary or primary. In Chapter XIII the opinion will be advocated that
the entire apparatus regulating sugar metabolism (central projection-fields,

CENTRAL NERVOUS SYSTEM AND DUCTLESS GLANDS 37

pancreas, and chromaffin tissue as organs affected by these fields) is diseased,
in the course of which disease process diminution of function in one part and
excess of function in another come. to exist in juxtaposition.

Nor can we explain the cause of the hyperfunction better if we regard
as its seat the central projection-fields. The problem is only shifted,
although we cannot deny that in this manner the solution of the symptom-
complex is made easier, or indeed first made possible.

Relation between Diseases of the Central Nervous System and the Duct-
less Glandular System

The knowledge that the ductless glands as vegetative organs indeed show
a certain autonomy, but in part, as far as their function is concerned, stand
under control of the central nervous system, together with the supposition
that we have to reckon with the possibility of a purely functional increase
or decrease of their secretion, requires of us that we now investigate whether
in the diseases of the central nervous system alterations of the ductless glands
are demonstrable. The investigations should first of all be important
for neuroses of the vegetative nervous system, but must also reach to the
psychoses and the other diseases of the central nervous system. So far as
the psychoses are concerned there have been pointed out very recently ap-
preciable variations in the condition of excitement and the tonus of the
vegetative organs. I refer, among other investigations, to the investigations
of Potzl, Eppinger, and Hess, who have found in melancholia a reduction
in the excitability of the vegetative nervous system, and in mania, especially
during the first attack, appreciable heightening of the excitability of the
vegetative nervous system. Also in other diseases of the central nervous
system, for example in tabes, symptoms on the part of the vegetative nervous
system become conspicuous in the disease picture.

This investigation seems to have so much the more force because later ob-
servations always confirm the view that in diseases of the nervous system and
in the psychoses1 the metabolism is often altered in a profound way. I would
here quote some examples. Rosenfeld first established that a considerable
nitrogen retention occurs in catatonics. Siege found enormous variation in
the nitrogen elimination in the circular psychoses. Especially intensive
studies on metabolism have been made by Kaufmann from Anton's clinic.
Especially mentionable are, for example, the enormous variations in body
weight in psychoses: for instance, Kaufmann found rapid fall of the body
weight in spite of copious forced feeding. According to Kaufmann, such rapid
variations are to be referred chiefly to disturbances in the amount of water in
the organism in the wake of nervous influences. In hysteria, Kaufmann found
considerable variations in the amount of urine and in body weight, together
with the fact that the pyschical disturbances may recede while the vegetative

1 For remarks as to the results of the Abderhalden reaction in mental diseases see foot-note,
p. 49. — Editor.

38 GENERAL PART

disturbances are still present. Also in progressive paralysis, in tabes, and in
a series of other brain diseases are alterations of the metabolism observed —
Paghini found in many brain diseases increase of the elimination of endogenous
uric and and of the xanthin bases. Lowe found increase in the elimination of
phosphorus after epileptic attacks and in definite phases of the paralysis and
in delirium tremens. The thought has also been expressed that the appreci-
able indicanuria accompanying brain diseases is sometimes of nervous origin.
There are also observed in cerebral and mental diseases considerable varia-
tions in the salt metabolism. As is known, there is frequently found in
neurasthenia considerable increase in the elimination of calcium. The
brittleness of the bones that is so often seen in tabes indicates a considerable
loss of calcium and phosphorus. Disturbances in the carbohydrate met-
abolism (especially appreciable lowering of the assimilation boundary) are
frequent phenomena in cerebral and mental disturbances. Disturbances
of the regulation of the heart are not at all a rare symptom. In progressive
paralysis Kaufmann often found hyperthermia, and in the akinetic diseases as
well as after epileptic attacks reduction of temperature. These few examples
might suffice. It can well be conceived that these alterations in metabolism
come about through a functional influencing of the ductless glandular system.

Special attention has been devoted in this respect to the behavior of the
ductless glands in the neuroses of the vegetative nervous system. Egger
saw in the vasomotor psychoneuroses increases of temperature that lasted for
months and years. In visceral neuroses, Pollitzer saw positive alimentary
galactosuria, while alimentary glycosuria was negative. This reminds one of
the alimentary levulosuria described by the author in some cases of Basedow's
disease, or in the disturbances in the qualitative decomposition of protein in
tetany. Curschmann saw a case of bronchial asthma with intermittent
exophthalmus, tremor, and tachycardia. In the vagal neurosis I regularly
found appreciable mononucleosis of the blood, and Eppinger and Hess ob-
served also hypereosinophilia. In the vasomotor neurosis Roth found in ad-
dition to marked lymphocytosis and lability of the pulse, also lability of the
temperature. Why rare cases of pentosuria and isolated levulosuria are almost
always associated with vasomotor neurosis is as yet unexplained. A short
time ago I saw a case of pentosuria with pronounced Herz's vasomotor ataxia.

In Raynaud's disease is often seen slight rise in temperature, distinct
trophic and secretory disturbances, and in the attack often marked rise in
blood-pressure; sometimes there is polyuria and in rare cases glycosuria.

Partially related to the vasomotor neurosis is perhaps that condition which
affects the group of diabetics in which the neurogenous factor especially pre-
dominates in the glycosuria. Here we usually find marked vasomotor ex-
citability, and under circumstances increase of the blood-pressure without
nephritis (hypertonic diabetes, see Chapter XIII).

Among the many symptoms of the vasomotor neuroses are found, accord-

39

ing to this, those which point to an alteration in the metabolism and in
general to a functional influencing of the ductless glandular system. It
seems to me that there is wanting in this case any secure foundation for
bringing a primary alteration of the ductless glandular system into an etio-
logical relationship.

Of the vasomotor neuroses, scleroderma seems to merit a more exact con-
sideration. In this affection there are a series of findings that point to a
marked involvement of the ductless glandular system, v. Strumpell has
pointed out a certain opposition in the symptom picture of scleroderma and
acromegaly. In the latter the bones and skin are hyperplastic, while in the
former there are processes of shrinkage in both organs. The opinion that
the basis of scleroderma is a functional disturbance of the hypophysis finds,
according to Roux, corroboration through the fact that in this case apparent
sclerotic processes are found in the hypophysis. Until the present, however,
this case has remained isolated; the opinion is often expressed that sclero-
derma depends on an alteration of function of the thyroid gland. After
v. Leube first pointed out the coexistence of scleroderma with Basedow's
disease, numerous pertinent cases were found in the literature, which have
been compiled by Saltier. Cassirer mentions, however, that in these cases
the diagnosis Basedow's disease is to be accepted with caution, as im-
portant symptoms of Basedow's disease, such as pigment displacements,
changes in the thyroid gland, irritability of the heart, also belong to sclero-
derma in itself. Even the exophthalmus may be stimulated by the sclero-
dermic mask. Cassirer himself calls attention to the fact that these symp-
toms similar to Basedow's do not always follow in their intensity the course
of sclerodermic process. The occasional appearance of myxedemic symptoms
(Grasset, Osier, Dehu, et al.} and the not rare finding of sclerotic changes in the
thyroid glands of those sick with scleroderma have permitted Jeanselme,
Singer, Hectoen, v. Notthajjt, Leredde and Thomas, and others to regard the
cause of the scleroderma as an insufficiency of the thyroid gland, the more
probably for the reason that in many cases good results are obtained by
thyroid medication. The common occurrence of pigmentations in sclero-
derma seems to indicate the associated involvement of the chromarfin tissue.
The pigmentations may simulate those of Addison's disease. In not rare
cases there are also observed typical smoke-gray discolorations of the mucous
membrane of the mouth. In a large number of cases the combination of
scleroderma with Addison's disease has also been assumed, although there are
numerous observations (Lichtwitz, Kren, and others} of scleroderma with
typical Addisonoid pigmentations of the skin and mucous membranes that
showed no alterations in the suprarenal glands at autopsy. Finally the
combination of scleroderma with tetany has been described in a case of
Dupre and Guillain's. In this case it seems as though a pronounced Addison's
disease were also present. As the supposition of change in one ductless

40 GENERAL PART

gland is not satisfactory, there has been upheld by several recent authors a
pluriglandular pathogenesis of scleroderma (Dupre and Kahn, Rasch, and
others). With regard to this, it is conceivable that sclerotic processes in
certain ductless glands in scleroderma do not mean very much. The sclero-
derma often spreads to the deeper-lying tissue and may also extend to the
bones and muscles; it is therefore not wonderful if now and then the proc-
ess should involve individual ductless glands. Moreover, there are found
in the majority of cases of scleroderma a great number of manifold symp-
toms on the part of the vegetative nervous system, conditions of excitement
of manifold nature, such as vasomotor disturbances, tachycardia, shivering,
faintings, rush of blood to the head, feeling of anxiety; as Klinger observed,
such conditions may occur in attacks. Hess and Kiinigstein saw in one case
of diffuse scleroderma, during such attacks, an especial sensitiveness against
adrenalin and marked excitement of the heart-action, associated with mani-
festations of acroparesthesia and with subsequent outbreaks of sweat. In
addition to this are found in the majority of cases a series of trophic distur-
bances, such as transitory edema, erythema, urticaria, etc. These make
the diagnosis of a coexistent Basedow's disease very much more difficult.
On the other hand, I do not doubt that in many of the cases there was
actually an increase of function of the thyroid gland, and that it was not
at all impossible that the pigmentations had their basis in a disturbance of
function of the chromaffin tissue. Nor do I doubt that in certain cases
slight symptoms of thyroid insufficiency may occur. When I acknowledge,
therefore, the possibility of pluriglandular symptoms in scleroderma, I would
regard them as only secondary, in part due to the sclerodermic process ex-
tending over the ductless glands, and still more due to functional influenc-
ing of the ductless glandular system. There are in addition cases of sclero-
derma in which the manifestations on the part of the vegetative nervous
system are much less prominent.

I agree fully with Cassirer in the supposition that in scleroderma the dis-
ease process is not primary in the ductless glandular system.

There has also been an attempt to bring another group of diseases, the
trophoneuroses, into relation with the ductless glandular system, diseases
such as acute circumscribed edema and symmetrical lipomata. In both
are regularly found neurosis symptoms on the part of the vegetative nervous
system. Here also is found the possibility of functional disturbances on
the part of the individual glands, although the symptoms are here less dis-
tinctly prominent. This same thing seems to me to hold good for adipositas
dolorosa. This condition will be considered in detail in Chapter XIV; here
I wish to dispense with the supposition of ductless glandular etiology. The
same is true for xanthelasma, the pathology of which Ckvostek has made
the subject of a penetrating study. Ckvostek in consideration of the occur-
rence [of xanthelasma] in gradations [schubweise], the kind of distribution,

CENTRAL NERVOUS SYSTEM AND DUCTLESS GLANDS 41

and especially the often rigid symmetry, comes to the conclusion that nervous
influences are the basis. The individual with xanthelasma shows a series
of symptoms on the part of the nervous system and especially on the part
of the vegetative nerves. Here also the changes in the ductless glands
seem to me to be only of a secondary nature.

Xot only in trophoneuroses, but also in other diseases of the central
nervous system, do we find the most manifold symptoms that point to dis-
turbances in the function of the vegetative nervous system. It seems to
me that the study of these conditions has been handled rather half-heartedly
by neurologists. Myasthenia, paralysis agitans, and myotonia have been
brought into etiological connection with the parathyroid glands. As we
shall see, however, in Chapter IV, I regard the hypothesis of a primary affec-
tion of the parathyroid glands in these diseases as insufficiently supported.
Myasthenia, because like scleroderma it is sometimes associated with slight
symptoms of Basedow's disease or tetany (Tobias), has been regarded as a
polyglandular disease (Markelojf), certainly not with more correctness than
has been scleroderma. Finally, I wish to make some remarks in this connec-
tion with regard to multiple sclerosis, tabes, and progressive paralysis. In
multiple sclerosis, often symptoms on the part of the vegetative nervous
system become distinctly prominent. There often exist tachycardia and
great lability of the pulse, mostly pronounced dermographism, furthermore,
sweats, inclination to hyperthermia, manifestations on the part of the gastro-
intestinal canal, polyuria, bladder disturbances, etc. In a series of cases
that we investigated we found a great sensitiveness against adrenalin and
pilocarpine, often appreciable alimentary glycosuria, strong diuretic action
of pituitrinum infundibulare, low degree of tolerance against thyroidin, etc.
In some cases even Chvostek's phenomenon was observed. It is further known
that in multiple scleroses the activity of the generative glands mostly dis-
appears early. I think that most will agree with me that if we speak of
pluriglandular disturbances in this disease, we shall have to assume a func-
tional and trophic influencing of the ductless glands. The relations in tabes
and progressive paralysis seem to me to be very similar. Kraepelin has
grouped paralysis with the diseases of metabolism, to which group Raymond
has ascribed tabes. This seems to me to be overdrawn. In the same manner
we could regard the infectious diseases as metabolic diseases. Indeed it is true
that in tabes and paralysis the alterations of metabolism are so prominent that
at times they almost dominate the clinical picture. I refer to the losses of
weight, to the marked cachexia of tabetics, to the decalcification of the bones,
which gives rise to the spontaneous fractures, to the positive alimentary
glycosuria that is so marked in this condition; also to the irritative symp-
toms on the part of the nervous system that are so fulminant, the tabetic
gastric crises, the vesico-intestinal crises, the enormous hypersecretion of
gastric juice, moreover the vasomotor disturbances, tachycardia, sweats,

42 GENERAL PART

dermographism, and the trophic disturbances, abnormal pigmentations,
mal perforant du pied, etc. If here I look around for symptoms on the part
of the ductless glands, I find almost only the degenerative changes in the
sexual glands that have been demonstrated by Marchand and others; these
may be conditioned by the syphilis, but it might also be conceived that they
exist on a trophic degenerative basis. I could regard any of the other
symptoms as ductless glandular, only in the sense that they might be second-
ary. R. Stern regards as the basis of the fact that only a percentage of persons
infected with lues become affected with metasyphilis the vulnerability
of the ductless glandular system in the mapping out [Anlage] of such persons.
According to this view, the affection of these glands furnishes the impulse for
the development of the tabes or the paralysis. Even though in my dis-
sertations I arrive at a standpoint that is almost the opposite of Stern's, I
would nevertheless recognize the ingenious character of Stern's work.

I would here summarize briefly the facts arrived at from the above exposi-
tion. Even though we may be inclined to refer to functional alterations of
the ductless glandular system changes in metabolism in the course of neuro-
ses of the vegetative nervous system or in the course of nervous diseases in
which manifestations on the part of the vegetative nervous system become
prominent, we are not on this account justified in regarding these diseases
as true ductless glandular affections. At all events it must be acknowledged
that it is not yet possible to draw a clear line of demarcation between certain
ductless glandular affections and the vegetative neuroses; the neurosis theory
of Basedow's disease has not as yet been fully rejected, nor is the supposition
that in the pathogenesis of diabetes mellitus there is the admixture of a
marked component of neurosis. But a sufficiently firm foundation has been
built by experimental pathology, in the majority of ductless glandular
affections, to justify a sharp demarcation from the vegetative neuroses, at
least nosologically.

Pluriglandular Disturbances

Proceeding from this standpoint, we now go on with a consideration of
the question of the pluriglandular disturbances. Of late this question has
been especially discussed in France. Claude and Gougerot, on the basis of
clinical observations and certain pathologico-anatomical findings, first
conceived the idea of an insuffisance pluriglandulaire. Proceeding from the
observation that under circumstances certain ductless glands may become
diseased simultaneously, they attempted to furnish the demonstration that
in the most diverse ductless glandular diseases symptoms are found almost
regularly that point to the affection of another ductless gland. The authors
have found many disciples. The direction of this is characterized by the
classification of Laignel-Lavastine. Laignel-Lavastine distinguishes "syn-
dromes pluriglandulaires a predominance thyreoidienne, a predominance

43

hypophysaire, a predominance genitale et sans predominance marquee."
Claude and Gougerot have further developed their teaching in that they point
out that also conditions of hyperfunction of several ductless glands may
exist simultaneously, and that not rarely conditions of hyperfunction of one
ductless gland are combined in the clinical picture with manifestations of
absence or deficiency of the function of another. They distinguish, of duct-
less glandular diseases, seven categories:

1. Syndromes uniglandulaires avec lesion pluriglandulaire; example,
classical myxedema.

2. Syndromes pauciglandulaires; that is, predominance of the disease in
one ductless gland, but distinct alteration in the others.

3. Syndromes d'insuffisance pluriglandulaire sans predominances.

4. Syndromes d'hyperfonction pluriglandulaire; example, acromegaly,
hyperfunction or dysfunction of the hypophysis with hyperfunction
of the thyroid gland, suprarenal glands, etc.

5. Syndromes pluriglandulaires de balancement; that is, a hyperfunction
that developed compensatorily as the result of a primary falling away
of the function; for example, Basedow's disease that follows a
"hypoovarie."

6. Syndromes pluriglandulaires disharmoniques ; example, Basedow's
disease combined with myxedema and " hypoovarie."

7. Cas d'attente a syndromes frustes.

Gougerot goes still further, including the glands with external secretion
in the pluriglandular syndrome; for instance, he describes: syndrome
Mikulicz, lacrymo-parotidien avec symptomes d'hypoovarie evidente, hy-
pothyreoi'die et hypoepinephrie probable. The disciples of Claude and
Gougerot have also included the trophoneuroses. Thus Siccard and Rousay,
later together with Berkowitsch, explain a case of Dercum's disease as in-
suffisance ovarothyreoi'dienne. From these views Renon and Delille have
drawn far-reaching therapeutic consequences, in that they propose an
"opotherapie associee" in those conditions hr which a trial with simple
opotherapy fails. Thus the authors found that in one case of Dercum's
disease ovarian substances, and later thyroidin, remained inactive, while
on the contrary the combination of these two remedies was effective. A case
of myasthenie bulbospinale was improved by the combined administration
of ovarian and hypophysial substances, a scleroderma by thyroidin and
ovarian substances, a Basedow's disease disappeared on the administration
of hypophysial and ovarian substances, a case of acromegaly was essentially
improved through ovarian substances and thyroidin, etc. R. Dupuy used
polyopotherapy for the development of individuals who had remained be-
hind or were at a standstill, and saw a striking improvement after one-half
to one year's treatment. The admixture of all nosological unities goes so
far that Grasset says: The insufficiency of a ductless gland always becomes

44 GENERAL PART

more and more a rarity or a "creation artificielle," the group of insuffisance
pluriglandulaires crowds the others more and more and perhaps in time will
quite replace them. With all this, who does not feel foundations wavering
under him?

I must not leave unmentioned the fact that voices, even in France,
have been raised against these extreme overdrawings. Roussy maintains a
very reserved attitude. He believes that they are an ingenious hypothesis,
but [regards] methodical sections as lacking.

The question seems to me to gain clearness if we distinguish between
pluriglandular insufficiency or pluriglandular syndromes on the one hand
and multiple ductless glandular sclerosis on the other, for the existence of a
pluriglandular syndrome does not signify the existence of a multiple ductless
glandular disease. On the basis of what I have already written, I must
assume that the pluriglandular syndrome comes about:

1. Through physiological correlation.

2. Purely functionally through influencing on the part of the vegetative
centers.

I have gone more intimately into the question of the latter factor in the
consideration of the vegetative neuroses. As far as the physiological corre-
lation is concerned, it seems to me that it affords no ground for a confusing
of the sharply delimited disease pictures of the individual ductless glandular
diseases. Let us first consider the diseases due to deficiency. That in
myxedema the activity of the glands of generation is diminished or that
in hypophysial dystrophy there occurs even marked degeneration of the
sexual glands belongs to the disease pictures themselves. On account of
this no doubt is cast on the view that in the first case the thyroid gland is
the central figure of the pathogenesis, in the second the hypophysis. The
disease pictures which, however, we assume as the result of a pathological cor-
relation already belong to multiple ductless glandular diseases: I refer once
more to the simultaneous degenerative lesions of the thyroid gland and the
glandular hypophysis, of the thyroid gland and the insular apparatus of the
pancreas, etc. The pathological correlation finds its most complete ex-
pression in that clinical picture, well characterized in a symptomatological
respect, which I have termed multiple ductless glandular sclerosis.

Undoubtedly more complicated are the relations in the hyperfunctional
diseases — not so very much in Basedow's disease. Although in this condi-
tion we may acknowledge a functional increase of the chromaffin tissue,
this is secondary and well enough explained by physiological correlation.
That long-continued oversaturation of the body with thyroid gland secretion
may give rise to disturbances of the functions of the sexual glands is not
at all remarkable, only the significance of the thymus hyperplasia is as yet
unclear. But on this account, not to wish to consider Basedow's disease
as a clinical entity seems to me incomprehensible. Sooner could aero-

THE DUCTLESS GLANDS AND CONSTITUTION 45

megaly be regarded as a pluriglandular disease; this is not new, however, but
was already mentioned by Pineles in his classical work. In addition to
hyperplasia of the hypophysis, we not rarely find, in acromegaly, symptoms
of Basedow's disease, in the later stages eventually symptoms similar to
myxedema, also to diabetes, and in the most cases, as is known, premature
disturbances on the part of the glands of generation, which may, however,
be sometimes preceded by temporary increase of their function. Of late
years, too, have been issued reports as to hyperplasia of the suprarenal
cortex ; briefly, in acromegaly there conies about a pluriglandular hyper-
plasia of the ductless glandular system, which mostly is rapidly followed by
a degeneration and exhaustion. This, however, likewise belongs to the dis-
ease picture of acromegaly, and on this account we would hardly be likely
to confuse a Basedow's disease with an acromegaly.

These pluriglandular disturbances are found much more pronouncedly
in many cases of gigantism. Here the hyperplasia would seem to be a par-
tial manifestation of an abnormal predisposition to growth of the entire body.

Concerning the therapeutic results of opotherapie mixte, that have been
hailed with such enthusiasm, they must be regarded with much scepsis, espe-
cially in so far as they are concerned with the trophoneuroses of the vege-
tative nervous system. However, I do not wish to deny the justification
for this therapy in combined diseases due to absence [Ausfall].

Desirable seems to me a sharper delimitation of the ductless glandular
diseases, not only from the vegetative neuroses, but also from certain vege-
tative disturbances. The regarding of chondrodystrophy as a ductless
glandular disease has been practically done away with. Mongolism is re-
garded to-day as a product of degeneration, in which a thyogenic component
is associated, at most. Lately, true dwarfism has been regarded as a disease
due to deficiency of the hypophysis, a view that will hardly meet with general
acceptance. Most obstinate are the attempts to obtain a place among the
ductless glandular diseases for true infantilism. In true infantilism the
organism, on account of a damage in fetal or postfetal life, does not progress
beyond the child stage of development. In this remaining behind, the
ductless glandular system participates, as well as the central nervous system
and every other organ of the body. There are, however, no indications that
the ductless glands functionate deficiently, which dictum holds also for the
sexual glands — these functionate, but only as in the child organism; if they
were not to functionate, the genitalia and dimensions of the body would be
eunuchoid, but not infantile.

The Ductless Glands and Constitution

After the above attempts to delimit the ductless glandular diseases from
the disease groups that are related to them, I would add a few remarks as to
the significance of the ductless glandular system for the total constitution of the

46 GENERAL PART

bodv. Martins says "die Gesamtkonstitution ist die Summe der Teilkon-
stitutionen" [the total constitution is the sum of the partial constitutions].
I might suppose that from the study of the physiology and pathology of the
ductless glandular system we have obtained a deeper insight into one of
these partial constitutions. At all events we must not accept the ductless
glandular system for itself alone, but must regard as a constitutional com-
ponent the ductless glands as vegetative organs together with the nervous
system regulating their functions. Wunderlich distinguishes a strong, an
irritable, and a lax constitution. This classification seems also to apply to
those components of the general constitution whose differentiation we are
at present concerned with. We can group individuals into those with
stabile, those with debile and those with labile, vegetative nervous systems,
and individuals with stabile, debile, and labile ductless glandular systems.
The certain degree of autonomy that is an attribute in general of the duct-
less glandular system has as a sequel the fact that the corresponding partial
constitutions may occur separately; the intimate relations that exist between
both systems would lead us to expect, however, that they are to be very often
found united in the same individual or that where one is present the other is
at least suggested. As the hereditary factor is very prominent in both, we
find them in the most diverse variations and combinations in members of the
same family. In individuals with a predisposition to a debile vegetative
nervous system there develop, under the demands that life makes on the
organism, an asthenia of the vegetative organs with general enteroptosis,
sluggishness of evacuations, anomalies of the secretion of gastric juice, de-
pressive mental attitude, in short the features that are an expression of Stiller's
asthenia. In the individuals predisposed to a labile vegetative nervous
system, readily accessible to irritations, there exists a tendency to neuras-
thenia, hysteria, and the vasomotor-trophic neuroses. It seems to me that
this classification may be applied in the smallest detail to the ductless
glandular system. The ductless glandular debile individuals are those in
whom there is not only a small functional breadth, but perhaps also a certain
tendency for certain diseases, especially for infections, or a slighter resistance
against alcohol or against certain toxins that may proceed from a focus of
infection somewhere in the body. To me the most interesting are the duct-
less glandular labile individuals. These are individuals who several times in
the month show extraordinary variations in the body weight, or those in
whom the thyroid swelling that occurs normally during pregnancy leads to
slight manifestations of Basedow's disease, or those in whom a strong emo-
tional excitement calls forth temporary glycosuria, or perhaps those in
whom slight symptoms of acromegaly occur during pregnancy, or women in
whom exist marked dysmenorrheic distresses. In this group are always to
be found, too, some symptoms that point to an especial lability of the vegeta-
tive nervous system. I need not attempt the description of the stabile in-

THE DUCTLESS GLANDS AND CONSTITUTION

47

dividuals. They are those with an enviable equilibrium of their vegetative
functions, their metabolism, and their psyche.

The relationship of both the disease groups is also shown, as has already
been mentioned, in the fact that they sometimes occur combined or alter-
nating in the members of one family. I here submit an example:

Grandfather

(Obesity and Gout)

Son Daughter Daughter

(Slight thyroid (Slight thyroid (Slight thyroid glan-
swelling, later glandular swell- dular swelling, mani-
light diabetes ing, climacteric festations of hyper-
with light Base- psychosis, light thyrosis.)
dow's symp- diabetes.)
toms.)

Son

(Obesity.)

i /

Granddaughter Granddaughter

(Severe exuda- (Obesity.)
tive diathesis,
later bronchial
asthma.)

I i

Granddaughter Granddaughter

(Pronounced lability of (Likewise lability
the ductless glandular of the ductless
system, great varia- glandular system,
tionsinthebody wieght migraine, parox-
during pregnancy, ysmal tachycar-
light Basedow's symp- dia.)
toms, great sensitive-
ness against cocaine.)

I would consider it probable that such family trees are not at all hard to
find, at least they do not occur isolated, but readily could be traced in the
family trees of families with diatheses.

This affords me the opportunity of saying a few words with regard to
the significance of the ductless glandular system for the diatheses. Accord-
ing to W. His we understand by diathesis an individual, congenital, and
often inherited condition, which consists in the fact that physiological
stimuli call forth an abnormal reaction, and that conditions of living, that
are borne without harm by the majority of the race, call forth conditions of
disease. The circumstance, that in the great group of arthritic diatheses, as
also under the diatheses of pediatrics and dermatology, there are found con-

48 GENERAL PART

ditions that we regard as vegetative neuroses, shows that the vegetative
nervous system has a prominent place here. Rapin sees also in a familial and
inherited lability of the nervous system the connecting link between the in-
dividual diatheses. In this connection we must turn our attention to the
ductless glandular system. Actually we find that diabetes and obesity
play a prominent part in the great group of arthritism. The connection
between gout and the ductless glandular system is, of course, at first hand as
yet quite unclear. In the pathogenesis of the spasmophilic diathesis we
must, even with the use of the utmost reserve, ascribe some significance to
the parathyroid glands. Also for the genesis of lymphatism the observations
that status lymphaticus is regularly associated with hypoplasia of the chrom-
affin tissue cannot be quite without significance. For the predisposition to
the dermatoses the processes in the sexual sphere are of importance, as
Block emphasizes, for just at the transitional periods, at puberty and at the
climacteric, certain dermatoses are very common, and others, like favus or
trichophytina, disappear with the beginning of puberty. Here the ductless
glandular system exerts a certain influence on the natural immunity.

A very much older observation concerns the known inclination of dia-
betics for furunculosis, and the great vulnerability of their tissue. This
may be shown experimentally: it is known that after extirpation of the pan-
creas it is not easy to obtain a reactionless healing of the laparotomy wound.
Block infected the skin of dogs with yeast before and after the extirpation
of the pancreas and found that the affection was much worse in the dogs
without a pancreas. The fact in itself cannot be gainsaid, but as yet we
are without any deep insight into the nature of this disease susceptibility.

As may be gathered from the elucidation of the idea of diathesis through
the summarizing "Referate" [references] of His, Pfaundler, and Block, we
are dealing in the diathesis not with sharply circumscribed disease pictures,
but with an exceedingly manifold disease susceptibility resting on as yet
hard to define factors; alterations in the function of the ductless glands
constitute only one of these factors; in a theoretical sense I would not,
however, estimate this factor as of slight importance, for if we see in the
interest that physicians have taken in the question of diathesis a sort of
resurrection of the old humoral pathology, and if we seek in an altered blood
admixture and the consequent changing of the tissues the cause of the
tendency to disease, we find that the little that the study of the ductless
glandular diseases has afforded for the knowledge of diathesis has up to the
present first furnished" an idea as to the genesis of this alteration of the
blood admixture and the tissue changes that follow it.

Finally a few words as to senility. Horsley first pointed out that the
alterations of the skin and other tissues that occur in old age, especially the
increase of the connective tissue, have a certain similarity with those that
occur after extirpation of the thyroid gland, and that on the other hand
localization of the fat deposits in old age is similar to that in eunuchoidism.

ADDENDUM 49

In a detailed study Lorand has upheld the idea that the degeneration of
the ductless glandular system is chiefly the cause of senility. I would not
concur with this, so far as physiological old age is concerned, but believe
much more, as does also Ewald, that the ductless glandular system like every
other organ participates in the involution of old age. There is, on the other
hand, a pathological old age, setting in prematurely or asspciated with dis-
tinct accentuation of the cachexia. The premature senility which develops
in most of the diseases due to giving out of function, and especially in mul-
tiple ductless glandular sclerosis, makes intelligible to me the fact that
degeneration in the ductless glandular system may be one of the causes
of pathological age.

Addendum

With regard to what has been written in toto, it may be said that the
author's views respecting the grouping, the reciprocal action, etc., of the
ductless glands, and their effects on the various organs and systems of the
body, are sound. On the whole they seem to be somewhat in advance of
the general conception in America of the purport and scope of the ductless
glandular apparatus, at least in regard to their definiteness. There seems
to be a tendency among some recent investigators to claim too much for the
ductless glandular system and to jump to conclusions, attributing effects to
the system of endocrine organs that might just as well be explained by
metabolic processes that are general, or that are part of constitutional fac-
tors at least one step removed from purely internal secretory activities.

The author's chapter on ductless glands and constitution has the tend-
ency to counterbalance this drift. Here the various ductless glandular
constitutional states are considered as part of a "total constitution," which
is made of factors that mutually influence each other, including the ductless
glandular system. If to the modern mind such an attempt to revive the
idea of "constitution" and its sister conception "diathesis" savors too
much of the old humoral pathology (which by the way in its serological
form has led or will lead to a later chemical aspect of the subject which will
perhaps be all-embracing so far as relation between cell and tissue juices is
concerned), it must not be forgotten that "constitution" itself represents
but one factor of a far more extensive subject — heredity, a subject that in
its last analysis resolves itself again into factors that are mechano-chemical,
and perhaps is part dependent on the activities of just these ductless glands.

The Abderhalden reaction has already furnished results with regard
to the reciprocal activities of the various ductless glands. To the editor's
mind it would seem that the importance of the significance of the Abder-
halden reaction (in general, not simply the pregnancy test) has not as yet
been sufficiently realized, at least in this country.1 That its basic principle,

1 Much work has recently been done with the Abderhalden reaction, especially in the field
of nervous and mental disease. Remarkably striking have been the labors of Fauser and his
followers, in the Abderhalden diagnosis of dementia precox I shall not enter into this matter
4

50 GENERAL PART

the formation of ferments — chemical substances — for the splitting up of
alien or other proteids, as a matter of "Abwehr," defense, is a biological
phenomenon at the basis of life itself, and it will be indeed strange if this
principle, capable as it is of exact chemical demonstration, does not yield
practical results far in advance of present indications.

The matter of "Abwehr" leads us to two other so-called discoveries of
recent years — the Freudian theory of the genesis and treatment of hysteria
and allied neuroses and the so-called "kinetic theory" of Crile. Of these
the latter merits discussion here because of its direct relation with the duct-
less glandular diseases, and the former because of the relation of the various
neuroses (and even psychoses) to the ductless glandular system. It is a
pity that Crile has not as yet (September, 1914) published the results of
his experiments in toto and in detail, as much of what he claims for his theory
(based as it is on painstaking examination of, among other objects, 40,000
nerve cells) seems to be substantiated by older and more recent theories of
the central nervous origin of such ductless glandular conditions as Basedow's
disease and diabetes mellitus. (Crile will be mentioned again in the ad-
dendum to the chapter on Basedow's disease.)

With regard to Freud, I have been anticipated in what I wished to say
by Cushing; as I consider the matter very well expressed by that author,
I shall quote in extenso passages from one of his works :

"The pituitary body and the germinal glands appear to be protagonists.
Hypophysial insufficiency and a lowering of the activity of the reproductive
functions go hand in hand, and in some of our examples of hypoplasia,
glandular feeding has unquestionably led to a restoration of potentia. The
reverse is probably also true, for, as stated, a libidinous tendency often ac-
companies states of secretory hyperplasia, and certain experiments under-
taken with Dr. Emil Goetsch have indicated that feeding pituitary extracts
to preadolescent animals leads to a precocious ovulation and spermato-
genesis. These observations, coupled with the knowledge that secretory
discharges from the hypophysis may be elicited through the sympathetic
nervous system, suggest that the liberation of a chemical messenger may
account for the recognized effect of the emotions upon the sexual sphere."

***********#*•******•***#•***

"It is plain that the two intracranial glands, hypophysis and epiphysis,
normally exercise a remarkable influence not only upon the nutrition and
skeletal growth, but also upon the sexual sphere, and it is not a matter for
surprise that in the presence of a definite pathological derangement of either
of these structures which dates from childhood, mentality should be so modi-

here but refer the reader to the bibliography appended to Abderhalden 's Abwehrfermente des
tieris chen Organismus, etc., or to that at the end of Ortows article (Am. J. Insanity, vol. 71,
I9IS» P- 573)- Allusions to the Abderhalden reaction will be found in certain of the addenda
to the chapters of the present work. — Editor.

ADDENDUM 5 I

ficcl as to produce peculiar if not defective individuals when measured by the
standard of the average.

"With this conception we may find some physiological or pathological
basis for what is regarded by many as a psychotherapeutic phantasy; for
the various neuroses and asthenias may arise primarily as the result of some
disturbance of internal secretion which proves the way for the dreams,
symbolisms, neurograms and other acrostical manifestations dissected by
the psychoanalyst. If therefore we are to swallow the Freudian doctrines
whole — a difficult morsel for many — and are to interpret hysteria and the
psychoneuroses solely as the resultant of early mental conflicts and com-
promises between the libido and its repressions, it will be easily seen that any
secretory duration which on the one hand excites, or on the other diminishes,
sexual activities must be an important element in modifying the terms
affecting the ultimate compromise.

"We have of course been considering extreme examples, but is quite
probable that the psychopathology of everyday life hinges largely upon
the effect of ductless gland discharges upon the nervous system. This is
particularly worthy of consideration in the study of child psychology^ in
its relation to puberty and adolescence, especially in those individuals in
whom there is some underlying, possibly inherited, functional deviation in
the chemistry of the internal secretion. At any age, however, in the pres-
ence of some ductless gland irregularity, which in chemically speaking more
stable individuals would be transient, may produce secretory disturbances,
characterized by more or less chronicity."

##*#######*#*####*#*#####-*

"It is hoped that some serological test, possibly in the direction of
Abderhalden's investigations on the serodiagnosis of pregnancy, will serve
to give as a chemical reaction of diagnostic value, at least, for states of over-
activity of individual glands . . . and we possibly may come to attach an im-
portance to the findings of pathological serology far greater than that which in
the past we have given to the cytological changes shown in the microscope. "

*###-*-x-*###########*##*##*-*

It was part of the philosophy of the ancients to explain change in matter
as due to the "love" of the elements. We still speak of chemical affinities.
Nowadays we resolve love into its chemical constituents. All of which
makes not one whit less, but rather much more wonderful, the phenomena
manifested by the various bindings together of atoms.

Thus is the Freudian theory placed on a materialistic basis with re-
gard to the genesis of certain of the epiphenomena of some of the neuroses.
That the underlying factor of heredity governs here the constitution, pre-
disposing either the ductless glandular or the nervous factor or both to ab-
normal action, there can be no doubt. One thing at least we may be assured
of: without internal secretion, no thoughts. The fact, however, that the
nervous tissue seems to be especially susceptible to the influence of the

^2 GENERAL PART

internal secretions of what is ordinarily known as the ductless glandular
system does not preclude its influencing by products of cellular activity
elaborated in the course of diseases that have nothing to do with the ductless
glandular system (I am indebted for this idea to remarks by McCarthy, in
an extempore address) or in which, as in the infectious diseases, the ductless
glandular system is influenced only indirectly. This subject last mentioned,
that of ductless glandular affection in the course of infectious disease has been
taken up especially by Sajous, to whom we are indebted so much for attract-
ing our attention to the importance and scope of ductless glandular affections.

What is especially noticeable in the ductless glandular diseases is the
employment of chemical substances or glandular extracts in their diagnosis —
a use for these substances or extracts that independently of the ameliorative
effect is perhaps new in the art of diagnosis, and that may perhaps mark
the beginning of a new science, that of pharmacodiagnosis.

Sajous has recently published a resume of his conclusions with regard to
the function of the various constituents of the ductless glandular system.
This resume approaches first principles to a greater extent than any of
Falta's conclusions, and is interesting as furnishing a basis of comparison
with the results of Falta's work. Sajous maintains that the thymus gland
supplies to all tissues the excess of phosphorus in organic combination
(possibly as nucleins) required to build up cell-nucleins while the animal or-
ganism is developing. The thyroparathyroid secretion (thyroidase) sensitizes
these nucleins to the action of oxygen. The adrenal secretion (through its
catalytic ferment, adrenoidase) endows the blood with its oxygenizing prop-
erties. The pancreas supplies the ferments which in the intestinal canal and
nutritional leucocytes change food materials into products harmonious to,
and for the building up of, tissue cells, that is, for the anabolic phases of
metabolism. The same pancreatic ferments also carry on the catabolic
phase of metabolism. All endogenous and exogenous substances that are
not appropriate for tissue-building — bacteria, toxins, toxic wastes, toxic
venoms, etc., are subjected in the phagocytic leucocytes, the tissue cells,
the lymphatic system and the blood plasma to the catabolic phase of
metabolism, which serves to convert them into eliminable end-products.

Crile (G. W.). The kinetic system, Cleveland M. J., Vol. XII, No. 4, October, 1913,
p. 665, associated with which is :

Hitchings (F. W.), Sloan (H. G.), and Austin (J. B.). Laboratory studies of the brain
and the adrenals in response to specific stimuli, Ibidem, pp. 684-691.

Crile (G. W.) andLower (W. E.). Anoci-association. W. B. Saunders Co., Phila., 1914.

Gushing (H.). Psychic disturbances associated with disorders of the ductless glands.
Am. J. Insanity No. 5, 1912, special number, pp. 965-990.

Sajous (C. E. de M.). Among other articles: Hypoadrenia as a cause of death in in-
fections and its treatment. Monthly Cyclopaedia and Medical Bulletin, Vol. IV, 1911,
pp. 725-729. Also his Internal secretions and the principles of medicine, 5th edition,
Phila., F. A. Davis and Co., 1912.

Sajous (C. E. de M.). The theory of the internal secretions. The Practitioner, Feb.,
1915, PP- 180-197.

CHAPTER II

THE DISEASES OF THE THYROID GLAND

Anatomy and Embryology. — The thyroid gland of man has the shape of a
butterfly. The two lobes lying on the lateral surfaces of the trachea and
larynx are joined together by the isthmus, which is sometimes prolonged
for a certain distance superiorly as the so-called processus pyramidalis.
The weight of the thyroid gland in the adult approximates 36-50 gm.

The isthmus is developed from an unpaired evagination from the ventral
wall of the head-gut cavity. In many of the lower animal classes the con-
nection with the head-gut — the ductus thyroglossus — is retained. Here the
thyroid is a gland with external secretion. In the higher animal classes the
ductus thyroglossus obliterates early. Con-
cerning the development of the lateral lobes
opinions to-day are still divided. It is safe
to say that a portion of the lateral thyroid
gland rests are developed through evagina-
tion from the median rest. It is further
certain, according to the investigations of
Erdheim and Schilder, that the so-called post-
branchial bodies, that originate from the
ventral wall of the fourth branchial pouch,
can give rise to thyroid gland tissue, for in F«>- 3. — Tr = Thyroid; /, //,
the cases of thyroaplasia in which the me- 7//' IV = Phary^eal P°uche*; '**

. = rudiments of the parathyroid

dmm rests of the thyroid remain rudimentary, glands; p = Abranchial bodies;

the indifferent rests of these bodies regularly Tm = rudiment of thymus.
contain some thyroid gland follicles. Only

uncertain, therefore, is to what extent -under normal conditions the lateral
rests of the thyroid gland take part in the formation of the lateral lobes.
To aid the better comprehension of the subject, I subjoin the accompany-
ing sketch taken from the work of Maurer in which is shown the devel-
opment of the parathyroid and the thymus glands.

The rudiments of the thyroid wander downward with the heart. Along the entire
tract from the root of the tongue to the aorta may be found cut-off portions of thyroid
glandular tissue, accessory thyroids, which may give occasion to the formation of ab-
normally situated goiters (tongue goiters, retrosternal goiters, etc.).

The thyroid is remarkably well vascularized. It consists histologically
of follicles lined with cubical or cylindrical epithelium, which for the most

53

54

THE DISEASES OF THE THYROID GLAND

part are filled with colloid. This contains the specific secretion, which, ac-
cording to the need, gets into the circulation, probably through the lymph
paths. Fr. Kraus therefore designates the thyroid a reserve or storage
gland. The thyroid is signalized by an especially high contents of iodine;
in the formation of the specific secretion, which is bound to an albuminous
body thyroglobulin.

We may divide the diseases of the thyroid gland into those which for the
most part do not especially restrict its functions, but chiefly produce local

FIG. 4.-

Normal thyroid gland with colloid formation.

symptoms, and those the principal symptoms of which depend on the
alteration of the internal secretory function. To the first belong certain
forms of the goiters, the tumors and the inflammations. The goiters are
discussed in the chapter on the cretinic degeneration.

Tumors of the Thyroid Gland. — Among the tumors are found most com-
monly adenoma, carcinoma, and sarcoma. The simultaneous occurrence of
sarcoma and adenoma in the thyroid gland has been reported (Saltykow
gives the literature). The tumors mentioned all show a great tendency
toward the formation of metastases. In carcinoma, bone-metastases are

INFLAMMATION 55

especially frequent, especially in the bones of the skull and in the sternum;
in sarcoma, metastases are frequently found in the lung. The metastases
of adenocarcinoma of the thyroid gland contain not inappreciable amounts
of iodine. Gierke reports two cases of carcinoma of the thyroid with metas-
tases in the vertebral column. In the case of Ewald, the highly decomposed
primary adenocarcinoma of the thyroid was iodine free; the metastases in
the lungs and lymph-glands contained iodine. The decision as to whether an
adenoma of the thyroid is malignant or benign is often very difficult (v.
Eiselsberg). Microscopically metastases may appear as gelatinous goiters,
and yet the very presence of metastases may in itself be regarded as the sign
of malignancy. Sometimes the metastases when examined microscopically
show a formation similar to carcinoma.

On account of the proximity to many important organs (trachea, esopha-
gus, sympathetic, vagus, etc.), tumors of the thyroid not infrequently cause
very manifold local manifestations, which will not be discussed further at
this place. They may also give rise to alterations in the thyroid function.
Symptoms of deficiency [of secretion] are relatively rare, and it may then
happen that the symptoms of myxedema retrogress when metastases de-
velop (v. Eiselsberg) or when accessory thyroids begin to grow. This may
even occur when the metastases have become degenerated carcinomatously.
Indeed v. Eiselsberg found in the metastases in such a case follicles still filled
with colloid. Not so very rarely malignant tumors of the thyroid gland
take on the characteristics of Basedow's disease. Saltier has collected
sixteen such cases, of which eleven were carcinomata, and three sarcomata,
while in two the character was not determinable. Indeed the Basedow's
symptoms may not appear until just at the time that the metastases develop
(/. Lowy has collected the literature). We find therefore that malignantly
altered thyroid gland tissue may not only affect the normal function, but,
when proliferation is rapid, may even lead to hyperfunction. The inter-
pretation of the symptoms of Basedow's as hypothyrosis (Minnich) is not
to be regarded as correct.

Inflammations of the Thyroid Gland. — We distinguish between thyroi-
ditis and strumitis. The first is very much rarer, as apparently the normal
thyroid shows little tendency for inflammatory processes, which has also been
determined experimentally on animals. In thyroiditis, too, as Jeanseline
mentions, the termination in suppuration is much rarer. A light inflamma-
tion of the thyroid is very often an accessory phenomenon of acute infections
{Roger and Gamier, Kashiwamura, de Quervain, Sarbach, and others). The
histological alterations, which consist in epithelial desquamation and dis-
appearance of the follicles, hyperemia, etc., may be not inappreciable after
scarlet fever and variola, and also after other infectious diseases. Thyroiditis
is not uncommon in the early stages of syphilis (according to Engel-Remiers
in 56 per cent, of cases). Slight sclerotic processes are often present in

56 THE DISEASES OF THE THYROID GLAND

tuberculosis and in severe alcoholism. Severe inflammatory processes in
the thyroid have been observed after typhoid fever, variola, influenza,
malaria, puerperal processes, etc. ; especially, however, after angina and acute
articular rheumatism. A detailed summary of the literature is that by de
Querv'ain. . The primary form of acute thyroiditis which does not go on to
suppuration, was first described by Mygind and more recently by de Quervain
in a very thorough report. The onset for the most part is sudden; with
evident general symptoms and fever the thyroid gland becomes swollen,
and there may be local symptoms of pressure. This is followed by severe
pains radiating to the ear and throat; the climax of the clinical mani-
festations is for the most part soon reached, and quickly, or more or
less slowly (lytically), all phenomena subside. The histologic picture of
the thyroid gland is in many respects similar to that of the Basedow thyroid.
Nothing is known as yet as to the causative agent. De Quervain recommends
quinine and salicylic acid for treatment; we must operate only when distinct
fluctuation is present.

Not infrequently the inflammations of the thyroid gland lead to pro-
nounced disturbances of function. In a case of Reinhold's symptoms of
Basedow's appeared after influenza, and in a case of Gilbert and Gastaigne's
in the convalescence of typhoid fever. Worth mentioning is a case of de
Quervain's with recurring articular rheumatism and parallel symptoms of
a slight thyroiditis and a Basedow's. Apelt reports a case of suppurative
inflammation of a goiter of the tongue; after three days a thyroiditis made
its appearance, to give rise to a Basedow's which later disappeared almost
entirely. Also the clinical primary forms may be associated with similar
manifestations. In a case of Breuer's a typical Basedow's developed imme-
diately after an acute thyroiditis. As Mobius has already pointed out, we
cannot deny for these observations a certain significance in the pathogenesis
of Basedow's disease.

Chronic inflammatory sclerosing processes commonly lead to myxedema
(see later).

I may not leave unmentioned that administration of iodine serves to
increase the acute thyroiditis (Dunger). In the case of Himmelheber the
thyroiditis appeared immediately after a gynecologic operation; Himmelheber
ascribed to the iodine absorbed from the iodine catgut; after high fever,
tachycardia, acute cardiac dilatation, and delirium, the thyroid swelling
rapidly disappeared.

The second group of diseases, those in which the internal secretory activity
of the thyroid gland stands in the foreground, may be divided into diseases
associated with increase of function and those with diminution or lack
of function. I begin with the first, as they are better adapted to give an
idea of the normal function of the thyroid gland.

BASEDOW'S DISEASE 57

a. Morbus Basedowi [Basedow's Disease] — Hyperthyrosis

Synonyms. — Graves' disease, Morbo di Flajani (Flajani's disease), goitre exophthal-
mique [exophthalmic goiter], [Parry's disease].

Historical. — In the year 1840, v. Basedow first thoroughly described three
cases of the disease named after him. Of his precursors, is especially Graves
to be mentioned, who in 1835 described cases of the disease and brought it
into close relationship with hysteria. Since the time of v. Basedow, the
views as to this disease have undergone great changes. The French school
regarded it as a neurosis, while Mobius first in 1886 assumed an abnormally
increased activity of the thyroid gland as the cause, and pointed out the
opposition that exists between this disease and myxedema.

Definition. — By Basedow's disease we understand to-day a disease which
is brought about principally by the abnormally increased activity of the thyroid
gland. This is almost always accompanied by an enlargement and increased
vascular engorgement of the thyroid gland and leads eventually, through the
local symptoms conditioned by the enlargement, to a great number of very mani-
fold manifestations, of which especially the tachycardia, the well-known eye
symptoms, the tremor, and the increase in metabolic processes are the most
important. Most of the manifestations are to be explained by a heightened
condition of excitement of the vegetative nerves. Regular and very manifold
is the involvement of other glands of internal secretions, which for the most
part is secondary. The syndrome that results depends therefore not upon
the degree of hyperf unction, but on the constitution of the individual affected,
that is, on the reaction capability of the ductless glandular apparatus. The
cause of hyperthyrosis is not at present known. The possibility exists that it is
conditioned centrally, and that many symptoms of Basedow's are coordinate
with the hyper thyroidism.

Occurrence. — Basedow's disease is rather irregularly distributed. A
careful collection as to its occurrence has been made by Saltier. Most of
the investigations concerned with this subject, founded in part on a very
great observation material, agree that the classic form of Basedow's disease
is relatively of rare occurrence in regions where goiter is endemic. I men-
tion only the contributions of H. Bircher, Fr. Kraus, and W. Scholz. In
Germany, for example, typical cases of Basedow's disease are very much
commoner in the northern parts; they seem to be especially numerous in the
Russian Baltic provinces (Kroug). It is very much more common in
the female sex than in the male. In Sattler's compilation 3120 of the 3800
cases were females. It is not very common in childhood (according to Saltier,
out of 3477 cases only 184 were in children under fifteen years of age). Base-
dow's disease in sucklings appears to be very rare. While Clifford has re-
ported a case. The mother of the child had also previously given birth to a
child affected with symptoms of Basedow's. In the case described there

58 THE DISEASES OF THE THYROID GLAND

were present exophthalmus and a struma, which microscopically gave a
picture very similar to that of a typical Basedow's struma. Familial oc-
currence of Basedow's disease is not at all uncommon. E. Frey reports a
family of five persons, of whom four suffered with Basedow's disease. Oster-
reich reports likewise a family in which ten members were affected with
Basedow's disease. In the familial type we find not rarely many mitigated
hyperthyroses or hypothyroses. In addition occur neuroses of the vegeta-
tive nervous system, diabetes mellitus, and even psychoses. Grober publishes
the family tree of such a family.

Finally it should be stated that the disease is met with in animals (dogs,
cows, horses), in isolated cases.

Symptomatology. — The pathologic alteration may develop in a pre-
viously normal thyroid gland or in a thyroid gland degenerated into a goiter.
The thyroid gland increases in volume, becomes soft and elastic, through
dilatation of the blood-vessels, and becomes very vascular through new
formation of blood-vessels; under circumstances it shows expansive pulsa-
tions and frequently also variations in volume, paralleling the phenomena
of Basedow's disease; in many cases the apparently not enlarged thyroid
may become palpable through voluntary increase of the intrathoracic pres-
sure (Fr. Kraus) . In acute cases the swelling of the thyroid may appear over
night and even lead to difficulty in breathing. It can subside just as sud-
denly (Trousseau, Mobius, et al.). On the application of a stethoscope ap-
plied to the gland, we can for the most part hear vascular murmurs
synchronous with the heart action (Guttmann) . The hand laid on the gland
feels a distinct thrill; we can diminish the size of the gland by pressure.
The enlargement of the gland is a very common symptom, yet there certainly
do occur cases with distinct manifestation of hyperthyrosis, in which the
enlargement of the thyroid gland is barely demonstrable. With longer
duration of the disease, the consistence of the gland becomes firmer.

The microscopical examination shows, in addition to increased vasculariza-
tion, rich new formation of epithelial plugs and of glandular acini which later
are often well filled with desquamated cells; in addition there are accumu-
lations of lymphoid cells (Gibson, Greenfeldt, F. Mtiller, Lubarsch, et al.),
Other authors (Farner and others) find less typical alterations, although
A skanazy points out correctly that the aberrant findings come from goiter
districts ; it may therefore be assumed that in these cases the alterations of
Basedow's have developed in thyroids that are already degenerated. Kocher
designates the typical Basedow struma as a struma hyperplastica paren-
chymatosa telangiectodes; it ordinarily contains no colloid, and for the most
part is poor in iodine.

Among the cardiovascular symptoms, tachycardia stands in the fore-
ground. For the most part there exists in addition an especial lability of
the pulse. It may happen that on complete rest the pulse lies only slightly

BASEDOW S DISEASE 59

above the normal, while slight psychic emotions or physical movements
send it up unusually high. Moreover, there exist increased strength of
the heart action and cardiac palpitation. The patients feel the heart beat
"up to the throat." The cardiac impulse is then increased and broadened,
and the thoracic wall is strongly agitated. Very often broadening of the
cardiac dullness occurs, depending more commonly on cardiac dilatation
than on hypertrophy. Frequently there are accidental systolic murmurs.
All manifestations on the part of the heart show great variations that
parallel the remainder of the manifestations of the course of the disease.

.• «, s , ,.' % !;r,.« _.; '.• , ,, '

&&& ^^^',l^\:'g:. *•:•&'"" .m, .-.-;'

..vv.^r'r-'^-;' ;i..' :v?^.v. .'•;••....-.*• O1 ;"

FIG. 5. — Basedow struma.

In the fully developed form of the disease the arteries of the gland often
pulsate very strongly, a phenomenon that gives these cases their own char-
acteristic feature. Especial cases may even go as far as a penetrating ve-
nous pulse in the thyroid gland or to a pulsatory shaking of the head (Mussel's
sign) or to choroid pulse (Becker). Also there have been observed marked
beating of the abdominal aorta, hepatic pulsation, and splenic pulsation
(C. Gerhardt). In opposition to increased heart action and the stormy pulsa-
tion in the neck, the radial pulse is often small and weak and the blood-
pressure not raised or even slightly diminished (Spietkojf, Donath}. Height-
ening of the blood-pressure is relatively rare. There occurs then an abnor-

60 THE DISEASES OF THE THYROID GLAND

mal fall from center to periphery (Fr. Kraus) which is explainable by the
abnormal laxity of the tonus in the peripheral vessels. Even the earlier
observers (Graves, Stokes, Hirsch, Trousseau, et al.) noticed this opposition
between the increased cardiac activity as evidenced on the part of the heart
and the vessels of the neck, and the relatively slight filling of the peripheral
vessels. To the slight tonus of the peripheral vessels testify also the often
observable reddening of the face, the ears, the tips of the fingers and the
nail matrices (A. Kocher).

So much for the clinical observation. Experimental investigations on
the action of the thyroid gland secretion upon the cardiovascular apparatus
are very numerous, but an agreement among them has not as yet been ob-
tained. Oliver and Schdfer, Fenyvessy, Haskovec, and others found after
intravenous administration of juice of thyroid gland sinking of the blood-
pressure and slowing of the pulse. Other observers found no action, or
acceleration of the pulse-rate. The different species of animals behave
differently, v. Cyon found that on the cat iodothyrin acted tonus-increasing
on the vagus and the depressor, v. Cyon and Oswald found the same true of
iodthyroglobulin, while iodine-free thyroglobulin is inactive. The increase
of excitability of the depressor nerve was also found by Asher and Flack.
v. Furth and Schwarz consider the depressor action of the extract not specific
for the thyroid gland, but attribute it to the cholin contained in the extract.
The differences in the results are to be explained by the fact that on the in-
travenous administration of thyroid gland, substances that influence the
cardiovascular apparatus are also introduced that have nothing to do with
the thyroid. According to the investigations of Falta, Newburgh, and Nobel,
the feeding of thyroid gland produced in most cases an increase in the fall of
blood-pressure from center to periphery, such as one observes in Basedow's
disease. Tachycardia is present, the blood-pressure taken at the brachial
remains the same (blood-pressure measurement according to Rocci} and fall
of the blood-pressure in the periphery (blood-pressure measurement accord-
ing to Gartner}.1 On the administration of large doses of thyroidin there
results a significant fall in the blood-pressure (Pilez). By the heightening of
the fall the velocity of the circulation is increased, which best corresponds to
the increased oxygen requirement.

The tachycardia is a result of the irritation of the accelerator, and the
slight tonus of the peripheral vessels is a result of irritation of the vasodilator ;
the dilation of the thyroid-gland vessels is the result of the irritation of -the
depressor nerve, as irritation of the root of the depressor nerve calls forth
an increase on the blood-pressure in the thyroid (v. Cyon). Also Asher and
Flack found that the excitability of the depressor nerve is increased by the
internal secretion of the thyroid gland. The increase of the blood stream

1 An exception to this is shown only by diabetics, who show an increase in blood-pressure (see
chapter on pancreas).

BASEDOW'S DISEASE 6l

favors the increased output of secretion and thus a circulus vitosus is es-
tablished. Perhaps also a secondary increase of the activity of the chrom-
affin tissue or a greater sensitivity to adrenalin of the organs supplied by
sympathetic nerves is associated with the cardiovascular symptoms (tachy-
cardia). The facts are that on the simultaneous administration of thyroid-
gland secretion and adrenalin, action pulses may also be produced in animals
(Kraus and Friedenthal] ; v. Cyan attributes to a simultaneous irritation of the
vagus and sympathetic, and to the fact that, according to Asher and Flack,
the thyroid-gland secretion may increase the activity of adrenalin.

The eye symptoms may be expressed in different degrees of intensity.
Often there is only a slightly heightened glitter of the eye, the alterations

FIG. 6. — Gaping of the palpebral fissures in Basedow's disease.

showing only on very exact examination; in other cases occur those strik-
ing alterations that Mobius compares with those of the facial expression of
intensest terror.

As an example I shall quote the following case:

Observation I. — Anna K., twenty-six years old. For about two months cardiac pal-
pitations, conditions of excitement, pains in the cardiac region, sweats, tremor, and en-
largement of the neck.

The increased width of the palpebral fissures is evident. Protrusion slight, rare blink-
ing, thyroid diffusely enlarged, weakly elastic vascular murmurs, tachycardia up to 361
[sic.],1 blood pressure (Riva-Roccd) 100. Increase of temperature up to 37.7° C.,
alimentary glycosuria negative.

*36i in the German edition — probably an error for 136. — Editor.

62 THE DISEASES OF THE THYROID GLAXD

In many cases the development of the eye symptoms comes about very
gradually. In other cases, the terrifying alterations may develop in a few
days, indeed over night. We should distinguish between protrusion and
widening of the palpebral fissures. In fully developed cases both symptoms

FIG. 7. — Protrusion of the eye-balls in Basedow's disease.

are for the most part really present together. The protrusion of the eye-
balls is well seen in the accompanying illustration.

Observation II. — K. I., fifty years old, the morbus Basedowi has lasted about ten
years, tachycardia, sweats, formerly profuse diarrhea, tremor, formerly marked emacia-
tion, and high-grade nervousness; lately condition better, for years a stationary condition.

The protrusion of the eye-balls is explained by most authors by an in-
creased fullness of the orbital vessels. The rapid variations in the intensity

BASKIMUY'S IHSKASK 63

that the protrusion of the eye-ball shows in many patients have led to this
assumption. The essential cause is, however, an abnormal tonus of the
Landstriim musculus palpebralis, which is innervated by the sympathetic.
The protrusion may be produced experimentally by electric stimulation of
the cervical sympathetic (Claude Bernard). The protrusion may be such
a high grade that the globe becomes displaced. In old Basedow's cases the
protrusion remains stationary, which may be explained through increased
deposition of retrobulbar fatty tissue. The gaping of the palpebral fissure
(Dalrymple-Slellivag's sign) on increased opening tension of the eye (L.
Bruns) is dependent on an abnormal tonus of the oculomotor nerve and
is, therefore, according to Eppinger and Hess, to be regarded as a sign of
autonomous irritation.

The exophthalmus may also be unilateral. A confusion with unilateral
affection of the sympathetic may be avoided by attention to the width of
the pupils; the latter should show no differences in Basedow's disease;
Roasenda has described three Basedow's cases with unilateral eye symptoms,
and in one of these cases this symptom always remained limited to the one
side. The unilateral exophthalmus sometimes accompanies unilateral en-
largement of the thyroid gland, either with homolateral or with contra-
lateral enlargement. Worms and Hamant have issued a compilation of such
cases.

?. Grafe's symptoms, i.e., the failure of the upper lid to follow, or only
retarded following of the upper lid when the vision' is turned slowly down-
ward, the white sclera thus becoming visible at the upper border of the
cornea, depends on an increased tonus of the levator palpebrae muscle.
v. Slellwag's symptom consists in a rarity and an incompleteness of the in-
voluntary blinking. Whereas in the normal individual the blinking move-
ment occurs three to five times in the minute, in Basedow's disease it may
not occur for minutes.

The eye symptoms are very hard to reproduce experimentally, a fact
that for a long time stood in the way of the hypothesis that Basedow's dis-
ease was a hyperthyrosis; however, Kraus and Friedental and Honicke were
finally successful, through the administration of very large amounts of thy-
roidin in inducing a widening of the palpebral fissures and an exophthalmus,
although not to a very marked degree. Recently through the use of material
obtained by the removal of struma at operation on human beings it was
possible to induce typical exophthalmus in a dog (Lampe, Li esc gang, and
Klose, and Baruch). Worthy of mention here is also the case of Notlnijft,
in which an evident protrusion developed after an excessive use of thyroid-
gland tablets.

Finally, Mobius's symptom consists in a weakness of convergence; by
fixation of the finger held near-by, the eye deviates without diplopia ; perhaps
this not common symptom is to be explained by a fatty degeneration of the

64 THE DISEASES OF THE THYROID GLAND

eye-muscles which is observed in severe cases of Basedow's disease. Also
pareses and paralyses of the eye-muscles have been observed. Kappis
describes a case in which the beginning of the illness occurred eleven years
previously; with gradual increase in all symptoms there developed an exten-
sive paralysis of the eye-muscles and other cranial nerves. Kappis has
collected forty cases of eye-muscle paralysis in morbus Basedowi.

Sometimes there occurs in Basedow's disease an excess of tears (Berger) ;
sometimes, however, an abnormal dryness of the eye. In high-grade pro-
trusion the cornea may ulcerate and erode, the lens may fall out, and the
panophthamtia that develops may lead to death. Patients with Basedow's
disease bear cataract operation badly (Mobius). In rare cases there is
observed atrophy of the optic nerves (also obtained experimentally through
administration of thyroid gland, Birch-Hirschfeld and Nonmbuo Ynvuye);
finally, mydriasis sometimes occurs on instillation of adrenalin (O. Lb'wi}.
The adrenalin mydriasis is also found in experimental hyperthyroidism
(Eppinger, Falta, and Rudinger).

The eye symptoms belong to the classic form of the disease. In the
formes frustes they may be absent or only suggested. In the following
briefly sketched case they were wanting altogether:

Observation III. — S. Schm, fifty-six years, shoemaker. For about thirty years diffuse
enlargement of the thyroid, circumference of the neck 42 cm. Until six months ago,
perfectly healthy. Then occurred gradual increase in the size of the neck to 43 cm. and
then to 44 cm. Lassitude, sweatings, difficulty in breathing. His physician ordered for
him an iodine cure, which rapidly made matters worse. Severe dyspnea, cardiac pal-
pitations, marked tremor, profuse sweats, and profuse watery diarrheas, the bowels
moving ten to twelve times daily, loss of weight about 18 kg.

Markedly emaciated, skin moist, eye symptoms not present. Both lobes of the
thyroid very much enlarged, the left somewhat larger, pulsation, vascular murmurs
weak. Perithyroidal lymph-glands palpable. Cardiac shadows widened to 13 cm. as
seen on X-ray examination, shadow of the aorta increased to 6 cm., tachycardia (110-130),
leucocytes 8500, of which only 33.3 per cent, are neutrophiles. Slight tremor, sweats
(Fig. 8).

Of the alterations in the respiratory organs should be mentioned first
soundlessness of the voice (Trousseau}, sensation of scratching in the throat,
and tormenting, irritating cough (Nothafft). The irritating cough was first
described by Pierre Marie; he found it in twelve of fifteen cases. This
symptom may be very tormenting and may start in as an early symptom.
It is accompanied by little or no expectoration. Murray, however, observed
some cases in which there existed a profuse expectoration, a veritable bron-
chorrhea, which he brings into analogy with the profuse watery diarrheas
of the patients (paroxysmal condition of excitement of the autonomous
nerves). Further we should mention the increase in the frequency of res-
piration, the superficial breathing, and the air hunger, symptoms which
occur paroxysmally even as early symptoms, but which often last for a long
time. These symptoms are closely allied with the increased need for oxy-

BASEDOW'S DISEASE 65

gen, that is, with the need for rapid loss of heat on account of the increased
heat production. Bryson's sign — the patients are not able to expand the
chest in the normal manner on deep inspiration of the thorax — has nothing
to do with this, but depends apparently on a weakened condition of the
respiratory muscles as a result of the fatty degeneration that was found by
Askanazy in all the bodily musculature. The acceleration and becoming
shallower of the respiration was also produced experimentally by Fenyvessy
by the feeding of the thyroid gland substance to dogs. It was absent after
cutting of the vagus nerves. The graphic registration of this breathing

FIG. 8.— Absence of the eye symptoms in Basedow's disease.

in Basedow's disease shows very clearly the shallowing of the respiratory
efforts and the periodic cessation of respiration (increased tonus of the vagus,
Hofbauer). Eppinger and Hess have observed these respiratory curves, es-
pecially in those Basedow patients who showed signs of increased tonus in
other autonomous nerves.

To the nervous symptoms belong almost all the symptoms of Basedow's,
as they are for the most part the expression of the condition of irritation
of the vegetative nervous system. Of the nervous symptoms in the narrower
sense is especially to be mentioned the tremor of the separated fingers, which
was first observed in 1862 by^Charcot and was later described by Marie in a
monograph as the principal and initial symptom of Basedow's disease.
Nothnagel has especially pointed out that the tremor is very fine. The
observations of A . Kocher give an idea as to the frequency [of occurrence] of

5

66 THE DISEASES OF THE THYROID GLAND

the tremor. Kocher found it clearly manifested in sixty cases out of sixty-
three. Slight psychic emotions can make the tremor more evident. In-
tended movements do not ordinarily increase it. Fine coordinated move-
ments may, however, be disturbed or made impossible on account of strong
tremor. Very strong tremor may also assume a choreic character. In
fully developed cases the patients are often in an "etat de vibration per-
petuelle." The tremor may also affect the tongue, eyelids, lips, the lower
extremities, diaphragm, and respiratory muscles; the number of vibrations
reaching about 8 to 9.5 in the second, as many as in progressive paralysis and
alcoholism; while in senile tremor and paralysis agitans the number is less.
The tremor may be readily reproduced experimentally by the feeding of
thyroid gland.

An exactly similar tremor is seen sometimes transitorily in hysteria and
neurasthenia, as the graphic registration has shown.

A further symptom is muscular weakness, even paraparesis of the legs
has been observed (giving away of the legs). Stern regards this as hysterical.
Also transitory monoplegias and hemiplegias have been observed. Not
rarely occur drawing pains in the entire body, or only in the arms or legs,
or in the shoulders, and especially in the neck. Kocher found them in a
great number of his cases. Mdbius does not believe that they are in direct
connection with hyperthyrosis. That there is, however, such a connection
is made certain by the investigations of Falta, Newburgh, and Nobel, who
obtained the pains in numerous cases after the administration of thyroid
gland substance. The same is also true of the headache which is very
common in Basedow's disease; indeed it may be the initial symptom and is
very common in artificial thyroidism. Also the insomnia of the Basedow
patient may occur as the initial symptom; in many cases it occurs for
weeks, varying [in intensity], and may reduce the patient very much.

Almost always occur alterations in the mental life, abnormal irritability,
unmotivated gaiety, hasty speech, rapid flow of thoughts, an indication of
flight of ideas, rapid change of mood, terrifying dreams; the character alters,
the patient becomes mistrustful, choleric, capricious, strikingly euphoric, or
often very much depressed. Mdbius happily compares this condition with a
very slight "Rausch" in which a maniacal mood may readily occur, and in
which a conversion into depression may readily follow. Attacks of laughing
and crying may occur, and combination with hysteria is not rare. Some-
times the condition terminates in delirium, confusion with hallucination, and
coma.

The transition of these mental alterations into a true psychosis is not
rare. Often it is the maniacal conditions, often the depressions, that pre-
vail. Also the picture of melancholia may develop. According to Saltier,
out of one hundred and fifty cases in literature, more than seventy belong
to manic-depressive insanity. For the comprehension of these alterations in

BASEDOW'S DISEASE 67

the psychic life the observation is important that in individual cases similar
conditions may occur after the administration of thyroid-gland tablets.
Conditions of excitement are not uncommon in thyroidism. Cases of
thyroidin intoxication insanity have also been observed (Boinet, Parhan and
Marbe). The authors last mentioned observed two cases, in whom after the
ingestion of great amounts of tablets there set in complete confusion and
hallucination. The manifestations disappeared with the withdrawal of the
administration of thyroid. The following case (Falla, Newburgh, and
Nobel) is instructive :

Observation IV. — Woman, aged fifty, who for a half a year had suffered loss of weight,
headaches, insomnia, associated with psychic depression and thoughts of suicide. There
was also present glycosuria. The condition gradually ameliorated and after some weeks'
stay at the clinic the patient felt very well. Then the patient took thyroid tablets for
three days, upon which the psychic depression and thoughts of suicide recurred. On
the withdrawal of the drug these disappeared.

Already Brunei mentioned that Basedow's disease is not associated with
any special psychosis ; when a true psychosis occurs in it, we may well assume
that a psychopathic predisposition already existed and that the hyper-
thyrosis constituted the determining factor.

Of the symptoms affecting the digestive tract we shall mention first in-
creased flow of saliva. This symptom often occurs paroxysmally, and even
initially; more rarely there is a dryness of the mouth. When the flow of
saliva is increased, there is an increased tonus of the nerves of the salivary
glands ; when the flow is diminished there is an increased tonus of the sympa-
thetic nerves of the salivary glands (formation of a thickly flowing secretion)
or irritation of the sympathetic nerves of the salivary glands (Eckhardi) ;
also the noticeably increased diuresis may exercise an influence here. The
slight degree of acidity of the gastric juice, that is usually observed in rare
cases of Basedow's disease (Eppinger and -Hess), points also toward an in-
creased gastric tonus. Sometimes crises of hyperacidity are observed
(Maranon). Ordinarily, however, subacidity is present (Wolpe). Especially
important symptoms are vomiting and diarrhea (Pierre Marie} , because they
greatly reduce the patient. Vomiting is found, according to Saltier, in 15
per cent, of all cases. Ordinarily it occurs paroxysmally, for the most
part without any relation to ingestion of food, often without any nausea.
When there has been no ingestion of food it is usually thin; the paroxysm
may last for a whole day, in which case the vomiting may occur thirty times
during the day and be uncontrollable. For the most part it is unaffected
by medication ; it may disappear as rapidly as it came, and may be followed
by a period of increased ingestion of food. More common are the profuse
watery diarrheas (according to Saltier in 30 per cent, of all cases). For the
most part they are painless. Twenty to thirty stools a day may occur.
They may lead to scaphoidal retraction of the abdomen as in cholera (Fr. v.

68 THE DISEASES OF THE THYROID GLAND

Midler). The diarrheas are hardly influenced by medication. In rarer
cases, admixture with blood may be observed. Vomiting and diarrhea
may also be produced in animal experimentation by feeding with or injec-
tion of thyroid gland substance. In human beings, administration of thyroid
gland tablets continued over only a short period may suffice to produce
action on the bowels. In two cases, Folia, Newburgh, and Nobel observed
that on the third day of the thyroid medication the previously solid stools,
that occurred only once a day, had now become soft and failed to show
the impressions of the haustra, and that on the third day two soft stools
occurred. On withdrawal of the medication, the stools again showed their
former consistency. Kocher observed one case with obstinate constipation,
in which simultaneously with the appearances of the rather acute develop-
ment of Basedow's, diarrheas developed. The statement of Kocher, that
in none of the sixty-three cases of Basedow's described by him did consti-
pation exist, dare not be generalized. I have seen several cases of formes
frustes with constipation (see Observation V). Mobius regards the profuse
diarrhea of morbus Basedowi as the expression of the effort to cast out the
thyroid gland substance that is circulating in excess. From this standpoint
it would not be uninteresting to test the stools as to their iodine contents. It
is safe indeed to assume a marked increase in the secretion in the intestines.
This and the paroxysmal occurrence confirms the assumption of Mobius.
In the higher degrees, there is, in addition, apparently slight inflamma-
tory swelling of the intestinal mucous membrane; at least we may observe
this in experiments on animals in which, in the highest degrees of thyroid-
ism, hemorrhages into the mucous membrane may occur. We may assume
also an increased secretion of the pancreatic juice, in accordance with the
experiments of Balint and Molndr; these authors found in the watery evacu-
ations an abnormal quantity of tryptic and diastatic ferment. Whether we
may regard the profuse diarrheas as an expression of vagotony, as Eppinger
and Hess believe, appears to me questionable, for vagotony is inclined to
be associated with spastic obstipation.

We should sharply distinguish from these profuse diarrheas the dis-
turbances of fat absorption that are sometimes found in morbus Basedowi.
Adolph Schmidt and H. Salomon have described one case apiece. I have
added seven cases, in which, as in Salomon's case, the fat-splitting was
relatively good, so that the disturbances lay especially in the absorption.
In the case very carefully investigated by me the dry substance contained 53
per cent, fat, of which 24.7 per cent, was neutral fat, 44.2 per cent, soaps,
and 31.1 per cent, fatty acids. Sometimes the fat stools are found only
on the overloading of the intestines with fat (v. Noorden). Of late Bittorf
has contributed a pertinent case. I here report two others:

Observation V. — Ad. K, thirty-three years, locomotive stoker, entered the first medical
clinic December, 1911. No hereditary taint, was always well until November, 1905.

BASEDOW'S DISEASK 69

Then struck by a locomotive, fell on the left side, for three weeks hematuria and fever. At
the beginning also unconsciousness, then severe headache, vertigo, nausea. Imme-
diately after the accident began tremors, palpitation, anxiety, insomnia, and twitchings
in the lower extremities. Eight days after the accident, the patient noticed an enlarge-
ment of the right lobe of the thyroid gland. Soon afterward marked pulsating in the
vessels of the neck and oppressive feeling of heat, and burning of the skin of the throat
and neck. This condition continued from this time on without essential alteration.
The patient states that he has become peevish and irritable and afraid of people. His
muscular strength has diminished, he tires easily, and often has drawing pains, also
headaches, vertigo, and sometimes vomiting, also very heavy sweats. Ordinarily slight
constipation, from time to time a period in which three or four broth-like evacuations of a
gray color occur daily.

Rather thin; the face especially, but also the skin of the throat and upper part of
the breast a burning red. On disrobing and on excitement the redness increases. Pro-
nounced dermographism. On stroking the skin with the handle of the percussion
hammer there are elicited streaks the breadth of which is that of a finger.

The right lobe of the thyroid is enlarged, about the size of an apple. Surface smooth,
elastic, but not hard in consistence, evident pulsation, vascular murmurs. In the neigh-
borhood, enlarged lymph-glands. Points of exit of the trigeminal nerves tender to
pressure. Slight paralysis of the sympathetic on the right. All eye symptoms negative.
To Rontgen examination slight widening of the shadow of the aorta to 6 cm., and of
the heart to 12^ cm. Pulse 120-140.

Blood pressure, according to Riva-Rocci, taken on the arm 140. On the left middle
finger (Gartner) 85.

Later measurements:
Riva-Rocci, 130-120;
Gartner, 70.
After two weeks:
Riva-Rocci, 120-110;
Gartner, 55.

Blood: Erythrocytes, 5,000,000.
Leucocytes 9200, of which:
Polynuclear neutrophiles, 55 per cent.
Lymphocytes, 32 per cent.
Large mononuclears, 14 per cent.
Eosinophiles, i per cent.

Several later blood examinations gave similar results.
Alimentary glycosuria (100 gm. dextrose) 4.24 gm. of sugar.

The stools frequently show the luster of fat and a gray color. After 250 gm. of oat-
meal and 300 gm. butter, typical fat stools. The microscopical examination shows little
neutral fat, but many soap balls and fat needles.

Profuse sweats, in which the bedclothes are soaked through. On the soles of the
feet exist pea- to bean-sized vesicles filled wjth serous fluid, which burst, and leave the
cutis exposed.

Marked tremor of the hands, intensified on movements.
Examination of the fundamental exchange (Dr. Bernstein}.

CQi Oj RQ Per kilogram body weight

237.6 289.0 0.804 I

220.2 293.0 0.741 '

230.1 296.5 0.7761 3'2;> *•"

70 THE DISEASES OF THE THYROID GLAND

The fundamental exchange is therefore somewhat increased.

Result: Forme fruste of Basedow's after trauma with all important symptoms
(tachycardia, sweats, tremor, increase of the fundamental exchange, mononucleosis)
with exception of the eye symptoms. In addition, fat stools and alimentary glycosuria.

Observation VI. — A. Schr., woman aged thirty-three years. First entered clinic Jan. 9,
1913. Father was very nervous and easily excited. Menstruation, which began at the
age of fourteen years, occurs regularly every four weeks, lasts four to eight days, not
painful. Seven years ago, luetic infection, after which unilateral headache, for one year
diplopia. Two children, that are very nervous, two miscarriages, the one before the in-
fection, the other after it. For three months menstruation very sparse.

The present illness began three months ago. At first insomnia and severe headaches,
then marked palpitations. Dyspnea, profuse sweats, severe tremors in the hands and
feet. Conditions of excitement, sometimes vomiting. During the last three months has
lost about 10 kg., the throat is enlarged, for six weeks the eyes protrude. During the first
week five to six stools daily, of normal consistence, but of a white-grayish color.

Exophthalmus distinct, but not marked. Thyroid enlarged, diffusely, distinct
tremor, marked tachycardia.

Blood-pressure. Gartner, 95. Riva-Rocci, 135.

Leucocytes 5500 (of which 55 per cent, polymorphonuclear neutrophiles and i per
cent, eosinophiles) .

Alimentary glycosuria positive (with 100 gm. dextrose 0.57 gm., with 50 gm. dextrose
2.4 per cent, with 30 gm. dextrose, negative).

Overloading with fat at present does not lead to fat stools. No diarrhea now.

The cases with fat stools all seem to show certain characteristics. Al-
most always they are formes frustes with absent or slightly developed eye
symptoms. In addition all cases up to the present have shown latent dis-
turbances in the carbohydrate metabolism. In three cases, the disease
developed after a trauma. For a close relationship between thyrogenic
glycosuria and fat stools speaks also the observation that both disturbances
retrogress simultaneously, either spontaneously or after therapeutic pro-
cedures (exposure to Rontgen rays). It is not unlikely that both come
about through an inhibition of the internal secretory activity of the pan-
creas. At least there must also be assumed a direct action of the excessively
produced thyroid-gland secretion on the intestinal mucous membrane, for
in diabetes mellitus the absorption capacity of fat is perfectly normal.
I do not speak here of the fat stools in cases of diabetes mellitus with closure
of the pancreatic ducts, as in these it is known that the disturbance in the
splitting of neutral fat is prominent. The observations of Balint and Molndr,
that I have already mentioned, do not speak, as these authors believe,
against my assumption, for they are dealing with watery diarrheas that have
nothing to do with fat stools and that mostly occur in the other forms of
Basedow's disease. Up to the present I have seen only one case with fat
stools in which formerly profuse diarrheas had existed.

The examination of the blood in Basedow's disease usually gives normal
figures for the red blood cells and the hemoglobin. In cases where a diminu-
tion is present, the iron-content is, according to the investigations of

BASEDOW S DISEASE 71

Rossin and Jellinek, very much reduced. The coagulation capacity of the
blood is in the most cases delayed. Kottmann and A . Lidsky found in thirty-
seven cases this delay in 78.3 per cent., a normal coagulation time in 5.4 per
cent., and an acceleration in 16.2 per cent. In the cases in which it was de-
layed, it approximated normal figures after operation. The delay also exists
in experimental hyperthyroidism (Kostlivy). These facts explain why in
operations on Basedow's patient the control of hemorrhage is often difficult.
According to Kottmann the serum of Basedow's patients works in a retarding
way on autolysis; also the freezing-point lies lower than under normal con-
ditions. Fr. Kraus and Friedenthal found that the blood-serum of Basedow's
patients acts in a mydriatic manner. A . Frdnkel found an increased action
on the wave-motions of the rabbit-uterus after the death of the animal.
These findings do not point absolutely to an existing adrenalinemia (O'Connor,
Falta, Fleming). Therefore the far-reaching conclusions that Kostlivy
has drawn from, these findings, as to the sympathcotonizing components
of the secretion of the thyroid gland, are purely hypothetical. Of greater
importance is the alteration in the leucocyte formula first described by
Th. Kocher. There exists at first a slight leucopenia and almost regularly,
even in the early stages, mononucleosis. The statements of Kocher have
been confirmed by numerous investigations (Caro, Ciuffini, Gordon and
v. Jagic, Roth, Buhler, Kappis, van Lier, Kostlivy, Turin and others). The
mononucleosis is also found in the formes frustes; but it is also common
in struma without Basedow's symptoms (Mutter, Ch. Kappis, van Lier,
and others). Cases of Basedow's with absent mononucleosis seems to belong
to the great exceptions (Kostlivy, Roth, Borchardt, the author).

Observation VII. — C. A., twenty-one years old, student. For about six weeks rapid
enlargement of the thyroid gland. Former circumference of the throat 39 cm., now 42
cm. Tachycardia, labile pulse, sweats, tremor, stools formerly sluggish, sluggish also at
present. Diffuse enlargement of the thyroid gland, consistence weak, pulsation of the
carotid. No eye symptoms. Apex-beat broadened and increased. In the urine traces
of sugar, after overloading (2 rolls, four pieces of sugar), 2 per cent.

Blood examination:

Leucocytes, 7000 of which:

Neutrophiles, 68.6 per cent.

Lymphocytes, 25.3 per cent.

Mononuclears, 4.6 per cent.

Eosinophiles, 1.5 per cent.

After several months, essential improvement in all manifestations, high tolerance for
carbohydrates.

It seems to me, however, that great caution is necessary in regarding the
blood picture in cases of Basedow's as normal, as the alterations of the
blood picture, like those of the other symptoms of Basedow's undergo great
changes. The following is a case in point:

Observation VIII. — Fl. R., woman, thirty-five years of age. First came under observa-

72 THE DISEASES OF THE THYROID GLAND

tion Dec. 12, 1912. Apparently no hereditary nervous predisposition. Menses first ap-
peared in the eleventh year of life, flow abundant, regular, lasts for three days every four
weeks. Five normal births. Three years ago a miscarriage at the second month. Since
that time, development of Basedow's disease. Since that time, too, menses are accompanied
with severe pain, especially backache. The flow is less in amount. When the exophthal-
mus first developed, her face took on a terrified appearance, which her acquaintances
observed; she felt very well otherwise, and the ophthalmologist made the diagnosis,
Basedow's disease. Only several months afterward began to develop watery diarrheas,
cardiac palpitations, dyspnea, nose-bleeds, headaches, rheumatoid pains in the extremi-
ties, lassitude, sensation of dizziness, and extraordinary psychic irritability; the condition
gradually became worse, with a transitory period of amelioration during the summer before
I saw her. There occurred moreover insomnia, sweats, pains in the calves, pain in the
forehead and eyes on reading, also transitory marked flow of tears. The appetite very
changeable, at times voracious appetite, then again anorexia.

Distinct protrusion, v. Grafe's symptoms plainly positive, Loivi's symptom plainly
positive. Tachycardia extremely variable, the pulse varying from 80 to 150. Subjec-
tively, rather marked oppressions; marked falling-out of hair, inclination to slight rises
of temperature. Marked sweats, very variable. Thyroid gland diffusely enlarged
(right lobe somewhat more than the left), soft, plainly pulsating, distinct palpable thrill,.
over it a diastolic vascular murmur.

Alimentary glycosuria (200 gm. dextrose) negative.

Blood-pressure — Riva Rocci 130, Gartner 85; these differences were regularly found on
repeated examinations.

At the beginning of the observation the above symptoms were present, except that
the tachycardia was very slight and the tremor of the hands scarcely demonstrable.

The blood examination now shows:

Leucocytes, 8000 of which:

Polymorphonuclear neutrophiles, 70 per cent.

Eosinophiles, 2 per cent.

Lymphocytes, 21 per cent.

Large mononuclears, 7 per cent.

Later the condition became worse, the pulse rate rose to about 130, the tremor be-
came distinct, the blood examination now showed 9000 leucocytes, of which:

Polymorphonuclear neutrophiles, 60 per cent.

Eosinophiles, 2 per cent.

Lymphocytes, 27 per cent.

Large mononuclears, n per cent.

Also the examination of the respiratory exchange of gases gave indeed always an
essential increase, but appreciable variations (Dr. Bernstein).

CO2

Ch

CC>2 per kg.
and m.

C>2 per kg.
and m.

RQ

On Jan.

1 2th

220. 5

280.5

3-82

4.86

0.786

iSth

213.1 270.8 3.67

4.67

0.787

1 6th

229.9

316.9 3.96

5-46

0.725

igth 238.6

284.5 4- 1 1

4.90

0.839

Also the examination of the excretion of urine showed in the first period 0.45 and 0.37
gm. U. (on the 7th and 8th day of the purin free diet).

BASEDOW S DISEASE 73

In the second period 0.52 — 3rd day of the purin free diet.

0.78 20 gm. sodium nucleinate (the greater part vomited).

0-53

0.75 200 gm. meat.

0.61

In this case we find therefore, in spite of very evident Basedow's symp-
toms, the blood picture at first normal, and then showing the typical
changes. I observed a short time ago a still more striking case. Here in
the beginning all the typical signs of a Basedow's disease were present.
The tremor was especially strong. The blood examination showed 8800
leucocytes with 65.8 per cent, polymorphonuclear neutrophiles, 2.2 per
cent, eosinophiles, 0.5 per cent, mast-cells, 5.5 per cent, transitionals, and
26 per cent, lymphocytes. After two weeks another blood examination
was made. This showed 53 per cent, polymorphonuclear neutrophiles, 7
per cent, eosinophiles, 0.5 per cent, mast cells, 45.5 per cent, lymphocytes.
The clinical picture was not essentially changed otherwise. It is worthy
of mention that for some days before the second count much meat had
been ingested.

For the interpretation of the blood alterations in Basedow's disease it is
important to note that the mononucleosis increases on the ingestion of thy-
roid-gland tablets, while, as we shall see later, it decreases in conditions
of athyrosis, the blood picture approaching the normal. This relationship
was first described by Falta, Newburgh, and Nobel; and lately Th. Kocher
apparently without knowing our work, has written about the practical
significance of this finding.

Intercurrent febrile diseases bring about the transitory disappearance of
the mononucleosis (Roth). I have seen a case of Basedow's disease, in which
a croupous pneumonia developed. Before the development of the pneu-
monia, there were 6200 leucocytes with 46 per cent, neutrophilic cells;
at the height of the pneumonia there were 17,100 leucocytes with 87 per
cent, neutrophiles. It is also known that a transitory neutrophilic hyper-
leucocytosis occurs in Basedow's patients a short time after the removal
of the struma.

The mononucleosis is readily produced experimentally by feeding with
thyroid-gland tablets. Berlelli, Schweeger, and / have regarded it as the
expression of an excitation of the autonomous system. Eppinger and Hess
have explained in like manner the hypereosinophilia sometimes observed in
Basedow's disease. We must consider in this connection not only the
absolute or often only relative increase in the mononuclear cells, but must
regard as of value the relative and always absolute diminution in the neutro-
philic cells in the peripheral vessels. In the cases with leucopenia the num-
ber of mononuclear cells is not increased absolutely, in spite of the marked
relative increase; here the alteration of the leucocyte formula is brought
about exclusively through the marked deficiency in neutrophilic cells. In

74 THE DISEASES OF THE THYROID GLAND

the initial stage, especially on sudden overdissemination of thyroid glandular
secretion, there may well be chiefly an abnormal distribution of the neutro-

FIG. 9. — Diffuse enlargement of the thyroid gland in Basedow's disease.

philes in the vascular tree, leading to the above-mentioned leucocytic for-
mula ; for after feeding with thyroid substance to dogs we found in the cap-
illary blood of the livers of these dogs hyperleucocytosis with marked pre-

BASEDOW S DISEASE 75

dominance of the neutrophilic cells. Later there occurs a permanent altera-
tion of the hematopoietic apparatus, consisting in a hyperplasia of the
lymphatic apparatus. With this alteration stand in harmony the swelling
of the lymph-glands so often observed in Basedow's disease (Cowers), espe-
cially the swelling of the perithyroidal lymph-glands (Fr. Muller, Passler,
Kocher, and others}, and also the perivascular round-cell infiltration of the
typical Basedow struma, the hyperplasia of the rest of the lymphatic appa-
ratus (Fr. Muller and others), the tonsils, lingual papillae, intestinal follicles,
the hyperplasia of the spleen and the thymus gland (Bonnet, Gierke, Thor-
becke, v. Hansemann, Rossle, Hart). In severe acute cases, a distinct splenic
tumor can appear as an early symptom. Schlesinger, a short time ago,
reported such a case. Of late great practical significance has been ascribed
to the hyperplasia of the thymus. According to Capelle's statistics, 44 per
cent, of the cases of Basedow's disease that died of intercurrent diseases
showed a hyperplasia of the thymus, 82 per cent, of the cases that died of
Basedow's disease itself, and almost 100 per cent, of the Basedow's cases
that died on operation. In these cases it is questionable whether the thy-
mus hyperplasia is responsible for the death. Perhaps death was due more
to the status lymphaticus, perhaps more to the failure of the chromaffin
organs. I shall defer the consideration of the thymogenic Basedow's disease
until the discussion of the theory.

Of the metabolic disturbances should be mentioned first of all the ema-
ciation, which is so important practically. A . Kocher found this in 88 per
cent, of the cases among his very large number. It is. present in the fully
developed form. It may set in very early and progress in a uniform
manner; in other cases it may increase in acute exacerbations that may
frequently be repeated (crises d' amaigrissement, Huchard). Almost regu-
larly such periods of increased emaciation are associated with the increase
of other Basedow's symptoms. In the fully developed forms 15-20 kilo-
grams may be lost in a few months. Even in the incomplete forms, a slight
grade of emaciation is absent relatively seldom. In the case of Basedow's
in which the emaciation is marked, there not infrequently develops a severe
grade of cachexia (cachexie thyreoidienne, Gauthier). In other patients
there may gradually set in a reversal of affairs, in which the loss may be more
or less rapidly made up. In rare cases, even obesity may develop. In the
great majority of cases the appetite is increased, especially at the beginning;
and there is often polyphagia. Of course, the increase of appetite often re-
mains behind the much greater requirements. Later the appetite often
becomes less. If vomiting or diarrheas are superadded, the body weight
rapidly falls.

The cause of emaciation in spite of the increased appetite depends in
part on an increase of the caloric production through the thyroid secretion
produced in excess. Fr. v. Muller first pointed out that in spite of the abun-

76

THE DISEASES OF THE THYROID GLAND

dant supply of calories, in Basedow's disease the body weight often falls.
The demonstration, that the fundamental exchange, that is the CO2 produc-
tion and the 62 consumption in a fasting condition with the exclusion of all
muscular activity, is increased in Basedow's disease, was first furnished by
Magnus-Levy, and later by Thiele and Nehring, Stuve, H. Salomon and others,
by means of the Zuntz apparatus. Steyrer investigated the increase of ex-
change by the Voit-Pettenkofer respiration apparatus. In the severer cases
the increase of exchange may reach 70 per cent. I reproduce here Magnus-
Leva's instructive table:

Age.
years

Height,
cm.

Weight,
kg.

02
cc.

CO*
cc.

02

cc. per
kg.

Per cent,
normal
values

i. Acute, very severe case

20

IS8

co. 7

348.9

295.0

6.89

170

2. Very severe chronic case

26

150

50.5

344.0

236. 2

6.80

170

3. Severe chronic case

22

161

CC. I

3oc. 8

2C.6.O

c. cc

142

4. Somewhat lighter chronic case . . .
5. Light case

55
20

156
148

43-9
ce.o

266.9
213. 2

299-3

181.1

5-31

4. 74

122
IDs

6. Cured by operation ten years ago.
7. Simple goiter

about 40
66

171
142

84.0

co. c,

282.8
176. 7

241.0
14^- 1

3-37
3-43

IOO
9O

A very interesting example is furnished by the following case investigated
by Dr. Bernstein.

Observation IX. — H. J., twenty-two years old, pronounced true infantilism. Two
years ago and one year ago tetany, simultaneously with aggravation of a stomach affec-
tion that had lasted a long time. With the decline of the second period of tetany pro-
nounced manifestations of hyperthyrosis. After a gastroenterostomy there was no
recurrence of the tetany. The Basedow's manifestations (tachycardia, sweats, tremors)
remained, or improved only a little. Eye symptoms were entirely absent. The in-
vestigations of the fundamental exchange gave

COj

182.2
180.2
185.6

02

229. i
227.4

222. I

RQ.

0.796 j

0-793 f
o.836j

Per kilogram of body weight
CO2 O2

4-45

5-6i

In other cases Salomon could show that the caloric production is also
present in the formes frustes. The case just detailed (Observation IX) and
Observation V agree in that they show that the increase of the exchange
may also be distinct in the formes frustes that pursue their course without
eye symptoms.

Furthermore, I would refer to Observation VIII where the examination of
the gaseous exchange showed that like the rest of the Basedow's symptoms
the caloric production is subject to great variation.

The increase of fundamental exchange may also be demonstrated ex-
perimentally through the administration of thyroid gland; it is, however, not
very great, and in some individuals remains absent.

The question as to which way the influence of the thyroid-gland secretion

BASEDOW'S DISEASE 77

acts in increasing the metabolism has been much discussed. The tremor
alone is not responsible for it, for after exclusion of the tremor by hyoscine
the exchange is not essentially reduced (Magnus-Levy). This author be-
lieves in a raising of the exchange in the resting cells. Andersson and Berg-
man have contradicted this, as after large doses of iodothyrin and thyroidin
they found no increase after complete relaxation of the muscles and during
sleep. These experiments however do not show very much, because, as
previously mentioned, many normal individuals behave refractorily to the
administration of thyroid gland. To my mind, we should not leave uncon-
sidered in the explanation of the increase of the fundamental exchange the
violent increase of tonus of the whole vegetative nervous system and the
heightened activity of the organs affected by it. The increase of the caloric
production cannot alone constitute the cause of the emaciation, but there
must be added to it a disturbance in the regulatory mechanism that governs
the taking up of nutrition. Here come into consideration especially the
disturbances of the stomach and intestines. I refer to what I have said on
this subject in the first chapter.

In Basedow's disease also the protein exchange is increased, that is, the
individuals affected need more protein or more oxygen-free energy especially
in the form of protein-sparing carbohydrates to maintain themselves in
nitrogen equilibrium. In the accounting of the equilibrium we must con-
sider also the N-loss on account of profuse sweats. Hirschlaff estimates it
as 2-4 gm. in twenty-four hours. As is the case with all the other Basedow's
symptoms, the increase of the protein exchange may show great variations.

The increase of the protein exchange is shown very prettily in the ex-
periments of Rudinger. In a nearly N-free diet, rich in carbohydrates and
fats (according to Lander green), in normal human beings, the nitrogen in- the
urine falls rapidly to 4-5 gm. a day. In Basedow's patients, Rudinger found
7-8 gm. N. on the fourth day. The increase of the protein exchange may
also be demonstrated experimentally by the feeding with thyroid-gland sub-
stance. Bleibtreu and Wendelstadt saw after administration of thyroid-gland
tablets in human beings a negative N-equilibrium that could be raised
by the addition of butter and sugar. Since the time of Bleibtreu and
W endelstadt"1 s experiments, many investigations have been carried out
that show the raise in the protein exchange through thyroid medication
(Mayerle). In an experiment of Matthes there was shown after strumectomy,
with the patient on the same diet, an improvement of a previously negative
N-equilibrium. On the administration of dried goiter, the excretion of ni-
trogen rose again. Also in animal experimentation could be demonstrated a
rise of the protein exchange (Fritz Voit). This was shown plainest in in-
vestigation of the metabolism during fasting (Eppinger,Falta, and Rudinger}.

The question whether in hyperthyroidism the increase of the protein
exchange is primary or only the result of an increased carbohydrate and fat

78 THE DISEASES OF THE THYROID GLAND

exchange is mostly answered that the increase of the protein of exchange
is primary. Fritz Voit found in dogs after feeding with thyroid-gland sub-
stance a negative nitrogen equilibrium even when the diet contained abun-
dant-fat, so that fat could even be deposited [in the body]. This experiment
does not seem conclusive as the nitrogen-free energy in the diet was exclu-
sively upheld by fat. The same objection may however be made against the
statement of Magnus-Levy that on the administration of fat or on abundant
fat deposition, the loss of nitrogen is indeed appreciably restricted, but not
entirely done away with. In the experiment of Rudinger the elimination
of nitrogen could be depressed to the Lander green's minimal quantity, if
larger quantities of nitrogen-free energy (with abundant carbohydrates)
were ingested for a long time. We can therefore conclude that in hyper-
thyroidism there exists only a heightening of. the physiological relations.
This is indeed true for the lighter grades, but in the higher grades the de-
generative changes of the muscular substances such as are described by
Askanzy, speak for a toxic disturbance.

Jaquet and Svenson state that in the Basedow's patients the exchange
after ingestion of food is raised higher than in normal individuals. In the
investigations of Forges and Pribram the fundamental exchange after transi-
tory copious administration of protein was found to be abnormally high. It
therefore seems as though the metabolism of Basedow's patients were espe-
cially labile, the administration of protein perhaps increasing the activity
of the thyroid gland in an especial manner. For this perhaps speaks also
the fact that we can make the thyroid of dogs extremely poor in iodine by
abundant administration of meat, this pointing to a rapidly leading off of
the specific secretion; also, as is known, the Basedow struma is characterized
by its very slight iodine contents.

The disturbances of carbohydrate metabolism in Basedow's disease do not
seem to be of a uniform nature. There exists a combination of hyper-
thyroidism with true diabetes (v. Noorden, Ewald, Grawitz, Hannemann,
Bettmann, Falta, and others). This diabetes shows only a slight dependence
on the course of the hyperthyroidism. In the cases I described, X-ray irra-
diation had only a slight influence on the elimination of the sugar. With this
agrees the fact that in true diabetes mellitus we can influence the sugar
elimination by administration of thyroid gland only in the aglycosuric con-
dition or on light glycosuria, while in the higher grades of glycosuria the
influence is not so prominent. Also in the dog after complete extirpation
of the pancreas, under the administration of thyroid-gland tablets there was
no appreciable increase of the D : N quotient. In my cases of diabetes and
Basedow's there were profuse diarrheas, while cases of true thyrogenic
glycosuria, of which I shall speak presently, show disturbances of fat ab-
sorption following overloading with fat.

The combination of Basedow's with true diabetes is not so very rare.

BASEDOW S DISEASE 79

Saltier has collected forty cases from the literature. In twenty-six cases the
Basedow's disease was present before the diabetes, in eight cases the dis-
eases appeared about the same time, in the rest the Basedow's occurred in
the course of the diabetes.

In many individuals the hyperthyroidism determines a predisposition
for glycosuria. The disturbance may be occult, that is, glycosuria appears
only on the administration of large amounts of pure grape-sugar. The ali-
mentary glycosuria in Basedow's disease was first described by Kraus and
Ludwig, and by Chvostek. It seems to have its complete experimental corre-
late in the alimentary glycosuria which may be elicited on the abundant ad-
ministration of thyroid-gland tablets in many normal individuals and in
animal experiment (Ewald, J. Dale, Dennig, v. Noorden, Bettmann, Georgjew-
sky, Strauss, and others). The disturbance in the carbohydrate metabolism
may, however, also be manifest, that is glycosuria is found on mixed diet.
Such cases of spontaneous glycosuria do not appear to be common (Lewin,
v. Nothafft, A. Kocher, Falta). Also Observation VII, reported previously,
belongs to this group. The glycosuria is characterized as thyrogenic by the
fact that it comes on with the development of Basedow's disease, and disappears
again with its amelioration, and that after the cure of the Basedow's also the
overloading tests show entirely normal relations. It is to be distinguished
from the alimentary glycosuria of Basedow's in degree only, as the alimentary
glycosurias also disappear on the spontaneous or therapeutically induced
improvement of the Basedow's. This is observed especially after X-ray
irradiation of the thyroid (Schwarz, Hirschl, Falta). The thyrogenic gly-
cosuria seems chiefly to occur in traumatic Basedow's, and, as had been
mentioned previously, is frequently combined with disturbances of fat
absorption.

In the combination of Basedow's with true diabetes there may well be
assumed, in addition to the disease of the thyroid gland, an independent
lesion of the insular apparatus of the pancreas. On the other hand I would
regard that in the true thyrogenic glycosuria the hyperthyroidism brings
with it a marked additional loading of the internal secretory activity of
the pancreas, with the implication that the internal secretory activity of the
pancreas is weakened, whether by the thyroid secretion or by other factors
is not known. If, however, the pancreas is not equal to the necessary breadth
of function, especially if an alimentary overloading is added, glycosuria makes
its appearance. This hypothesis seems to be explained in an unforced
manner: i. by the fact that hyperthyroidism does not lead to glycosuria in
all individuals; 2. that the glycosuria disappears with the retrogression of
the hyperthyroidism, and that after this retrogression alimentary overload-
ing does not lead to glycosuria. Distinction of the pancreatogenic from the
thyrogenic glycosuria is not attended with any difficulty; but there are, how-

80 THE DISEASES OF THE THYROID GLAND

ever, transitions, that is to say those cases in which the glycosuria occurs
under the use of thyroidin medication (Fried. Mutter). In such cases, just
as in the case of Ewald (myxedema in which diabetes developed on the
continued use of thyroidin medication and persisted after its withdrawal)
there might very well be supposed also a disease of the insular apparatus,
which up to the time had been latent, and which had been made manifest
through the thyroidin medication.

For the understanding of many of the characteristics of the metabolism
in Basedow's patients we must note that the action of thyroidin depends
on the constitution of the affected individual. As was mentioned previously,
in normal individuals the action of thyroidin on the gas exchange, the protein
and the carbohydrate metabolism is often intensive, while other indi-
viduals are entirely refractory to the same dose of thyroidin. The consti-
tutional differences probably lie in the different degrees of excitability of
the vegetative nervous system, and this has perhaps its deeper foundation
in the different reaction capability of the ductless glandular system. Now
it seems that in Basedow's patients alterations of constitution occur in
the course of the disease. So, for example, -o. Wagner mentions a case of
Basedow's disease, in which the initial rapid emaciation was followed by the
development of an obesity, that had the characteristics of an essential obesity.
Not so very rarely, too, are observed cases of Basedow's disease in which the
initial rapid emaciation changes to a condition in which the patients not only
recover what they have lost, but when placed on a little superfluous diet,
they become fat in spite of the fact that they may still show symptoms of
hyperthyroidism. Magnus-Levy reports a case of Basedow's that after
subjective and objective amelioration received daily for four and one-half
weeks two or three thyroidin tablets, without there occurring an aggrava-
tion of the Basedow's symptoms or an increase of the exchange of gases.
A similar case was observed by the author. It was that of a forme fruste
with distinct Basedow's symptoms (without eye symptoms) and glycosuria.
After X-ray irradiation of the thyroid gland all symptoms disappeared;
and high tolerance for carbohydrates soon came on. When the patient
again presented himself after several months, thyroidin medication for
three days (nine tablets a day) could be administered without an appear-
ance of increase of the pulse rate or of alimentary glycosuria.

The thyroid-gland secretion has an enormous influence on the salt met-
abolism. As W. Scholz first pointed out, it increases the elimination of phos-
phorus, especially through the intestine. The increase [of the phosphorus]
in the feces may reach as much as 25 per cent. Older observations of v.
Noorden and the later ones of Oeri have shown that the distribution of
phosphorus to the kidney and intestine is exclusively dependent on the elimi-
nation of calcium ; of calcium only a very slight part is to be found in the urine,
by far the greater part is to be found in the feces. When the calcium elimi-

BASEDOW'S DISEASE 8 1

nation increases, a part of the phosphorus goes to the intestine with the
calcium. Investigations of Bolaffio, Tedesco and the author on fasting dogs
show that under the influence of thyroidin the N : ?2O5 quotient in the urine is
markedly increased, and that further, in agreement with Scholz, the elimina-
tion of phosphorus in the feces is very much increased and that the ab-
normal distribution of phosphorus to the kidneys and intestine is called
forth by an increase of the calcium elimination by way of the intestine.

It should be mentioned further that in Basedow's disease Forschbach
found strikingly slight amounts of creatinin in the urine. Also the ex-
ogenous factor (addition of meat extract) seems to be very small. In many
a case of Basedow's disease there exists in addition a pronounced polyuria,
that cannot be explained alone by the greater gram molecular amount
[Molenmenge] of the urine on account of the increased metabolism. Here
there is well present an excitation of the nerves of the renal vessels.

Later investigations, not as yet published, by Zehner and me as to the
uric acid metabolism in Basedow's disease have led to a very remarkable
result. We found in all the severe cases thus far investigated by us not only
that the endogenous factor of the U-elimination was strikingly small, but
that also the exogenous U-elimination was quite unusually small. I have
reported such an investigation in Observation VIII, and would express the
opinion that a portion of the uric acid is further decomposed under the
influence of the hyperthyroidism.

There are found not rarely in Basedow's disease ephemeral increases in
temperature. These were first described by Bertoye. Already Charcot had
mentioned in opposition to Bertoye that they were very much less frequent
than Bertoye stated. Among his numerous cases, they were never seen by
Kocher. They have been seen however by Saltier. At all events, it is cer-
tain that in many cases of Basedow's disease the equilibrium of heat is very
labile, and that on slight provocations the regulation is broken through in
the sense of a hyperthemia. Frederick Muller saw regularly in one case
marked rises of temperature after the administration of quinine. Eppinger
and Hess saw them in cases after the injection of atropine. Moreover cases
of peracute Basedow's disease are described that previous to death showed
marked tachycardia with delirium, and a simultaneous rise of temperature
to 4o-4i°C. (Friedr. Muller). Also Hirschlajj saw in a case a terminal
rise of temperature to 40°. I have often seen in severe cases of Basedow's
disease transitory rises of temperature to 39°, without finding a ground for
them in the examination. After goiter operations, as is known, there have
been observed marked rises of temperature that last for several days (Ber-
gert, Reinbach, Kocher, Lanz). Riedel found them also after the operation
for ordinary goiter, although those which occur after operations for
exophthalmic goiter are essentially higher. Kostlivy found in all cases after
operation pronounced neutrophilic hyperleucocytoses, but postoperative

82 THE DISEASES OF THE THYROID GLAND

hyperthermia only in cases with thyrotoxic symptoms or in true Basedow's.
Kochcr, Lanz, v. Bruns, and Schultze explain this hyperthermia as an absorp-
tion fever, as in operations on the throat there are present especially favor-
able conditions for the formation of hematomata. More probable is the
explanation that in consequence of the manipulation of the gland more thy-
roid secretion is absorbed and perhaps also the cervical sympathetic is irri-
tated mechanically. The objection of Schultze that the injection of extracts
from such strumas calls forth no essential rises of temperature in other people
does not seem to me tenable, as normal individuals do not possess the lability
of thermal equilibrium that exists in the Basedow's patients.

The skin in Basedow's disease is usually delicate, pliable, moist, readily
reddened, showing well a lively play of the vasomotors. Increased sweat
secretion is almost constant and is mostly present from the beginning of the
disease. As is the case with all the symptoms of Basedow's disease, the
sweats undergo great variations; sometimes they occur only at night, and
often they are influenced greatly by psychic excitations. In rare cases, the
sweats have an odor (v. Basedow's, Dauscher, Observation V, previously re-
ported). Many of the patients sweat more on one side. In consequence of
the abnormal moisture of the skin due to the sweats there is found in most
Basedow's patients a reduction of the resistance to the passage of an electrical
current; this was first described by F. Chvostek and Vigouroux and was more
exactly studied by O. Kahler. On account of the marked excretion of sweat,
miliaria sometimes occur; the formation of larger vesicles with elevation
of the epidermis, as in Case K. (Observation V), seems to be a very rare
occurrence.

Pigmentations are found in about half of all cases, and indeed on the eye-
lids, lips, throat, on the lines of constriction of the corset laces, on the
nipples, in the axillae, on the linea alba, exceptionally on the mucous mem-
branes, and also on the genitalia. In rare cases is found a diffuse brown
coloration of the skin of the extremities, indeed even a bronzing. In many
cases occur edematous swellings, especially of the eye-lids, but also on the
extremities; they are firm and do not pit on pressure. They probably differ
in nature. Trophedemas are apparently not very rare in Basedow's disease.
In many cases it seems as though we were dealing with a kind of lipodystrophy ,
as for example in the case reported by v. Schrotter, in which simultaneously
with the emaciation of the upper half of the body there developed a con-
siderable swelling of the lower half of the body, looking just like myxedema.
Microscopical examination showed a lipomatosis with extraordinary large
fat lobules. In this case there was found also a quite extraordinary pigmen-
tation of the skin in the form of sharply circumscribed surfaces. I shall
refer later, in the discussion of the pathogenesis, to the myxedematous swell-
ings in this disease. There may be found also in certain cases hemorrhages
into the skin and the mucous membranes. A common symptom in Base-

BASEDOW'S DISEASE. 83

dow's disease is the falling out of the hair, that sometimes may lead almost
to baldness. Also the nails are sometimes fissured.

Alterations of the osseous system occur mostly if the Basedow's disease
has developed in an individual who is youthful. Holmgren has pointed out
that youthful Basedow's patients show an accelerated growth in height and
a somewhat premature closure of the epiphysial junctures. Very instructive
is a case of Schkarine in a four and one-half-year-old girl who showed an
abnormally rapid growth. Also Ballet reports a nineteen-year-old girl with
Basedow's disease and "gigantism." The skeleton of the patient with Base-
dow's is mostly slender; the end phalanges are mostly pointed (Revilliod).
v. Jaksch and Rotky describe in a case of Basedow's painful distentions at
the distal ends of the forearm bones, and later also of the ribs, shoulder-
blades, upper-arm, thighs, etc. Later the case developed kyphoscoliosis and
paraplegia. The simultaneous occurrence of Basedow's and rheumatoid
arthritis has been frequently described (Jones and others).

The alterations in the genitalia are mostly more pronounced in men, and
in severe cases there may sometimes be decrease of libido and impotence.
In women there are usually alterations of menstruation — sometimes cessa-
tion of menstruation is an early symptom. On longer duration of the disease
there may come about an atrophy of the entire genital apparatus (Cheadle,
Askanazy, et a/.). In the case of Kleinwachter there occurred, in addition to
a pronounced atrophy of the external and internal genitalia, even an atrophy
of the mammae. The relation between the genital sphere and the thyroid
gland is found also in the fact, known for so long, that there is an increase of
the volume of the thyroid at the time of puberty and during pregnancy.
There may also occur during the period of pregnancy a development of a
goiter (Lawson Tail) , which disappears after labor and recurs during the next
pregnancy. Vermorel refers the tachycardia and the cardiac palpitations
that sometimes occur at the time of puberty to a light grade of hyperthy-
roidism. At any rate it is noteworthy from this point of view that Base-
dow's disease is not at all rare. During pregnancy the Basedow's symptoms
mostly become exaggerated (Cholmogorojf and others'). As the tendency to
Basedow's disease is sometimes inherited and as in the decline of Basedow's
patient frequently other diseases — neuroses of the vegetative nervous
diseases, diabetes, etc. — occur, matrimony is to be advised against to
Basedow's patients, or in it conception is to be avoided (/. Novak).

Basedow's disease can naturally be combined with many other diseases.
We should mention the not rare combination with the trophoneuroses, espe-
cially with scleroderma. Such a case was first reported by Leube. Since
that time numerous cases have been reported. An accurate compilation has
been made by Saltier. Basedow's disease may be added to an already exist-
ing scleroderma, or sclerodermic symptoms may develop in the course of a
Basedow's disease. Observers have often found that an improvement of the

84 THE DISEASES OF THE THYROID GLAND

Basedow's disease is associated with an improvement of the scleroderma.
There are, however, cases that take another course. Also complications of
Basedow's disease with tetany have often been observed (see Chapter IV).

Pathogenesis. — Before I enter into the consideration of the individual
forms of Basedow's disease, I should like to make a few remarks as to the
theory. The observation of File/me and of Dourdoufi and Bienfait that in
animals after the transection of the corpora restiformia there occur tachy-
cardia, exophthalmus, and hyperemia of the thyroid gland (unilateral opera-
tions are attended with these phenomena on one side only), for a long time
attracted many adherents to the bulbar theory, which attributed all the
Basedow's symptoms to alterations in the brain stem. Actually many
symptoms point to a bulbar origin, as for instance the glycosuria that some-
times occurs, the alterations of the voice, and eventually the pareses of the
various cranial nerves (Saltier} . It is indeed true that in certain cases altera-
tions are found in the medulla oblongata (Mendel and others), but in the
majority of cases these findings are absent. The French school, especially
Charcot, Trousseau and Gauthier, and in Germany Gerhardt and Buschan,
have regarded Basedow's disease as a neurosis, assuming that the entire
nervous system is diseased. Then Mo'bius, as has already been mentioned
in the beginning, placed the thyroid gland as the central figure in the patho-
genesis, assumed a poisoning of the body by the copious production of a
harmful secretion, and expressed the thought that all forms of Basedow's
disease (goiters that have become associated with Basedow's symptoms,
formes frustes, and the fully developed Basedow's disease) all depend on a
uniform basis. Mobius first pointed out the opposition between the symp-
tom picture of Basedow's disease and the disease condition that ensues
after extirpation of the thyroid gland. Mobius's teaching gained ground
rapidly, the predominant place of the thyroid gland in the pathogenesis of
Basedow's disease finding general recognition; but on the contrary the views
as to the kind of functional disturbance diverged greatly. The view first
advocated by Notki and later by Blum, that certain poisons existing in the
body were rendered nontoxic (i.e., detoxicated) in the thyroid gland and that
in Basedow's disease this detoxication is incomplete, may to-day be regarded
as untenable. It was displaced by the secretion theory, which maintained
that from the thyroid gland a specific active secretion is given off to the
blood path that is necessary for the retention of certain body functions, or,
according to the supposition of others, to the paralyzing of certain poisons
circulating in the body. The detoxication theory, although in an essentially
modified form, again greets us in the view last-mentioned. In this form,
however, there is as little evidence for it as in its older form. The known
experiment of Reid Hunt, according to which the resistances of animals to
methyl cyanide is somewhat raised, is not evidence for the detoxication
theory as, as Reid Hunt himself emphasizes, the heightening of resistance can

BASEDOW'S DISEASE 8$

be called forth by the heightening of the metabolic processes that ensues in
consequence of the administration of the thyroid.

Oswald, Minnie h, and others assume that in Basedow's disease the thyroid
furnishes a less active secretion (hypothyrosis or dysthyrosis) ; Mobius
believes, as already mentioned, in the increased secretion of a substance that
is qualitatively altered; while most authors, especially Fr. Kraus, advocate
the mere increase of the thyroid function without qualitative alteration
(hyperthyroidism). For this supposition, which I also advocate, speaks:

1. The opposition in the symptom picture of Basedow's disease and
myxedema.

2. The fact that on exothyropexy (conduction of the secretion of the
thyroid gland to the exterior) the thyroid gland in Basedow's disease fur-
nishes more secretion than the thyroid of the ordinary strumas.

3. The results of surgical treatment (diminution of the secreting
parenchyma).

4. The aggravation of Basedow's disease on the administration of
thyroid glandular substances and finally,

5. Artificial thyroidism.

Against these points many objections have been raised of which I shall
mention only the most important. Against point 5 has been objected
that while it is true that most of the symptoms of Basedow's disease may
be produced on the administration of thyroid gland, they remain much be-
hind those of true Basedow's disease in intensity, and some of them, for
instance the eye symptoms, are not produced in artificial thyroidism at all.
As far as the eye symptoms are concerned, I must again mention that Kraus
and Friedenthal observed exophthalmus after the injection into the blood
of rabbits of the thyroid glandular juice contained in the serum, as did
Heinecke on long-continued treatment with large amounts of thyroid glandu-
lar substance. In addition to-day exophthalmus can be produced in dogs
on the use of juice expressed from human strumas (Lampe, Liesegang, and
Klose, Baruch}.

Lampe, Liesegang, and Klose, on the intravenous -injection into certain
breeds of dogs of fresh juice expressed from Basedow strumas, have found
marked increase of the temperature and pulse rate, exophthalmus, glyco-
suria and albuminurta. Death occurred in convulsions. Expressed juices
that were obtained from normal thyroid glands or ordinary strumas had no
effect, or very little effect. The authors regard these experiments as evidence
that in Basedow's disease there exists no hyperthyroidism but a dysthyroid-
ism. The experiments are very significant, but I do not regard them as
furnishing evidence for a dysthyroidism. It will not do to leave altogether
unconsidered the long-known fact that, as stated above, through the feed-
ing with normal thyroid glandular substances all the symptoms of Base-
dow's can be produced in a more or less well-pronounced manner. Also

86 THE DISEASES OF THE THYROID GLAND

BamcJi. who experimented in a manner quite analogous to that of Lampe,
Liesegang, and Klose, and had similar results, does not agree with these
authors' interpretation.

Much cited is the case of v. Nothajft, which I shall describe in detail on
account of the interest that it has attracted. It was that of a forty-five-
year-old man with a corpulency that had been increasing for several years.
In the course of about five weeks he took almost 1000 thyroid-gland tablets.
Inashort time there developed a complement of Basedow's symptomsof which
I will mention irritating cough, tachycardia, acceleration of respiration,
slight increase of temperature, bilateral exophthalmus, tremor of the whole
body, even of the tongue, increased strangury, glycosuria (up to i per cent.),
morose mood, excitement, and finally swelling of the thyroid gland. The
irritating cough disappeared eight days after the onset of the thyroid
glandular therapy, as did also the sugar, without alteration of the diet; the
tremor disappeared after four weeks; the struma, the exophthalmus, and the
rest of the eye signs lasted nearly one-half year and then retrogressed almost
entirely. Although here almost the entire symptom-complex of Basedow's
disease developed, the case is however not entirely convincing. We shall
see later that in many persons often relatively small amounts of iodine are
sufficient to occasion an enormous increase of the function of the thyroid
gland. Also in the case of v. Nothafft the amounts of iodine contained in the
administered thyroid gland material may have sufficed for the purpose, as
speaks also the transitory development of a struma. This objection might
very well be raised to an artificial hyper thyroidism, unless the thyroid gland
in the affected individual were absent. Now in myxedema after thyroid
operation we may indeed frequently observe an extraordinarily high toler-
ance for thyroid-gland substances, but on the other hand, symptoms of
hyperthyroidism may be elicited after the administration of enormous
amounts. At all events, we must not forget that we do not know anything
as to the amount of thyroid-gland secretion given off to the blood in Base-
dow's disease. Probably it is very large. We should further consider that
on the peroral administration of large amounts the absorption would soon
suffer harm.

Although I therefore do not recognize the arguments advanced up to the
present time as convincing, I shall have to acknowledge that artificial
thyroidism has not as yet furnished complete evidence for the opinion
here advocated. The greater intensity of the symptoms in true Basedow's
always admits of the possibility that hyperthyroidism is only a partial phe-
nomenon of an alteration of the central nervous system and that the organism of
the Basedow's patient reacts to hyperthyroidism in a different manner than
the normal. The foundation for this can perhaps be seen in a constitutional
alteration, of which the cause lies in the associated involvement and perhaps
in a functional increase of other ductless glands. The final cause of all the
manifestations could well be regarded as lying in the central nervous system.

BASEDOW S DISEASE

It has been pointed out that the multiplicity of the Basedow's symptoms
cannot well be explained by the functional increase of the thyroid gland
alone, and that therefore also on this ground a qualitative alteration of the
secretion must be supposed. This objection does not hold in this general
interpretation. All the symptoms of Basedow's disease may be produced,
at least in miniature, after the administration of normal thyroid gland.
What syndrome will develop all depends on the constitution of the affected
individual (Falta, Newburgh, and Nobel).

Objections have been raised to point 4. It is true that in the most
cases we observe under thyroid medication distinct aggravation of the
Basedow's symptoms, such as increase of the tachycardia, arrhythmia,
sleeplessness, excitement, profuse sweats, gastrointestinal disturbances,
severe prostration, etc. But there have been reported cases in which
the thyroid medication acted favorably. Quite complicated theories have
been advanced for the explanation of these cases; thus, for example, Mb'bius
believes that the increased activity of the thyroid gland retrogresses if
through the administration of thyroid glandular substance the gland is given
time to recover itself. Such cases may be explained without overdrawing
by the observation that in many cured cases of Basedow's disease the
counter-regulations develop strongly. I previously mentioned a case in
which, after the cure of the Basedow's, thyroid-gland tablets even in large
quantities would bring forth no distinct relief. If, therefore, thyroid medica-
tion takes place in the declining stage of the disease, slight favorable results
may be readily induced.

The most important point is point i, the opposition in the symptom
picture of Basedow's disease and of myxedema. I here reproduce the ex-
cellent table of Kocher:

Cachexia Thyreopriva
Absence or atrophy of the thyroid
gland.

Slow, small, regular pulse.

On application of cold to the skin, all
vasomotor changes are absent.

Listless quiet gaze without expression
and animation.

Narrow palpebral fissures.

Retarded digestion and excretion,
poor appetite, few demands.

Slowed metabolism.

Thick, nontransparent, folded, dry to
scaly skin.

Short, thick fingers often broadened
at the ends.

Sleepiness and tendency to sleep.

Morbus Basedowi

Swelling of the thyroid gland — mostly
of a diffuse nature, hypervascularization.

Frequent, often tense, rapid, now and
then irregular, pulse.

Extraordinarily irritable vascular nerv-
ous system.

Anxious, unsteady gaze which is choleric
on fixation.

Wide palpebral fissures, exophthalmus.

Abundant evacuations, mostly abnormal
appetite, increased demands.

Increased metabolism.

Thin, transparent, finely injected, moist
skin.

Long, slender fingers with pointed end
phalanges.

Sleeplessness and disturbed sleep.

88 THE DISEASES OF THE THYROID GLAND

Cai-lu-xia Thyreopriva Morbus Basedmvi

Retarded sensation, apperception, and Accelerated sensation, apperception, and

action. action.

'Deficiency of thoughts, listlessness, and Flight of thoughts, psychic excitement

loss of emotivity. as far as hallucination, mania and melan-

cholia.

Awkwardness and clumsiness. Constant unrest and haste.

Stiffness of the extremities. Trembling extremities, increased mo-

bility of the joints.

Remaining behind of bone growth — Slender skeletal build, now and then

bones short and thick, and often de- weak and thin bones,
formed.

Constant feeling of cold. Unbearable sensation of heat.

Retarded, heavy, breathing. Superficial breathing with deficient

inspiratory expansion of the thorax.

Increase of body weight. Reduction of body weight.

Senile appearance, even when the Youthful luxuriant body development,

patients are young. at least in the initial stages.

A. Kocher distinguishes, in addition to these opposed symptoms, symptoms
that are similar in both diseases and reckons under these certain forms of
edema, dryness and becoming gray of the hair, pigmentations, and the
diminution of the secretion of the salivary and lachrymal glands that is ob-
served in many cases of Basedow's disease. One may add to these symp-
toms the dryness of the skin seen in rare cases of Basedow's disease and the
glycosuria of quite rare cases of myxedema. These "exceptions to the
rule" will hardly suffice to limit essentially the opposition in the symptom
picture of the two conditions. For the explanation of many of these ex-
ceptions, constitutional differences may be called into account; for example,
they may suffice for the explanation of the dryness of the hair and of the
skin, and for the diminution of the salivary secretion. Eppinger and Hess
regard the cause of the opposed behavior of the sweat formation in
different cases of Basedow's disease as a different tonus of the sympathetic
or of the autonomous nerves; surely such behavior does not furnish suf-
ficient argument against the hypothesis of hyperthyrosis, because also in
artificial hyperthyroidism we saw, in certain cases, a diminution of the
sweat formation under the influence of the thyroid medication. As far
as the behavior of the hair is concerned, in Basedow's disease the hair in-
deed may be dry but is also thin, while in myxedema it tends to be thick,
loose, and brittle. The explanation of other "similar" symptoms may
be attributed to the pathological correlations; for instance, the rare
glycosuria in myxedema may well point to a simultaneous insufficiency of
the pancreas. I would enter more fully only into a discussion of one of the
symptoms detailed, as it is regarded by the adherents of dysthyrosis as
an especially important argument. It is the combination of Basedow's
and myxedematous symptoms in the same patients. In Sattler's work

BASEDOW'S DISEASE 89

will be found a compilation of such cases. The observation that a fully
developed Basedow's may gradually go over into a myxedema has nothing
striking about it, for an overfunctionating thyroid may degenerate and
become functionally insufficient. Such a case was first described by Jojfroy
and A chard. In a twenty- three-year-old woman there first developed a
typical Basedow's disease, then great weakness, swelling of the feet, legs,
trunk, the upper extremities and the face, apathy, great fatigability. Au-
topsy showed a sarcoma of the pleura and disappearance of the thyroid
parenchyma, in the place of which was found connective tissue. Confer
also the case of Gauthier.

Concerning the cases with simultaneous occurrence of Basedow's disease
and myxedema, I would remark that in many of these cases the diagnosis
myxedema seems to me very doubtful indeed. I call to mind the above-
mentioned case of v. Schrotter, which microscopical examination showed to be
lipomatosis. Perhaps something analogous is to be seen in the case of
Hirschl, in which the skin of the ankle-joint was entirely normal and the
swelling of the leg ended in a sharp ring. In this case, too, the swelling of
the face was limited to a pad-like thickening on the lower border of the
lower jar. The circumstance that the skin was dry is no evidence for myx-
edema; otherwise there was a typical Basedow's disease. Also in both of
Loeiv's cases — otherwise typical cases of Basedow's disease — there existed
a thickening of the extremities that involved the backs of the feet little
if at all. Thyroid medication had no influence on this thickening.

It seems to me further noteworthy that almost all the cases that Saltier
quotes show peculiar complications. In two cases (cases of Mobius and of
Hirschl) there existed at the same time osteomalacia. In the case of S oilier,
the myxedematous swellings occurred especially at the time of menstruation,
in the case of Ulrich there were choreiform twitchings, in the case of Kow-
alewsky epilepsy since youth, in the case of Holub there was marked Chvo-
stek's sign, and in Osier's case there later occurred under thyroid medica-
tion marked glycosuria. Moreover, I consider it possible that cases that
stand on the border-line of thyroid glandular insufficiency would under cer-
tain conditions show lowered tolerance for thyroid-gland preparations.
As example I cite the following case:

Observation X. — Mrs. B., forty-eight years, has nad five confinements. After the last
confinement there was a gradual taking on of body weight, until she weighed about 125 kg.
About twenty years ago she underwent a reduction cure, in the course of which she rapidly
lost 14 kg. At the time, also, thyroid-gland tablets were administered. After the treat-
ment marked excitability, cardiac oppressions, diarrheas, sweats, and tremor occurred.
These symptoms lasted a long time. Then they retrogressed and the body weight again
increased. Three years ago after inunction of an iodine salve, there was a gradual in-
crease of the Basedow's symptoms. The thyroid gland had formerly been large, and now
enlarged still more. Two years ago the right lobe of the thyroid gland was extirpated.
After the operation there was gradual increase of body weight, about 12 kg., sensation of

9O THE DISEASES OF THE THYROID GLAND

cold (can scarcely warm herself), skin dry and cold, mental sluggishness, constipation.
For several months thyroid medication. The skin again became moist, cardiac manifesta-
tions, tachycardia, and arrhythmia again appeared, the patient was excited, the consti-
pation disappeared. Body weight decreased. When the thyroid medication was discon-
tinued, the weight increased again and the myxedematous symptoms reappeared. Since
that time, periods of thyroid administration were many times introduced, and regularly
after the use of only two to three tablets a day for a short time Basedow's manifestations
appeared. At present, after a three weeks' thyroid treatment, there is a slight tachycardia
and especially marked arrhythmia. The heart is dilated, the pulse is poorly filled, the
skin is moist, there are stary eyes and a very slight fine-waved tremor.

Later, in the chapter on myxedema, I shall cite similar cases. The
slight tolerance toward thyroid preparations is in this case certainly re-
markable, as high tolerance is characteristic for typical cases of myxedema.
To my mind there is in this case no necessary basis for the assumption of a
dysthyrosis. It is well known that a degenerated heart muscle is extra-
ordinarily sensitive toward thyroidin. It can very well be conjectured that
a slight excess of thyroidin would already damage the .heart muscle, if the
myxedematous symptoms have not as yet altogether disappeared. Finally,
it remains to be investigated whether in similar cases the myxedematous
swellings of the skin are always dependent exclusively on the thyroid glandu-
lar insufficiency. Much speaks for the fact, as above indicated, that in
such cases frequently also other ductless glands are degenerated. Especially
frequently there occurs a simultaneous affection of thyroid and hypophysis.
As is known, there is found an insufficiency of the pituitary gland, alterations
of the skin and trophic disturbances that are similar to those of myxedema.
In many Basedow's cases with myxedematoid symptoms, and in cases of
myxedema that react to thyroid treatment with only partial improvement
and that may even show signs of hyperthyroidism rapidly, it is quite prob-
able that these myxedematoid manifestations depend on a hypophysial in-
sufficiency (see also the chapter on the hypophysis).

Many authors are disposed to ascribe to thymus hyperplasia an important
role in the pathogenesis of Basedow's disease. Already v. Hansemann was
of the opinion that the cases of "thymus Basedow" could be distinguished
also clinically. Hart refers the cardiac manifestations in Basedow's disease
to the thymus hyperplasia alone and sees in such cases thyroid hyperplasia
as something secondary. On the other hand, Gebele regards the enlargement
of the thymus gland as a compensating process that serves to weaken the
hyperthyroidism. Especially worthy of notice are the reports of Garre and of
Capelle and Bayer, concerning the extirpation of the thymus gland in Base-
dow's disease. In the case of Capelle and Bayer, thymectomy seemed to have
no influence on the struma, the exophthalmus, or the bulbar symptoms, but
the cardiac symptoms seemed to improve. After some weeks the mononu-
cleosis had disappeared. Gebele, however, does not regard the thymus in
this case as enlarged, and points out that five months after the thymectomy

BASEDOW S DISEASE 91

an operative procedure on the thyroid was necessary on account of pro-
nounced symptoms of Basedow's. According to E. Bircher, implantation
into the abdominal cavity of dogs of thymus gland that came from an indi-
vidual who died from thymic death at operation called forth temporary
tachycardia, conditions of excitement, and tremor, and also a struma.
Present clinical and experimental contributions to this subject seem to
me far inadequate to ascribe to the thymus gland so great a significance as
to warrant the delimitation of a thymogenic Basedow's.

Just a few words as to the place of iodine in the physiology and pathology
of the thyroid gland. Iodine is found in very many organs, as in the skin,
the lungs, the ovaries, the small intestines, the blood, the liver, the bile, the
hairs, and in the glandular part of the hypophysis (Blum, Bourget, Hejfter,
Drechsler and others}. The iodine-contents of the thyroid gland is, how-
ever, much larger (according to Justus eight to ten times) than that of the
other organs relatively rich in iodine. The normal thyroid gland of man
contains according to Magnus-Levy about 0.3-0.9 mg. of iodine for i kg. of dry
substance. The entire gland contains about 2-9 mg. (Baumann, Oswald).
The thyroid glands of fetuses and new-born children are iodine-free. The
thyroid glands of herbivora have very high iodine-contents, while the thyroid
glands of carnivora have the lowest iodine-contents (Baumann, Roos,
Oswald}. Copious feeding of meats to dogs makes the thyroid gland very
poor in iodine. The activity of the thyroid glandular substance is bound
with its iodine-contents and parallels these. As is known, all the symptoms
of deprivation after extirpation of the thyroid gland may be alleviated by
the administration of iodine-containing thyroid glandular substance. The
iodine-containing albuminous substances obtained by Oswald from the
thyroid gland, iodthyroglobulin, contains about 1.75 per cent, of iodine.
The.iodothyrin obtained by Baumann by splitting with acids contains about
9.3 per cent. Oswald obtained from thyroglobulin by splitting with acid a
still richer iodothyrin with 14.29 per cent, of iodine. While the iodthy-
roglobulin seems to possess the complete action of dried thyroid-gland sub-
stance, iodothyrin is less active, even though it possesses a greater height-
ening power on metabolism and a greater action on the cardiovascular
apparatus than artificially iodized albuminous bodies. Its action is, how-
ever, much less than that of dried thyroid glandular substance. While, for
example, we could obtain with 2.7 gm. of Bourrough, Wellcome, and Co.'s
tablets distinct tachycardia and other slight symptoms of thyroidism in three
days, later twenty-one Bayer's iodothyrin tablets daily, administered for a
long time, were without effect (experiment of Dr. Fleming) . The iodothyrin
is also incapable of alleviating the manifestations of deprivation that occur
in youthful animals after thyroidectomy (Pick and Pineles}. Just as after
splitting with acids, the thyroid-gland substance, after exposure to digestive
ferments, loses in activity. Exposure of short duration to peptic and tryp-

92 THE DISEASES OF THE THYROID GLAND

tic digestion does not seem to alter the specific substances, as we are able
to bring about the complete action even on peroral administration. All
experiments point to the fact that the thyroid gland carries iodine in a specific
organic combination, perhaps iodthyroglobulin.

The iodine-contents of pathological glands varies greatly. The purely
parenchymatous Basedow strumas contain almost no iodine; strumas
rich in colloid are also rich in iodine. Investigations by Oswald, A . Kocher.
and others have shown that the iodine-contents of strumas rich in colloid
is really not absolutely greater than in the normal thyroid-gland, but that
relatively, that is, taken in relation to the amount of thyroid-gland sub-
stance, it is less. On the contrary, the holding in thyroglobulin is abso-
lutely and relatively greater; in colloid goiters there is found, therefore,
either an iodthyroglobulin poor in iodine or less iodthyroglobulin and more
thyroglobulin. Probably in the Basedow struma the formed iodothyro-
globulin reaches the circulation immediately in consequence of the increased
permeation with blood.

The function of the thyroid gland, if the organ is altered pathologically,
may be influenced by the administration of inorganic iodine. Individuals
with normal thyroid glands separate out again the excess of iodine rather
promptly, without any disturbance of the iodine equilibrium. Strumous
individuals, according to the investigations of A. Kocher, behave very
diversely; in strumas with abundantly functionating parenchyma more
iodine is excreted than is introduced, so that thyroid-gland tissue is melted
down and symptoms of thyroidism may appear. In strumas with relatively
iodine-poor colloid this is first iodized; there therefore occurs an iodine re-
tention, but on continued treatment with iodine there may come about
melting down of the colloid and thyroidism. Administration of the phos-
phates should favor the action of iodine and keep back the melting down of
tissues. This experiment renders intelligible the old experience that in
certain forms of struma the administration even of very small amounts of
iodine leads to manifestations of thyroidism.

Kocher's investigations stand in the most intimate relation to the
older experience as to the so-called iodine Basedow's. Coindet, in Geneva,
introduced iodine into therapy in 1820. Shortly afterward it was reported
by Coindet himself and by Gautier, d'Espine, Relliet, and others that after the
administration of iodine there often occurs a series of symptoms that are
sharply distinguished from those of pure iodism (acne, catarrh of the mucous
membranes, etc.). These symptoms (tachycardia, tremor, emaciation, etc.)
could develop in strumous individuals after the administration of mimimal
amounts of iodine, and long outlast the medication. Already Lebert ad-
vocated the opinion that in such cases the administration of iodine led to
rapid absorption of thyroid glandular substance and the symptoms mentioned
could be referred to this. Breuer explained the contradiction that these

BASEDOW'S DISEASE 93

observations met with in Paris by the fact that only certain forms of struma,
as those for example in Geneva or Vienna, reacted to the administration of
iodine in this manner. The regional difference in the sensitiveness toward
iodine can be elicited from the large series of experiments of Fleischmann.
Fleischmann after the administration of iodine to the persons under inves-
tigation in Basel saw acceleration of the pulse in 68 per cent., in Berne in 23
per cent., in Berlin in only 3.7 per cent. In Heidelberg, the use of iodine
was warned against by Krehl. According to the statement of Breuer,
Kocher, Mobius, Ortner, Goldflam (the last on the injection of iodipin into a
person with tabes), there even a typical morbus Basedowi may develop, even
in cases in which no struma existed before the treatment with iodine; or in
cases of cured Basedow's there may occur a severe relapse with a new
enlargement of the thyroid gland. Case B. (Observation X), previously
reported, furnishes a good example of this; or an existing Basedow's dis-
ease may be considerably aggravated by iodine therapy (compare case S.
Schm). In Vienna, according to my observations, conditions are such that
one must directly warn young persons with diffuse soft strumas against the
use of iodine. Pineles has seen especially frequently, after the use of iodine,
the occurrence of the manifestations of thyroidism in goitrous individuals in
families in which Basedow's disease or diabetes has occurred or in which a
neuropathic disposition has existed. This was the case even when the
iodine was given in very small quantities.

It would really be correct to separate the cases of simple iodothyroidism
from those of iodine Basedow's, although there are transitions between the two
groups. In the first group of cases administration of iodine brings about a
rapid melting down of thyroid-gland tissue and hence the manifestations of
thyroidism. After the discontinuation of the iodine medication the mani-
festations for the most part rapidly retrogress, the thyroid gland remaining
the same in size or becoming smaller. In the cases of iodine Basedow, on
the contrary, the thyroid gland increases in volume, and the Basedow's
manifestations can long outlast the iodine medication.

As to the etiology of Basedow's disease we do not know anything definite.
The goiter noxus can play only a subordinate role, as just the fully developed
forms of Basedow's disease are rare in goiter districts. Neuropathic pre-
disposition is to be regarded at the most as a predisposing factor; psychic
and bodily traumata as well as iodine and thyroid glandular medication are
to be regarded as determining factors. Frequently Basedow's disease de-
velops at the close of acute infectious diseases (acute articular rheuma-
tism, angina, typhoid fever, scarlet fever, etc.). In some cases an idio-
pathic thyroiditis passes over into it. Finally, Kahn and myself in several
cases of declining tetany saw occurrence of thyroid glandular swelling and
distinct Basedow's symptoms. As furthermore the true Basedow's struma
shows accumulations of lymphocytes and as the parathyroid glands in such

94 THE DISEASES OF THE THYROID GLAND

cases are swollen, many authors have thought of an infectious etiology of
Basedow's disease. This assumption is not however satisfactory, as many
cases of Basedow's disease develop in complete health and are entirely fever-
free. Hence the acute infection is regarded by Mobius, de Quervain and
others only as the connecting link. As I have already mentioned, the
assumption of a thymogenic Basedow's disease seems to-day to have but
little foundation. Even those who refer all the symptoms of Basedow's
disease to an increase of function of the thyroid gland must recognize that
the cause proper of this increase of function is as yet unknown. As the
secretion of the thyroid gland is regulated by the central nervous system,
lately nervous centers have again been assumed (Wiener), constituting, in'j'a
manner, a revival of the bulbar theory of Char cot and Geigel (Oppenheim).
According to this theory many of the Basedow's symptoms, above all the
eye symptoms which are so hard to produce by artificial thyroidism, are
coordinated with those of the thyroid glandular swelling. This theory would
at least explain the rare observation that the exophthalmus may occur
unilaterally (Fr. Muller, Roasenda, Kocher, and others).

The statements as to the theory and etiology of hyperthyrosis bring to
recognition the fact that the cause of Basedow's disease is not as yet explained.
Most of the symptoms can be referred to the hyper thyroidism; the cause of the
hyperthyroidism is possibly conditioned centrally, and thus perhaps a series
of symptoms and alterations in the function of other ductless glands are coordinate
with the hyperthyroidism. Finally, we should point out that the not unusual
combination of the trophoneuroses (scleroderma) with symptoms similar
to those of Basedow's disease or even typical hyperthyrosis obtain some
value in this connection (see Chapter I).

Forms of Basedow's Disease. — In consequence of the great variability
which Basedow's disease presents in its manifestations and in its course,
there has existed from former years the attempt to bring forward certain
symptoms as cardinal symptoms and to lend to certain apparently more re-
mote symptoms a greater nosological independence. Originally the symptoms
of the so-called Merseburg triad — exophthalmus, goiter, and tachycardia —
were taken as the cardinal symptoms. However, exophthalmus is wanting
in a not inconsiderable part of the cases of this condition and, moreover,
Pierre Marie added a new cardinal symptom — the tremor. The fact that the
exophthalmus is often permanently absent led Pierre Marie to the establish-
ment of the formes frustes, the effaced, or better, the incomplete forms, while
formerly Charcot understood by forme fruste the residual condition after
improvement of the classic form. Gautier and Buschan distinguished true
Basedow's disease and the pseudo- or secondary Basedow's disease, regard-
ing the former as a general neurosis with the predominance of the psychic
and vasomotor sphere, while the latter is brought about by other changes
in the organism among others also a disturbance of function of the thyroid

BASEDOW'S DISEASE 95

gland. Mobius distinguished primary and secondary Basedow's disease
according as to whether the alteration of function developed in a previously
normal or in a goitrously degenerated thyroid gland. Secondary Basedow's
disease ordinarily pursues a chronic course and is often incomplete; the
primary is often acute and rich in symptoms. The secondary form corre-
sponds to the goitre basedowifie (Revilliod and Pierre Marie] . Mobius does
not however ascribe so very great a significance to this distinction, as he regards
the alteration of function of the thyroid gland as the central figure. "The
cardinal symptom is just the tachycardia." Th. Kocher distinguishes between
the fully developed forms and the so-called hyperthyrotoxic equivalents.

Fr. Kraus has separated out the so-called goiter heart as an especial
independent form. Apart from those cardiac disturbances which come about
through mechanical obstruction to the circulation or respiration, there exists
additionally in goiters, according to Kraus, a cardiac disturbance associated
with other hyperthyroidal symptoms, which cardiac disturbance is produced
by the thyroidal secretion acting at a distance.

Eppinger and Hess distinguish between sympathicotonic and vagotonic
forms, according to whether the symptoms of excitation predominate on the
part of the autonomous or of the sympathetic nerves. Characteristic
for the vagotonic cases would be "a relatively slight degree of tachycardia,
with, however, markedly pronounced heart oppressions, distinctly marked
v. Grdfe, and wide palpebral fissures, absent Mobius, slight protrusion of
eyeballs, the marked secretion of tears, outbreaks of sweats, diarrheas, dis-
tresses that are to be referred to hyperacidity, eventually eosinophilia, and
disturbances of the rhythm and mechanism of respiration, absent alimentary
glycosuria;" in the sympathicotonic cases, Eppinger and Hess found "marked
protrusion of the eye-balls, greatly increased cardiac activity with slight ac-
centuation of the subjective disturbances, absence of sweats and diarrheas,
marked falling out of the hair, inclination to increase of fever, absence of
eosinophilia, no disturbances of respiration, alimentary glycosuria."

The position of many of these symptoms as sympathicotonic or vagotonic
is as yet quite insecure. Thus, for example, the interpretation of the sweats
as vagotonic is not sufficiently founded, because as yet we have known noth-
ing as to the course of autonomous nerves of the skin. The significance of
the individual phenomena is rendered the more difficult because there exist
both sympathetic accelerator [fordernde] and inhibitor and autonomous ac-
celerator and inhibitor fibers. I cannot look upon the alimentary glycosuria
as sympathicotonic, as according to our investigations the alimentary factor
is to be sharply separated from the nervous factor, and for the former the
functional breadth of the pancreas is the determining factor. Moreover,
there are undoubtedly cases, as Eppinger and Hess and recently v. Noorden,
Jr., bring out, in the course of which at times the sympathicotonic, at times
the autonomotonic, symptoms predominate. Before everything else, how-

96 THE DISEASES OF THE THYROID GLAND

ever, the tachycardia is evidently to be regarded as the cardinal symptom
of Basedow's disease; and, on the other hand, the sweats or the marked moist-
ening of the skin is so extraordinarily frequent that almost never can we
speak of a purely sympathetic type in the sense of Eppinger and Hess. In
my opinion everything speaks for the fact that in Basedow's disease the
entire nervous system is in a condition of overexcitement and that the pictures
presented by the vegetative nervous system are uncommonly manifold and
always changing.

Very recently Stern has entered the list for the greater independence of
certain forms of Basedow's that he regards as Basedowoid. In a certain
sense there is in this a reversal to the views of Gautier and Buschan. Stern
divides the classic form into true and degenerative Basedow's disease,
according to whether the disease develops in a previously normal or in a
neuropathic individual. From the great group of formes frustes Stern
separates out Kraus's goiter heart; the remaining forms are based regularly
on an original degenerative neuropathic foundation. Basedowoid and
Basedow's according to this view are distinguished from each other essen-
tially by their beginning, course, and prognosis. According to Stern, they
never pass over into each other. Chvostek agrees with Stern on the whole,
except that he would regard as- formes frustes the relatively abortive cases
of true Basedow's that pursue a light course. Langelaan regards Stern's
Basedowoid as Basedow's on an asthenic basis. The practical significance of
a clinical differentiation of the individual formes is in themselves intelligible
if through them deductions as to the prognosis and therapy can be given.
On the other hand, I would point out with emphasis the danger that exists in
the fact that through the accentuation of the distinguishing features, the
painstakingly wrought-out conception of the pathogenetic unity, the hy-
per thyroidal syndrome, is relegated too much to the background. The
same is true as to the statement as to which symptoms must be present, if
we wish to establish the diagnosis of hyperthyrosis, that is, Basedow's disease
in a wider sense. It seems to me suitable to approach this question from
another direction, and to establish what symptom or what symptoms are con-
stant in artificial thyroidism and the earliest to appear. According to our
investigations on this subject it appears that without doubt the cardio-
vascular symptoms, especially the tachycardia, here predominate. To the
tachycardia may be added sweats, or mononucleosis, or psychic excitability,
or headaches, etc. The symptom that occurs twice as frequently is accord-
ing to our observation the greater moisture of the skin, which is absent only
in rare cases. If other symptoms are added to this, we obtain syndromes
such as tachycardia, sweats, headaches, or tachycardia, sweats, tremor, or
tachycardia, sweats, mononucleosis, etc. Hence by this route we come back
to the conception of Char cot and Mobius that just cardiac or vascular disturb-
ances are to be regarded as the cardinal symptom, to which is added in most

BASEDOW'S DISEASE 97

cases the increase in metabolism; with somewhat longer action of the hyper-
thyroidism, tachycardia, mononucleosis, and tremor may well be regarded
as cardinal symptoms. From these symptoms to pronounced exophthalmus
is indeed a wide stride; probably there is added an enormous flooding of
the blood with thyroid secretion; and perhaps other constitutional factors
whose nature is unknown to us. In the fully developed cases we have always
before us a marked condition of excitation of almost the entire vegetative nervous
system. This way of looking at the subject brings us back to Mobius's
view that all the syndromes of Basedow's disease have a common nucleus.
The classic form of Basedow's is characterized only by the more pronounced
accentuation of the eye symptoms, by a more considerable increase of the
metabolic processes, and by its rapid origin, while Stern's Basedowoid ordi-
narily shows from the beginning an insidious course.

From both these forms — the classic form and the forme fruste — is to be
delimited sharply only the Kraus-Minnich goiter heart. The newer in-
vestigations show that here the cardiac disturbances are not of pure hy-
perthyroidal origin, but that the goiter noxus is involved in their coming
about. I shall therefore speak of this form under cretinic degeneration.

Course.- — The classic forms of Basedow's disease as well as the formes
f rustes show the greatest variability in their course. The classic form may de-
velop in the midst of complete health, often in a peracute manner, for ex-
ample, during swimming (Pribram) or a few hours after a tonsillotomy
(Patterson); the condition may again return to normal, with a disappearance
of the eye symptoms, or may lead to death under stormy manifestations (de-
lirium, premortal increase of temperature), or may go over into a chronic form
with remissions and renewals. It can, however, after several years show a
surprising turn toward amelioration, and may eventually heal with the re-
tention of the exophthalmus, which has now become definite; relapses of
this form are frequent; in other cases it leads to severe irreparable cachexia.
The classical form may also begin gradually both in previously normal and
in neuropathically affected individuals, or may show quite the picture of a
forme fruste, and only later develop fully under any determining factor or
without ascertainable cause.

Among the formes frustes are slight abortive cases of sudden onset.
The cases with fat stools and glycosuria are mostly cases of abortive formes
frustes (without eye symptoms). Many of the cases that I observed set in
after trauma, but in the great majority of formes frustes a quite gradual
beginning is the rule; especially in those forms existing on a neuropathic
basis, the forms that Stern designated as Basedowoid, the beginning goes as
far back as youth, and decades may lapse before the disease is to any degree
distinct. In such characteristic cases the trophic disturbances are mark-
edly prominent. It is Stern's great service to have shown that in these
cases there is quoad sanationem a very favorable prognosis. On the con-
7

98 THE DISEASES OF THE THYROID GLAND

trary I cannot agree with Stern that "Basedowoid" cases never go over
into the classic form of Basedow's. It seems to me that the typical Base-
dow's on a degenerative foundation (Stern's degenerative Basedow's) can
hardly be anything else than a Basedow's with acute exacerbations.

The diagnosis of the classic form is easy, differential diagnostic diffi-
culties presenting only in the formes frustes. Alcoholism and nicotinism
may produce tachycardia and tremor; the history or finally the demonstra-
tion of a central scotoma will set the diagnosis right (Chvostek). Fr. Muller
has pointed out the similarity of chronic lead poisoning to the formes frustes.
Here the lead line and the granular erythrocytes will set matters clear,
although I have seen a case of the combination of the two conditions [lead
poisoning and Basedow's]. Difficulties may also attend the decision of the
question whether such Basedow's symptoms as tachycardia, pigmentations,
lability of the vascular system which often accompany such trophoneurosis
of the vegetative nervous system as scleroderma, depend on a simultaneous
hyperthyrosis or the fundamental disease as such. Cassirer further points
out that a slight grade of exophthalmus is often simulated by the sclero-
dermic mask. The presence of a Basedow's struma in four such cases enables
us to speak with probability of a combination with Basedow's disease.
Most difficult is the differential diagnosis from the cardiovascular neurosis
of Chvostek in which occur tachycardia, dermographism, inclination for sweats
and fine-waved tremor. Great lability of the heart manifestations speak
for neurosis, enlargement of the thyroid gland and slight eye symptoms,
heightening of the [metabolic] exchange (v. Noorden) and especially a mono-
nucleosis speak for hyperthyroidism. In many cases, as Chvostek emphasizes,
a certain diagnosis can be first established from the course of the disease.
In persons that come to the physician with complaints as to slight emacia-
tion, nervousness, cardiac palpitations, and psychic excitation, light will
often be thrown on the matter by the fact that they have been using iodine.
For the judgment of the fat stools the evacuation of unsplit neutral fats and
the predominance of finely divided soap balls and fatty acid needles is decisive.
Evidence for the diagnosis of a complicating glycosuria is afforded by the
fact that the true thyrogenic glycosuria usually is of slight intensity and
that with the improvement or the retrogression of the Basedow's symp-
toms it not only disappears, but high or normal tolerance for carbohydrates
reappears very rapidly.

Prognosis and Treatment. — Since the beginning of the operative era in
the treatment of Basedow's disease the question of especial interest has been
whether surgical treatment should supersede the medical treatment. One
has but to consider the great variability in the course of Basedow's disease
to understand that this question can be solved only by great statistical
material. We must therefore bring up the question as to the prognosis
of the cases of Basedow's disease treated purely medically. The greatest

BASEDOW'S DISEASE 99

difficulty lies in the fact that the internist publishes only the severest, be-
cause interesting, cases, and that further, this material comes especially
from clinics and dispensaries, hence from the poorer classes of the popula-
tion; and yet v. Noorden mentions the fact that the course of Basedow's disease
is to a great extent dependent on whether the patient for a long time can
be placed under favorable living conditions until he has had time to regain
his health. The material of the individual statistics is therefore very
dissimilar. All statements by the internists agree on the one point that
in mild forms of Basedow's disease, recovery is the rule, as far as the
patients can spare time for a proper treatment (v. Noorden, Oppenheim,
Pribram, Chvostek, Mackenzie, Murray, Quine, and many others). Special
statements as to the curability of severe cases are not at hand. The state-
ments as to curability are concerned only with the slight and severe forms
together. I mention A. Kocher's statistics (internal cases) 18 per cent.,
Syllaba's 26 per cent., Stern's (of 19 cases, 9 almost cured), Mackenzie's 50
per cent, (very good result), Quine's 60-70 per cent., Klemm's 25 recoveries
among 32 cases. Just as difficult is any idea as to the mortality (death from
Basedow's disease itself, not from intercurrent affections). Saltier has col-
lected the literature that is not too one-sided, and arrives at n per cent.,
Kocher states 22 per cent., Leischer and Marburg, 12-25 Per cent., Mackenzie
estimates the mortality in the acute cases as at 30 per cent., in cases in which
icterus develops, the prognosis is extremely grave. Between these two ex-
tremes— recovery and death- — lie the chronic and more or less improved cases,
concerning the relationship of which to each other the figures again vary
widely. Thus Kocher states 33 per cent, uncured, 27 per cent, improved;
Syllaba 36 per cent, improved, Stern, of 19 cases of classic morbus Basedowi,
6 with slight improvement, 3 uncured. Stern mentions that the improve-
ment may set in even after years. Stern's work is of great practical impor-
tance in so far as it shows that cases on a degenerative-neuropathic basis
progress to full height, rarely die of Basedow's disease itself, and on the
contrary, very rarely recover entirely.

In spite of the quantity of the material, its dissimilarity, as previously men-
tioned, gives no certain result, at least not until according to v. Noorden' s
proposition there are separate statistics as to the disease in the well-to-do
and the poor classes. Before I go into the question of internal treatment I
would like to make a few remarks as to the results of operation. Concern-
ing the method of operation, it should be mentioned that the ligation of
arteries of the thyroid gland has to-day for the most part been discarded, be-
cause unsafe, and that enucleation methods are mostly practised, and some-
times excision and ligation are combined. The resection of the sympathetic,
introduced by Jaboulay, practised especially by Jonnescu and by Abadie, has
found but little vogue. Lately Berard has stated that among 40 operations,
there were 8 complete cures, 5 died at operation, 16 retained a small goiter,

IOO THE DISEASES OF THE THYROID GLAND

5 were improved and 5 remained uninfluenced. The latest statistics of
Kocher include 376 of his own cases, of which 76 per cent, were cured (in one-
fourth of these the exophthalmus was retained). The mortality was 3.9 per
cent., the rest was improved or not cured; one-third of these cases were oper-
ated on more than once before the desired result was obtained. Leischner
and Marburg report 45 cases (without compression symptoms) from v.
Eiselberg's clinic, of which there were 6 cases of death (3 of the first 4 cases
operated on died), 18 cured, 8 improved. Mayo has 4.75 per cent, mortality
in 405 cases and 70 per cent, cures; Schultze (Riedef) reports among 50 cases
72 per cent, cured, 12 per cent, improved, 2 per cent, poor results, 12 per
cent, deaths. Landstrb'm reports among 38 cases 52.6 per cent, cured, 18.4
per cent, improvement, 29 per cent, poor result, among which 5.5 per cent,
death. I shall not enter into the older compilations, they are less valuable,
as the methods of operation have improved since their time and also the
indications for operation have changed somewhat. [See the tabulated list of
operative results in the addendum to this chapter.]

If we consider that among the cases operated on just the mild cases seem
to be rare from the better situated classes, that therefore the surgical statistics
contain the especially severe cases, there is no doubt that all the surgical
treatment in general surpasses the medical. To this should be added that
after the operation the tachycardia usually diminishes; in a relatively short
time, the body weight rapidly increases, even without hospital care, and
working capability is rapidly attained. The difficult point of the question
to-day is concerned with the indications for operation. Mild cases among the
better situated classes should indeed not be recommended operation, nor
should the chronic formes frustes on a degenerative-neuropathic basis (Stem's
Basedowoid). Also Kocher points out that the results in these cases are less
satisfactory. Operation is indicated in cases with compression symptoms.
In the cases of pure Basedow's the social status should be decisive, because,
as already mentioned, without doubt, operation leads more rapidly and
certainly to working capability. A certain risk is always associated with
operation, especially if a status thymico-lymphaticus is present. According
to the statistics of Capelle, already mentioned, nearly 100 per cent, of the cases
of Basedow's disease that died at operation had a hyperplastic thymus.
Hotz therefore proposed to avoid operation if the X-ray transillumination
shows a shadow [indicating an enlarged thymus gland]. The demonstra-
tion of an enlarged thymus gland by means of the Rb'ntgen procedure is
however very uncertain. Kostlivy believes that the operation is especially
dangerous in the cases without mononucleosis. This does not however meet
with my view, because mononucleosis in the one and the same case may vary
greatly (vide ante). All these questions have not as yet been worked
out fully.

Another question is as to whether one should operate early, or should await

BASEDOW'S DISEASE IOI

the results of internal therapy. A long period of awaiting is at all events
unsuitable if the cardiac manifestations are well pronounced, as operation
represents so much the less result the broader the cardiac dilatation and the
more advanced the degenerative alterations of the cardiac muscle and of the
other organs. On the other hand Kocher recommends a medical pretreat-
ment as preferable, as far as no indicatio vitalis does not make an immediate
operation necessary.

Of late a lively discussion has arisen concerning the reliability or the value
of the irradiation of the thyroid gland with the X-rays. This was dis-
covered by Beck, first used in Germany by Gorl, and is warmly recommended
in Vienna by Holzknecht and G. Schwarz. Schwarz has reported 40 cases in
which after the irradiation the nervous symptoms always disappeared, and
the tachycardia almost always; in two-thirds of the cases there were gains
in weight, in about half the cases the exophthalmus retrogressed; only in one-
third was the struma decreased in size. The cases that Holzknecht later re-
ported showed a similar good result, v. Eiselsberg points out, however,
that in three of the cases that had been treated with X-rays and that
he operated on later, he found adhesions of the thyroid gland to the neigh-
boring parts; on account of this the operation was essentially more difficult.
Also Hochenegg reports three similar cases. It does not seem to me a priori
that such adhesions are to be referred exclusively to the X-ray therapy.
Kocher mentions especially that the operations of Basedow's strumas are
made especially difficult through an especial density of the peristrumal con-
nective tissues, by adherence of the external goiter capsule to the struma,
in short by alterations that are similar to those of a chronic inflam-
mation and are often found in strumas after a long treatment with
iodine salve; on the other hand it is to be expected that there are tissue
reactions to X-ray illumination that especially favor the development of
such adhesions and that the fragility of the blood-vessels constitute a
danger. In the discussion that followed Holzknecht 's presentation in the
Wiener Gesellschaft fur Arzte [Vienna Association of Physicians], v. Noorden
and v. Strumpell assumed an expectant attitude with regard to X-ray therapy,
while v. Wagner and Chvostek condemned it. In a number of cases that I
published from the first medical clinic since that time I have seen a right good
result as the consequence of X-ray therapy.

I quote the following example: In one case the spontaneous glycosuria disappeared
from the day of the first irradiation, in another case the weight curve, which in spite of
week-long hospital treatment had continually sunk, began to rise only a few days after
the first irradiation, the diarrheas disappeared, and after a few weeks the patient could
again resume his studies as technician.

As far as the internal treatment of Basedow's disease is concerned, it must
be sorrowfully said that all attempts to find a specific method of treatment
have up to the present not led to certain results. Ballet and Eniquez first

102 THE DISEASES OF THE THYROID GLAND

used for therapeutic purposes the serum of thyroidectomized animals,
Bunghart and Blumenthal the serum of myxedema patients, Sorgo the meat
of thyroidless herbivorous animals. Mb'bius used the serum of thyroidless
animals (antithyroidin, Merck's preparation) or thyroidectin (Parke, Davis
&• Co.), Lanz used the milk of thyroidless animals (Rodagen-milk powder of
thyroidless goats' milk sugar). Lepine obtained an "immune serum" from
the feeding of thyroidin to goats. Finally we must mention the thyro-
toxic serum of Beebe. v. Mikulicz recommended the feeding of thymus sub-
stance. All these therapeutic propositions were for the most part greeted
in the beginning with enthusiasm, but improvement was seen only in the
light cases, in which the amelioration could not be attended with certainty by
the means employed. In recent years to have the statements as to favor-
able results become always sparser. The scepsis is the more justified for the
reason that all authors who have investigated the influence of thymus, rodagen,
or antithyroidin serum on the metabolism have been able to elicit only nega-
tive results (Magnus-Levy, Stuve, Salomon). — A. Kocher recommends neutral
sodium phosphate (up to 6 gm. per day), which should prevent the dissemi-
nation of the iodine-containing substance from the thyroid gland. Views
do not agree as to the value of this means of treatment. Otherwise medical
treatment seems to fail almost always. All authors are, for example, of the
opinion that digitalis rather aggravates the cardiac conditions. Also the
diarrheas and vomiting are but little influenced by drugs.

v. Muller and Saxl proceeding from the experimental elicitation of Loeb,
and of Frohlich and Chiari that calcium exercises a dampening influence on
certain conditions of irritation of the nervous system, have used in Basedow's
disease intramuscular injections of calcium chloride gelatine (5-7 cc. of
Merck's preparation "Kalzine"). They found in the typical cases mostly
an essential improvement, while the treatment usually seems to fail in the
case of an heredito-neuropathic basis.

The dietetic and physical treatment of Basedow's disease still occupies the
central place of internal therapy. Most important is rest, in the severest
cases rest in bed and the avoidance of every excitement, combined with the
dietetic treatment; beneficial is the action of slight hydro therapeutic pro-
cedures, such as were first recommended by Winternitz, eventually slight gal-
vanization and faradization of the sympathetic, especially in strumas rich in
blood-vessels, and the air of heights (600-1000 m.). Now a few words as to
dietetic treatment. In the first place this must tend to prevent loss of
weight and to enable gain in weight. As in Basedow's disease there exists an
increased exchange, it was believed that this could be made up by an abun-
dance of protein food. On the basis of our own investigations we were how-
ever compelled to accept the idea that administration of protein increases the
secretion of the thyroid gland. With this stands in harmony the fact that
on administration of meat in experiments, we can make the thyroid gland

ATHYROSIS OR HYPOTHYROSIS 103

extremely poor in iodine, thus bringing the stored secretion into the cir-
culation on account of the greater need. I refer once more to the experi-
ments of Rudinger carried out on the basis of these convictions, which
showed that on almost protein-free diet, very rich, however, in carbohy-
drates, we can depress the increased exchange to the normal. When there-
fore we administer abundant nitrogen-free energy carriers, we do not have
to fear a loss of protein. From such a diet should be expected not only
a favorable influencing of the body weight, but also a certain mitigating in-
fluence on the hypersecretion of the thyroid gland; to which must be added
that such a diet oppresses the least the gastrointestinal tract. As important
as must be our endeavors to increase the body weight in Basedow's, not the
less important is the avoidance of overfeeding (v. Noorden), as the improvement
of the cardiac activity does not keep pace with the increase of weight, and
cases are known in which the increased demands on the heart, in consequence
of the increase of weight, led to a sudden collapse.

b. Athyrosis or Hypothyrosis

Historical. — The first experiments as to the influence of extirpation
of the thyroid gland on the animal organism originated with Schijj. To
about the same time belong also the first clinical descriptions of myxedema
on the part of Gull, Ord, and Char cot. Gull, in 1873, described five cases of
"A Cretinoid State supervening in Adult Life in Women." Ord, in 1878,
was the first to designate such cases as "myxedema." ' Charcot, in 1879,
called the attention of the French to this clinical picture, terming it "cachexie
pachydermique." The demonstration of the connection of this disease with
the absence of thyroid function was furnished in 1882 and 1883, by Th.
Kocher and Reverdin. In the period that followed this, thought was rendered
confused by the fact that the symptoms following upon the removal of the
parathyroids together with the thyroid were attributed to the absence of the
thyroid. Investigation distinguished between acute and chronic cachexia
thyreopriva. Only at the end of the nineteenth century did the clinical
pictures of athyrosis assume stabile forms, through the detachment of the
symptoms due to the absence of the parathyroids (Gley, Vassale andGenerali,
Erdheim, Pineles, Biedt). About this time, too, Hertoghe called attention
to the mitigated forms of athyrosis. To-day one of the hardest problems
is the relation of myxedema to cretinic degeneration. Although the fact that
congenital absence of the thyroid as well as a severe disease of this organ
in early life (infantile myxedema) had been established by animal experi-
mentation and the recognition of the significance of thyroaplasia by Pineles
in 1902, the careful analysis of the clinical manifestations between sporadic
and endemic cretinism permit a recognition of far-reaching differences.
Among these is the fact that in the first condition thyroid therapy is always

104 THE DISEASES OF THE THYROID GLAND

successful, in the latter it sometimes fails. While we must ascribe certain
of the important symptoms of endemic cretinism to thyroid insufficiency,
ma'ny facts speak for the separate position of this illness.

I shall first describe those clinical pictures that develop through the failure
of the thyroid-gland function in the fully developed organism because here
the relations may be supervised more readily.

i. Myxcedema Adultorum or Cachexia Thyreopriva Adultorum

Definition. — This condition, resulting from the absence or insufficiency of
the function of the thyroid gland in the adult organism, is characterized by
the diminution of all vital processes and by certain trophic manifestations. The
diminution affects the vegetative functions as well as the psychic life. There
is found slowing of the entire metabolism and diminution of the excitability of
the whole vegetative nervous system. The trophic disturbances affect especially
the ectodermal tissues, skin, hair, nails, and teeth, although almost all organs may
show regressive metamorphoses, especially the vascular system, which tends to
be the seat of a premature arteriosclerosis.

Occurrence. — Spontaneous myxedema of adults is a rare disease that is
found somewhat more commonly in England and Holland [than on the conti-
nent]. In goiter districts typical myxedema seems to be relatively rare.
Hereditary and familial occurrence is described by some authors (Maclll-
waine, Ewald, et al.).

Symptomatology.- — I begin with the description of the alterations in the
skin, the most important of which has furnished for the disease its name
myxedema. The myxedematous swelling may affect the skin of the entire
body; it shows, however, a predilection for certain sites, the cheeks, lids,
nose, supraclavicular fossae, neck, backs of the hands and feet. The cheeks
become yellowish in color, but on account of small venectases are colored
bluish-red in the middle. The nose and lips are also of this bluish-red
color. On account of the swelling of the eyelids the palpebral fissures are
much narrowed, and the deficient play of the features makes the expression
of the face rigid and sleepy. In the supraclavicular fossa? develop thick
cushions or pads that feel granular to palpation. The cushion-like swelling
of the backs of the hands and feet make the extremities appear claw-like.

For the most part the swelling invades also the mucous membranes, the
mucous membrane of the mouth assuming a whitish color, while the par-
ticipation of the mucosa of the larynx leads to alterations of the voice; this
becomes harsh and, according to Magnus-Levy, singing becomes impossible.
The swelling of the uvula and the tonsils makes nasal breathing impossible;
the patients breathe with open mouth and snore at night. The Eustachian
tube and the tympanic cavity may also become involved by the swelling,
causing a diminution in hearing- ability; and finally the female genitalia
and the anus may become swollen. The tongue increases greatly in volume,

MYXEDEMA 105

so that it becomes visible between the rows of teeth, and shows impressions
of the teeth. The increase in volume depends not only on the swelling of
the lingual mucosa but also on alterations in the more deeply lying parts.
Histological examination shows alterations of the muscle fibers and increase
in connective tissue; the latter contains numerous nuclei and numerous new
formed capillary vessels. The tongue papillae, too, become hypertrophic
(Maccone) .

The myxedematous skin looks like alabaster. It feels elastic, pressure
with the finger evinces no pitting. It is dry and scales very much; the scales
are mostly clayey. Stevenson and Halliburton ascribe the clay-like texture
of the skin to the increased contents in mucin. They found the mucin-
contents also increased in the salivary glands and tendons. Halliburton
found in the blood and in the parotid of thyroprivic monkeys that the albu-
minous bodies precipitating to acetic acid amount to 3 per cent., while they
were not demonstrable in the blood of normal monkeys. Munk also
found mucin in the parotid secretion of a case of myxedema described by
Mendel. But other authors found that the mucin-contents of the myxede-
matous skin was not increased, while Bournemlle maintains that in the
investigations just mentioned it is not certain that the substance dealt
with was mucin, as in his investigations no reducing substance was yielded
by decomposition by means of acid. The microscopical investigation of the
myxedematous skin shows nuclear proliferation and new formation of 'con-
nective-tissue fibrils, especially around the sweat-glands and.sebaceous glands
and around the hair follicles (English Myxedema Commission, Virchow).
Unna found in skin of myxedemics substances that stained similarly to
mucin, while v. Wagner and Schlagenhaufer found them in the skins of
endemically cretinoid dogs and thyroprivic goats. A substance similar to
mucin could also be observed (Halliburton and Scholz) in other organs, such
as the kidney, the muscles, and the brain. That presence of this substance
similar to mucin was missed by certain authors has perhaps its explanation
in the fact that the accumulations of this substance are subject to much
variation, and in cases of long standing they sometimes disappear. The
skin then regains a flaccid lax texture and, in contradistinction to typical
myxedematous skin, can be moved about on the underlying tissue.

Pigmentations of the skin occur relatively rarely.

The hair of the head and beard, the eyebrows, the axillary and pubic
hairs become dry and brittle, and often, in part, fall out. On the skull
then develop large bald spots, that may lead to complete baldness. The
nails become dry and cracked, the teeth become carious and fall out, and
in the case to be described (Observation XII) the crowns of the teeth, in the
course of the year that the myxedema had existed, had ground off entirely.
The incisor teeth consisted of only short stumps provided with broad grind-
ing surfaces.

io6

THE DISEASES OF THE THYROID GLAND

The circulation is sluggish, the body temperature reduces, the patients
are chilly, and can warm themselves with difficulty. The pulse is small
and weak and slow — often only 50 to 60 beats a minute are observed.
On body movements, dyspnea readily occurs.

FIG. 10. — Postoperative myxedema.

The excitability of the entire vegetative nervous system and especially that of
the nerves regulating the heart is diminished.

I here quote the clinical history of two myxedema patients in whom
experiments were made as to the excitability of the vegetative nerves.

Observation XI. — Karoline K., sixty-four years, single. Entered clinic Nov., 1913.
One uncle and one aunt on the mother's side suffered with struma. As a young girl the

MYXEDEMA 1 07

patient had a large neck, and of late years this has increased, producing difficulty in swal-
lowing, difficulty in breathing, and indeed attacks of suffocation, on which account the
patient was operated on in June, 1909. Nine days after the operation the patient was
entirely well. In March, 1910, the hands and feet began to swell, the condition being
taken for rheumatism. In the summer of 1910, myxedema was diagnosed, and an order
given for thyroid tablets. Under this treatment the swellings retrogressed, but the
patient became thin (loss of weight of 9 kg. in five weeks) and developed a marked tremor.

At present are seen swellings of the backs of the hands and feet, of the supraclavicular
fossae, and also of the face, especially in the vicinity of the eyes. The pulse is about 70.
The skin is dry to the touch.

o.oi gm. pilocarpine subcutaneously; after one-half hour slight flow of saliva, no
sweat.

100 gm. grape-sugar, no dextrose in the urine.

150 gm. grape-sugar, no dextrose in the urine.

Leucocytes, 6200, of which:

Polymorphonuclear neutrophiles, 62.6 per cent.

Eosinophiles, 5 per cent.

Lymphocytes and large mononuclears, 32.4 per cent.

After the instillation of homatropine into the eye, mydriasis occurs after about forty-
eight hours.

A fully normal sella turcica to Rontgen examination.

In addition to the myxedematous manifestations are present slight signs of a primary
chronic articular rheumatism (dry form).

Moderate constipation.

Observation XII. — Schw. F., thirty-eight years, entered September, 1910. First men-
struated at twelve years of age. The flow was always regular and abundant. Two
labors; since the last (eight years ago), which was followed by a hemorrhage, the menses
have ceased. Since this time very poor appetite, patient always constipated. For one
year the hands and feet often seem as if asleep, sensation of cold, formication in hands
and feet. Speech has become slower. Often vertigo. Status: Skin pale, thickened and
dry to the touch, hands cool, hairs thinned out and dry. Teeth small and loose, the
chewing surfaces much worn down, so that the teeth are reduced to about one-half
their length. In the axillae and on the pubis the hairs are entirely absent. The facial
expression is slightly catatonic, both lobes of the thyroid are palpable, internal genitalia
atrophic, blood-pressure very low (between 60 and 70, Gartner), o.ooi gm.1 adrenalin
subcutaneously; no glycosuria, no increase in blood-pressure.

100 gm. dextrose by mouth and at the same time 0.002 gm.1 adrenalin subcutaneously;
no glycosuria.

o.oi gm. pilocarpine; no salivation, sweating very slight. Slight increase in blood-
pressure.

Erythrocytes, 3,500,000.

Hemoglobin, 70 per cent.

Leucocytes 7000, of which:

Polymorphonuclear neutrophile, 52 per cent.

Lymphocytes and large mononuclears, 42 per cent.

Eosinophiles, 6 per cent.

After the instillation of homatropine, mydriasis occurs after about thirty-six hours.

From the middle of October, thyroid tablets. At the beginning of November swelling
of the face has disappeared, the skin about the eyes and on the clavicles very loose,
facial expression very much livelier, hands now warm and less cyanotic.

1 German edition states mg. [ = milligram]; evidently gm. is intended. — Editor.

io8

THE DISEASES OF THE THYROID GLAND

A diminution in the excitability of the vegetative nervous system is
demonstrated also by the experimental investigations in thyroidless animals.
i'. Cyon found a diminution of the excitability to electrical stimulation of
the vagi nerves in such animals. The hyperexcitability of the accelerator
nerves that he asserted to be present could not be confirmed. It is far more
likely that the excitability of the sympathetic nerves is diminished. For
this view speaks the failure of the glycosuric action of adrenalin in thyroid-
ectomized animals and in myxedema patients. As regards the diminution
of the pressor action of adrenalin we (Eppinger, Folia, and Rudinger) did not
arrive at a certain result; while on the contrary, later investigations of
Bertelli and myself show definite alterations in the reaction of the vascular
system of thyroidless dogs against adrenalin.

As I regard the experiments important, I shall quote them in extenso.
15 kg. dog, ten days ago total extirpation of the thyroid gland with
avoidance of the parathyroids. Electrical excitability remains unaltered.

Erythrocytes

Hemoglobin

Specific gravity

Before the injection

5 hours after the infusion of 3.69 mg. adrenalin
24 hours after this

4,900,000
4,100,000
3,936,000

45 per cent.
45 per cent.
45 per cent.

1054
1050
1051

Dog, 16 kg., total extirpation of the thyroid six weeks ago. Electrical
excitability remains unaltered.

Erythrocytes

Hemoglobin

Specific gravity

Before the injection 5,056,000

60 per cent.

1050

i}-£ hours after infusion of 3.69 mg 5,932,000

65 per cent.

1055

5 hours after 5,680,000

63 per cent.

1055

72 hours after 5,016,000

55 per cent.

1052

According to investigations of Bertelli, Schweiger, and myself, the erythro-
cyte count in normal dogs after the injection of adrenalin increases extra-
ordinarily rapidly; after ten minutes it may reach 40 per cent., after five
hours 70 per cent. In an experiment in which 4.36 mg. adrenalin was
injected, it reached 100 per cent, after twenty-four hours; in another
experiment after 3.69 mg. the hyperglobulia was indeed distinct, but had
already begun markedly to decline. Although of course there occurred indi-
vidual differences in the intensity and duration of the reaction, there was to
be observed in all normal dogs a distinct rise. The hemoglobin contents
showed a very much less increase. The specific gravity regularly showed a
slight increase.

While, then, normal animals show after injection of adrenalin a high-
grade hyperglobulia, in the production of which there is surely concerned,

MYXEDEMA IOQ

in addition to alterations in the permeability of the endothelium of the blood-
vessels, also the pressing out of plasma on account of the long-continued
contracted condition of the vessels, this manifestation was absolutely lacking
or was essentially weaker in the thyroidless dogs. In this respect, individuals
without thyroids show similarity to individuals with cachexia, who, as is
known, do not react with hyperglobulia to the use of the lung suction-mask,
or to sudden transference to great heights.

The autonomous nerves too show a diminution of their tonus and their
excitability, v. Cyan observed, as already mentioned, a diminution of the
electrical excitability of the vagi. The miotic action of pilocarpine in thy-
roidless dogs lasts for a shorter time (Eppinger, Falta, and Rudinger). The
observations of Asher have already shown that in dogs with thyroid insuffi- ,
ciency the mydriatic action of atropine lasts for an abnormally long time.
Hence the autonomous nerves are more readily paralyzed than under nor-
mal relations. Also in blood-pressure investigations on thyroidless dogs
Rudinger and / observed that ruling out of the vagi through atropine lasts
extraordinarily long. Finally, in some cases of myxedema I could estab-
lish an abnormally long mydriatic action on the instillation of homatropine
into the eye (confer the analogous experiments in sporadic cretinism).
Fleischmann observed that the blood of normal animals destroys the activ-
ity of added atropine more rapidly than the blood of strumous animals.

The previously mentioned alteration in the reaction of the vascular endo-
thelium to adrenalin depends perhaps on the disturbances in nutrition, and
these could be the cause of the premature arteriosclerosis of thyroidless
animals, such as Eiselsberg, Pick, Pineles, and others have described. Also in
myxedema patients we frequently find striking grades of arteriosclerosis
and depositions of lime salts, the latter even in other organs, such as the
kidney, liver, etc. (Abrikosojf) . Finally also in thyroaplasia has high-
grade atheroma been found in the aorta and other vascular territories
(Bournemlle, Maresch, Machand, Heyn, and others). The occurrence of arlerio-
sclerotic alterations in thyroid-gland insufficiency has been brought forward
as the explanation of the senile degeneration. Horsley first pointed out that
the thyroid gland in old age becomes atrophic, Vermehren compares old age
with a chronic myxedema, while in more recent times Lorand has elaborated
on this view. In opposition to this, Ewald has already shown that in maras-
mus senilis there is initiated not only an atrophy of the thyroid (and the
other ductless glands) but also a degenerative atrophy of the other organs,
especially the gastrointestinal tract. At all events, we should not use thy-
roid medication in old age uncritically (v. Noorden).

The diminution of the tonus or the excitability of the vegetative nerves
is spoken for also by the failure of the sweat secretion in myxedema patients.
The secretion of sweat may fail entirely on bodily movements, or even when
there exists high external temperature. Mann observed that in myx-

IIO THE DISEASES OF THE THYROID GLAND

edemics infusion of jaborandi did not bring about secretion of sweat. I,
too, observed, in the above-mentioned cases, after pilocarpine injection
only slight salivation and no or only minimal sweating. In myxedema there
is also a diminution of the function of the sebaceous glands (deficient oiling
of the skin and hair) . I have not been able to find in the literature statements
as to the secretion of gastric juice or pancreatic juice.

To a slight tonus of the autonomous nerves points the high-grade atony
of the intestines that is the cause of the well-known obstipation of myxedema
patients. Defecation in well-developed cases, if purgatives be not employed,
may not occur for two or three weeks.

Almost constantly do alterations of the psychic functions accompany
myxedema. The English Myxedema Commission found the apathy char-
acteristic of myxedema absent in only three of one hundred and nine cases.
This may develop relatively early, and in the light cases may consist only
in a sluggishness of the previously mentally and bodily active patients,
in a retardation of the psychic functions, in an inability to form rapid conclu-
sions and in a slowing and monotony of the speech. According to Magnus-
Levy, in light cases the "capability of reacting to strong stimuli" is for the
most part not lost. In more well-developed cases there is a complete dullness,
the patients brood, and there exists marked desire for sleep. The speech
may be markedly slowed "als ob die Sprachwerkzeuge eingefroren waren"
[as if the speech-mechanism were frozen in] (Meltzer). Char cot compares
such patients to hibernating animals. In such individuals, too, the intellect
tends to deteriorate and the memory, especially that for recent occurrences,
is lost.

In such high-grade cases there are rarely lacking, in addition to this
decided apathy, signs of a more deeply seated mental disturbance. Already
at the beginning of the myxedematous disease or in the formes frustes are
hallucinations commonly present, concerning which, as Murray says, the
patient does not willingly speak.

The English Myxedema Commission found among the myxedema patients
investigated by them illusions 18 times, hallucinations 16 times, and a
frank psychosis 16 times. The psychoses belong to various types, although
the melancholoid conditions predominate; and may of course consist only of
a combination with myxedema. Very commonly, however, they stand in an
intimate relation with myxedema in this respect — that through the myxedema
a previously existing predisposition becomes manifest. In these cases the
symptoms of the psychosis develop simultaneously with those of the myxe-
dema and vanish after thyroid therapy has been instituted, to reappear
again when the therapy is discontinued. Such a case has been described by
Pilcz. In many cases, especially at the beginning, the inhibition is suddenly
interrupted, and the condition may transitorily go as far as excitation.
Horsley distinguished between a neurotic stage that occurs at first, and a

MYXEDEMA III

myxedematous or cretinoid stage, although this distinction may have
been influenced by the tetanoid manifestations after thyroid-gland extirpa-
tion which at that time were ascribed to the absence of the thyroid.

Other coarse disturbances that are routinely looked for on the investiga-
tion of the nervous status are not as a rule found. The reflexes are for the
most part normal, only rarely are they increased or diminished. Not
rarely the patients complain of paresthesias and of rheumatic pains. The
test for sensibility for the most part normal, at the most it has been
stated that slowing of conduction is present, although this finding is by no
means constant. It has been recognized that testing of sensation is hard to
carry out in heavily apathetic patients. The same holds good for tests of
the smell, taste, and hearing. Most common of these disturbances are those
of hearing. These were found by the English Commission in almost half of
the cases it investigated. The cause for them has not as yet been certainly
ascertained. Wagner v. Jauregg assumes that they are produced by myxe-
dematous swelling of the mucous membrane of the tympanic cavity and the
tube. It is, however, often very hard to determine what part the lessened
power of apprehension of the central apparatus and the lacking appercep-
tion plays in this; in any case it is significant that the disturbances of hearing
react promptly to thyroid medication.

The conductivity of the skin for the electric current is diminished on
account of the high degree of dryness. Authorities also state that in many
cases there is diminution of the electrical excitability of the nerves and
muscles. In one case Erb found it normal. Rudinger and myself found
an appreciable diminution of the galvanic excitability of the nerves in
thyroidless dogs. The investigation was conducted three months to one and
one-half years after extirpation of the thyroid. Instead of the normal value
of 1.2-1.5 milliamperes we needed 2-3 milliamperes in order to produce (test
of the sciatic nerve) a cathodal closing contraction. In one case of myxedema
Erb found a slow twitching of the muscle to mechanical irritation. The
motor processes, too, are conducted slowly. The movements are extremely
slowed, the gait heavy, slow, and slightly staggering. One of the early
symptoms is a rapid tiring, only on the longer duration of the disease is the
motor power diminished. The cause of all alterations in function of the
central and vegetative nervous system lies in nutritive disturbances. Walter,
and Marinesco and Minea found in thyroidless dogs a slowing of degeneration
and regeneration of the nerves.

There is not much known concerning alterations in the osseous system
in myxedema. Stubenrauch describes in a case symmetrical changes of
the bones and joints of the feet. Both first interphalangeal joints were
destroyed, the middle and end phalanges showed in part abnormal transpar-
ence and in certain places direct loss of substance. In the absence of further

112 THE DISEASES OF THE THYROID GLAND

observations, we should be cautious about bringing such alterations into
relationship with myxedema.

The examination of the blood shows decrease of the red cells, and es-
pecially of the hemoglobin, the latter to 60 per cent, or even 40 per cent.;
also decrease in the dry residue and increased coagulability (Bultschenko and
Drinkmann, Kottman). The leucocytic formula is altered, consisting in
mononucleosis and mostly hypereosinophilia (Bence and Engel, and the
author) .

In many cases are observed erythroblasts and slight poikilocytosis,
in others also Turk's irritation forms and myeloblasts. In one of the cases
herein quoted were found indeed isolated myeloblasts. Similar blood changes
are also found in thyroprivic animals (v. Eiselsberg, Zitschmann, Kishi,
Esser, Bertilli's investigations on our own dogs). The anemia quickly
ameliorates on the administration of thyroid-gland substance, and there
occurs a "paradoxical" reaction of the leucocytes, i.e., the leucocytic formula
approaches the normal, while in healthy individuals it is known that thy-
roidin produces mononucleosis (Falta, Newburgh, and Nobel}. More recent
investigations of Fonio agree with these; interruption of the thyroid-gland
therapy for the most part brings about a recurrence of the mononucleosis
(von Korczynski} , while the poverty in hemoglobin also is essentially amelio-
rated by the thyroid-gland therapy.

The metabolism of myxedemics is reduced to a marked degree. We are
indebted to Magnus-Levy for the discovery of this. He found a reduction
of the fundamental exchange to 58 per cent. Treatment with thyroidin
brings the fundamental exchange to normal or supernormal figures.

If the thyroid-gland therapy be interrupted, the amount of oxygen con-
sumed gradually sinks as the clinical symptoms recur. Also the twenty-
four-hour exchange is reduced, that is, myxedemics maintain an equilibrium
with a much less amount of calories and take on fat more readily than
does the normal individual.

Sometimes accumulations of fat are found at entirely abnormal sites.
Thus Abrikosoff found in a fifty- two-year myxedematous woman accumula-
tions of fat in the lingual mucous membrane and in the submucosa of the
intestine. If myxedemics are nourished abundantly, the twenty-four-hour
exchange does not necessarily have to be below normal, and thyroidin
administration will then produce an enormous increase in the caloric pro-
duction. Steyrer found in his case an increase of 83 per cent, (investiga-
tion in Voit-Pettenkofer's apparatus) . Especially fat is concerned, while the
number of calories from protein is rather less than normal. Again, the pro-
tein exchange lies low, the protein requirements are light, and there may
be an addition of protein to the body. The relations in investigations as
to the hunger protein exchange are very clear. In thyroidless dogs we
found this distinctly reduced.

MYXEDEMA 113

The time consumed in the protein destruction in thyroidless dogs is,
according to the investigations of Pari, not altered. Administration of
thyroidin leads, in the wake of the consumption of myxedematous tissue, at
first to a significant increase of the nitrogen excretion, this giving place to
normal relations. The relations of the salt metabolism in myxedemics is
not as yet fully explained; it is to be expected that the need for salt is slighter
and that less calcium is cast off in the feces, as the administration of thy-
roidin allows more calcium to pass out through the intestine. The amounts
of urine in myxedemics as a rule are very small. Often slight albuminuria
is found, that may probably be attributed to nutritive disturbances in the
kidneys.

The assimilation limits for grape-sugar, in myxedemics, is raised (Hirschl,
Knopf elmacher). Hirschl found no glycosuria even after the administration
of 500 gm. of dextrose. Also in thyroprivic dogs the administration of sugar
(up to 200 gm.) does not lead to glycosuria, although in dogs the assimilation
limits lie relatively low. In thyroprivic dogs the glycosuric action of
adrenalin is reduced (Eppinger, Falta, and Rudinger, Pick and Pineles).1
Myxedemics show the same relation.

In a case of Herz's the administration of dextrose with the simultaneous
injection of adrenalin did not lead to glycosuria. I found the same thing in
the case described above (Observation XII) (100 gm. dextrose together
with the simultaneous administration of 2 mg. adrenalin subcutaneously).
After a long-continued thyroidin medication the relations become normal
again. In the case of Herz, after successful thyroidin treatment, traces of
sugar appeared in the urine after only 100 gm. of dextrose. Adrenalin now
again produced glycosuria.

The inclination to glycosuria can also remain after the withdrawal of
thyroidin treatment. As example I quote the following case:

Observation XIII. — Rosa L. Entered the clinic June, 1895, then fifty-two years old.
From the history taken at the time, three confinements, first menstruation at the age of
fifteen years. After the confinement the menses were irregular and sparse, and ceased
three years ago. Then abdominal pains, jaundice, followed by a marked swelling of the
neck that gradually retrogressed again. Since that time there has gradually developed,
especially since the winter of this year, the following disease-condition; great languor,
rapid fatigability, rheumatoid pain, swelling of the upper and lower extremities, the
face, the eyelids, hoarseness of the voice, constipation and distention of the abdomen,
bloated condition of the face, swelling of the lips, tongue, and eyelids. The swelling of
the tongue and lips is so intense that it hinders eating. There are subjective sensations
of cold, especially on the back. Often severe headaches, sensation of vacancy in the head,
and feeling of anxiety.

From the status: Skin of the extremities and on the abdomen thick, cool, and cyanotic.

1 The alimentary glycosuria that is observed in thyroparathyroprivic dogs (Falckenberg,
R. IlirscK) is to be ascribed to the absence of the function of the parathyroids. (Confer also
Falta and Rudinger.)

114 THE DISEASES OF THE THYROID GLAND

There are present on the upper and lower extremities, and in part on the trunk, signs
of ichthyosis. The face, and especially the eyelids, are swollen out, so that the skin in the
vicinity of the eyes is markedly wrinkled. The facial expression is exquisitely sleepy,
the forehead transversely wrinkled so that an astonished expression is produced; the hairs
are dry and very much thinned out (of late years especially have fallen out). Face
somewhat markedly pigmented, lips protruded in a somewhat snout-like manner, the
teeth for the most part are missing or are loose. In both supraclavicular fossae slight
cushion formation. On the left the lateral lobe of the thyroid somewhat palpable.
Great drowsiness, and slowness of all movements. Speech very slow. Weakness of
memory. Gait awkward, dragging. Great fatigability. The patient was given at times
thyroidin tablets, which however produced cardiac palpitations and turned the constipa-
tion into diarrhea. However, under this treatment the swellings disappeared very rapidly.
In 1897 she tried thyroidin tablets, without deleterious effects. She took them ordinarily

FIG. ii. — Case of myx edema with tendency to glycosuria.

for about fourteen days, during which time she lost weight rapidly, then she would dis-
continue them for about four weeks, until the pockets on the eyelids and the thickenings
on the abdomen appeared again. In 1895 the patient was almost bald; later the hair
grew again and at present she has a growth of hair about usual for a woman of her age.
She perspires hardly at all. For two months she has again discontinued the thyroidin
medication, and all the above-mentioned manifestations have recurred to an exaggerated
degree. After 100 gm. of grape-sugar the patient shows a distinct although not very
strong glycosuria; sharply delimited cyanosis of the cheeks.

There is indeed no doubt that since the year 1895 the patient has suffered from a
typical myxedema. Perhaps at that time a thyroiditis appeared together with the
jaundice, which gradually led to insufficiency of the thyroid gland. The combination with
ichthyosis had been often described by French authors. From the beginning, the case
showed no high tolerance for thyroidin, although there was already present a myodegen-
eratio cordis. I can readily appreciate that in such cases palpitations can occur even
when the doses are not too high.

The observation that the alimentary glycosuria resulted positive, in spite of the two
months' cessation of thyroidin medication, points to the fact that here, in addition to the
thyroid gland, the pancreatic insular apparatus is also degenerated.

MYXEDEMA 115

In this case I prescribed small doses of thyroidin, and at the same time hypophysis
tablets, as I suspected a degeneration of the glandular portion of the hypophysis also.
I need only mention the fact that this medication was borne for several months without
calling forth the previous cardiac distresses, and that thereby the recurrence of the myxe-
dema symptoms was prevented. The puffiness on the neck and face had disappeared,
the scaling of the skin which has existed for eighteen years has disappeared, the skin has
become smooth and elastic, the itching has ameliorated; only the brittleness of the nails
has remained unaltered (communication by letter).

The explanation for the simultaneous existence of myxedema and an
inclination to glycosuria that I sought in this case would serve also for any
case that under thyroid therapy proceeded to spontaneous glycosuria
(Macfie Campbell, Bramwell, Ewald, Osier, et al.}, or that without thyroid
therapy showed a tendency to glycosuria (Gamier and Lebret). Also com-
binations of myxedema and diabetes are observed, but indeed appear to be
very rare. The case of A pert was that of sporadic cretinism with distinct
myxedematous manifestations. In this case growth ceased only at the age
of thirty-six years. Later, diabetes appeared. I believe that it is intelligible
that absence or insufficiency of the function of the thyroid leads to hyperfunc-
tion of the pancreatic insular apparatus only when this is capable of function-
ating. If the pancreas itself is diseased, diabetes may occur, even when the
thyroid fails. This is shown by the experiments of Eppinger, Rudinger, and
myself on the pancreatic diabetes of thyroidless dogs. If, however, myxe-
dema is superadded to an already present glycosuria, the glycosuria tends
to disappear. Thus v. Noorden reports fourteen cases of endogenous obe-
sity, of whom seven formerly excreted slight quantities of sugar. With
the development of the forme fruste of myxedema the sugar disappeared,
and even a high tolerance for carbohydrates commenced. Only in one case
did the glycosuria persist, in mild form, during the myxedema.

The diminution in the general metabolic processes in myxedema expresses
itself also in hypothermia; this belongs to the commonest symptoms of the
fully developed forms. The rectal temperature varies between 36° and 37°
Celsius, and may even be below 36°. It stands in relationship with the
sensations of cold complained of by the patients. Myxedemics feel com-
fortable only when the external temperature is high; their condition aggra-
vates in the cold season of the year; it has even been stated that in summer
time we may need to administer smaller doses of thyroid-gland substance
in order to compensate for the deficiency, and must increase the dose in
winter. Strong stimuli, as for example, infectious diseases, may, however,
also bring about hyperthermia, as numerous examples in the literature bear
witness.

In severe cases of myxedema there regularly develop disturbances in
the sphere of the genitalia. Women develop irregularities of menstruation;
either the menses cease or there occur profuse floodings. In the long-stand-
ing cases premature climacteric occurs, and often a high degree of atrophy

Il6 THE DISEASES OF THE THYROID GLAND

of the genital apparatus (Landau, Szanto}. In two women with distinct
cachexia strumipriva, Langhans found pronounced small-cystic degenera-
tion of the ovaries. Allen Starr, Kirk, Schotten and after them many others
have testified to the occurrence of menorrhagia. In men, libido is lost.
Very instructive in this connection is a case of Magnus-Levy, in which a fifty-
four-year-old man lost libido completely, and regained it after cure of his ill-
ness. Herz observed a similar case in which a forty-five-year-old man re-
gained erections and ejaculations two weeks after the beginning of treatment.
Treatment by thyroid gland also affects favorably the menstrual disturbances
in women. These do not signify sterility, as there are cases of myxedema
that become normally pregnant. It is shown also by animal experimenta-
tion (Hoisted} that partial extirpation of the thyroid does not prevent normal
carrying of young. In such cases the thyroids of the fetuses seemed to act
compensatorily. In other words, Hoisted observed in the new-born pups
an enormous hypertrophy of this organ. The thyroids were about twenty
times as large as in a normal new-born pup. In cases with a long-standing
high-grade deficiency of thyroid function, there occurs atrophy of the ovaries.
In this case the disturbance seems to be irreparable.

In cases of myxedema the hypophysis is commonly described as altered.
Boyce and Beadles found enlargement of this organ, as did also Ponfick in a
case. In a case of Abrikosojf's the glandular portion of the hypophysis was
enlarged, and indeed the chromophilic cell-columns were increased, the cells
enlarged, their protoplasm showing colloid degeneration. Comte earlier ob-
served a similar condition and considered the enlargement of the hypophysis
as a compensatory hypertrophy. In other cases there has occurred a
pronounced sclerotic degeneration of the glandular hypophysis (2nd case of
Ponfick} or cystic degeneration (Sainton and Rathery, and others}. In both
the cases of myxedema above reported sella turcica as shown by X-ray
was normal.

An enlargement of the hypophysis after extirpation of the thyroid has
been observed in animal experimentation. In grown animals, Bertelli and
myself (reports not published in detail) could not find anything similar after
a one and one-half years' duration of the thyroprivic condition. I think
that the findings described are overestimated as to their significance for the
reciprocal action between thyroid gland and the glandular hypophysis. The
vicarious action of the hypophysis for the thyroid gland, as Comte assumed,
need not be considered in this connection. It is just as if in contracted
kidney the liver acts vicariously for the kidney. In myxedema adultorum
the hypophysis sustains mostly changes of a strumous character, or simultane-
ously with these, changes of a chronic inflammatory nature (as for example
in the cases of Ponfick, Sainton and Rathery, et al.}, such as we shall meet
with again in the consideration of multiple ductless glandular sclerosis.
Simultaneous disease of the thyroid gland and the glandular hypophysis

MYXEDEMA I I 7

(pathological correlation) is very rare. I shall deal with it in detail in the
chapter on the hypophysis. Often in such cases thyroid-gland medication
causes a disappearance of only a portion of the cachectic symptoms. We
shall deal later with the alterations in the hypophysis in infantile myxe-
dema. The combination of myxedema with tetany is considered in the
fourth chapter.

Etiology and Course. — We to-day possess a complete explanation of the
etiology of myxedema operations. Total extirpation of the thyroid gland
always leads to myxedema, which in very rare cases may be only slight
and may heal spontaneously, this manifestation being due to the compen-
satory hypertrophy of accessory thyroids (cases of Vollmann and Reverdin).
It is very noteworthy that in cases of accessory struma of the base of the
tongue, extirpation of the tongue struma led to myxedema. Seldowitsch
and Chamisso have each reported such a case. After operations for struma,
mitigated forms of myxedema operations often appear, forms that show, for
example, only disturbances of growth, or only fat deposits, or only apathy.
Among thirty-eight cases of cachexia strumipriva, Kocher saw the miti-
gated form only nine times; here recurrences of the goiters developed.
If a thorough continual treatment with thyroidin be not instituted there is
shortening of the thyroidectomized individual's life. Total thyroidectomies
are to-day still performed only on malignant degenerations of the thyroid
gland. Mitigated operative myxedema may also occur to-day where there
is intense degeneration of the part left behind.

The pathologico-anatomical finding in the thyroid in so-called spontaneous
myxedema is ordinarily sclerosis with destruction, or a high-grade goitrous
degeneration. In many cases of spontaneous myxedema only fat and con-
nective tissue (Abrikosoff) is found on the site of the thyroid. Only in rare
cases is the etiology of the inflammatory cirrhosis clear, as for example in
Kohler's cases of syphilis and actinomycosis respectively of the thyroid, the
first yielding to the effects of potassium iodide, the latter to operation, v.
Wagner observed two cases of formes frustes in the eruptive stage of syphilis;
in the later stages of syphilis infiltrates and gummata are present. Tuber-
culosis of the thyroid gland is relatively not very common. Also miliary
tuberculosis has been observed. Primary tuberous tuberculosis seems to be
very rare. In certain cases of multiple sclerosis of the ductless glands there is
found in the thyroid, in addition to diffuse chronic processes, also, in some
places, tuberculous foci. In most of the cases of spontaneous myxedema
there were perhaps other infections than those stated. The territory has
not as yet been explored bacteriologically. An index is furnished by those
cases of myxedema that appear after cases of infectious diseases. Thus
Reinlinger reports a case of an individual, twenty-two years old, who after
a gastric fever (typhoid?) developed cachexia, myxedema of the skin, apathy,
dementia, and falling out of the axillary and pubic hair. Thyroid therapy

Il8 THE DISEASES OF THE THYROID GLAXD

produced good results. Marfan saw myxedema develop after an acute artic-
ular-rheumatism with angina. Sometimes, as previously mentioned, the hy-
perplasia of Basedow's disease goes over into atrophy. The investigations
of Roger and Gamier, de Queroain, Sarbach, Bayon, and others have shown,
however, that in severe infections diseases there regularly develop in the
thyroid inflammatory processes, and in chronic intoxications cirrhotic
processes.

The reason that myxedema is commoner in women than in men should
be sought in the fact that the normal sexual processes in women determine
an important affection of the function of the thyroid, and that an exhaustion
of this is produced the more easily by damages to the parenchyma due to
common infections or intoxications. For this assumption speaks the fact
that mitigated forms of hypothyrosis tend to become worse during pregnancy
and that not rarely the myxedematous symptoms disappear at the sexual
involution.

Finally, it should here be mentioned that sclerotic processes are found
in the thyroid in numerous cases of scleroderma (Singer, Hektoen, Rouoc,
Leredde and Thomas, and others}. Eventually, in many cases of sclero-
derma are found also symptoms that remind one of myxedema (Cresset,
Osier, and others). As scleroderma involves in sympathy the most diverse
organs, we readily see that we should best regard the alterations in
the thyroid as a partial phenomenon of the fundamental processes (see
Chapter I).

Differential diagnosis is concerned first of all with nephritic edema.
Slight presence of albumin [in the urine] may also occur in myxedema. We
should especially consider the density of the swellings, the failure of hyper-
tonia, and the presence of psychic alterations. Also, in myxedema, the
swellings are often more distinct in the morning than in the evenings.

Stabile erysipeloid edema, indurative syphilitic edema, and pachyderma
are distinguished from myxedema by normal psychic relations ; nor do they
react to administration of thyroidin. Thyroid medication may affect
favorably scleroderma (stimulation of metabolism, Ewald) ; the same holds
good of certain cases of lipomatosis dolorosa (Dercum) . In many such cases
alterations are found in the thyroid, in others in the hypophysis (see
Chapter XIV).

The incomplete forms of myxedema are of difficult diagnosis. Hertoghe
first drew attention to these, designating them chronic benign hypothyroid-
ism. They are much commoner and more multiform in women. They often
begin with chronic muscular pain, which may disturb sleep. Rachialgias
are especially frequent, to which may be added great lassitude, especially
in the morning hours, menstrual disturbances, menorrhagias or amenorrhea,
sensation of cold, even shiverings, hoarseness of the voice, and, especially
often, rather obstinate constipation. The picture becomes clearer when

MYXEDEMA

IIQ

the hair begins to fall out, especially the hairs over the occiput, and when
apathy and depression are added. Sometimes many persons in the same
family are found with the signs of chronic mitigated thyroid insufficiency.
Hertoghe mentions that pronounced signs of myxedema in children first
drew his attention to the signs mentioned in the mother, and that thyroid
treatment of the mother brought about good results. Gluzinski remarks
that such abortive forms of myxedema in women occur not rarely in the
years just before the climacteric and retrogress when the climacteric has
been completed. The last statement has also been mentioned by Hertoghe.
Kocher and Fr. Kraus agree with Hertoghe concerning the frequency of such
forms. Kocher mentions that manifestations of chronic rheumatism that
are associated with pains, stiffness, and heaviness of the extremities not
infrequently depend upon a larval hypothyrosis. The diagnosis may also be
made more difficult by the fact that distentions of the joints develop. Parhan
and Papiniam have described a case of chronic rheumatism which they re-
garded as dysthyrogenic. Rothschild and Levi have tried thyroid therapy
on a large group of cases of chronic articular rheumatism. There were
twenty moderately severe and light cases among thirty-nine cases varying
from twelve to fifteen years of age. Of these, eighteen were cured or es-
sentially improved, while of the severe cases, two were cured and thirteen
improved. One should be very careful about regarding these forms of articu-
lar rheumatism as thyrogenic, as it is not unlikely that good results may be
brought about solely by the stimulation of the metabolism through the
thyroid medication.

Hertoghe certainly goes too far when he brings myomata, retroflexion
of the uterus, emphysema, congestion of the liver, and gall-stone formation
directly into relation with the thyroid gland insufficiency (Kocher, Fr.
Kraus). That on the other hand we were justified in ascribing, in many
cases, the above-cited manifold disturbances to a chronic light thyroid
insufficiency speaks the fact, quite apart from therapeutic results, that Kocher
not rarely saw such "thyroprivic equivalents" occur after strumectomy.

The diagnosis of such benign forms of thyroid-gland insufficiency can,
as can readily be understood, present great difficulties, especially when only
a few of the manifold symptoms are present, for instance, increased
heaviness of the nasal breathing, hoarseness of the voice, or a slight degree
of deafness. Especial attention is to be directed in these cases to the
presence of pseudolipomata in the supraclavicular fossae or to transverse
folds in the forehead (v. Wagner). Often the diagnosis can only be made
tentatively ex juvantibus.

An especial form of mitigated thyroid insufficiency is thyrogenic obesity.
In contradistinction to so-called dietary obesity there are cases in which
obesity develops in spite of slight supply of calories, and remains present
when the supply of calories is so restricted that normal individuals of the

120 THE DISEASES OF THE THYROID GLAND

same size, of the same weight, and under the same living conditions would
rapidly lose in bodily weight under such conditions. The cause of endoge-
nous obesity is of very diverse nature (see also Chapter VI, on the hypophysis,
and the various forms of obesity, Chapter XIV). But it can hardly be
doubted that one of these causes is a slight grade of thyroid insufficiency.
The thyrogenous obesity may depend on inherited predisposition or may
follow infectious diseases (v. Noorden). Also it may be preceded by a Base-
dow's disease. I refer to the cases of Basedow's disease in which the initial
emaciation is followed by a progressive increase in weight. For the diagnosis
of thyrogenous obesity, important also are other symptoms such as phlegma
and constipation, especially if they have existed before the development of
obesity. Such cases belong in the domain of thyroid treatment; restriction
of calories in such cases can, especially in older persons, lead to a marked
exhaustion and cardiac collapse, without lessening the amount of fat, while
administration of thyroid gland reduces the body weight with amelioration
of the general condition (v. Noorden).

The cause of the manifoldness of the hypothyroidal syndrome may be re-
garded, as in the hyperthyroidal syndrome, as differences in the constitutions
of the individuals affected.

The course of myxedema in untreated cases may be progressive and give
rise to a cachexia; then intercurrent affections often occur, and lead to
death. Spontaneous improvement may also occur, not rarely with the
development of a goiter, in rare cases with hypertrophy of the accessory
thyroid glands.

The treatment of myxedema will be considered after the description of
sporadic cretinism.

2. Sporadic Cretinism

Definition. — In the preceding section we drew disease pictures that
originate in an organism already fully developed, when the thyroid becomes
insufficient or loses its function entirely. When the disturbance in thyroid
function develops in an organism as yet unfinished, there occur in addition
profound developmental disturbances that are the more intense the earlier
the disturbance begins. The conception of sporadic cretinism as hypo-
thyrosis or athyrosis of the youthful organism is decisively proved in the first
place by the sad experiences that were sometimes met with at a time when the
functions of the thyroid were not known, in strumectomies on children, and in
the second place by the fundamental researches on total extirpation of the
thyroid in animals (of Hofmeister and of v. Eiselsberg) . The thyroprivic
animals of v. Eiselsberg that were kept under the same conditions as the control
animals showed after a few weeks, as against the control animals of the same
brood, a considerable remaining behind in size and in body weight. The dis-
turbance in growth affected more the long bones than the trunk. The bones

SPORADIC CRETINISM 121

became coarse and showed decrease in solidity. After a longer time the
bodily weight of the control animal often attained to three times that of the
thyroprivic animal. In addition were found distention of the abdomen,
anemia, atheromatous degenerations of the great vessels, atrophy of the geni-
talia, reduction in temperature, curving of the bones, trophic alterations of
the hair, dryness of the skin, senile marasmus, and pronounced idiocy, in
short the picture of idiotic dwarfism. The changes in human beings when the
function of the thyroid becomes deficient in early life are entirely analogous.
The lack of thyroid may be either congenital (thyroaplasia or thyrohypoplasia)
or the same changes that cause myxedema of adults may affect the thyroid in
early life (spontaneous infantile myxedema), or, as already mentioned, a
surgical procedure may lead to thyroid insufficiency (postoperative infantile
myxedema) .

Pineles, who was the first to separate thyroaplasia from the entire group
as an etiologically unitary form, wished to avoid the expression sporadic
:retinism and to distinguish only between thyroaplasia and infantile
myxedema. It seems to me, however, that this sharp distinction is not
practicable. It is true that infantile myxedema makes its first appearance
in the fifth or sixth year of life, while in thyroaplasia the exhibition of develop-
ment begins gradually to manifest itself already in the first year of life.
Infantile myxedema may, however, also develop at the earliest age. If
the damage to the thyroid in these cases is a material damage, the intensity
)f the inhibition of development is the same as in thyroaplasia, and as the
inding on palpation when negative is not decisive, so a certain differentiation
>etween these two conditions is hardly attainable in vivo, especially if the
idividuals first undergo an exact physical examination at a later stage of life,
therefore wish to retain the name sporadic cretinism for the entire group.
Siegert embraces all the cases of lack or deficiency of the thyroid gland in
:hildren, together with endemic cretinism, under the name myxidiotie
[myxidiocy]. As I do not regard endemic and sporadic cretinism as entirely
)f similar nature, I cannot subscribe to this designation.

In his excellent work on thyroaplasia, Pineles collects from the older litera-
ture twelve cases in which the thyroid was absent microscopically at autopsy.
Almost all the individuals affected died at an early age; in the fewer older
idividuals who had attained the age of puberty it seems that the demonstra-
tion of a complete aplasia of the thyroid was not certain, or the cases had been
reated with thyroid tablets (MacCallum and Fabyan). Also Thomas Erwin
remarks this. In the case of Fletcher-Beach, that concerned a fifteen-year-old
jirl, a certain intelligence had developed. She had learned to write and use
igures, and had menstruated two or three times. The autopsy indeed
showed absence of the thyroid gland, but as such a development is hardly
)ossible with a complete thyroaplasia — the publication of this case occurs
)efore the era of thyroid-gland therapy — it is possible that here accessory

122 THE DISEASES OF THE THYROID GLAND

thyroids were present, which could not, however, fully compensate the
deficiency. Pineles then cites seven works of a more recent date in which an
exact microscopical examination failed to find any remnants of thyroid gland
(Kocher-Langhans, Muratov, Maresch, Peucker, Aschoff, Erdheim, Knopfel-
macher). The case of Maresch was that of an eleven-year-old girl whose
brothers and sisters were perfectly well; according to the statements of the
parents, growth ceased almost entirely at one and a half years of age. At
eleven years of age, the girl was 77 cm. tall, the skull had a circumference of
49 cm., the abdomen 53 cm., the great fontanelle measured 4^ cm. by
\}^, cm. The girl could not walk, could only sit, and could speak only a few
syllables. The skin was myxedematous (also on microscopical examination) ,
the hypophysis was of normal size, the thymus gland corresponded with the
age. Pancreas and suprarenals were of normal size.

The contribution of Maresch was of fundamental importance, because
Maresch established for the first time in his case the presence of the parathy-
roid glands. Also later investigators found the parathyroid glands intact.
Only in a few cases was the simultaneous absence of parathyroid glands re-
ported (Quincke, Case I, Rocazet Cruchet, two cases of Siegert). Here, how-
ever, no serial sections were made.

Very exactly studied are the cases of Aschoff, of Erdheim, and of Dieterle.

The case of Aschoff was that of a half-year-old child of 53 cm. length.
The hypophysis was very much enlarged (o. 5 gm.) . A schoff found at the root
of the tongue a cystic tumor that he regarded as the remnant of the lingual
duct. In addition, there was found at the site of the lateral thyroid lobe a
half-pea-sized vesicle that he regarded as the remnant of the branchial pouch.
The case of Erdheim was a thirteen-month-old child, the thirteenth child of
healthy parents. High-grade constipation had been present (palpable fecal
tumor). Here also was found the vesicle as in the case of Aschoff; micro-
scopical examination showed that it consisted of an ectodermal formation,
as to the origin of which from the fourth branchial pouch there could be no
question, as Erdheim found the same cysts on this side in two cases of
unilateral thyroaplasia, in which cysts on the normal side were absent.

Very recently have been added the cases of Ungermann (vicarious tongue-
struma), MacCallum and Fabyan (cysts in the neighborhood of the superior
parathyroids), and finally three cases of Schilder. In all cases exactly in-
vestigated up to the present these cysts have been found at the site of the
lateral lobe of the thyroid. Dieterle could demonstrate in his case the
absence of the rudiments of the superior thyroid arteries.

We are therefore justified in the assumption that in these cases an anomaly
of formation is present that consists in an agenesis of the lateral rudiments
of the thyroid. The vesicles found at their site consist in indifferent rests
of the postbranchial bodies, in which under circumstances isolated thyroid
follicles may be imbedded. At the root of the tongue are found, at the site

SPORADIC CRETINISM 123

of the median rudiment of the thyroid gland, analogous indifferent rests with
traces of thyroid-gland tissue, which not infrequently give occasion to tumor
formation. The cases described affect children who have reached the elev-
enth year of life at most. The girls were far in the majority; they were all
well developed at birth. Only in the second half of the first year of life
did there gradually occur a standstill in the development. Among the
numerous cases of sporadic cretinism described in the literature a large
number certainly belong to thyroaplasia. Diederle counts, among others, also
the two cases of Kocher and the known case of Bourneville (Pacha de Bicetre) .
Also two cases of Magnus -Levy belong to this group. The above-mentioned
case of Bourneville attained an age of thirty-six years. As I have said be-
fore, I would rather not take up the question whether pure cases of thyro-
aplasia can reach so old an age, especially if they have not been previously
treated. In any case it is established that also in complete absence of the
thyroid gland, life and a certain degree of development is possible.

Symptomatology. — I shall now describe the clinical picture of sporadic
cretinism without regard to the etiology of special cases. We must in every
respect consider that only those cases which show the fully developed clinical
picture can belong to the thyroaplastic form, while in the incomplete forms
there is only a relative insufficiency of the thyroid function which must have
begun later in life.

I would like to describe three cases of sporadic cretinism that Herr Hofrat
Wagner v. Janeregg kindly allowed me to examine.

Observation XIV. — Margerete H., two and one-half years. Entered the psychiatric
clinic (of Wagner) Nov. 4, 1909. Father has a goiter, avowedly from blowing the bugle-
horn. Otherwise no goiter in the family. Her mother's mother was insane. Parents
have never been away from Vienna. A five-year-old child of the parents is entirely
normal. The birth of the patient was normal; she was nursed by the mother until
the end of the second year. From birth lusty and lively; large, well developed; from
the eighth month on the parents first remarked that the child did not take on more
weight and since that time has remained at a standstill. The child has had an umbilical
hernia since birth. It has never spoken.

Height 62 cm.

Circumference of skull, 42 cm.

Breadth of shoulders, 45 cm.

Circumference of breast, 45 cm.

Pulse, 1 20.

Rectal temperature, 36°.

Panniculus adiposus soft, lax; myxedematous texture of the skin; walking and stand-
ing impossible. Forehead arched forward, root of the nose somewhat sunken in; no teeth
as yet. Eyelids enormously swollen, tongue thick, abdomen markedly arched forward;
umbilical hernia. Body weight 7.1 kg. From Dec. 2, 1909, on, thyroidin tablet every
third day.

Nov. 10, 1910. — 71 cm. long, weighs 9.1 kg. Treatment discontinued.

Entrance into the first medical clinic on Oct. 15. Can only stand when it holds fast
on a support, cannot speak, is, however, otherwise lively and busies itself. All fontanelles
closed.

124

THE DISEASES OF THE THYROID GLAND

Circumference of skull, 46 cm.
Circumference of breast, 50 cm.
Circumference of abdomen, 48 cm.
Anterior superior spine to internal malleolus, 30 cm.
Acromion to olecranon, 13 cm.
Olecranon to styloid process of radius, 12 cm.

Skin somewhat dry, no distinct myxedema. Root of nose sunken in only a little.
Tongue always protrudes from the mouth ; left anteriorly below, one tooth nucleus pal-

FIG. 12. — X-ray picture of a hand of a sporadic cretin (Observation XIV).

pable, otherwise no teeth. Hearing apparently entirely normal. Thyroid gland not
palpable j'abdomen distended, liver is palpable, indication of umbilical hernia; the tickling
reflexes of the external auditory meatus are present. Does not tell when she wishes to
pass feces or urine. Nervous status, as far as elicited by tests, normal.
Patellar reflexes somewhat lively.

Oct. 15. — 30 gm. dextrose, no sugar.

Nov. ii. — 50 gm. dextrose, no sugar.

Oct. 24. — Erythrocytes, 4,560,000.

SPORADIC CRETINISM

125

Leucocytes, 6800, of which:
Polymorphonuclear neutrophiles, 48.4 per cent.
Large mononuclears, 8.3 per cent.
Lymphocytes, 40 per cent.
Eosinophiles, 3.3 per cent.
Nov. ii. — Erythrocytes, 5,250,000.
Hb., 55 per cent.
Leucocytes, 8200, of which:
Polymorphonuclear neutrophiles, 38 per cent.
Large mononuclears, 37 per cent.
Lymphocytes, 54 per cent.
Eosinophiles, 4.3 per cent.
Nov. 26. — 0.0005 gin. adrenalin sub-
cutaneously and 50 gm. dextrose per os.
After four hours 3.2 per cent, sugar.

Nov. 29. — One drop homatropine in eye;
twenty-four hours later, still slight mydriasis.
Nov. 30. — Adrenalin, 0.0005 gm., no
sugar.

Nov. 20. — 0.005 gm- pilocarpine sub-
cutaneously, weak sweat, no salivation.

From Dec. 2 on, two thyroidin tablets
daily; from 6th on, three daily; from 8th on,
five daily.

Dec. 14. — Pulse that was formerly no,
now 130; thyroidin medication now reduced
to one tablet.

Summary. — We are dealing with a case of
sporadic cretinism, probably depending on a
congenital aplasia or hypoplasia of the
thyroid.

Here are worthy of note the high assim-
ilation boundary for sugar, the failure of

adrenalin glycosuria, the strong action of atropine and the weak action of pilocarpine;
there is, -however, found an unusually high glycosuria on combination of dextrose and
adrenalin. There occurs in this case a somewhat high tolerance for thyroidin.

Rontgen investigamm of the skeleton of the hand, Nov., 1911: The bone-nuclei
of the os magnum and the unciform bone are present. Those for the epiphysis of the
radius and the basal epiphysis are still absent. The skeleton corresponds to that of a
six- to eight-month-old child (Fig. 12).

Sella turcica corresponding to the size of the skull.

Observation XV. — Franz N. (see Fig. 13). Entered the psychiatric clinic of Wagner
Oct. 6, 1909, four and one-half years old, from Rudoletz in Mahren.

The fourth child of healthy parents. Birth easy, at the right time. Head at birth
already large. Speech up to the second year of life consisted of the simplest words
only; words were such as tata, mamma, and since this time the child has not spoken
much otherwise.

Parents and the entire family to the great-grandparents of the child have not suffered
from goiter. Nowhere in the neighborhood does the father know of a similar case.

Length of body 85 cm., weight 19.2 kg. Head extremely large without, however, any
hydrocephalic formation. Bones of the head of hard consistency. Strong development

FIG. 13. — Sporadic cretinism.

126 THE DISEASES OF THE THYROID GLAND

of the skeleton of the face. Very low forehead, eyes stand wide apart. Saddle-nose,
epicanthus; short, very broad cartilaginous nasal framework; cushiony lips; thick,
broad tongue, that protrudes from the mouth. Cushiony ear lobes that lie close to the
head. Cheeks very thick, throat thick and stubby. Thyroid not palpable. Thick
lanugo hair on back. Skin of the body, especially in the supraclavicular grooves and
on the backs of the hands and feet, springy, elastic; hands and fingers chubby. Abdomen
much distended. Circumference 65^5 cm. Reducible umbilical hernia. Reflexes, as
far as can be tested, present. Noise tests were without any reaction.

From June 23 on was given one thyroidin tablet daily, until Oct. 24. Entrance into
the first medical clinic. Now length of body 91.25 cm., weight 21 kg. Treatment is
now discontinued.

Circumference of the head now 56 cm., circumference of the abdomen 65 cm., cir-
cumference of breast 49 cm.

Anterior superior spine to internal malleolus 44.5 cm.

Circumference of neck 36 cm.

Heart dullness somewhat broadened (also by X-ray, heart of characteristic spherical
shape). Heart sounds pure.

Border of the liver palpable 10 cm. below the margin of the ribs in the mid-line,
two fingers' breadth below in the right mammillary line.

Umbilical hernia about 3 cm. long, and its insertion 2.5 cm. in diameter. Penis very
small, testicles have not descended. The child does not go to the toilet to void urine or
feces. Slight heightening of the patellar reflexes, otherwise the reflexes normal. Nervous
status, so far as can be tested, normal.

The child often stares into space for a long time, but at times is right lively and cries
loudly. No trace of speech. Puts all objects into his mouth, even his own feces. Im-
pressions of hearing entirely absent, no reaction of the eyelids to sounds.

Nov. 2. — 50 gm. dextrose per os, no sugar. After several days 100 gm. dextrose
of which he vomited a small amount, no sugar in the urine.

Nov. 9. — Erythrocytes, 5,480,000.
Hemoglobin, 70 per cent.
Leucocytes, 9000, of which:
Polymorphonuclear neutrophiles, 42.5 per cent.
Large mononuclears, 8 per cent.
Lymphocytes, 41 per cent.
Eosinophiles, 8.5 per cent.

A later count yielded:

Erythrocytes, 5,400,000.
Hemoglobin, 70 per cent.
Leucocytes, 11,000.
Eosinophiles, 12 per cent.

Nov. 21. — o.oi gm. pilocarpine. Sweat extremely slight, salivation negative.

Nov. 22. — Homatropine evinces weak mydriasis only, which however is positive after
twenty-four hours.

Nov. 26. — o.ooi gm. adrenalin subcutaneously and 50 gm. dextrose per os. After
four hours 4.2 per cent, sugar.

Nov. 29. — Weak mydriasis forty-eight hours after installation of homatropine.

Nov. 30. — o.ooi gm. adrenalin subcutaneously, no sugar. From Dec. 2 on, three thy-
roid tablets a day; from Dec. 5 on, five tablets daily; from Dec. 8 on, seven tablets daily.

Dec. 13. — Marked scaling of the skin, no trace of moisture, even of the palms.

Dec. 22. — Pulse irregular, only 72 to the minute, although frequent abortive beats.

SPORADIC CRETINISM 127

The dose was reduced to three tablets and after some days, when the pulse had become
entirely regular again, five tablets were given continuously.

Jan. 8. — Leucocytes, 4800, of which:

Polymorphonuclear neutrophiles, 61.5 per cent.
Lymphocytes, 20.5 per cent.
Large mononuclears, 12.5 per cent.
Eosinophiles, 5.5 per cent.

Jan. 19. — The examination of the hearing now shows certainly that the patient reacts
to loud noises. Distinct lid-reflexes.

March 29. — Thyroidin medication has now been continued in the large doses without
producing manifestations of poisoning. The hearing is still better, the enlargement of
the liver has essentially diminished in size; otherwise there is no change.

December, 1910. — The nuclei of the os magnum and the unciformbone are alone visible
in the carpus, while at this time the nuclei of the entire skeleton of the carpus should
have been laid down. The epiphysis of the radius is present. The skeleton corresponds
to that of a one and one-half to two-year child.

Summary. — The patient is from a goiter-free neighborhood. There exist no other
grounds for the assumption of an endemic cretinism. We are indeed dealing with sporadic
cretinism, probably dependent on aplasia or high-grade hypoplasia of the thyroid gland;
and perhaps later there was added some other factor that we are not able to define that
made the insufficiency still greater.

Thyroid medication here succeeded less than in the preceding case. It was also
introduced much later. Apparently the thyroid insufficiency is here very much greater.

The investigation with adrenalin and pilocarpine several weeks after the discon-
tinuation of thyroid-gland therapy shows slight or negative action. The test as to ali-
mentary glycosuria results negative. It is very interesting also that in this case adrenalin
plus dextrose leads to an entirely usual degree of glycosuria.

Worthy of note in this case is the enormous tolerance for thyroidin and also the
action of thyroidin on the disturbance of hearing and on the enlargement of the liver.

Observation XVI. — H. A., entrance into the psychiatric clinic (of Wagner) Jan. 21,
1009. Fifteen years old, female dwarf (95 cm.); face puffy, skin of the entire body myxe-
dematous, dry and scaly. Supraclavicular fossae filled with pad-like masses. Con-
junctivitis eczematosa. Fundus normal. Circumference of skull 50^ cm. Root of
nose sunken, tongue thick, also the lips; the teeth with transverse ridges, in great part
carious, have remained very much behind in their development. Abdomen markedly
distended, umbilical hernia.

Measurements. — Height, 95 cm.
Circumference of skull, 50% cm.
Upper arm (acromion to olecranon), 19 cm.
Arm proper, 13 cm.
Lower extremity (spine [anterior superior] to heel), 46 cm.

Intelligence that of a four-year child. Can speak, can understand questions and state-
ments addressed to her; can, however, not write nor read, and can say, of a prayer, only
the words at the beginning. Weight 20 gm.

From April 27 on, 0.5 gm. sodium iodide, after which she became livelier; from June
8 on, one thyroid-gland tablet a day. Body weight at the beginning of July had gained
16.9 kg. The bowel movements, which formerly frequently occurred only every two or
three days, have gradually become entirely normal. Rapid mental development. Is
much more active, plays much, wants a looking glass, a net for her hair, begins to sing.

Jan. 18, 1910. — 101 cm. Myxedematous texture of the skin much lessened, slight
sweating of the palms of the hands. Dermographism.

128

THE DISEASES OF THE THYROID GLAXD

Oct. 13, 1910. — The patient, sixteen and three-fourths years old, now enters the
medical clinic. Length no cm., weight 23 kg. The thyroid-gland medication is now
discontinued. Circumference of the skull 57^ cm.

Hair soft, skin somewhat dry, only the palms of the hands moist, tongue not enlarged,
teeth much behind in their development. Circumference of abdomen 62 cm.; there still

FIG. 14.

Sporadic cretinism.

FIG. 15.

remain indications of an umbilical hernia. Liver palpable two fingers' breadth below
the margin of the ribs. Pubis and axillae entirely devoid of hair. External genitalia
hypoplastic. Has never menstruated. The entire trachea is distinctly palpable, there
is nothing to be felt of the thyroid. She gives correct information as to where she has
been the last year. Cannot reckon, counting impossible.
Oct. 15. — 100 gm. dextrose, weakly positive.

129

Erythrocytes, 4,540,000.
Leucocytes, 11,200, of which:
Lymphocytes, 49 per cent.
Large mononuclears, 9.5 per cent.
Lymphocytes, 51.0 per cent.
Eosinophiles, 7 per cent.

Oct. 25. — 100 gm. dextrose, no sugar.

Nov. i. — Hands feel cool to the touch; patient has gained 1.7 kg. since her entrance.

FIG. 1 6. — Sporadic cretinism, seventeen-year-old girl. In spite of a long-continued thyroid
treatment the development of the skeleton of the hand is that of a normal girl aged ten years
(see Fig. 17).

Nov. 3. — Leucocytes, 12,100, of which:
Polymorphonuclear neutrophiles, 40.6 per cent.
Large mononuclears, 4.6 per cent.
Lymphocytes, 49 per cent.
Eosinophiles, 5.8 per cent.

\ov. 9. — Leucocytes, 11,500.
Hemoglobin, 65 per cent.
9

130 THE DISEASES OF THE THYROID GLAND

X'ov. 10. — 150 gm. dextrose, no sugar.

Nov. 16. — Skin entirely dry. o.oi gm. pilocarpine; no salivation, only slight sweating.

"Nov. 19. — Nervous status. Superficial abdominal reflexes increased and also plantar
reflex lively; otherwise normal, as far as can be investigated.

Only very slight mydriasis after homatropine. On Nov. 22, o.ooi gm. adrenalin
subcutaneously and 100 gm. grape-sugar by mouth. Minimal increase in blood-pressure,
lasting only for a very short time. Pulse only 84 to 92. In the first two-hour period, no
sugar; in the second, 4.25 per cent, in 15 cc. urine; in the next twelve-hour period, Trammer
still strongly positive.

Xov. 26. — o.ooi gm. adrenalin, no sugar.

Xov. 29. — Circumference of skull, 56^ cm., total height, in cm. Circumference of
abdomen, 62 cm., circumference of breast (mammillae), 64 cm., circumference of neck, 28
cm. Upper arm (acromion to olecranon), 21.5 cm., arm proper, 18.5 cm., lower extremity
([anterior superior] spine to heel), 52 cm.

Dec. 2. — Up to this time, pulse between 100 and no. Bowel movements not entirely
regular, in that one bowel movement is wanting every three to five days. From now on,
five thyroidin tablets a day. From Dec. 6 on, seven tablets a day. Dec. 8, nine tablets
a day.

During the next days the pulse rises up to 145 and sinks to its former count only on
Dec. 22.

Leucocytes: 10,200, of which:
Polymorphonuclear neutrophiles, 67.2 per cent.
Large mononuclears, 8.2 per cent.
Lymphocytes, 22.6 per cent.
Eosinophiles, 2 per cent.

X-ray examination of the hand skeleton. The epiphysial junctures of the fingers
and metacarpal bones are still open. The skeleton of the carpus is as yet laid out in the
form of round bone-nuclei. At this age the carpal bones should be fully developed,
and the epiphysial junctures should be closing up (Fig. 16). Sella turcica corresponding
to the size of the skuli.

Summary. — Sporadic cretinism probably due to aplasia or high-grade hypoplasia of
the thyroid gland. The thyroid-gland therapy instituted in the sixteenth year is able to
affect the growth not inappreciably and to further intellectual development. We may
readily comprehend that the marked inhibition of development that has existed for
sixteen years cannot entirely be done away with.

The investigation of the carbohydrate metabolism showed that after the year-long
administration of thyroidin the assimilation limits for grape-sugar lay abnormally low.
It is very instructive that with the discontinuation of the thyroid medication the assimila-
tion limits rose immediately, so that after several weeks as much as 150 gm. dextrose
would be borne. Also adrenalin produces no glycosuria, while, on the contrary, adrenalin
and grape-sugar produce abundant glycosuria.

An over-loading test with thyroidin showed that the tolerance in this case was at
any rate rather high, as symptoms of poisoning first occurred only with large doses.
Under the test with thyroidin, the number of neutrophiles rose considerably, and the
assimilation limits for grape-sugar again sank rapidly.

In the clinical picture of sporadic cretinism the phenomenon most be-
fore the eyes is the disturbance in growth. Buschan collects from the litera-
ture thirty-four cases of sporadic cretinism that showed evident dwarf-
ism. In the cases with high-grade disturbance of the function of the thyroid

SPORADIC CRETINISM

gland the length of the body was mostly below i meter. Siegert describes
a two-and-a-half-year-old child of 50 cm. length; v. Eiselsberg a thirteen-year-
old girl of 80 cm. length. In addition to the disturbance in the growth in
height are found delay in the appearance of the bone-nuclei, and in the clo-

FIG. 17. — X-ray picture of the hand of a normal ten-year-old girl.

sures of the epiphyses (Hertoghe, v. Wyss, Kassowitz, Diderle, Siegert, and
others}. The original statement of Virchow that the calcification appears
prematurely was later found to be incorrect; the case investigated by

132 THE DISEASES OF THE THYROID GLAND

V ire June was one of chondrodystrophy (Kauj'mami). This was further
confirmed by Weygandt through the microscopical examination of Virchou'~s
case.

Already Argutinsky had mentioned that the development of the bone-
nuclei in sporadic cretinism is even more intensely delayed than is the growth
in height. If, for example, the size of a twenty-year-old cretin corresponds
to that of a six-year-old child, the retardation in the deposition of the nuclei
lies even farther behind. In the pure cases with complete lack of thyroid
gland the epiphysial joints do not close. In the known case of Bourneville,
autopsy, in the thirty-sixth year of age, showed epiphyses that were com-
pletely open. The closure of the fontanelles is markedly delayed. In
the case mentioned the great fontanelle was still open in the twentieth
year. At autopsy in the thirty-sixth year its place was filled by a trans-
lucent bony plate. Also Kassowitz mentions cases of infantile myxe-
dema with markedly delayed closure of the fontanelles; thus in a thirteen-
year-old individual he found the frontal fontanelles still distinctly open.
The measurements of the bones, with regard to their thickness and length,
correspond to the relations of childhood ; this is then a proportional dwarfism,
deviating from the normal proportions of childhood only in the development
of the skull. The circumference of the skull does not indeed correspond
to the age of the individual, but is distinctly larger than would be repre-
sented by the rest of the body structure. In addition there is a remaining
behind in the growth of the vomer, that results in a retraction of the root of the
nose; this lends to the face the characteristic cretinoid expression, which
does not, however, reach the extreme grade as seen in chondrodystrophy. In
the four-month-old case, with pure thyroaplasia, of Dieterle, the measure-
ments of the bones showed that they about corresponded to those of a new-
born child. The disturbance in growth had therefore apparently first made
its appearance after birth, and not already in fetal life. The histological
examination of the bones in sporadic cretinism showed diminution in the size
of the zone of cartilage proliferation, narrowing of the marrow cavity, abun-
dant fat-contents of the marrow, and poverty of the marrow spaces in cells.
According to Dieterle there also occurs a slowing of apposition and absorption,
with normal calcification. This gives rise to a certain degree of sclerosis.
With this agrees the observation of Kassowitz and of Dieterle that the bones,
when once formed, show an unusual hardness, thus differing from their
condition in rachitis. The histological picture of the bones shows a cer-
tain senility; the disturbance depends on an equalized delay of the endo-
chondral and periosteal ossification.

It is further characteristic for the disturbance in growth in sporadic
cretinism that it reacts to thyroid therapy in a pronounced manner, even
when the therapy is first begun after the twentieth year. We shall speak of
this in the consideration of the therapy.

SPORADIC CRETINISM 133

In the incomplete forms of sporadic cretinism the disturbances of growth
are characterized by their slighter intensity. Here closure of the epiphysial
junctures may occur, even in advanced years. I mention as example a
case of Magnus-Levy, in which the treatment, instituted in the forty-fifth
year — the patient was 132 cm. tall — failed to exercise any influence on
growth, as the epiphysial junctures were already fully ossified.

Disturbances in dentition go hand-in-hand with those of growth of the
bones. When the thyroid gland is entirely absent the children during the
first year remain completely toothless. In the later years the milk-teeth
develop very slowly and finally remain partially retained. (Often in addition
to the retained milk-teeth are found the rudiments of the permanent teeth.)
Here thyroid therapy, as we shall see later, may elicit excellent results.

Umbilical hernia is a constant finding in the higher grades of sporadic
cretinism. Kassowitz observed it sixteen times in twenty- two cases of
infantile myxedema. The eldest of these children was twelve years old.
The hernia may attain the size of an apple. Therewith the abdomen is
distended, the navel is markedly deep (Argutnisky), there is high-grade
obstipation, which in the case of Maresch led to prolapse of the rectum. The
myxedematous texture of the skin is for the most part distinctly evident; in
the older cases, however, the skin is on the other hand rather atrophic, only the
pad-like swellings of the supraclavicular grooves and the slight puffiness of
the face, especially the eyelids, remain. For the most part the limit of the
hair zone is far back on the forehead, to which are added protuberance of the
malar bones, retraction of the root of the nose, cushiony lips, protrusion of
enlarged tongue; all this lends the impression of something of an animal
appearance to the face.

Inspection of the mouth shows that the palatine arches are for the most
part high, deepened with furrows, the tonsils enlarged; and often in the
pharyngeal space there are adenoids. The hypertrophic rhinitis which is
present disturbs breathing; the children snuffle and snore; in most cases
there is a discharge from the nose. In two of the above cases I found a
distinct enlargement of the liver. In the case of Argutinsky there is the state-
ment that the border of the liver was palpable two and one-half finger-
breadths below the margin of the ribs.

It should also be mentioned that in the fully developed cases, the breath-
ing is extraordinarily slowed. A twenty-eight-year-old case of Magnus-
Levy's, who at the age of fourteen years had sustained a total strumectomy,
breathed only six times in the minute.

The sweat-inducing action of pilocarpine, in the three cases cited, was very
slight; salivation failed entirely; the mydriatic action of homatropine lasted
very long.

The developmental disturbances of the genitalia are always very marked.
In females the labia majora are stunted and do not cover the labia minora;

134 THE DISEASES OF THE THYROID GLAND

uterus and ovaries are highly hypoplastic and the breasts fail to develop.
In males the penis is very small, the testicles do not descend at all or descend
very late, and in many cases are essentially smaller than in the normal indi-
vidual. The pubic and axillary hair does not develop. With the failure of
sexual maturity in boys, there occurs also the failure of the change of voice.

The hematopoietic system also suffers in development. The hemoglobin
contents is for the most part much reduced, more than the number of erythro-
cytes. This behavior was very well illustrated in the three cases described
although all three had been treated for a long time with thyroid tablets. For
the most part the number of leucocytes is increased. The differential count
of these shows an enormous reduction in the polymorphonuclear neutrophiles
and a corresponding increase of the mononuclear cells, even when we con-
sider that in children the number of neutrophile cells is smaller than in adults.
The leucocytic picture shows the type of earlier stages of development
(Meunacher). Among the mononuclear cells are found a great number of
granular cells. Also Turk's irritation forms are observed (Esser).

The number of eosinophile cells is mostly very much increased. In my
three cases the percentage was 12 to 33.

Thus the blood findings behave similarly to those of adult myxedemics,
only the deviations from the normal are more strongly expressed. Also the
pathologico-anatomical findings agree with this. While thyroidectomy in
adult animals does not lead to a distinct alteration of the bone marrow, there
has been observed by Kraus in young animals after thyroidectomy a lym-
phoid metamorphosis of the bone marrow; also Aschojf found in his case of
thyroaplasia a lymphoid metaplasia of the marrow of the femur.

In sporadic cretinism, as in myxedema adultorum, there is found a para-
doxical action of the thyroid substance on the leucocytic formula. While
the administration of thyroid-gland substance in normal individuals increases
the count of mononuclears at the cost of polymorphonuclear neutrophiles,
we find in conditions of hypothyrosis under thyroid medication, together
with the increase in hemoglobin and the number of red cells, also an increase
in neutrophile cells, with a decrease in mononuclears. The abnormal forms
vanish from the blood and the leucocytic formula approaches its normal
constitution. In a case of juvenile myxedema (complicated with symptoms
of deficiency on the part of the other ductless gland), I observed that the
count of neutrophiles increased from 54 per cent, to 84 per cent, during a
two months' thyroid treatment.

Esser saw in a myxedemic child the count of neutrophiles increase under
thyroid treatment from 19 per cent, to 41 per cent. ; later, intoxication symp-
toms developed and with these the count of neutrophiles again sank to 19
per cent. I offered in explanation of this case, that at first the thyroid
medication exercised its usual favorable influence on the blood picture of
hypothyrosis, but that later with the appearance of the intoxication symptom
it assumed the character of hyperthyrosis.

SPORADIC CRETINISM

135

In case N., Observation XV (sporadic cretinism), the neutrophilic count
rose from 42.5 per cent. (Nov. 9) to 61.5 per cent. (Jan. 18); in case A., Ob-
servation XVI, from 32.5 per cent. (Oct. 15) to 67.2 per cent. (Dec. 22), under
treatment with large doses of thyroidin.

Summarizing these observations, it may be said that on the absence or
insufficient production of thyroid extract in the juvenile organism, the devel-
opment of the hematopoietic system is severely inhibited. Agreeing with
this is Diederle's observation that the disturbance in the growth of bone
does not lie in the marrow of the epiphysial cartilage alone, but also in the
bone marrow itself. Especially does the development of the neutrophilic
cells suffer damage. There exists a slight grade of status lymphaticus that
perhaps is in relationship with the faulty development of the chromaffin
tissue.

The metabolism of sporadic cretinism has been carefully studied in the
excellent investigation of Magnus-Levy. I reproduce from the table of this
author the following figures:

Age,
years

Length,
cm.

Weight,
kg.

Cc.,
02

Cc.,
CO2

Cc., Oz
per kg.

Relation of the Oi excre-
tion to that of a healthy
individual

Case I

29

98.0

21. I

77-5

54-5

3-67

48 per cent.

Case 11

14 84.0 15.8

72.6

59-4 4-62

60 per cent.

Case III

46

132.0 42.5

122.4 I°4-9 2.88

• 53 per cent.

Case V 14

131.5 29.5 154.1 137-0 5-22

96 per cent.

(light)

In the fully developed form, the fundamental exchange is therefore much
reduced.

With this agrees the experiment of v. Bergmann. He investigated the met-
abolism of a one-year-old child, employing the Voit-Pettenkofer apparatus.
The child was put in equilibrium with a supply of calories that was far below
that needed for a healthy child of like weight. Concerning the albuminous
metabolism, I shall refer to the chapter on myxedema adultorum. The salt
metabolism in infantile myxedema is dealt with in investigations of Haugardy
and Langstein. These authors found that in their case the assimilation of
calcium amounted to about one-third of that of a normal child the same age.
In this the intensity of the inhibition of bone growth finds expression in a
pretty manner.

As concerns the carbohydrate metabolism, I might mention that in the
three cases of sporadic cretinism that we investigated the assimilation limits
for carbohydrates lay rather high several weeks after the withdrawal of thyroid
medication. Also injection of adrenalin did not lend to glycosuria, while on
the contrary injection of adrenalin with simultaneous administration of sugar
always yielded strikingly high sugar percentages in the urine. Perhaps we
may seek the cause of this in the fact that in sporadic cretinism also the de-

136 THE DISEASES OF THE THYROID GLAND

velopment of the other ductless glands suffer damage on account of the
disturbances appearing in early youth, so that the simultaneous overburden-
ing of the alimentary and the nervous factors bring about an appreciable
insufficiency.

The reduction of the metabolic processes expresses itself, here as in
myxedema adultorum, in a hypothermia. For the most part the temperatures
lie near 36°; also in my cases, the level of temperature was low.

In his case Diederle found during the last week of the life of the patient
33.4°. Then again an increase of temperature may remain absent when
infectious processes occur. However, this is not usually the case. In the
case of Bourneville, already mentioned many times, the temperature during
a case of erysipelas rose to 40° Celsius.

The statements as to the behavior of the hypophysis in sporadic cretinism
do not agree. Extirpation of the thyroid gland in young rabbits leads to
enlargement of the hypophysis (Rogowitsch, Gley, and others). Microscopical
alterations of an apparently degenerative nature have been many times
described. Again, in many cases of sporadic cretinism the hypophysis or
the sella turcica is enlarged. In my case, however, the X-ray examination of
the skull showed no enlargement of the sella. Schilder likewise found in his
three cases of thyroaplasia no enlargement of the sella; but on microscopical
examination he found peculiar cells that approached near to the so-called
"pregnancy cells" of the hypophysis.

In sporadic cretinism the thymus gland often seems hypoplastic ; Pineles
found thyroaplasia and thymus aplasia combined. Bernheim-Karrer and
Rucacz-Gruchet found only slight rests of the thymus. Other observers
found the thymus normally developed.

The marked inhibition in the development of the osseous and the blood
systems and the ductless glandular system would lead us to expect that there
would also be something wanting in the development of the central nervous
system. This in the high-grade cases expresses itself not only in the absence
or remaining backward of the mental and psychical development, but even
in the inability to carry out the movements that subserve finer coordination.
As Kassowitz observes, the children learn late to balance their heads, to sit,
and to walk.

Such cases, as for instance the case of N. described (Observation XV),
have almost nothing human left about them. They give utterance to only
some inarticulate sounds and almost every sign of mentality is absent.
They do not go to the toilet to void urine or feces. N. always devoured his
feces whenever he could get access to them. In lighter cases the disturbance
of mental development is somewhat shorter. Usually the sense of smell is
well developed.

The statements as to disturbances of hearing in sporadic cretinism are very
diverse. The assumptions as to the cause of these diverge greatly. It is

SPORADIC CRETINISM 137

certain that the absence or insufficiency to the function of the thyroid may
lead to disturbances of hearing. I refer to the results of thyroid medica-
tion that are often attained in a striking manner in these cases. It is just as
certain, however, that with complete failure of the thyroid gland the organ of
hearing may be completely developed from birth on. Siebermann examined
the organ of hearing in Dieterle's cases of congenital thyroaplasia and found
entirely normal relationships in an anatomical sense. Even in a functional
sense, disturbances do not necessarily have to be present — for Maresck's
case of thyroaplasia showed no deafness. Hence what is under dispute is
only how to explain the disturbances that occur in many cases, v. Wagner
was the first to express the opinion that myxedematous swelling of the
mucous membrane of the tympanum, the Eustachian tube, etc., could fur-
nish the cause of the hardness of hearing. On the contrary, Denker states that
thyroidectomized animals after operation are completely deaf, show as the
result of histological examination no myxedematous alterations of the
mucous membrane and the organ of hearing, nor any degenerative alterations
in the nervous organ of hearing or in the bulbar centers. The hypothesis of
a dysthyric hardness of hearing (Block) is therefore denied. It is feasible
to think, as many otologists assume, that central perception of the stimulus
of sound suffers. There is then concerned a form of cortical deafness, or that
form of deafness which Heller describes as psychical deafness, in which the
perception of words does not come to consciousness, or as Gutzmann suggests,
serious defects of attention or a high-grade weakness of memory for speech
make their perception of words entirely impossible. Not entirely easy is
differential diagnosis from sensory aphasia. The distinction is made possible
only by the characteristic signs of feeble-mindedness. One of my cases
(case N.) seemed to be deaf-and-dumb. This was striking as otherwise
complete hearing mutism [Horstummheit] does not seem to occur in sporadic
cretinism. The ear tickling reflex was present. From the side of the spec-
ialists, hearing mutism [Horstummheit] was supposed to be present (Dr.
Frbschels). The conception of hearing mutism is not, however, uniform
among otologists. Gutzmann, Nadoleczny, H. Stern and others speak of hear-
ing mutism only when it concerns individuals (mostly children from third
to seventh year) who are mute in spite of intact intelligence and intact
hearing. These cases of pure hearing mutism are not common. In the case
of N. there indeed occurred, after several months' treatment with large doses
of thyroidin (to seven tablets a day), a slight, but distinct, degree of ability
to hear (lid reflex). Unclear however remains the circumstance that also in
complete absence of thyroid gland from birth, deafness does not always de-
velop; as has already been mentioned, there occur cases of thyroaplasia that
heard. Also I should not neglect to mention that in the numerous dogs on
which I myself performed thyroidectomy, and on which later exact investi-
gation disproved any existence of accessory thyroids, there were never to be

138 THE DISEASES OF THE THYROID GLAND

observed perceptible mutism even after a period of observation lasting up
to two years. The question still needs careful study.

In cases in which the power of hearing is markedly affected or is absent, the
development of speech is of course also slight; in the case mentioned, case X.,
it was limited to a few inarticulate sounds.

We know nothing as to the etiology of thyroaplasia and thyrohypoplasia.
Pineles states that there are sometimes malformations, tuberculosis, or alco-
holism in the ancestry, but this statement does not explain much. For in-
fantile myxedema, all those damaging influences come into consideration that
were set forth for myxedema adultorum. Worthy of note is the statement of
Spolverini, that sucklings who were nursed by women with goiter developed
myxedema. All of Spolverini' s observations, however, do not seem to me to be
free from objection. It seems well in this case for us to assume an expectant
attitude, until more observations have been made. The thyroid secretion
does not seem to go over in the milk, as according to many observations
(Lange and others) it was found that sucklings who were nursed by healthy
women, might yet develop myxedema.

Differential Diagnosis. — In the diagnosis of infantile myxedema all those
points are to be considered that were mentioned in the diagnosis of myxedema
adultorum. To these are added in infantile myxedema the ear marks of the
remaining behind in the physical and the mental development. Among
these the inhibition of ossification is especially important. Siegert is justified
in emphasizing this. One should not forget, however, that in many vegetative
disturbances, that have nothing to do with the thyroid gland, a delay in
ossification may exist. As far as it affects only the closure of the epiphyses,
as for instance in the case in eunuchoidism, it offers no difficulty from the
standpoint of differential diagnosis, as in infantile myxedema the delay in
growth and that in the occurrence of the bone nuclei is very evident. On the
contrary, there occurs in true infantilism and in hypophysial dwarfism an en-
tirely similar, although in most cases not such a severe, delay in ossification
as in infantile myxedema. It is true that growth in infantilism may some-
times be hastened through thyroid medication, but not in such a manner as
in sporadic cretinism. Hypophysial dwarfism tends to behave similarly (see
Chap. VI). In both conditions, moreover, the assimilation boundaries for
thyroidin lie essentially lower than in sporadic cretinism.

The distinguishing of the etiologically different forms of cretinism in vivo
is often difficult, and in many cases quite impossible. Light cases, or those in
which the delay in development sets in at a later stage are to be counted as
infantile myxedema. In the severe cases that occur quite early the assump-
tion of a thyroaplasia is better warranted, but is not to be relied on in vivo,
as the negative finding on palpation is valueless.

We shall consider in the third chapter the delimitation from endemic
cretinism.

TREATMENT OF ATHYROSIS AND HYPOTHYROSIS 139

Treatment of Athyrosis and Hypothyrosis

Light grades of thyroid insufficiency may heal spontaneously or under the
use of thyroid-gland tablets (probably on account of the stimulating action
of the iodine they contain on the thyroid and on account of the raising of
all metabolic processes). In the severe cases, and especially those with com-
plete absence of the thyroid, an ideal therapy would be the implantation of
a new thyroid gland.

Already A. Schijf tried to remedy the deficiency, in animals in whom the
thyroid gland had been extirpated, by the implantation of a new thyroid.
H. Bircher was the first, in 1889, to succeed in the implantation of a thyroid
in a case of very severe cachexia strumipriva.1 He implanted with good re-
sults a human thyroid into the abdominal cavity ; there soon, however, occurred
a relapse. A new implantation brought about considerable improvement,
indeed even there was a return of the menses, which had ceased for a year;
but this result too was not permanent. Later Collins and Macpherson re-
ported results in myxedema that lasted from one and one-half to two years.
In these cases there were many renewed transplantations. Even more
favorable results are reported by Gibson and others in sporadic cretinism.
Horsley proposed that thyroids of monkeys or sheep be transplanted under the
skin of the breast, Rehn under the skin of the throat. New hopes were aroused
by the attempt of Payr to transplant thyroid tissue into the spleen, at first in
animals, later in a four-year-old case of sporadic cretinism. In the case last
mentioned the thyroid tissue came from the mothers. There occurred an
essential improvement which affected, in addition to the myxedematous
symptoms referable to the skin, also the intelligence and the growth of bone
(12 cm. in five months). But also in this case the result was not permanent.
Kocher suggested transplanting thyroid gland into the bone marrow. Mos-
zkowicz implanted thyroid-gland tissue into the tibia of a six-year-old myxe-
dematous child. Here too the result was good, but only transitory. (Per-
sonal communication.) Also the results attained by Bramann seem to have
been only transitory.

New hopes have been awakened through the important investigations of
Carrel on the suture of vessels. Stick and Makkas succeeded in doing auto-
plasty on dogs; heteroplasty did not however succeed. Enderlen and Borst
come, on the ground of their interesting experiments, to the conclusion that
autotransplantation, that is, the transplantation of the thyroid gland from
one part of the body to another of the same individual represents per-
manent results. Homiotransplantation, that is the transplantation of the
thyroid gland of an individual to another of the same species, for instance,
from dog to dog, or from goat to goat, remained without results even when
tin- animals were from the same parents. The vessel suture indeed healed,
1 The experiments of v. Eiselsberg are of extraordinary interest for tetany and will be con-
sidered under that caption.

140 THE DISEASES OF THE THYROID GLAND

the vessels remained patulous, the glands however became absorbed. Ex-
periments on cretins likewise led to negative results. The thyroid artery
and vein from the upper pole of the thyroids obtained from struma operations
on man were united to the axillary vessels of the cretins; but here also there
came about a gradual absorption of the glands. Enderlen and Borst con-
cluded that already the slight biochemical differences that exist between
the tissues of different individuals of the same species are sufficient to prevent
a permanent functionating of the engrafted organ.

Therefore the sovereign method of treatment to-day is still the administration
of thyroid-gland substance.

Murray first proposed the treatment of myxedema with carbolated glyc-
erin extracts from the thyroids of animals and practised this with good
results. Also Kocher, Leichtenstern, Ewald, and others saw good results.
Since that time, however, Fox, Mackenzie, and others found that they could
succeed in inducing the action of the active principle also by administering it
by mouth; this method superseded all others and to-day is alone practised.
At the beginning one saw individual cases of severe acute intoxication. In
many of these death occurred with profuse diarrhea after the ingestion of a
very slight amount of thyroid-gland substance. Here the effect must have
been due to putrefied preparations, as the symptoms deviated from those of
thyroidin, and the latter appeared only after the ingestion of much larger
doses.

Of the numerous thyroid-gland preparations that are found on the market
to-day the tablets of Burroughs, Wellcome &° Co. [England] and those of
Parke, Davis &• Co. [America] are characterized by the intensity and uni-
formity of their action. They consist of dried sheep thyroid and come
on the market in doses of 0.1-0.3 gm.

Of other preparations I mention the thyreoidinum siccatum (Merck},
thyraden (Kocher), in pills or tablets representing 0.0007 gm- iodine, and iodo-
thyrin or thyroiodin (Bayer), i gm. contains 3 mg. active substance or 0.3
mg. iodine, representing the iodine content of i gm. fresh lamb's thyroid.

According to the investigations of Fonio, the action of thyroid prepara-
tions on the metabolic processes (protein decomposition, diuresis, body
weight, etc.) parallels their iodine content. This does not hold good for all
actions of the thyroid-gland substance. For instance there occurred in my
own experiments with iodothyrin in every dose (to 7 gm. daily) action on the
metabolism much greater than that on the cardiovascular apparatus. Then,
too, much larger doses of iodothyrin than of tabloids are needed to induce
symptoms of hyper thyroidism. In his substitution experiments Magnus-
Levy ascribes to iodothyrin the same activity as that of thyroidin. It is quite
undoubted that iodothyrin exerted a powerful influence on the fundamental
exchange of Magnus-Levy's patients — yet we cannot make out from Magnus-
Levy's protocols whether on long-continued administration also the influence

TREATMENT OF ATHYROSIS AND HYPOTHYROSIS 141

on bone growth was the same. According to this it is not at all likely that, as
Pick and Pineles state, in young thyroprivic dogs the symptoms of deficiency
are not fully combated by iodothyrin, but that they are combated by the
English tablets.

Thyroantitoxin, potassium iodide, and hypophysis substance are, as
shown by the experiments of Magnus-Levy, entirely actionless.

As far as the dose is concerned, it is well in every case to begin with small
doses and gradually to increase. In adults we give one to two English tablets
daily and can gradually increase to from three to five. If we have attained
a favorable result, we may again decrease the dose to two or one tablet.
Children are usually first given one-half tablet, which may be increased to
from two to three tablets. In my cases of sporadic cretinism I went transi-
torially as high as seven tablets, in one case indeed to nine. Kassowitz recom-
mends thyreoid elixir (Allen H anbury, London), of which one coffee-spoonful
represents about one-sixth of a sheep's thyroid gland. Children under a half
year should be given one-half coffee-spoonful daily, later increased to one
coffee-spoonful. Only in children over twelve years of age did Kassowitz
order up to two coffee-spoonfuls per day.

The result of thyroid-gland medication in myxedema adultorum is in the
most cases an immediate one. The myxedematous swellings may undergo
an appreciable reduction even in a few days. Together with this there goes
for the most part, a loss of the body protein, that for the most part depends
on the rapid melting down of the myxedematous tissue. In the cases in
which very marked swellings have occurred, the skin is lax and wrinkled.
It acts very rapidly on the secretion of sweat, in that the previously dry
skin becomes moist; then too, the marked scaling ceases. The action on
the trophic disturbances naturally takes a long time, but are no less striking.
The bald spots on the head cover again with new hair ; the hair on the axillae
and on the genitalia become thicker, the hairs again feel soft and pliable.
The pulse becomes more rapid, the protein exchange and the fundamental
exchange rise to normal, the appetite increases, the beginning loss of weight
supersedes the gradual increase in weight. The diuresis becomes more abun-
dant, the lowered temperature rises at first somewhat above the normal, and
then remains normal. The action on the blood is usually slower; usually
a medication of several weeks' or several months' duration is required
before the red cells and the amount of hemoglobin come back to normal and
before the differential counts of the white cells show normal values. The
mental condition improves much more rapidly. The apathy may appreci-
ably improve after only a few days, the patients become more active, they
take a more active interest in their environment, and the memory improves.
Also the mental disturbances accompanying the myxedematous condition
show a pronounced improvement and under the thyroid medication may even
become entirely normal. In the case of Pilcz already mentioned the illusive

142 THE DISEASES OF THE THYROID GLAND

ideas disappeared entirely; with the withdrawal of the medication the myxe-
dema and also the mental disturbance recurred. A renewal of the therapy
again brought about cure, that remained definite in spite of discontinuation of
the treatment. This patient had a goiter. Pilcz supposes that in this case
the thyroid gland regained its activities through the stimulating influence of
thyroid medication. Also the hardness-of-hearing sometimes accompanying
myxedema often shows a decided improvement. The English Myxedema
Commission found that among one hundred and nine cases of myxedema,
nearly the half showed disturbances of hearing; this disappeared under
thyroid treatment. Also speech becomes livelier, even at the beginning
of treatment, as Magnus-Levy states. In many of the cases stuttering
appears at the beginning of the medication. Gutzmann explains this in the
fact that the desire for speaking becomes rapidly increased, while there is a
certain awkwardness of speech due to inhibition of the peripheral speech
mechanism (swelling of the mucous membrane of the mouth, the nose, the
throat, and slight mobility of the velum palati). Then, too, the disturbances
in the sexual sphere improve, often astonishingly. The dysmenorrhea dis-
appears, the long-absent menstruation may recur, in men potency may
again return. Existing albuminurias tend to disappear.

The results of thyroid medication' in typical cases is to be regarded as
almost certain. Already Heinzheimer has collected one hundred and fifty
cases from the literature in which a complete favorable result was brought
about by the treatment. Cure can occur even when myxedema has existed
for a long time. In a case of Dunlop the myxedema had existed for twelve
years.

In the cases of formes frustes of myxedema the results are just as satis-
factory. Especially in the cases of thyrogenic obesity, thyroid medication,
as already mentioned, brings about, with diet freely chosen and with improve-
ment of the general conditions, a rapid reduction in weight, while marked re-
duction of the caloric supply only produces conditions of weakness.

Sometimes, indeed, the results of thyroid medication in myxedema are not
so revolutionary. In the first place it may happen that on account of the long
duration of the disease more deeply seated disturbances have developed,
for example, high-grade anemia, which then furnishes a slight resistance to
the administration of thyroid gland. In other cases symptoms of thyroidism
rapidly appear, which call for the limitation or eventually the discontinuation
of the agent. In such cases it may happen that the symptoms of myxedema
are only a little influenced while tachycardia, insomnia, excitation, etc., make
their appearance rapidly. Such a case was first described by Beclere. Here
the myxedema gradually disappeared. There occurred, however, rapid loss
of weight, tachycardia, insomnia, excitations, polyuria, albuminuria, partial
paraplegia, sensation of heat, sweats, tachypnea, transitory tremor, and a
slight grade of exophthalmus.

TREATMENT OF ATHYROSIS AND HYPOTHYROSIS 143

Mabille believes that the simultaneous administration of small doses of
arsenic prevents the occurrence of symptoms of hyperthyroidism. Ewald
agrees with him. Magnus-Levy missed this action of arsenic. Hertoghe
warns against the administration of alcohol or morphine during the thyroid
medication. He recommends administration of sodium bicarbonate, or,
when diarrhea occurs, of bismuth.

In general we may well assume that typical cases of myxedema show a
high tolerance for thyroidin. When manifestations of thyroidism occur, the
cause of these may lie in a simultaneous degeneration of the heart muscle,
that reacts more quickly to thyroid medication, or we are probably not deal-
ing with typical myxedema, but with a combination of myxedema symptoms
with symptoms of deficiency on the part of the other ductless glands (see
multiple sclerosis of the ductless glands).

The action of thyroid medication in sporadic cretinism deviates in many
points from that just described. On the one hand, there here occurs a num-
ber of other disturbances which relate to the existing disturbances in develop-
ment (growth in size, dentition, sexual sphere, etc.); on the other hand, it
is intelligible that with the long existence of the inhibition of development
degenerative conditions have become established that are no longer reparable.
Very significant results are hence to be expected only in light forms or when
the treatment has been started early. Very significant seems to be the
influence on growth. Already in 1896, Buschan collected from the literature
thirty-two cases which showed rapid growth under thyroid medication.
Latterly, statements as to this subject have considerably increased.

X-ray examination shows that with the increased growth in height there
occurs rapid appearance and growth of the bone nuclei, or rapid ossification
of the epiphysial junctures.

Hertoghe states that in myxedematous children under certain circum-
stances, administration of thyroid may lead to such a rapidly increased
growth in height that scoliosis or kyphoscoliosis develop. In the fully
developed form of sporadic cretinism in which the epiphysial junctures are
often fully open in the third and fourth decade, there may still occur under
thyroid medication, appreciable growth in height and finally closure of the
epiphysial junctures and the fontanelles.

As is the case with ossification, the previously retarded dentition also
shows a sudden acceleration. I cite from the reports of Kassowitz the
following example: A twenty- two-month-old child had not a single tooth;
after a six months' treatment sixteen teeth had erupted. A similar accelerat-
ing influence is exercised on the formation of the permanent teeth. A ten-
year-old girl had only remnants of the milk-teeth; after one year's treatment
she possessed six, after two years' treatment eighteen permanent teeth.
Very pretty examples of the stimulation of growth through thyroid medica-
tion are found also in Oppenheim's text-book of neurology and in Siegert.

144 THE DISEASES OF THE THYROID GLAND

Under the influence of the medication the umbilical hernias disappear,
not rarely in a few weeks, sometimes] after a month. These are almost
constant in infantile myxedema, and often appreciably large.

Finally, just as significant is the influence on the genitalia and the second-
ary sexual characters. Magnus-Levy reports the case of a forty-five-year-old
cretin, in whom at the beginning of medication the pubic hair began to
develop and the penis began to increase in size. In a case of cachexia
strumipriva, in whom the struma had been totally extirpated at the age of
fourteen, thyroid medication was begun in the twenty-eighth year. Al-
ready after two years there was noticed a certain sexual development, after
seven years all sexual characters were present and sexual maturity was at-
tained. In the fully developed form of sporadic cretinism it is not, of course,
to be expected that a late-introduced treatment is able to bring about pro-
creative capacity.

Also the mental development takes part in this general impetus.

In the severe cases of infantile myxedema permanent administration of
thyroid substance is necessary; when the therapy is discontinued relapses
occur, even when the administration of the larger doses have transitorially
brought about symptoms of hyperthyroidism (Knopf elmacher) . In slight
cases the result is mostly a permanent one; in such cases we assume that
under the stimulating influence of the therapy the thyroid gland has held
fast to its development, or the less altered parts have recovered.

Thyroid therapy has been tried in a great number of disease conditions that
have nothing directly to do with myxedema and is often very much valued.
I shall speak of its value in obesity in the consideration of the various forms
of obesity at the end of this book. Its influence in diseases of the hypoph-
ysis, the sexual glands, infantilism, and multiple sclerosis of the ductless
glands, I shall refer to in the appropriate chapters. Very much under dis-
cussion is the use of thyroidin in the treatment of scleroderma. Since
Singer first reported as to the favorable results a series of good results have
been published. In other cases there were soon manifested symptoms of
thyroidism with only slight improvement of the sclerodermic symptoms, in
still other cases, finally, the treatment failed entirely. The literature as to
this subject is found in detail in Cassirer's communication, v. Notthaft is
of the opinion that favorable results, where they have been obtained,
depend only on the stimulation of the general metabolism (consult also the
statements as to the ductless gland theory of scleroderma in the first chapter).
As to therapeutic results in endemic cretinism see the next chapter.

Addendum

With regard to inflammations of the thyroid, cases of acute idiopathic
thyroiditis have been reported by Dutrow and others. In Dutrow's case,
which was accompanied with a leucocytosis of 12,000, prompt relief was ob-

ADDENDUM 145

tained on incision. In the majority of cases, such energetic treatment will
not be necessary. The application of cold to the neck in this case is a means
of physical treatment that must not be forgotten or dispensed with.

The question of dysfunction in the cases of Basedow's disease has by no
means been disposed of, and in America has attracted no less an authority
than Halsted, who has been much impressed with recent experiments of,
among others, Klose, Lampe, and Liesegang. Lampe has been active in
applying to the sera of Basedow's patients the Abderhalden reaction, with
various organs as the objects to be acted on, with the result that he finds
present in the sera ferments against ovaries, thyroid, thymus, and no other
organs. Deutsch has also experimented along these lines and has found that
thymus gland tissue is split up also by normal serum. The significance of
these experiments would seem to point to some defect of thyroid secretions;
whether or not the positive results of the experiments mentioned above would
tend to rule out simply a mere excess of thyroid secretion is not known to the
editor.

The fact that the sera act on ovaries in the Abderhalden test would point
to some defect in ovarian action. It is well known that Basedow's disease is
often associated with, in addition to the menstrual disturbances that seem to
be a part of the disease itself, pelvic disturbances, and that the disease is often
considerably ameliorated, if not cured, with the remedying of these pelvic
conditions. This fact has been repeatedly pointed out, and is mentioned
among others by Porter. According to Lampe, dysfunction of the branchio-
genic organs leads to dysfunction of the sexual glands. In some women,
there is no doubt that the pelvic or the sexual trouble has led to marital un-
happiness, this even when there is no gross gynecological lesion. According
to Thomas, who in speaking of the subjects of exophthalmic goiter states that
"nearly every married woman with whom I have discussed the matter has
admitted some sort of incompatibility with her husband, and since it almost
always appears during the active sexual life, I strongly suspect a distinct
relationship."

The transition into the sexual sphere leads us once more into the confines
of the Freudian hypothesis. Scarcely any of the most ardent of the advo-
cates of Freud would venture the assertion that Basedow's disease is the re-
sult of a suppressed sexual experience of childhood, yet such a Freudian dis-
ciple might find evidence for it in a case of Basedow's in a child fifteen years
old, that I saw at the St. Agnes Hospital, Philadelphia. This child had been
the victim of an attempt at rape, immediately after which it developed the
classical symptoms of Basedow's disease (I am not certain as to the pres-
ence of an enlarged thyroid) and almost utter inability to speak, which
symptoms had persisted for some months. I am not certain as to the ulti-
mate fate of the child, as she had been referred to the hospital from a country
district, and paid only one visit to the hospital.

146 THE DISEASES OF THE THYROID GLAND

It is evident that in the above case the sexual element if present at all was
subordinate to that of the factor of fright, which was present also in the
present case, seen by me at the St. Agnes Hospital. It was that of a highly
religious, intelligent married woman, M. H., aged twenty-nine years, who
during the strain of nursing a sick father, sustained a fright, during which
she found that a burglar had entered her store. A few weeks later her
father died. Since the time of his death she suffers from obsession of
a religious and " immoral" nature, in the course of which she dares God to
do his worst by her, and wishes harm to people. Sometimes the obses-
sions are of a sexual nature, and objects in her environment suggest to her
thoughts that she is ashamed of. The patient dreams very much, but
none of the dreams have a sexual content, at least so far as she states.
Her mental and physical conditions have improved somewhat recently, in
consequence of a stay at a sanitarium. She has been happily married for
five years, shows a moderate amount of libido (it increased very little during
the earlier stages of her illness), but has had no children, not because she uses
means to prevent conception, but because according to a doctor her "womb
is turned/' There is some evidence of hyperthyrosis, fine tremor, pulse 112,
rather large thyroid, suggestion of exophthalmos, leucopenia of 2000 and
various accessory signs (tendency to looseness of bowels rather than con-
stipation, hair has become finer and more luxuriant).

The factor of fright in the etiology of Basedow's disease has been empha-
sized by Crile, whose name is important in the ductless glandular diseases in
general, not only because of the fact that he has developed an ingenious theory
for the explanation of certain of these diseases (especially Basedow's disease),
but also because of his theory and practice of treatment in operating on Base-
dow's disease and in general (principle of anoci-association). Crile agrees
with the author that Basedow's disease is conditioned by a state affecting the
central nervous system; in the course of this the nerve cells of the cerebral
cortex become chromatolytic, at the same time that the cells of the liver and
the suprarenals become less granular. These organs together with the thy-
roid gland, and the muscular elements constitute the kinetic system, the pur-
pose of which in the organism is the conversion of potential energy into
kinetic energy. The above changes, if I understand Crile rightly, are more or
less theoretical for Basedow's disease, but have been obtained by him in a
number of conditions such as the various forms of traumatic, emotional, and
toxic, foreign proteid, and anaphylactic shock, as well as in various forms of
drug poisoning and anemia. As has been stated, Crile has formulated on the
basis of theory his principle of anoci-association upon which is founded a
method of operating in which the deleterious effects of shock are minimized
by a combination of local and general anesthesia. The method has been
applied especially to operations on the thyroid gland. Whether or not the
good results attest to the truth of the theory, or whether the combination of

ADDENDUM 147

the two forms of anesthesia summate in some other way is of theoretical im-
portance ; practically, the good results speak for themselves, and are attested
to by Frazier and Mutter. The method is attended with a number of refine-
ments of technique for the consideration of which the reader is referred to
Crile's work. One of the important factors is a sort of psychic treatment,
consisting in the fact that the .patient is gradually habituated on successive
days to the method of general anesthesia, while under the impression that
he is receiving treatments. As has already been stated at another place,
Crile's theory is based on observations on 40,000 nerve cells, and forms an
interesting explanation for the r61e of the central nervous system in the
etiology of Basedow's disease.

The effect of thyroid secretion on the central nervous system, the close
connection of the central nervous system with the thyroid is instanced in the
association of epilepsy with thyroid disease, especially exophthalmic goiter.
This association which is acknowledged cursorily by Kocher and Gushing was
pointed out by the translator some time ago. It is interesting that a short
time after the translator presented his cases, through courtesy of Potts he
presented the history of an adult female who developed epileptiform convul-
sion for the first time after the use of double the prescribed doses of thyroid
extract. It is probable that in this case, and in some of the cases previously
reported by the translator, the thyroid-gland substance acted as a toxic
agent on a central nervous system already predisposed to the occurrence of
epilepsy. It is interesting, however, that the thyroid extract is one of the
metabolic products that acts in this way.

With regard to the laboratory symptomatology of Basedow's disease,
Kocher has corroborated his conclusions as to the blood picture in Basedow's
disease by over 670. cases that have been operated on. He regards the blood
examination as of the greatest diagnostic importance in light and obscure
cases of Basedow's and myxedema. In 155 cases of myxedema there were
only twenty-six that did not show a leucopenia. The degree of absolute
leucopenia is more considerable than in Basedow's disease, lying between 3000
and 6000. Lymphocytosis lies between 30-40 per cent, less than in Base-
dow's disease. The mast-cells are 0.2-0.4 per cent. In myxedema the
coagulation time is decreased, to as low as six minutes. This hastening of
coagulation is very constant. The blood picture approaches the normal
with favorable therapeutic procedures.

Cases of diffuse colloid goiter approach the type of blood picture of myxe-
dema. Nodular goiters show, as a rule, a normal blood picture, or, occasion-
ally that of hyperthyrosis.

This blood picture has been much discussed, and is worthy of even more
close study than it has received, especially in view of the more recent studies
of the pathology of the thyroid gland in goiter by Wilson and by Plummer,
stated below.

148 THE DISEASES OF THE THYROID GLAND

Fonio's experiments have shown that when thyroid or colloid goiter or
Basedow's struma preparations are administered to myxedemics there
occurred an increased elimination of nitrogen, increased diuresis, and de-
crease of the body weight, and that the nitrogen elimination varied directly
as the iodine content of the preparation administered. In the two cases
he worked on, he was unable to substantiate a hyperleucocytosis or an
eosinophilia.

In passing, the editor would state that in America the condition myxe-
dema seems to be relatively rare.

So far as the pathology of the thyroid gland is concerned, MacCarty,
from a study of over 2500 thyroid glands removed at operation, divided these
into the symmetrical and the asymmetrical or nodular. The symmetrical
glands contain various combinations of an adult and a fetal type of tissue
element or of hypertrophied acini containing colloid, or of acini that contain
little or no colloid material, but that possess lumina almost completely filled
with large hypertrophic or hyperplastic cells. The simple nodular or simple
symmetric thyroids contain nodules with a fetal type of cell, while the re-
mainder of the parenchyma of the thyroid gland possesses various combina-
tions of the tissue elements described under the symmetric thyroids. The
complex nonsymmetric thyroids may show, in addition, various combina-
tions of the tissue-element types in the nodules.

Still more recent studies on the pathology of the thyroid gland have been
made by Wilson and byPlummer, who base their conclusions on the enormous
material of the Mayo Clinic. These authors divide goiters with symptoms
of intoxication into, clinically, the exophthalmic and nonexophthalmic
forms. In the first form only is there a true hypertrophy and hyperplasia
of the gland tissue. The pathology of toxic nonexophthalmic goiter is one
of increased parenchyma through regenerative changes in atrophic paren-
chyma, or the formation of new parenchyma of the fetal type with an increase
in each instance of secretory activity and of absorption. The process is a
chronic one, but one sufficiently active to cause the patient to consult a
surgeon earlier than do the true exophthalmic goiter patients, in whom the
disease is acute.

Gilbride has examined the thyroids in six cases of exophthalmic goiter
bacteriologically, and isolated a bacterium in one case only — micrococcus
tetragenes.

With regard to the treatment of Basedow's disease, internists and
surgeons occupy hostile camps. More and more has the opinion gained
ground that the condition is an affection demanding surgical attention.
Nevertheless border-line cases should first be given the benefit of properly
directed medicinal dietary and physiotherapeutic measures.

5. Solis-Cohen has a strong conviction that surgical measures are indicated
only in a small minority of the cases of exophthalmic goiter that come under

ADDENDUM 149

the eye of the alert physician. He recognizes the following indications for
treatment.

1. When the disease has persisted and, despite proper medical and hy-
gienic care, is advancing.

2. When the disease is progressive or far advanced.

3. When the patient's means or social status is such that rest is im-
practicable, and the disease, although slight, has persisted under treat-
ment for a year or more without signs of yielding.

This author estimates the number of cases in which surgical intervention
is necessary at about 5 per cent, of the total number. He recommends in-
dividualization in treatment, the keynote of which is rest. Correction of
the eye conditions, fresh air, proper diet, the drinking of hot water for its
diuretic and eliminative action, intestinal antiseptics, neutral quinine hydro-
bromide (5 gr. or more thrice daily), ergot, picro toxin, calcium chloride, digi-
talis, strophanthus, and even cactus all have their place in the medicinal
therapy. In addition hydrotherapeutic measures, electricity (ionic appli-
cation of iodine to the gland or to the cervical sympathetic, or the high-
frequency discharge to the neck or to the vertebra prominens) and the ice-
bag or ice-coil to the heart or gland or spine. Among organic extracts the
author recommends especially thymus extract (0.5-3 gm- Per diem) or a
combination of thymus gland with adrenalin.

Falta has in the text cited the fact that in many cases of Basedow's the
thymus gland is enlarged. The use of thymus extract in BasedoVs disease
had better be dispensed with. The editor would advise against the employ-
ment of adrenalin on account of the tendency to glycosuria in Basedow's
disease.

Musser summarizes the results of consideration of medical and surgical
treatment in the dealing with goiter, especially exophthalmic goiter, as
follows :

1. "Endemic goiter should not be treated surgically until proper general
treatment has been employed for a long time.

2. Surgical intervention should not be advised in cases of goiter associated
with functional or organic disturbances of other secretory organs
until the associated disorders are removed or relieved.

3. If relapses occur in spite of general treatment, or in spite of treatment
directed against the disorders of other organs, a goiter should then be
treated surgically.

4. Medical treatment should be continued from six to twenty-four months.
Favorable results should not be promised unless the patient is under
the absolute control of a physician, so that treatment by rest, diet,
bathing, physical therapy and so forth may be carried out with pre-
cision and continuity.

150 THE DISEASES OF THE THYROID GLAND

5. Surgical intervention requires the same rigid and prolonged after-
treatment to give permanent results."

Musser believes that the surgeon does too much, the internist too little,
in the treatment of goiter.

Abrams recommends for exophthalmic goiter stimulation of the vagus
nerve by direct percussion or concussion over the seventh cervical spine.
In addition, he recommends pilocarpine, hypodermically or in doses of Y\§
gr. three times daily by mouth. With regard to this treatment it may
be said that Abrams uses it to give tone to the vagus nerve. If it is granted
that this method of procedure really does stimulate the vagus nerve, the
treatment is certainly not indicated in the so-called vagotonic forms of the
disease.

Stoney reports forty-one cases of exophthalmic goiter (various types)
treated by X-rays. (The anode is 6 in. from the skin, which is protected with
four layers of blankets. One-half to i milliampere of current is run through
the secondary.) Of the forty-one cases fourteen were completely cured, some
of these remaining well for over two years after the treatments, twenty-two
more have improved very much, four were somewhat better, only one did not
do well. Snow in a discussion of Stoney 's report stated that he had seen good
results from the application of the static wave current, and from the use of
Abram's percussion method.

Lewi reports a series of thirty-four cases of exophthalmic goiter and
perverted thyroid secretion [?] that he treated with high-frequency currents,
with results that he considers exceptionally good.

The editor believes that no harm is done by expectant treatment with high-
frequency currents, combined with rest and other rational methods of physio-
therapeutics ; and that such currents might be used as an alternative for the
X-rays, or as a substitute for them before they are used. Temporizing with
such methods should not, however, supersede surgical procedures in appro-
priate cases. The use of radium is mentioned by Marine in a review, and
Turner reports that results from local irradiation with radium were as favor-
able as those of the X-ray.

After hearing what these internists and physiotherapeutists have to say
let us turn our attention to the surgical side of the question. According
to Mayo, the early operation of ligation cures many cases. Early as well as
advanced cases can be cured by partial thyroidectomy. The mortality in
these cases will vary from i to 4 per cent. Combined operations are often
indicated in bad cases: first ligating one or both superior vessel areas, and,
later, doing a partial thyroidectomy.

Local anesthesia is indicated in most ligations. Local or combined or
straight ether anesthesia are the methods used for thyroidectomies, according
to the preference or experience of the individual operator.

In 900 operations performed on the thyroid in St. Mary's Hospital,

ADDENDUM i$I

Rochester, Minn., during the first ten months of 1911, the mortality was i
per cent.

Halsted in his recent article on thymectomy as a surgical procedure in
the treatment of Basedow's disease publishes the following instructive table,
which he in turn has copied from Klose (Die Basedowsche Krankheit, Ergebn.
d. inn. Med. u. Kinderh., Band X, 1913).

RESULTS OF OPERATIONS FOR BASEDOW'S DISEASE

Year

Authors

No. of

cases

Cures,
per
cent.

Considerable
improvement,
per cent.

• Slight
improve-
ment,
per cent.

No
im-
prove-
ment,
per
cent.

Deaths,
per
cent.

1806

Schultz

2O

QO.O

e O

So

1808

Wolf

0

66. <;

22 c.

1900

Helferich

6

66.6

16.7

IQOO

Reinbach (V. Mikulicz)

18

66. c,

22 . C,

c c

c c

IQO2

Witmer (Kronlein)

23

4.O.Q

•2.6 2

92

92

92

IQO2

Th. Kocher

CQ

76.O

14. O

3-2

6 7

I9O3

Curtis

II

6O.O

10.0

•2.O O

I QO4

Mayo

4O

67. c.

17. ^

I C. O

IQOC,

Lessing (Konig)

8

^O. 2

27 -i

12 C

I CO?

Hartley

21

87.5

12. ^

IOO6

K. Schultze (Riedel)

CO

72 O

12 O

2 O

14 O

IQO7

A. Kocher

167

Q2 . 7

6.*.

IQO7

Itzina

7

8? 7

14 ?

IQO7

Mayo (only new cases)

1^6

78. 2

IO 6

2 . 2

1907

Landstrom

c,4

^O. 2

1C. 7

2Q. O

e. c

1908

Moses (Garre)

28

16.0

41 .6

24.9

12. C.

4- J

I9O8

Klemm. .

•?2

Ql . 2

7.4

2.4.

I9O8

Th. Kocher

icj

98.7

y /

I. •»

IQOO

MacCosh.

22

14. ^

72. 7

8.2

4.6

4.6

IQO9

Hanel

21

38.1

42.8

IQII

Sudeck

"26

84 6

4 O

4.0

I9II

Baruch . .

4O

72. C.

12. C,

11. O

15.8

I9II

v. Eiselsburg ? . .

44

6l .4

M. I

4.0

I9II

Enderlen

4O

70 o

2O. O

2. 2

2. 2

1912

Klose.

61

7C. e

9.8

1.6

IS- I

IQI2

Weispfenning

T.Q

60 O

6.6

23. •?

IO.O

Kuttner in a discussion tells of the results of his researches among old
subjects of exophthalmic goiter, with results that speak immeasurably in favor
of the surgical procedure. He stated that it was especially important to
study the remote results of operation in cases of Basedow's disease, and that
we should not consider of such vital importance merely the immediate results.
Of twenty-one well-marked cases treated conservatively, none had recovered
health, nine having been treated for a period of at least fifteen years, 35.7
per cent, had died, and only one was able to work. Of the cases of the
same series that were operated on only 17.3 per cent, had died, and of those

152 THE DISEASES OF THE THYROID GLAND

living, 86.2 per cent, had either entirely recovered or were able to do their
work.

Halsted himself has done about 650 operations in 500 patients with Base-
dow's disease. A one-sided lobectomy resulted in an approximate cure in
possibly 60 per cent, of the cases. For scientific purposes, to ascertain the
role of the thymus in Basedow's disease he recommends primary thymectomy,
or secondary thymectomy where both lobes of the thyroid have been
removed without proper effect. He states, however, that he is sorely tempted
to remove a portion of an enlarged thymus when he meets with it in the
course of an operation for Basedow's disease.

Kendall has recently succeeded in obtaining from the thyroid gland a
substance containing 60 per cent, iodine. Apparently it is di-iodo-di-
hydroxy-indol and it represents the main physiologic activity of the gland.

REFERENCES

Dutrow (H. V.). Idiopathic nonpurulent acute thyroiditis; report of a case with
complete recovery. Jr. Am. M. Ass., 1911, LVIII, p. 1761.

Halsted (W. S.). The significance of the thymus gland in Graves' disease. Bulletin
of the Johns Hopkins Hospital, Vol. XXXV, No. 282, August, 1914, pp. 223-234.

Klose, Lampe, and Liesegang. Die Basedowische Krankheit Beitrage zur klinischen
Chirurgie, XXXVII, 1912, p. 601-779.

Lampe (A. E.). Basedowsche Krankheit und Genitale. Untersuchungen mit Helfe
des Abderhaldenschen Dialysierverfahren. Monatsschrift fur Geburtshilfe und Gynako-
logie, 38, 1913, pp. 45-51. See also Lampe and Papazolu, Munch, med. Wchsch., 1913;
and Lampe, Fortschritte der naturwissenschriftlichen Forschung, herausgegeben von
E. Abderhalden, Bd. 9, 1913.

Deutsch (H.). Erfahrungen mit dem Abderhaldenschen Dialysierverfahren I.
Mitteilung. Abbau von Thymusgewebe durch normales Serum. Wien. klin. Wchsch.,
38, 26, 1913, pp. 1492-1493.

Porter (M. F.}. Diseases of the thyroid in the female. Am. J. Obst., LXIV, pp.
781-790.

Thomas (C. P.). The thyroid gland and some of its diseases. International Journal
of Surgery, Vol. XXV, Jan., 1912, pp. 6-8.

Crile (G. W.) and Lower (W. E.). Anoci-Association. W. B. Saunders & Co., 1914.

Crile (G. W.}. The kinetic system. Cleveland M. J., Vol. XI, No. 4, Oct., 1913,
p. 665. In connection with which, Hitchins (G. W.), Sloan (H. A.), and Austin (J. B.).
Laboratory studies of the activities of the brain and the adrenals in response to specific
stimuli. Cleveland M. J., Vol. XI, No. 4, Oct., 1913, pp. 684-691.

Crile (G. W.). The kinetic theory of Graves' disease. Am. J. M. Sc., New Series,
Vol. CXLV, Jan., 1913, p. 28.

Miiller [and Frazier}. Discussion of Guthne's article. Pennsylvania Medical
Journal, Vol. XVII, No. 9, June, 1914, p. 687.

Gushing (H.}. The pituitary body and its disorders. J. B. Lippincott Co., Phila.,
1912.

Kocher. "Surgery of Thyroid" in Keen's System of Surgery.

Meyers (M. K.}. Epilepsy in adult life in association with thyroid disease, a report
of seven cases. Monthly Cyclopedia and Medical Bulletin, Vol. V, No. 5, May, 1912,
pp. 266-277.

ADDENDUM 153

Meyers (M. K.). Report of a case in which epilepsy in adult life developed after the
overuse of thyroid-gland extract. Monthly Cyclopedia and Medical Bulletin, Vol. V,
No. 6, June, 1912.

Kocher (Th.~). Das Blutbild bie Cachexia thyreopriva (Myxodem. Cretinoide Zu-
stande). Archiv fur klinische Chirurgie, 99, 1912, pp. 280-303.

Fonio (A.). Ueber den Einfluss von Basedowstruma und Kolloidstrumapraparaten
und Thyreoidin auf den Stickstoffwechsel und auf das Blutbild von Myxodem, unter
Beriicksichtigung ihres Jodgehaltes. Mitteilungen aus den Grenzgebieten der Medizin
und Chirurgie, Vol. XXIV, 1911-1912, pp. 123-159.

MacCarty (W . E.). Pathological anatomy of goiter. New York State Journal of
Medicine, Vol. XII, No. 10, Oct., 1912, pp. 595-599.

Wilson (L. B.}. A study of the pathology of the thyroids from cases of toxic non-
exophthalmic goiter. Journal-Lancet, Minneapolis, Vol. XXXIV, No. 4, Feb. 15,
1914, p. 97. Also, the pathology of the thyroid in exophthalmic goiter. Tr. Ass. Am.
Phys., Vol. XXVIII, 1913, pp. 576-586.

Plummer (H. L.}. The clinical and pathological relationship of simple and exoph-
thalmic goiter. Am. J. M. Sc., Vol. CXLVI, Dec., 1913, p. 790. Also, Tr. Ass. Am.
Phys., Vol. XXVIII, 1913, PP- 587-594.

Solis-Cohen (S.). The nonsurgical treatment of exophthalmic goiter. Am. J.
M. Sc., New Series, CXLIX, July, 1912, pp. 13-20.

Musser (J. H.). Problems in the treatment of exophthalmic goiter. Am. J. M. Sc.,
Vol. CXLIII, June, 1912, pp. 810-815.

Abrams (A.). Treatment of exophthalmic goiter. International Clinics, Series 22,
Vol. IV, 1912, pp. 35-44-

Stoney (F. A.). On the results of treating exophthalmic goiter with X-rays. Brit.
M. J., Aug. 31, 1912, pp. 476-480.

Lewi (W. G.}. Exophthalmic goiter and perverted thyroid secretion and their
treatment with high-frequency electricity. Albany Medical Annals, Vol. XXXIV,
No. 2, Feb., 1913, pp. 63-73.

Mayo (C. H.). Diseases of the thyroid. Journal of the Michigan State Medical
Society, Vol. XI, No. i, Jan., 1912, pp. 1-2.

Kilttner. [Discussion.] Annals of Surgery, Vol. LV, 1912, p. 148.

Turner (D.). Radium rays in the treatment of hypersecretion of the thyroid gland.
Lancet, Sept. 27, 1913, pp. 924-925.

Marine (D.). Some remarks on the thyroid gland in its relation to Basedow's syn-
drome. Cleveland M. J., Jan., 1913, pp. 21-29.

Gilbride (J. J.). Cultures from the thyroid gland in goiter; a bacteriological study
of fourteen cases. J. Am. M. Ass., LVII, 1911, p. 1988.

Kendall (E. E.). The isolation in crystalline form of the compound containing iodine
which occurs in the thyroid. J. Am. M. Ass., Vol. LXIV, No. 25, June 19, 1915.

THE CRETINIC DEGENERATION

The enormous social significance of the cretinic degeneration in the coun-
tries affected by it may be seen by a glimpse at the following figures, which
I take for the most part from the works of Ewald and E. Bircher. In Switzer-
land 7.2 per cent, of the applicants for military service must be rejected on
account of goiter, and 2 per cent, must later be discharged. In Cisleithania
there occurred for every 100,000 inhabitants 71 cretins; in many strongly
infested districts, for example, in Murrau, in the Steiermark, there are more
than 1000 cretins per 100,000 inhabitants. In France, in 1873, there were
about i per cent, goitrous among the inhabitants and 0.3 per cent, cretins
and idiots; in Piedmont in 1883 about 0.15 per cent, of cretins; inLombardy
0.2 per cent., etc. The etiology of this affection is not as yet explained.
The study of the geographical distribution shows that goiter, goiter heart,
endemic cretinism, and endemic mutism belong together. Typical Basedow's
disease is rare in goitrous districts. Manifestations of hyperthyrosis are
commonly found there combined with those of goiter heart. The parallelism
in the distribution of endemic mutism with that of endemic cretinism is
convincingly shown by the investigations of Bircher for Switzerland, and the
statistics of v. Wagner for Austria. For lower France, there are the observa-
tions of Lobenhojfer. The group relationship of goiter and endemic cretinism
is seen not only in the fact that the cretins are almost always goiter carriers,
but also through the almost unexceptional occurrence of goiters in the ancestry
of the cretins. This and other established facts point to a common etiological
factor in the different forms of the cretinic degeneration. As to this all ob-
servers agree. On the contrary, there is as yet no agreement as to the ques-
tion whether the manifold manifestations of the cretinic degeneration are
called into existence only by the mediation of the strumous degeneration of
the thyroid gland, or whether a part of these are directly produced by the
strumous noxus and thus are coordinate with the struma.

The cretinic degeneration is found in Europe especially in the central
Alps; large goitrous districts exist in addition in the Carpathians, the German
middle mountains, and the Pyrenees. In the other parts of the earth, also,
the goiter districts lie in mountainous districts. The goiter districts change;
localities that were formerly infested become goiter-free, and conversely.
Sometimes there occurs an epidemiform breaking-out. When the affection
retrogresses in one district, first the most severe forms of the cretinic degenera-
tion disappear for the most part, while the goiter alone remains for some time

154

GOITER 155

(for example, in Baden and Thuringen). Persons who come from a nongoi-
ter neighborhood into a goiter neighborhood often develop goiter, or become
affected with it after their return. E. Bircher here cites an instructive ex-
ample. A family in a nongoiter neighborhood had healthy children. When
they came into a goiter district, the parents themselves remained non-
goitrous but had a cretin for a child. Kocher reports another example: The
parents were healthy, and as long as they lived in a goiter-fr^e district had
nine healthy children. When they came into a goiter district, they had three
cretin children, of which the first was the most pronouncedly affected.
Again the thirteenth child was normal, but very small. Breitner has recently
published a similarly instructive case. Enormous outbreaks of goiter have
been often observed in regiments after their stationing in goiter districts.
Families that remove from goiter districts can soon lose their goiters. Also
the occurrence of goiters is not rarely observed in animals, after their trans-
ference to a goiter district.

The noxus of goiter is bound in the drinking water. In the goiter terri-
tories there exist indeed especial goiter brooks; there are numerous examples
in the literature of goiter communities becoming free of goiter after they
had established drinking-water conduits from goiter-free vicinities.

The occurrence of the goiter noxus in the water is bound together with a definite
geological structure of the soil. This view has been especially promulgated by Bircher,
Jr., on the ground of his penetrating studies and excellent observations. According to
Bircher, cretinic degeneration is found only upon the marine deposits of the paleozoic
ages, the dryassic, and the tertiary ages, while the eruptive formations, the Jurassic and
fresh-water deposits, are free from the noxus. This view is not generally shared, but is,
however, set upon a working basis by the works of Johannesen, and latterly by Bircher,
Jr., and Lobenhofer. The practical significance of the investigations of Bircher, Sr.,
is seen at its best in that the community Rupperswill has become goiter-free since it
has led its water from springs lying in Jurassic deposits. A like example is furnished by
the village Asp.

Previously healthy animals may become goitrous on having goiter water

furnished to them. The noxus goiter goes through a Berkefeld filter; it is

destroyed by temperature higher than 7o°C. (E. Bircher). Therefore it is

'likely, as Wilms first assumed, that the noxus is not a miasma, but a toxin or

toxalbumin from an organic substance.

It does not dialyze, therefore behaving like a colloidal emulsion. The
struma produced shows histologically changes that are degenerative, and on
the use of weaker goiter water, also hyperplastic. The animals developed
cardiac hypertrophy, and many remained behind in growth.

i. Goiter

We understand by this term a noninflammatory, diseased alteration of the
thyroid, mostly associated with enlargement of this gland, while the thyroid in

156 THE CRETINIC DEGENERATION

most cases slioics hyper plastic manifestations, and always degenerative manifes-
tations. The hyperplasia may affect the parenchyma as well as the vessels.
The degenerative nature of the alteration is seen in the fact that the hyper-
plasia of the parenchyma is for the most part unaccompanied with increase in
function. . Therefore either the parenchyma must be less capable of function-
ating or the giving off of secretion is hindered by the sclerotic process. For
the most part there is found sufficient parenchyma capable of functionating.
According to the stronger or weaker participation of the hyperplastic or de-
generative processes we distinguish parenchymatous, vascular, or fibrous —
further, diffuse or circumscribed — goiters; when the stagnation of the secretion
is greater, we have colloid or cystic goiters. In goiter neighborhoods there
also occur hyperplastic congenital goiters. There seems to exist a certain
relationship between goiter and myomata of the uterus. At least it has been
observed that in strumous women who also suffer with myomata, the struma
also decreases in size with the retrogression of the myoma at the menopause
(Ullmann). Concerning the further distinctions, the differential diagnosis,
and the surgical treatment, I shall refer [the reader] to v. Eiselsberg's mono-
graph. Among the nonsurgical methods of treatment, I mention only the
iodine treatment. This is the more effective the more the hyperplastic altera-
tions and the less the degenerative alterations are present. That in certain
neighborhoods iodine therapy often leads to manifestations of hypsrthyrosis
has already been mentioned in detail in the chapter on Basedow's disease.
The thyroid therapy recommended by v. Bruns is less used nowadays.
Not much can be expected from the treatment of ordinary goiter by the
X-rays.

2. Goiter Heart

The coincidence of goiter and cardiac disturbance is very common. The
statistics of Schranz, which are based on an investigation of two hundred and
sixty-four goitrous school children, one hundred and seventeen goitrous adults,
and seven hundred and twenty autopsy protocols of the Innsbruck Patho-
logico-anatomical Institute, show that after subtraction of the valvular de-
fects, 23 per cent, of the children and 49 per cent, of the adults suffered from
heart trouble. Of the autopsied cases one hundred and eighty-eight showed
degenerative alterations of the cardiac muscle, some with hypertrophy.
While these figures can only partially stand ground against criticism (Wolfler,
Fr. Kraus, Minnich] they are indeed, even when reduced, sufficient to show
the common coincidence of goiter and cardiac disturbances. Rose showed, be-
fore Schranz, that the stagnation [congestion] in the lesser circulation caused
by the large goiter can lead to dilatation and insufficiency of the right heart
(so-called Rose's goiter heart). When the embarrassment to respiration on
account of the goiter enters more into the foreground we call the condition,
following the lead of Kocher, pneumonic goiter heart. Conversely, primary

GOITER HEART 157

stagnation in the lesser circulation may lead to enlargement of the thyroid
gland with greater or less manifestations of hyperthyroidism (Revilloid's
"goitre cardiaque").

Revilloid already mentioned that slight manifestations of hyperthyroid-
ism may occur with this "goitre cardiaque." This was later made intelligible
by the experiments of Blum which showed that ligation of the thyroid veins
leads to an eddying out of the thyroid-gland secretion and therewith to a
slight hyperthyrosis. Later, cirrhotic changes occur in such thyroids.

Fr. Kraus first mentioned that there were numerous cases of cardiac dis-
turbances in goiter in which all stagnation is absent, and in which, therefore,
the mechanical factor as a cause does not come into consideration. In the
light forms of these are found tachycardia, often dicrotism of the pulse, slight
strengthening of the apex impulse, beating of the carotids, sometimes arrhyth-
mia, glittering eye, sometimes indeed a slight degree of exophthalmus, in-
clination to sweating, trembling, and eventually slight heightening of the
fundamental exchange, in short phenomena of a slight hyperthyrosis. In the
severer forms are found, in addition, hypertrophy and dilatation of the heart
and degenerative changes in the cardiac muscle. Also v. Mukulicz and
Reinbach found similar symptoms in a great percentage of the goitrous that
they examined.

The fact that hypertrophy and premature degeneration of the cardiac
muscle is found so frequently in the goitrous with cardiac disturbances indi-
cates that we are here not dealing with the ordinary forms of hyperthyroid-
ism. Fr. Kraus first championed the greater nosological independence of this
form; the newer investigation, results of Minnich and E. Bircher seem fully
to corroborate his contention. The opinions of Minnich, in his significant
monograph, in so far as he regards these Basedow's manifestations as the
expression of a diminished thyroid-gland function, are not shared by the
author. Entirely new views, however, are opened by Minnich in his descrip-
tion of cardiac disturbances in relatively young strumous individuals of
)oth sexes, which mostly set in with new impulses in the growth of the goiter
and lead objectively to enlargement of the heart, eventually with the gradual
development of a protrusion of the precordium, and frequently also of
accidental murmurs and subjectively to pains in the cardiac region, pricking
pains, pressure, painful precordial points of tenderness, and cardiac palpita-
tions. Such cases may remain stationary a long time, or even become cured,
>r they may go over into tachycardia. This was the case in eleven of twenty
:ases. Here, therefore, we are dealing with a form of goiter heart in which,
it least in the beginning, hyperthyroidal symptoms were hardly present.

The fundamental significance of these observations is supported by the
experiments of E. Bircher. Bircher saw enlargement of the heart almost
regularly in the animals in which he artificially induced struma by giving
them goiter water to drink. The weight of these hearts averaged one-third

158 THE CRETINIC DEGENERATION

more than that of the hearts of the control animals. The heart muscle
microscopically for the most part showed degenerative changes. Bircher
refers the cardiac damage directly to the goiter noxus ,and in agreement
with Minnie h sees in it a disease sui generis.

According to a personal communication from Prof. Scholz also the endemic
cretins usually have bad hearts, but no hypertrophy ; this fact may hang to-
gether with the gradually and long-continued action of the goiter noxus, per-
haps also with the slight "expressions of life" [Lebensausserungen] of such
individuals.

3. Endemic Cretinism

Symptomatology. — The habitus of endemic cretinism shows a much
greater multiformity than that of sporadic cretinism. Dieterle compares
the photographs of seven youthful cretins of eighteen years of age from Bern
with that of sporadic cretins from fourteen months to twenty-one years of
age, and shows that despite the fact that the latter come from different
countries, they show much similarity to one another, while the others re-
semble one another less strongly although they come from the same family.
Dieterle cites the doctrine of Majfeis, that there is no cretinic prototype.
The skulls, too, in endemic cretinism show greater differences; in many
endemic cretins the skull is small, the forehead low and receding; in others the
skull is abnormally large. Regularly the root of the nose is retracted, al-
though never to so great a degree as in chondrodystrophy; for the most part
the eyes stand wide apart, the throat is short and thick, the lips are cushiony,
the facial expression morose. Ordinarily the skeleton shows abnormalities
— ankyloses, scolioses, etc. Scholz describes flattening of the head of the
femur. The pelvis is often narrowed in all dimensions, and the bones are
provided -with swellings [Wiilsten]. Also there is difference in the degree of
dwarfism. v. Wagner observed individuals under 90 cm., although there
are full cretins over 150 cm. in body length. E. Bircher of Aarau has kindly
provided me with Figs. 18-22. Fig. 18 shows the multiformity of the facial
expression and the shape of the skull in endemic cretinism.

The duration of life of the cretins is in most cases shortened, yet some
cretins attain a very high age. Kocher reports about seventy-year-old and
even one-hundred-year-old cretins.

The figure is awkward, the gait inelastic, the muscles are poorly developed ;
individuals with completely developed forms can indeed not walk, but can
only creep. This depends, however, not as much on the muscular weakness
as on the want of every fine coordination. The skin of the face is often very
lax, numerous transverse wrinkles traverse the forehead and lend to the
face an old appearance. The development of the myxedema is very diverse.
Magnus-Levy and v. Wagner found in many cases typical supraclavicular
pseudolipomata, and also on other places of the skin very evident pad-like

ENDEMIC CRETINISM 159

swelling and myxedematous alteration of the mucous membrane. Scholz
found the skin only atrophic. In 60 per cent, of the cases investigated by
E. Bircher the myxedematous swelling of the skin was absent. There are
also cases that sweat profusely. The hairs are for the most part short and
bristly, the nails torn, the teeth defective, the hair in the axilla:! and on the
pubes may be absent or only sparsely developed. Umbilical hernia in chil-
dren as well as obstipation and distention of the abdomen is just as frequent
as in sporadic cretinism. Often conjunctivitides are found, and as a result

FIG. 18. — Group of endemic cretins from Aarau.

of these, eczema of the palpebral borders. According to Hitschmann, the
conjunctivitides probably develop through disturbance in the leading off of
the tears on account of the saddle nose. There mostly occurs a fairly high
degree of anemia. The disturbances of intelligence of the cretins may vary
from the slight grades of feeble-mindedness up through all the grades to the
failure of all mental expression — the so-called plant man. In such cases
all development of speech is also absent. In most cases, however, some psy-
chical development is still present. The perception, however, is somewhat

i6o

THE CRETINIC DEGENERATION

slowed, the memory very poor; as for the emotions, the cretins show a certain
clinging for the persons who feed them or hate against those whom they
regard as enemies.

The pathologico-anatomical findings in the brains of cretins are very di-
verse. Often they are only trivial; in most cases, however, there are found
several alterations, and these of greater intensity. Scholz and Zingerle
found at times chronic meningitic alterations and a slight grade of hydro-

FIG. 19. — Endemic cretinism. FIG. 20. — Cretins with myxedematous facial expression.

cephalus. The brain may be smaller in to to — or in individual lobes; often it
is highly asymmetric, sometimes there is found a persistence of the juvenile
developmental stages, or in rare cases excessive development. The dis-
turbances of development may affect the hemispheres as well as the brain-
stem, the cerebellum, etc. The confirmation of the surface of the brain
is often pathologically affected in that the convolutions are smaller or their
number lessened. In abnormally small brains of cretins it may well be sup-
posed that the smallness of the brain is primary, that of the skull secondary;

ENDEMIC CRETINISM

161

as Bournei'ille taught of idiots' brains. The brain substance of cretins, accord-
ing to Scholz and Zingerle, is often strikingly compact, the amount of gray
matter [relatively] exceeding in mass the white.1 The disturbances of de-
velopment may affect different parts in very different ways. The inhibition
of the development of the sense organs is certainly to be ascribed, in part, to
the faulty development of the central organs.

The nervous status commonly shows increase of the reflexes, according to
Scholz in 52 per cent.; the field of vision was found by Ottolenghi to be re-
stricted, especially outward and upward. Hitschmann found the eye
grounds normal in nearly all his cases; only in certain cases were crescents
directed downward found, relationship of which with the cretinic degenera-
tion was entirely obscure. The testing of sensibility, of the sense of taste and
smell, naturally presents great difficulties.

FIG. 21.

FIG. 22.

FIGS. 21 AND 22. — Cretins with myxedematous facial expression.

The disturbances of hearing are of very diverse degrees. In many cases,
the power of hearing is fully intact. In others, there exists a slight or severe
grade of hardness-of-hearing or mutism. Frightfully large is the number of
mutes who are completely deaf.

Endemic Mutism. — In all countries in which cretinism is endemic there
is found a large number of deaf-mutes. According to the older statements
of St. Lager, Switzerland possesses five thousand cretins and four thousand deaf-
mutes. To the latter, of course, belong some cases of sporadic mutism, that is,
those which depend on a meningitis in earliest youth, on otitides or formation

1 1 have here rectified the author's error by reference fo Scholz and Zingerle' s article. The
German text here transposes "white" and "gray." — Editor.
ii

1 62 THE CRETINIC DEGENERATION

anomalies of the brain, and which have nothing to do with the goiter noxus. A
very great number, however, belong to endemic cretinism (according to
E. Bircher, So per cent, in Switzerland). Also in Austria, and especially in
the Stiermark, are found an enormous number of deaf-mutes. Scholz found
among the cretins examined by him 29 per cent, deaf-mutes and 32 per cent,
hard-of-hearing. The intensity of the disturbance of hearing does not go
parallel throughout with that of the remaining cretinic symptoms. There
are complete cretins that show only slight disturbances of hearing and speech.
In others the mutism may be the chief symptom of the cretinic degeneration
(larval form of v. Eiselsberg) .

The statements as to the functional disturbances or the pathologico-
anatomical findings in the deaf cretins and in the endemic deaf-mutes diverge
greatly. Hammerschlag, whom we have to thank for the first exact investiga-
tions, found on the one hand alterations in the peripheral hearing apparatus,
and on the other only disturbance of the perception of sound, as also found
Scholz, Froschel, and others. Further, there was found in endemic cretinism
incomplete ossification of the stapes, inhibition of development of the epi-
thelial cells in the ductus cochlearis (Habermann, Alexander), shortening of
the base of the skull and thereby disturbance in the development of the organ
of hearing (Danzinger, Bircher), incomplete ossification of the organ of hearing
with hyperostotic growths at other places (Moos and Steinbrugge) . Anom-
alies of the malleus (Nager), myxedematous thickening of the tympanic
mucous membrane, etc., have been regarded as the cause of the hardness-
of-hearing. Recently, E. Bircher has strenuously criticised a portion of these
findings or their significance. To-day we may safely assume that we may
ascribe great importance to the degeneration in the cortical centers or the
developmental inhibitions in the cortical centers, and that the different altera-
tions are directly elicited by the goiter noxus and are coordinated with an
insufficiency of the thyroid, which finally sets in (Pineles).

The inhibition of the development of speech in endemic cretinism is extra-
ordinarily different [in degree]; where hearing is entirely absent, of course,
the development of speech is also absent. We do, however, see cases in
which in spite of high-grade disturbances of hearing only relatively slight
defects of intelligence are present. Of course, in these cases articulation is
poor (Hammer schlag) . In other cases, in spite of good hearing, intelligence
and the development of speech are minimal. Here also we assume a de-
velopmental inhibition of cortical centers (Scholz and Zingerle). Where
the endemic shows less intensity, defects of intelligence may be entirely
absent (H. Bircher).

Investigations as to the metabolism in endemic cretins have been pub-
lished only by Scholz. Scholz designates the metabolism as very sluggish.
The amounts of urine were very slight, as well as the exchange of protein and
of salts. The excretion of nitrogen, uric acid, creatinin, and sodium chloride

ENDEMIC CRETINISM 163

was very slight, and that of urea, the xanthin bases, ammonia, and sulphuric
acid showed corresponding proportions. There was further noted a tendency
to retention of phosphorus and nitrogen. The metabolism therefore shows
a relation analogous to that in myxedema.1 Very interesting are the results
of feeding with thyroid gland. Diuresis increases. The nitrogen elimination
was not, however, essentially influenced, while the body weight diminished.
Therefore chiefly nitrogen-free substances must be consumed.

As the cretins investigated showed no distinct myxedematous swellings,
it was not to have been expected that the initial increase of the protein
combustion observed in myxedema would be present. The experiments
all show that the depressed protein exchange in endemic cretinism cannot be
stimulated so easily as in myxedema. I cannot see in this an analogy to
Basedow's disease, as Scholz does, as the absence of a further increase of
nitrogen elimination through thyroid substance in Basedow's disease may
have its ground in the circumstance that the excess of thyroid-gland secretion
does not come distinctly into action, if in higher grades of hyperthyrosis the
energy of the protein decomposition has reached a great intensity. Scholz
further observed in his experiments that under the influence of administra-
tion of thyroid gland, the calcium in the urine decreases markedly and in-
creases in the feces, as we have also observed in normal individuals.2

For the most part there is found in cretins a fairly evident hypoplasia of
the genitalia. In women the labia and the uterus are mostly small, but it
may happen that the external genitalia are relatively well developed; the
ovaries are small and often show small cystic degeneration; the menses are
absent or are scanty and irregular; the mammae are poorly developed and with-
out glandular tissue. In men the penis is often very small, the testicles are
not well descended, and on microscopical examination show spermatozoa
very sparingly. The scrotum is lax. In both sexes the secondary sexual
characters are for the most part very defectively developed; the sexual in-
stinct is entirely absent or is very weak only; in many a light case, however,
procreative power and conception are observed. E. Bircher reports con-
cerning a cretin of the most severe grade who conceived; the fetuses, how-
ever, are not capable of living, even when, as in a case of Eppinger, they show
no sign of cretinic degeneration. The genitalia can, however, like ossifica-
tion, still show a late development.

Worthy of observation are Schonemann's investigations, which show that
in neighborhoods where goiter is endemic strumous alterations are found
very commonly in the glandular part of the hypophysis. Among one hundred
twelve cases, the hypophysis was normal in only twenty-seven. These

1 "Not however to experimental athyrosis proper." This statement of Scholz is unintelligible
to me, as according to my knowledge, an essential difference between the metabolism of myxe-
dema and that of cachexia thyreopriva does not exist.

2 See the chapter on hyperthyroidism.

164 THE CRETINIC DEGENERATION

•

persons did not have a goiter. Among the cases with goiter, there was only
one in whom was found a hypophysis that could be regarded as probably
normal. "In persons with struma of the thyroid, there was always found
enlargement of the hypophysis, and indeed either proliferation of the con-
nective stroma, also chromophilic strumas, strumas with especially vascular
development of the stroma and hyaline degeneration and swelling up of the
columns of cells, and finally those with marked colloid formation." v. Cyon
found strumous alterations of the hypophysis very frequently in Bernese
dogs. The goiter poison therefore works deleteriously on the hypophysis.

As in sporadic cretinism, the disturbance in bone-growth consists of delay
in the epiphysial closures and in retarded appearance of the bone-nuclei.
Langhans first described, in the skeletons of five cretins, the remaining behind
in the ossification and commented that also the cretinoids show a similar,
although less marked, remaining behind. "The bones previously laid out in
cartilage grow slowly in their length; the epiphyses remain low, the boundaries
of ossification progress very slowly, the nuclei of ossification in the epiphyses
occur very late, and the epiphysial discs are retained for long beyond the
normal term. Remnants of these discs are still to be found in the forty-fifth
year." v. Wyss has confirmed the observations of Langhans by means of the
X-ray examination of numerous cretins and cretinoids — and incidentally has
finally contradicted the previous view that in cretins premature ossification
of the epiphysial junctures occurs. This delay in the epiphysial closure
makes intelligible, as v. Wyss emphasizes, the former observations of v.
Wagner that in endemic cretins, even in late life, the growth in height may go
on. To this extent the disturbance in the ossification agrees fully with that
in sporadic cretinism, although on the other hand there are differences that
are important from the point of view of differential diagnosis. Already
v. Wyss pointed out that the retardation in the ossification for the most part
lasts only a few years, so that only rarely are the epiphysial junctures found
to be open after the twenty-fifth year.

Dieterle mentions especially the extensive difference from thyroaplasia in
this behavior of the epiphysial junctures, which in thyroaplasia, if thyroid
therapy be not introduced, often remain open. In youthful age in endemic
cretinism, however, the remaining of the ossification behind that of the normal
individual is not inappreciable. Dieterle publishes a very instructive table
in which he compares the ages of the cretins of v. Wyss as estimated from the
radiograms of the hands with the actual ages of the individuals. He finds in
eleven cretins between the ages of seven and eighteen years a remaining
behind of ossification of from three to seven years. Breus and Kolisko
state moreover that in six of the cretin skeletons examined by them never did
all the epiphysial junctures remain open until an advanced age, therefore
there did not exist in all bones the same degree of disturbance of growth, and
that there resulted from this a dispro portioned skeleton; the extremities are

ENDEMIC CRETINISM 165

slender but shortened near the trunk, and there exists in this respect a differ-
ence between the cretinic dwarfism and the true dwarf described by A . Pal-
tauf, in which all epiphysial closures remain behind, in like manner, as in a
former child stage of development. In those cases of endemic cretinism in
which the epiphysial closures are already ossified, thyroid therapy can natu-
rally no longer lead to growth in height.

E. Bircher has recently studied the disturbances in growth in endemic
cretinism in a large number of cases (fifty-six) and has come to the same
results as Breus and Kolisko. The inhibition of the ossification affects
only the age of development. After thirty years of life the epiphyses and
synchondrosis were found open only exceptionally. Also Bircher found
throughout that the inhibition in the individual bones is quite dissimilar
and leads to a disproportioned skeleton. Not rarely E. Bircher found a
coxa vara or a humerus varus.

Of quite a manifold nature are the findings as to the teeth of cretins.
Kranz examined thirty cretins from the Knittelfeld Institute in Steiermark
as to jaw and tooth formation, and found numerous anomalies of the jaws,
retarded teething, and factors giving rise to anomalies of the position of
the teeth. Further he commonly found alterations of the structure, de-
fects of the enamel, hypoplasias and erosions and very frequently caries.
That these anomalies were not produced by the experimental extirpation of
the thyroid gland in animals is made intelligible by the conception that
athyrosis or hypothyrosis and endemic cretins are different conditions.

Very frequently statements are made that endemic cretins are anemic;
with this agrees the fact that Langhans found in a grown cretin much fat
marrow and little functioning marrow in the long bones. I was unable to
find statements as to the leucocytic formula in endemic cretinism. Mc-
Carisson, however, reports on the basis of over one hundred blood examina-
tions in endemic goiter a regular increase of lymphocytes and in most cases
hypereosinophilia.

The statements as to the thyroid gland in endemic cretins vary greatly.
v. Wagner found not a single normal thyroid in inspection of the neck of two
hundred cretins. Very commonly the thyroid is not palpable, but very little
value can be ascribed to this statement. In the most cases are found goitrous
degeneration with atrophy. DeCoulon found in the thyroid gland of five
cretins, who died at the age of twenty-six to thirty years, very little normal
thyroid-gland parenchyma. One of these cases was fairly well developed
mentally. Hanau examined three thyroid glands that all were small and
showed a marked disappearance of the parenchyma. Also Bayon and Get-
zowa found high-grade degenerative processes, marked diminution of the
functionating parenchyma, and enormous development of hyaline-degener-
ated connective tissue. Getzowa found, however, similar alterations also in
the thyroids of idiots and microcephalies who did not show dwarfism. On the

1 66 THE CRETINIC DEGENERATION

other hand, Bircher, Sr., found abundant normal thyroid-gland tissue in the
thyroid gland of one of the cretins that he operated on. Recently E. Bircher
reports on the examination of over sixty cretins' thyroids, obtained at
autopsy or at operation. Degenerative processes were present in all, but
were of extremely varying intensity, which often did not run parallel with the
intensity of the affection. In all thyroids moreover were found large por-
tions of normal thyroid-gland tissue. E. Bircher found similar conditions in a
series of endemic deaf-mutes. Accordingly there were found in almost all cases
sclerotic and atrophic processes, but in addition always some functionating
parenchyma. Hence there was no struma whose histological picture was
characteristic for cretinism, v. Werdt arrives at the same conclusion on
the ground of the examination of five strumas that histologically showed
entirely the picture of a cretin's thyroid, without there being any sign of
cretinism whatsoever in the actual cases.

No essential alterations have as yet been found in the parathyroid glands
in cretinism (Scholz, Getzowa, E. Bircher}.

Treatment. — Before I consider the question as to the role that thyroid
insufficiency plays in endemic cretinism, I should like to speak about the
results of thyroid therapy. There are in the literature very contradictory
statements as to this. v. Wagner saw very good results. They consisted in
the disappearance of the myxedematous swellings, in the rapid development
of the genitalia, which had remained behind, in the diminution in size of the
enlarged tongue, and even in the disappearance of an umbilical hernia, in
falling out of the bristly hair and development of new hair of normal texture,
in acceleration of dentition, before all, however, in the diminution in size of
the fontanelles that had remained open, in the acceleration of ossification and
in increase in height. The least satisfactory were its results on the psyche;
it is true that there was usually a decrease in the apathy and in the lack of
movements, yet the increase in the intellectual capability was usually very
slight.

v. Wagner lays especial stress on the earliest possible beginning of the
therapy. He also saw good results in individual cases from administration of
small doses of iodine (through stimulation of the activity of the thyroid
gland?). Still better results were obtained by Magnus-Levy in fourteen
individuals from three neighboring villages from upper Munstertal in the
Vosges. These individuals came from seven families. The cretinism had
appeared in this neighborhood only a short time previously; goiters were
usually present in the relatives, and also the parents showed symptoms of
slight goitrous degeneration. In the individuals themselves the thyroid was
in many cases not palpable, only in a few goitrously degenerated. The
majority showed fairly well pronounced myxedematous symptoms. In the
severest cases were present lordosis and pendulous abdomen, in all constipa-
tion and faulty development of the genitalia. One case was highly deaf.

ENDEMIC CRETINISM 167

It is further worthy of note that a case that had developed fairly normally up
to the tenth year first showed signs of cretinic degeneration at the close of an
attack of pertussis, and finally in the sixteenth year showed a rapid deteriora-
tion with distinct signs of myxedema; in none of the cases did there exist com-
plete dementia. In all these cases there was a distinct improvement already,
four to six weeks after the institution of thyroid therapy. After one and one-
half years only one case showed an increase in height as low as 4 cm. — all the
rest 11-17 cm- The myxedematous manifestations disappeared, and the
intellectual ability improved considerably. Also v. Eysselt saw good results
in forty-six cretins in the Littauer Amtbezirke [official district] in Mahren.
In two the development of the genitalia was especially influenced. Also
Safer saw favorable influencing of the growth, and in addition also a severe
loss in weight. In two later communications v. Wagner reports about nu-
merous cases that were treated with very good results. Also in these com-
munications v. Wagner points out that the results were more favorable the
sooner the treatment was begun. In certain light cases a cure may be ob-
tained which persists even after withdrawal of the therapy. But even when
the therapy is begun in late life good results can be obtained. In the
severer grades of cretinism the result was indeed not so satisfactory.

Also the hardness-of-hearing may become essentially improved. Many
cases of hardness-of-hearing, however, do not improve.

According to v. Wagner, cretinism for the most part is not congenital, but
in the great majority of cases signs of cretinism first make their appearance in
the first years of life. For an early diagnosis are important, first of all, the
absence of disturbances of gait and speech, then the pale color of the face, the
swellings of the skin, the apathy, the retardation of the closure of the fontan-
elles and the dentition, the gradual retraction of the root of the nose and the
remaining behind in growth. In such cases of acquired cretinism a much
better result of thyroid treatment may be expected.

As an especially pretty example of the increase in height, I shall quote the
following case of v. Wagner: A fifteen-year-old boy is 105 cm. tall at the
beginning of the treatment; after a four years' treatment he has grown about
43 cm. that is about 29 cm. more than corresponds to the average growth at
this period of life. The typical saddle-nose and the apathy have dis-
appeared, he articulates fairly well, the hearing has improved, etc. On the
contrary, cases in which the cretinism appears so early that we must assume a
congenital cretinism are for the most part fairly refractory. In these cases an
influencing of the disturbances of speech and intelligence is completely absent.
But also in such cases a result seems possible when the treatment is instituted
a short time after birth. Those cases of v. Wagner which after an initial nor-
mal development first remained behind in body and mental development after
an infectious disease could indeed in part also be classified with sporadic
cretinism.

1 68 THE CRETINIC DEGENERATION

On a still larger material is based the report of v. Kutschera as to the treat-
ment of endemic cretinism in the Steiermark at the cost of the state. The
treatment was given to one thousand eleven cretins; of these a great num-
ber was treated for only a short time on account of the insufficient interest
of the parents and could not be considered in the judgment of the result.
Also there were found numerous individuals who could not be considered as
cretins, and who were separated out at a later sifting. Only in 2.4 per cent,
of all treated were the tablets not borne well. High-grade idiots and cases
of pure mutism were rejected. Of great interest were the cases the growth
of which could be followed for a long time. They were four hundred forty
in number, of which only 10.2 per cent, showed only a less growth than corre-
sponded with the age of life, 4.1 per cent, showed a growth corresponding
with this age; 85.7 per cent., however, a growth that exceeded the normal at
that age. Especially in the first years of life was the increase in height very
significant, but it occurred, too, in individuals at the beginning of the third
decade, in whom, under normal conditions, growth would have ceased. As to
the total results, which also took into consideration other cretinic symptoms,
among six hundred seventy-seven cases there was an appreciable improve-
ment in 42.8 per cent., a distinct improvement in 48.6 per cent., and in 8.6
per cent, no improvement at all.

Again, v. Kutschera reports light, previously treated cases, in which
complete cure was obtained after a relatively short treatment.

In rather sharp opposition to these good results are the bad results of
Scholz and also of Lombroso. The bad results of Lombroso are concerned with
old cretins. Scholz reports concerning a very large number of cases. Scholz
treated with thyroid tablets one hundred cretinous children in the infirmary
at Knittenfeld. He began with one tablet and gradually increased to three
tablets, and in certain cases up to eight tablets, per diem. The results
throughout were unfavorable. The body weights quickly sank (in certain
cases as much as 36 per cent.). The children became extremely weak, even
bed-ridden, the appetite diminished, vomiting and diarrhea occurred, apathy
increased; three children died. Increase in height was not observed. Also
there were observed other symptoms of hyperthyroidism, such as tachycardia,
sweats, etc. v. Wagner believes that these unfavorable results of Scholz
depend on too high dosage, v. Wagner and. v. Kutschera gave only a half-
tablet to small children and gradually increased to one tablet. Also older
individuals were mostly given only one tablet a day. Scholz began with one
tablet and increased apparently rather quickly to three tablets, in certain
cases even higher. In my cases of sporadic cretinism, however, even much
larger doses were necessary over even a longer time before the first manifesta-
tions of hyperthyroidism manifested themselves. Scholz later stated that he
could not obtain any good results with small doses. Also v. Wagner stated
that many severe cases, especially those which he regards as congenital

ENDEMIC CRETINISM 169

cretinism, are either fully refractory, or that at least certain symptoms,
especially the disturbances of intelligence and speech, can remain uninfluenced.
The hypothesis that in such cases, in which the noxus has already done harm
at a former period, already definitive irreparable damage has been done,
especially in the central nervous system, can explain only a slight result, but
not the complete failure of the thyroid-gland treatment, as these conditions
also obtain in sporadic cretinism, and here thyroid-gland therapy is never
entirely without [good] results.

We now take up the question as to what role the disease of the thyroid
plays in endemic cretinism.

Pathogenesis. — Kocher and v. Wagner identify sporadic and endemic
cretinism, referring all manifestations to a damaging of the thyroid gland.
Bircher, Ewald, and Scholz ascribe to the arthyrosis component only a cer-
tain signification, and see in it only one manifestation of cretinic degenera-
tion which is coordinated with other derangements.

The following is a list of the factors that speak against the hypothesis
of a thyroid disturbance alone:

1. The action of thyroid therapy is not so constant as in sporadic cretinism.

2 . The myxedematous symptoms are wanting in many cases or are only very
slightly expressed.

3 . The forms of the clinical manifestations of endemic cretinism are much
more manifold. To it belong the frequent association with mutism,
further the occurrence of mutism in cases that otherwise show only
few signs of cretinic degeneration. In endemic cretinism there is an
incongruence between the inhibition of the mental disturbances and
the other signs of the cretinic degeneration; cases that on the one
hand show struma and rather high-grade disturbance of growth are,
however, well developed mentally; on the other hand, cases that are
highly idiotic have remained behind in growth only a little.

4. Further, there exists a quantitative and qualitative difference in the
disturbance in growth. This in endemic cretinism is only delayed;
even in the highest grades there occurs later closure of the most of the
epiphysial junctures; the disturbance in growth is disproportionate
(Breus and Kolisko).

5. The hypophysis is often goitrously degenerated.

I believe, therefore, that I shall have to concur in the opinion of those
authors who ascribe to the noxus of cretinic degeneration a direct deleteri-
ous influence on the central nervous system and other tissues, probably also
on the other ductless glands. Also the independent position that according
to the later investigations we must ascribe to goiter heart is embraced in the
confines of this view.

On the other hand, the significant results of thyroid-gland therapy in many
cases of endemic cretinism force us to ascribe to the athyrosis components a greater,

170 THE CRETINIC DEGENERATION

indeed in many cases an almost determining significance. The complete
setting aside of this factor, as we see in the works of H. Bircher and Scholz,
is not in my opinion correct. E. Bircher also surely goes too far when he
explains the striking influencing of the inhibition of growth, which was ob-
served in many cases of endemic cretinism under the thyroid medication,
simply through the evidence that also the normal cartilages react to the
administration of thyroid gland, and that Scholz and Zingerle favorably in-
fluenced the growth of rachitic dwarfs through thyroidin tablets. Such re-
sults, that are to be striven after in all cases, are not to be attained in all.
I quote examples of this in the chapter on infantilism, in which the inhibition
of the osseous growth behaves refractory to thyroid therapy. The cause
of the divergence of views I would especially see in the fact that up to the
present we have too little considered that a variable importance attaches to the
athyrosis components in different individuals and in different epidemics. So,
for instance, in the epidemic that Magnus-Levy described it stood entirely
in the foreground; it is not without significance in this respect that the
epidemic that Magnus-Levy described had lasted only for a short time. Also
in numerous cases of Kocher and v. Wagner is the athyrosis predominant.
However, v. Wagner states that the cases originating in Judenburg did not
react at all to the administration of thyroid. The same is true of the severest
forms of cretinism in the Steiermark that Scholz observed, and of the cases
of Bircher. It is therefore to be supposed that at different places the noxus
works with different intensity. Significant also is the fact as to whether
the population has suffered from the affection for a long time; finally it is
probable that bad living conditions, in-breeding, and many other factors
contribute to the intensity and the clinical symptoms of the endemic.

How complicated the question is, is shown by a communication of v.
Wagner's as to marine cretinism. It is known that the seacoasts are almost
free from goiter and cretinism. Now v. Wagner observed on the island
Veglia, belonging to the Guarneric Islands, fifteen dwarfs, mostly about
100 cm. tall. The closure of the fontanelles was delayed; in most, but not
in all, the root of the nose was retracted, there existed more or less distinctly
well-expressed myxedema of the skin, high voice; there was absence of hair on
the pubic and in the axillary regions ; the genitals showed high-grade infantil-
ism, in men the mons Veneris was abundant in fat and, as is shown in the
photographs accompanying v. Wagners's publication, was limited above by a
horizontal line ; frequently there existed constipation, dentition was delayed,
the intelligence in some was only very slight, in others there existed only
slight apathy; many could not read and write; the hearing was well developed
in all. The thyroid gland was not palpable in all of them. v. Wagner
discusses the question whether these cases are to be classified under endemic
cretinism. As ground against such classification, v. Wagner adduces: the
complete freedom from goiter of the neighborhood, the marked dwarfism of

ENDEMIC CRETINISM 1 71

all individuals, the marked dysgenitalism, the normal development of hearing
and the relatively good development of speech, v. Wagner believes that
the in-breeding that exists on this island — also albinism is indigenous here —
perhaps plays a role in this, but that also the insufficiency of the thyroid
gland is the decisive factor. Very striking seems to me the circumstance
that in all individuals at first the development was entirely normal up to the
third, the fifth, indeed even the tenth year and the inhibition of growth did
not set in until this age ; the accompanying photograph shows, in addition to
the marked dysgenitalism, a form of obesity such as we are wont to find in
dystrophia adiposo-genitalis and to refer to the insufficiency of the inter-
stitial glands or of the hypophysis. The disturbance of growth seems to
me to speak decisively for the hypophysis. A strumous degeneration of the
hypophysis could perhaps have been demonstrated by an enlargement of the
sella on X-ray examination; in other cases there did exist, however, un-
doubted myxedematous alterations. Such an endemic degeneration of the
ductless glandular system with predominant involvement of the glandular hy-
pophysis occurring in earliest youth is, at all events up to the present, unique.
I cannot at first hand answer with certainty the question as to whether or
not a variety of cretinic degeneration exists in such a case.

Surveying once more the field covered in the preceding observations it
seems to me that the separation of the cretinic degeneration from the chapter
of the pathology of the thyroid gland is indeed possible and desi fable, on the other
hand it would be a mistake to relegate too far to the background the intimate
connecting associations with the thyroid gland. The separate position depends
on the localization to certain territories, depending on the fact that the noxus
contained in the thyroid gland produces very frequently, perhaps even
regularly, alterations not only in the thyroid gland but also in numerous
organs such as the heart and the central nervous system.

But there are other attempts at explanation that I have not as yet men-
tioned, v. Kutschera supposes an infectious noxus; he bases the assumption
on the following observation: dogs that have been brought up in the bed of a
cretin remained behind in development and became typically cretinic. Of
course it must be considered that these dogs were under the same external
conditions as human beings and drank the same water. Very difficult to
interpret is also the observation of v. Wagner that a dog with typical endemic
cretinism shows extensive retrogression of the cretinic symptoms after extirpa-
tion of the goiter, v. Wagner assumes that the manifold symptoms of en-
demic cretinism are produced by a poison emanating from the goiter, and
therefore, as previously mentioned, places the thyroid gland as the central
figure in the pathogenesis.

Differential Diagnosis. — The differentiation between sporadic and en-
demic cretinism is often difficult and in certain cases may be impossible. The
fact that the cretin comes from a locality in which cretinism is endemic

172 THE CRETINIC DEGENERATION

naturally is not evidence, as sporadic cretinism may also occur in some
infested neighborhood. The coming from a neighborhood where only goiter
but not cretinism is endemic cannot, without other factors, be used against
the diagnosis of endemic cretinism, as in such neighborhoods endemic cre-
tinism may occur. I refer once more to the small endemic described by
Magnus-Levy. Here too, seems to me, belongs the interesting observation
of Eller. Eller describes three cases of cretinism in a Vienna family. The
patients were goitrous and had never been out of Vienna; three sisters were
entirely well; the cretins themselves had strumas. The result of the treat-
ment with thyroid, which was not carried out perseveringly, was not
satisfactory.

The finding of a struma, slight or absent myxedematous consistency of
the skin, incongruity between mental development and the rest of the symp-
toms, relatively slight inhibition of ossification and closure of the fontanelles,
unequal remaining behind of the epiphysial closures, slight or absent
results of treatment, impossibility of stimulating the metabolism with
thyroidin, low tolerance for thyroid-gland substance speak for endemic
cretinism. As far as the disturbance in ossification is concerned, it must be
considered that this occurs in many vegetative disturbances that have noth-
ing to do either with the thyroid gland or with endemic cretinism, v. Wyss
already pointed this out; he found in four of seven individuals who, without
showing striking symptoms of cretinism had remained behind physically and
mentally, pronounced inhibition of growth and of ossification, which were in
no wise different from those which are typical for endemic cretinism. We
must therefore agree with v. Wyss that in a country in which cretinism is
endemic the differentiation between cretins and idiots is extraordinarily
difficult. The delay in ossification seems to be found regularly in cretinoids
without mental defect.

Addendum

Goiter is not at all uncommon in the United States. A close study
would perhaps show that goiter is confined in this country to certain districts.
Clark and Pierce mention that there are certain districts of endemic goiter in
the region of the Great Lakes and certain sections of West Virginia.

McCarrison was able to produce swelling of the thyroid experimentally
in men by administering to them the filtrate of boiled water from a goitrous
district. This author cites facts that make it very probable that the noxus of
goiter exists in the soil, and may possibly be transmissible from individuals.

Blood counts from seventy-three cases of goiter made under the direction
of McCarrison showed a lessening of the polymorphonuclear leucocytes in
98.9 per cent, of the cases and increase of the small mononuclear leucocytes
in 92.5 per cent., an increase of the eosinophiles in 88 per cent., and an in-
crease of the large mononuclear cells in only 23 per cent, of cases. The

ADDENDUM 173

author regards as misleading and valueless Kocher's blood count as a cri-
terion of differentiation between exophthalmic and nonexophthalmic goiter.
He treats goiter, with striking reduction of the goiter, by the use of intes-
tinal antiseptics such as salol and thymol, milk soured by the bacillus bul-
garicus and the injection of vaccines prepared from bacillus coli. His
publication contains a map showing how goiter is distributed.

Gilbride has made a bacteriological examination of the contents of eight
cystic goiters, with negative results, save in one case in which he found the
streptococcus vermiformis of Sternberg. McCarrison states that Horand has
reported the presence of a parasite in a goitrous cyst, but adds that in
neither this work nor in that of Gilbride is there sufficient evidence to justify
the suspicion that the organisms found are causal agents in the production of
goiter.

REFERENCES

„

Clark (7\), and Pierce (C. C.). Endemic goiter. Its possible relationship to water
.pply. U. S. Public Health Reports, April 17, 1914.

McCarrison (R.). The etiology of endemic goiter. London, John Bale Sons &
Danielsson, 1913.

Gilbride (J. /.). Cultures from the thyroid gland in goiter. A bacteriologic study
of fourteen cases. J. Am. M. Ass., Chicago, 1911, LVII, p. 1988.

Horand (R.). Examen a 1'ultramicroscope du liquide du goitre kystique; presence
d'un parasite. Rev. gen. de Clin. et de Therap. Par., 1911, XXV, p. 71.

CHAPTER IV

THE DISEASES OF THE PARATHYROID GLANDS
(Glandulae Parathyreoidae)

[Parathyroid Glandules, Epithelial Bodies, Epithelkorperchen]

Anatomy. — The parathyroid glands are paired organs showing intimate
spatial relationship with the thyroid gland. In man there are usually
two parathyroid glands on each side. They have a length diameter of
3-15 mm. and a thickness or width of about 2 mm. According to Erd-
heim, the upper parathyroid glands (epithelial bodies) lie against the posterior

Gl. pth.

Gl. pth.

FIG. 23. — Parathyroid bodies of man (according to Zuckerkandl) . Posterior view of organs of
neck. Gl. pth. = parathyroid glands.

surfaces of the lateral lobes of the thyroid gland about the middle of the
height of the lobes, and the lower parathyroids lie toward the lower pole
of these lobes ; but not rarely there are exceptions with regard to both number
and position of the parathyroids. On one side there may be as many as
three or four of these bodies (Schrieber et al.) ; the lower bodies may lie- as

174

ANATOMY AND EMBRYOLOGY

175

low as against the upper pole of the thymus. Statements even exist that
accessory parathyroids are pushed down to the pericardial fatty tissue
(Vassale and Piano). The bodies, especially the upper, are bound to the
thyroid gland by connective tissue, and the upper may also in part be inter-
polated in the thyroid tissue. We find in the different species of animals
great variations in the number and position of the parathyroids. In the
cat, the upper parathyroid is always imbedded in the thyroid tissue; in the
dog it is sometimes fully imbedded there (inner parathyroid, Kohn), so that
extirpation of the parathyroids alone may be attended with great difficulty.

60S. C.

, •*'"' " " •'•'••'.'•'.' •":*:-. ^ -

C. C.
FIG. 24. — Parathyroid gland. F. C. = fat cells; eos. C. = eosinophilic cells; C. C. = chief cells.

It is especially important, moreover, that in herbivorous animals the para-
thyroids are entirely apart, spatially from the thyroid gland.

The parathyroids are very abundantly supplied with blood. Between
the individual cell groups are found numerous strikingly wide capillaries.
The glands are supplied by the inferior thyroid artery.

Histologically the parathyroids are characterized by great richness in
cells. According to Welsh, large polygonal chief cells and smaller so-called
oxyphilic cells are to be distinguished from each other.

Embryology. — The parathyroids are entodermal glands (Verdun). Fig. 3
shows how the parathyroids and the thymus gland originate from the
branchial arches.

The epithelial bodies (e3 and £4) come from the dorsal part of the third

176 THE DISEASES OF THE PARATHYROID GLANDS

and fourth branchial pouch. The thymus gland comes from the ventral part
of the third pouch.

If the bilaterally arranged thymus gland becomes pushed down the para-
thyroids may come to rest on the thymus gland or even to be included in its
substance. From the illustration it will be also seen that the relationship
of the parathyroids to the thyroid is purely topographical. _E4 represents
the inner parathyroid gland which may eventually become included in the
tissue of the thyroid.

Historical. — It will be seen from the intimate spatial relationship between
the thyroid and the parathyroids why for a long time the functional inde-
pendence of the parathyroids was not recognized. As a sequence of the
first attempts at total thyroidectomy, by Schiff, Kocher, Rivardin, v. Eisel-
berg and others, there were observed, in addition to the results of the absence
of the thyroid as described in Chapter II, severe acute manifestations that
were uncommonly like the tetany that had formerly been observed in
human pathology. The difference in topography of the parathyroids in
different animal species, as just described, makes intelligible why in some
species thyroid extirpation led to cachexia strumipriva, in others to tetany.
The discovery of the parathyroids, in 1880, by Sandstrom, first made a
change in this respect. Indeed Sandstrom at first regarded the bodies described
by him as the embryonal stages of thyroid tissue that had remained at a
standstill; Gley, who in 1891 first discussed the physiological significance of
the parathyroids, believed that these bodies would assume the function
of the thyroid on extirpation of that gland. A. Kohn first taught the
anatomical independence of the parathyroids; Moussu, and Vassale and
Generate their functional independence. Kohn also introduced the term
"Epithelkorperchen." The investigations of Pineles, Biedl, Erdheim and
others to-day place the independence of the parathyroids beyond question.
The observations of aplasia of the thyroid with retention of the parathyroids,
as detailed in chapter on the thyroid, showing the complete picture of
deficiency of the thyroid with no symptoms whatever of tetany, further
the fact that the absence or deficiency of thyroid gland only, not however
that of the parathyroids, is made good by thyroidin therapy, and finally the
fact established in animal experimentation that extirpation of the para-^
thyroids alone leads to tetany but not to myxedema, make certain the
teaching of the physiological independence of the parathyroids and have furnished
the demonstration that tetany has nothing to do with the absence of thyroid
gland, but depends on an insufficiency of the function of the parathyroids.

It is only one step from this knowledge to the view that the different forms
of tetany observed in human pathology (parathyroprivic tetany), idiopathic
or occupation tetany, tetany of children, tetany of maternity, stomach
tetany, tetany in infectious diseases and poisonings, etc., depend on a
uniform pathological basis, and that at the bottom of all is an absolute or

TETANY 177

relative insufficiency of the parathyroids (Jeandelize, Pineles, Escherich,
Erdheim, Chvostek, Jr., Rudinger, and others).

a. Aparathyrosis or Hypoparathyrosis, Tetany

Definition. — By letany we mean an abnormally increased condition of
excitement of the nervous system, which is demonstrable in a heightened excitability
of the motor, sensible, sensory and vegetative neroes, and under certain circum-
stances, in paresthesias, and bilateral intermittent, for the most part painful,
spasms, with intact consciousness, or which becomes manifest through phenomena
of irritation on the part of the vegetative nerves. To the picture of tetany belong
also trophic and certain metabolic disturbances. The manifestations are the
result of an insufficiency of the parathyroid glands.

Symptomatology/ — Increase in the electric excitability is to be regarded,
next to spasms, as the most important cardinal symptom of tetany. It
affects in the first place the peripheral motor nerves (Erb), although the sen-
sory senses (Hoffman], and the nerves of special sense (acusticus-Chvostek,
Jr.), are overexcitable to electricity. This hyperexcitability is found espe-
cially on the use of the galvanic current; the faradic excitability is most often
normal. The ulnar nerve serves best for testing in adults; the peroneal
nerve in children. We should use Stintzing's normal electrode (3 sq. cm.)
and Edelmann's horizontal galvanometer. The hyperexcitability expresses
itself not only in a lessening of the irritation threshold against the cathodal
closing contraction, but also in a definite alteration of the contraction formula.
In normal individuals the lower limits for the C.C.C. lies at about 0.9 milli-
ampere for the ulnar nerves, for the A.C.C. at about 1.5 to 2 milliamperes,
for the A.O.C. about 2.5-3 milliamperes, for the C.C.Te about 5 milli-
amperes, and the C.O.C. can hardly be obtained even with high amperage.
Now in tetany the C.C.C. can fall to very low values (as low as o. i milli-
ampere, and also the values for A.C.C. fall (even to 0.5 milliampere) ; it is
important, however, that the value for the A.O.C. fall and eventually be-
come lower than that of A.C.C. and even lower than that of C.C.C. Further
C.C.Te occurs at very low values, and finally also C.O.C. may be ob-
tained. Also A.C.Te and A.O.Te may be obtained sooner. The first
statements as to the galvanic hyperexcitability came from Kussmaul and
Benedict; the first exact measurements were made by Erb. In the tetany
of children, first Escherich and Jauregg v. Wagner pointed out the galvanic
hyperexcitability. Thiemich regarded the falling of C.O.C. below 5 milli-
amperes as conclusive for the diagnosis. It was shown, however, by v.
Pirquel that this relation obtains only in the most severe cases and that the
slight grades of tetany are first recognized in a falling of the value for A.O.C.,
in the so-called anodal hyperexcitability.

ErVs phenomenon may be present in the most of the motor nerves ac-

178 THE DISEASES OF THE PARATHYROID GLANDS

cessible for the test. For the most part it is present in like intensity in
symmetrical nerves, although there are exceptions to this rule. For in-
stance v. Frankl-Hochwart found in the right ulnar in a case a C.C.C. of 0.3
milliampere, in the left ulnar a C.C.C. of o.i milliampere. Erb's phenom-
enon, like all the symptoms of tetany, shows great variations. It is most
distinct at the onset or during the acute exacerbations, less distinct, as a
rule, during the intervals. In the chronic tetany that extends through many
years the galvanic excitability can, during the interval free from attacks, ap-
proach the lower limiting values of the normal, and may even show values
as high as for normal individuals. As v. Frankl-Hochwart points out, this
relation is beautifully shown in the tetany of maternity; here the galvanic
hyper excitability is seen only during pregnancy or lactation. Erb's phe-
nomenon is the most important symptom of tetany, because we as yet know
of no other condition in which it occurs. It is also very frequent, v. Frankl-
Hochwart says that he has not seen any acute case of tetany with normal
electrical excitability; exceptions do, however, extremely rarely, occur.
Kahn and / observed a case of chronic tetany with acute exacerbations, in
which all the important symptoms of tetany were present pronouncedly, but
Erb's phenomenon, in spite of the presence of severe spasms, was absent
during the first days. The condition ameliorated; Erb's phenomenon was
positive only on an acute exacerbation of the illness, which occurred after
about two weeks.

A heightened excitability to the electric current is shown by the sensory
nerves also (Hoffmann). We usually test the ulnar nerve. Paresthesias
occur in its distribution even on very low values of the C.C.C. There occurs
too an analogous change in the sensation formula. Finally the nerves of
special sense may be hyper excitable. With relatively low current strengths,
Chvostek, Jr., found sensory reactions in the acoustic nerve with analogous
alterations in the formula of sensation in six out of seven cases of tetany. v.
Frankl-Hochwart found a similar relation to the galvanic current of the
taste sensations. Occasionally, in testing the electrical excitability, when
the electrode is placed over the mastoid process there occur with very low
current strength, and often before the occurrence of contraction, ear noises
and finally a bitter taste sensation (Falta and Kahn). These symptoms are
subject to great variation.

Another certain symptom of latent as well as manifest tetany is the
mechanical hyperexcitability of the motor and sensory nerves. Chvostek, Sr.,
first pointed out in this regard, that in tetany percussion of the motor nerve
trunks and especially the facial trunk leads to lightning-like contractions in
the muscles supplied. When the facial trunk is struck, the contractions
rarely affect the muscles of the forehead, v. Frankl-Hochwart distinguishes
three degrees of the phenomenon depending on the intensity. In Chvostek
I on percussion of the vicinity of the auditory meatus contractions occur in

TEXAN Y 179

the muscles that close the eyelids, in those of the alae nasi, and in those of
the corner of the mouth. They may even be brought about by slight
stroking of the front of the ear with the handle of the percussion hammer
(Sckultzc}. In Chvostek II there are contractions of the alae nasi and
muscles of the corner of the mouth on percussion under the zygomatic
arch. In Chvostek III percussion here causes contractions of the corner of
the mouth only. As to the pathognomonic significance of the different
degrees of Chvostek1 s phenomena for tetany opinions are at variance.

The phenomenon is certainly very frequent in tetany, yet it may be
wanting in pronounced cases and often shows great variations. On the
other hand slight degrees of it may occur in numerous cases of neurasthenia,
hysteria, and epilepsy, v. Frankl-Hochwart and Schlesinger found Chvostek
II and /// in nearly one-half of patients with phthisis: However, other
authors, for example Schonborn (Heidelberg), do not find this phenomenon
so frequent. It is found commonly also in rachitis. Kahn and 7 found
it several times in rachitis tarda. Mager found it very frequently in
enteroptosis, v. Frankl-Hochwart in strumous individuals. It is especially
frequent in all possible sorts of cachexia, especially when this is associated
with much loss of water from the body. Curschmann especially has pointed
this out. Kahn and / observed it also in severe diabetes, and also in almost
all cases of Reichmann's disease. It is probable that in a great number of
such cases this phenomenon depends not so much on the mechanical ex-
citability of the nerves as on that of the levator anguli oris muscle, as we
tap too on the insertion of this muscle in the procedure. For this view
speaks the fact that in the conditions named idiomuscular prominences were
produced regularly on the various muscles.

Chvostek II and /// are also seen not rarely in entirely normal individuals.
Hence they are not pathognomonic for tetany, although it should be noted
that these phenomena are very frequent in the localities in which tetany is
endemic at the season of the tetany, and that in cases of tuberculosis in
which they were present they were not infrequently found associated with
caseation of certain of the parathyroids. Chvostek 7, when pronounced,
speaks very loudly for tetany; although absence of the symptom does not
speak against tetany, as it may be wanting in the acute stages, and like all
symptoms of tetany, shows great variations. The mechanical hyperex-
citability of the sensory nerves expresses itself in the occurrence of a burn-
ing sensation on percussion of the nerve trunk or on pressure over the same.
I shall speak later about the mechanical excitability of the sympathetic
nerves of the blood-vessels.

Trousseau' 's phenomenon consists in the circumstance that pressure
on a nerve trunk will bring about a typical tetanic spasm in the area of dis-
tribution of the same, or that the constriction of an extremity with a rubber
bandage will also induce such a spasm. This phenomenon has nothing

l8o THE DISEASES OF THE PARATHYROID GLANDS

to do with alterations in the circulation, but depends on the excitability
of the nerve itself (v. Frankl-Hochii'art). However, it cannot be so simply
explained by the increased motor irritability of the nerve alone, for v. Frankl-
Hochwart saw bilateral spasms occur after pressure on the nerve plexus of
one extremity, and Schlesinger shows that this phenomenon cannot be in-
duced on the purely motor facial nerve, but only on the mixed nerves. Hence
to the hyperexcitability of the motor nerves must be superadded that of
the sensory nerves or of their spinal centers and their connecting links
[Schaltstiicke].

In similar manner would be explained the leg- phenomenon lately de-
scribed by Schlesinger. On flexion at the hip-joint of the leg that is ex-
tended at the knee there can be induced under circumstances during the time
of the freedom from attacks, a painful tonic spasm in the extremity, after
from a few seconds to three minutes. Finally should be mentioned here
the thermic hyperexcitability described by Kashida. This expresses itself
in the occurrence of paresthesias and spasms on the application of cold or
hot irritants.

In tetany the tendon reflexes are mostly normal, in the attack not rarely
diminished.

Finally it should be mentioned that the patient frequently complains
of pains in the bones or joints (Falta and Kahn), especially after severe tetanic
attacks. I shall later report such a case.

We now come to a symptom that in the full development of tetany makes
it one of the most dreadful diseases, and that has furnished its name, i.e., the
tetanic spasm. Here we meet with the greatest differences in the phenomena,
and here the individual forms of tetany show the greatest variations in the
localization of the spasm. In tetany of adults usually the upper extremities
are involved symmetrically in the spasm, and indeed in the known obstetri-
cian's position, yet there sometimes occur fist-positions with extended
thumbs, and spasms may occur unilaterally (v. Frankl-Hoclrwart, v. Jaksck,
Curschmann, et al.}. When the lower extremities are affected, they are
extended, the foot is in a slight equinovarus position, the toes are bent plan-
tarly, sometimes, however, dorsally. The spasms are exquisitely painful.

As example I cite the following case (Case VI of Falta and Kahn} .

Observation XVII. — Augustine Sch., four and one-half years old, from Vienna.
Entered the clinic Nov. 24, 1911. For three weeks emaciation, and very poor appetite.
One of the two children of the same parents died in 1909, in the first year of life, of spasm
of the glottis. The patient herself had had spasms at two and one-half years, that lasted
two days and were associated with fever. No rickets. Aug., 1910 to Jan., 1911 pertussis,
then pneumonia with measles. Since that time frequent severe diarrheas for eight days;
on Feb. 22 vomiting daily, since which six to seven bowel movements daily. Since this
morning tonic spasms in the feet.

The illustration shows the typical obstetrician's position of the hands. Also there
is distinct spasm of the left leg, as is to be seen by the tension of the tendon of the tibialis

TETANY

181

anticus muscle and by the dorsal flexion of the great toe. The diarrheas ceased on Feb.
15 (administration of tanningen), and the tetanic attacks disappeared.

In children there occurs the so-called carpopedal spasms in which the
fingers do not, as in the previous case, assume the obstetrician's position,
but are spread out. In involvement of the face, this expresses itself in a
tension of the muscles, in spasm of the lids, in slight pointing of the mouth
(fish-mouth position, "tetany face" of Ujfenheimer), in spasms of the masse-
ter, of the geniohyoglossus, and hyoglossus muscles (yawning spasms), in
difficulty of speech on account of the tonic rigidity of the tongue, and eventu-
ally in convergence or strabismus with the occurrence of double vision.
Sometimes the trunkal, nuchal, and abdominal
musculature is involved. Finally the diaphrag-
matic and the intercostal muscles may be
affected, producing dyspnea. Bechterew could
produce spasm of the diaphragm directly by
pressure over the phrenic nerve. As is known,
the involvement of the muscles of the larynx is
very common in children. Here the laryngo-
spasm often stands well in the foreground.
Moreover, the rest of the respiratory muscles
are mostly involved. There occurs inspiratory
retraction, and even lightning-like closure of the
glottis (tetanus aponicus) ; more rarely expira-
tory apnea also (Eschericti). Also in adults
laryngospasms occur not at all rarely, as
Pineles points out especially. Finally we must
mention the rare retching spasms. In the
tetany of animals in which the parathyroids
have been removed, these occur not at all
rarely; here it is associated with vomiting. The
transversely striated sphincters of the bladder
and rectum for the most part remain free, al-
though difficulty in urinating is sometimes seen
(v. Frankl-Hochwart] .

The duration of the spasms is often very
short, although at times it is hours long. The
patients often sit for a long time with retracted abdomen, the extrem-
ities in the position described, incapable of movement. Sometimes there
occurs only a single spasmodic attack; in other cases the attacks are
repeated at longer or shorter intervals; in children are observed as many
as eighty laryngospastic attacks a day.

The most manifold factors may bring about the spasm. In acute cases
a slight excitation, percussion of the abdominal musculature, may lead to a

FIG. 25. — Obstetrician's posi-
tion of the hands in tetany.

182 THE DISEASES OF THE PARATHYROID GLANDS

spasm. In latent tetany a febrile affection (angina, tuberculin injection,
gastrointestinal indisposition, introduction of the stomach sound, pregnancy,
an intoxication, etc.) may render the tetany manifest.

Ckvostek, Jr., observed the occurrence of spasms after injection of tuber-
culin. Rudinger and 7 regularly saw spasms in the acute stages occur after
injection of adrenalin. Kahn and / saw in the acute stage, also regularly, the
occurrence of increase in intensity of the tetanic symptoms during the hours
following the injection (as will be considered later).

Fibrillary contraction of the muscles, which are constant in the tetany
of parathyroidectomized animals, occur in human tetany rarely. The same
is also true as regards the pareses, which occur very frequently in totally
parathyroidectomized animals, especially in the hind extremities.

Weakness of the extremities, especially after the spasms, may also occur
in human beings. Also paralysis is observed in man (v. Frankl-Hochwari).
Chvostek, Jr., observed for instance a temporary paralysis in the ulnar terri-
tory after a spasm that was long in duration, which he attributed to the long
drawn-out extreme position of flexion. Also slight ataxias occur in human
beings as well as in animals. Spastic contractures are rare.

In adults, the sensorium is mostly uninvolved, in children it is very fre-
quently clouded, although also in adults, in the severe cases, especially in
the parathyroprivic tetany and in stomach tetany, there may occur clouding
or indeed complete loss of consciousness.

The coincidence of epileptic attacks with tetany is not rare (v. Frankl-
Hochwart, Freund, Hirschl, Fries, Falta and Kahn, Redlich, et al.). Redlich
has collected seventy-two cases from the literature. Typical epilepsy may
have existed for years, to which tetany is then superadded, or epileptic attacks
may occur in the course of tetany, or may set in simultaneously with it. Espe-
cially in parathyroprivic individuals have been observed severe unilateral or
bilateral epileptiform convulsions with loss of consciousness and slowness
or absence of pupillary reaction. Such cases may rapidly come to a lethal
end; or the tetany may altogether subside, and death follow later in status
epilepticus, or tetany and epilepsy may pass over into a chronic stage (cases
of Westphal and of Redlich) . In children severe eclamptic attacks may enter
into the course of tetany, or may occupy a position in the foreground. In the
discussion of the pathogenesis I shall take up the question of the relation of
the two conditions.

Finally it should be mentioned that in the severest forms of tetany, espe-
cially in the parathyroprivic forms and in stomach tetany, myotonic symp-
toms are observed not infrequently, v. Frankl-Hochwart designates them
as intention spasms [Intentionskrampf e] ; they express themselves in such
a manner that on such an attempted intentional movement as closure of the
hand for instance, the hand cannot be opened again for several seconds

TETAXV 183

(Schultze, Hoffmann, Bettmann, Kasparek, v. Voss, Schiejfferdecker and
Schultze, v. Orzechowski, et al.).

In such cases we also observe mechanical hyperexcitability of the muscles
and formation of pits on percussion, indeed even typical myotonic reaction
on testing with the galvanic and faradic currents. We shall consider this
more fully in the discussion of the pathogenesis.

I have already mentioned disturbances of the sensorium. In a series of
cases psychoses have also been observed (v. Frankl-Hochwart, Kraepelin,
Hirschl, and others). In acute cases, v. Frankl-Hochwart several times saw
typical hallucinatory confusion or deep depression; he found abnormal
psychical excitement and even depressive mental attitudes, fourteen times
among thirty-seven cases. Erdheim saw characteristic conditions of excite-
ment also in parathyroidectomized rats.

Finally it remains to be mentioned that in certain cases a slight grade
of choked disc or neuroretinitis has been observed (v. Jaksch, Hanke).

I now come to the description of the behavior of the vegetative nerves in
this condition. In the literature there have appeared up to the present
only a few scattered references as to this question; nevertheless I can find
ground for my statements in the work 1 did in collaboration with Eppinger
and Rudinger and especially with Fr. Kahn; in addition, there is a detailed
work on the subject of Ibrahim. The vegetative nerves show in tetany
manifestations of increased excitability on one hand and long-continued
heightening of tone on the other.

Kahn and 7 in one case observed hyperexcitability of the sympathetic
nerves accompanying the vessels. After application of the bandage for the
elicitation of Trousseau's phenomenon there occurred in addition to this
phenomenon, pronounced anemia of the phalanges of the third, fourth, and
fifth finger. Since that time I have seen this symptom once, in the case of
E. C. to be described later (Observation XVIII). In this case there occurred
regularly on application of the bandage to the upper arm or thigh, simul-
taneously with Trousseau's phenomenon, a pronounced anemia of the ex-
tremity. Here also belongs the pronounced dermographism that we find so
extraordinarily frequent in the acute stage of the disease.

The electrical hyperexcitability of the vegetative nerves in man is hard
to demonstrate. On the other hand, we may readily show the chemical
hyperexcitability as seen in the behavior of the patient on the action of
adrenalin or pilocarpine. After subcutaneous injection of adrenalin in the
acute stage of tetany there occurs almost regularly an abnormally strong
action on the blood-pressure, on the heart action, on the contraction of the
vessels of the skin, and also on the tetanic spasm. The increase in the
blood-pressure and the pulse rate was especially rapid. To it were often
added extreme paleness of the face and the skin of the entire body, strength-
ening of the heart action, subjective cardiac palpitations, and even extra-

184 THE DISEASES OF THE PARATHYROID GLANDS

systoles. In almost all cases there was an acute exacerbation of the tetanic
conditions, together with paresthesias or spasms. In the declining stage
of the disease, all these manifestations were very much less pronounced.

An abnormally strong vascular action of the adrenalin could also be
demonstrated on the parathyroidectomized dog.

Later, in the consideration of the metabolism, I will take up the question
of the glycosuric action of adrenalin in tetany.

Again, the sensitiveness to pilocarpine is essentially increased in the
acute stage of tetany. There occurs abnormally strong outbreak of sweat
or salivation, together with flow of tears, initial contraction of the erectores
pilorum muscles (gooseflesh), later marked reddening of the skin of the body
with sensation of heat and rushes to the head, abnormal increase of the
secretion of gastric juice and relaxations of stomach tonus; further, symptoms
that we do hardly see on the administration of this pilocarpine; symptoms
such as nausea, diarrhea, urinary and rectal pressure. Also pilocarpine
induces frequent tetanic spasms in the various muscular territories. The
manifestations of an increased tonus in the vegetative nerves in the first stage
of tetany are of very manifold nature. Here I follow almost verbatim the
expositions on the subject in the work of Kahn and myself.

Spasmodic conditions of the smooth ciliary muscle seem to occur very
rarely. Kunn and Fr. Muller saw mydriasis in the attack (spasm of the
dilatator papillae?). Peer and also Escherich observed transitory differences
in the size of the pupils, that Peer regarded as spasmodic conditions. A .
Fuchs saw during the attack appreciable diminution in the time of pupillary
reaction. Finkelstein saw pupillary rigidity. Ibrahim saw pupillary
differences in one case (unilateral spasm of the dilator pupillae). In this
case the neck, pharyngeal and eye muscles were especially involved in the
spasm, thus simulating the picture of a meningitis. The cerebrospinal fluid
was clear, however.

Little is known as to lachrymation in tetany; evidence as to the proba-
bility of its occurrence is furnished in one case only, that of Kahn and myself.
Here there existed slight redness of the conjunctiva and there was often an
increase in the lachrymation simultaneously with the exacerbation of the
tetany, as well as an increased flow of saliva.

Marked sweats are frequently found in the acute stage of tetany.

In tetany it is difficult to refer changes in the type of breathing to al-
terations in the tonus of the smooth musculature of the bronchi, as we must
not overlook what part spasms of the diaphragm and of the intercostal
muscles eventually play in its production. Ibrahim, Finkelstein and Popper
report cases of tachypnea. We saw dyspnea occur very frequently.

Disturbances of the action of the heart seem to be very frequent. Kahn
and / could observe in almost all cases in the acute stage strengthening of
the cardiac action, loud sounds at the apex, and even accentuated second

TETANY 185

pulmonic sound, in one case an accentuated aortic second. To this is added
lability of the heart action, in other words, slight tachycardia on psychical
excitement and abnormally high pulse rate on working. Complaints as to
cardiac palpitations are frequent. In two cases we observed, toward the
end of the stay at the hospital, occurrences of mitral systolic murmurs
that surely were not there previously.

Very noteworthy are the statements of Ibrahim. This author saw sudden
death without spasm of the glottis in three cases of tetany of sucklings,
without signs of suffocation showing at autopsy. Signs of status thymico-
lymphaticus were in these cases absent or only slightly developed. In two
of these cases the heart was relaxed in dilatation. In the third case the right
ventricle was relaxed, the left unusually hard and forcibly contracted.
Ibrahim thought of tetany of the heart, probably called forth by vagal or
sympathetic excitement. We do not as yet know how far abnormal condi-
tions of excitability of the autonomous heart ganglia or heart regulating
nerves are responsible for the manifestations mentioned.

In tetany of adults manifestations on the part of the vascular apparatus
are very pronounced. In the acute stage all tetanics have pronounced vaso-
motor disturbances. They all look pale, in spite of the fact that, as we
shall see later, blood counts show high figures for red cells and a hemoglobin
value not lowered. Emotions often call forth abnormally intensive varia-
tions of tonus in the vessels; and the edematous swellings that are observed
not infrequently are to be regarded as angiospastic manifestations. Ibrahim
saw, in a suckling suffering with tetany, edema of the legs, with kidneys in-
tact, and Kahn and / several times saw marked edema of the skin over the
metacarpo-phalangeal joints after severe attacks. Curschmann described
pronounced angiospastic manifestations, vascular spasms of the fingers
and toes. Heat relieved the attacks. Here too would belong the char-
acteristic puffiness of the face which was first described by v. Frankl-Hoch-
wart and which we have also frequently observed. The face is pale but does
not possess the livid coloration that tends to appear in myxedema.

I now take up the question of the blood picture in tetany, as it stands in
intimate relationship with the manifestations on the part of the vascular
apparatus. Until the appearance of our work, the statements as to blood
changes in tetany were concerned only with cases of so-called stomach tetany.
In isolated cases there has been observed appreciable increase in the number
of red cells, or increase in the specific gravity (F. M tiller, Fleiner, Kuckein,
also ourselves), and attempts had been made to refer these to the organism's
poverty in water, that might have been brought about by deficiency in
absorption on account of pyloric stenosis, or the vomiting of large amounts
of gastric juice. Our investigations showed decisively that this polyglobulia
is directly a tetany symptom. Above all, it could be shown that in the case
of "stomach tetany" this polyglobulia existed only in the acute stages, and

1 86 . THE DISEASES OF THE PARATHYROID GLANDS

with the decline of the tetany it again made way for normal relations; the in-
vestigations also showed that the polyglobulia may be for a time appreci-
ably increased during an acute attack, in one case rising from 5,106,000 to
7,808,000 red cells; finally, the investigations showed that in the cases of
occupation tetany the red-cell count is higher during the acute stages, and
that it is temporarily raised even higher during an acute attack. As ex-
ample, I cite the following case:

Observation XVIII. — C. E. Entered the clinic May 14, 1912. Carpenter, forty
years old. For about four years the patient felt a striking sensation of fatigue in the
arms and legs, especially after heavy work and after long walks. He also had par-
esthesias in the arms and legs (formication, "going to sleep" of the left leg). For two
years slight gastric disturbances, consisting in brief spasmodic pains, and in acid eructa-
tions, sometimes associated with vomiting. For the last year, the patient has felt quite
well.

Two days ago he suddenly experienced nausea, acid eructations, vomiting, and a colicky
pain in the region of the stomach. Some hours later he experienced spasmodic drawing
together of the hands (according to the description, the typical obstetrician's position),
and formications in the tips of the fingers and twitchings of the muscles of the face.
Later there were also spasms of the lower extremities, which became quite rigid. The
spasms seem to have lasted three to four hours. The patient was conscious throughout
the spasm. Since then the spasms have been repeated several times.

Rather strong potator. Inclination to bronchitides.

Rather vigorous, large patient, pale color of the face, facial expression as if he were
going to cry, skin moist, apical dullness on the left, vesicular murmurs sharpened, at
places rhonchial and whistling murmurs. Cardiac findings normal. Liver two finger-
breadths below the margin of the ribs. Very well pronounced dermographism.

Chvostek I and // strongly positive; also the frontal muscles twitch on application of
the test; Trousseau markedly positive, Hoffman markedly positive, Schlesinger markedly
positive.

Electrical examination Ulnar Facial

C.C.C. i.o 0.6

An C.C. 2.5 1.8

An O.C. 3.4 i.o

C.C.Te. 8.0 1.2

An C.Te. not attainable not attainable

Mechanical hyperexcitability of the muscles very pronounced. Idiomuscular ridges
make their appearance.

Patellar reflexes markedly exaggerated, suggestion of a patellar clonus.

Coarse tremor of the fingers.

Blood-pressure (Gartner), 125.

In urine traces of albumin, reactions for urobilin and urobilinogen markedly positive.

Tubercle bacilli in the sputum.

Increase of temperature up to 37.3°.

May 14. — During the day and also during the preceding night many severe tetanic
spasms in the upper and lower extremities, that always lasted for several hours.

On elicitation of Trousseau's phenomenon by means of the bandage fibrillary con-
tractions occur in the musculature of the arms or feet respectively. Together with the
spasm there regularly appears, on application of the bandage, a pronounced anemia of the
extremity in question.

TETANY 187

May 15. — Severe attack this morning, at 10 o'clock, during which blood was with-
drawn from the ear. The blood is dark red.

Erythrocytes, 6,500,000.

Leucocytes, 4200, of which:

Polymorphonuclear neutrophiles, 63 per cent.

Large mononuclear cells, 36 per cent.

Eosinophiles, i per cent.

May 1 6. — Blood findings during the attack-free interval.

Erythrocytes, 5,600,000.

Trousseau positive; after the decline, the patient complained of severe bone pains in
the extremity affected.

May 20. — No attack since the i6th. Face still slightly swollen, facial expression still
somewhat as if the patient were going to weep.

May 22. — Erythrocytes, 5,200,000.

May 24. — Trousseau can no longer be elicited.

May 25-31. — :Patient feels well, no paresthesias; he has gained as much as 5 kg.,
appetite excellent, no gastric disturbances.

In a case reported by Falta and Kahn the following values were found :
At the beginning of the observation about 4,000,000 erythrocytes and 9
gm. hemoglobin. Three weeks later during a long-continued severe attack
7,808,000 erythrocytes and 14.86 gm.1 hemoglobin. The next day, during
a period of almost free attacks there was 5,106,000 erythrocytes. Later
after amelioration of the spasms 4,160,000. This was a case of tetany
in the course of a Reichmann's disease. In another case (Observation XXIII)
that I report below, we likewise see a distinct agreement between the varia-
tion of the erythrocyte count and the tetanic condition. I would suppose
that the behavior of the erythrocytes furnishes a good criterion for the
course of the disease, just as the leucocyte formula does in Basedow's disease.

In dogs, also, we have seen, after parathyroidectomy, the count of erythro-
cytes in the acute stage rise to 7,000,000. Such polyglobulias occurring dur-
ing the acute stage can be explained in no other way than that they are
due to vascular spasm, analogous to those polyglobulias which are observed
after injection of adrenalin (Bertelli, Falta, and Schweeger). But one is not
justified in assuming, on this account, that during the tetanic attack there is
an increased production of adrenalin ; we should rather suppose that in analogy
with all other conditions of excitement in tetany the seat of the hyperexcita-
bility is to be found in the ganglia. We have noticed no increase of blood-
pressure during the attack, which however does not speak against, our
supposition — for vascular spasm need not occur in all portions of the body
simultaneously and thus an equalization of blood pressure may occur very
readily. The polyglobulia of the so-called stomach tetany is to be explained
in the same way.

The leucocyte count in tetany is mostly normal. Leastwise in individual

1In German edition "per cent." This has been corrected to "gm." on reference to the
original article. — Editor.

1 88 THE DISEASES OF THE PARATHYROID GLANDS

cases, we saw, during severe attacks, transitory hyperleucocytosis up to
19,000. Differential counts of the leucocytes showed, in the great majority
of cases, a rather distinct lymphocytosis or a relative and absolute diminu-
tion of the neutrophilic cells. In these cases there also were found, for the
most part, swellings of the lymph glands at the portions of the body accessible
to palpation, enlargement of the tonsils and papillae of the base of the tongue,
hence a slight status lymphaticus.

With more exact investigation, there could also be demonstrated in the
great number of cases of tetany slight or severe disturbances in the function
of the gastrointestinal tract. In this connection we could distinguish two cate-
gories of cases. In one the tetany develops in individuals who have been
sick for a long time with gastric and intestinal complaints, especially with
those which lead to a high-grade stagnation of the gastric or intestinal con-
tents. To this group I shall refer more in detail in the consideration of
the individual forms of tetany. In the second category the gastroin-
testinal disturbances occur at or after the outbreak of the tetany. Many
such cases have been observed by Kahn and myself. Of such disturbances
I would mention: First, a certain hyperexcitability which, as already
mentioned, manifests itself in the experiment with pilocarpine in an ab-
normally marked laxity of the stomach and in a very pronounced stratifica-
tion of the gastric contents, eventually in tenesmus and diarrheas. Second,
manifestations of increased secretion of the gastric or intestinal glands; in
certain cases there is found for example a slight grade of hyper chlorhydria,
such as has been described by Jonas and Rudinger. On increased secretional
processes in the intestinal tract may depend the diarrheas we observed so
frequently. In many cases the tetany is ushered in with diarrheas or
vomiting.

As example I cite the following:

Observation XIX. — A. W. (Case VII oiFalta and Kahn), twenty-seven-year-old woman
from Vienna. Entered the first medical clinic March 16, 1909. Marked chlorosis at
the age of sixteen. Menstruation from the age of eighteen on, regular. Three normal
confinements. Three days ago suffered with severe pains in the abdomen, that were
associated with fever, eructations, and constipation. On the next morning typical tet-
anic spasms in the upper extremities, hands in the obstetrician's position, flexion at the
elbows, upper arms drawn to the body. At least six such attacks each of about five min-
utes' duration. The spasms were painful. The galvanic excitability was increased.
Rapid recovery.

Still more instructive is the following case, in which the gastric dis-
turbance set in at the same time as the tetanic spasms:

Observation XX. — L. E. (Case VIII oiFalta and Kahn), twenty-year-old woman from
Vienna. Entered the first medical clinic on March 23, 1911. One normal confinement.
Present illness began six days ago with severe pains in the back and hypogastrium,
with the vomiting of green-colored masses of bitter taste, and a painful spasmodic attack
affecting the hands and legs. The hands were in typical obstetrician's position. Two
days later again severe pains in the abdomen, with vomiting, associated with typical attack

TETANY

189

of tetanic spasms in the upper extremities and later abdominal pains of a twitching
character. Temperature as high as 38°. Indican much increased. Rapid recovery.

In other cases the gastric disturbances occur later, and are made worse
by a later exacerbation of the tetany. We find likewise that in the cases of
the first category the gastrointestinal disturbances may increase markedly at
the time that the tetany is added to the clinical picture.

FIG. 26. — Tetany face (Observation XXI).

In many cases, as seen by the fluoroscope, there is an abnormally rapid
emptying of the stomach. In some cases there is a marked pyloric spasm,
in the acute stage, that leads to acute dilatation of the stomach. The cases
that belong here, which Kahn and myself have reported, are those of
the first category, in which gastric disturbances existed previously. It is
probable that the tetany increases the pyloric spasm, or in many cases

i go

THE DISEASES OF THE PARATHYROID GLANDS

directly brings it about. A short time ago, I saw also a case of typical
occupation tetany that showed the same thing. The report of it follows:

Observation XXI. — B., seventeen years old, shoemaker. Entered the clinic Jan. 14, 1913.
First attack of tetany in winter of 1911. The convulsions then lasted with interruptions
throughout the winter, disappearing only in April. Throughout the summer, the patient
felt quite well; two days ago spasms reappeared, especially in the upper extremities, and to
it were added formications. The symptoms, varying in intensity, have lasted until to-day.

The patient shows the typical crying facial expression of the tetanic. There exists
great vasomotor excitability. All the typical symptoms of tetany are present. The
galvanic excitability is much increased. The examination of the blood shows 6,250,000
erythrocytes. There exist painful spasms, especially in the upper extremities, that are
often repeated throughout the day. Temperature as high as 37.5°.

Jan. 1 8. — For three days no spasmodic attacks, the electrical excitability is less in-
creased; in blood, 4,870,000 erythrocytes. Chvostek's and Trousseau's phenomena no
more elicitable.

FIG. 27. — Spasm of the stomach in tetany (Falta and Kahn, Ztsch. f. klin. Med., Bd. LXXIV)-

Jan. 23. — Fresh spasms, the symptoms of tetany present once more, 5,820,000 ery-
throcytes.

Jan. 24. — X-ray examination two hours after breakfast shows a dilated stomach filled to
a marked degree with fluid; it reaches to three finger-breadths Mow the umbilicus; there
exists lengthened lime for emptying of the stomach, in short, signs of a hypersecretion with
pyloric stenosis.

Jan. 31. — Chwstek still positive, more spasms, 6,400,000 erythrocytes.

Feb. 6. — No spasms any more, but there still exists paresthesias. Chwstek and
Trousseau negative.

From now on the tetanic symptoms decline, the count of erythrocytes becomes normal
(4,500,000-4,800,000), the X-ray examination of the stomach, that has been taken three
times in the course of the last two weeks, now always shows normal relations; after a
breakfast the X-rays show that the stomach reaches to two finger-breadths below the
umbilicus. Peristalsis and time of emptying are now normal.

In this case, therefore, is to be found an ''attack" of pylorospasm and
hypersecretion and consecutive dilatation of the stomach occurring in the

TETANY

FIG. 28.— Spasm of the stomach in tetany (after Falta and Kahn, Ztsch. f. klin. Med., Bd. LXXIV).

acute stage of tetany. Also Ibrahim is of the opinion that the pylorospasm
can occur in the course of a tetany of childhood.

Especially significant for this question are two observations that have
been reported by Kahn and myself. I would therefore go into the question
more accurately at this point. In the one case (Observation 'XXII — Case
1 8 of Falta and Kahn), X-ray examination at the time that only slight signs
of tetany existed showed an elongated but otherwise normal stomach.
On a later examination, during an acute exacerbation of the tetany, there
was found a retraction of the greater curvature, completely the picture of
an hour-glass stomach (see Fig. 27). The tetanic spasms rapidly decreased
in intensity, the stomach assuming normal relations after a few days. In
the case there were no grounds for the assumption of an ulcus ventriculi.
In a second case (Observation XXIII — Case 17 of Falta and Kahn) the
stomach, as found on X-ray examination at the time of an acute exacerbation
of the tetany and indeed during an attack, was small, markedly contracted,
divided in two parts like an hour-glass stomach; in addition there was
insufficiency of the pylorus; there was present therefore a total spasm of the
stomach, that affected also the longitudinal musculature. At the next
examination, this phenomenon occurred again, gradually decreasing in
intensity, however, with the amelioration of the tetany; and later, when the
tetany had disappeared entirely, the stomach showed normal relations on
X-ray examination (see Fig. 28). We regarded these manifestations as
conditions of tetanic spasms.

Also in thyroprivic animals I several times observed that the spasm
was ushered in with vomiting and bowel movement.

All observations detailed point to the fact that in the acute stage of
tetany the gastrointestinal tract may show symptoms of increased ex-
citability and a heightened tonus, which later may increase up to a spas-
modic condition. To which are added heightening of the secretory processes.

Ibrahim further describes, in the case of suckling tetany, spasm of the
sphincter of the bladder that led to marked retention of urine, and mentions
similar observations of Sachs, Escherich and Hagenbach-Burckl.ardt. v.
Frankl-Hochwart had mentioned still earlier a retention of urine in tetany of
adults. Ibrahim further assumes involvement of the sphincter ani in the
tetanic spasms as he often observed in suckling tetany an intense gaseous
distention of the abdomen (flatulent colic). After introduction of an in-
testinal tube there were emptied large amounts of gas — or even spontaneously
there occurred an "explosion-like expulsion of flatus with frequent clonic
twitchings of the abdominal muscles." Also Koeppe had already supposed,
as Ibrahim states, that the internal sphincter became contracted in the
eclamptic attack.

Finally we mention the disturbances of the regulation of heat. In para-
thyroprivic dogs there often occur, during attacks, increases in temperature;

TETANY

193

in very intense spasms we even observed on several occasions values signify-
ing hyperpyrexia. Such disturbances of heat regulation also occur in human
tetany. In the attack-free interval, the body temperature, as v. Jaksch and v.
Frankl-Hochwart have emphasized, is often abnormally low. In thirty-five
observations on acute cases v. Jaksch saw more or less fever at the beginning of
the disease nine times. Kahn and my observations agree with these. We
frequently saw with the acute stage temperature as high as 37.8°, in one
case up to 38.5°, without exact investigation affording any ground that
there was any cause for the increase of temperature other than the tetany.
Later, after decline of the tetany, the temperature sank to normal or slightly
subnormal values. In certain cases we found in the acute stage transitory
rises of temperature after the injection of substances that otherwise do not
tend to induce fever (antithyroidin (Mobius}, pituitrium glandulare of Parke,
Davis 6* Co.}. This points to an especial lability of the regulation of heat.
One could be tempted to regard the increase of temperature in the sense of
those authors who consider idiopathic tetany as an infectious disease. The
fact that it is found to still higher degrees in experimental thyroprivic tet-
any has led Kahn and myself to the assumption that it is probably the ex-
pression of a condition of excitability of the vegetative nerves.

Summarizing again all observations that can be advanced for the vegeta-
tive organs, we find that in the acute stage of tetany the hyperexcitability or
the abnormal conditions of irritability are not limited throughout to the central
nervous system and to the peripheral nerves, but that they involve also the vegeta-
tive nervous system. With the decline of the acute tetanic condition there
also occurs a decline of the condition of irritability of the vegetative nerves.

Also the metabolism in tetany shows alterations.

Disturbances in the carbohydrate metabolism are almost constant in the
tetanic dogs. First a few remarks as to the glycosuric action of adrenalin
in tetany. In the thyroidless dog it is known that the glycosuric action of
adrenalin is reduced. In dogs that have had only their parathyroids re-
moved it is mostly increased, so far as a tetanic spasm is not induced by the
injection (Eppinger, Falta, and Rudinger}. In the idiopathic human tetany
Rudinger and / never found in the acute stage glycosuria following injec-
tion of adrenalin; but on the contrary, as already mentioned, almost always
a strong reaction of the cardiovascular apparatus. This dissociation of
the action of adrenalin has its foundation chiefly in the increase of sugar
consumption through the enormous vasoconstriction and eventually in
the attack induced by means of injection. In the declining stage of tetany
we find, contrariwise, frequently a distinct glycosuric action due to adrenalin.

In parathyroidectomized dogs the assimilation limits for dextrose are

regularly reduced. Falkenburg and R. Hirsch, and also Frank P. Undcrhill

and Tadasu Saiki, found this after thyroparathyroidectomy and referred it

to the absence of the thyroid gland. This, however, leads to a heightening

13

IQ4 THE DISEASES OF THE PARATHYROID GLANDS

of the tolerance boundary. According to the experiments of Eppinger,
Rudinger, and myself the glycosuria after thyroparathyroidectomy depends
on the absence of the parathyroids. In a dog almost completely parathy-
roidectomized we found that when a diet rich in starch was administered
veen large amounts of sugar would appear in the urine for a long time.
After the extirpation of the pancreas and three parathyroids we found in
many experiments a higher D to N quotient than could be obtained on
extirpation of the pancreas alone. In human beings ill with tetany we
never found reduction of the assimilation limits for dextrose, and Kahn and
/ can adduce an observation that shows that also in human beings the in-
sufficiency of the function of the parathyroids exercises an indirect in-
fluence on the function of the pancreas. In a case of Basedow's disease
complicated with tetany the test for alimentary glycosuria immediately
after the tetanic attack yielded 4.1 gm. of sugar. Later, after the acute
tetany had subsided, many tests for alimentary glycosuria resulted negative.
In the literature is found only a statement of Miller that he observed transi-
tory glycosuria after an attack of tetany.

MacCattum and Vogtlin, and also we, saw the protein exchange in para-
thyroidectomized dogs appreciably increased. There do not exist similar
investigations on human beings. There also occur regularly disturbances
of the intermediate protein exchange. MacCattum and Vogtlin found in
thyroparathyroprivic dogs , increase of the elimination of ammonia in the

NH3N

urine and of the quotient — ^ — , and in addition increased creatinin elimi-
nation. In human idiopathic tetany Kahn and 7 found in the acute
stage the elimination of ammonia for the most part relatively and absolutely
increased. The amino-acid fraction was for the most part normal; on the
contrary, the peptid-N in our experiments was often even appreciably
increased. Administration of glycocoll increased this value mostly only
unessentially. Immediately after the decline of the acute tetany this value
for the peptid-N was mostly still high, but distinctly lower than in the
acute stage, or it had already become normal. Also the heightening of the
ammonia value can apparently outlast for some time the acute stage. The
findings described are to be distinguished from those in lesions of the liver in
that in the latter the amino-acid-N is ordinarily increased as much as, or
even more, than the peptid-N, and the administration of glycocoll almost
always causes an increase of these factors. Perhaps these disturbances of
the intermediary metabolism in tetany are the expression of a condition of
nervous hyperirritability of the liver.

Systematic investigations as to the gaseous metabolism in tetany have as
yet not been made. That the exchange of calories in the acute stage, and
especially in the severe attack is markedly increased, needs no especial in-
vestigation. More interesting would be the investigation of the funda-

TETANV 195

mental exchange in chronic tetany. Partially parathyroidectomized animals
often show a severe cachexia; and often in human idiopathic tetany, cachetic
manifestations later make their appearance (v. Frankl-Hochwart}. The cases
of relapsing tetany that Kahn and / observed all showed more or less dis-
tinct signs of cachexia (see later the relations to the thyroid gland). Here
there must be a profound disturbance of metabolism, as has been mentioned
by Segale and others.

The behavior of the calcium metabolism in tetany has been much studied.
Stimulating were the observations of Sabbatani and Loeb. Sabbatani found
that application of calcium salts to the surface of the brain reduced the
excitability, application of sodium salts increased it; Loeb found that sub-
stances that precipitate calcium heightened the excitability of the nerves.
This holds true also for the vegetative nerves (R. Chiari and A. Frohlich).
MacCallum and Vogtlin as well as Parhon and Orechie have tried to influence
favorably the tetanic spasms of parathyroidectomized dogs by the subcu-
taneous or peroral administration of calcium. Magnesium salts work directly,
as do the calcium salts, but show in addition strong toxic action. Potassium

ilts increase the irritability. Quest had already stated before this that the

>rain of new-born infants, which is relatively slightly excitable, is very
rich in calcium, but that later the calcium-contents of the brain reduces.

te further states that diet poor in calcium makes the animal hyperexci table,
ind that the brains of children after they have died of tetany are very

>oor in calcium. MacCallum and Vogtlin found the calcium-contents of
the brain of parathyroidectomized dogs lowered, as well as those of the blood,
elimination of calcium through the urine and feces was increased. This
last fact was also found by us. The same was also observed by Cattaneo.
Neuralh, who estimated the so-called active calcium in the blood of children
with tetany by Wright's method, found very low values. Investigations as
the calcium balance in children with tetany frequently show increased
elimination of calcium (L. V. Iddo and Sarle, and others}. Aschenheim has
recently pointed out that there does not exist so much an absolute calcium

>overty of the tissues as there does [an increase of] the relation of alkalies to
earthy alkalies. He found in children who had died of spasmophilia an
increase of this quotient just as in parathyroidectomized dogs. Finkel-
stein and Rosenstern arrived at similar views. According to Rosenstern the

g

administration of common salt to children brings forth anodal hyperexcita-
bility, and indeed even laryngospasm.

Experimental investigations show also that the function of the para-
thyroids influences bone formation. Morel and Canal found in parathy-
roidectomized dogs that the healing of fractures is delayed and the callus
formation slowed. Erdheim showed that such callus is remarkably poor in
calcium. Leopold and v. Reuss found the skeletons of youthful parathyroidec-
tomized rats poorer in calcium than those of the control animals. To a loss

196 THE DISEASES OF THE PARATHYROID GLANDS

of calcium in the parathyroid insufficiency points also the finding of Schullcr
that the bones in chronic tetany show in the Rontgen picture a characteristic
rarefaction of the trabeculae and marked atrophy, an observation that we
could confirm in almost all the cases, in which we paid attention to it. We
found this, however, in cases that had never had tetany.

Summarizing that which has been said as to the metabolism, we find that
in the acute stage of tetany there exists an appreciable increase of the metabolism,
that is related to very many factors of the same. As most probable, we may sup-
pose that only in experimental, but also in human, tetany there exists an
increased breaking down of albumin with disturbances in the intermediary
albuminous decomposition, increased exchange of carbohydrates, increased pro-
duction of calories, and apparently also increased elimination of calcium. A
part of these alterations in metabolism may well depend on increased
irritability in the vegetative nervous system. We may expect in the chronic
stages of tetany alterations of metabolism that to-day we cannot well
define.

The trophic disturbances in tetany affect epithelial parts exclusively,
the hairs, nails, skin, enamel, and ciliary epithelium. In chronic tetany there
are frequent statements as to a thinned-out growth of hair (Hoffmann,
v. Frankl-Hochwart, and others}. An acute exacerbation may be introduced
with rapid falling out of the hair. Adler and Thaler in their experiments on
dogs found the falling out of hair a direct premonitory symptom of tetany.

Also Pfeiffer and Meier observed in ectomized animals falling out of hair
as the direct symptom of tetany. Speigler in a case of chronic tetany found
that the thinned-out and very thin hair was split at the point (trichorrhexis) .
Also the nails frequently show trophic disturbances, they become brittle and
there may occur complete necrosis that leads to casting off of the nails; rapid
substitution occurs, however, after subsidence of the acute stage. In a new
attack the process may be repeated. An instructive case is reported by
Hoffmann. It is that of a woman who had passed through five normal de-
liveries. After the fifth pregnancy, she developed tetany with distinct
edema of the hands. The finger nails fell out. A year later tetany recurred.
This time the hair fell out. After a year, new pregnancy and tetany; after
the delivery again trophic alterations of the finger nails. After a half year,
at the time of a new pregnancy, again tetany, with which was associated loss
of nails and hair. In the tetany of children loss of the finger-nails seems
to be very rare. Pineles found in the literature only one observation by
Hoffmann, in a three and one-half-year-old child.

The skin of the face and of the extremities shows in acute cases a puffy
appearance (angiospasm[?], see what is stated previously), causing a character-
istic expression of crying.

Pigmentations of the skin are rare. Kocher states that after total ex-
cision of the thyroid gland in many individuals there occur, if the tetany

TETANY 197

symptoms predominate, marked pigmentations progressing as far as bronzed
skin.

Of greatest interest is the formation of cataracts. Already Meinert had
observed in tetany a case of cataract, and the first exact investigations began
with Peters. Important information was furnished by Erdheim, Pineles,
Zirm, Sperber, Bartels, v. Frankl-Hochwart, Schonborn, and others. The
cataract of tetany is characterized by its very rapid development. It is not
at all rare in children. It is especially frequent in the tetany of pregnancy,
and in women between the ages of eighteen and forty years, as observed by
Zirm and Sperber. In youthful individuals it occurs more frequently as nuclear
cataract, in older individuals as cortical cataract. Peters was the first to
show that the cataract formation was brought about by degenerative changes
in the ciliary epithelium. This caused a molecular concentration of the
ater in the chamber, thereby damaging the lens. Erdheim produced tetany
cataract by parathyroidectomy in rats. We are indebted to Pineles for the
information that the cataract formation occurs in all forms of tetany.

Hanke on histological examination of the globe of the forty-nine-year-old
man who suffered with chronic tetany and cataract found optic neuritis and a
characteristic degeneration of the pigment epithelium of the posterior sur-
face of the iris, similar to that observed in diabetes mellitus. Pineles had
already attached theoretic value to the circumstance that cataract formation
could occur in tetany as well as in diabetes.

Of recent date are the investigations concerning the disturbances in
tooth formation. Erdheim first observed that there occurred in rats, one and
one-half to two and one-half months after the operation, opaque spots on the
anterior surface of the incisor teeth which gradually advanced toward the
points with the teeth's growth. Either the tooth breaks off at this point or
the defect in the enamel heals, leaving behind a shallow groove. The tooth
may also break in the alveolus, in which case suppuration of the latter occurs.
Erdheim observed a deficient calcification of the dentine. Even the short
cessation of parathyroid function that occurs in autotransplantation of the
parathyroid is sufficient to determine the appearance of stripes poor in cal-
cium in the dentine of young rats. An especial clinical interest to Erdheim' s
studies is given by the investigations of Fleischmann. This worker held the
view that the defect of enamel so commonly observed was due, not as was
formerly supposed to rachitis, but to tetany. He points to the dispropor-
tion between the frequency of rachitis and hypoplasia of the enamel. In
rachitis are regularly found alterations in the dentine; in tetany, however,
one always finds hypoplasia of the enamel leading to the formation of hori-
zontal transverse surfaces. When frequent exacerbations of the tetany
have occurred, are found numerous furrows below one another. Fleisch-
mann investigated ten children who had suffered from tetany and found in
all the above-mentioned hypoplasia, and indeed this was present only on

198 THE DISEASES OF THE PARATHYROID GLANDS

those teeth that had been present during the course of the illness. Nearly
all of the children had also had rachitis. Flcischmann points out, however,
that rachitis lasts much longer than tetany, and also attains its acme much
later. Fleischmann also finds support for his view in the statement of
Fuchs that children with lamellar cataract almost always show hypoplasia
of the enamel. In individuals with hypoplasia of the enamel, in whom
nothing is known of their having had tetany, there may have existed a
latent tetanic condition in early childhood. Very convincing is an obser-
vation of Spiegler in a case of recurring tetany, who had an attack every
spring during eight years. In this case it was known that the tetany had
first made its appearance at the end of the second year of life. All teeth
whose crowns must have been formed at this time were normal, while the
teeth whose crowns developed later showed defects of the enamel. An

FIG. 29. — Enamel defect in tetany.

entirely similar case was observed by Kahn and myself (Observation XXIII) .
Here were found on the canine and incisor teeth punctiform defects of
enamel often arranged in parallel rows; the upper parts of the molars were
partly broken off. The patient's mother stated definitely that already in
the first year of life, but more especially in the second and third years, he
had spasms of the glottis and spasms of the hands, while a severe rachitis
was added to the picture only in the third year.

The above illustration (Fig. 29) shows the defects of enamel observed by
us in another case.

The connection between tetany and defects of the enamel is by all this
evidence put on a sound basis; and I shall not discuss the possibility of
these defects being brought about by other causes.

Perhaps the conjunctivitis accompanying tetany may also be regarded as
a trophic disturbance. De Quervain observed that parathyroidectomized
dogs often suffer from severe conjunctivitis. I saw this almost regularly in

TETANY 199

parathyroidectomized dogs and cats. In the case previously mentioned (Ob-
servation XXIII) it happened that the conjunctivitis regularly became
exacerbated with the aggravation of the tetany.

Yet a few words with regard to growth disturbances in tetany. Schuller
investigated five cases of rachitis tarda and found, besides pronounced
Chvosiek's symptoms, remaining behind in growth, delayed ossification and
dentition, and marked atrophy of the bones; the last was also found in an
exactly investigated case of the chronic recurring form of tetany, and also in
three juvenile cases of occupation tetany. On the contrary, a case of tetany
after strumectomy, and some cases of tetany of maternity showed normal
relations. Schuller points out that tetany may also occur in combination
with osteomalacia, and believes that tetany may induce rachitic alterations
before the cessation of bone growth, and osteomalacia after it. A similar
view is held by Erdheim on the basis of histological examination of the
skeleton, and especially of callus formation in rats after parathyroidectomy.
Kassowitz had before this supposed a casual connection between rachitis
and tetany.

This view I would not subscribe to. It is to be expected that high-grade,
and especially, long-continued, absence of parathyroid function in youthful
life would lead to disturbances in growth of bones. We also saw certain cases
of chronic recurring tetany, in which the individuals were remarkably small
and showed retarded epiphysial closure. The disturbance has certainly
nothing to do with true rachitis. Sometimes, indeed, it is difficult to separate
the two conditions, as combinations of rachitis and tetany are extremely
frequent, and according to Escherich, not less than 80-90 per cent, of all
tetany in children is associated with rachitis. There are certainly, however,
cases of tetany without rachitis, and cases of rachitis with tetany constitute
only an extremely small percentage of the whole number of cases. Also
the rarefaction of the bone trabeculae described by Schuller is not charac-
teristic for a withstood tetany, for we have found them in individuals who
have not had tetany. Experimental experiences speak, too, against a direct
connection between rachitis and tetany. Iselin observed remaining behind
in growth in parathyroidectomized rats; and similar observations have been
made by Jeandelize, Moussu, and Vassale and Generali on other species of
animals. Iselin's animals remained well proportioned, however, and showed
no bone perversions.

I decline to subscribe to the doctrine of a connection between tetany
and osteomalacia. The number of cases in which the diseases coexisted is
not large. BlaZiceck, Weber, E. Freund, Schultze, Becker, have reported such
cases. An exception in this respect is only the markworthy observation of
Krajewska from Bosnia; she found tetany present among one hundred fifty
cases of osteomalacia no fewer than forty-eight times. All forty-eight cases
affected puerperal women.

200 THE DISEASES OF THE PARATHYROID GLANDS

H ence there may be regarded as the symptom belonging to chronic
tetany at most the rarefaction of the bone trabeculae and the atrophy. It
is shown by the statistics of late years that a chronic tetany existing from
earliest youth may damage the development of the entire body. Disturb-
an ces of the development of speech and of the intelligence are especially
frequent (see prognosis). The development of the sexual glands does not
appear to suffer; in isolated cases we can find at least no remaining behind
in sexual development although tetany spasms may have existed for years,
from early youth or from just at the time of puberty.

The symptomatology of tetany would be incomplete were I to neglect
to mention a series of symptoms that depend on a functional disturbance of
other ductless glands, but are very frequently combined with tetany.

As has already been mentioned, Kocher states that after total extirpation
of the thyroid in human beings, there occur in individuals in whom the symp-
toms of tetany predominate, marked pigmentations progressing as far as
bronzed skin. Probably in such chronic cachectic conditions there is a re-
d uction in the activity of the chromaffin tissue. Oftenest occur symptoms
that depend on an alteration of thyroid function. Not so very rare in chronic
tetany are symptoms of myxedema. v. Frankl-Hochwart, in looking over his
cases, found symptoms of myxedema as many as thirteen times among
twenty-six cases. We saw this alteration once. These myxedematous
alterations of the skin occurring in chronic tetany should not be confused
with the pufnness of the face previously described, or with the edema of the
backs of the hands that occurs in the acute stage, which phenomena are
properly regarded as angiospastic.

Kahn and / have reported an observation, which in the clinical sense is
not of less significance. In a series of our own cases we saw develop in the
acute stage or immediately at its close a slight hyperthyrosis. This con-
sisted especially in tachycardia, headache, slight rise of temperature, increase
in blood-pressure, sweats, slight tremor, and slight diffuse enlargement of
the thyroid. The connection between our observations and those of Frankl-
Hochwart is perhaps this: that in many cases of tetany at the conclusion of the
acute stage or during an acute exacerbation there occurs an increase of
thyroid activity and even an appreciable enlargement of the thyroid gland,
which is succeeded, in the stage of chronic tetany, by a slight degree of thyroid
insufficiency (see the section on the idiopathic form of tetany).

Pathogenesis of Tetany

It seems to me suitable first to set forth in detail the pathogenesis of
parathyroprivic tetany; and then later in the exposition of the individual
forms of tetany, to speak of their etiology separately.

As I have already mentioned at the beginning, to-day we may regard

!' ATHOGENESIS OF TETANY 2OI

as established that experimental tetany depends on the loss or marked
damaging of the parathyroid glands. This holds good for all species of
animals. The course of tetany in different animals is, however, different.
In some after total extirpation of all the parathyroids there occurs an acute
tetany, which after a short time leads to death. In others, for instance in
monkeys, the course is chronic. Does the complete loss of parathyroid
glands lead to tetany always?

Here should be mentioned that all authors are agreed that older animals
resist the operative attack more readily than young ones. Important in
this respect are the investigations of Iselin, who found that the young of
partially parathyroidectomized rats are especially sensitive to the extirpa-
tion of the parathyroids, and die in a few hours with fulminating epilepti-
form seizures. Moreover, there are numerous statements that the simul-
taneous extirpation of thyroid gland and parathyroids is better borne than
isolated parathyroidectomy. Many hypotheses have been advanced to
explain this fact, a fact that our own investigations fully substantiate. The
most natural of these seems to me to be the conception that on the simul-
taneous extirpation of the thyroid glands the metabolism and with it the ex-
citability of the entire nervous system is reduced, and the function of the
parathyroid glands is then reduced in its action. On the other hand, we
know that procedures of the most diverse kinds and conditions that make
great demands on the nervous system accelerate the outbreak of tetany or
allow latent forms to pass over into the acute forms. If we here recog-
nize too that the influences that may modify the course and acuity of the
process may be manifold, we may well assume that the complete loss of all
parathyroids leads to death in all species of animals, under the manifesta-
tions of an acute or more chronic tetany, hence that the loss of the para-
thyroid function is incompatible with the long continuation of life. I would
not off-hand relinquish this assumption on account of the quite isolated
contrary statements. Haberfeld and Schilder state that rabbits in which at
first the four parathyroids are removed, and later the thymus gland with
the accessory thyroid, continue to live. Continuous serial sections show
the absence of any parathyroid tissue. Wiener even asserts that of forty-five
parathyroidectomized animals, 20 per cent, did not show any manifestations
of tetany. In my own numerous experiments on dogs, cats and rabbits, I
have never seen an animal survive. The unconditional importance of the
function of parathyroids for life is also held by Biedl, Hagenbach, and
others. As long, therefore, as no further statements as to this question
exist, I would still believe that in the experiments of Haberfeld and Schilder
and Wiener that have been mentioned, accessory thyroids may have escaped
demonstration.

As regards the mechanism of parathyroid function, numerous opin-
ions have been promulgated. In the foreground stands the views as to

202 THE DISEASES OF THE PARATHYROID GLANDS

the detoxicating function. The parathyroids would seem to furnish to the
blood-path a hormone which renders innocuous poisons that exist in the
body. Originally the thyroid gland was looked upon as the organ preparing
the poison (Vassale and Generali). Lately Pineles, Pfeiffer and Meyer, Oni
and Beste, Berkeley and Beebe, and most recently, especially Wiener, have
turned attention from the thyroid and have assumed that in the bodies of
animals with tetany there circulates a specific poison or one originating other-
wise in metabolic processes.

It is impossible for me to enter intimately into the numerous experiments
that have been instituted for the establishment of the hypothesis. I would
mention only the most important. Pfei/er and Meyer state that in the sera
collected in the death agony, of seventeen dogs affected with tetany, they have
found in six a toxic principle which injured partially parathyroidectomized
mice, while the sera of normal dogs were inactive. The fact that animals with
tetany are very sensitive to the various procedures tends to make one sceptical
as to the value of these experiments. Ceni and Besta have tried to obtain
an immune serum, injecting the serum of totally ectomized dogs into rabbits
and goats, and reinjecting the sera of these into the tetanic dogs. Almost
regularly they cured the acute manifestations, although none of the animals
remained alive. H. Wiener followed a similar course for experimentation,
except that he used cats both for immunization and for treatment. In some
animals (not all) he succeeded in combating the tetanc symptoms per-
manently. The residual thyroid glands of these animals were examined and
found to contain no piece of parathyroid tissue. The assumption of Wiener
that in cats there are no accessory parathyroids must, in consideration of the
importance of such experiments, first be shown by painstaking investigations.
The doubt is increased by the statement of Wiener that in some experiments
also the injection of entirely normal serum permanently set aside the tetanic
symptoms.

Although, up to the present, the detoxication theory of tetany cannot be
refuted, it does not seem to me to have been satisfactory. The assumption
of a detoxicating function has, up to the present, played a great role in the
pathology of all the ductless glands. However, it seems to me that up to the
present there does not exist a single fact that strictly demonstrates this
supposition. As with the other ductless glands, so with the parathyroids,
another supposition seems plausible, a supposition that was first suggested
by Rudinger and myself and then further developed, with modifications, by
Kahn and myself.

The cardinal symptoms of tetany depend on increased excitability or
abnormal conditions of irritability of the nervous system. As to the seat
of the abnormal irritability we may say the following: Schiff had already
shown that in tetany tremors and spasms ceased after the section of the
peripheral nerves. Rudinger and / have repeated these experiments, and

PATHOGENESIS OF TETANY 203

have modified them in various ways. When we had extirpated the para-
thyroids in cats and at the same time had cut the sciatic nerve, immediately
below its exit from the pelvis, no hyperexcitability made its appearance in the
nerve peripherally from the site of the section; much more did the nerve
gradually become excitable to the galvanic current in about the same time as
after the section in normal animals.1 If, however, we first obtain our tetany
through parathyroidectomy and then transect the nerve when it had already
become hyperexcitable, we find that the hyperexcitability continues for some
time, and then only gradually passes through a period of normal irritability
(with normal electrical reaction) into the condition of nonexcitability. In
some experiments it takes nine days before this condition is reached. From
this, in reliance on former experiments of Frohlich and Lowi on nerve-muscle
preparations of the octopod Eledona moschata, we have concluded that
under normal circumstances the nerve is supplied [loaded, stored, ausladen]
from its trophic center, the ganglion-cell, with an as yet unknown, indefinite
substance, and that separation from this center is followed by a gradual loss
of this supply and by degeneration, and that in tetany there exists an ab-
normally high loading of the ganglion-cell or of whole neuron proceeding from
it. Biedl had set forward to this experiment the objection that pressure on
the nerve below the point of severance can no longer elicit muscular spasm.
According to Schlesinger's explanation of Trousseau's phenomenon, however
(reflex-process on account of irritation of sensory nerves), nothing else than
this is to be expected. That, moreover, no muscular spasm appears any
longer in the extremity in question is not remarkable, as every new impulse
from the ganglion-cell, which is always storing anew, is lacking.

Further investigations have shown, moreover, that an association of
the ganglion-cells of the spinal cord with higher centers is not necessary to
render possible in tetany or to obtain in it the abnormal loading of the
ganglion-cells. Already Munk had stated that after transection of the
spinal cord the spasms in the paralyzed hind-extremity persisted, and
Horsley and Lam have since ascertained that after extirpation of the cortical
motor areas on one side, the tetany may persist on the other half of the body.

Our own investigations showed that after section of the spinal cord in
animals suffering with tetany the hyperexcitability in the paralyzed hind-
extremities remained exactly as in the fore-extremities until death. BiedVs
statement that there appeared in the paralyzed extremities lightning-like
contractions and fibrillary muscular twitchings, but that all traces of a toxic
rigidity were absent, are in direct contradiction to Hunk's statement and
our own. In addition we could most definitely assure ourselves that we

1 In more recent investigations MacCallum (Journal of the American Medical Association, 19,
1912, p. 319) found that the peripheral part of the nerve also becomes hyperexcitable, if it had
been cut off before the parathyroid had been excised. I cannot state off-hand the explanation
for the divergence of our observations.

204 THE DISEASES OF THE PARATHYROID GLANDS

saw in the paralyzed extremities, in certain cases, in cats and dogs, after
complete section of the spinal cord, the occurrence of most intense spasms
in the paralyzed extremities in the acute attack. Moreover, the occurrence
of such spasms was not at all necessary. The exact demonstration of the
galvanic hyperexcitability of the nerves of the posterior extremities, which
develop even when the transection of the spinal cord has been done at the
same time with the extirpation of the parathyroids, shows with certainty
that the cause of the tetanic changes lies in the ganglion-cells of the spinal cord,
and not, as MacCallum and Biedl believe, in the higher centers. By this we do
not mean to assert that in tetany the higher centers do not likewise share in
the condition of hyperexcitability, and that the course of the twitchings in
the tetanic attack may not under circumstances be concomitantly influenced
by the centers that lie higher.

Just as the motor nerves maintain their hyperexcitability, we may
assume that the same is true of the sensory and vegetative nerves. It
is very probable that the neurons of different orders become involved in a
definite sequence. In the slight grades of human tetany it is especially the
neurons of the first order that are affected. Here the occurrence of, as a rule,
bilateral spasms, convulsions, and pains, points to the spinal cord or to the
medulla oblongata as the seat of the affection. In the acute stage the vege-
tative nervous system is also affected concomitantly. In the severe cases
phenomena tend to occur that point to involvement of still higher centers.
Forced movements point to the mid-brain, disturbances of equilibrium to
the cerebellum, epileptiform convulsions to participation of the motor
cortical areas, and psychoses that of the cortex in general. A similar train
of thought was followed by de Quervain in 1893, and later by Ast, and others.
In children we actually find a mounting from cord to cerebrum, with in-
creasing intensity. Here, as Escherich emphasizes, the higher centers are
more frequently and more strongly involved. The retrogression of the
condition tends to follow a reversed series of involvements.

Here I quote verbatim the conclusions arrived at in the work of Kahn
and myself. "In tetany there exists an abnormal irritability of the motor,
sensory, special sensory, and vegetative ganglion-cells that from here as a
starting-point involves the entire neuron. It is principally the peripheral
neurons that are found in this state of hyperirritability. Neurons of higher
orders may, however, be concomitantly involved. This abnormal state
expresses itself chiefly in a heightened excitability to mechanical, electrical,
or chemical irritants (latent tetany). Nevertheless the abnormal tension
in the ganglion-cell, either per se or through any other occasioning factor,
may lead to a heightened irritability in the organs supplied by it, and may
become manifest in tonic spasms and fibrillary twitchings of the trans-
versely striated muscles, in paresthesias, in tonic contractures of the smooth
muscles, in heightened secretional processes, etc.

PATHOGENESIS OF TETANY 2O$

"Thereby is found a partial unloading of the ganglion-cells, although
apparently not in very great degree, so that the hyperexcitability is still
present after the attack. This conception explains why at one time an
occasioning factor may call forth a spasm, while a short time afterward it
is inactive, perhaps becoming active again on the next day, and why the
spontaneous condition of hyperirritability in tetanics is subject to such
significant rapid change. This behavior may be observed especially beauti-
fully on animals that have been parathyroidectomized ; these dogs and cats
may be the victims of the most severe spasms, and yet a few hours later may
play as vivaciously as ever. Only the exact investigation of the electrical
and mechanical hyperexcitability now affords knowledge as to the latent
tetanic condition. This view also makes appear intelligible the fact that
certain nerve territories that have immediately met with numerous irrita-
tions (peripheral neurons) are especially preferred, and that the conditions
of irritability in the different nerve territories are of different strengths, and
may be subject to considerable change.

"In what relation do the parathyroids stand to the hyperexcitability
or to the condition of excitability of the ganglion-cells? 'Everywhere where
excitation is, is also present inhibition' (Meltzer). According to Bechterew,
the inhibitory processes are to be regarded as an indispensable protective
arrangement of the central nervous system. The normal -condition of
irritability of the ganglion-cells is guaranteed only by the finest regulation of
increase of activity [Forderung] and inhibition. Falta and Rudinger have
expressed the opinion that the parathyroid glands exercise inhibitory influences
on the ganglia by a hormone, and that the diminution or complete with-
drawal of this inhibition leads to an abnormal loading of the cell with energy.

"We do not know anything more intimately as to the action of this
hormone. It is not impossible, however, to bring this hypothesis into com-
bination with that developed by MacCallum and Vogtlin, by our following
the assumption of these authors that the parathyroid glands influence the
calcium metabolism in the central nervous system by means of a hormone.
The hormone of the parathyroid glands might thus be regarded as an as-
similatory hormone, with the withdrawal of which there occurs loss of cal-
cium in the ganglion-cells and hyperirritability of these."

The details up to the present confine themselves to the mechanism by
which insufficiency of the parathyroids leads to tetany; they set forth that
all forms of tetany depend on an absolute, or at least, a relative insufficiency
of the parathyroids. The different causes of parathyroid insufficiency
will be discussed later, with the exposition of the different forms of tetany
and the pathological anatomy.

We shall add a few words as to the relation of myotonia, epilepsy and
eclampsia to tetany. The occurrence in tetany of symptoms similar to
those of myotonia is, as already mentioned, not rare. The fact that they

206 THE DISEASES OF THE PARATHYROID GLANDS

are also observed in experimental tetany, ensures relationship to tetany.
The intention spasms may be explained by the fact that the will impulse
furnishes the determining factor for a tetany spasm. In addition there
often occurs, however, pitting on percussion and the myotonic electrical reac-
tion. On the other hand there occur true cases of myotonia congenita to
which are superadded the clinical picture of tetany.

In these cases, as v. Orzechowski points out, the symptoms of tetany are
only of a slight grade; with the decline of the tetany, the myotonia remains.
This coincidence of tetany and myotonia has been sufficient for Lundburg
and others to ascribe the cause of myotonia to an insufficiency of the para-
thyroids. The assumption seems to me to be fully unsubstantiated, as in
true myotonia all symptoms, that according to experimental experiences we
have come to regard as the cardinal symptoms of parathyroid insufficiency,
are absent. Myotonia is an affection of the muscles (Erb, Schultze and
Schiejjendecker and others). The occurrence of symptoms similar to those
of myotonia in tetany perhaps finds its explanation in a definite alteration of
the metabolism. It is remarkable that just those animals in whom the thy-
roids and parathyroids have been removed show these manifestations.
Furthermore, there is a case of Hoffmann's in whom the myotonic symp-
toms disappeared on the administration of thyroid gland, and in whom they
reappeared after withdrawal of the treatment, while the tetanic symptoms
were not essentially affected. Perhaps there is a certain relation between
myotonia and the high-grade mechanical hyperexcitability of the muscles
such as is not rarely seen in cachectic conditions.

As for epilepsy, we have already mentioned in the consideration of the
symptomatology that tetany may develop on an epilepsy that has lasted for
a long time, and that tetany and epilepsy may develop simultaneously in
individuals not previously epileptic, and indeed may improve simultaneously.
In many cases the epileptic convulsions occurring in severe tetanic at-
tacks may remain the sole manifestation of epilepsy. It should fur-
ther be mentioned that Chvostek's phenomenon is not rarely elicitable
in epileptics, and that Fleischmann and Poetzl as reported by Redlich found
twenty-eight times defects of the enamel among sixty epileptics, a fact
that perhaps indicates that individuals who in early years have passed
through tetany, later often become epileptics. Most important for the
relationship between tetany and epilepsy are the cases of parathyroprivic
tetany with epilepsy. Redlich has collected twenty such cases from the
literature and adds a case of his own. The frequent coincidence of tetany
and epilepsy shows that this combination is "no accidental happening"
(v. Frankl-Hochwart, Schultze, Redlich}. As to the intimate connection
we really know nothing certain. Westphal supposed that tetany and
epilepsy depended on the same toxic cause, which, as Chvostek later elabo-
rated, led both to alterations in the central nervous system and to func-

PARATHYROPRIVIC OR TRAUMATIC TETANY 2O"J

tional disturbances of the epithelial bodies. Pineles supposed that the
toxin of tetany produced a latent predisposition to epilepsy; Curschmann that
it increased the excitability of the cortex and subcortex. Experimental
pathology has as yet furnished no reliable evidence. In a cat in which Kreidl
extirpated three parathyroids, epileptic attacks regularly followed operations
on different parts of the cortex. Redlich could not confirm the results of
this experiment when he repeated it. Only in one experiment, an opera-
tion on the brain cortex after total thyroparathyroidectomy, did he notice
the simultaneous occurrence of severe tetanic and severe epileptic attacks.

Attempts have also been made to refer epilepsy without tetany to an
insufficiency of the parathyroids. As was to have been expected, pathological
anatomy did not substantiate this hypothesis. Erdheim examined the
parathyroid glands in two cases of status epilepticus; in one they were en-
tirely normal and in the other they were slightly sclerotic. Claude and
Schmiergeld found no constant change of tissue in thirteen cases.

The relationship of tetany to eclampsia has not yet been cleared up in a
satisfactory manner. In the years of childhood tetany may occur under
the guise of eclamptic attacks, as has been mentioned already. It has been
held that children who have suffered with eclampsia, later became epi-
leptic. Birk could not find this in his material, to which are opposed the
statements of Potpetschnigg. The eclampsia of adults is as -a rule to be
separated from tetany; for in eclampsia the cardinal symptom of parathy-
roid insufficiency, the galvanic excitability, is absent. Erdheim could not cor-
roborate the statements of Pepere and Zanfrognini, who found a lessened
number of parathyroid glands in their cases of eclampsia. In four cases
of eclampsia examined by Erdheim the parathyroids were normal, except
for the fact that they were very hyperemic and were permeated with small
hemorrhages, which manifestations are certainly to be regarded as secondary.

FORMS OF TETANY AND PATHOLOGICAL ANATOMY

i. The Parathyroprivic or Traumatic Tetany

It was first noticed by Nathan Weiss that in Billrotk's clinic the extirpation
of the thyroid gland was often followed by tetany. Since that time the
literature as to this subject has grown enormously. The question is handled
with especial thoroughness in the publications of v. Eiselsberg and Kocher.
v. Eiselsberg in his "Diseases of the Thyroid Gland" publishes a classic
description of tetany after extirpation of the thyroid gland. In Vienna tetania
" strumipriva " was observed much more frequently than in Bern. Among
forty cases of total extirpation of the thyroid gland, tetany was seen by Kocher
only nine times, of which number only three were pronounced cases; among
thirty cases of partial extirpation only six were acute tetany; among ninety-

208 THE DISEASES OF THE PARATHYROID GLANDS

seven operations in Basedow's disease, only five were tetany; one case of liga-
tion of all four arteries supplying the thyroid gland led to peracute tetany.
Epileptiform tetany has been observed by v. Eiselsberg, Kocher, and others, in
the wake of partial extirpation. Originally tetany was attributed to the fail-
ure of the thyroid gland. With the awakening knowledge of the significance
of the parathyroid function were heard loud voices referring thyroid-gland
tetany to the simultaneous damaging or removal of the parathyroids.
Fundamental for this view are the investigations of Pineles, and of Erdheim.
The latter observed three cases that had died of more or less acute tetany
after strumectomy. In the first case, which had shown a more chronic
course, the entire throat portion was cut in the serial sections; it was found
that all four parathyroids were missing, although two small accessory para-
thyroids were found in the midst of the thymus tissue. In both the other
cases, which had pursued a more acute course, parathyroids capable of func-
tionating were not to be found. Erdheim pointed out that the great fre-
quency of strumiprivic tetany in Vienna had its explanation in the fact that
there the operations on the thyroid gland were conducted according to the
old methods, while Mikulicz's wedge resection or Kocher1 s resection enuclea-
tion are rather adapted to avoid the parathyroids. However, the genius
loci must not be entirely overlooked in the explanation of the fact.

To-day, when we are well informed as to the significance and topography
of the parathyroids, tetany after operations belongs to the greatest of rarities.
A preparatory search for the parathyroids is not necessary; sufficient is
adherence to the propositions of Pineles and Erdheim to let remain both the
lower lobes; search for the parathyroids is directly indicated only when in
malignant struma, it becomes necessary to remove the entire thyroid gland,
v. Eiselsberg has reported a case in which the greater part of the thyroid
gland was removed for malignant adenoma. Myxedema developed, and
retrogressed after the appearance of metastases in the sternum. Ex-
tirpation of these metastases (healing by secondary intention) was fol-
lowed by a recurrence of the myxedematous symptoms and by tetany.
Erdheim explains this case by the fact that at the first operation there was
left behind one of the lower chief parathyroids, and that this became sac-
rificed at the second operation.

The etiology of the thyroprivic tetany is thus clear. This form of tetany
depends on the loss or the damaging of the parathyroids at the operation.

Proescher and Diller report a case of traumatic tetany in the adult. A
young man developed typical tetany eight days after a severe blow. At
autopsy there were found numerous small fresh hemorrhages in parathyroids,
which were in addition hypoplastic. Belonging to traumatic tetany are also
numerous cases of the tetany of sucklings, as we shall see later in the section
on tetany in children.

TETANY IN INFECTIOUS DISEASES AND INTOXICATIONS 209

2. Tetany in Diseases of the Thyroid Gland

Cases of tetany in myxedema are rare. They are strikingly frequent,
combined with epilepsy (cases of Stewart, Schonborn, and myself).

Cases of thyroiditis with tetany were observed by v. Eiselsberg, and
Kocher. Although there are no pathologico-anatomical investigations,
yet it may readily be supposed that acute inflammatory or sclerosing proc-
esses that attack the thyroid also involve the parathyroid in sympathy. In
strumous degeneration of the thyroid gland the parathyroids associated
with the capsule may become involved and thus are brought to atrophy.
Such cases have been reported by Steinlechner, Fraisseix, Hirschl, Marinesco,
Jacobi, and others. I shall speak in the consideration of idiopathic tetany
of the triad described by v. Frankl-Hochwart— tachycardia, tremor, and
Chvostek's symptoms (II and .III), with struma and vasomotor excitability.
This condition was called "tetanoid" by v. Frankl-Hochwart (see above
for the consideration of the hyperthyrosis or hypothyrosis in tetany).

3. Tetany in Infectious Diseases and Intoxications

Tetany has been observed in the most diverse infectious diseases.
Most quoted is the frequent association of tetany in epidemics of typhoid
fever (Aran and Rabaud). Tetany has also been observed in angina, in-
fluenza, acute articular rheumatism, croupous pneumonia, and many other
infectious diseases. For the most part these cases occur in places where
tetany is common and during the time of the occurrence of tetany. There-
fore it is very probable that in the majority of these cases the infectious
disease constitutes only the determining factor, that no form sui generis
is present, but that these cases belong to the idiopathic tetany to be de-
scribed later. At all events it is not improbable that a generalized infectious
process would affect also the parathyroids, and lead to infiltration or at least
to parenchymatous degeneration of these organs, thus temporarily deranging
their function.

In this category belong the cases of tuberculosis of the parathyroids.
There have been already published numerous statements as to the occurrence
of this condition (Benjamin, Carnot and Delion, Pepere, Kb'nigstein, Stumme,
Schmorl and Eggers) . Carnot and Delion, and Pepere, observed typical tetanic
symptoms in phthisis, in the days immediately preceding death. Stumme
observed Ckvostek's phenomenon. These findings are certainly interesting
in consideration of the frequent occurrence of CkuosteVs phenomenon in
tuberculosis, as mentioned previously.

We can regard the cases that occur in poisonings as a less independent
group. The most diverse poisons, such as ergotin, phosphorus, carbonic
oxide, spermin (Oppenheim), lead, morphine, chloroform, etc., may lead to
14

210 THE DISEASES OF THE PARATHYROID GLANDS

an outbreak of tetany. The assumption that the poisoning constitutes only
the determining factor has a firm basis in the investigations of Rudinger.
Rudinger first determined that in cats the peroral administration of calomel,
the subcutaneous administration of morphine, atropine, tuberculin, and
ergo tin, and the inhalation of ether does not influence in any way the elec-
trical excitability. After these animals had been placed in the condition of
latent tetany by a partial parathyroidectomy, the administration of these
poisons led to spasms.

4. Idiopathic Tetany (Occupation Tetany)

In the description of this form I chiefly follow the exposition of v. Frankl-
Hochwart. Idiopathic tetany shows the characteristic that it chiefly occurs
in persons following certain occupations, that it is especially frequent in
certain localities, and that it shows an epidemic-like increase during certain
months. The last observation was first made by N. Weiss and v. Jaksch.
The statistics of v. Frankl-Eochwart from the years 1880 to 1905 embrace
five hundred and seventy-six cases (among which, however, only five hundred
and twenty-eight were cases of occupation tetany). Of these occurred in

Jan. 66 Apr. in July 12 Oct. 10

Feb. 88 May 52 Aug. 9 Nov. 15

Mar. 137 June 36 Sept. 9 Dec. 31 cases

The especial predisposition of the followers of various occupations was
first mentioned by v. Murdoch, later by von Jaksch, Mader, Hoffmann,
Schultze, and others. It is especially cobblers and tailors that become af-
fected with tetany. Among five hundred twenty-eight cases of v. Frankl-
Hochwart were two hundred twenty-three cobblers, one hundred seventeen
tailors, thirty-eight carpenters, thirty locksmiths, thirty turners and the
remainder were divided among the other occupational classes. In women,
it is especially the maids [i.e., lady's maids] that become affected (thirty-
two of ninety-nine female cases) . Also soldiers become affected with it not
at all rarely (M attauschek) .

Another characteristic of occupation tetany is as has already been
mentioned that it prefers certain cities. It is most frequent in Vienna,
Heidelberg, and is not rare in Budapest; it is, however, especially the lead
workers who become its victims (Jakobi). Moreover, its epidemic exten-
sion presents variations. For instance it was very frequent in Paris in the
years 1830-1860. Since that time it has been very rare there. In Heidel-
berg also according to the most recent statement of Schonborn has it become
rarer. In the other cities that now harbor it, it shows a large increase in
certain years. Thus Mattauschek observed an epidemic among soldiers of
the Vienna garrison in the year 1896. Outside these cities, tetany is sporadic
nearly all over. In several places, small epidemics have been observed.

IDIOPATHIC TETANY 211

Idiopathic tetany shows a great inclination for relapses. After the first
attack it passes over in the latent stage, and tends to recur the next year at
the time for tetany (acute relapsing form of tetany, v. Jakscti). There is in
addition a chronic form in which the disease never entirely disappears.
The first form may pass over in the latter (see prognosis).

Concerning the etiology of idiopathic tetany we know nothing that is
certain. The endemic-epidemic occurrence, as is intelligible, has a priori
given occasion to the thought of an infection. This is supported by the
increase in temperature that occurs in the acute stages; I mentioned before
that this is rather due to disturbances in the regulation of heat, which may
serve as a partial manifestation of the irritable condition of the vegetative
nervous system; it may be said it occurs to a much greater degree after
parathyroidectomy. Recently A . Fucks has pointed out the resemblance of
the clinical pictures of tetany and ergotism (typical form of spasms, pares-
thesias, trophic disturbances, cataract formation, epilepsy, psychoses, etc.),
and is inclined to refer occupation tetany to poisoning with bad corn. Biedl
comments on this hypothesis, stating that there is formed in the putrefaction
of histidin an amino-base (imidoazolyethylamin) that is identical with the
active agent in ergotin'. I shall assume an expectant attitude with regard to
Fuck's hypothesis, as insufficient facts are at our command.

Very important for the etiology of idiopathic tetany appears to me a
contribution by McCarrison. In certain valleys among the Himalaya
mountains exists much epidemic tetany, and indeed just in those places where
there is epidemic goiter. The disease affects most solely women, and the only
man in whom McCarrison observed it was not affected with goiter. The epi-
demic of tetany takes on in numbers in spring, as with us, and is increased dur-
ing pregnancy and lactation. The goiter that predominates in this locality is
of a marked degenerative character. Numerous cases of tetany observed show
also signs of an incomplete myxedema; very noteworthy is also the statement
that persons that suffer from tetany become free of this affection when they
go into tetany-free districts, and finally reacquire the tetany when they return
to the original spot. In the light of this observation seems to me important
the fact that our localities for tetany, Vienna and Heidelberg, show an
especial form of goiter in the clinical sense, further the fact already men-
tioned that v. Frankl-Hochwart has observed that a great number of cases
of tetany later show distinct symptoms of myxedema, and finally the fact that
Kahn and 7 have described the observation that manifestations of a slight
hyperthyrosis and thyroid swelling can develop in the acute stage, or im-
mediately at the close of the acute stage. As tetany is not frequent through-
out in any goiter districts — in Steiermark and Tyrol it practically is absent,
and in Switzerland very rare — we may suppose that not every goiter noxus
may bring about idiopathic tetany, but an especial goiter noxus or^a
noxus that is similar to the goiter noxus. But even such an assumption

212 THE DISEASES OF THE PARATHYROID GLANDS

is, as I fully know, not satisfactory in certain directions. It does not explain
why tetany is so frequent in the springtime nor why certain occupations are
preferred in such a striking manner. I believe moreover that it would be
worth while to pursue the problem further.

5. The Tetany of Children

• The tetany of children is characterized by its great multiformity of mani-
festations. The assumption of the collectivity of these manifestations is of
recent date. In 1887 Cheadle had already stated that laryngospasm, tetany,
and convulsions were only the varying expression of the same "consti-
tutional morbid state." Since the year 1890 Escherich and v. Wagner,
Ganghofner, and later especially the school of Escherich maintained the teach-
ing of the belonging together of laryngospasm and the eclampsia of child-
hood, and, in spite of much opposition, have held to these doctrines, by the
demonstration of the increased electrical excitability and the delimination
from similar manifestations of another kind. The pathologico-anatomical
investigations of Erdheim and Yanasse seem adapted for establishing this
view on a safe basis. Tetany of early childhood occurs chiefly in the third
to the twentieth month of life. This is the form that deviates from the clinical
picture of tetany of adults through the multiplicity of its manifestations.
The tetany that sets in from the third year of life on is essentially similar
to the tetany of adults. The tetany of sucklings which often manifests it-
self only through increased galvanic, and especially anodic, hyperexcitability
is extraordinarily frequent in rachitic children and especially also in children
that have been fed artificially. This occurs almost always in the cold time
of the year. It shows a preference, as does rachitis, for northern countries
especially, but is distinguished from the tetany of adults by its uniform
extension.

The investigations of Erdheim and Yanasse, already mentioned, have
furnished an interesting elucidation for the etiology of this form of tetany.
Already in 1903 Erdheim had mentioned the finding of hemorrhage in the
parathyroids of new-born children, and in 1906 he reported like findings in two
of the sucklings that had died of tetany. Yanasse then examined system-
atically the parathyroids of thirty-five children who had died at the age
of fifteen months. He found that in cases in which the electrical excitability
had been normal during life, the parathyroids were normal. In those chil-
dren, however, in whom there had existed electrical hyperexcitability, he
found almost constantly hemorrhages or the remains of hemorrhages (in 71
of the 104 cases investigated). The hemorrhages are demonstrable at about
the twelfth month, and are very probably to be referred to trauma during
birth. According to the later investigations of Haberfeld, the damaging in-
fluence of the hemorrhages does not act so much on the destruction of the

TETANY OF MATERNITY 213

parathyroid parenchyma as on the inhibition in growth of these organs con-
ditioned by it. Erdheim and his collaborators, on the basis of their investi-
gations, adhere to the view that the tetania infantum depends on a hypo-
parathyroidism, and that the artificial nourishment constitutes only the
occasioning factor. Erdheim is corroborated by Peters, Schmorl, v. Verebely
and Strada. Auerbach, Grosser and Betke, Bliss, Raymond, Jorgensen and
others have pronounced against the assumptions on the ground of patho-
logico-anatomical investigations. Thus Escherich's views in their universal
form are to-day not generally shared.

Heubner has grouped together the diseases mentioned under the less
prejudicial name of spasmophilic diathesis.

The etiology of the tetany of later childhood (puerile tetany according
to Escherich] is as yet unknown; perhaps it is identical with that of the idio-
pathic form.

6. The Tetany of Maternity

Under this heading we understand the tetany observed in pregnant,
child-bearing, or puerperal women, v. Frankl-Hochwart has collected fifty-
three certain cases from the literature, and adds to them twenty-three of his
own. Of these twenty-eight affected women who were pregnant, nineteen
occurred after the delivery, and twenty-nine during the puerperium. The
beginning of tetany in pregnant women occurs in the sixth to the eighth
month [of pregnancy].

To-day maternity tetany can scarcely make a bid for the distinction of
a form sui generis. A portion of the cases belong in the group of tetany
after strumectomy, the rest in great part to the group of idiopathic tetany;
these come from places affected with tetany and occur especially in the
tetany months, and it seems to me noteworthy that there do occur epidemics
chiefly in the form of maternity tetany. While for example, according to
the summary of Adler and Thaler, maternity tetany is relatively rare in Vienna
(at the first gynecological clinic at Vienna only nine cases of the tetany of
maternity were observed among about 30,000 cases) ; a great number of the
cases described by Krajewska and also by McCarrison belong to this group.
In all the forms the pregnancy or lactation plays the role of the determining
factor only. This has been established by numerous experiments on animals.
At first Horsley, later Vassale, Pineles, Erdheim, and especially Adler and
Thaler, showed that in partially ectomized animals that show no signs of
tetany, the tetany comes to expression with the progress of the pregnancy.
In cases of slight parathyroid insufficiency, this may occur only in the course
of the second pregnancy, or, as has repeatedly been observed, there may even
occur a normal pregnancy interpolated between pregnancies complicated
with tetany. A very interesting case of this sort is reported by Meinert.
In this case there had been two births that were normal, then in the third there

214 THE DISEASES OF THE PARATHYROID GLANDS

was tetany; then there were two more normal births, to be succeeded by a
sixth pregnancy in which the tetany recurred. A strikingly marked atony
of the uterus has been observed after the delivery in women who have tetany
(cases of Erdheim and of Neumann). The tetany during pregnancy tends
to have a very unfavorable influence on the fetus. The birth of macerated
fetuses has been reported several times (Pick, Neumann) ; or the statements are
that the children indeed were delivered, but soon died in convulsions (Kocher,
v. Frankl-Hochwart). These last statements are very important with respect
to the investigations of Iselin.

The question as to why pregnancy calls forth tetany in predisposed in-
dividuals is not as yet fully explained. We may readily conceive that preg-
nancy makes increased demands on all the ductless glands and thus unmasks
a latent insufficiency. Perhaps similar relations are to be found with respect
to tetany combined with osteomalacia. In osteomalacia, Erdheim found
hyperplasia of the parathyroids. He assumes that in osteomalacia there are
especial demands made on these glands. The statement of Erdheim has
been often corroborated. Schmorl found the parathyroids normal in four
cases of rickets, but in a case of osteomalacia the parathyroids were markedly
hypoplastic. In three other cases the parathyroids were normal, although
Erdheim points out that the islands were not examined with the use of the
osmium stain. Strada found the parathyroids enlarged in a case of osteo-
malacia, and unaltered in two cases; in one case Bauer found in one para-
thyroid an adenoma, and foci of proliferation in three others. Finally the
parathyroids of twenty-four individuals were examined by Todyo. He found
hyperplastic processes as described by Erdheim four times. In seven cases
of osteomalacia they were, however, absent only once, and in six cases only
one parathyroid was examined. In eleven cases of senile osteoporosis he
found, on the contrary, hypoplasia eight times.

7. Tetany in Gastrointestinal Diseases

Tetany is observed in the most diverse gastric and intestinal affections.
I mention only acute dyspepsia, acute and chronic enteritides, and helmin-
thiasis. Especially are those cases brought into relief in which on account
of some obstruction there occurred a dilatation of the stomach, or (in rare
cases) a dilatation of the intestine, and a stagnation of the gastric and in-
testinal contents. From the great group of gastrointestinal tetany a number
of cases are to be singled out in which the gastrointestinal disturbances con-
stitute only one symptom of the tetany. I would agree with Chvostek that
these cases are not at all rare. This has been taken up in detail in the con-
sideration of the symptomatology. In a further group of cases an indisposi-
tion of the stomach or intestines may constitute the determining factor for
the tetany.

TETANY IN GASTROINTESTINAL DISEASES 215

An especial interest attaches to that form which occurs when the gastric
or intestinal disturbance has existed for a long time. Attention to this
form was directed first by Kussmaul. Since that time there have been pub-
lished numerous reports concerning it (Fleiner, Fr. Muller, Gerhardt, Bouveret
and Devic, Ewald, Albu, Schlesinger, v. Frankl-Hochwart, Rudinger and Jonas,
Wirth). The most various conditions have been found: Cicatrized ulcer of
the pylorus or the duodenum, hour-glass stomach, malignant processes
(such as carcinoma or sarcoma) in the neighborhood of the pylorus, or
tumors of the gall-bladder or of the pancreas that lead to stenosis, torsion
of the stomach, acute paralytic dilatation of the upper small intestines,
in children dilatation of the colon, etc.

There has also been reported a group of cases of dilatation of the stomach
without demonstrable stenosis. I mention from the newer literature only
the cases of Ferrannini and of Fleiner.

The tetany that occurs in all these conditions may be quite rudimentary.
Not rarely, however, it is of the most severe forms, forms that are attended
with universal spasms and loss of consciousness.

Bouveret and Devic distinguish a simple form attended with paresthesia
and typical spasms of the extremities, and a " tetanisme plus ou moin general-
ise" that may lead to dyspnea and death from asphyxia principally through
involvement of the muscles of respiration, and a form attended with loss of
consciousness and coma. These severe forms of stomach tetany leave the
prognosis always somewhat doubtful. The present statistics show a mor-
tality of about 60-70 per cent.

Numerous hypotheses have been brought forward to explain this form.
In a certain number of the cases perhaps an affection of the gastrointestinal
tract may play the determining role. This may be likely through the
circumstance that, as the figures of v. Frankl-Hochwart show, a great number
of these cases occur during the tetany months. On the grounds of this ob-
servation Rudinger and Jonas have upheld the supposition that the tetany of
gastrodilatation is nothing more than tetany acquired in the course of a
gastrodilatation. This explanation does not seem to me to be entirely
satisfactory. Before everything else, it is striking that this form of tetany
is less confined to the tetany districts. Kussmaul supposed that the tetany
was caused by a thickening of the blood, due to the frequent vomiting and the
diminished absorption of water. Fleiner has adopted this theory, pointing
to the hyperglobulia observed by Fr. Muller and also himself. This hy-
perglobulia is, however, as we have already seen, not the cause of tetany
spasms, but their effect. Gerhardt, Palliard, Ewald, Albu, and others have
supposed that toxic substances bring about the tetany, their origin being due
to the stagnation of the gastric and intestinal contents (autointoxication
theory). The finding of diamines in the stomach contents and in the urine
of such patients means nothing, as they are also found there in other diseases.

2l6 THE DISEASES OF THE PARATHYROID GLANDS

It is certain, however, that in many cases, the tetany promptly disappears on
combating of the stagnation (for example washing out of the stomach).
The explanation of this subject has as yet received no elucidation from
pathologico-anatomical investigations. Erdheim found the parathyroids
entirely normal, first in a case of severe gastric tetany, then in a second case
with slight gastric manifestations, and third in the case of tetany in the
course of enteritis. MacCallum in a case of gastric tetany found five rather
large parathyroids whose cells showed abundant mitoses. This he re-
garded as hyperplasia. Kinnicutt found in a case of gastric tetany the
parathyroids normal. It seems, therefore, that in a group of these cases
there is present only a relative, insufficiency of the function of the para-
thyroids with, however, markedly increased demands on them; we should
consider further the possibility that in high-grade stagnation in the gastro-
intestinal tract substances are formed and absorbed that increase the ex-
citability of the nervous system so markedly that under circumstances the
action of the parathyroids no longer suffice; we must also assume, however, a
certain predisposition of the individuals affected, as conditions of stagna-
tion in gastrointestinal conditions are rather frequent, while complication
with tetany is very rare.

If we pass in review what has been said concerning the individual forms
of tetany and their etiology, we find that we cannot deny that the view that
all forms of tetany may be grouped together from the point of view of
relative or absolute insufficiency of the parathyroids is, as a result of
pathological anatomy, not sufficiently proved. All the rest of the patho-
logico-anatomical findings that up to the present have been brought into
relief in tetany, findings such as alterations in the ganglion-cells of the spinal
column, in the marrow, or in the nerve fibers themselves, have been incon-
stant. As yet unelucidated as to its significance is the finding of a premature
sclerosis of the fine and finest cerebral vessels, especially in the medulla
of the cerebrum and in the cerebellum, such as A . Pick pointed out in four
cases of chronic tetany.

Differential Diagnosis. — We distinguish an acute relapsing and an acute
recurring form of tetany. We should also appropriately distinguish be-
tween a manifest and latent tetany unattended with spasms, and finally
between fully developed form of the formes frustes (the expression tetanoid
I regard as less to the purpose) ; it is the latter differentiation that is attended
with differential diagnostic difficulties. In general, the diagnosis of tetany is
easy, as its most important criterion, the galvanic hyperexcitability, has as
yet been observed in no other condition. As has previously been mentioned,
Erb's phenomenon may be temporarily absent even in the acute stage. In
such cases great value can be attached to Chvostek's phenomenon only
when it is pronounced. If in addition there are present paresthesias in
the territory of the ulnar nerve and complaints as the sensations of tension

TETANY IN GASTROINTESTINAL DISEASES 217

in the hands and feet, the diagnosis of tetany appears to be very likely; often
there occur in the further course of the disease fibrillary contractions, or
Trousseau's phenomenon, or only transitorially a slight degree of heightened
galvanic hyperexcitability thus making entirely certain the diagnosis.
Not rarely, during the tetany season, Reichmann's disease may be attended
with quite rudimentary forms of tetany.

v. Frankl-Hochwart and Fleiner have regarded certain cases of gastric
tetany described in the literature as spurious, as they showed only sensa-
tion of tension in the hands, with the absence of Erb's phenomenon. During
the last few years I have observed six cases of gastric tetany (see also Falta
and Kahn) ; in almost all I was dealing with a typical Reichmann's disease
with marked dilatation of the stomach and increased peristalsis, indeed even
antiperistalsis, phenomena that retrogress in many such cases on appro-
priate treatment. In some galvanic hyperexcitability, mostly of a slight
grade, was present quite transitorily. However, the paresthesias and the
sensation of tension outlasted Erb's phenomenon for a long time. Therefore,
in the formes frustes we may miss Erb's phenomenon, even on repeated
examinations. We fully recognize its prominent importance for the diag-
nosis; there do occur, however, isolated cases in which it is absent and
in which the diagnosis tetany can be established in spite of this fact.

Concerning diseases that may be confused with tetany I mention only
the following: Tetanus is readily distinguished from it by the increase in
reflexes, by the noninvolvement of the hands, and by the absence of the
typical symptoms of tetany. Also the delimitation from meningitis, from
acroparesthesia in chronic poisonings and from occupational spasms is
always easy, as in these diseases the typical distinguishing symptoms of
tetany are absent. Hysteria may occur combined with tetany, and in such a
way that tetany spasms and hysterical spasms are present simultaneously, or
the hysterical spasms may come to the fore on the retrogression of the tetany,
or hysteria alone may exist simulating tetany (pseudotetany) (E. Freund,
H. Curschmann, F. Chvostek). In this form, naturally Erb's phenomenon
is absent, but hysterical stigmata are present. The pseudotetany attacks
may simulate the true tetany attacks in an illusory manner. The uni-
lateral occurrence of the spasms would rather point to the thought of hys-
teria. Yet it should not be forgotten that a few true cases of hemitetany
have been known (H. Freund, v. Frankl-Hochwart, v. Jaksch, E. Freund, et
a/.). Too, Trousseau's phenomena is often simulated illusorily. Especially
to be considered is the absence of the paresthesias usually attending tetany
attacks, and of Erb's phenomenon, and the presence of fibrillary contrac-
tions. If these cases of pronounced hysterical symptoms are added to
a true tetany, Erb's phenomenon is decisive.

In the differential diagnosis between epilepsy and tetany it is especially
important to determine whether epileptiform convulsions belong to tetany

2l8 THE DISEASES OF THE PARATHYROID GLANDS

or whether there exists a true epilepsy in addition to the tetany. Especial
attention must be directed to the aura, to the incontinence of urine and feces
during the attack and to the postepileptic stupor. Loss of consciousness in
tetany is very rare, in epilepsy it is the principal symptom. In similar
fashion a case of tetany with symptoms of myotonia must be investigated
with regard to the cardinal symptoms of true myotonia (myotonic reaction) .

The galvanic hyperexcitability is important, according to Escherich,
for differentiation from eclamptic convulsions of the years of childhood.

The prognosis for the different clinical forms of tetany is not the same,
and in strumiprivic tetany the prognosis quoad vitam may be very un-
favorable. To-day such cases scarcely come into consideration. The
prognosis of idiopathic tetany quoad sanitationem was formerly regarded as
favorable. Since v. Frankl-Hochwart has reviewed his cases the views as to
this point have changed considerably. Of fifty-five cases only nine were
entirely healthy, seven showed chronic tetany, general nervousness and
chronic invalidism, nineteen showed slight tetany symptoms and trophic
disturbances, six showed chronic invalidism without symptoms of tetany,
eleven had died four to eleven years after the outset of the tetany. Saiz
furnishes similar unfavorable statistics. He states that of nine cases only
one remained free of distress, and that also this individual had sustained a re-
currence. Cases of death from tetany of maternity have been reported
(Trousseau, Schundlechner, Blazicek, et al.). Also transition into chronic
tetany has been observed, v. Frankl-Hochwart, Adler, and Thaler and
Novak, in contradistinction of Fellner, hold therefore the prognosis as doubt-
ful. Especially unfavorable is the prognosis in tetania gastrica; here it
happens that the stomach affection itself frequently influences the prognosis
unfavorably. Also in the tetany of childhood the revisions of the more
recent period have furnished rather unfavorable results as to the length
of life and especially as to the further development (Escherich, Thiemich,
Birk, and Potpetschnigg) .

According to Escherich, 25 per cent, of the nurslings at the hospitals who
are sick with tetany die, and Thiemich and Birk in Breslau and Potpetschnigg
in Graz have concerned themselves with the later fate of children who have
been sick with tetany. Both statistics come to the result that a not in-
considerable number of such children soon die. Those investigated were
only rarely quite normal. In the majority of cases they showed disturbances
of the psychical and intellectual development and especially remaining be-
hind in the development of speech.

The treatment of tetany should be concerned first of all with efforts to
replace the lacking parathyroid function or to improve the insufficient para-
thyroid function. It is a pity that up to the present all attempts have been
futile. The substitution therapy that was so valuable in thyroid insufficiency
has in this case up to the present led to no certain result. It is intelligible

TETANY IN GASTROINTESTINAL DISEASES 2 19

to-day why the thyroid medication formerly employed in tetany was without
results. It is remarkable, however, that no decisive results are obtained by
the administration of subcutaneous employment of dried parathyroid gland
or of extracts of parathyroids. The favorable statements of a few authors
(parathyroid tablets, Marinesco, Lowenthal, Wieprecht; parathyroantitoxin,
Vassale) stand in contradiction to the negative results of the exact trials of
Pineles and the statements of many other authors.

Pineles found that neither stomachal, nor subcutaneous, nor intra-
peritoneal administration of parathyroid extract in large doses served to
influence in any way parathyroprivic tetany. Again, the feeding of very
large amount of the extract of the parathyroids of horses, remained without
results in human beings. One is reminded of the negative results of pancreas
feeding (islands of Langerhans) in diabetes. The parathyroids are, like the
pancreas, no storage glands.

The attempts to transplant the parathyroids at first awakened great
hopes; v. Eiselsberg and later Payr transplanted the thyroid gland in the
abdominal wall or in the spleen and (on account of associated transplantation
of the parathyroids) prevented the outbreak of the tetany. Enderlen first
showed microscopically that the parathyroids transplanted with the thyroid
gland remained capable of .functionating, in that in part they regenerated.
Since that time numerous transplantations have been undertaken by Biedl,
Pfeiffer and Meyer, Halstead, Harvey, Cristiani, Leischner, et a/.); favorable
results have also been reported in man (first by v. Eiselsberg) ; favorable
results were reported by Pool-Kocher (transplantation into the bone marrow),
v. Garre, Boese and Lorenz, and Danielsen. The clinic of v. Eiselsberg later
met with unfavorable results. On this account, the question was restudied
by Leischner and Kohler, who concluded that the parathyroids behave
quite similarly to the thyroid, that is, that only autotransplantation is at-
tended with favorable results; while on homiotransplantation it is true
that the parathyroids functionate for a time at first, but later they become
absorbed.

The administration of calcium salts has been regarded by MacCallum and
Vogtlin as a causal therapy. Theoretically, the condition of excitability in
ectomized animals should become dampened. Improvement is reported by
Curschmann in three cases of tetany in man, and by E. Meyer in a case of
tetany of pregnancy. Kahn and I studied the excitability of the nerves at in-
tervals of two to three hours, and, after the administration of even a large
amount of calcium lactate never observed a distinct influence on the same.
Also the intramuscular administration of "Kalzine" (v. Muller and Saxt)
was ineffective. If the assumption that in tetany the assimilation of calcium
in the nervous system is disturbed holds good, it seems to me that the nega-
tive results become intelligible; the person with tetany behaves against in-
creased administration of calcium just as a patient with pancreatic diabetes

220 THE DISEASES OF THE PARATHYROID GLANDS

behaves against increased administration of sugar. We should expect, on
the contrary, in conditions of increased dissipation of calcium, a result from
the calcium administration. Perhaps we may explain in this manner the
favorable results of calcium treatment in Basedow's disease.

There therefore remains for the treatment of tetany only symptomatic
therapy, a therapy that likewise is almost ineffective. Weak sedatives such
as the bromides and valerian are especially ineffective. In severer cases we
can occasionally ameliorate the condition by the use of chloral. Levi
claims to have had good results through blood-letting, and Narbut through
lumbar puncture. The means that have proved best are rest in bed, diet
poor in meats, protracted warm baths, and roborants. The phosphorus
liver oil had been especially recommended in cases complicated with osteo-
malacia. In the tetany of sucklings, Escherich recommends the interpolation
of days with just adequate diet; it is especially important to substitute
natural feeding for cow's milk whenever possible. Worthy of notice is the
statement of McCarrison that some cases of tetany disappeared when the
patient moved to another place. In women conception should be pre-
vented or even pregnancy interrupted. Certain drugs, such as ergo tin,
are to be avoided in the tetany of pregnancy (Novak) .

Gastric tetany deserves an especial consideration. Here the question of
operation (gastroenterostomy) has met with lively discussion. While Albu
recommends operation as soon as possible, Fleiner would first await the results
of internal therapy. Also Chvostek favors internal treatment. The results
of the surgical treatment now seem very much to encourage this method of
treatment. According to the latest statistics by Wirth, of twenty-one oper-
ated cases, seventeen remained permanently cured, while according to
older statistics of Albu the mortality of cases treated internally reached 77 per
cent. The question is, however, rather more complicated than one would
gather from these statistics. In case of assured pyloric stenosis, operation is
indeed not to be rejected, the question is only whether operation should be
undertaken immediately or whether it should be postponed until we find
that we can accomplish no good by attempts to improve through internal
treatment. Much will depend upon whether gastric lavage can be borne.
The chief difficulty is met with in the diagnosis of the pyloric stenosis.
Cases of Reichmann's disease may present all the symptoms of pyloric
stenosis — increased peristalsis in front of a fluoroscope, indeed even anti-
peristalsis. Even in cases of true gastric tetany we saw not only a
disappearance of the tetanic symptoms but also a lessening of the size of the
stomach and a cessation of the spasm of the pylorus — this as the result of
gastric lavage every evening, and the administration of a dry diet rich in
fats and of enemas to satisfy thirst. In such cases perhaps operation
would be without curative results.

ADDENDUM 221

b. Conditions of Hyperfunction of the Parathyroids

Certain cases of adenoma of the parathyroids are known, without there
having been found conditions that would be regarded as those of hyper-
function (Erdheim). Also the tumors, in size up to that of a child's head,
described by Benjamin, Hulst, and de Santi, were attended with symptoms
that were purely local, and otherwise remained without symptoms. In
paralysis agitans, which was brought into relation with the parathyroids by
Roussy and Clunet, Erdheim found the parathyroids normal in three cases.
Lundborg and Chvostek ascribed myasthenia pseudoparalytica to hyper-
function of the parathyroids. Chvostek sought to establish that the clinical
pictures of myasthenia and tetany were diametrically opposed to each
other. Both would seem to affect the voluntary muscles with nonin-
volvement of the sphincters. The electrical behavior in myasthenia is
directly opposite to that in tetany; and in the one is found fatigue of accom-
modation, in the other accommodation spasm. Each sometimes accom-
panies myxedema or Basedow's disease. The finding of the collection of
cellular infiltrations and of discontinuous fatty degeneration of the muscle
fibers, that is extraordinarily frequent (for literature see Marburg), points
rather to the fact that myasthenia belongs more to the diseases of the
muscular system; moreover, Haberfeld recently has been unable to find any
alteration of the parathyroids in the cases of myasthenia gravis (see also the
first chapter).

Addendum

The author's criticism that some of the negative results ofthyropara-
thyroidectomy may be due to the leaving behind of inaccessible parathyroids
or portions of parathyroids seems also to the opinion of MacCallum, Thomson,
and Murphy. At all events it appears that adult herbivorous animals (the
sheep, Simpson) are capable of sustaining thyroparathyroidectomy without
appreciable effect, although in Simpson's experiments the lambs that were
operated on developed acute tetany and died.

The results obtained by Mustard on transection of the spinal cord agree
with BiedVs and MacCallum's in that they are diametrically opposed to
Munk's and to F alto's as to noncontinuance of tonic contractions in the
parts below the seat of cutting after transection of the spinal cord. It
is a pity that the divergence in results — whether they are due to differences
in interpretation or differences in technique — have not as yet been explained.

Has kins and Wheeler have tested the effects of the injection of nicotin,
adrenalin, and pituitrin in parathyroidectomized dogs, and have found that
in these dogs there is a marked increase of vasomotor irritability affecting
all components of the vasomotor mechanism, sympathetic cells, myoneural
junctions, and musculature.

222 THE DISEASES OF THE PARATHYROID GLANDS

Underhill and Blather-week show that during the tetany which develops
after thyroparathyroidectomy, glycogen disappears entirely from the liver
and the sugar content of the blood is markedly lowered or may even be re-
duced to zero. It is probable that this action may be ascribed to the lack
of parathyroid tissue, since the phenomena may be observed when all the
parathyroids are removed and some thyroid tissue remains.

Poll and Turnure have transplanted a parathyroid into the preperitoneal
tissue behind the sheath of the rectus muscle, in a case of tetany due to
supposed operative removal of the parathyroids, with apparently good
results, including cessation of the tetany.

Following the idea suggested to him by Meltzer's experiments, Berend
treats, with unusual success, cases of tetany with subcutaneous injections of
magnesium sulphate solution (15.20 cgm. magnesium sulphate per kilogram
of body weight). The electrical hyperirritability and the carpopedal spasm
diminish, and there is a shortening of the disease's duration. The treat-
ment is combined with a salt-free diet. An 8% solution of magnesium
sulphate should be used, and the water for dissolving it should be freshly
distilled. 15.20 c.c. of this solution is the usual dose for a young infant.

REFERENCES

Simpson (S.). The influence of age following thyroparathyroidectomy. Proc. Soc.
Experim. Biol. and Med., Vol. IX, 1911-1912, pp. 2-4.

Mustard (H. J.). A study of certain tonic and reflex nervous impulses as factors in
parathyroid tetany. Am. J. Physiol., 1911-1912, XXIX, 311-316.

Hoskins (R. G.) and Wheelan. Parathyroid deficiency and sympathetic irritability.
Am. J. Physiol., Vol. XXXIV, No. 3, June i, 1914.

Underhill (G. P.) and Blatherweck (N. P.). The influence of thyreopurathyroidec-
tomy upon the sugar content of the blood and the glycogen content of the liver. J. Biol.
Chem., Vol. XVIII, No. i, June, 1914, pp. 87-90.

Pool and Turnure. Annals of Surgery, Vol. LVI, 2, 1912; Vol. LVI, Nov., 1912,
No. 2, pp. 804-807.

Berend (N.). Die Magnesiumsulfat behandlung der spasmophilic Krampfe. Monat-
schrift fur Kinderheil Kunde Bd. 12. Originalien. 1914, pp. 269-331. Also, Ver-
handlungen der Gesellschaft deutscher Naturforscher und Arzte. Pt. 2, 2nd half, 1913,
p. 596-598.

CHAPTER V
THE DISEASES OF THE THYMUS GLAND

It has not been long that the thymus gland has been classed with the
hormonopoietic system. Originally it was regarded as a constituent of the
lymphatic apparatus.

Anatomy and Embryology. — The thymus gland develops as a paired
organ from the ventral part of the third branchial cleft. (See illustration 3,
p. 53). -The pairs unite very early; at birth the organ lies behind the
sternum, backward as far as the pericardium, reaching above somewhat
higher than the jugular notch. In the human being there may occur ac-
cessory lobes of the thymus which may be either independent, or be united
with the thyroid gland, or even the thymus gland itself. The thymus gland
is of entodermal origin; although at present there is no unity of opinion
with regard to the origin of the pictures resembling lymphocytes found
in the completed thymus and especially in its cortex. Since the inves-
tigations of Hammar the entodermal origin of the polymorphic fixed
reticular elements lying chiefly in the medulla, and of the so-called Hassal's
corpuscles stands assured. Stohr regards the origin of the thymus lympho-
cytes as due to division of the epithelial cells while recently Hammar and
Maximow, following the older assumption of His and Stieda, adhere to the
assumption of a secondary ingrowth of mesodermal pictures. According to
the latter view, the thymus gland therefore belongs to the lymphatic ap-
paratus; there is found In it a "symbiosis of cells of the different germinal
layers;" it is concerned with the production of lymphocytes. According to
Nagele it is indeed the principal site in the formation of the lymphocytes in
early life. The same author states that this view is also favored by phylo-
genetic factors, for in the amphibians the thymus is the source of lymphocytes
when the lymph glands are still absent. The statement of Ivar Bang that the
thymus gland contains at least five or six times more nucleinate than the
lymphatic glands does not speak unconditionally against this assumption,
as the analysis included the epithelial elements.

The weight of the thymus gland increases after birth, according to the
statement of Hammar, v. Sury, Schridde, Ronconi, Pappenheimer, and others,
the growth ceasing only with the beginning of sexual maturity; the thymus
tissue gradually atrophies and is partly replaced by fat, although appreciable
remnants of thymus tissue are retained until late life. In late life too were
found, by Hammar, mitotic proliferation of lymphocytes and new formation

223

224 THE DISEASES OF THE THYMUS GLAND

of Hassal's corpuscles. In addition to this involution of age an accidental
involution also occurs; Hammar and Jonson have shown that in fasting ani-
mals the weight of the thymus gland reduces very rapidly, especially through
loss of lymphocytes. Also in the melting down of the thymus gland on
irradiation with X-rays, the reticulum shows itself much more resistant than
the lymphocytes. The accidental involution is found among chronic dis-
eases that lead to marasmus. It is especially well expressed in pedatrophy
(Farret). Also, according to Hammar, accidental involution may occur in
older people, an evidence that glandular tissue capable of functionating has
still been present.

Physiology. — The question as to whether the thymus gland is an organ
important for the life of the organism has not until recent times received
a uniform answer. Friedleben, Langerhans, and others saw animals in which
the thymus gland had been removed go undisturbed in their development,
while other authors on the contrary, of whom I here mention only Tarulli
and LoMonaco, Ghika, Cozzolino, Basch, Sommer and Florken; Ranzi and
Tandler saw occur in dogs, rabbits, cats, and other animals, temporary
serious disturbances of growth which later disappeared. The most recent
investigations are those of Klose and Vogt and of Matti. The investigations
make it very likely that the disturbances mentioned can no longer disap-
pear when the extirpation of the thymus gland has been done on very
young animals only a few days old.

Klose and Vogt operated on twenty-five dogs. The phenomena observed
are briefly as follows: After the latent stage of about fourteen days the ani-
mals gradually showed a spongy, soft skin, a "pasty habitus." They began
to remain behind in growth on account of a lessened growth in length of the
extremities. The bones were distinctly more flexible. In agreement with
Basch, Klose and Vogt found that the ossification is retarded and that if
the bones are fractured callus formation is very poor or does not occur at
all. The ash contents of the bones is essentially diminished. Basch also
found that in this stage the elimination of calcium is essentially increased.

The hyperexcitability to galvanism which Basch found in thymectomized
animals is to be referred to the associated extirpation of the parathyroid
bodies imbedded in the thymus tissue.

According to Ranzi and Tandler, the dentition is also delayed in this stage ;
the dogs take on abundant fat (stadium adipositatis, according to Klose and
Vogt). This is followed by a stadium cachecticum; in spite of increased
hunger the animals gradually lose weight, muscular tremors occur, the hemo-
globin contents and erythrocyte contents of the blood reduce, and chemotactic
irritants, such for examples, injection of nucleinic acid, remain inactive. The
animals become indolent and tired, begin to suffer with disturbances of coordi-
nation and finally die in a coma-like condition. Feeding with thymus gland
or injection of it only aggravates the condition.

PATHOLOGY AND SEMIOLOGY 225

H. Matti describes the condition after thymectomy in very young animals
as somewhat different. After the latent period of about four weeks, during
which the animals remain behind in growth, manifestations occur in the osse-
ous system that are very much like those of high-grade rachitis. There occur
a high-grade softening and bowing of the bones and a rosary formation; there
is found a deficient apposition of calcium in the bones, the bone marrow is
hyperemic and the metaplasia in the fat marrow is slowed. The epiphysial
junctures are several times broadened. The examination of the blood only
shows that the decrease in lymphocytes which normally occurs with increas-
ing age and the increase in neutrophilic elements is slowed. Matti found
a broadening of the suprarenal medulla and a slight enlargement of the
thyroid gland and of the pancreas. The gray substance of the spinal
cord shows, as Klose and Vogt have already stated, signs of an increased
breaking up. At the close the animals lose the ability to walk and there
ensues marked cachexia that leads to death. The muscles show high-grade
atrophy of inactivity, with transitions to degenerative atrophy.

In thymectomy in somewhat older animals these manifestations occur
only temporarily, yet when the extirpation was associated with removal of the
spleen, the animals, according to Klose and Vogt, for the most part died.
This would signify that the spleen takes over at least a part of the function of
the thymus gland. Matti could not find this.

It should be mentioned further that castration in young animals essentially
delays the involution of the thymus gland and that increased sexual activity
accelerates it (Calzolari, Henderson, N. Paton, and Goddall, and others).
With this agrees the fact that in eunuchs, Tandler and Grosz found the thymus
gland hyperplastic.

Svehla's experiments on hyperthymization have in part lost their signifi-
cance, as it has been shown by Popper that the depressor action of thymus
extracts intravenously is not specific, but is dependent on clots in the blood
path.

Pathology and Semiology. — Our knowledge as to the significance of the
thymus gland in clinical medicine is extremely deficient. As far as symptoms
in the absence of the thyroid gland in human beings is concerned we know next
to nothing.

In the autopsy of new born and very small children aplasia of the thymus
gland has sometimes been found. The first statement is that of Bischojf.
Clark described an eight-month-old child that remained well up to the sixth
month. Then there developed hydropic swellings. Autopsy showed left-
sided hydronephrosis and aplasia of the thyroid gland, v. Sury describes a
case of congenital total defect of the thymus gland in a three-month-old child
who died of pneumonia. Aplasia of the thymus gland seems very frequently
to be associated with other malformations, especially developmental de-
fects of the brain (Winslow, Borneville, Katz, and others). On the other
15

226 THE DISEASES OF THE THYMUS GLAND

hand, G. Anton shows the simultaneous occurrence of thymus hyperplasia
and brain hypertrophy.

Lately total extirpation of the thymus gland has been carried out on
account of stenosis of the trachea (see below). Very worthy of note is the
statement of Koenig, that after resection of the thymus gland such as was
undertaken in a nine-month-old child on account of dyspnea, breathing be-
came normal and afterwards a severe rachitis developed on account of
which the child first learned to walk as late as the age of four and one-half
years. In the rest of the cases there are no statements as to the further course.
According to the experiences in animals, the experiments up to the present,
total extirpation of the thymus gland in very young children is to be advised
against.

Up to the present the entire clinical interest has been turned to the cases
which have shown a hyperplasia of the thymus gland and a persistence or
reviviscence of the same.1 Kopp in 1855 first attracted the interest of
the medical world to the cases of sudden death in early life which occurred
with cyanosis and stridor and which on section showed nothing but hyper-
plastic thymus gland. The extensive investigations of Friedleben, which
culminated in the aphorism " there exists no thymic asthma," for a long time
suppressed this teaching. First in the year 1888 Grawitz on the evidence of
two cases pointed out the forensic significance of thymic hyperplasia. Up to
this time only purely mechanical factors in these cases of death had been con-
sidered. Then, in 1889, A. Paltauf, finding out the frequent combination of
thymic hyperplasia, status lymphaticus, and narrowing of the vascular system
regarded the cause of death not as a mechanical factor but as a vegetative dis-
turbance which he designated as lymphato-chlorotic constitution. Among
others, Ortner reported congenital narrowing of the aortic system in these cases
of sudden death, v. Kundrat status lymphaticus with more or less large thy-
mus gland in cases of sudden death in narcosis, Schnitzler and others narcotic
death in cases of Basedow's disease with persistence of the thymus and status
lymphaticus. With Pott originated an excellent description of the cases of
sudden death in the years of childhood. Most authors agree with the
view of A . Paltauf, in that they regard the mechanical factor as without sig-
nificance and place in the foreground the lability of the organism or the
cardio-vascular system that is dependent on toxic factors. Especially in-
teresting are the observations of the familial occurrence of these species of
sudden death (Perrin, Hedinger, and others}. Certain authors, however,
hold fast to the mechanical cause through compression of the trachea by the
thymus gland.

1 Persistence of the thymus gland is, properly speaking, an incorrect expression as every
human being possesses a thymus gland for his whole lifetime. Better than "persistence" is
higher parenchymal value than corresponds to the age; also a reviviscence is really not certain,
as we do not possess a criterion for it.

PATHOLOGY AND SEMIOLOGY 227

The question is not completely cleared up at the present day although the
direction in which we may expect the clearing is indicated. What makes the
question especially difficult is the circumstance that status lymphaticus and
enlarged thymus gland occur so frequently in associationship. Apparently,
however, they stand to each other in a conditioned relation. As we shall see
later in another paragraph, the finding of an intumescence of the lymphatic
apparatus eventually with a mononucleosis in the blood is very frequent in-
deed. We find this in numerous diseases of the ductless glands, in chronic
infectious diseases, in neurosis of the vagus nerve, etc. These hyperplasias
deviate markedly from one another histologically. In addition, it is per-
fectly clear that not every chronic swelling of the lymphatic apparatus is
associated with increased chemic function. Also the thymic hyperplasia or
thymic persistence or reviviscence is extraordinarily frequent just in these
diseases of the ductless glands. If we accept the view that the thymus
gland is in part of mesodermal origin, therefore in part belongs to the lym-
phatic apparatus, this frequent combination of enlarged thymus gland and
status lymphaticus would not be inexplicable. There certainly exists,
however, an abnormally large thymus gland without status lymphaticus,
hence a status thymicus.

Recent investigations seem to have furnished a significant differentiating
criterion. Wiesel and Hedinger have shown that status lymphaticus is asso-
ciated with a hyperplasia of the chromaffin tissue. Thus Hedinger found in
five cases of pure thymic hyperplasia entirely normal development of the
suprarenals and the entire chromaffin tissue, also on microscopical exami-
nation. Again, v. Sury points out that in the so-called thymic death of the
new-born the chromaffin tissue is always well developed and that the hypo-
plasia of the chromaffin tissue sets in only with the development of status
lymphaticus. In cases of pure thymus hyperplasia the lymphocytosis of the
blood would seem to be absent.1

Let us now turn again to the question of thymic death, v. Sury has
treated this subject in an elucidative exposition, one especially adequate on
account of its rigid critique. He bases his conclusions on the material of two
hundred medicolegal autopsies in which the thymus gland was taken into
account, v. Sury shows first that the thymus gland varies extraordinarily
in size and that therefore the diagnosis of a thymus hyperplasia is often very
arbitrary. He mentions further that in the cases of sudden death in children
apparently healthy beforehand there exists very frequently capillary bronchi-
tides which are very common and which are very easily overlooked. In spite
of this we can hardly deny the significance of the mechanical factor in the
cases of "thymic asthma " published in recent years — cases which after partial

1 Often in pure status thymicus the epithelial thymic tissue, that is, the reticulum and its
derivatives, is found hyperplastic while the small thymic cells do not necessarily have to be in-
creased, in contrast with status lymphaticus (Wiesel).

228 THE DISEASES OF THE THYMUS GLAND

or complete extirpation of the thymus gland became greatly relieved of their
oppressive symptoms. Klose and Vogt have collected eight such cases. The
first case was operated on by Rehn (reported by Parucker}. It was that of a
two-and-a-half-year-old child. Since that time a series of other cases have
been operated on (see the literature in Wieset). Especially to be mentioned
is the case of Hinrichs in which the hyperplastic thymus gland led, in addition
to a hindrance of breathing, to a high-grade disturbance of the ingestion of
food. Lately the action of the X-rays has also been recommended (Fried-
lander, Myers, Rachford, Ribideau and Weil) . The case of Ribideau was that
of a two-month-old child with marked need for air on account of hyperplasia
of the thymus. After extensive irradiation with X-rays the dyspneic mani-
festations disappeared within two days; somewhat later the child died
from measles. The autopsy showed fibrous atrophy of the thymus gland.

The attacks of dyspnea, cyanosis, stridor, and eventually hoarseness, that
were observed in all these cases speak indeed for a purely mechanical factor.
Whether in the pure cases of status thymicus in addition to this mechanical
factor there exists a toxic factor on account of hyperthymization we must for
the present leave undecided; although I have hardly been able to discover any
grounds for this assumption. Up to the present the cases of Basedow's dis-
ease in which death occurred suddenly in narcosis regularly showed in ad-
dition to thymus hyperplasia a pronounced status lymphaticus and were in
addition complicated by other factors.

It should be mentioned further that the thymus gland can also be the seat
of malignant tumors or of inflammatory processes. The numerous thymic
tumors thus far observed have not furnished any information as to the physi-
ology of the gland, v. Neusser described a case of sarcoma of the thymus
gland ; a twenty-five-year-old patient was remarkably large and showed hy-
perplasia of the genitalia. A short time ago we observed a case of carcinoma;
here also there existed gigantism; the development of the genitalia
was, however, entirely normal. There should also be mentioned the case of
Bramivell in which was found, in addition to the sarcoma of the suprarenal
gland, a carcinoma of the thymus. Finally in numerous, but not all, cases of
myasthenia gravis there were found hyperplasia of the thymus gland and
alterations in the muscles that were regarded as lymphosarcoma. This in-
terpretation is not however certain, as HassaVs corpuscles occur in the
muscle metastases. In these cases we are dealing rather with reticulum
tumors.

If our trying to draw a resume out of the facts detailed, we find that it
cannot be denied that in spite of the enormous labor that up to the present
has been spent on this subject, the physiological significance of the thymus
gland is still unclear. The destruction of the organ through tumors or in-
flammatory processes which have otherwise furnished us with so much im-
portant information in the pathology of the other ductless glands is here

ADDENDUM 22Q

apparently entirely without significance. Operative extirpations of the gland
in earliest childhood have, except in the single case of Komg previously
mentioned, furnished no symptoms of absence. However, we should not for-
get that we mostly deal with cases of resections and that also in most of the
cases statements as to the further course are absent. Then again we must
consider the presence in such cases of accessory lobules of the thymus.

Just as little clarified appears to me the significance of thymic hyper-
plasia for pathology. In many cases only the significance of the mechanical
factors remain certain; this is however quite without significance for the ques-
tion of hyperthymization. For the rest we really only know that in a great
number of very diverse conditions we find thymus glands with supernormal
parenchymal values. Especially is this true for diseases of the ductless
glands. We find thymus hyperplasia very frequently in Basedow's disease,
apparently also in acromegaly, in hypophysial dystrophy, in myxedema, in
eunuchoidism, etc. It therefore occurs as well in conditions of glandular hyper-
function as1 in hypo/unction. I believe, therefore, that we should exercise
great scepticism concerning theories that would explain the frequent
coincidence of Basedow's disease and thymic hyperplasia. On the same
ground I regard as at present quite hypothetical the correlations that
according to the views of many modern authors exist between the thymus
gland and the other glands of internal secretion.

Also the experiments to produce hyperthymization artificially have up to
the present seemed scarcely satisfactory. The old experiments of Svehla are,
as has already been mentioned, not of value as evidence. The fewer ex-
periments of Hart with injection of powdered Basedow's thymus and those
of Bircher with implantation of Basedow's thymus in animals are worthy of
notice but do not furnish sufficient grounds for the support of a teaching of
hyperthymization.1 Also the hypothesis that Wiesel provides at the end
of his unusually well-prepared work on the pathology of the thymus seems to
me on the face of it as still too little supported. Wiesel supposes that the
thymus gland furnishes to the blood path a secretion that acts vagotonically,
and he regards especially the eosinophilic cells present so abundantly in the
thymus gland as the seat of origin of this principle that acts antagonistically
to adrenalin. In this respect Wiesel identifies status thymicus and status
lymphaticus, although he does take pains to separate the two conditions
from each other in an anatomical sense.

Addendum

Boggs points out, without regards to the dulness due to enlarged thymus
is partially higher and more superficial than that due to diseased mediastinal

1 Concerning the "thymogenic" Basedow's disease see chapter on thyroid gland, pp. 75
and go.

230 THE DISEASES OF THE THYMUS GLAND

lymph glands or other forms of mediastinitis; that it is constantly much more
marked on the left of the sternum than the right, and the dulness is movable,
the lower border rising as much as an interspace when the head is shifted from
extreme flexion to extreme extension, with the patient in the sitting position.
"In some cases of persistent or enlarged thymus there may be no dulness in
the first interspace, but only in the second and below it. In such instances a
shift in both upper and lower borders of dulness may be made out."

The movement in the dulness of the thymus is explained by this author as
due to the movability of the thymus itself. He found the thymus to be en-
larged or persistent in thirty-five of sixty-six colored girls, between the ages
of five and eighteen years, fourteen of whom had suffered from measles.
He remarked that lymphatic hyperplasia seems more common in the colored
race. Jacobi, in the discussion on Bogg's article, recommends percussing
with the child in the prone position.

Park and McGuire, however, on the basis of twenty-nine autopsies, have
determined that the thymus gland is a relatively immobile organ and that
the methods of percussion used by Jacobi and by Boggs bring out a movable
dulness that is due to other factors, probably to the upward advance of the
lung margins.

Of recent cases of apparent thymic death, it is probable that death in the
cases of Ginsburg and of Kennedy was due to mechanical factors, while in
Veeder's case, it is not at all certain that the thymus had anything to do in
the matter.

In a recent review, Ricketts mentions the various surgical procedures on
the thymus gland, and points out that in case of impending suffocation due to
enlarged thymus, intubation or tracheotomy may be done.

According to Halsted, Klose warns against X-ray irradiation of the
thymus region in young children, because of the marked susceptibility of the
gland to the influence of the X-ray.

REFERENCES

Boggs (T. R.}. Percussion signs of persistent or enlarged thymus. Tr. Ass. Am.
Phys., Vol. XXVI, 191 1, pp.- 3 53-3 56.

Park (E. A.) and McGuire (W. C.). A criticism of two percussion methods for the
diagnosis of enlarged thymus. Arch. Int. Med., Vol. X, No. 3, Sept., 1912, pp. 214-218.

Ginsburg (N.). Thoracic viscera in a case of thymic enlargement. Proc. Path.
Soc. Phila., N. S., Vol. XIV, 1911, p. 82.

Kennedy (A. M.). Enlargement of the thymus; a remarkable case. Glasgow M.
J., Vol. XXVII, Jan., 1912, pp. 31-37.

Veeder (B. S.). Hemorrhage into the parathyroid glands in a case of "thymic death."
Proc. Path. Soc. Phila., N. S., Vol. XIV, 1911, p. 83.

Halsted (W. S.). The significance of the thymus gland in Graves' disease. Bulletin
of the Johns Hopkins Hospital, Vol. XXV, No. 282, Aug., 1914, pp. 223-228.

CHAPTER VI
THE DISEASES OF THE HYPOPHYSIS [PITUITARY GLAND]

Since Pierre Marie delineated the clinical picture of acromegaly and
placed it in an etiological relationship to the hypophysis, the literature on
the experimental research and clinical study of the hypophysis has grown
enormously. In spite of this fact there as yet prevails in our views as to the
pathogenesis of the clinical pictures concerned with the hypophysis very
little uniformity. The chiefest cause of this is that as yet we know but little
as to this organ's physiological significance, at least much less than we know
about the thyroid. The blame resides principally in the difficult accessibility
of the gland for experimental purposes, and further the fact that here we
have to do with two organs intimately bound together and enclosed in a rigid
bony cavity. A certain physiological independence of these two organs might
be expected from their, morphological and embryological independence.
Hence we may speak of a hypophysial apparatus showing certain analogies
with the thyroid apparatus (thyroid gland and parathyroid glands) and with
the corresponding suprarenal apparatus (cortex and chromaffin medulla),
hereafter to be described. The differentiation of the pathological mani-
festations accruing to the two systems is made more difficult than that of the
pathological manifestations affecting the other ductless gland groups because
on account of the enclosure in a rigid cavity an affection of one of the organs
seldom leaves the other entirely uninvolved.

In an attempt to delimit and to explain the clinical pictures presented
by the hypophysial apparatus the following four points seem to begin to be
important, i. The characteristic typographical relations, 2. the embryo-
logical development, 3. a certain physiological independence, and 4. the mani-
fold analogies that exist between the glandular hypophysis and the thyroid
gland.

Anatomy and Embryology. — The normal hypophysis of man weighs on
the average somewhat more than 0.5 gm. It consists in a glandular anterior
lobe and a nervous posterior lobe. Both lie in the sella turcica, into which
cavity the dura penetrates through the foramen sellae turcicae and surrounds
them both in common. From the anterior lobe a small process projects
forward in the so-called peduncle of the hypophysis while the posterior lobe
is directly in communication with the brain by means of the infundibulum.
A tapering cleft, the recessus infundibuli, in communication with the third
ventricle, penetrates deeply into the peduncle.

The following scheme after Erdheim shows these relations: Ch. =

231

232

THE DISEASES OF THE HYPOPHYSIS

chiasm; V.L. = anterior lobe;
lations of squamous epithelium;

H.L. = posterior lobe; Pl.eh. = accumu-
R.C. = Rathke's cyst; F = process; E =
terminal enlargement of process; r.i.
= recessus infundibuli; /. = infun-
dibulum; D. = dura; D» = dia-
phragma sellae; A. = arachnoid.

The anterior lobe is supplied by
small branches of the internal car-
otid artery, the posterior lobe by ves-
sels of the pia. The veins end in the
sinus circulosus Ridleyi. Anterior
and posterior lobes are surrounded
by a capsule of the dura mater, which
capsule overhangs the entrance to
the sellae in the form of a diaphragm
that is perforated by the infundibular
peduncle.

The anterior lobe for the most part consists in epithelial columns. Here
are found chromophilic cells in which Benda by the employment of a specific
stain has demonstrated eosinophilic and basophilic granules. Here are also

h.

R.C.

v.

J).

FIG. 30. — Diagram of the structure of the hy-
pophysis (after Erdheim).

c. c.

B. C.

E.G.

FIG. 31. — Anterior lobe of the hypophysis. £.C. = eosinophile cells. 5.C. = basophile cells.

C.C. = chief cells.

ANATOMY AND EMBRYOLOGY

233

found cells that are nongranular: the so-called principal cells, which during
pregnancy, according to Erdheim and Stumme, develop into the so-called
pregnancy cells.

Posteriorly the anterior lobe is delimited from the so-called pars inter-
media by a poorly vascularized layer of connective tissue. The especial
histological character of the pars intermedia has been emphasized by Her-
ring. Here are found follicle-like pictures filled with colloid. This cellular
layer has also been called the cork layer or Peremeschko's medullary layer.
Here lies also the so-called Rathke's cyst.

The posterior lobe is made up of glial tissue
and scattered cells, the character of which has
not as yet been established, and of nerve fibers.

The hypophysis of man undergoes character-
istic alterations during pregnancy. First Comte,
in six pregnant women, found enlargement of
the hypophysis and multiplication of all the sorts
of cells. Later Erdheim and Stumme made a
careful study of the alterations. According to
both these authors the enlargements affect only
the anterior lobe. The differences in size are
very appreciable. While the weight of the
hypophysis in a nuHipara is about 61.8 cgm.
on the average, Erdheim and Stumme found it
to be on the average 84.7 cgm. in primiparae
and 106 cgm. in multipart. ^

Through its position the hypophysis shows
special relations to the chiasm of the optic
nerves and to the third and sixth cranial nerves.

The embryological development of the hypo-
physial apparatus is shown in the following
three sketches, which are taken from the works
of Erdheim and of Mihalkovic.

FIG.

32. — Development of the
hypophysis.

i = infundibulum.

h = Rathke's pouch.

x = boundary between epithelium originating from the primary

ectodermal oral diverticulum and the entodermal head-gut.
Pi = solid process (anterior lobe) .

g = hypophysial duct.

x = original insertion of the hypophysial duct.
pi = process of the grown-out [ausgewachsen] normal hypophysis.

x = collection of accumulations of squamous epithelium, probably
remnants of the hypophysial duct originating from the epi-

234 THE DISEASES OF THE HYPOPHYSIS

thelium of the oral diverticulum, while the epithelium of the
hypophysial duct is cubical.

The nervous lobe of the hypophysis originates from the diencephalon.
Here there develops a pouch-like protrusion (processus inf undibularis) , which
during the fourth week adjoins a similar pouch originating from the epithe-
lium of the oral diverticulum (Rathke's hypophysial pouch). In the lower
classes of animals there exists an intimate spatial relationship between the
two, due to the fact that the infundibular peduncle, which in these animals
is much better developed, is overlain in a cup-like manner by the epithelial
part (see Edinger, Bau der nervosen Zentralorgane des Menschen und der
Tiere, 2, Bd. 7 Edition, 1908). In man this intimate relationship between
anterior and posterior lobes is by no means so extensive. Here principally
the posterior lobe is very much less well developed.

The question as to whether the pars intermedia belongs to the anterior
or to the posterior lobe seems to me, according to what I can find in the
literature as to this subject, as yet not cleared up. At all events the facts
are important that on separation of the anterior lobe from the posterior the
pars intermedia always remains with the posterior — & fact also mentioned
by Gushing — and that, as had already been mentioned, the anterior lobe and
the pars intermedia are always separated by a layer of connective tissue.
This question seems to me to be a very important one from the clinical
standpoint. As is known, the posterior lobe and the pars intermedia contain
a substance that increases blood-pressure and acts as a diuretic, a substance
that in its action shows a certain similarity to adrenalin. It is, therefore, not
impossible that the pars intermedia possesses in its relation to the nervous
system similar embryological relations to those which have been demon-
strated for the chromafrin tissue.

The analogy in the development of the glandular lobe of the hypophysis
with that of the development of the thyroid is apparent. Both originally are
glands with external secretion. Just as is the case with the hypophysial
duct, the ductus thyreoglossus undergoes atrophy ; this also leaves behind cell
accumulations which consist chiefly of stratified plaster epithelium. Accord-
ing to the recent investigations of Haberfeld the hypophysial duct may, espe-
cially when there are malformations of the skull, persist. This has also been
observed in acromegaly (Ettore Levi). It is of especial significance for the
pathogenesis of acromegaly, as we shall see later, that accumulations of
typical glandular epithelium may be found on the roof of the pharynx as well
as along the persistent craniopharyngeal canal, from which accumulations
may be formed adenomata.

The glandular anterior lobe of the hypophysis is a triie ductless gland.
The opinion has been expressed that its secretion streams off through the
posterior lobe. Against this speaks first the separate blood supplies, then

ACROMEGALY 235

the fact that the posterior lobe may be removed without the anterior lobe's
losing its function (Crowe, Gushing and Romans] , and finally the observation
of v. Cyan that in hypophyses of cattle and sheep the anterior and posterior
lobes may be separated from each other by small plates of bone. It may well
be supposed that, as is true for the external secretion of the thyroid, the exit
channel for the internal secretion of the anterior lobe is formed by the lymph-
vessels or the blood-vessels.

The secretion of the posterior lobe would seem to pour out into the third
ventricle through the recessus infundibuli. Gushing and Gotsch in animal
experiments found that the cerebrospinal fluid increases the blood-pressure
in a manner analogous to the action of infundibular extract. I would like
to see demonstrated the fact that the cerebrospinal fluid acts as a diuretic as
does pituitrinum infundibulare.

a. Acromegaly
Hyperpituitarism, Marie's Disease

Definition. — By acromegaly we understand a disease that is characterized by
the gradual enlargement of the peaked [gipfelnde, i.e., peaked, acral] parts (nose,
lips, tongue, lower jaw, hands and feet) and by hyper plastic alterations in the
entire osseous system. . There mostly develops an appreciable enlargement of the
hypophysis, which leads to broadening of the sella turcica. Associated with this
is localization of corresponding symptoms of brain pressure. To this are
added very frequently alterations of the thyroid gland of a hyper plastic character,
marked accentuation of the function of the interstitial glands; also, very frequently,
loss of function of the genital glands after preliminary transitory increase of
function, and, apparently frequently, hyperplasia of the suprarenal cortex.
Also the condition of excitability of the vegetative nerves is sometimes increased
in manifold ways. Very frequently there occurs rapid withering away of the
body and manifestations of degeneration of manifold nature. The pathological
anatomical finding in the hypophysis is an adenoma or adenocarcinoma of
the anterior lobe. To-day we refer acromegaly to an increase of function of the
glandular hypophysis.

Occurrence. — Acromegaly is not a very rare disease. It does not seem to
give preference to any country or to any race of people. It usually begins
between the ages of twenty and forty years, most frequently between
the twentieth and thirtieth year of life (Sternburg). According to this author
it usually occurs in women later than in men. There are also rare cases
of acromegaly that begin in the years of childhood or adolescence. These
are of special importance. I shall refer to them in greater detail in the
consideration of the pathogenesis. Hereditary or familial occurrence
seems to be very rare. I have found very few statements as to this ques-
tion in the literature and all these are very indefinite. Thus Arnold in

236 THE DISEASES OF THE HYPOPHYSIS

1891 described in detail a case of acromegaly that began in the eighteenth
year of life. One of the patient's brothers was affected with the same
disease earlier in life. Also Franlzel describes a case in which the affec-
tion began in boyhood; in the eleven-year-old daughter of which patient
the disease was also recognizable. In this family were many individuals
who were very tall. We find a statement of Schwoner's that the mother
of the female patient who was seventy-three years old apparently be-
came sick with acromegaly at the age of fifty; the father of the patient
was also very large. Frankel, Stadelmann and Benda state that the father
of two blood relations of the case described by them was said to have shown
the same anomaly. In the case reported by H. Salomon, we find the state-
ment that the mother of the patient seems to have suffered with acromegaly
and diabetes.

Symptomatology. — I begin with a description of the alterations in the
bones and soft parts. The alteration of the face in fully developed cases can
be so marked that the individuals actually become unrecognizable. The nose
is monstrously thickened, the superciliary arches and malar bones protrude
markedly; this is chiefly dependent on an increase in volume of the pneu-
matic cavities. I refer to the X-ray illustration of Observation XXV in
which the large frontal cavity is to be seen as a light space. Such an enlarge-
ment may bring about narrowing of the auditory passages and of the orbits.
In the case of youthful acromegaly described by Schultze and Fischer there
occurred almost complete deafness probably due to the thickening of the
internal ear. Also the cranial skull may increase essentially in circumference,
so that the hats no longer fit. The sutures often close prematurely. The
external occipital protuberance is in most cases enormously developed. The
narrowing of the orbits may bring about exophthalmus although this may be
also brought about by other causes such as enlargements of the eye-balls and
stagnation in the cavernous sinuses (Benda) . In many of the cases associated
with symptoms of Basedow's disease the cause of an existing exophthalmus
may be due also to a heightened tonus of Muller-Landstrom's muscle. The
great variation that the exophthalmus shows in such cases may be as well
explained in this manner as by the cause assigned by Benda.

Very characteristic is the spreading apart of the teeth on account of the
enlargement of the upper jaw, especially of the lower jaw. On account of the
marked prognathia of the lower jaw, and on account of the oblique position
of the alveolar process due to this, chewing becomes almost impossible. The
mucous membrane of the oral cavity is for the most part thickened, the
tongue can so increase in size that in spite of the enlargement of the jaws it
projects over the teeth. The mucous membrane of the tongue becomes thick-
ened, the papillae are enlarged, the microscopic examination showed enormous
proliferation of the interstitial tissue, while the muscle fibers show, at least in
the later stages, signs of atrophy and degeneration. On account of the thick-

ACROMEGALY 237

ening and the weight of the tongue articulation may be affected. The larynx
is often considerably enlarged, the voice is deep and, on account of the reson-
ance in the enlarged pneumatic spaces, abnormally loud. This is true for
both male and female individuals. The clavicles, especially, are enlarged.
Often there develops rather quickly a pronounced kyphosis of the lower cer-
vical and upper thoracic spine and a lordosis of the lumbar spine.

Then, too, there may occur ankylosis of the vertebral bodies. The ribs are
thickened and broadened. Very characteristic is the tremendous thickening
of the places for the insertion of the muscles, the widening of the vascular for-
amina and the deepening of . the vascular furrows (Slernberg); the entire
osseous system can be enlarged in all dimensions as in the cases of Schultze
and Fischer.

On the hands only the soft parts are considerably thickened, the thicken-
ing occasioning a spreading apart of the metacarpal bones. The hands
become paw-like. The X-ray picture does not show anything especially
beyond a slight thickening of the places of muscular insertion (type en large,
Pierre Marie), (see St, Observation XXX, reported later). In other cases
there is in addition to this an increased growth in length, leading to a true
giant hand (type en long see Ti, Observation XXV). Here are found both
lengthening and broadening of the hands and feet. Launois and Roy find the
type en long in acromegalic gigantism. The feet may behave similarly.

X-ray examination of the skeleton shows a thickening of the walls of the
skull, enlargement of the pneumatic cavities, increase in size of the lower jaw
and broadening of the epiphyses of the long bones, formation of osteophytes
on these, thickening of the phalanges of the fingers and toes (Schuller) ; in the
later stages of acromegaly there is found considerable atrophy of the osseous
structure; on section Deitnch found especially the spongiosa atrophic. He
regards this as neuropathic atrophy. Frankel, Stadelmann, and Benda in
each of four cases found pronounced atrophy, in one case distinct porosis and
always formation of osteophytes.

As in the later stages the muscles of the arms and legs are for the most
part markedly atrophic, the amorphic condition of the extremities becomes
that much the more conspicuous.

As example of the skeletal alterations in acromegaly I cite the following
case:

Observation XXIV. — V. U., thirty-two years old, entered the clinic Jan. 10, 1912, car-
penter. No hereditary predisposition to disease, no similar sickness in the family.
Married seven years. One year after the marriage a child was born that died soon
after birth. One illegitimate- child is ten years old.

The present disease began seven years ago with a feeling of furriness in both hands,
formications, and a characteristic sensation of stiffness especially in the morning. For
some months severe pains in the hands and forearms so that the patient had to get up often
at nights and walk about the room. Soon afterward the patient noticed gradual enlarge-
ment of the hands, and a short time after this the chin became larger so that chewing was

238

THE DISEASES OF THE HYPOPHYSIS

done only with the lateral teeth, as also the jaw was pushed forward. The pains and pares-
thesias were always worse in summer than in winter. For five and one-half years gradual
loss of libido, and later loss of erectibility of the penis. Entirely impotent for five years.
The acromegalic alterations greatly increased in intensity. The patient denied headache
and disturbances of vision. Lately there have reappeared drawing pains, especially in the
knees and ready fatigability; in addition to these, severe sweats. Alcoholism; patient
denies lues.

Status. — 168 cm. tall, coarsening of the facial features, cushioning of the lips, circum-
ference of the skull 58 cm. Marked protrusion of the orbital borders and the frontal pro-
tuberances. Circumference of the skull from the point of the chin to the top of the occiput
74 cm. Nose coarse, large, lower jaw markedly protruding, lower row of teeth is 1.5
cm. anterior to the upper row. The lower incisor teeth gape 3 mm. Tongue markedly

FIG. 33. FIG. 34-

Case of acromegaly (Observation XXIV).

thickened and broadened and on account of the thick tongue, articulation is poor. Uvula
broad, tonsils enlarged, neck broad and compressed 34^ cm- m circumference. Submaxil-
lary glands palpable. Thyroid enlarged, left lobe more enlarged than right.

The skin and visible mucous membranes somewhat pale. The skin rather thick but
may be readily raised from the underlying tissues in great thick folds. The hair of the
head rather abundant, the hairiness of the genitalia rather marked and also the thigh and
legs are rather pronouncedly covered with hair.

Distinct kyphosis of the upper dorsal part of the vertebral column, slight lumbar

ACROMEGALY 239

lordosis. Thorax is barrel shaped, compressed, reaching deep downward in front. Cir-
cumference of the thorax at the level of the nipple is on deep inspiration 104 cm., on
strong expiration 101 cm. The clavicles are markedly thickened. The ribs and the
intercostal spaces are strikingly broad. The upper and lower extremities have taken on
in circumference in their distal parts. Abnormal breadth of the middle of the hand.
Circumference of the middle finger 8% cm. Right hand displaces 625 cc. of water,
left hand 640 cc. of water. X-ray examination shows chiefly hypertrophy of the soft
parts. The metacarpi are biscuit-shaped on account of the pressure of the increased
soft parts and decrease in size at their diaphysial portions. Also the middle portion of
the foot is enormously broadened, showing a similar picture to the X-ray. Enormous
thickening of the toes.

Transverse diameter of the heart to the X-ray 13 cm. Otherwise cardiac findings normal.
A slight decrease of tachycardia. Liver and spleen not palpable. On X-ray examina-
tion the stomach is not enlarged.

Examination of the eye. (Docent Ulbrich) O. D. ^, O. S. jjf 0. External halves of
the papillae pale, with however a large physiological excavation so that the diagnosis
paling is not possible. Visual fields for white and colors are normal.

X-ray Examination of the Skull. — Enormous enlargement of the entire skull, especially
the facial bones. Sella turcica enlarged to the size of a gulden. Clivus sharpened.

Erythrocytes, about 4,500,000.

Hemoglobin, 75 per cent.

Leucocytes, 6,240 of which:

Polymorphonuclear neutrophiles, 57.6 per cent.

Lymphocytes, 25.4 per cent.

Large mononuclears, 15.7 per cent.

Eosinophiles, 1.3 per cent.

Examination as to alimentary glycosuria was unsuccessful, as the patient vomited
No sugar in the urine on the administration of a diet rich in carbohydrates.

Pulse between 90 and 100.

Examination of the exchange of gases (Dr. Bernstein).

CO2 0 . Respiratory CO2 O2

quotient

235.7 288.8 0.816

240.7 296.3 0.793 3-!56 3-857

243.2 298.4 0.781

The examination of the elimination of uric acid on a purin-free diet shows a marked
increase of the endogenous factor. This lies higher than double the normal average
of the (Novaczinsky and Falta).1

Examination of ammonia, amino-acids, and polypeptid elimination shows normal
relations as may be seen by few figures here adduced.

N N(NH3) N. (amino acid) N. polyp.

16.64 gm. 0.7202 0.2718 0.0683

18.65 gm. 0.6902 0.2842 0.1561

On Feb. 28, a portion of the hypophysis of the patient was removed by the endonasal
route by Dr. Hirsch.

Mar. 5, the patient was retransferred to the clinic.

Mar. 15, patient has fallen off in weight and the acromegalic symptoms have not as

1 On the administration of sodium nucleinate there was -a-^ prompt and rather high increase
of the uric-acid elimination.

240

THE DISEASES OF THE HYPOPHYSIS

FIG. 35. — X-ray picture of hand in acromegaly (Observation XXV).

ACROMEGALY

241

yet retrogressed. Several times at the beginning the patient showed a rise in temperature,
but at present the temperature is normal. Headaches at times. Examination of the
purin metabolism shows just as decided an increase of the endogenous elimination of uric
acid as before the operation.

i
In many cases the muscle

strength is not diminished in the
initial stages. Sometimes such in-
dividuals show even an extraordi-
nary strength. There is, however,
from the beginning a gradually in-
creasing and rapid fatigability, and
in the later stages such individuals
cannot long follow their occupation
on account of muscular weakness.
Microscopically such muscles show
increase of the connective tissue
and degeneration and atrophy of
the muscle fibers. Arnold de-
scribes vacuolization, multiplica-
tion of the nuclei, and atrophy of
the muscle fibers, increase in the
number of nuclei, and growth of
interstitial connective tissue, also
the occurrence of fat cells in- the
connective tissues.

Also in the skin are found, es-
pecially in the sacral parts, sclerotic
processes affecting both the epider-
mis and cutis. The papillae are
enlarged, and the sclerosis ex-
tends to the nerves and vessels
and to the connective tissue fasci-
culae surrounding the glands. Fre-
quently abnormal pigmentations
are found. In spite of sclerosing
processes the skin may be readily
raised up in folds, which fact is
important in the differential diag-
nosis from myxedema. In the
later stages true myxedematous
alterations of the skin are found not rarely (see below) .

Pierre Marie found mollusca pendula in numerous cases

FIG. 36.— Abnormally strong growth of hair in
acromegaly (Observation XXV).

The secretion of

16

242

THE DISEASES OF THE HYPOPHYSIS

FIG. 37. — Widened sella turcica in acromegaly (Observation XXV).

ACROMEGALY 243

the sebaceous glands is increased (see below for information concerning
increased sweat secretion).

The growth of hair on the head is often remarkably dense, and the individual
hairs are thick. In the course of the disease abnormal hair growth occurs
on the trunk and extremities, as may be seen in the following observation.

Observation XXV. — T., thirty-one years old, cobbler, entered the clinic Dec., 1911.
First admitted Nov. 16, 1905. Since 1903 gradual enlargement of the hands. All mili-
tary gloves were too small for him. Also face has become broader, nose and lips have
become larger, weight somewhat less. Headache, pigmentations of the skin, thyroid
slightly enlarged. Eye-grounds normal. No hemianopsia. Sella turcica uniformly
enlarged to the size of a cherry. The dorsum sellae thinned. The clinoid processes
pushed backward. Skeleton of the hands and feet show appreciable thickening of the
soft parts.

Nov., 1907. Headache has become much more severe. The hairiness of the body
has increased markedy. The hairs are brittle. Marked hairiness of the genitalia, abnormal
hairiness of the abdomen and extremities.

Arcus superciliares enormously developed. Nose enlarged. Lower jaw slightly
prognathous. Cushion-like ear lobules. Mustache bristly. Hairiness of the linea alba
very strong. Very deep wrinkle formation on forehead. Potency entirely normal.

Sella turcica deepened three times more than is normal. Dorsum sellae much thinned
and elongated.

Alimentary glycosuria negative.

Dec., 1911. During the last year the hairiness has become even denser. . Libido is un-
altered, the potency has decreased slightly. Typical acromegalic alterations of the skeleton
and the soft parts, no tachycardia. Slight enlargement of the thyroid gland.

Investigations of the Exchange of Gases (Dr. Bernstein).

Per kg. of body weight
CO2 O2 RQ CO2 O2

233.5 288.7 ' 0.809

275-5 342.o 0.753 2.733 3.55

266.7 329.8 0.748

Alimentary glycosuria strongly positive (0.78 gm. dextrose)

Erythrocytes, 4,490,000

Hemoglobin, 95 per cent.

Leucocytes, 4900, of which:

Polymorphonuclear neutrophiles, 56.7 per cent.

Lymphocytes, 30.5 per cent.

Large mononuclears, 12.6 per cent.

Eosinophiles, 0.2 per cent.

Investigation of the elimination of uric acid on purin-free diet shows values between
0.72 and 0.97 gm. — therefore is very appreciably increased.

The following is an -additional example of abnormal hairiness in
acromegaly.

Observation XXVI. — I. Bo., thirty-one years, entered May, 1911. The sickness began
in 1905. First enlargement of the fingers, then, about simultaneously, enlargement of the
feet, the skull, the nose, the neck. In 1908 began enlargement of the lower jaw. Also
the ears became somewhat thickened. Since 1909 the forearms and the metatarsus, too,
have grown. Also the circumference of the chest has increased and the hairiness of the

244

THE DISEASES OF THE HYPOPHYSIS

trunk has become essentially stronger. Number of collar formerly 41, now 46. For two
or three years on every psychical excitement, and less on every bodily movement, in-
stantaneous occurrence of outbreaks of sweats; potency not entirely normal since the age of
twenty, since the beginning of the disease rapid diminution of libido, and now it is lost
utterly. Appetite increases at times. In 1910 thyroidin administered at home; this led to
palpitations of the heart, that have persisted to the present. Thyroidin also acted unfavorably
on the sweats. A cousin of his father's also suffered from acromegaly. For six or seven
months headaches on the vertex and occiput. Power of attention has considerably
decreased. Often cramps of the musculature of the feet, and calves, and sticking pains
in the bones of the hands and feet.

FIG. 38. — Case of acromegaly (Observation XXV).

Moderately compact body build. Head enormously big. Orbital margins protrude.
Root of nose very much broadened. Nose very thick, lower jaw extraordinarily massive.
Lower row of teeth about 2 cm. forward; the teeth of the lower jaw stand far apart from
one another. The color of the face is pale. Hair of the head dense and turns gray easily.
Circumference of the skull 62.5 cm. Circumference of the neck 45 cm., larynx enlarged.
Thyroid gland not enlarged. Enormous growth of hair on thorax. Circumference of the
thorax 107 cm. on inspiration, 97 cm. on expiration. Large erectile nipples.

Pulse 56. Extremities enormously thickened in the distal parts.

For example: Circumference of each thumb 8.5 cm., circumference of middle finger
8.5 cm.

ACROMEGALY

Erythrocytes, 5,210,000.
Hemoglobin, 85 per cent.
Leucocytes, 8840, of which:
Polymorphonuclear neutrophiles, 63.8 per cent.
Lymphocytes, 29.7 per cent.
Large mononuclears, 4.2 per cent.
Eosinophiles, 2.3 per cent.

Alimentary glycosuria (100 grh. dextrose) negative.
Pituitrinum infundibulare (2 cc.) no influence on diuresis, no glycosuria.

245

FIG. 39. — Abnormally strong growth of hair in acromegaly.

X-ray examination (Decent Schiiller) skull thick with enormous frontal sinuses. Sella
markedly widened, dorsum sellae lengthened, coarse, reclining; anterior clinoid process
broad, no sphenoidal sinuses.

Eye examination (Prof. Sachs). Vision and field of vision normal.

Operation was undertaken by Dr. Hirsch on May 29, under local anesthesia, by the
endonasal route. For the details I refer to 0. Hirsch's publications. The cavity made
in the hypophysis by operation reached about 2% cm. in the sagittal and \% cm. in
the vertical diameter. The temperature rose to 38.0° transitorily, falling back to normal
in a few days. On June 2, the patient already made the observation that the size of the
end-phalanges of the fingers had decreased. There must also have occurred a diminution
in the size of the feet, for the slippers, which were formerly too small, now fit him. On

THE DISEASES OF THE HYPOPHYSIS

June 3, the patient observed that his hat, that also had been too small, now fell down
on his forehead. On June 9, an improvement in the attention became apparent. The
patient, who was a doctor of mathematics, could, before the onset of his illness, repeat
all of 12 two-digit figures that were told to him at intervals of five seconds. Before the
operation he could remember only 7. Now he regularly repeated n. June n, the
greatest circumference of the head which before the operation reached 62.5 cm., is now
61.4 cm. The greatest circumference of the neck, formerly 46 cm., now is 43 cm. The
water displacement of the hands which formerly was 700 cc. is now 600 cc. The thicken-
ings about the eyes have now retrogressed, and the soft parts of the cheeks and chin have
also distinctly fallen off. On June 19, the patient left for his home.

Histological examination of the material obtained on operation (D. Erdheim) showed
an adenoma consisting in small round cells that look alike, with round vesicular nuclei
and a well-developed protoplasm; at regular intervals the tissue is permeated with blood-
vessels with capillary walls, giving to the tumor a trabecular, in some places an alveolar,
appearance. At places proliferation and hyaline degeneration of the stroma, often with
extensive hemorrhage. I mention briefly, from the patient's report in July that the sweats
have improved considerably, from his report in August that the circumference of the head
has decreased still more, the thirst has subsided, but there has been no alteration in the
vita sexualis. In January, 1912, he reported that retrogression of the acromegalic mani-
festations had not gone further; that lately even an aggravation had set in, this consisting
in the fact that the tongue had become thicker, the mental attitude was that of depression,
the thirst had again become greater, but there was no more polyphagia.

Often too the eyebrows became bushy. In women often hairs develop
on the upper lip, and bristly hairs on the chin and on the lower lip, similar to
the chin-beard in man, also hairs on the cheeks, and especially on the inner
side of the thigh and even on the linea alba (also a case of Stumme's} . This
occurrence of abnormal hairiness in women is illustrated by the following
case:

Observation XXVII. — E. T., thirty-three years, entered Nov., 1909. Menstruated
first at the age of twelve years, followed regularly at intervals of four weeks, the flow
lasting eight days, profuse. Lues at the age of nineteen years, primary sore on the left
labium minor, twelve injections, after six weeks papules in the genitals, nineteen inunc-
tions. The end of 1895, an abortion, and 1898 apparently a purulent parametritic exur
date, 1907 another abortion.

The present illness began in 1902 and within one-half year had attained almost its
present intensity. First paresthesias in the upper extremities and shoulders, then thick-
ening of the fingers, so that the patient had to discard her rings. A half year later en-
largement of the feet, so that the shoes became very much too small. At the same time
occurred enlargement of the lips and nose. The circumference of the neck had increased
about 4 cm., the abdomen also became thicker, and hair began to grow on the breast and
calves. The breasts did not become especially larger, but milk began to be secreted by them.
Periods extremely irregular, at one time remained away for seventeen months, libido
at first increased, then diminished. The voice right at the onset became deeper. Lately
frequent outbreaks of sweat. Occasional voracious hunger and great thirst. Often
frontal headache.

Typical acromegalic appearance. Hands and feet enormously large. Skin very
moist, marked hairiness of both arms, hairs between the breasts and on the genitals, the hairs
of the mons veneris reach as high as the navel. Hairiness therefore that of a man. Cir-

ACROMEGALY 247

cumanal and perineal hairs abundant. Also the leg is markedly covered with hair. Nose
and lips markedly thickened, lower jaw protrudes rather strongly. The incisor teeth of
the lower jaw are far apart from each other. Tongue very much more enlarged. Thy-
roid enlarged. Colostrum can be expressed from the breasts on light pressure. Eye-grounds
and field of vision normal. Lordosis of the lumbar spine. Enlargement of the nose and
lower jaw, hands, and feet. X-ray: Sella turcica much widened, as big as a crown piece.
The posterior clinoid process consumed.

Dec. 3 — 100 gm. dextrose — 3.58 gm. dextrose in urine. On a purin-free diet the values
of uric acid were 0.765, 0.720, 1.204, 1.296, "1.050, 1.097, 1.080, 0.762, 1.155, i-ou, 0.855.

Blood examination erythrocytes, 4,975,000.

Hemoglobin, 12 gm.

Leucocytes 5600, of which:

Polymorphonuclear neutrophiles, 76 per cent.

Lymphocytes, 22 per cent.

Eosinophiles, 2 per cent.

FIG. 40. — Case of acromegaly.

Dec. 8 — o.ooi gm. adrenalin subcutaneously. Pulse gradually rose from 72 to 102.
Blood-pressure from 95 to 115. After twenty minutes return to normal. Slight head-
ache, tremors, slight arrhythmia, considerable increase in diuresis, no sugar.

Abundant carbohydrate diet leads to glycosuria.

Dec. 14 — o.ooi gm. adrenalin subcutaneously. Pulse from 72 to 96, blood-pressure
from 115 to 125, slight headache, slight arrhythmia, no sugar, diuresis from 950 to 2000.

Dec. 15 — i cc. pituitrinum infundibulare, marked diuresis, no sugar.

Dec. 16 — 100 gm. dextrose, sugar strongly positive.

Dec. 17 — 100 gm. dextrose, in urine 2.1 gm. dextrose.

Dec. 21 — o.oi gm. pilocarpine, moderate sweating, moderate flow of saliva.

248 THE DISEASES OF THE HYPOPHYSIS

Very noteworthy in acromegaly are alterations in the genitalia, that is,
the manifestations that may be ascribed to functional alterations of the sexual
glands. We shall see later that for the comprehension of especially the
genital disturbances in acromegaly and for the pathogenesis and theory of
acromegaly in general there seems 'necessary a sharp distinction between the
function of the interstitial glands and the generative glands, at least so far as
this is possible, according to our present-day knowledge. As will be seen
from the description of the alteration in the hairiness, there is almost never
found in acromegaly a retrenchment of the so-called secondary sexual
characters and a retrogression of the external genitalia. An exception to
this is perhaps certain cases of acromegaly in childhood, which I shall speak
of in detail later. In acromegaly of adults, on the contrary, there is mostly
sharp accentuation of the secondary sexual characters. As has been men-
tioned there is often seen a strikingly strong development of the hairs of the
beard; the axillary hairs, the hairs on the genitalia and on the perineum grow
more strongly, and often there develops a marked hairiness along the linea
alba; the hairiness in women, as v. Noorden mentions, often assumes in this
case a virile type. Moreover the external genitalia often show a distinct
hyperplasia. The penis, the labia majora and the clitoris may appreciably
increase in dimensions.

These phenomena persist until the end of the disease. In certain cases
we can at least say that a distinct retrogression does not occur.

The function of the glands of generation behaves otherwise. Here we
mostly find premature lessening or loss of function. There are, however,
numerous exceptions, that I shall speak of first. At the beginning of the dis-
ease there is found not at all rarely signs of the increased function. Thus
there was for instance at the beginning, in the case of Buday and Janczo
(acromegalic gigantism) increased potency.

In women, too, libido may be increased at the beginning; I here allude to
Observation XXVII. In this case the illness had lasted seven years; in spite
of this menstruation, although irregular, persisted; the libido at first in-
creased, later decreased. Colostrum could be expressed from the breasts.
Cases of persistent galactorrhea have been described byGajkievicz and Fazio.
In other cases the function of the glands of generation last until in the fully
developed disease. I refer to Observation XXV. . In this case the disease
began in 1903, in the year 1907 the potency and libido were entirely normal,
1911 the libido was as yet entirely retained, but the potency had to a certain
extent diminished.

In such cases signs of increased activity of the sexual glands may be found
at autopsy. Thus Schultze and Fischer state that in a man aged fifty-six
(Case 2) in whom the acromegaly had lasted seven years, strikingly abun-
dant spermatogenesis was to be found in the testicles, and the prostate was
enlarged and in a condition of abundant secretion.

ACROMEGALY

249

The following case, although not so instructive, seems a further example of
the preservation of the generative function:

Observation XXVIII. — F. Da., thirty-eight years old. Ambulant patient in 1911.
For nine years married, three children. Wife has had one abortion; for about one and
one-half years the hands and feet have become thickened, etc. Collar number has risen
from 41 to 44, hat number from 55 to 58^. One year ago the incisor teeth spread
apart from each other, and the lower jaw projected. Often polydipsia. Dyspnea on
ascending stairs. More readily excited than formerly. Body weight has increased from
7 kg. to 83 kg. Arching of the chest has increased. Potency not altered. Typical
acromegaly. External genitalia strongly developed, large amount of hair on them.

FIG. 41. — Case of acromegaly (Observation XXIX).

Erythrocytes, 5,300,000.
Hemoglobin, 90 per cent.
Leucocytes, 8100, of which:
Neutrophiles, 74 per cent.
Lymphocytes, 20 per cent.
Eosinophiles, 6 per cent.
Test as to alimentary glycosuria (100 gm. dextrose) — in urine 1.3 per cent. = 0.88

gm.

Eye findings normal, sella turcica almost the size of a gulden piece.

Menstruation may be present for a long time in acromegalic women.
In Becker's case the menstruation ceased as late as eighteen years after the

250

THE DISEASES OF THE HYPOPHYSIS

beginning of the affection; in a case of Ddbbelin's there was entirely normal
genital function. A short time ago I even saw a case in which it was very
likely that in a course of a very chronic acromegaly conception had occurred
several times, and children had been carried to term. I here quote the case
in extenso:

Observation XXIX. — S. Ad., fifty-six years old. Entered the clinic Oct., 1912. The
father of the patient seems to have been rather vigorous, and in his later years his condi-
tion seems to have exhibited some resemblance to the patient. From the age of fifty-

ACROMEGALY 251

six years on his face became broader. He died of pneumonia in his seventieth year.
No ductless glandular diseases in the family. The patient has seven brothers and
sisters, all well. She has five children, the first child born when she was in her twenty-
eighth year, the last when she was in her fortieth year. All the births were normal,
and all the children were well developed. Menstruated first at the age of twenty-two
years, the menses were always rather profuse, lasting two to three days, and occurring
regularly every four weeks, menopause at the forty-sixth year. For two years headaches,
especially at the roof of the skull of the right side, which headaches have increased in
intensity. The pains now exist day and night and for the most part are so intense
that the patient cannot sleep. During the last four to five months she has always
remained in bed on account of these headaches, and on account of the fact that when
she attempted to get up she would suffer with attacks of vertigo. The patient had
also had headaches for some time before this but she did not give them much attention.
She states definitely that the enlargement of the hands and feet developed gradually
between the twentieth and thirtieth year of life. At the time of the birth of her first
child in her twenty-eighth year the hands and feet were much larger and thicker than
at present, and have gradually decreased in circumference. Also the prognathism
of the lower jaw has existed since that time. She never suffered from sweats or from
pains in the extremities.

The patient looks at least fifteen to twenty years older than she is. Height 145.5
cm., span width 150.5 cm. Layer of fat well developed. Skin pale, smooth and dry,
musculature weak, build of bones medium, considerable kyphosis; the extremities are
extraordinarily heavy, head farge, fronto-occipital circumference 56 cm., nose large with
broad insertion; distance from between the eyebrows to the tip of the nose 5.8 cm.;
breadth of the nose 4.5 cm., distinct prognathism. From temporomaxillary joint to
tempo romaxillary joint, over chin, 26 cm. Lower lips thick, cushiony, and prominent.
The teeth are in greater part absent, the two lower incisor teeth are present and are
spread apart from each other. The clavicles are rather broad; the extremities extraor-
dinarily awkward. The fingers are markedly thickened and the X-ray shows that the
thickening affects the weak spots exclusively. The metacarpal bones are pushed apart
from each other, only very slight bone formation at the seat of the muscular insertions.
Also the feet are awkward. Axillary hair and pubic hair well developed. Isolated
hairs on the upper lips. Slight arteriosclerosis.

Alimentary glycosuria (100 gm. dextrose), 0.8 gm.
Blood findings: Leucocytes, 9800, of which:
Polymorpho nuclear neutrophiles, 66 per cent.
Lymphocytes, 30 per cent.
Large mononuclears, 3 per cent.
Eosinophiles, i per cent.

One week later repetition of the test for alimentary glycosuria after two injections
4 cm. pituitrinum glandulare intramuscularly (100 gm. dextrose) 0.9 gm.

X-ray examination of the skull (Dr. Schwarz) : Widening of the sella turcica to the size
of a 2-crown piece. Deepening of the floor of the sellae, processus clinoidei sharpened.
Entrance to the sellae widened.

Eye examination (Docent Ulbricli) papillae normal, the inner borders slightly effaced
and slightly prominent. Nothing certainly pathological; on the contrary, vision O. D.
3/36, O. S. 1/36, but there is an old trachoma with corneal scars; visual field on each side,
so far as can be tested, normal; also normal for colors.

The examination of the uric-acid elimination on purin-free diet shows values between
0.4-0.5 gm., therefore no increase.

252 THE DISEASES OF THE HYPOPHYSIS

As far as I have been able to find, a similar case of conception in acro-
megaly has been reported only by Pirie.

However, in the great majority of cases of acromegaly, as has already
been mentioned, there occur sooner or later signs of extinction of tlje function
of the generative glands. This may occur even early, constituting a differ-
ential diagnostic difficulty. In man there soon comes to pass lessening or
complete loss of potency and libido, and in woman amenorrhea. As the latter
is attended with a cessation of ovulation, it may very well be supposed that as
yet no case of conception has been observed in an amenorrheic acromegalic
woman.

In such cases the sexual glands and the internal generative organs gradu-
ally atrophy. Tandler and Grosz found total retrogression of the primordial
follicles and cessation of the formation of Graafian follicles, and in man
alteration of the epithelium of the seminal tubules and, finally, also alteration
of the interstitial cells. On gynecological examination the uterus is usually
found to be small. Not rarely cystic degeneration of the ovaries is also
present. Atrophy of the internal genitalia was found in 36.4 per cent, of
118 cases, according to the statistics of Creutzfeldl.

That even on long-continued amenorrhea the follicular apparatus may not
degenerate entirely is shown by a case of Cagnetto; menstruation ceased at the
age of nineteen years; at the age of forty-six years it reappeared and continued
to the age of forty-eight years, when it disappeared for good ; autopsy showed
cystic degeneration of the tumor of the pituitary; in this case it is not unlikely
that the hyperfunction was restricted by the cystic degeneration.

We may therefore briefly sketch the relation between hypophysis and
sexual glands, thus: increased activity of the hypophysis stimulates the ac-
tivity of the interstitial glands (apparently also the suprarenal cortex).
The glands of generation are sometimes also stimulated to increased activity
at first, but more often the activity is suspended. Conversely we find that
on increased activity of the sexual glands there is also increased activity
of the hypophysis. I believe, in opposition to the prevailing teaching, that
there is in pregnancy an increased activity of the sexual glands, as I regard
the developing fetus as a prolonged ovulation (see chapter on the sexual
glands) — there is found enlargement of the hypophysis and signs of an in-
creased function of that organ, coarsening of the facial features, etc. (Tandler
and Grosz). Indeed a transitory acromegaly may even occur during this
period. Such a case is reported by R. Marek. Pronounced acromegalic
symptoms occurred during pregnancy in a twenty-seven-year-old primipara.
Nose, tongue, and jaws became larger, the teeth spread apart, the hands and
tongue increased in circumference, the tonsils swelled, glycosuria, lassitude,
sleeplessness and insomnia, and also drawing pains in the muscles made
their appearance. All signs disappeared during the puerperium.

In such cases of formes frustes of acromegaly during pregnancy, we may

ACROMEGALY 253

think very plausibly of an existing predisposition; we might also be inclined
to believe that repetition of the pregnancy would lead to permanent manifes-
tation of the disease.

Goiters and alterations in the function of the thyroid occur in acromegaly with
great frequence. The development of the goiter may occur about simulta-
neously with that of acromegaly, and thus symptoms of hyperthyrosis or hypo-
thyrosis may become manifest simultaneously with acromegalic symptoms.
Manifestations of a slight hyperthyrosis in acromegaly are especially common.
Magnus-Levy and Salamon have especially directed attention to this subject.
Later, in the consideration of the manifestations on the part of the vegetative
nervous system, we shall see that among the more frequent symptoms in
acromegaly are sweats. We shall have to consider, however, whether we are
justified in regarding them as a symp torn of a simultaneous hyperf unction, and
whether they do not signify rather that certain organs of supply of the vegeta-
tive nervous system are not directly influenced by the irritation of these
nerves, on account of the hyperfunction of the hypophysis. A tachycardia
might be regarded as a surer symptom of hyperthyrosis especially when there
exists thyroid swelling and increased fall in blood-pressure.

In case U (Observation XXIV) the thyroid was enlarged. There existed
profuse sweats and a slight grade of tachycardia. Slight enlargement of the
thyroid was present also in case T, Observation XXV, but in this case symp-
toms of hyperthyrosis were not distinct.

Of the remaining symptoms, of Basedow's the following have been stated
to have occurred in the course of acromegaly: tremor, transitory rises of
temperature, cardiac palpitation, increased psychical irritability.

The following is a very instructive example of the simultaneous develop-
ment of acromegaly and a slight hyperthyrosis.

Observation XXX. — M. St., thirty-seven years old. First admission at hospital in De-
cember, 1896. Menses appeared first at the eighteenth year, and were regular up to the
twenty-fourth year of life. From then on they remained absent. At the thirty-first year
tearing pains in all the members appeared, especially at night. The fingers were swollen,
and there were sometimes intense sensations of heat. Since that time there have existed
severe headaches. Finally there developed about this time a goiter. In addition there
appeared pains in the neighborhood of the thyroid gland, which recurred every month. Lately
forgetfulness, lassitude, and weakness. The motor power has weakened.

Typical acromegaly and thickening of the nose, hands and feet. Circumference of the
throat 44 cm. Slight degree of anemia. (Hemoglobin 65 per cent., erythrocytes 4,000,-
ooo.) Enormous struma of the thyroid, both lobes diffusely enlarged, with circumscribed
nodules, no hemianopsia, no disturbances of vision. Slight kyphosis.

Second admission, March, 1892. Now marked kyphoscoliosis. The acromegaly has
advanced.

Third admission, August, 1899.

Fourth admission, December, 1899. Fine tremor, exophthalmus, tachycardia, marked
alimentary glycosuria 2.25 per cent, dextrose in urine when 100 gm. dextrose administered.

To 100 gm. levulose, Trommer at times distinctly oositive.

254

THE DISEASES OF THE HYPOPHYSIS

Fifth admission, May, 1907. For two years there has been a gradual diminution in the
motor power. Goiter seems to be smaller. Appreciable enlargement of the sella turcica.
The enlargement of the hands depends only on the enlargement of the soft parts. Frontal

mm

FIG. 43. — X-ray picture of the hand in acromegaly (^ natural size).

cavities enormously widened. Eye-findings normal. Alimentary glycosuria (50 gm.)
now negative. Death from pneumonia.

Autopsy. — Tumor of the hypophysis of soft confluent consistence and grayish-red
color. Besides, in various organs, numerous tuberculomata.

ACROMEGALY

255

In this case then in the thirty-first year of life the goiter appeared simulta-
neously with acromegaly, the goiter subsequently developed enormously and

led to pronounced symptoms of hyperthyrosis (tremor, exophthalmus, tachy-
cardia, etc.). Also the alimentary glycosuria could have been a symptom of
the hyperthyroidism, at least it disappeared later, when the goiter became re-

256 THE DISEASES OF THE HYPOPHYSIS

duced. Such a retrogression of a preceding goiter occurs frequently in the
later stages of acromegaly. With its disappearance may be associated not
only a disappearance of the Basedow's symptoms, but also, as in this case, the
appearance of symptoms of true myxedema.

Observation XXXI. — A. Str. First entered the clinic in February, 1896, then thirty-
one years old.

Chlorosis at the age of eighteen years. Menstruated first at the age of fifteen years;
menstruation was regular until her marriage in her twenty-first year. Pregnancy and
delivery normal, child well. Since that time has never menstruated, and has become pro-
gressively weaker. Two years after the confinement (1898) the hands and feet began to
become thicker and coarser, the wedding ring had to be filed off and enlarged, and it had
to be made even larger in 1890 and 1893 respectively. Also the shoes had to be made
larger. The rest of her body became always thicker and more awkward, the neck
became swollen, but the breasts became progressively smaller. The facial features altered
more and more so that at times she was not recognized as herself by good friends. In spite

FIG. 450. — Before the disease. FIG. 456. — At the height of the disease.

Case of acromegaly.

of the increase in body she became progressively weaker. Burning pains in the fingers oc-
curred early in the course of the disease, pains that were increased at night by the warmth
of her bed. Later were added day-sweats and night-sweats, so that night-clothing and bed-
linen had to be changed several times during the night. The eyes protruded distinctly.
Occasionally she had headache and vertigo. Speech became rough and nasal, the tongue
has become heavier, thicker and longer, so that it was often caught by the teeth when
she spoke. Formerly set of teeth was quite regular. At present the anterior incisor
teeth of the lower jaw incline outward, are spread apart from each other, and do not fit
those of the upper jaw. At first she suffered with constipation; often there was no
evacuation for fourteen days, latterly she often has diarrheas. She is very nervous, and
frequently has cardiac palpitations and difficulty in breathing. Slight tremor. The
powers of memory have suffered, the [mental] attitude is depressed and she is easily excited.

Circumference of skull, 57.7 cm.

Length of nose, 5.5. cm.

ACROMEGALY

257

Distance apart of the alae of the nose, 4.2 cm.

Circumference of the neck, 40.0 cm.

Circumference of the waist, 86 cm.

Height, 163 cm.

Eye-grounds and perimetry normal.

Second entrance, January, 1901. There now exist slight swellings of certain joints,
especially of the knee and elbows, where crepitation is present on palpation. The cardiac
oppression has become intense. The voice seems to have improved. The distance
between the middle and upper incisors is now about i mm., that between the lower middle
incisors 9 mm. The tongue is enormous; hands and feet have greatly broadened. The
tubera parietalia project markedly, and does also the arcus superciliares; alae of the nose,
the lips and lower jaw have enlarged enormously. The spinous processes are sensitive
to pressure. Pain in the entire vertebral column is elicited by pressure on the head.
Eye findings normal. The circumference of the throat has increased about 3 cm.

Third entrance to clinic, January, 1903. Attacks of frontal headache with insomnia.
Alimentary glycosuria, a trace of sugar on the ingestion of 100 gm. dextrose.

FIG. 46. — Acromegalic and normal hands.

FIG. 47. — Acromegalic feet.

Gynecological examination: Flat pelvis with very slight osteomalacic changes. Pain-
fulness of the bones, Chvostek's phenomenon positive l One time it was possible to elicit
Trousseau's sign.

Flexion of the hip- and knee-joints much restricted. Spasms of the adductors. The
knee-joints greatly distended, crepitation. Electrical irritability normal. Eye findings
nornial.

Erythrocytes, 4,278,000.

Hemoglobin, 10.2 gm.

Leucocytes, 2900, of which:

Polymorphonuclear neutrophiles, 6 per cent.

X-ray: Skull capsule thickened. Sella turcica irregularly widened, clinoid processes
hyperostotic. The thickening of the extremities affects the soft part exclusively. The
bones are atrophic.

JOn account of these manifold symptoms, the case was exhibited by A. M tiller before the
Wiener Gesellschaft f. innere Medizin und Kinderheilkunde.
17

258

THE DISEASES OF THE HYPOPHYSIS

Fourth entrance to the clinic, April, 1909. Copious night-sweats, cardiac palpita-
tions. Circumference of the throat 38 cm. Alimentary glycosuria negative.

Pigmentation on the face, hands, and neck o.ooi gm. adrenalin subcutaneously, no sugar.

Fifth entrance to the clinic, November, 1909. Circumference of the neck 35 cm.
Heart enlarged, extra systoles; Chwstek negative.

Sixth entrance to the clinic, April, 1910. Alimentary glycosuria (100 gm.) negative.
Adrenalin o.ooi gm., no sugar.

Three thyroidin tablets administered thrice daily for three days, the pulse rate was
somewhat increased. Cardiac palpitations slight, the neutrophilic leucocytes are from
71.5 per cent, to 84 per cent. Alimentary glycosuria after the beginning of thyroidin
medication negative (confer Falta, Newburgh, and Nobel).

X-ray: The sella turcica is destroyed to the extent that its site is no longer sharply

FIG. 48. FIG. 49.

Case of acromegaly (Observation XXXI).

delimited below and in front; it has given place to a cavity about the size of a chestnut.
The anterior clinoid processes are replaced by washed-out bone masses; this is true also of
the greater part of the floor, especially anteriorly. The somewhat enlarged clivus pro-
jects forward as a characteristically nipple-shaped mass.

Lately the patient has developed a pronounced cachexia. To this are added slight
signs of a myxedema, especially a cushion-like thickening of the backs of the hands and of
the skin of the supraclavicular fossae. The pulse rate in the fever-free intervals (the
patient now frequently suffers with bronchopneumonias) is about 70; the blood-pressure
(Gartner) lies near the figure 70; the former rather frequent diarrheas now occur only in
single isolated attacks. There is mostly constipation. The circumference of the throat,
it is true, has indeed increased, but a myxedematous thickening of the soft parts may
indeed play a part in it.

The behavior of the thyroid gland in this case is instructive. We are
dealing with typical case of acromegaly, which for a long time has shown signs

ACROMEGALY 259

of hyperthyroidism (sweats, tachycardia, tremor, slight exophthalmus,
diarrhea, etc.). Later with the development of a cachexia, symptoms of
hyperthyroidism retrogress more and more, to give place to a slight thyroid
insufficiency.

The regressive changes in the thyroid gland that so frequently become
established in the later stages of acromegaly might well be regarded as a
partial phenomena of the degenerative alterations that in the later stages of
acromegaly involve not only these organs that are the seat of the tendency to
growth fostered by the acromegaly, but also the entire body as well. Hence
in the later stages of acromegaly we may often see myxedematous symptoms,
even in the absence of previous manifestations of hyperthyrosis. Pineles
reports two cases of acromegaly with myxedema of the skin, stupidity, and
weakness of memory. Improvement of the myxedema symptoms followed
the administration of thyroid gland, although they were not influenced by
hypophysis tablets.

The pathologico-anatomical finding in the thyroid gland in acromegaly
almost always shows something abnormal. When hyperthyrosis has existed,
there is found the picture of a Basedow's struma. Otherwise there is seen
almost always connective tissue proliferation, such as is found also in other
organs in acromegaly, or coltoid degeneration in combination with, eventually ,
high-grade sclerosing and atrophy of the parenchyma. Gaussel found a
thyroid gland that was normal.

The vascular system in the later stages of acromegaly almost always shows
changes. A slight grade of arteriosclerosis develops. Microscopical examina-
tion shows that the three vascular coats are involved in these changes, and
that the media becomes poor in muscle fibers. The heart not infrequently
hypertrophies, and the cardiac muscle soon degenerates. Especially those
cases that are attended with other symptoms of Basedow's disease often
show in the initial stages a slight degree of tachycardia; in all cases manifesta-
tions of insufficiency of the heart-muscle develop in the later stages. Varices
are strikingly frequent.

In many cases the enlargement of the heart may very well be a partial
manifestation of the true splanchnomegaly. Humphry describes a consider-
able cardiac hypertrophy without valvular changes in a man aged thirty-nine
years. The case reported above (Observation XXIV) there was a broaden-
ing of the cardiac shadow, on X-ray examination, to 13 cm. The patient
was thirty-two years old. Not rarely in addition to the enlargement of the
heart there is found an enlargement of the liver, the spleen, the stomach,
and the intestines. The enlargement of the liver is often only the sequel of
an existing cardiac insufficiency, sometimes, however, the partial manifesta-
tion of a true splanchnomegaly. The enlargement of the spleen is a partial
manifestation of the enlargement of the lymphatic apparatus to be described
later. The dilatation of the stomach has been brought into association with

260 THE DISEASES OF THE HYPOPHYSIS

the frequently observed polyphagia. Cunningham describes, in a case, a
doubling of the length of the small intestines. Also the kidneys are often
strikingly large, and in the urine a slight grade of albuminuria is not infre-
quently found. In two cases Fischer found enormous suprarenals, the en-
largement affected especially the cortex; also Delille saw this several times.
Lately Fischer and Schultze found enlargement of the suprarenals in two cases
of acromegaly, in one of which (a case of early acromegaly) the suprarenals
were enlarged about five times at least. Histological examination showed
that the suprarenals in toto were quite uniformly enlarged. Also the kidneys
were enlarged, showing on microscopical examination enormously large
glomeruli.

In many cases the pancreas was found to be sclerosed, in other cases the
pancreas was found to have been entirely normal (see later the combination of
acromegaly and diabetes) . In many cases of acromegalic gigantism the pan-
creas were of quite enormous size (up to 270 gm., Launois and Roy). A per-
sistent thymus gland in acromegaly was already found by Klebs and Fritsche.
Since their time this finding has been reported very frequently (Dalton,
Arnold and others}; detailed references as to the literature can be found in
Borchardt (Deutsches Archiv fur klin. Med.) Pierre Marie regards the enlarge-
ment of the thymus as a reviviscence. The enlarged thymus may pro-
duce a distinct dullness over the upper half of the sternum, although nothing
should be concluded as to the enlargement of 'the thymus when this dullness
is found, as in acromegalics the sternum is often thickened enormously.

The examination of the blood in acromegaly shows not rarely a reduction
in the number of erythrocytes and in the hemoglobin contents. This was ob-
served by Sabrazes and Bonnes. Messedaglia saw it in seven cases, Rotky
in five cases. In the cases reported above, the case Str (Observation
XXXI) had 4,700,000 red blood cells, 70 per cent, hemoglobin; the case Ta
(Observation XXVII), 4,900,000 red cells and 82 per cent, hemoglobin;
the case Ti (Observation XXV), 4,490,000 red cells and 95 per cent, hemo-
globin; the case Bo (Observation XXVI) 5,210,000 red cells and 85 per
cent, hemoglobin. Hence it seems that in the latter stages the erythrocyte
count and hemoglobin contents are reduced.

The number of leucocytes is mostly normal (Rotky}, although there is
often found a somewhat reduced count. In my cases the case Ad (Observa-
tion XXVIII), showed 9800; case Bo (Observation XXVI) 8840; case Ta
(Observation XXVII) 5600; case Un (Observation XXIV) 6240, and finally
case Str (Observation XXXI) only 2900.

In the majority of cases the differential count shows a mononucleosis and
not rarely an increase in the number of eosinophiles. Sabrazes and Bonnes
found this in two cases, Messedaglia in seven cases (30-37.8 per cent, lym-
phocytes), Rathy in five cases; Exner in one case found 39 per cent, mono-
nuclear cells and 61 per cent, eosinophiles. Likewise Franchini and Giglioli

ACROMEGALY 261

found mononucleosis in four cases, and among these hypereosinophilia in
two cases. Mendel in one case found even 18 per cent, eosinophilia. Also
Messedaglia and Rathy found for the most part an increase in the eosinophiles.
In my own case Ta (Observation XXVII) showed 76 per cent, neutrophiles
and 2 per cent, eosinophiles; case Da (Observation XXVIII) 74 per cent,
neutrophiles and 6 per cent, eosinophiles; case Bo (Observation XXVI)
63.8 per cent, neutrophiles and 2.3 per cent, eosinophiles; case Ad (Obser-
vation XXIX) 66 per cent, neutrophiles and i per cent, eosinophiles; case
Str (Observation XXXI) 60 per cent, neutrophiles; case Un (Observation
XXIV) 57.6 per cent, neutrophiles and 1.3 per cent, eosinophiles, and in
case Ti (Observation XXV) 56.7 per cent, neutrophiles and 0.2 per cent,
eosinophiles.

Lately a report on the blood-findings in three cases has been contributed
by Borchardt. He found the erythrocytes approaching normal, the poly-
morphonuclear neutrophiles but little reduced, the eosinophiles mostly
increased.

Hence the leucocyte count rather frequently shows, especially in the later
stages, a relative and perhaps also an absolute reduction in the number of
neutrophilic cells, and a relative increase in the large mononuclears; perhaps
this is the expression of a more or less well pronounced status lymphaticus, as
has been found in several autopsies. (Messedaglia, Schultze, Fi-scher, Rothy,
Claude and Baudouin, et al.).

The anomalies of metabolism in acromegaly need a very exact exposition.
In many cases there exists obesity, as in the much-quoted case of Stritmpell,
although this was reported as- simply "layer of fat abundant." Lately
Schultze and Fischer have reported a case of early acromegaly who was fat.
Also the patient in Observation XXIX was fat. In a review of the literature
I have never found pronounced obesity. Frequently there exists voracious
hunger and polyphagia, relatively rarely lasting for long periods, and for the
greater part intermittent. Whether this symptom should always be re-
garded as a sign of hyperthyrosis, or whether it belongs to acromegaly proper,
I shall leave unanswered.

Observations as to the exchange of gases in acromegaly have been carried
out only by Zantz-Geppert's apparatus (Magnus-Levy, H. Salomon, and the
recent investigations of Bernstein and myself}. I have summarized these in-
vestigations as follows:

The investigations concerning the respiratory exchange of gases made up
to the present do not appear to decide with complete certainty the question
as to whether in acromegaly there occurs an increase in the caloric production
that may be ascribed to the disease as such. In the case of Magnus-Levy the
oxygen consumption and the production of carbonic acid doubtlessly are
appreciably increased. But just here, according to the statement of the
authors, there were present symptoms of hyperthyrosis that were not appre-

262

THE DISEASES OF THE HYPOPHYSIS

ciable. In case i of Salomon the exchange of gases is not appreciably height-
ened, in proportion to the size and body weight of the individual. The
slight glycosuria can certainly not be regarded as a sign of increase (confer
later on, in the chapter on the pancreas, the statements as to the exchange of
gases in diabetes mellitus) . Whether the sweats that occur in this case and
the voracious hunger that occurred from time to time are to be referred to a
hyperthyrosis is not at all certain in itself.

Author

Sex and
age

Height
in cm.

Weight

•d t..c

S.Sti
§'•30.6

Remarks

Magnus-Levy

FS2

147

52.0

S. 19

4- 2S

No diabetes.

Salomon case i

M 49

183

112. O

4.9

4.33

Sick for about 19 years, copi-

ous sweats, often voracious

hunger and increased thirst.

Potency not disturbed, built

on herculean lines, diabetes

(elimination of sugar reaches

a few gm.).

Salomon case 2

FSI

1 60

70.6

4 3

3 . 04

The mother is also sick with

1 y . \j

O T^

acromegaly and diabetes. For

7 years alterations in face, for 3

years great thirst. Diabetes

gravis, rather fat.

Salomon case 3

M 42

158

70. 6

1 06

3.O4

Sick for about 20 years, no

J

t y

J ' T^

disturbance of potency.

Salomon case 4 .

F 36

14.2

-0- _

400

•3 . -2

Amenorrhea for 8 years, no

4O

. w

O O

diabetes.

Bernstein and Falta

M 31

I7C

80.0

•2 . ce

2. 73

Strongly built, thyroid slightly

O

/ o

y ' v

O «JO

1 <J

enlarged, but no distinct signs

of hyperthyrosis, alimentary gly-

cosuria.

Bernstein and Falta

M32

168

7S-o

3.87

3.16

Thyroid gland enlarged, slight

signs of hyperthyrosis, no gly-

cosuria on overloading.

In case 2 the consumption of oxygen in proportion to the size of the
patient is high. But there exists a severe diabetes. Also in case 3 the
oxygen values lie somewhat above the upper limits of the normal. In case
4 the exchange seems to be normal. A heightening of the exchange of gases
cannot be concluded from the cases reported by Bernstein and myself. On
the whole the conclusion that Magnus-Levy and also Salomon have arrived at,
namely, that in uncomplicated acromegaly the exchange of gases is not in-
creased is correct. In the later stages of the cachexia and the decay, the
exchange seems to be rather lower, especially when also the thyroid gland
degenerates and myxedematous symptoms are added.

Up to the present only very few investigations have been made with re-
gard to the sail metabolism. Von Moraczewski found in a case of acromegaly

ACROMEGALY 263

pronounced retention of phosphorus, calcium, magnesium, and chlorine (and
also nitrogen), and explains this by the increased growth of the tissue.

Investigations as to purin metabolism have been instituted by Nowaczinsky
and me in three cases. There were the cases already described as case T (Ob-
servation XXV), U (Observation XXIV), and Ta (Observation XXVII).
In case T (thirty-one years old) we found on purin-free diet a uric-acid elimi-
nation between 0.72 gm. and 0.92 gm. in twenty-four hours. In case U
(thirty-two years old) between 0.89 gm. and 1.16 gm.; fourteen days after
the operation still higher values were found. As has already been men-
tioned, in this case the operation had no influence on the acromegaly.
After the administration of sodium nucleinate there occurred a prompt
increase of uric-acid elimination. In case Ta (thirty-three years) there
were uric-acid values between 0.72 gm. and 1.29 gm.

Hence in all three cases were found values for the elimination of endogen-
ous uric acid that reached the double or more than the double of the endog-
enous uric-acid factor observed in normal individuals. Any complications
can hardly be regarded as the cause of this enormous increase. The patients
were all free of fever; in case U there existed very slight symptoms of hyper-
thyrosis, which was however absent in both other cases. Ta had had lues,
but now no symptoms of lues were present. Hence we must assume that the
increase of uric-acid elimination in acromegaly occurs as such; the more so
because in some cases of hypophysial dystrophia adipiso-genitalis we find
strikingly low endogenous uric-acid values. In one case of acromegaly there
occurred after the administration of purin-free material a prompt increase in
the elimination of uric acid, while in the cases of hypophysial dystrophy the
elimination of uric acid was extraordinarily reduced.

Such high values for the endogenous uric-acid elimination as we found in
three cases of acromegaly have as yet been observed only in diseases in which
much lymphatic tissue is destroyed, or in certain febrile processes attended
with marked hyperleucocytosis (acute articular rheumatism). In the
cases of acromegaly the leucocyte counts were rather lower than normal.
There was no ground whatever for the assumption of an increased melting
down of lymphatic tissue. Further investigations as to this question are
very desirable (see Chapter I).

Lately Dr. Vias has examined a quite chronically progressive case of
acromegaly, and has observed no increase in the endogenous uric-acid
elimination.

Quite especially frequent is acromegaly complicated with glycosuria or
with diabetes mellilus. Already Pierre Marie had stated that in a third or a
half of the cases of acromegaly glycosuria was found. Detailed references
to the literature are to be found in the articles of Launois, and Roy arid of
Borchardt.

Borchardt collects from the literature 176 cases of acromegaly in which

264 THE DISEASES OF THE HYPOPHYSIS

there exist specific statements as to the examination of the urine. In
sixty- three cases, that is 35.5 per cent., diabetes was found; in eight cases
alimentary glycosuria. In many cases the diabetes shows the ordinary course
and eventually leads to death in coma. In many cases, however, as v.
Noorden first emphasized, the glycosuria shows a striking independence
from the sugar- value of the diet. The cases reported by me behaved thus:

Observation XXIV. — U, on diet rich in carbohydrates neg.

XXV. — T, alimentary glycosuria (100) pos.

XXVI. — Bo (distinct hyperthyrosis from thyroidin) neg.

XXVII. — Ta, alimentary glycosuria also on diet remarkably rich in

carbohydrates strongly pos.

XXVIII. — Da, alimentary glycosuria pos.

XXIX. — Ad, alimentary glycosuria pos.

XXX. — St, alimentary glycosuria (also from levulose) pos.

XXXI. — Str, at first alimentary glycosuria pos.

then later, on many investigations neg.

Of eight cases, five were distinctly positive, and one for a time weakly
positive. In one case (Ta) we may even speak of a very light diabetes.

The behavior toward adrenalin was tested in two cases (Observation St
and Observation Ta) with negative results.

In many cases alimentary glycosuria or diabetes occurs only in the initial
stages of acromegaly; later these cases show a marked tolerance. W.
Schlesinger and Borchardt each report such a case. Lately also Gushing has
reported about such cases. In the case of Borchardt the diabetes had existed
five years; and later there occurred no glycosuria on the injection of 1 50 gm. of
grape-sugar. It should be mentioned that not rarely such diabetic disturb-
ances of metabolism occur in Basedow's disease (thyrogenic glycosuria).

In the few cases in which I examined the excitability of the vegetative
nerves showed a very diverse behavior. In the case Ta there occurred, after
the injection of adrenalin, marked rise of blood-pressure, tachycardia and
arrhythmia. There also occurred marked diuresis, but not glycosuria. As
in this case sugar appeared in the urine after overloading with carbohydrates,
it stands as a fine example of the independence of the alimentary and the
nervous factors (Falta, Newburgh, and Nobel, Case 43). Also the in-
jection of pituitrinum infundibulare acted as a marked diuretic. After
the injection of pilocarpine there occurred only moderate sweats and a
moderate flow of saliva; although the patient stated that she suffered with
crises of copious sweats. In other cases the action of pilocarpine on the ex-
citability of the sweat glands was more distinct. Hence there may occur
temporary conditions of marked irritability of the sweat glands, without
hyperexcitability of them existing during the interval. The outbreaks of
sweat are known to be a very common symptom of acromegaly. Magnus-
Levy and Salomon in their cases of acromegaly regard the sweats as the symp-

ACROMEGALY 265

torn of hyperthyrosis; however, it seems to me certain that the outbreaks
depend on another cause lying in the nature of acromegaly itself, for we see
them also in the cases in which other symptoms of Basedow's disease — above
all, the cardinal symptom of the hyperthyrosis, the tachycardia — are absent.
This was the case, for instance, in case Ti (Observation XXV).

The polyuria may also be looked upon as dependent on an abnormal
condition of excitability of the vegetative nerves. This also usually occurs
only temporarily, in crises. The specific gravity of the urine may sink in
these attacks to very low values, reminding us of a true diabetes insipidus.
As I have mentioned before, there may exist in many cases an especial
sensitivity of the nerves of the kidney for adrenalin or for pituitrinum in-
fundibulare. It is not clear how far such changes in the condition of ex-
citability of certain vegetative nerves may be brought into relationship with
functional alteration of the hypophysis. At most we may conjecture that
the critic polyuria may be associated with temporary irritation of the posterior
lobe and with the increased production of hypophysial "diuretin."

The fact that complication with hyperthyrosis or hypothyrosis influences
the condition of excitability of the vegetative nerves in many ways needs no
further consideration in detail.

Very often the pathologico-anatomical examination in advanced cases,
shows proliferation of the connective-tissue elements in the vegetative nerves
and ganglia (Marie and Marinescu}.

The symptoms on the part of the somatic nervous system are very manifold.
To the early symptoms often belong the very burdensome rheumatoid pains
and eventually acroparesthesias (Sternberg). In many cases the pains
occur during night, so that the patient must get up and walk around the
room (Observation XXIV) . Also sensation of heat in the fingers may occur.
In one case there occurred transitory swelling of the finger-joints simul-
taneously with the pains. Whether combinations with continued articular
swellings and chronic deforming processes in the joints, as was present in
Str, Observation XXXI, are common, I have not been able to glean from the
literature. The behavior of the reflexes varies. Sometimes they are in-
creased, sometimes reduced.

Also alterations of the mind and intelligence occur in acromegaly. In
many cases there exists a characteristic apathy, a want of initiative, and a
slowing of the speech. In rare cases, conditions of exaltation are observed.
The pathologico-anatomical examination of the nervous system shows no
constant findings; except that in the later stages there occurs regularly an
increase of the connective-tissue elements in the nerves.

Among the symptoms of acromegaly there is still a group that has
nothing to do with the disease process in itself but is produced mechanically
by the enlargement of the hypophysis. To these belong first of all the changes
in the sella turcica; Oppenheim was the first to recognize enlargement of

266 THE DISEASES OF THE HYPOPHYSIS

the sella during life by means of the X-rays. Since that time X-ray technique
has improved wonderfully and has become of important diagnostic aid.
The changes in the sella may be very different; frequently when the tumor
is situated purely intrasellarly there exists a widening out of the sella with
deepening of the floor. This may bring the bony partition between sella
and sphenoidal sinuses to paper-like thinness or to actual perforation; even
when the tumors are large the clinoid processes may remain intact. In
very large tumors too, however, there may be a widening of the entrance to the
sella and final destruction of the clinoid processes. The tumor may also
calcify. Calcifications of the dura are not rare.

The following X-ray finding in a typical case of acromegaly serves as an
example :

Observation XXXII. — U, Dec. 9. The sella turcica is not only widened on the whole
to twice its size (measured in the sagittal direction) but also is very roomy at its introitus.
This also is at least double as wide as normal. The floor of the sella turcica has its homo-
geneous rotundity infringed upon, and is polygonal with washed-out borders. Several
crumbly calcareous masses in the interior of the sella may well be supposed to be calcined
tumor-masses. The widening that is here present shows itself in a sharpening at its base.

The lack of an enlargement of the sella does not militate against acro-
megaly. On the one hand, as we shall see later, there may be present specific
microscopical alterations also in hypophyses that are scarcely enlarged,
especially in the initial stages of the disease; and on the other hand there
may be present a tumor of the hypophysis in the sphenoidal sinuses pro-
ceeding from epithelial rests of the hypophysial duct, or such a tumor of
the hypophysis of the pharyngeal vault. In the first case the floor of the
sella may be even eroded from below, and thus the connection with the hypo-
physis be established secondarily (Erdheim).

Later, in the consideration of the tumors of hypophysis, we shall come
back to the subject of the differential diagnostic significance of the altera-
tions of the sella.

To the symptoms called into existence by the pressure of the growing
tumor belong also headache, and eventually dizziness and vomiting. But
the last two symptoms as well as paresis of the cranial nerves are relatively
rare in this disease.

On the contrary there are found more frequently disturbances on the
part of the optic nerves, disturbances not rarely in the form of bitemporal
hemianopsia and hemianopic pupillary reaction; the latter according to
researches of Wernicke and of Dijerine almost surely indicate a hypophysial
tumor.

In addition to the hemianopsia there is found, also commonly, simple
amblyopia; these manifestations may occur unilaterally. They can lead to
blindness of one or both eyes; examination of the eye-grounds shows for the
most part alterations of the papillae in the sense of a neuritis (in 40 per cent.)

PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 267

or of an atrophy, rarely choked disc. I shall return to the manifestations of
brain-pressure in the consideration of the subject of nonacromegalic hypo-
physial tumors.

Pathological Anatomy of the Hypophysis

I now turn to the treatment of the nature of the hypophysial tumors in
acromegaly. Although this subject is the most important, I have placed it at
the end of the long series of symptoms, because it acts as transition to the
subject of the pathogenesis of the disease. To-day we may state with great
probability that in every typical case of acromegaly there exist in the
anterior lobe of the hypophysis adenomata or adenocarcinomata, which in
rare cases are dystopic, proceeding from cut-off hypophysial cells. The
questions on this subject that have been energetically discussed during the
last decade are: Are there cases of acromegaly without hypophysial tumor,
or without the adenomatous changes in the hypophysis regarded as specific;
and, are there cases of such tumors that do not show any of the symptoms of
acromegaly? These questions have recently been discussed with tempera-
ment in a monograph by B. Fischer; I shall refer the reader to the literature
on the subject and shall attempt here only to bring to the front the principal
opinions on this subject.

Hanau first pointed out that in the overwhelming majority of cases of
acromegaly, adenoma of 'the hypophysis was observed. Through the dis-
covery of a specific coloration, for the cell granules in the chromophilic
cells by Benda the recognition of the adenomatous tumors has become es-
sentially easier. Benda himself found in three of four cases of acromegaly the
cell granules in monstrous excess in the adenomatously degenerated anterior
lobe of the hypophysis. For most part the forms of adenoma are benign. In
the malignant form, which does occur, and in which growth is very rapid, the
cells may remain very small. In such cases under circumstances the presence
of these among the gland-cells can be determined only by the use of Benda's
stain. Such malignant adenomata were for the most part formerly regarded
as carcinomata. Fischer says that the other kinds of tumors, such as carcino-
mata, sarcomata, endotheliomata, etc., never produce acromegaly; this state-
ment seems to be correct except that the position of the cases of typical acro-
megaly in which the pathological finding points to adenocarcinoma. I refer
to the case of Cagnetto. Cagnetto described a large adenocarcinoma with
abundant secretion granules, proceeding from the glandular part of the
hypophysis, which led to metastases in the spinal cord; in these metastases
the chromophilic cells were demonstrable. Fig. 50, for which I am indebted
to Prof. Stoerck, shows a similar case. The hypophysis is in this respect
analogous to the thyroid gland, in which adenocarcinomata associated with
metastases and manifestations of Basedow's disease are described. If in
cases with malignant degeneration of the adenomata of the hypophysis the

268

THE DISEASES OF THE HYPOPHYSIS

chromophilic cells are sometimes very few, this would not militate against
the applicability of the above-mentioned postulate,1 as in malignant tumor
there frequently sets in an anaplasia of the cells, as Fischer correctly points
out. Again cases of acromegaly have been described, in which the sec-
tions indeed disclosed tumors proceeding from the glandular part of the
hypophysis, which tumors, however, were cystically degenerated, and
showed but very little glandular tissue. Here it is indeed remarkable how
rapidly after extirpation of the part of the tumor, in the cases thus far operated
on, the manifestations of acromegaly ameliorate. These cases, however,
are fresh ones; in very old cases with acromegaly they perhaps would not

- / £>**<£

*< "io.***1

> v y ° • #* \
.•- V^ "^ v%^

*.<<"• */iy.

FIG. 50. — Adenocarcinoma of the hypophysis made up, in great part, of eosinophilic cells.

ameliorate so rapidly. Finally the cases with colloid struma of the hypo-
physis have been brought as evidence against the postulate, in that in
acromegaly such strumas may be found without proper adenomatous forma-
tion, and on the other hand there may be found typical strumas with small
adenomata without acromegaly. As example of the first type I mention
the case of Widal, Roy, and Froin. Here there existed typical acromegaly
in a sixty-six-year-old man, and atrophy and sclerosis of the gland substance
which was permeated with colloid cysts; in spite of the atrophy there could be
found rather numerous chromophilic cells. As example of the second type
I refer to the cases of Zack and Cagnetto. The case of Cagnetto was that of a

1 z. e., that in every typical case of acromegaly the anterior lobe of the hypophysis shows
adenoma or adenocarcinoma. — Editor.

PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 269

thirty- two-year-old woman without acromegaly; the hypophysis weighed
1.55 gm. which is thrice the normal weight; microscopically was found a
typical struma, in which small adenomatous portions alternated with
strumous portions. The analogous relation with the thyroid furnishes a
key in this case. There are also cases of Basedow's disease in which only
"Basedow's islands" are to be found in the thyroids.

Pathogenesis. — Already Pierre Marie had recognized the connection of
acromegaly with the hypophysis; at all events he supposed that the tumor
destroyed the functionating pituitary tissue, v. Strumpell, Arnold and others
advocated the opinion that enlargement of the hypophysis was coordinated
with that of the acral parts, in other words that it is only a partial phenome-
non of a general disturbance of metabolism (endogenous theory). The
theory of hyperfunction was first upheld by Tamburini, Benda, and Massa-
longo. Other authors have supposed a primary disturbance of function of
the sexual glands (Freund, Verstraeten, Stumme, lately E. Mayer, especially).

Finally the endogenous theory has been modified by other authors
(Claude, Delllle) in that they regard acromegaly as a pluriglandular affection.

The assumption of a loss of function of the hypophysis in acromegaly
can at the present day no longer be regarded as correct. We shall see later
that processes that destroy the glandular hypophysis never lead to- acro-
megalic symptoms, but to symptoms of an entirely different kind. The
same thing occurs in animals after the hypophysis has been extirpated. The
supposition of a primary functional disturbance of the sexual glands is no
longer tenable, in that, as we shall see later, there are cases of acromegaly in
which the sexual glands still functionate, even although the disease has been
fully developed for several years. Against the endogenous theory, speaks,
among other facts, the results of the partial extirpation of the tumor of the
hypophysis, as will be dealt with more in detail later. This places the
hypophysis as the central figure of the pathogenesis of acromegaly. That
in acromegaly other ductless glands are involved very frequently was already
mentioned by Pineles, which fact, as we have seen, makes the disease picture
very manifold. The circumstance that this involvement is a very diverse
one, that, for example, at one time there occurs on the part of the thyroid
symptoms of hyperfunction and at another time symptoms of those of
insufficiency shows once more the predominating position of the hypo-
physis. Hence only those manifestations may be regarded as cardinal
symptoms of acromegaly, which are to be referred directly to the altera-
tion of the hypophysis; there are in addition to these a herd of secondary
symptoms.

Besides the results of the surgical treatment it is especially the similarity
of the pathologico-anatomical findings in the hypophysis in acromegaly
with those of the thyroid in Basedow's disease that indicate that acromegaly
is brought about through an increase in the function of the glandular hypophysis.

270 THE DISEASES OF THE HYPOPHYSIS *

Against this assumption there has been objected that in many cases as
above mentioned, there are found strumas of the glandular hypophysis in
which degenerative manifestations predominate, and that on the other hand
the strumas or small adenomata occur without acromegaly. ] believe that
the dictum of Kocher that there are strumas and strumas holds for the hypo-
physis as well as for the thyroid. To-day no one would be surprised that,
especially in the old Basedow's cases, parts of the thyroid are degenerated,
and that on the other hand small adenomata of the thyroid gland are often
unattended with any of the manifestations of Basedow's disease. The
morphological finding does not always indicate the functional condition.
Finally should be mentioned that in rare cases of acromegaly entirely normal
hypophyses are found. In many of these cases the diagnosis of acromegaly
is doubtful (syringomyela, congenital abnormal size of the acra, etc.1). In
other cases we find dystopic adenomata of the hypophysis which proceed
from cut-off cells [versprengte Keime] (Erdheim and Haberfeld).

I have already referred several times to the manifold analogies that exist
between the lesion of the thyroid gland and those of the hypophysis. As
we shall see later the assumption that hypophysial dystrophia adiposo-
genitalis depends on a lessened function of the hypophysis is based on ex-
perimental pathology in a fashion analogous to that in which the assumption
of myxedema is a hypothyrosis has been demonstrated by experiment.
On the contrary the conditions for acromegaly are to-day very much more
unfavorable than those for Basedow's disease. The most important support
for the theory that it depends on a hyperfunction of the hypophysis lies, as
I have mentioned previously, in the results of the surgical treatment of
acromegaly. Reduction in the size of the hypophysis through extirpation
of portion of the gland leads in many cases to a retrogression of the acromeg-
alic manifestations. That this is not true in all cases, for example, in the
case of U (Observation XXIV), does not seem to me of great significance,
as on account of the slight visibility of the field of operation, we do not know
anything as to the size and value of the piece of tumor left behind. In
analogy with experiences in Basedow's disease it is very probable that a
result could have been obtained by a further reduction of the tumor.

On the contrary, the attempts to produce a hyperfunction of the hypo-
physis experiments have hitherto been attended with very slight results.
The stimulating [fordernd] influence of the hypophysis on the growth as
inferred from the clinical observations, has as yet not been demonstrated

1 Also tall eunuchoids have been confused with acromegalics. Thus for instance we find
described by Gallais a case of "gigantisme acromegalique sans elargissement de la selle turcique"
with "inversion sexuelle and feminisme mental." In this case quite sudden rapid growth started
at fourteen and one-half years of age, that was also present to lesser degree in the twenty-fifth
year. Hands and feet were very long and slender. In the illustration that accompanies the
report of the case absolutely nothing of acromegaly is to be seen. It shows however typical
eunuchoid obesity.

PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 271

experimentally with certainty. The attempt to feed growing animals
with hypophysis substance seems to me not to have furnished convincing
results as yet. Worthy of note in this regard are the statements of Exner
that implantation of several hypophyses hastened the growth of young rats.

The investigations with injection of pituitary extracts have indeed led
to recognition that the latter possess not inappreciable physiological actions,
but, nevertheless, we have not been able to bring them into relation with
the pathogenesis of acromegaly with such certainty as is the case in analo-
gous experiments in Basedow's disease. It is to be regarded as established,
however, that the physiological actions of the extracts from the anterior
lobe are quite other than those of extracts of the pars intermedia and pos-
terior lobe. Let us first consider the action of the latter.

The extract from the pars intermedia and posterior lobe, that has been
made entirely free of albumin, has in many respects actions similar to
adrenalin, without however giving the color reactions of adrenalin. The
extract from the entire hypophysis acts as a blood-pressure-raising agent
and a pulse-slowing agent by contraction of the peripheral vessels (Oliver
and Schafer) . Howell later- found that this action is due solely to the ex-
tract of the infundibular part. The initial lowering of blood-pressure that is
sometimes observed, may be referred to the admixture with other substances,
perhaps with those which are identical with what are found in large amounts
in the glandular extract. These can be separated from the other by ex-
traction with alcohol. The blood-raising action of pituitrinum infundibulare
distinguishes from that of adrenalin in that it often remains absent on short
spaced repetition of the injections. The vasoconstrictor action can, in rrian,
be very readily shown. After subcutaneous injection of i to 2 cc. we mostly
find a distinctly pronounced local ischemia that often lasts longer than an
hour. Subcutaneous injection of so small an amount raises the blood-pres-
sure, in man, for a long time after the injection. Also it produces mydriasis
of the isolated ball of a frog's eye. Further it acts as a strong diuretic (Mag-
nus and Schafer) by a dilatation of the renal vessels (Haliburton) ; according to
Pal only the peripheral section of the renal artery dilates, while the proximal
part contracts. The different vascular distributions behave especially
diversely to the action of the drug. The diuresis may be, in man, very con-
siderable; in case Ta, Observation XXVII, we saw an increase in the amount
of twenty-four-hour urine from 800 cc. to 1200 cc. According to Kepinow
pituitrinum infundibulare sensitizes the points of attack of adrenalin. The
actions of pituitrinum infundibulare thus far detailed have, with the exception
)f the slowing of the pulse, all adjusted to the irritation of the sympathetic
icrves. It also acts, however, on certain organs supplied by autonomous
nerves in the sense of a stimulation through the autonomous nerves. While
according to Frankl-Hochwart and Frohlich the autonomous vagal cardiac, the
nerves of the pancreas, the chorda tympani, and the nervi erigentes are not

272 THE DISEASES OF THE HYPOPHYSIS

influenced as to their excitability, the excitability of the nerves of the urinary
bladder and the musculature of the uterus are markedly heightened, or the
uterine musculature is brought to strong contraction. This action, according
to the experiments of Fleming and myself may be set aside through the use
of atropine. It is only constant in the gravid uterus, while in the virginal
uterus there may even occur inhibition of the peristaltic waves. Also cer-
tain chemotactic actions (mononucleosis, hypereosinophilia) are perhaps to
be referred to the irritation of autonomous nerves. According to Ott and
Scott, and Schdfer and Mackenzie, the extract of the posterior lobe contains
galactogogue substances.

Also the actions on the metabolism are very appreciable. Schijf after
feeding a case of acromegaly saw with hypophysis tablets a 16 per cent,
increase of elimination of phosphorus, in a case of paralysis a 25 per cent,
increase. The increase principally affected the elimination through the
feces. According to our investigations (Bolajjio and Tedesco) this action
is to be referred to the pituitrinum infundibulare, as we saw appreciable
increase in the elimination of phosphorus after its injection. That a large
part of the phosphorus is eliminated through the feces finds its explanation
in the fact that also the calcium elimination through the feces is much in-
creased, and the calcium travels with the phosphorus in the intestine. We
also found an appreciable increase in elimination of nitrogen in fasting dogs
and in those in whom the nitrogen metabolism was in equilibrium. In a case
of acromegaly to whom he administered hypophysis tablets, v. Moraczewski
found an increase in the elimination of nitrogen, but not in that of calcium.

Gushing recently states that, according to his investigations, extracts
from the posterior lobe of the hypophysis or from the pars intermedia, also
possess an action on carbohydrate metabolism. Intravenous injection of
posterior lobe extracts into a rabbit always produces glycosuria. Further-
more, subcutaneous or intravenous injection of extract of posterior lobes re-
duce the tolerance limits for carbohydrates even in animals with heightened
tolerance limits in which the hypophysis had been removed. Bernstein and /
could not corroborate Gushing' 's statement in experiments that we instituted,
using the otherwise active pituitrin of Parke, Davis &* Co. First, on the in-
jection of large quantities (up to 33 cc.) to rabbits and dogs, we never saw the
appearance of glycosuria. Nor, according to earlier experiments of Priestley
and myself is there an increase in the blood sugar-contents. Second, in
experiments on man we have never been able to influence [by its use] the
tolerance limits for carbohydrates. After the injection of pituitrinum in-
fundibulare (up to 3 cc.) we never saw the occurrence of alimentary gly-
cosuria on the administration of 100 gm. dextrose, and in individuals who
already had alimentary glycosuria, this was never increased under the
influence of pituitrinum infundibulare. Nor did we see an increase in
the elimination of sugar in diabetics. Especially important seem to me the

PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 273

experiments on diabetics who at the time were sugar-free. Here if the
tolerance limits for sugar were reduced as a result of the injection, we would
expect to see a recurrence of the sugar. Finally in respiratory experiments on
men there occurred regularly after the injection of pituitrinum, an increase
in the production of carbonic acid or of consumption of oxygen, but never
a distinct rise of the respiratory quotient.

As example I cite the following experiment: Case Ti (Acromegaly)

Date CO2 O2 RQ

February 14... 257.5 342- o 0.753

February 16.. 247.7 329-8 0.748

40 min. after the injection of 2 cc. pit. inf 297.0 393-9 °-754

Whether the investigation was made a short or a long time after the in-
jection, there could never be observed a distinct rise of the respiratory quo-
tients. The increase in the respiratory metabolism that we found after
the injection of pituitrinum infundibulare may very well be referred to an
increased stimulation of smooth-muscled organs probably also to an in-
creased activity of the liver. At least the hyperemia of the liver that
E. Neubauer found in oncometric experiments seems to point that way.

Miller and Dean Lewis state that intravenous or intraperitoneal injec-
tions of extracts of posterior (and anterior) lobes of the hypophysis in dogs
indeed may sometimes induce transitory, very weak, glycosuria; it is here
very questionable, however, whether this has anything to do with the in-
ternal secretion of the hypophysis.

The extract of the glandular portion of the hypophysis was formerly
regarded as entirely without action. Ivkovic and / found, however, that one
of the extracts furnished to us for trial by the firm of Parke, Davis 6* Co.
possessed a pronounced depressor action; after the intravenous injection of
2 to 3 cc. of this extract there occurred a depression of the blood-pressure,
which latterly again returned spontaneously to the normal; previous ad-
ministration of atropine would not hasten this return to normal, but on the
contrary would retard it. When large doses of the extracts were used, in
two of our experiments the blood-pressure sank to zero, and there was
cessation of respiratory and cardiac action; in one of these experiments the
heart could be made to beat again by administration of pituitrinum in-
fundibulare; the blood-pressure gradually rose to normal again, and the
animal entirely recovered. Later Hamburger without knowing about our
experiments, likewise reported concerning the depressor action of the ex-
tract of the glandular hypophysis. In numerous experiments that Bern-
stein and 7 made on human beings since that time we could never demonstrate
a distinct sinking of blood-pressure after the subcutaneous or intravenous in-
jection of several cubic centimeters of this extract. Hence the dog seems
very much more sensitive in this direction. We did observe in human beings,
however, an extremely striking action. Shortly after the injection of a

18

274 THE DISEASES OF THE HYPOPHYSIS

slight amount of the extract — often 2 cc. intramuscularly was sufficient —
the production of COz and the consumption of oxygen were reduced. At
the same time the respiratory quotient rose appreciably. This rise in the
respiratory quotient lasts in man for thirty to forty-five minutes, then
it gradually sinks to the normal, while ordinarily the lowering of the total
respiratory exchange of gases lasts much longer.

I cite the following experiment as an example: Case Ti (Acromegaly)

Date ' CO2 O2 RQ

February 23 256.1 327.9 0.780

One-half hour after intravascular injection of pit. gl. . 230.77 246.96 0.935

In experiments on a dog we found that on much longer doses (up to
30 cc.) the lowering of the respiratory exchange of gases was much the less
distinctly pronounced, and that the rise in the respiratory quotient also was
not so well expressed as in man.

The extract used is albumin-free, but often gives a biuret reaction. The
slight amounts of albumoses present could not cause the depressor actions
that we observed, as the action occurred just as promptly after the albumoses
were removed. Also the chloretone employed with the extract furnished to
us could not account for this action. Finally it could be shown that the
active principle is not cholin, as the depressor action on the blood-pressure
continued after the previous administration of atropine.

The interpretation of these results is attended with great difficulties.
The circumstance that we were not able to observe a depressor action in
man does not signify very much. It is possible that also here a dilatation
of the vessels occurs, but the action of this on the blood-pressure is neutral-
ized by counter-regulations. The depressor action on the exchange of gases
would let it be supposed that temporarily the tonus of organs with smooth
musculature or that the activity of the great glands of the body is reduced.1
Still harder to explain is the action on the respiratory quotient. We
originally thought that the extract called for a mobilizing or increased com-
bustion of the carbohydrates, and that on account of this there occurred also
a reduction in the total combustion. But in experiments on two severe dia-
betics it was shown that here also there occurred a lowering of the respiratory
metabolism, but here the respiratory quotient remained quite unaffected.
The experiments also speak against the objection that the rise in the respira-
tory quotients has its foundation in an alteration in mechanism of breathing.
Further it was shown in numerous experiments that were constantly modi-
fied, that this extract does not act as a glycosuretic, and does not essentially
influence an existing alimentary glycosuria. Exceptions perhaps are certain
experiments on diabetics on whom after institution on a very low elimi-

1 E. Neubauer was so kind as to make a onco metric experiment on the liver of rabbits. He
found after injection of pituitrinum glandulare distinct reduction of the liver volume.

PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 275

nation of sugar, there several times occurred a slight increase in the glycosuria
after injection. Finally, however, it was shown that after the injection of
this extract there was never observed either in experiments on man or on
dogs, an increase of the blood sugar-contents, but on the contrary there
was a decrease. Borchardt saw the occurrence of glycosuria after the in-
jection of hypophysis extract in the rabbit. In dogs for the most part this
was wanting. According to our experiment I would not estimate very
highly the value of the evidence of the experiments on the rabbit. After
all that I have said thus far as to the action of the extract of the glandular
part of the hypophysis, it may well be assumed that the latter in some manner
involves the carbohydrate metabolism, not, however, by mobilizing carbo-
hydrates in the liver, but rather by an increase of the combustion of the
sugar in the periphery. With this agrees very well the decrease in the
blood sugar. I am fully aware, however, that this is nothing more than a
hypothesis.

If we consider once more the individual physiological actions that have
thus far been demonstrated for the glandular or the infundibular extract of
the hypothesis, we readily see that they furnish very little information for
the pathogenesis of acromegaly. The function of the cardiovascular ap-
paratus is ordinarily not altered in acromegaly in a striking manner, if
manifestations of hyperthyrosis or hypothyrosis are not present at the same
time.

Closest lies the idea that the polyuria sometimes observed may be
referred to a temporary irritation of the posterior lobe through the growing
adenoma of the anterior lobe. This conception may explain the fact that
such polyurias also frequently occur in tumors of the hypophysis of other
sorts, that are associated not with phenomena of hyperfunction of the hypo-
physis but on the contrary with those of insufficiency (see later). As far as
the genital disturbances in acromegaly are concerned, the described action
of the infundibular extract on the genital organs has not as yet helped to
make them more intelligible. In acromegaly we find, as has been stated in
detail before, rather an increased activity of the interstitial glands, and even-
tually, after transitory increase of function, setting aside of the functions
of the sexual glands. In hypophysial dystrophy there exists a severe dys-
trophy of the genital organs that includes also the interstitial glands. It is
therefore very much more likely that these alterations of the genital function
rather stand in correlation with alterations in the function of the glandular
hypophysis. Nothing at all is thus far known, however, as to the action of
the glandular extract on the sexual glands. The respiratory exchange of
gases does not tend to become altered in acromegaly, at least as far as there
exist no complications with hyperthyrosis, and in dystrophia adiposo-geni-
talis it is, as we shall see later, perhaps sometimes reduced. The depressor
action of the glandular extract and the furthering action of the infundibular

276 THE DISEASES OF THE HYPOPHYSIS

extract can hardly be called upon to explain this disease picture. Also the
explanation of the disturbance of carbohydrate metabolism so commonly ob-
served in acromegaly seems to me to encounter unsurmountable obstacles.

Rath and later Loeb supposed that in acromegaly the tumor of the hypo-
physis pressed on a neighboring sugar center; the diabetes in acromegaly
would thus be placed in analogy to the glycosuria sometimes occurring in
apoplexy. This view has recently been adopted by Aschner. This author
succeeded in demonstrating that a sympathetic center lies in the subthalmic
region, the irritation of which causes glycosuria. The glycosuria does not
occur after transection of the splanchnic nerves and therefore like that of
Claude-Bernard's piqure goes over the chromaffin tissue. In spite of the
convincing experiment of Aschner, I cannot agree with his conclusion; it is
not clear to me why just in acromegaly, a developing hypophysis tumor
should press on this center, while the tumors of the hypophysis without
acromegaly, that often lie in the hypophysial duct or even extrasellary, and
that give occasion to symptoms of great brain pressure, produce no diabetes;
in these cases, on the contrary, as we shall see later, the tolerance limits
for carbohydrates are practically always appreciably raised.

Pineles supposes a correlative affection of the pancreas. Actually
Hansemann and Dallemagne have found atrophy of the pancreas in acro-
megalic diabetes. It is indeed very probable that in the cases of acromegaly
combined with severe diabetes the pancreatic genesis stands in the fore-
ground. We see in acromegaly degenerative changes in almost all the organs
occur simultaneously with or in the course of the period of increased tendency
for growth, and the insular apparatus may rapidly become involved in the
process, just as are involved the sensitive glands of generation.

Schlesinger assumes in acromegaly not only the occurrence of a true
pancreatic diabetes but also of a brain-tumor diabetes. Lorand is of the
opinion that the glycosuria of acromegaly is thyrogenic as a result of the
relationship of the hypophysis to the thyroid gland. The views may be
very well true for a part of the cases, namely, that part in which distinct mani-
festations of the hyperthyrosis are present. How shall we explain, however,
the inclination of alimentary glycosuria or even a spontaneous glycosuria
in these cases in which, as in case Ti (Observation XXV) the hyperthyrosis
is entirely absent, quite apart from the cases with severe diabetes or diabetes
leading to coma? Naunyn and later Borchardt regard the diabetes in acro-
megaly as directly hypophysial, that is brought about through the production
of an agent that induces glycosuria. The view seems to me to have a
certain support in the repeatedly mentioned investigations of Bernstein and
myself. I have previously stated in detail that the glandular extract some-
how seems to enter in the regulation of the carbohydrate metabolism, but
I am not in the position to say anything exact about this action. We are
thus evidently guided by opinions, and I would like to be understood as

PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 277

believing that in the majority of cases a premature degeneration of the
insular apparatus seems the most likely explanation.

Pathological physiology has as yet furnished with very little for the
understanding of the pathogenesis of acromegaly. As yet just the most
important symptoms, the increased tendency for growth of a certain part of
the organism, especially the osseous system, have not been reproduced ex-
perimentally. In spite of this the supposition of a hyperfunction of the
hypophysis in acromegaly is to-day the only satisfactory one.

For this assumption speaks:

1. The opposition of the clinical pictures of acromegaly and hypophysial
dystrophy.

2. The fact that the latter may be produced by extirpation of the
hypophysis.

3. The results of surgical interference.

4. The analogy with affections of the thyroid gland.

Early Acromegaly. — The statements thus far set forth as to the patho-
genesis of acromegaly are concerned with the clinical picture that we meet
with in adults. Acromegaly indeed develops almost exclusively after the
twentieth year. We must now consider the important question as to whether
there exists an acromegaly of child or adolescent life, and whether the picture
of early acromegaly deviates from that of adults. Brissaud, and Launois and
Roy adopt the view that hyperfunction of a hypophysis in early youth before
the closure of the epiphysial juncture leads to gigantism and after the definite
ending of growth to acromegaly. According to this view all pathological
gigantism would then be acromegaly. This view was already vigorously
opposed by Pierre Marie. I shall deal with this question later in the chapter
on gigantism, and only would remark here, that I also cannot subscribe
to this view, as may be plainly seen on the perusal of the following details.
I believe much more that there exists an early acromegaly with gigantism;
only it seems that this condition is relatively very rare, and is much more
manifold as to its symptomatology than is the typical acromegaly of adults.

It here seems to me necessary to enter more in detail concerning the re-
ports on this subject that occur in the literature. Most intelligible is a group
of cases in which the clinical picture is very similar to the acromegaly of
adults. To this group belongs the case described by Arnold as early as 1891.
According to the definite statement of the author the acromegalic manifesta-
tions in this patient began to develop distinctly in the eighteenth year of life.
In a brother of the patient, who also suffered from acromegaly, the be-
ginning of the affection came on at a still earlier period of life. There is
no doubt at all that this case was one of acromegaly; this was shown by the
typical thickening of the bones that increased in intensity toward the
periphery. Also the exact microscopical examination of the bones showed
architecture typical for acromegaly. In the muscles, in the peripheral nerves,

278 THE DISEASES OF THE HYPOPHYSIS

the vessels, and the weak parts, there may everywhere be found hyperplasia
of the connective tissue. It is worthy of note in this case that the sella
turcica was not essentially widened, and that further there was a markedly
developed hairiness, especially of the extremities. Hence although in this
case the beginning of the affection occurred at the time at which normally
the epiphyses are not as yet closed, increase in height was not present in
this case. In this respect it seems to me significant that there were not
eunuchoid manifestations in this case; on the contrary, as was evinced by
the hairiness, rather was there an accentuation of the function of the inter-
stitial glands.

A case of Claude's shows that in acromegaly the closure of the epiphysial
junctures may occur prematurely. It was that of a girl nineteen years old in
whom the acromegalic manifestations had gradually developed since the
fifteenth year. The epiphysial junctures were completely closed, and there
was no tendency to abnormal height.

Very important is the case recently reported by Schultze and Fischer.
Here the disease began at the eleventh year of life. Since that time had ex-
isted headache, vomitings, and temporary salivations. The patient had
never menstruated. In the course of three days she became blind and
almost deaf (probably on account of narrowing of the inner ear on account of
osseous thickening).

The girl was 167 cm. tall, weighed 81.5 kg. At various places there
were pronounced pigmentations, the skin of the entire body was rather dark,
from the navel there was marked development of the hair in the middle line,
also hair on the upper lip. At various places dark nevi. Inclination for
sweats. Head very long, horizontal circumference 59 cm. Upper lip mark-
edly cushioned, nose thick. Tongue enormously thickened, alimentary
glycosuria negative. Bilateral choked disc and atrophy. Death .manifestly
due to cerebral pressure. Pronounced obesity. Thymus hyperplastic.
General splanchnomegaly. Also the liver, kidneys, and especially the
suprarenal glands greatly enlarged (the last to five times their size). Uterus
small, infantile cysts of the ovaries, no formation of follicles. The tumor
of the hypophysis was of abnormal size (6.5 to 4.5 cm.). Microscopically
typical adenoma rich in cells.

Schultze and Fischer regard this case as a mixed form between an ordi-
nary typical acromegaly and dystrophia adiposo-genitalis.

Another type is found by the case described by Pel, a type that I herewith
describe in detail. The case was that of a sixteen-year-old youth. Since birth
the size of the hands and feet had been strikingly large and they gradually
increased in growth; especially of late, after a febrile affection, they have be-
come of enormous dimensions. In this increase in size the increase in the
dimensions of the individual bones of the extremities at the distal parts was
quite extraordinary. Thus the forearms were 29 cm. long, the circumfer-

PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 279

ences of the elbows about 27 cm., the middle finger about u cm. long, the
thumbs 7-7^ cm., the circumference of the knee 40-41 cm., the length of
the feet about 31 cm., the left leg weighed 4.85 kg., the right 5.1 kg. With all
this the total height of the body was not very great (172 cm.). The body
weight was 50 kg. The head was small, only the nose and the tabular part
of the occipital bone were somewhat larger; the teeth, especially the upper
incisors, were strikingly large. The dimensions were eunuchoid (lower
length 112 cm.), the genital organs were entirely infantile (penis 5 cm.),
the secondary sexual characters were not developed. X-ray examination
showed that the sella turcica was widened, and that only the body parts of
the extremities were so considerably enlarged. From youth on there had
existed pains of a lancinating character; lately there were very profuse
sweats, great muscular weakness, and sensitiveness of the periosteum of
the long bones to pressure. It is further noteworthy that veins of the en-
larged parts were markedly dilated. A nearly analogous case was recently
observed in the Hochenegg clinic and was exhibited by Demmer before the
Gesellschaft der Arzte in Vienna [Vienna Medical Society]. Pel termed
this case "acromegalie partielle avec infantilisme."

Another type is described by Babonneix. The case was that-of a seventeen-
year-old epileptic, 174 cm. tall, two years ago gradual beginning of abnormal
growth of the extremities. The hands became strikingly 'long, the feet
"laughably" voluminous, this together with alteration of the disposition,
polyphagia and polydipsia; pubic hairs sufficiently developed, genitalia
strikingly well developed, especially the penis and testicles, the frontal
sinuses remarkably large, eye-grounds normal, sella turcica not enlarged.
Babonneix speaks of an acromegaliform syndrome. A similar case was
exhibited by Mosse before the Societe de neurologic of Paris in May, 1911.

Still another type is described by Renon and Delille. A sixteen-and-one-
half-year-old girl, who was normal up to the sixteenth year of life, became
affected with eye-disturbances, headaches and backaches with vomiting,
increased growth. Now 168 cm. tall (lower length 103 cm., span width 180
cm.) outbreaks of sweat, obesity especially in the loins and on the abdomen,
breasts poorly developed (fat is painful). Slight hairiness of the pubic
region and axillae. Has not as yet menstruated, sella turcica much enlarged,
optic atrophy. The authors regard this case as a polyglandular disturbance.

Finally there are reports as to the occurrence of acromegaly in early
childhood. Salle reports the following: The nose of a new-born infant was
strikingly large, the chin prominent, the auricles large, flap-like, the tongue
large. The relation of the extremities and of the head to the total length was
that of a two-year-old child. Hands and feet especially large, fingers and toes
strikingly large. Ossification corresponds to that of a three- to four-year-old
child. The child died at the age of two and one-half months. The sella
turcica was very large, the hypophysis was deformed in the shape of a bean

280 THE DISEASES OF THE HYPOPHYSIS

through the projection of an exostosis into the sella turcica; it was as large
as that of an adult, the enlargement affected especially the glandular part.
Microscopically was found a very considerable richness in eosinophilic cells,
such as is found in adults but not in children.1

Finally Hutinel describes a case with enlargement of the acra in a thirteen-
and-one-half-year-old boy.

The cases set forth suffice to indicate the great multiplicity of the forms
of early acromegaly. In one is found a large tumor of the hypophysis, in
the others the sella turcica is not at all abnormally large; but despite this
latter fact I would not doubt that in these cases (Arnold, Pel, Demmer, etc.}
the diagnosis acromegaly is certain or at least hardly doubtful. Further,
the deformation of the bones is also very varied. A manifestation that ap-
parently may occur in early acromegaly in an especially well-marked manner,
is the entirely irrelative increase in size of the bones of the extremities in a
distal direction. Very diverse, too, is the proportioning, in that in many cases
the eunuchoid proportion is very prominently in the foreground; then
again the condition of the genitalia is very different too; in some cases there
is hyperplasia, in others hypoplasia and faulty development of the secondary
sexual characters, even association with eunuchoid obesity; then, as in the
case of Schultze and Fischer, hypoplasia of the genitalia and obesity, but
marked hairiness (hyperplasia of the suprarenals) .

The cause of this great multiplicity of type can perhaps be seen in the
fact that the child organism or the ductless glandular apparatus of children
reacts to a hyperfunction of the hypophysis in a very much more diverse
manner than that of adults. Especially the developing genital glands that
are involved can behave differently, in that here the interstitial glands may
be damaged and thus may bring to the total picture admixture with features
of eunuchoidism. Then again, dependent to a large extent on the behavior
of the genital glands is the premature, normal, or delayed closure of the
epiphysial junctures. Also the dimensioning of the body may be influenced
on account of this. I would, however, treat of one point with emphasis. In
some cases the diagnosis may very well be doubted, in fact in some cases it is
even made by the respective authors with reserve. In other cases, however,
there is no room for doubt; and we must reckon with the fact that acromegalic
alterations in the extremities may occur also in youth, and that therefore
the hyperfunction of the hypophysis in early youth does not necessarily lead to
gigantism.

Differential Diagnosis. — The point of difficulty in the diagnosis of
acromegaly lies in the disproportionate growth of the peripheral parts, not
in the enlargement itself, as this may be congenital. There is found for in-

1 Also Benda (Med. Klin., 1912, 284) regards the histological alterations as typical, but does
not regard the fact ruled out that the alterations of the jaws, tongue, and hands, may simply
have been inherited.

PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 281

stance a cranium progeneum in many other conditions that have nothing to
do with acromegaly (Sternberg) . Confusion with osteitis deformans of Paget
is hardly likely on careful examination. In osteitis deformans the cranium
is enlarged chiefly in circumference, the long bones soon show curvatures,
the alterations in the skeleton are very asymmetrical. In osteoarthropathie
hypertrophiante pneumonique the skull remains unaltered, only the nose may
be larger. In this condition we have a dorsolumbal kyphosis, in acromegaly
a cervicodorsal kyphosis; the end phalanges show the well-known drumstick
form, the nails show curving and longitudinal ridges; while chiefly the region of
the knuckles is very much swollen up, the metacarpal and metatarsal region,
as Souza Leithe points out, show but slight increase in volume. Under cir-
cumstances there may occur in the osteoarthropathy club-like swellings of the
hands and feet, that may have given occasion to confusion with acromegaly
(confer the case of Schultz and Fischer}. Combination with symptoms of
Basedow's disease or myxedema may in the beginning occasion an overlooking
of the acromegaly. Early 'genital disturbances or rheumatoid pains may
lead to a faulty diagnosis. Syringomyelia may also lead to an increase in
volume of the extremities, but in this condition there are usually found in
addition deformations and the well-known dissociation of the sensation-
qualities. In ordinary macrosomia only single members are affected, never
both upper extremities and both lower extremities simultaneously. Cases
in which hands and feet were enormously enlarged I have already discussed
in the consideration of early acromegaly (Pel, Demmer). We must not for-
get that the acra of the face may begin to become enlarged very much
later. Erb saw such a case; the enlargement of the extremities had existed
for about twenty years before the tongue and nose began to enlarge.

Finally we must refer to the significance of the demonstration of the
enlargement of the sella turcica by Rontgen transillumination, as first demon-
strated by Oppenheim.

In acromegaly there is usually found deepening of the floor of the sella
without material widening of the introitus, while in the tumors of the
hypophysis without acromegaly dilatation of the introitus and destruction
of the clinoid process is commoner, although there are exceptions.

Important for a differential-diagnostic standpoint is, finally, the cir-
cumstance that genital disturbances may occur. Salbey reports a case in
which oophorectomy was undertaken because of amenorrhea and pains in
the back and abdomen. Several months later there developed a picture of
acromegaly.

Until lately the treatment was utterly ineffective. Striking results were
irst brought about by the resection of the hypophysis tumor first inaugu-
rated by Horsley,bySchlo/er, and byv. Eiselsberg and first happily carried out
by Hochenegg. I refer to the consideration of hypophysial dystrophy for
a discussion of the method of operation. In the first two cases of Hochenegg

282 THE DISEASES OF THE HYPOPHYSIS

(reported by Stumme and Exner) there occurred not only a disappearance of
the symptoms of cerebral pressure but also a retrogression of the acromegaly
manifestations as well. The teeth of the upper jaw again approached each
other, the acra became smaller, the skin softer and wrinkly, the menses re-
turned, and the abnormal hairiness again retrogressed; the retrogression of
the acromegalic skeletal alterations could also be demonstrated by the X-ray
(Hochenegg). In two cases, Exner saw an enlargement of the thyroid set in
after the operation. Since this time a number of other operated cases have
been reported, in part with good results (v. Eiselsberg, Kocher, Moskovitz,
Lecene, Gushing, O. Hirsch, and others). Especially striking was the result in
the case of 0. Hirsch, in which rheumatoid pains disappeared, the acra de-
creased in size, and the menses recurred and since that time remained regular.
Hochenegg, on the basis of a third case that pursued an unfavorable course,
points out that in cases in which the tumor is chiefly extrasellar the chances
of operation are always very much less. Considerable destruction of the
clinoid processes and slight deepening of the floor of the sella must, like
myodegeneratio cordis and status lymphaticus, be taken in consideration
when the question of operation arises.

I refer again to the cases already described in detail that were operated
on by O. Hirsch. In one there came about an essential subjective and ob-
jective improvement. In the other case, which I saw again after a half
year, there had been no improvement at all.

If in cases of acromegaly with high-grade brain-pressure affections a
radical operation is not possible, a palliative trepanation or an Anton's
"Balkenstich" [puncture of the corpus callosum] is to be thought of.

The X-ray treatment of acromegaly was first suggested by Gramegna
and first practised by Beclere. It is stated that retrogression of the symptoms
of cerebral pressure and improvement in the visual disturbances have been
obtained (see also treatment of hypophysial dystrophia adiposo-genitalis) .
A result can be expected from thyroid-gland therapy only in cases complicated
with myxedema. Concerning the treatment of the more prominent symp-
toms of complicating Basedow's, I refer to the chapter on Basedow's dis-
ease. Otherwise in acromegaly the therapy can at most assuage pain by
means of antineuralgics and eventually combat cardiac insufficiency and the
decay of strength by means of general roborant measures.

b. Hypophysial Dystrophy

Hypopituitarismus, type Frohlich; dystrophia or degeneratio adiposo-genitalis.

Historical. — The occurrence of cerebral adiposity or of dysgenitalism
in tumors of the hypophysis was mentioned already by Babinski, Anderson,
Shuster, Uhthoff, and others.

HYPOPHYSIAL DYSTROPHY 283

In the year 1901, A. Frohlich on the exhibition of a case that came from
v. Frankl-Hochwart's dispensary first coined the diagnostic dictum that
rapidly developing obesity, infantilism of the genitalia, and myxedematous
alterations of the skin suggest tumor of the hypophysis.

The case reported by Frohlich was that of a fourteen-year-old boy in whom
the disease began two years before the presentation, with headaches, vomit-
ing, and rapid increase in weight. He had a characteristic distribution
of fat, such as will be described later, the genitalia remained entirely infantile,
there was no hairiness of the genitalia, the axillary region and the trunk,
and the skin showed slight signs of myxedema. Since that time numerous
cases such as this have been reported by v. Frankl-Hochwart's assistants,
A . Berger, by Erdheim, Zak, A . Fuchs, Bartels, Madelung, Launois and Cleret,
Babonneix and Peisseau, Creutzfeld, Neurath, Bychowski, Marinesco and
Goldstein, Jutaka Kon and others, and finally several cases by v. Frankl-
Hochwart. A series of cases'is presented by the author in course of the follow-
ing exposition.

Definition. — By hypophysial dystrophy we understand a clinical picture
characterized by accumulations of fat in definite places or eventually by pro-
nounced obesity of definite localization, such as is found in eunuchs and eu-
nuchoids; further by inhibition of development or by subsequent atrophy of the
interstitial glands and the glands of generation, and corresponding inhibition
of development; or by more or less distinct retrogression of the secondary sexual
characters and of the genitalia; further, when the disease occurs in youthful
years, by inhibition of growth and inhibition of ossification. Finally, on account
of a sluggishness of the entire metabolism, there is often added as a symptom
of irritation a polyuria; there are also added symptoms of pressure on the part
of the optic nerves. A lessening or a loss of the function of the glandular
hypophysis called forth by processes in the hypophysis itself or in the vicinity
of the hypophysis may be looked upon as a cause of this condition.

Symptomatology. — One of the most important symptoms is the obesity,
with a quite definite type of fat-distribution, such as is found also in primary
inhibition of development of the genitalia. The agreement in the distribu-
tion of fat in the two types (the primary genital and the hypophysial dystro-
phia adiposo-genitalis) was first mentioned by v. Noorden. The accumula-
tion of fat is chiefly localized to the hips, the buttocks, the mons Veneris,
and the mammae.

In the higher degrees of the fattening the abdominal wall is affected
especially in its lower part, where there may develop thick fatty layers.
These were seen in several cases; when they were removed the patients felt
considerably relieved. The supraclavicular and infraclavicular fossae may
become quite covered over by pads of fat. There is found, moreover, a collar-
like collection of fat on the neck, and as Launois and Cleret call them, fatty
cuffs on the malleoli. The obesity may attain an excessive grade, but it

284 THE DISEASES OF THE HYPOPHYSIS

attracts attention also when it is developed only relatively slightly on ac-
count of its characteristic distribution. Moreover, the literature frequently
emphasizes that in spite of the slight ingestion of food, even in spite of the
development of a certain cachexia, antemortem, the retrogression of fat
was only very slight. I shall later report a case (case Sch, Observation
XXXVII) in which a marked adiposity developed in a short time. Then
attacks of cerebral vomiting occurred several months, on account of which
the ingestion of food was prevented sometimes for days. The boy now lost
in weight, it is true, but on account of the residual cushion of fat on the
mons Veneris and the delicate texture of the skin the type remained still
unmistakable.

There also exist cases of hypophysial dystrophia without obesity. Rennie
reports such a case and remarks that he was unable to find a similar case in
the literature. Probably in such cases the abnormal distribution of fat
would, however, be recognizable. Such a case is reported by Kummel. I
also shall later report such a case (Observation Gr, XLV). Moreover, I
shall report a case of dystrophia adiposo-genitalia, probably of hypophysial
origin (Observation Fr, XLIV) who on his entrance into the clinic was
very much emaciated on account of a nutritional disturbance. In him also
the fat collection on the mons Veneris was unmistakable in spite of the ema-
ciation. When he came under better condition for nourishment in the clinic,
the obesity with the typical fat distribution developed rapidly.

The excessive degree of obesity is regarded as endogenous. This con-
ception is based, as we shall see later, on the investigations of the respiratory
exchange of gases, which in some cases of hypophysial dystrophy shows pro-
nounced lowering of the fundamental exchange, while in other cases the
lowering is not at all considerable.

It is to be expected that in hypophysial dystrophy just as in primary
genital adiposity the muscles are permeated with fat, as they are, as is known,
in castrated animals. Up to the present this condition has had very little
attention paid to it except that Marinesco andGoldstein report a case of typical
dystrophy with microscopically recognizable damaging of the hypophysis
through a hydrocephalus, in which the fat-permeation of the muscles was
apparently found. At all events Marinesco and Goldstein assume a specific
nutritional disturbance of the muscles.

In dystrophia adiposo-genitalis the skin shows a quite characteristic
texture. It is often described as alabaster-like, is remarkably delicate and
white, mostly is cool to the touch, and sometimes is dry and exfoliates readily.
In some, apparently rare, cases myxedematous-like swellings of the skin are
distinctly present. Some cases are reported to have falling-out of the hair
(see Observation XXXIV). On the contrary, the trophic alterations of
the nails seem to be rare.

The following case shows typical distribution of fat:

HYPOPHYSIAL DYSTROPHY 285

Observation XXXIII. — J. L., ten and one-half years old. Entered the clinic June,

1909. Has a poor heredity. Father and two sisters are insane. An eight-year-old
brother is hard of hearing. Three years ago began violent headaches, that gradually
increased, and recently there occur, now and then, slight attacks of vertigo. Some-
times the lad sees indistinctly and with blurring. Sometimes there occur parching sen-
sations of thirst, polydipsia and polyuria. Obesity has developed only recently. For two
years growth has been at a standstill.

The boy is rather small for his age.

Height, 131 cm.

Circumference of skull, 56 cm.

Jugulm-symphysis, 45^ cm.

Chest circumference, 80 cm.

Distance between the spines, 30 cm.

Upper extremities, 62 cm.

Upper arm, 24^ cm.

Anterior superior spine to lower border of patella, 38 cm.

From there to internal malleolus, 31 cm.

The boy is very fat, especialy in the pelvic region, on the outer side of the thigh, and
on the mons Veneris. The penis is abnormally small, the testicles also small, the mammae
are very rich in fat, genua valga.

The intelligence is normal, the status of the nervous system shows normal conditions,
with the exception of nystagmoid twitching in all end-positions. Fundus and perimetry
are normal, the development of the hand-skeleton about corresponds to the patient's age,
no alimentary glycosuria (100 gm. dextrose).

The X-ray examination of the skull shows:

Sella turcica not deepened, but the entrance to the sella is remarkably broad. This
makes the clivus somewhat more sharpened.

Adrenalin o.ooi gm. subcutaneously, no glycosuria.

Diagnosis: Dystrophia adiposo-genitalis, probably hypophysial.

I cite the following as a typical case of hypophysial dystrophia adiposo-
genitalis.

Observation XXXIV.1 — L. S. B. [female] from Russia. Sixteen years old. Entered
the clinic Nov. i, 1911. Family history shows nothing bearing on the case. Nine years
ago the patient sustained a febrile disorder which she states was typhoid fever. After the
recovery the body weight began gradually to increase. She eats a fair amount of food since
that time, but especially has she noticed an increase of thirst, so that she often has to get up
at night to drink. She also urinates very frequently. The patient believes herself to
have been well otherwise until about three years ago. At that time she began gradu-
ally to complain of severe headaches, especially at night. She complained of formications in
the hands, and remarked that there was a decrease in the power of vision. Already at that
time an eye doctor had forbidden her to read. Lately the headaches have gradually
become worse, especially at nights, the patient readily becomes fatigued, and four months
ago she remarked one day that she could not see at all with the left eye. At the end of May,

1910, an eye doctor diagnosed bitemporal hemianopsia, optic nerve atrophy, vision O. D.
10/40, O. S. 10/70. At the end of August, 1911, there was a supplementary report, O. D.
10/50, O. S.: Counts fingers just in front of the eye.

At present there are headaches almost daily; for six months there has existed falling
out of the hair, the nails have not become brittle; however, the patient is almost always

. l The case has been also published in detail by O. Hirsch.

286

THE DISEASES OF THE HYPOPHYSIS

listless and indifferent to all things that occur around her, she yawns very much, but
sleeps very little at night. According to her statement she sweats hardly at all. There
is no vomiting. As yet she has not menstruated.

The patient is small, about 145. cm. The build of the bones is slender, the musculature
poorly developed, the layer of fat very abundant. Especially fat are the mammae, in
which no trace of glandular substance is palpable. The nipples are small and retracted.
Especial accumulations of fat are found on the hips, on the outer sides of the thighs, and on
the mons Veneris. The axilla as well as the mons Veneris possess only a very few hairs.
The genitalia are rudimentary. The labia minora are scarcely developed. The clitoris
is very short, hymen intact. The uterus very small, the ovaries are not felt.

FIG. 51. — Case of dystrophia adiposo-genitalis. FIG. 52. — Hypophysial dystrophy.

The patient shows great difficulty in thinking. She speaks German well enough it is
true, but responds to only very simple questions. In Russian she converses rather fluently.
She lies in bed very much, and is indifferent to her surroundings. During the examination
she yawned very much.

The left eye is amaurotic, the pupils do not react although the consensual reaction is
present. On the right side is temporal hemianopsia and temporal hemianopic pupillary
reaction. Vision of O. D. i/io. Both papillae are sharply demarcated and atrophic. The
reflexes are normal. The neck is short, thick, the thyroid not palpable. The supra-
clavicular and infraclavicular fossa as well as the intercostal spaces are entirely obliterated
by the pads of fat. The abdominal walls are extremely fat. The fatty tissue of the skin

HYPOPHYSIAL DYSTROPHY 287

is everywhere markedly sensitive to pressure. The amount of urine is 4000 cc., specific
gravity, 1008.

FIG. 53. — Widened and deepened sella in hypophysial dystrophy (Observation XXXIV).

Hemoglobin, according to Sdhli, 75 per cent.
Leucocytes, 8400 of which:

288

THE DISEASES OF THE HYPOPHYSIS

\eutrophiles, 56.1 per cent.

Lymphocytes, 35.8 per cent.

Eosinophiles, 3.2 per cent.

Large mononuclears, 4.9 per cent.

Body weight, 62 kg.

Temperature varies between 36° and 36.6°

Alimentary glycosuria (200 gm. dextrose) negative

The blood sugar is 0.0826 per cent. (Dr. Bernstein]

FIG. 54. — X-ray picture in Observation XXXIV.

X-ray. — Cranial vault of normal size and form. Internal surface smooth, sutures are
present, sella moderately widened and deepened. Its floor shows an anterior arching
forward and a thinning. The dorsum sellae is thinned, the anterior clinoid processes are
retained. Sphenoidal sinuses capacious. The ossification of the hand skeleton about
fits in with the age.

HYPOPHYSIAL DYSTROPHY 289

The patient was operated on Nov. 29, 1911, by Dr. O. Hirsch at the Urbantschitsch
clinic, under local anesthesia. The septum was subjected to a submucous resection,
both sphenoidal sinuses were opened, the floor of the sella was chiseled off, and the tumor
partially curetted out, and partially removed through suction through a glass tube. The
total mass together with the blood, measured about 45-50 cc. There was no fever for the
first two days after the operation, then on the third day the temperature suddenly rose
to 39.5°. Vomiting that lasted for five days. There was probably a hematoma in the
dural sac of the hypophysis, that went over into suppuration, was in part absorbed,
and in part flowed off (Hirsch); for several days the fever was very high, 39-40.5°. The
third and fourth weeks it gradually declined. At the end of the fourth week the patient
was retransferred to the first medical clinic. The patient now makes an entirely different
impression, she is incomparably more lively, is interested in the surroundings and promptly
answers all questions. The falling out of hair has lessened. The thirst still exists. She
yawns much less, the hairiness of the axillae and of the mons Veneris has increased, the
visual power of O. D. has risen from i/io to 1.67/10. The headache disappeared entirely
after the operation, but reappeared again four weeks afterward. Very noteworthy are the
blood-findings. The differential count now shows:

Neutrophiles 71 per cent.

Lymphocytes, 25 per cent.

Eosinophiles, i per cent.

Mononuclears, 2 per cent.

Transitional forms, i per cent.

There is now distinct reduction on the ingestion of 100 gm. of dextrose.

The patient has lost about 6 kg. >

In typical dystrophia adiposo-genitalis is found, in addition to the
fattening, an inhibition of the development of the genitalia and of the secondary
sexual characters; in male individuals the penis remains quite small and
may even be entirely buried in the fat cushions (see Observation Sch,
XXXVII), the scrotum also remains small, the testicles remain quite
diminutive and are usually entirely undescended or partially descended on
one or on both sides. Also the prostate remains abnormally small. In
female individuals the external and internal genitalia remain quite infantile ;
the labia minora are developed but very poorly, the clitoris is short, the uterus
infantile, the ovaries may be not palpable, the breasts as a rule are indeed
very rich in fat, but are poor in glandular substances (see Observation
XXXIV). The nipples are small and retracted. Moreover there is either
no hairiness of the axillae, the pubic region, and the perineum, or in the pubic
region there are only a few bristly hairs. Men remain beardless. The voice
does not change or changes very incompletely. The vita sexualis does not
develop, and menstruation and ovulation do not occur. In certain cases in
which the disease has developed after puberty, there have been reports as
to subsequent falling out of the beard hair and the pubic hair, in men im-
potence sets in, and there is a cessation of erection and ejaculation; in
women there is a cessation of menstruation. Libido disappears in both the
sexes. There may also occur a partial retrogression of an accessory genital
apparatus that once was fully developed (see Observation G, XLV).
19

THE DISEASES OF THE HYPOPHYSIS

The Metabolism. — Very few investigations as to the metabolism of
hypophysial insufficiency have as yet been made. Already clinical observa-
tions would indicate that in hypophysial dystrophy there are considerable
alterations in metabolism. We not rarely find the statement that on the
one hand, at the beginning of the disease there occur a transitory polyphagia
and increased appetite. I refer to S, Observation XXXIV and Sch, Observa-
tion XXXVII, to be reported later. On the other hand, obesity that develops
gradually and which in certain cases may attain an excessive degree suggests
a reduction in the metabolism.

Also the observation that after operation there is often an appreciable
reduction of body weight speaks to the same effect. Statements as to this
question are made by v. Frankl-Hochwart, concerning the first case that
v. Eiselsberg operated on with good results. Also in the case of Hirsch,
previously mentioned (Observation S, XXXIV), a reduction of 6 kg. in
weight followed during a short time after the operation.

The investigations as to the fundamental exchange or the rest exchange
in dogs in which the hypophysis had been removed show unequivocally
an appreciable reduction of the respiratory gaseous "exchange (Benedict and
Romans, Forges and Aschner).

The first experiments, in two cases of hypophysial dystrophy as reported
in the second edition of v. Noorden's book on "Obesity." These experiments
which were carried out by Forges gave rather normal values. The cases were
undoubted cases of hypophysial dystrophy and had been described by v.
Frankl-Hochwart. Later Bernstein found an appreciable reduction in one
case. Finally Bernstein and / have recently investigated a case. I here
tabulate the cases thus far investigated.

Forges, ci
Bernstein.
Bernstein

.ed by v. Noorden .

25
28

15

166
149

121

70
65-62

33
(25, fori

3

2

6

35
94
ii

G. Wi

Fr.

2. 29
5-14

nerly)

and Falta

The few cases do not furnish any certain conclusion. Only in Bern-
stein's case is the respiratory metabolism certainly reduced. This obser-
vation hence coincides with the experiences met with in animal experimenta-
tion. In case Fr, Observation XXXIV, values of comparison with values
furnished by a normal individual equally heavy and tall are lacking.

The observation as to the carbohydrate metabolism in hypophysial dys-
trophy show a noteworthy opposite behavior to that in acromegaly. While
in acromegaly, in the great majority of cases, we find the tolerance for carbo-
hydrates more or less reduced, this has not as yet been found in hypophysial
dystrophy. On the contrary it seems, so far as investigations up to the

HYPOPHYSIAL DYSTROPHY 2QI

present have shown, that the limits of assimilation are raised (Bondi, cited
by v. Frankl-Hochwart; v. Noorden, and others). I here publish all of my own
observations of dystrophy, equally whether the diagnosis hypophysial dis-
turbance has made certain, or whether it is merely tentative.

Observation L, XXXIII, alimentary glycosuria (100 gm.) negative.

Observation Si, XXXIV, alimentary glycosuria (200 gm.) negative.

Observation Si, XXXIV, after operation, alimentary glycosuria (100 gm.) distinct re-
duction.

Observation Sch, XXXVII, alimentary glycosuria (100 gm. D) negative.

Observation K, XXXVIII, alimentary glycosuria (100 gm. D) negative.

Observation W, XXXIX, alimentary glycosuria (100 gm. D) negative.

Observation P, XLIII, alimentary glycosuria (200 gm. D) negative.

Observation F, XLIV, alimentary glycosuria (200 gm. D) negative.

Observation G, XLV, alimentary glycosuria (200 gm. D) negative.

Observation G, Wi., XXXVI, 'alimentary glycosuria (100 gm. D) negative, alimentary
glycosuria (200 gm. D) trace.

Observation E. M., XXXV (200 gm. D) negative.

From the observation on pertinent cases in the literature as well as the
cases here reported is elicited the fact that in hypophysial dystrophy there is
no inclination to glycosuria, but on the contrary an abnormal high tolerance for
carbohydrates. A single exception exists in the case of Link, a case of hypophy-
sial tumor without acromegaly and with diabetes. We shall simply state this
fact here and return to it in the discussion of the theory.

Investigations as to the contents of sugar in the blood are up to the
present scarce. Gushing states that in certain cases he found an abnormally
low amount of sugar in the blood. Bernstein estimated the sugar in the blood
in two of the cases here reported. Both were certain cases, in one of which
(Observation S, XXXIV) the diagnosis was verified on operation, in the other
(Observation G, XLV) at autopsy. The values were 0.082 per cent, in case
S, 0.081 per cent, in case Gr, therefore normal.

Investigations as to purin metabolism have as yet been carried out only
by Nowacznski and myself.

In the one case the following was noted:

Observation XXXV. — E. M., forty-four years old. Entered clinic March 29, 1912.
Six years ago sustained a sprain of the lumbar spine by a blow from a stay. Present
disease began about six weeks ago with vomiting. Severe headache, twelve days ago
diplopia. Flickering before the eyes, weakness of vision. Patient is a heavy drinker;
no venereal diseases; for several months increase of weight, reduction of libido and
potency.

Vigorous man, sensorium unimpaired, distinct abducens palsy of left eye. Left
palpebral fissure narrower than right. Left pupil wider than right. Pupillary reaction on
right prompt, on the left delayed. Diplopia on looking toward the left. Nystagmus of
left eye on looking toward left. Facialis normal. Tremor of the hands, otherwise no
motor or sensory disturbance.

No ataxia. Reflexes normal. X-ray: Sella turcica itself is normal, but the clivus is.
atrophic as corresponds to the generally increased cerebral pressure.

2Q2 THE DISEASES OF THE HYPOPHYSIS

Alimentary glycosuria (200 gm.) negative.

Diagnosis: Dystrophia adipose-genital is due to tumor in the region of the hypophysis.

The investigation of elimination of uric acid on a purin-free diet gave the following
values:

o.398-o.4o6-(2o gm. sodium nucleinate by mouth) 0.434-0.593. The endogenous
uric acid value hence lies rather low, at all events the elimination of uric acid after the
administration of purin is very low.

The second case was the following:

Observation XXXVI. — G. Wi., twenty-eight years old [female]. Entered the clinic
May i, 1912. For one year headache without definite localization. Vertigo, vomiting,
ear noises at intervals of months, which for the last three months have occurred almost
weekly. Since childhood, slight weakness of vision on the left.. For the last six months,
decrease of vision on both sides, amaurosis on the left, still some vision remains on the
right, for the last months increase of weight. Absent menstruation for the last nine
months. Lues denied.

Findings as concerning the lungs, heart, etc., normal; rather fat, especially on the
abdomen. Pupils unequal, left larger than the right. The left has lost its round contour,
does not react to light, the right reacts slowly. Accommodation on both sides good, globe
free, no nystagmus, corneal and conjunctival reflexes present. Fundus normal, right
temporal hemianopsia, basal limitation of the visual field, left amaurosis; facial nerve nor-
mal. Face hyperalgetic; trigeminus sensibility, temperature-sense, pain-sense, motility
and motor power normal. Patellar reflexes lively. Suspicious Babinski reflex on the left.
Abdominal reflexes present. No vertigo, no diplopia.

X-ray: Sella turcica dilated quite lightly, especially in the infundibular part. This
finding does not speak unconditionally for hypophysial tumor, but may be present in other
brain tumors.

Alimentary glycosuria: (100 gm. D) negative; (200 gm. D) trace.
The investigations of the uric-acid elimination on a purin-free diet show the following
values:

o.287~o.334-(2o gm. sodium nucleinate by mouth) 0.513-0.206-0.298-0.214.
Hence the endogenous factor lies even lower than in the preceding case. Administra-
tion of purin increases the elimination of uric acid but very little.

Quantities of urine up to 2400 cc. with specific gravities between 1005 and 1010.
Investigations as to the gaseous exchange (Bernstein) — average of seven investigations.
COj elimination, 2.29
62 consumption 2.94
Blood-count: Erythrocytes, 4,600 ooo
Hemoglobin, 84 per cent.
Leucocytes, 7800 of which:
Polymorphonuclear leucocytes, 74.1 per cent.
Lymphocytes, 19.5 per cent.
Eosinophiles, 0.7 per cent.
Large mononuclears, 5.7 per cent.

At the beginning of the stay at the clinic the patient was very sleepy, and uninterested.
Later there developed a clinical picture similar to Korsakof's psychosis, and the patient
was transferred to 11. Wagner's clinic. Increasing weakness, lately Babinksi reflex positive
on each side. Facial palsy on the left and pareses of the lower extremities. Pneumonia.
Death.

August 6, 1912. Necropsy (assistant Erdheim) showed: Cystic hypophysial tumor
of the size of an apple, at the base of the brain, at the site of the infundibulum, with pro-

HYPOPHYSIAL DYSTROPHY 293

trusion of the tumor into the third ventricle and giving off of the peduncle of the hypo-
physis from its lower surface. The tumor extends to the circle of Willis and hollows out
considerably both the temporal lobes; at the anterior pole of the tumor lie the flattened
optic nerves, which are wedged in between the tumor and the anterior cerebral arteries
and which show a squeezing together at this place; more on the left than on the right; the
lower pole of the tumor lies at the entrance to the sella turcica and dilates it. The dorsum
sellae is moderately eroded, the floor of the sella distinctly eroded, but moderately deep-
ened. In the sella is the hypophysis, which is of normal size with a slight concavity of its
upper surface. The tumor is a unilocular thin-walled cyst, in the clear yellowish contents
of which float consistent opaque flakes. General adiposity.

A third case, which since this time has been investigated by Dr. Vias and
myself, is later set forth in detail. (Observation F, XLIV). It was that
of a juvenile dystrophy, the hypophysial origin of which is only conjectural.

Therefore, in all three cases the endogenous uric-acid value is at the
lower limit of the normal, and the elimination of any purin that is adminis-
tered is protracted. Of course there exists the possibility that in such cases
the absorption of sodium nucleinate is incomplete. After all, even in this
respect, there is a noticeable difference from the state of affairs in the cases
of acromegaly investigated.

Investigations as to the behavior of the vegetative nervous system in
hypophysial dystrophy are up to the present very scarce. As far as the ex-
citability of the vegetative nerves through pharmacological "means is con-
cerned, I can mention only the following: the glycosuric action of adrenalin
(i mg.) has failed in the cases I have thus far examined (Observations
XXXIII and XLIII, see later).

After the injection of o.oi gm. of pilocarpine in case Si (XXXIV), there
was only a very slight sweat. After the injection of pituitrinum infundibu-
lare (2-3 cc. Parke, Davis 6* Co.'s preparation) there could be obtained a
marked diuretic action. Hence the excitability of the vegetative nerves
seems to be, as in myxedema, generally reduced. Perhaps the nervous
mechanism regulating temperature forms an exception to this (see part deal-
ing with the temperature).

Many circumstances speak for the fact that there is a reduction in the
tonus of certain vegetative nerves. In all cases we find, for example, state-
ments as to the dryness of the skin and the lessened tendency to sweats.

Here I might mention the statements of v. Frankl-Hochwart, and Frohlich,
that in hypophysial dystrophy there not infrequently occur vesical disturb-
ances. For the most part they have been referred to the compression of the
pes pedunculi by the growing hypophysial tumor; both authors express the
opinion that perhaps a reduction of the function of the posterior lobe and
lack of pituitrinum infundibulare is responsible. It would indeed be impor-
tant to pay attention to the behavior of the vesical disturbances in those
cases in which transitory polyuria points to an irritation of the posterior
lobe. I shall consider this symptom somewhat in detail.

294

THE DISEASES OF THE HYPOPHYSIS

We find that polyuria or polydipsia has been mentioned in the history
rather frequently. In v. Frankl-Hoctncart's statistics the picture of diabetes
insipidus occurred seven times. When I turn to the newer literature I find
that polyuria or at least transitory attacks of thirst are very frequent. I
cite the following case:

Case i of Zack. — Transitory polyuria, with urine of 1000 specific gravity.
Case Fucks.. — At times attacks of thirst.

Case Rosenhaupt. — An average of 5^ liters of urine. Autopsy showed a
sarcoma of the anterior lobe of the pituitary.

Case i of Bartels. — Twenty-one-year-old man.
Polydipsia very pronounced.

Case i of Cagnetto.- — Nine-year-old girl, poly-
dipsia.

Case Gotzl-Erdheim. — Diabetes insipidus.
Own Observation (L, XXXIII) . — Sometimes
intense feeling of thirst and polyuria.

Own Observation (Si, XXXIV).— Polydipsia
and polyuria, must get up several times at night.
Own Observation (Wi, XXXVI).— At times
polyuria, with urine of low specific gravity.

Own Observation (F, XLIV). — Amounts of
urine up to 4000, specific gravity 1005-1010.

Also a case of Frank's perhaps belongs here:
a thirty-nine-year-old corpulent man several years
ago attempted suicide by firing two bullets into
the right temple. Six to seven liters of urine
daily, of specific gravity 1005, Libido lost; X-ray
shows one of the bullets in the median line, pro-
jecting into the sella turcica from above.

Hence there are found in a great number of
cases of hypophysial dystrophy, transitory or more
permanent polyuria, indeed in many cases
the condition may assume the picture of a severe
diabetes insipidus.

The combination with polyuria occurs not
only in diseases of the hypophysis but also in dis-
eases that affect the neighborhood of the hypophysis (vicinity of the chiasma,
subthalmic region, etc.). As we shall consider these cases later in the dis-
cussion of the pathogenesis I shall bring to the front the most essential facts
in the existing clinical material. Oppenheim first pointed out that polyuria
frequently occurs in gummatous diseases of the chiasm. Of thirty-six
cases of basal luetic meningitis from the literature, twelve had polyuria.
Oppenheim himself reports two cases with autopsies. Spanbeck and Stein-

FIG. 55. — Tumor of the
subthalmic region with
diabetes insipidus.

HYPOPHYSIAL DYSTROPHY 295

haus found diabetes insipidus eleven times among fifty cases with bitemporal
hemianopsia. They themselves report a case of typical hemianopsia, which
eliminated 6—7 liters of urine with a specific gravity of 1002. Mercury and
iodine treatment brought about complete cure.

I here report a case I saw a long time ago that in many respects is very
interesting.

Observation XXXVII. — A. Sch., fifteen years old. Entered the clinic Sept., 1909.
Father and mother well; no nervous affection in the family. The mother had had four
deliveries and three abortions. The first child is entirely well, the second is the patient.
The third and fourth children had had transitory illnesses that were without relevance
to the patient's condition.

The patient has had a remarkably large head ever since birth. The first tooth ap-
peared in the sixth month, and he began to walk at the age of two years. At this time he
was remarkably tall — a giant child. At three years of age there developed gradually
convergent strabismus that has existed up to the present time. The boy learned well at
school, and was even very intelligent and lively. From the age of twelve years there
developed a gradual lessening of visual power; vertigo often occurred, the boy had very great
thirst, had to drink very much and urinated very much. Also the statement is made by the
mother that at this time the boy had a remarkably large appetite. He also had to expecto-
rate very much. Gradual increase of body weight became apparent.

In 1908 the patient had been at v. Neusser's clinic. There it was noted that there was
marked panniculus adiposis. Body weight 46.8 kg. Slight concomitant convergent
strabismus. The movements of the' eye-balls toward all directions are -very good, how-
ever. The penis is small, no pubic hair, patellar reflexes lively, temporal paleness of both
papilla. Field of vision normal. Amounts of urine between 2500 and 4500. Specific
gravity about 1008.

According to mother's statement the emaciation began during the mentioned stay at
the clinic. Since that stay there have also existed severe headaches that occur about twice
weekly and are especially localized in the frontal region. During severe attacks there
exist marked sensation of heat and reddening of the skin of the face with outbreak of sweat,
•vertigo and flickering before the eyes and mostly severe vomiting. Between these attacks
there exists great tendency to sleep, the boy sleeping twelve hours uninterruptedly.
According to the mother, there is a common inclination for yawning. The boy states
that now and then erections occur. The polyuria is now very considerable. It now is
as much as seventy-one times daily, and he must get up often at nights to urinate.
A ccording to the definite statement of the mother, the boy has not grown for a year.

The boy is tall, the body shows the following measurements:

Jugulum to ant. sup. spine, 38.5 cm.
Jugulum to symphysis, 46 cm.
Vertebra prominens to coccyx, 47 cm.
Circumference of chest, 72 cm.
Circumference of pelvis, 71 cm.
Upper extremities, 68 ,cm.
Lower extremities, 72 cm.

The face has a more childish expression than corresponds to the age. The intelligence
is entirely normal, rather more mature than corresponds to the age. Hair is absent in the
axillae and on the pubes, also on the perineum. The boy is extremely emaciated, especially
on the extremities; the most fat is found on the outer surface of the thighs. The mons Veneris

296

THE DISEASES OF THE HYPOPHYSIS

is trrv riih in fat. Tlic penis is small, and on both sides the very small testicles remain in the
inguinal canal.

The strabismus remains unaltered. The examination of the fundus shows on both sides
temporal paling of the papillcc. Perimeter normal.

X-ray examination that had been made even before the patient's entrance into the
clinic shows entirely normal relations of the sella turcica. Examination of the hand-skeleton
shows that the epiphysial junctures and the rudiments of the hand-skeleton correspond
fully to the age. The patellar reflexes are lively, but with the exception of the nervous
status there is nothing else especial.

Alimentary glycosuria (100 gm. D) negative.

The amounts of urine vary between 4000 cm. and 6700 cm. The specific gravity is
1002-1003.

During the stay at the clinic an attack of headache and vomiting occurred such as
is already described. This lasted for two and one-half days, the vomiting was uncontrol-
lable. Ingestion of food during this time nil. Ingestion of fluid very slight, only 1600

cm., or 500 cm., or 1050 cm. The specific
gravity (of the urine) rose to 1013. The boy
during this time lost 3 kg., falling from 37^
kg. to 34^ kg.

The patient died a half-year after his en-
trance into the clinic.

Summary. — When the patient came into
the clinic, he showed the entire picture of dys-
trophia adiposo-genitalis. As X-ray exami-
nation shows the sella turcica to be normal,
it may well be assumed that a tumor pressed
on the hypophysial peduncle from above.
Also the diabetes insipidus fits into the pic-
ture, also the undoubted temporal paling of
the papillae, which had not as yet led to a
demonstrable hemianopsia. It is further
noteworthy that the concentrating power of
rfie kidneys was still present under certain
circumstances.

FIG. 56. — Genitalia of Observation
XXXVII.

Very noticeable is also the statement of Strauss as to cases of diabetes
insipidus combined with corpulency of the hypophysial type, with lack of
pubic and axillary hair and with hypoplasia of the genitals. In many
such cases we are perhaps dealing with developing tumors of the vicinity
of the hypophysis, even though there are as yet no other signs of brain
tumor.

As an example of this type, I cite the following case:

Observation XXXVIII. — S. K., twenty-one years old. Entered the clinic July 12,
1912. Mother of the patient was corpulent, and died of brain tumor. The patient's
corpulency began in the thirteenth year of life, together with increased sensation of thirst,
the patient sometimes drinking 5 liters of water a day. Corresponding polyuria. This
has continued since that time, and only during the last three years has it become somewhat
slighter. For years violent headaches, which of late have been increasing in intensity and
frequency. The patient has not as yet had sexual intercourse, although according to his

HYPOPHYSIAL DYSTROPHY 297

statement there exists a certain amount of libido and vita sexualis, and he believes that
he would have potentia coeundi. He states, however, that nightly pollutions almost never
occur.

About 170 cm. tall, the skin quite soft, mustache and beard are almost completely ab-
sent, axillae show but very sparse hairiness, on the mons Veneris rather good, closing off
above in a horizontal line, otherwise hairiness of the trunk and extremities is entirely
absent.

Typical eunuchoid fat deposits. Mammae extremely rich in fat, as are also the vicin-
ity of the hip, and the mons Veneris. The small penis is embedded in a cushion of fat.
Testicles of rather normal size and consistency. Genu valgum on each side.
Alimentary glycosuria (100 gm. dextrose), negative.
Blood count: Erythrocytes, 4,240,000
Hemoglobin (Sahli), 65 per cent.
Leucocytes, 6500, of which:
Neutrophiles, 65 per cent.
Mononuclears, 28 per cent.
Eosinophiles, 7 per cent.

X-ray examination of the skull shows normal relations.

On freely chosen administration of liquid, an average of 7400 cc. of urine per day.
The investigation as to the specific gravity of the urine at different times of the day shows

6-1 1 A.M. 1550 cc. 1008

11-4 P.M. 1300 cc. 1008

4-9 P.M. 1900 cc. 1004

9-6 A.M. 1600 CC. IOO2

After addition of 15 gm. of common salt to the breakfast

6-1 1 A.M. 1200 cc. 1007

11-4 P.M. 1850 cc. 106*7

4-9 P.M. 1950 CC. 1007

J9~6 A.M. 2600 cc. 1004

Summary. — Combination of eunuchoid obesity and deficient development of the
condary sexual characters with diabetes insipidus. Growth-disturbance is absent, as is
so any disturbance worth while in the ossification. Probably disease of the brain-stem
unknown nature.

•a. Frankl-Hochwart emphasizes that in tumors of the hypophysis without
acromegaly, often the temperature is established at subnormal values; he
himself observed this in three of ten cases. In the case of Gotzl-Erdheim the
temperature varied between 35° and 36°, only exceptionally rising as high
as 36.3°. Among my cases this was very evident in case Si, Observation
XXXIV, here the temperature varied for a time between 36° and 36.6°;
and in case F, Observation XLIV (see later), the temperature varied for a
while between 36° and 36.4°; and later even between 35.8° and 36.2°. We
could bring this reduction of body temperature into relation with the
reduction of the metabolism, as is the case in myxedema. Everything
speaks for the point of view that also in hypophysial dystrophy the vegeta-
tive functions proceed slower than in normal individuals.

It seems, however, almost as though in hypophysial dystrophy the regu-

298 THE DISEASES OF THE HYPOPHYSIS

lating of temperature may under circumstances show an especial lability.
F. Frankl-Hochu'art has already pointed out the fact that in tumors of the
hypophysis without acromegaly sometimes hyperthermia occurs, dishing
further reports that the injection of glandular extract into hypophysioprivic
animals leads to an increase of temperature, while in normal animals this
increase after the injection never occurs. Gushing has used this " thermoreac-
tion" as a diagnostic aid, and assumes a state of hypophysial insufficiency
in all cases of pituitary disease in which the increase of temperature occurs
after the injection of 2 cc. of a 5 per cent, extract of the anterior lobe of the
ox hypophysis.

Kahn and myself in studies on tetany have several times seen in the acute
stages, after the injection of 2-4 cc. of pituitrinum glandulare of Parke,
Davis 6* Co. that, as was shown especially actively in investigations on
respiratory metabolism, there occurred an increase of temperature to over
38°. Lately Bernstein and myself instituted experiments on twenty indi-
viduals, some of whom were normal and some affected with various diseases,
injecting them subcutaneously with 2 cc. and eventually 10 cc. of the glandu-
lar extract. Never did there occur an increase of temperature. In one
case of very chronic acromegaly, the experiment was negative (case Ad, Ob-
servation XXIX). We saw, on the contrary, in case F, Observation
XL IV, which will later be reported in detail, no distinct action after the
injection of 4 cc., but later on repetition with 5 cc. twice an increase of
temperature of more than 2°.

I would not attempt an explanation of this remarkable phenomenon.
More extensive observations are necessary to establish the diagnostic
significance of the reaction.

Almost regularly in hypophysial dystrophy are found alterations of the
blood picture.

I have carried out investigations as to this point for years, at first in
collaboration with Dr. Bertelli, in a series of cases at the clinic.

Through the kindness of Prof. v. Frankl-Hochwart, we were permit-
ted to examine some of the cases reported by him. I cite the following
observations:

Observation XXXIX. — W., twenty-six years old, typical case of hypophysial dystro-
phy. Examination of the blood in July, 1907. At that time diplopia, reduction of the
visual power, bitemporal hemianopsia ; since the nineteenth year of life no erections, and no
libido, genitalia infantile, pubic hair and axillary hair almost entirely absent. X-ray
shows widening of the sella turcica.

Alimentary glycosuria (100 gm. dextrose), negative.

Erythrocytes, 4,800.000.

Leucocytes, 5600

Hemoglobin, 7.5 g.

Dec., 1907, operation by Prof. r. Eiselsberg, after which improvement of the power of
vision and of headache.

HYPOPHYSIAL DYSTROPHY 299

March, 1908: erythrocytes, 5,260,000
Leucocytes, 7500
Hemoglobin, 8.2 g.

Observation XL. — D., twenty-one-year-old man, Nov., 1909, for ten years gradually
occurring headaches and vomiting. For eight years, diminution of the visual acuity.
At that time temporal hemianopsia. Pronounced obesity, genitalia infantile, pubic and
axillary hairs absent. Destruction of the body of the sphenoid bone and of the dorsum
sellae. June, 1907, operation by Prof . v. Eiselsberg. Cyst of the hypophysis, histologically
carcinoma. Improvement of the power of vision. May, 1908, occurrence of erections.
August, 1908, voice deeper. October, 1909, sparse hairiness in the axillae and on the
pubes. Eye-findings as formerly. No erections. Body weight now 62% kg. (formerly
65.2 kg.).

Blood count: Erythrocytes, 4,200,000
Hemoglobin, 9.4 gm.
Leucocytes, 8200

Polymorphonuclear leucocytes, 52 per cent.
Large mononuclears, 7 per cent.
Lymphocytes, 37 per cent.
Eosinophiles, 4 per cent.

Observation XLI. — O. M., girl, twenty-three years old, Dec. 3, 1909. No hereditary
taint, always well, except that from childhood she has been strikingly pale. One menstrua-
tion at the age of twelve years, she mensturated regularly between the ages of fourteen
and nineteen yeais, then sudden cessation, with normal genitalia. Now and then mod-
erate pressure in the head. March, 1909, influenza, after which dietary treatment with-
out rest in bed. Increased in weight 8.5 kg. (from 53.5 to 62 kg.). At the beginning of
October, 1909, blurring before the left eye, since which time things have remained station-
ary. No headache, no vertigo, no vomiting, no fainting-spells, no insomnia, no yawning,
no disturbance of movements, no rhinorrhea.

Eyes. — 0. D. normal, O. S. 6/12 fundus normal, L. P. temp, scotoma for white. Bi-
temporal color hemianopsia. The nerve findings negative. Internal findings and urinary
findings negative. Moderate struma, patient is of medium height, strikingly pale, does
not make an impression of corpulency, except that a rather large collection of fat is present
on the abdomen. Hair of the head abundant, axillary and genital hairiness normal. The
fingers seem somewhat puffed up and thickened. Slight development of hair on the upper
lip and chin.

X-ray (Decent Dr. Keinbock] : Sella turcica appreciably enlarged, especially below and
behind. The dorsum sellae is visible only as a small bolt-shadow strip.

Weight 61 kg. Temperature on Dec. 6 and Dec. 7 varied between 36.2 and 36.7.
Blood count: Erythrocytes, 4,464,000
Hemoglobin (according to Sahli), 70 per cent.
Leucocytes, 5900

Polymorphonuclear leucocytes, 60.8 per cent.
Lymphocytes, 30.8 per cent.
Large mononuclear, 4 per cent.
Eosinophiles, 4 per cent.
Mast-cells, 0.4 per cent.

Observation XLII. — K. L., seventeen years old. Dec., 1909. Up to this time has
not yet menstruated, since the autumn of 1906 headaches, decrease of visual power and
rapid increase of body weight. Bitemporal hemianopsia. Genitals infantile. Axil-
lary hair poorly developed. X-ray shows dilatation of the sella.
Operation by Prof. v. Eiselsberg.

300

THE DISEASES OF THE HYPOPHYSIS

Blood count, Dec., 1909: Erythrocytes, 4,680,000
Hemoglobin, 9.34 gm.
Leucocytes, 9400 of which:
Polymorphonuclear neutrophiles, 56.3 per cent.
Lymphocytes, 31.3 per cent.
Large mononuclears, 7.9 per cent.
Eosinophiles, 3.3 per cent.
Mast-cells, 1.2 per cent.

I tabulate these observations together with those of the other observations
reported in detail in this book, in the following list:

Observation

Erythrocytes

Hb

Leucocytes

Neutro-
philes

Eosino-
philes

Observation XXXIX, W,

4,600,000

7 . 5 gm.

5,600

before operation.

four months after opera-

5,260,000

8. 2 gm.

7,^00

tion.

Observation XL, D, two

4,200,000

9.4 gm.

8,2OO

52.0

4-0

and one-fourth years

after operation.

Observation XLI, Olga M.

4,460,000

70 per cent.

5,900

60.8

4.0

Observation XLII, K. L.,

4,680,000

9-34gm.

9,400

56.5

3-3

after operation.

Observation XXXIV, S.. . .

75 per cent.

8,400

s6. i

3- 2

about 5 wks. after opera-

71.0

i .0

tion.

Observation XLIII, P

5,000,000

IO,OOO

SO. I

S- S

Observation XLIV, F

4,680,000

s.OOO

64.0

5-5

Observation XXXVIII, Ka

6,500

6s. o

7.0

Observation XLV, Gr

4,800,000

57 per cent.

15,000

62.0

9.0

later

3,300,000

45 per cent.

13,000

58.0

25.0

Observation XXXVI, G.W.

4,600,000

84 per cent.

7,800

74-1

0.7

Lately there are observations of Borchardt in four cases, in which he found
the red blood cells to be somewhat reduced, the leucocytes at the lower limits
of normal, the neutrophiles mostly markedly reduced, the eosinophiles
somewhat high, in one case up to 11.5 per cent.

If we summarize all these cases, we find that there is mostly only a slight
reduction of erythrocyte count or none at all (or even after operation an in-
crease in the number of erythrocytes), while in all cases there was a not in-
appreciable reduction of hemoglobin; the leucocyte count is often diminished,
and in one case increased. Most important is the result of the differential
count of the leucocytes. Almost in all cases the number of neutrophilic
cells is, relatively, markedly reduced, while that of the mononuclears, and
especially the lymphocytes, relatively and also absolutely raised. The
eosinophiles show in many cases an appreciable increase. After operation
the leucocyte picture may revert to normal (Observation Si, XXXIV).
In two cases (Observations D and K.L.) there were, however, marked mono-

HYPOPHYSIAL DYSTROPHY 3OI

nucleosis after the operation. In these cases the hemoglobin remained
markedly reduced after the operation. Perhaps the mononucleosis is the ex-
pression of a slight grade of status lymphaticus. The blood-count in general,
as far as mononucleosis and poverty in hemoglobin are concerned, is similar
to that of myxedema.

I enter more in detail into the consideration of a symptom which up to
the present has not been sufficiently regarded in the differential diagnosis.
I refer to the inhibition of growth. Already v. Frankl-Hochwart emphasized
that the cases of tumor of the hypophysis without acromegaly in youth
almost always affect small individuals. Almost in all cases in which the
disease began in the years between childhood and adolescent life is remain-
ing behind in growth reported. I here quote what I have been able to find
in this subject:

Case of Berger. — Began at twelve years.

Case i of Bychowski. — K. L., seventeen-year-old girl, very small, 132
cm. tall (operated on by v. Eiselsberg), cyst of the hypophysis.

Case 2 of Bychowski. — Reported very briefly. Growth ceased at the
age of thirteen years, 132 cm. tall.

Case 2 of Nazari. — Normal development up to between the sixth and
seventh years, then remaining behind in growth; at twenty years of age,
125 cm. tall.

Case i of Babonneix and Paisseau. — From eleven and one-half years
on, height remained stationary.

Case i of Erdheim. — Twenty-year-old woman, "body very small."

Case of Zollner. — One hundred forty-five centimeter tall individual.

Case of Uhthojf. — Dwarfism with bitemporal hemianopsia.

Case i of Ettore Lem. — Twenty-and-one-half-year-old woman, from ten
years old on cessation of growth, 130 cm. tall, lower length 71 cm., geni-
talia infantile, sella turcica considerably widened.

Case i of Bartels. — Twenty-one-year-old man, cessation of growth at
the fourteenth year.

Case 2 of Bregman and Steinhaus. — Seven-year-old girl, "relatively
small."

Case of Mixter and Quackenboss. — Twenty-seven-year-old man who
looks as if he were eighteen years old, enlargement of the sella, operation.
Epithel. congen. of the hypophysis with cystic degeneration.

Case of Kummel. — Twenty-three-year-old man, looks as if he were
fourteen years old, no obesity.

Case of Leman and Van Wart. — Twenty-four-year-old woman, infantile.

Case of Bournier. — Twenty-six year-old man, 125 cm. tall, eye disturb-
ances since his eighth year, disturbance of growth since his tenth year.

Case of Rennie. — Cessation of growth at the same time as the appearance
of manifestations of hypophysial tumor.

302 THE DISEASES OF THE HYPOPHYSIS

Own Observation XXXIII (L). — One hundred thirty-one centimeters
tall since ten years old. Has not grown for two years.

Own Observation XXXIV (Si} .—Sixteen-year-old girl, 145 cm. tall.

Own Observation XXXVII (ScH). — At the beginning very marked growth,
cessation of growth at thirteen years of age.

Also the cases of dystrophia adiposo-genitalis with brain processes in
which a limitation of the function of the hypophysis may be suspected, show
the inhibition of growth.

Case of E. Muller.

Case i of Goldstein. — Cessation of growth at the fifth year.

Also Case 3 of Goldstein is called "small." Both were diagnosed serous
meningitis.

Case 2 of Neurath. — Scarlet fever at seven years of age, shortly afterward
cessation of growth; at ten years of age 109 cm. (instead of 130 cm.), prob-
ably hydrocephalus due to meningitis (see later, case Fr, Observation
XLIV).

The following case may be regarded as a case sui generis of hypophysial
dwarfism :

Case of Jutaka Kon. — A thirty-seven-year-old "dwarfishy built man"
(147 cm. tall), could not visit the school on account of weakness of the eyes.
Now and then epileptic attacks, coarse, glittering face, skin dry, lately in-
creasing mental slowness, no hairiness on the mons Veneris, on the scrotum,
or near the lips. Genitalia entirely infantile. Autopsy showed a slight hy-
poplasia of the thyroid gland and an enormous calcified tumor of the in-
fundibulum, that histologically was a teratoma. The teratoma has existed
since earliest youth, it was "evidently congenital."

The case of Benda was that of a thirty-eight-year-old dwarf. There was
found a hazelnut-sized teratoma of the hypophysis. The remnant of the
gland was atrophic, the genitalia were infantile. Here likewise there was a
teratoma, so that it is probable that it had existed since youth and was re-
sponsible for the dwarfism and the genital dystrophy.

The case of Woods Hutchinson is correctly regarded by Breus and
Kolisko as chondrodystrophy.

In the case of Hagenbach (sarcoma of the hypophysis in an individual
103 cm. tall) the connection between the growth disturbance and the tumor
of the hypophysis is, as the author points out, hard to show, as it is not known
when the tumor began to form.

Aschner describes a case of dwarfism which he regards as hypophysial—
entirely incorrectly. In this case there does not exist a single symptom that
points to this hypophysis. I regard this case as a true infantilism.

The case of Hueter, quoted by Aschner, is quite uncertain. Hueter him-
self is of the opinion that the tuberculous disease of the hypophysis, in the
forty-two-year-old woman, is of recent date, and therefore has nothing to

HYPOPHYSIAL DYSTROPHY

303

do with the dwarfism. In this case the sexual organs were well developed.
This speaks against the existence of the hypophysial affection since youth.

In May, 1911, 1 observed a case that perhaps belongs to this category.

Observation XLIII. — M. S. P., forty-one years old, from Palestine. Entered the
clinic May, 1911. Family history good. The patient states that his genitals have
been of the present size since childhood. In spite of the fact that the penis is diminu-
tively small, it is subject to erections. First coitus at the age of twenty-two years.
Coitus was then practised several times a month up to the
twenty-sixth year. The pleasurable sensation was very
great, but there h#d never occurred an ejaculation. Also
now the penis sometimes becomes erect, the erections last-
ing for six to eight hours; they are associated with intense
voluptuous sensations. We ourselves saw such an erection,
the penis measuring 3 cm.

For three years the patient has suffered with violent
right-sided headaches. There exists a slight right-sided
ptosis and paresis of the superior oblique and inferior oblique
muscles with diplopia.

The patient is 154 cm. tall; span width 172 cm., lower
length 97 cm.; he is somewhat fat, and there are abundant
accumulations of fat on the hips and on the mons Veneris.
Hairs of the beard are entirely absent, and there is very sparse
hairiness of the mons Veneris and the axillae. The penis is
diminutive, and there is a slight hypospadias . The scrotum
is very small. There is bilateral cryptorchidism.

X-ray. Both clivi sharpened, entrance to sella widened.
Floor of sella not essentially deepened.

Examination of the eye-grounds; both papillae present a
washed-out appearance, old neuritis.

Blood count: Erythrocytes, 5,000,000
Hemoglobin, 65 per cent., according to Sahli
Leucocytes, 10,000, of which:
Polymorphonuclear neutrophiles, 50.1 per cent.
Large mononuclears, 15.0 per cent.
Lymphocytes, 24.4 per cent.
Eosinophiles, 0.5 per cent.

Adrenalin subcutaneously (o.ooi gm.), no glycosuria.

At first I regarded this case as a eunuchoid, in which a certain function
of the genitalia was retained. Also the proportioning of the body seems to
me to speak to the same effect. Against pure dysgenitalisTn speaks however :

1. The disturbance in growth (both patient's parents are large in-
dividuals) .

2. The disturbance of eye muscles, the symptoms of brain pressure, and
the X-ray findings.

As the genital disturbance had action already in earliest youth, the eye-
muscle disturbance first becoming apparent only about four years ago, we
must think of a gradually developing hypophysial tumor. This may be a
teratoma.

FIG. 57. — Teratoma of_the
hypophysis.

304 THE DISEASES OF THE HYPOPHYSIS

Lately Sprinzels has shown a case before the Wiener Gesellschaft der
Arzte [Vienna Association of Physiciansl that, on account of the interest it
affords, I shall describe in detail. It was that of a young man seventeen
years old. In the third year of his life after a knock he sustained spasms,
probably of a toxic character. Since that time, great thirst and polyuria.
Since the fifth year of life cessation in growth, sometimes headache, intelli-
gence well developed, gay temperament. Height 106 cm., circumference of
head 52.5 cm., physiognomy that of a mature individual, skin soft, smooth,
rough and scaly only at certain places, dry, no secretion of sweat. Abun-
dant deposition of fat on chest and abdomen (mons Veneris?), no hairiness
on the trunk. Voice childish, several of the teeth belonging to the milk

FIG. 58. — Genitalia of Observation XLIII.

set, genitals correspond to those of a six-year-old boy (erections were ob-
served, however). Amount of urine 3500-4000 cm., specific gravity 1002-
1003. Ossification relations correspond to those of a four-and-one-half
to five-year-old child. Sella turcica shows no tendency to bone destruc-
tion. "A shadow focus coming into the sella from above, and filling out
the sella like a bolt, leaving a light zone free," no disturbance of vision.
Diagnosis benign tumor of the hypophysis or in the vicinity of the hy-
pophysis, probably teratoma.

I quote the following as a further case of marked disturbance in growth,
apparently due to a destruction of function of the hypophysis. We shall
find that it will interest us later, in the consideration of the proportioning of
the body and the behavior of ossification.

HYPOPHYSIAL DYSTROPHY

305

Observation XLIV. — Case F., fifteen years old. Entered the clinic September,
1912. The mother of the patient states that the birth was normal, but that she cannot
say with certainty when the growth disturbance first began; but that there was rachitis
at the eighth year. The child walked late. The abdomen at that time was distended.
At all events it is to be supposed that the growth disturbance goes back very far. When
the mother was asked concerning fat stools, she answered that these had existed as long as
she can remember. Measles at six years of age. In early childhood, patient had frequent
sweats. Of late years, he has become thin, and has felt very weak; he became silent
and melancholy. He complains of" violent vertigo and of
headache. For three weeks diarrheal evacuations, that have
seemed fatty. The development of the intelligence was ap-
parently normal.

The boy measures 121 cm., the span width is 121 cm.,
lower length (from ant. sup. spine to internal malleolus) 63
cm. The skull has the form of a tower; the greatest circum-
ference measures 61% cm. The tubera frontalia project to
a degree, no saddle-nose, the teeth are very bad, the incisor
teeth are much ridged, certain teeth belonging to the milk
set. Genua valga. The color of the face is pale, the skin of
the entire body is white, remarkably delicate, quite feminine.
The patient is thin, but nevertheless there are deposits of
fat on the hips and nates, in the hypogastric regions and
somewhat more distinctly on the mons Veneris. No rosary
formation; no bending of the extremities. No glands pal-
pable. Lung-findings normal. The heart sounds are clear,
after several sittings extrasystoles. Examination with the
electrocardiogram shows complete dissociation.

The development of the genitalia has remained behind to a
marked degree. The penis is small, prepuce well developed.
The inguinal canals are pervious for two fingers, the testicles
lie in the inguinal canal and come down a little only on
marked coughing. They are about the size of beans and
very soft; the paradidymis is hardly delimitable. The hairi-
ness on the trunk and genitalia is entirely absent.

Wassermann reaction negative. Alimentary glycosuria
(200 gm. dextrose) negative.

Blood count: Erythrocytes, 4,800,000

Hemoglobin, 45 per cent.

Leucocytes, 5900 of which :

Polymorphonuclear leucocytes, 64 per cent.

Lymphocytes, 25 per cent.

Large mononuclears, 4^ per cent.

Eosinophiles, $% per cent.

Mast-cells, i per cent.

The eye examination shows prominent eye-balls, oblique palpebral fissures, dilated pupils,
icrves pale, well delimited; the vessels, especially the veins and the peripheral and muscular
tranches are appreciably convoluted without dilation, old neuritis (?) (Docent Ulbrich).
X-ray. Skull strikingly large and high; hydrocephalus, sella of normal dimensions,
dilated only at its entrance, its contour retained. The dilatation of the entrance to the
sella is perhaps only a partial manifestation of the hydrocephalic extension of the skull
(Docent S chillier).

FIG. 59.

306 THE DISEASES OF THE HYPOPHYSIS

The examination of the respiratory gas exchange (Dr. Bcnisetiit) shows:

CO" elimination 5.14 1 ...

> Average of three well-concurring observations.
O2 consumption o.n J

The temperature is instituted at a low level, ordinarily between 36° and 36.4°.

Injection of 4 cc. pituitrinum glandulare intramuscularly shows slight increase of
temperature, up to 37°.

Nov. 6. Injection of 5 cc. pituitrinum glandulare intramuscularly at 9 A.M. causes an
afternoon rise of temperature to 38.5° (4 o'clock). At 8 o'clock still 38°. On the next
morning temperature again 36.2°, no subjective manifestations.

The investigation of the gaseous exchange after the injection shows a very marked
decrease of the carbonic acid production and the oxygen consumption. There was appre-
ciable increase of respiratory quotient.

Repetition of the experiment on Nov. 13 with 5 cc. of pituitrinum glandulare (intra-
muscularly) brought about an increase of temperature to over 38°C.

The amount of urine varied between 2000 and 4000 cc. Correspondingly the specific
gravities varied between 1010 and 1006, exceeding 1010 very rarely.

At the beginning several bowel movements daily, later only one or two. The stools are
mostly more or less brothy, whitish, glistening like fat, containing, as is shown on micro-
scopical examination, many needles of soap fatty acids and of neutral fat.

Appetite and general condition improve rapidly, also a rapid increase of body weight
from 24 kg. to 32^ kg. in the course of five weeks, with distinct prominence of the abnor-
mal distribution of fat on the buttocks, mons Veneris, etc.

The intelligence of the boy is in general well developed, temperament is gay. The
complaints as to headache are less.

X-ray examination of the hand shows marked developmental disturbance of ossifica-
tion. The development of the bone-nuclei about corresponds with that of an eight- to
nine-year-old boy.

In this case we are dealing with a chronic hydrocephalus that apparently
has led since earliest youth to disturbance of the function of the hypophysis
through pressure on the entrance to the sellae. For the disturbance of hypo-
physial function speak: i. The growth disturbance and the disturbance in
ossification and dentition. 2. The genital dystrophy with the typical obesity.
3. Perhaps the "thermoreaction." Whether there exists here a disturb-
ance in metabolism we cannot decide, as there are no values of comparison
with normal individuals of the corresponding size and weight. Fitting in
with the diagnosis are also the behavior of the carbohydrate metabolism,
the blood-count, the hypothemia, and the slight degree of polyuria.

There are as yet no statements in the literature as to the proportioning
of the skeleton and the ossification conditions. In the study of my cases I
made certain observations that seem to me important for the differential
diagnosis of the hypophysial dystrophy from the primary genital dystrophy.

The proportioning is sometimes more of an infantile, sometimes more of a
eunuchoid type, that is, in the latter case the lower length considerably ex-
ceeds the upper length. In a case of Ettore-Levi the total length was 130 cm.,
the lower length 71 cm. In my case L, Observation XXXIII, the total
length was 131 cm., the distance from the anterior superior spine to the in-

HYPOPHYSIAL DYSTROPHY

307

FIG. 60.— Sella turcica of Observation XLIV.

3°8

THE DISEASES OF THE HYPOPHYSIS

FIG. 61. — X-ray picture of hand of Observation XLIV.

HYPOPHYSIAL DYSTROPHY

309

I

FIG. 62. — X-ray picture of the hand of a normal individual of the same age as

Observation XLIV.

310 TIIF. DISEASES OF THE HYPOPHYSIS

terior malleolus 69 cm.; also in case Si, Observation XXXIV, the lower length
is not essentially greater than the upper length. Quite infantile are the
dimensions in case Fr, Observation XLIV. On the contrary in case Sch,
Observation XXXVII, the lower length again distinctly exceeds the upper
length, as it does also in case P, Observation XLIII. It seems to me that
here two factors are working in opposite directions. The one is a genital
disturbance, which brings about tallness and excess of the lower length
over the upper length, the other is a growth disturbance conditioned by the
falling out of hypophysial function. According as the one or the other
predominates do the proportions approach the eunuchoid or the infantile
type. In the severest cases it is indeed mostly infantile.1

A distinct difference exists in the ossification conditions of hypophysial
dystrophy and eunuchoidism. As we shall see later, in the latter only the
epiphysial closure is disturbed; the development of the bone nuclei, however,
according to what has been observed up to the present, is not essentially
delayed. But the delay in the epiphysial closure is, however, of a high grade
and lasts until late life.

How are the conditions in hypophysial dystrophy? Case W. (Observa-
tion XXXIX) reported by v. Frankl-Hochwart and v. Eiselsberg, was, when I
examined him, twenty-seven and one-half years old. The first symptoms had
set in at nineteen years of age; the condition of ossification was entirely
normal. In an eunuchoidism that had set in so late certain epiphysial junc-
tures would have remained open, and there would have been an additional
growth of some centimeters. In case L. (Observation XXXIII) and in
case Si (Observation XXXIV) the behavior of ossification approached the
normal.

Quite otherwise are the relations in the cases in which the severe dis-
turbance of growth sets in early. In Case F. (Observation XLII) the
development of the bone nuclei corresponded to that of an eight- to nine-
year-old boy rather than to that of a fifteen-year-old boy. I refer to the
X-ray picture of this case as compared with that of a normal fifteen-year-old
boy (Figs. 61 and 62).

Hence in these cases the growth disturbance is similar to that in hypo-
thyroidism. From the literature I can quote only the case of Bournier,
which shows that in the high degrees of growth disturbance also the closure
of certain epiphyses is markedly delayed. In the twenty-six-year-old patient
the proximal epiphyses of the phalanges and of the first metacarpal bones,
and the distal epiphyses of the ulna and radius, are still open. Finally the
case reported by Sprinzel in which ossification has remained behind much
farther than in my case F.

From all this seems to be inferred, that the disturbance of ossification in
light grades of hypophysial dystrophy is not very pronounced, in severer grades

1 1 refer to Chapters X and XII.

HYPOPHYSIAL DYSTROPHY 311

it affects in the same manner the occurrence of the bone-nuclei and of the epiphysial
closure, -while in pure eunuchoidism the epiphysial closure is indeed involved,
but this disturbance lasts until late in life.

To the above-described manifestations is added, according to the process
that damages the hypophysis, a series of manifold symptoms. Most common
are tumor symptoms, such as tend to appear in tumors of the middle fossa of
the skull. Most frequent are heacfaches, that for the most part are not lo-
calized; also disturbances of vision (bilateral hemianopsia or simple amblyo-
pia and amaurosis, genuine atrophy, and not rarely choked disc). First
there appears bilateral hemianopsia for colors, and only later for white; in
quite rare cases there may occur a homonymous hemianopsia owing to de-
struction of the tract by a tumor (a case of O. Hirsch's) ; in addition vertigo,
insomnia, frequent yawning (little sleep at night however), apathy, finally
psychic disturbances, sometimes also nasal discharge of cerebrospinal fluid.
With these symptoms are associated paresis of the eye-muscles, disturbances
of smell, taste, and hearing, vomiting, manifestations of a hydrocephalus,
bilateral clonic twitching, eventually paresis of the extremities. Exophthal-
mus may also occur, owing to penetration of the tumor into the orbit (case
of Pechkranz) .

According to the nature of the picture, the X-ray examinations show
widening of the introitus to the s"ella with destruction of the clmoid processes
and eventually with deepening of the sellar floor (especially in tumor of the
hypophysis), but in extrasellar processes sharpening of the clinoid processes,
and only later destruction of these (Erdheim and Schuller) , deepening of the
impressiones digitata? in youthful individuals, eventual enlargement of the
skull and essential thinning of its bony walls.

Noticeable, finally, are certain alterations of the psyche, v. Frankl-
Hochwart emphasizes that in these patients there is a remarkable restlessness
and resignation, and that in spite of the existing headache they often show
a gay temperament. In youthful individuals, at all events, this gay tempera-
ment (case F., Observation XLIV, and the case of Sprinzet) contrasts mark-
edly with the stupidity and moroseness of hypothyroidism in childhood.
In many cases of hypophysial dystrophy there may, of course, also occur a
fairly appreciable degree of uninterestedness, which, however, may be much
benefited by operation (confer case Si., Observation XXXIV). Now and
then there develop also more or less pronounced psychoses. Finally it should
be mentioned that also hypophysoprivic dogs show characteristic psychic
alterations.

The pathologico-anatomical findings that are found in this syndrome are
extremely manifold. First of all, there are tumors of the hypophysis itself;
a detailed summary of the tumors of the hypophysis without acromegaly
is found in the publications of v. Kollarits and of v . Frankl-Hochwart.

v. Frankl-Hochwart has collected ninety-seven cases of tumors of the

312 THE DISEASES OF THE HYPOPHYSIS

hypophysis (without acromegaly). Among these are twelve carcinomata,
thirteen adenomata,1 nine strumas, and twenty-seven sarcomata. Among
the carcinomata are especially worthy of mention the hypophysial duct flat-
celled epithelial carcinomata, described by Erdheim. These proceed from
the accumulations of pavement epithelium, which lie in the process of the
glandular anterior lobe that extends into the hypophysial peduncle, and
which constitutes remnants of the hypophysial duct cut off from the oral
ectoderm. (See Figs. 30 and 32.) Histologically they consist in epithelial
nests and concentric layers lying very close to each other. Erdheim compares
them with adamantinomata, which also originate from cut-off parts of the oral
epithelium, as the remnants of the rudiments of the teeth. It may be readily
understood that tumors of the hypophysial duct mostly lead first to a dilata-
tion of the sellar introitus. Then the glandular hypophysis microscopically
may appear normal, as in case of Bregmann and Steinhaus.

Further, there were to be observed, according to v. Frankl-Hochwart,
fifteen cysts, among them the interesting case K. L., that was operated on by
v. Eiselsberg, and that was more accurately described by Bychowski. Finally
a vascular tumor of indefinite texture, three gliomata, two teratomata,
seven tubercles, three gummas, and one case each of steatoma, chondroma
and fibroma.

A case that is very important for the pathogenesis of hypophysial dys-
trophy was that of a cyst of the hypophysis recently reported by Maranon.
It occurred in a man about forty years old with typical dystrophy. Micro-
scopically the hypophysis was apparently normal, and on microscopical
examination more than three-fourths of the glandular part was found to be
destroyed by an old focus of hemorrhage.

I report another case that I observed a short time ago:

Observation XLV. — G. J., fifty-five years old, tailoi. Entered the clinic May 30, 1912.
Part of the history was furnished by the wife. Until ten years ago entirely normal. Then
marked pains in the frontal region, attacks of vertigo and lomiting. These pulled him down
very much, and the attacks were attended with high fever. He was confined to his bed
for six months, then he could again take up his occupation, but since that time his libido
has been markedly weakened, and finally disappeared altogether. Also complete impotence
came on. The axillary hairs gradually fell out. Since that time attacks of vertigo have
been less frequent. In the course of the year 1910 there gradually developed a swelling of
the thyroid and slight hoarseness. Otherwise there were no other complaints. Dec.,
19 1 1, influenza. Remained in bed for six to seven weeks, after which there were lightning-
like pains and formications in the [lower] legs. Also the bones were tender. Five weeks
ago, according to statement, suddenly a toxic spasm in the right hand and then also in the
left hand.

Markedly emaciated cachectic individual. Skin pale, dry, scaly, the visible mucous
membranes pale. Patient often cannot recollect well, right pupil wider than the left.
Reaction somewhat sluggish. Eye-grounds normal. The middle lobe of the thyroid

1 1 have already mentioned that not every adenoma must have an increased function and lead
to acromegaly.

HYPOPHYSIAL DYSTROPHY 313

gland is of the size of an apple, rather hard, and extends under the sternum, as is seen on
examination of the X-ray plate. Circumference of the neck 44^ cm. Voice slightly
roughened. Chvostek I positive. Electric excitability normal.

Blood-pressure (according to Gartner) go

Blood count: Erythrocytes, 4,800,000
Hemoglobin (Sahli), 57 per cent.
Leucocytes, 15,000, of which:
Polymorphonuclear neutrophiles, 62 per cent.
Lymphocytes, 19 per cent.
Large mononuclears, 10 per cent.
Eosinophiles, 9 per cent.

Pirquel's reaction negative. Patellar reflexes weak. Hyperesthesia of both lower
extremities. Nerve trunks slightly tender. Especial hyperesthesia of the soles of the
feet. No hairs in the axillae. No mustache hairs. Beard hairs almost entirely absent.
Hair on the body absent with the exception of the pubic hair that is still present somewhat
copiously. There are no hairs at all on the perineum. The entire body is extremely thin,
and there is a cushion of fat still indicated only on the mons Veneris. The penis is strikingly
small, prostate hardly palpable. Nipples quite stunted.

X-ray examination of the skull showed considerable enlargement of the sella lurcica to
the size of a two-crown piece. Sellar introitus apparently intact.

Alimentary glycosuria (200 gm. dextrose), negative.

Sugar in blood, 0.081 per cent.

Rapidly increasing cachexia, development of a pneumonia that led to an increase of
temperature. Kernig's symptom is positive, lumbar puncture negative. On July 5,
the blood count was:

Erythrocytes, 3,300,000

Hemoglobin (according to Sahli), 45 per cent.

Leucocytes, 13,900, of which:

Neutrophiles, 58 per cent.

Lymphocytes and large mononuclears, 17 per cent.

Eosinophiles, 25 per cent.

On both sides the struma decreases very much in size, so that on July i the circumference
of the throat was only 39 cm.

Death on July 23.

Autopsy (Assistant Erdheim): Hazelnut- sized cyst of the hypophysis with marked
pressure atrophy of the pituitary parenchyma and dilatation of the sella turcica. The
peduncle of the hypophysis and the base of the skull unaltered. The operculum sellae
deeply retracted. Cerebral hernias with erosion of the vitreous table in the domains of
the posterior and middle cerebral fossae. But the convolutions are not flattened. Grow-
ing struma (Langhans) proceeding from the middle lobe of the thyroid gland with exten-
sive pressure atrophy of the thyroid parenchyma proper. The thymus small, rich in fat,
the suprarenal markedly atrophic, the atrophy affecting exclusively the cortex, the Medulla
remaining abundantly developed. Atrophy of the testicles, marked general marasmus,
marked senile atrophy of the upper and lower jaws without almost complete absence of
teeth. Lobular pneumonia, etc.

The microscopical examination of the hypophysis in the sagittal direction, for which I
am indebted to Dr. Erdheim, shows the following: The hypophysis is taken up centrally
by a single-chambered, smooth-walled cyst, which is partly filled with a homogeneous
portion and partly with a shreddy portion. The cyst for the most part is not lined
with epithelium, there being present a single layer of epithelial cells for a short distance

314 THE DISEASES OF THE HYPOPHYSIS

only. The tissue surrounding the cyst is J£ mm. thick and constitutes the markedly
pressure atrophied, strongly fibrous, glandular tissue of the hypophysis. This is bounded
externally by the fibrous capsule of the hypophysis.

The microscopical examination of a piece of the thyroid gland showed a well-limited
benign epithelial tumor with numerous cavities filled with colloid, that are separated from
each other by septa that are purely epithelial.

In this case there is surely a marked retrenchment of function of the
hypophysis of ten years' standing with a gradual increasing cachexia. The
disease was ushered in with an unknown infectious process. Perhaps this
also affected the hypophysis and gave occasion for the cyst formation. At
all events we find since that time a disturbance of the generative function, a
gradual partial retrogression of the secondary sexual characters, slight
atrophy of the accessory genital apparatus, especially the prostate. Perhaps
the marked atrophy of the suprarenal cortex plays a part in the retrogression
of the genitals and of the secondary sexual characters.

Worthy of mention in this case is also the uncommonly rapid diminution
of the struma. At the beginning this was so hard that originally we thought
of a malignant process.

Much cited is the case of Madelung. This concerned a nine-year-old girl.
At the age of six years, a shot injury from a Flobert gun. The girl has re-
mained behind in mental development, is very quiet. Considerable adiposity
which first developed after the injury (at the time the patient remained in
bed for five months) . The shot had penetrated the sella turcica via the left
eye; there was a slight dragging of the left leg and weakness of the left
arm.

Besides these tumors originating from the hypophysis there are numerous
processes in the neighborhood of the hypophysis in which such cases of
dystrophia adiposo-genitalis are found. To these belong tumors that pro-
ceed from the brain membranes or the bones, or brain tumors. All possible
brain processes can lead to genital disturbances and adiposity, in so far as they
apparently call forth an increase of pressure in the third ventricle. Already
in 1855, Fr. Konig reported a case that seems to me to belong in this category.
It was that of an eighteen-year-old girl with undeveloped genitalia; she
had never menstruated. The visual power was disturbed. The head was
very large. Here was found a hydrops of all ventricles and atrophy of
the optic nerves; in the cerebellum, on the left, an echinococcus. This case,
on account of the deficient ossification of the pelvis was considered by A.
Paltauf one of the true dwarfism. For the first exact description of such
cases we have to thank E. M tiller; but Axenfeld, already in 1903, had pointed
out that tumors at the base of the brain may produce permanent amenorrhea
even at the beginning of the disease. In many of E. Mutter's cases there
developed a pronounced obesity. There was observed in the two autopsied
cases a tumor of the cerebellum, and a tumor of the occipital lobe respect-

HYPOPHYSIAL DYSTROPHY 315

ively. In the cases that he observed only clinically there was probably sec-
ondary ventricular hydrops after brain tumors.

Marinesco and Goldstein described two cases of hydrocephalus with genital
hypoplasia and obesity (no autopsy). Like the case of E. Mutter, the patients
were small of stature. Neurath further reports cases of hydrocephalus with
obesity in children. The genital disturbance was not always distinct. We
have to consider however that in children the genital disturbance would not
be so prominent as in adolescents. In a review of the pertinent literature
I have received the impression that in the slight grades of hypophysial
insufficiency the first sign is the development of an obesity.

Also case 2 and case 3 of Babonneix and Paisseau belong to the group
just mentioned. In case 2 as in case i of Neurath the hydrocephalus de-
veloped after scarlet fever.

Pathogenesis. — The views as to the pathogenesis of the clinical picture
described , or as to the r61e that the hypophysis plays in it, deviate from one
another markedly. Even although at the present we are not in the position
to clarify satisfactorily all the manifestations belonging to this picture, I
still believe that the later results of pathological physiology and the evident
analogies with those diseases of the thyroid that are well-known have fur-
nished us with a valuable criterion. Let us first consider the results of the
pathological physiology. The difficult accessibility of the organ and its
immediate vicinity to centers important for life have made extraordinarily
difficult the experimental studies of the symptoms dependent on loss of the
hypophysial apparatus. Only recent years have brought comparative clear-
ness to the solution of the problem. In stating the experiments and their
results I shall confine myself to the most important. Paulesco was the first to
succeed in the complete extirpation of the whole hypophysial apparatus.
He and Gushing used the method of trepanation and pushing aside the
cerebral hemispheres. Both authors came to the result that the complete
extirpation of the entire hypophysial apparatus in dogs leads to death under
fall of temperature and blood-pressure, slowing of the pulse, increasing
apathy, and deep coma, and they inferred that the hypophysis is an organ
important for life, of which the anterior lobe is the part important for life;
this because complete extirpation of this alone led to all the manifestations
described. According to Gushing total extirpation of the posterior lobe
in several cases called forth convulsions and sexual overexcitement, but
mostly was without especial action. On the contrary B. Aschner on the basis
of his very beautiful experiments upheld the opinion that the lethal result
described depends on an injury to the tuber cinereum. Aschner used the
buccal method and found lethal coma on injury to the tuber cinereum and
opening of the third ventricle. Less severe injuries or wound infection brings
about the appearance of the so-called hypophysoprivic cachexia (marked
fall of temperature, apathy, anorexia, polyuria, eventually glycosuria, also

316 THE DISEASES OF THE HYPOPHYSIS

adynamia, crying-out of the animals under experimentation, tonic and clonic
convulsions and death). On the contrary when the hypophysis is removed
without injury to the hypophysial peduncle, the manifestations detailed re-
main absent, the animals are again lively a few hours after the operation, and
remain alive. There develops, especially in youthful animals a condition
that in the most important features simulates hypophysial dystrophia
adiposo-genitalis. The animals become fat, they remain appreciably be-
hind in development, the dentition and the ossification are markedly delayed,
the epiphysial junctures can remain open for a long while, the childish
proportions are retained, and the epidermoidal structures, such as the
hairs and claws, show developmental disturbances. The genitalia remain
markedly infantile, spermatogenesis is extremely sparse, the sexual instinct
is markedly reduced, in female animals rut is weakened and never is there
pregnancy. Investigations as to the metabolism of such animals shows that
there is great similarity with alterations that Eppinger, Rudinger, and 7
found in animals without thyroids. The fasting protein exchange is
markedly reduced. The glycosuric action of adrenalin is reduced, and is
associated with a slowing of the pulse and of breathing, reduction of the
body temperature, and an appreciable reduction of caloric production.
Benedict and Romans have demonstrated the reduction in the carbonic acid
production, Aschner and Forges the reduction of oxygen consumption, in
such animals. The alterations described must be referred to the extirpation
of the glandular hypophysis, as extirpation of the posterior lobe alone calls
forth no essential alteration. The traces of the epithelial seam of the inter-
media that must remain behind in the hypophysial peduncle do not, as
Aschner supposes, come into consideration.

It is perhaps hardly necessary to describe in detail the great similarity
of this symptom complex produced by extirpation of the hypophysial appa-
ratus with that of hypophysial dystrophy. In spite of this I must enter
into a discussion of the individual symptoms and their relation to the hy-
pophysis, as just on this point the opinions differ from each other consider-
ably. In this discussion we shall have to keep our attention directed to the
fact that, as in acromegaly, the cardinal symptoms due to the deficiency of
function of the hypophysis (in acromegaly, the excess of hypophysis function)
must be kept separated from the symptoms that are due to the pressure of
the growing tumor on the neighboring organs or due to the associated disease
of other ductless glands.

To-day the view of most authors is that hypophysial dystrophy with
both of these cardinal symptoms — the genital disturbances and the obesity —
depends on a loss or diminution of function of the hypophysis (v. Noorden,
Fettsucht [Obesity] 2nd edition). The relation of both these symptoms to
the hypophysis has, however, been called into question. Erdheim assumed
that the tumor on growing out from the sella actuated an as yet unknown

HYPOPHYSIAL DYSTROPHY 317

center at the base of the brain, occasioning obesity. Erdheim was forced to
this conception by the observations that also tumors situated extrasellarly
can lead to obesity. Among those authors who refer the obesity directly to
the loss of function the hypophysis, there are some who refer the tumor to the
loss of function of the nervous lobe, others to that of the glandular. Espe-
cially B. Fischer is an adherent to the doctrine that it is due to the nervous
lobe. He states as a chief argument the fact that the genital disturbance
belongs to the early symptoms of acromegaly too. Here it is produced by
pressure on the nervous lobe. Also Gushing, who formerly in common with
Crowe and Romans, brought the obesity into relation with the glandular
hypophysis, now agrees with Goetsch and Jacobson as to the significance of
the posterior lobe. Finally, another much discussed question is as to whether
the obesity is produced directly by the alteration of function of the hypo-
physis or secondarily by the functional disturbance of the sexual glands.
Lately B. Aschner has again taken up Erdheim's hypophysis and has cham-
pioned an atrophic center at the base of the brain, the function of which is dis-
turbed by the pressure of the growing tumor. He bases his opinion on the
fact that in growing animals total extirpation of the hypophysis never leads
to a marked grade of obesity, nor to such distinctly pronounced genital
disturbances as in youthful human beings. The result of the operation
on tumors of the hypophysis in human beings, so far as concerns the les-
sening of the obesity and the improvement of the genital function, depends
on a release of pressure from the hypothalamic region. Aschner sees an
especially strong support for his opinion in the experiments, the results of
which were recently published, through which it was possible to produce
marked trophic disturbance of the sexual glands through injury to the hypo-
thalamic region. To this view, E. Mutter has already opposed the fact that
trophic disturbances in processes at the base of the skull must be ascribed to
the compression of the hypophysis, as dystrophy and sexual glandular
disturbances are absent in brain tumors unattended with hydrocephalus
that have not involved the hypophysis. Also Marinesco and Goldstein
incline to this opinion, v. Noorden regards the obesity as thyrogenic (through
secondary influencing of the function of the thyroid gland). Finally, here,
as in acromegaly, the attempt has been made to place in the foreground
a primary disturbance of the sexual glands (Schuller, Tandler and Grosz).
Novak, on the other hand, influenced by the fact that operation may bring
about an improvement of the genital function without essential effect on
the obesity, is of the opinion that the obesity is independent of the genital
disturbance. We see almost "quot capita, tot sententiae."

I shall first describe the genital disturbance, as I am of the opinion that
the obesity is given its characteristic expression through the genital disturb-
ance. It must here again be mentioned that the genital disturbance in hypo-
physiardystrophy is throughout not identical with that of acromegaly, as

318 THE DISEASES OF THE HYPOPHYSIS

was formerly assumed to be the case, and which has recently again been up-
held by B. Fischer, Gushing and very recently also by Biedl. We find on the
contrary that the beginning of acromegaly the genital disturbance is exactly
the opposite from what it is in hypophysial dystrophy, and also varies from it
later on in the disease. In acromegaly is found at first even increase of the
generative function, at all events always a marked accentuation of the func-
tion of the interstitial glands or at least no signs of a disturbance. Apart
from rare exceptions, that are becoming even fewer, the condition lasts until
well in the course of the disease. On the contrary we find in hypophysial
dystrophy from the beginning, in addition to the disturbance in the function
of the generative glands, disturbances of the interstitial glands. This is the
more pronounced the younger the individual affected. Moreover, the cases
in which the disease begins in later life are very rare. In them the dis-
turbance of the generative function is more distinct than that of the interstitial
glands, indeed it appears as though the retrogression of the once fully devel-
oped secondary sexual characters only becomes more distinct when atrophic
processes in the other ductless glands, especially the suprarenal cortex, are
added, as happened in the case I reported (Observation XLV). Here indeed
may occur all transitions to multiple ductless glandular sclerosis with its pro-
nounced late eunuchoidism. Aschner mentions that the disturbances of the
function of the sexual glands in animals experimented on are found wholly
pronounced only when the extirpation of the hypophysis has been undertaken
in an animal that is still developing. It seems to me that this does not con-
stitute a contradiction to, but rather an agreement with, the experiences met
with in human pathology.

Clinical experience further teaches us that in hypophysial dystrophy the
genital disturbances may develop fully even if the pathological process is
limited to the hypophysis and entirely intrasellar. I refer to the case of
Maranon or to Observation XLV. If for the existence of the genital disturb-
ance there was necessary a pressure on a center lying in the hypothalamic
region, therefore a forward growth of the tumor, in these cases the occurrence
of the genital disturbance would be as inexplicable as in animal experimenta-
tion after extirpation of the hypophysis. Also in many cases of acromegaly
in which the sellar introitus is dilated, in which growing out of the tumor
leads to visual disturbances, perhaps early, and in which there are manifesta-
tions of an increased brain pressure, we would then find genital disturbances
of the type of hypophysial dystrophy. From all this seems to me to be
elicited the fact that loss of function of the hypophysial function alone can
lead to gential disturbances of the type of hypophysial dystrophy, just as
conditions of hyperfunction of the hypophysis may lead to those of the acro-
megalic type. The results of the operative treatment of hypophysial dys-
trophy throughout — as I already mentioned in 1908 — do not speak against
this supposition. The most essential result consists in the relief of the head-

HYPOPHYSIAL DYSTROPHY 319

aches and an improvement in the visual power and manifestations that are
intelligible as the result of the release of pressure. In some cases are also
observed the occurrence of slight menstrual hemorrhages or of erections.
As far as I know, this improvement in the activity of the sexual glands is
only slight, and may also be explained by the release of the pressure from the
part of the hypophysis that is still capable of functionating.

I must naturally leave open the question of the possibility that through
damaging of centers in the hypothalamic region similar disturbances may be
brought about in genital function, and that in the cases of diseases of the
mid-brain which lead to hypophysial dystrophy, without any essential patho-
logico-anatomical alterations of the hypophysis, the disturbance may per-
haps find its explanation in the fact — and indeed even in such cases does the
position seem to me just as capable of being maintained in discussion as in
the cases mentioned above — that through such processes the function of the
hypophysis is disturbed on account of the characteristic topographic rela-
tions, the more so because in such cases we tend to find also other symptoms
of hypophysial dystrophy, symptoms such as disturbance in growth, raising of
the limit of assimilation of carbohydrates, alterations of the blood picture, etc.

Let us now consider the obesity. The obesity to be observed in cases of
hypophysial tumors without acromegaly shows in respect to the distribution
of fat full analogies with that which is seen in eunuchs arid eunuchoids.
(v. Noorden) . Especially important seems to me the circumstance that even
where there is no obesity proper the abnormal distribution of fat is always
indicated. This holds true almost always, even in markedly cachectic
emaciated individuals. Moreover, we hardly find this distribution of fat
expressed in typical manner unless there is present at least some degree of
insufficiency. Finally I would again point out that in the predominating
majority of the observations reported up to the present the beginning of the
disease occurred in youth. Among the cases that have developed the dis-
ease later are apparently those in which the abnormal distribution of fat is
indeed indicated, but in whom there is otherwise no obesity, but marked
emaciation rather.

The loss of the function of the hypophysis hence seems to lead to obesity
only under certain conditions. Marked cachexia may prevent the occurrence
of the obesity, apart from the suggestion of the abnormal distribution of fat.
As example, I quote the above accurately reported Observation XLV, or
the case of Sokolojj in which a large gumma was found in the hypophysis.
For the most part this seems to be the case in sclerotic processes that involve
not only the hypophysis, but also other ductless glands. In multiple duct-
less glandular sclerosis, we come to recognize the rapidly developing cachexia
as an important symptom; here is found at most a suggestion of the abnormal
distribution of fat, or no obesity, even when the hypophysis is seriously in-
volved (see Chapter XI).

320 THE DISEASES OF THE HYPOPHYSIS

If we assume, as does Aschner, in agreement with Erdheim's hypothesis,
that the higher grades of obesity only come about through the pressure of the
superiorly growing tumor on a center lying in the hypothalamic region, the
occurrence of these in cases in which the process is limited to the sella would
be unintelligible. We would therefore find obesity likewise in those cases of
acromegaly in which the tumor grows out of the sella and leads to marked
eye disturbance. In these diseases, however, obesity belongs to the rarities,
and is even then apparently not of a high grade. Finally, as is even of more
weight, we never find in typical acromegaly an indication of eunuchoid fat
distribution, such as we always find in the dystrophy. Hence it seems to me,
that the obesity depends entirely on the genital disturbance and to be a re-
sidual manifestation of the same. Under circumstances we also find in pure
eunuchoidism an obesity of quite the same type as in hypophysial dystrophy;
the same distribution of fat and in addition the same softness and delicacy of
the skin; here, however, there can be no question that there is no process in
the hypothalamic region.

Also the remaining cardinal symptoms speak for the supposition that the
clinical picture depends on a loss or decrease of function of the hypophysial
apparatus. The reduction in the exchange of gases fits in well with the re-
sults of experimental physiology, as does also the reduction of the excitability
of the vegetative nerves observed in my cases, and also the sluggishness of carbo-
hydrate metabolism. The supposition of Aschner as to the genesis of glyco-
suria in acromegaly is made quite unlikely by the fact that then we would
have to expect glycosuria very much more frequently in intrasellar or
extrasellar tumors without acromegaly than in acromegaly, while as already
mentioned the carbohydrate metabolism shows in all cases the abnormal
sluggishness. The case of Link, with tumor of the hypophysis (without
acromegaly) and diabetes, does not mean anything. An occasional individ-
ual may have degeneration of the insular apparatus and diabetes and also a
tumor of the hypophysis.

Finally the growth disturbance! On a careful review of the literature, I have
been able to ascertain that all cases that begin in youth are associated with a
disturbance of growth, so that in this respect there is an entire agreement
with experimental pathology. I cannot agree with the conjecture of Aschner
that true dwarfism depends on a lessening of the function of the hypophysial
apparatus (see Chapter XII).

On taking into consideration all the facts and convictions set forth above
it is my opinion that to-day we are justified in the assertion that the disease
picture of hypophysial dystrophy depends on a loss or lessening of the function
of the hypophysial apparatus.

Finally the question comes up for discussion as to which part of the
hypophysial dystrophy is to be ascribed to the involvement of the glandular
lobe of the hypophysis and which part to that of the nervous lobe. B. Fischer

HYPOPHYSIAL DYSTROPHY 321

has upheld the opinion that the obesity and the genital disturbances are due to
the involvement of the nervous lobe; Gushing has agreed with him and would
ascribe to the glandular lobe only the growth disturbance. Fischer regards
as the principal support of his argument the similarity of the kind of genital
disturbance in acromegaly and hypophysial dystrophy. I need hardly again
mention that this is not correct. A further support for the view is found in
the known tonic actions of the extracts of the posterior lobe on the genitalia,
and further the circumstance that in certain typical cases of hypophysial dys-
trophy, especially in squamous epithelial carcinoma, the sellar introitus is very
much distended and the nervous lobe is found to be destroyed, while the
glandular part is well retained (for example, case 2 of Bregman and Steinhaus),
although we find a very much larger number of cases in which the glandular
hypophysis has been destroyed by cyst formation, gummas, etc., while the
nervous lobe was found to be intact. The known tonic action of the extracts
of the posterior lobe applies only, as before mentioned, to the nerves of the
uterus, and on the contrary an activating influence on the sexual glands is not
at all known. Against a direct connection of a disturbance of the function of
the posterior lobe with the genital disturbance speaks, however, the following:
It is very probable that the polyurias of longer or shorter duration that occur
so frequently depend on an irritation of the posterior lobe. Now such poly-
urias of long duration are found also in cases with pronounced genital disturb-
ance. If, therefore, we refer the polyuria to a hyperfunction and the genital
disturbance to a falling away of the function of the posterior lobe, we would
not expect to find them both occurring together. In addition polyuria is
found eventually in acromegaly, also in cases with increased function of the
genitalia, or at least with failure of a functional disturbance of the interstitial
glands, hence it is quite independent of the nature of the genital disturbance.

I must consider the question of polyuria somewhat more intimately.
Let us remember that transitory or more permanent polyurias, that eventu-
ally may show the entire disease picture of diabetes insipidus, are found very
frequently in the most diverse hypophysial diseases without acromegaly,
and indeed sometimes in acromegaly, and that the same thing is observed
also in tumors and other diseases of the brain-stem. Very important facts
for the origin of these polyurias are furnished by experimental pathology.
As has been previously presented, there may be obtained from the nervous
lobe of the hypophysis an albumin-free heat-stabile extract that possesses
in addition to its known action on the blood-pressure, exquisite diuretic
characteristics. Schafer states further that the polyuria occurs in the different
classes of animals also after feeding with the posterior lobe. Furthermore,
implantation of the hypophysis causes an increase of the amount of urine
(Crowe, Gushing and Romans} that again disappears after extirpation of the
transplant. Under circumstances the polyuria lasts for several days.

Furthermore, polyuria that may last for many days is very frequent in

322 THE DISEASES OF THE HYPOPHYSIS

operations on the hypophyses, as all later authors agree (Schafer. Pushing
and others). Schafer found a similar polyuria in nonbloody mechanical
or chemical irritation of the hypophysis. All these experiments seem to
indicate that increased production of this secretion through chronic condi-
tions of irritation (pressure, inflammation, etc.) can occasion a polyuria.

On the other hand it is known that in the medulla oblongata and also
further up in the brain-stem, there are found loci, the irritation of which
may cause marked polyuria lasting for days. As is known, Bernard's piqure
is associated with polyuria. If, however, the puncture is done further up,
exclusively, polyuria results.

Hence the conditions are such as the conditions with regard to the genital
disturbance. Extirpation of the hypophysis or destruction of a place in the
subthalmic region lying above the hypophysis leads to genital atrophy; irritation
of the posterior lobe or irritation of a definite place in the brain-stem leads to
polyuria.

Hence one can readily conceive that in tumors or inflammatory processes
in the brain-stem or at the base [of the brain], a continuing condition of irri-
tation may be set up in these centers, and on account of it a transitory or
permanent polyuria.

The following possibilities should be considered: These polyurias may
be always the result of a condition of irritation or of hyperfunction of the
pars intermedia or the posterior lobe, assuming that tumors proceeding
from the glandular hypophysis or from the peduncle, and other lesions,
irritate the posterior lobe for a longer or shorter time, and that disease
processes localized to the brain-stem also influence the hypophysis in like
manner; or all these polyurias may originate through irritation of the
nervous centers lying in the brain-stem; or, finally, it is possible that there
is a nervous connection between those centers and the nervous posterior lobe,
and that irritation of the former spurs on the latter to increased secretion.
The decision of this question is not as yet possible. However, it seems to
me very improbable that the exquisite diuretic action of infundibular ex-
tracts stands in direct relation with the polyurias of the tumors of the hypo-
physis. Also it seems very probable that in processes in the immediate
neighborhood of the hypophysial peduncle, the same series of actions is in
play; naturally we must acknowledge the possibility that such polyurias may
come about through stimulation of centers in the brain-stem, without media-
tion of the hypophysis.

Finally we must consider the questions as to whether there are any
grounds for the fact that also idiopathic diabetes insipidus may be referred to
an increase of function of the pars intermedia. The question has been re-
cently discussed by Frank, among others. As up to the present there are no
pathologico-anatomical findings corresponding to diabetes insipidus — and we
must also not neglect to mention that not enough attention has been directed

HYPOPHYSIAL DYSTROPHY 323

to the hypophysis in this respect — it seems to be worth while to approach the
question by asking whether there exist any essential differences between the
polyurias of idiopathic and of symptomatic diabetes insipidus. Forschbach
and Weber assume that in idiopathic diabetes insipidus the kidneys are
especially sensitive and irritable, so that they react to a diet rich in gram
molecules [molenreich] with more marked diuresis. Talquist and E. Meyer
formulate their opinion by the assumption that the kidneys are incapable
of concentrating the urine. Breuning believes, from a collection of the per-
tinent cases from the literature, that he is able to conclude that (also in symp-
tomatic diabetes insipidus) the kidneys have lost the capacity of concentra-
tion. Also Frank found it absent in his case. I must point out in opposition
to this that this dictum in a general sense does not hold for symptomatic
diabetes insipidus. I refer to Observation XXXVII, in which the specific
gravity of the urine, after several days of vomiting, rapidly rose to 1013.
Also the test in case K, Observation XXXVIII, showed, after increase of
salt to the diet, an increase in the elimination of salt, but during this day
the total amount of urine did not increase. I would here mention some ex-
periments that we carried \put on rabbits. In these injection of pituitrinum
infundibulare produces marked diuresis. When sodium chloride is adminis-
tered at the same time there occurred, in spite of diuresis, an appreciable
increase of the concentration of the urine. Hence it appears to me that we
must leave the question of the genesis of idiopathic diabetes insipidus open.

For the comprehension of the diseases of the hypophysis, a careful con-
sideration of the relations between the hypophysis and the thyroid gland seems
indispensable, so that I shall here enter into a more intimate discussion of
these relations. First some experimental facts. After extirpation of the
thyroid gland in young animals there has been observed an enlargement of
the hypophysis (Gley and others). The enlargement affects the glandular
part. Vacuoles are found in the cells. Conversely, an enlargement of the
thyroid gland occurs after extirpation of a part of the adenoma in acromegaly.
In myxedema the hypophysis has been found to be enlarged; sometimes,
not always. In such cases the enlargement may well depend on strumous
degeneration. On the other hand, Benda has stated that in Basedow's dis-
ease the glandular hypophysis is small. The statements as to the physio-
logical correlations between the two ductless glands evidently do not agree.
Of greater clinical interest seem to me the pathological correlations between
hypophysis and thyroid.

I already have often referred to this question. Thus in endemic cretinism
we have seen that not the thyroid alone, but mostly also the hypophysis is
strumously degenerated. Josefson reports associated hyperplasia of the
hypophysis in a case of congenital struma of the thyroid gland. Also quite
other kinds of processes seem to occur spontaneously in the two ductless
glands. Thus Rosenhaupt reports a case of sarcoma of the anterior lobe of

324 THE DISEASES OF THE HYPOPHYSIS

the hypophysis, in which there was also a similar tumor of the thyroid
gland. We have also seen that in acromegaly, often manifestations of
hyperthyrosis occur, or, especially in the later stages, hyperthyrosis with
corresponding pathologico-anatomical alterations of the thyroid gland.
Moreover, we shall see later that in multiple ductless glandular sclerosis,
the sclerotic process affects almost regularly thyroid gland and hypophysis.
A slight degree of the thyroid gland insufficiency does not seem to be rare
also in hypophysial dystrophy — at least, a myxedemoid puffiness of the face
may be observed, especially in the later stages. Finally, the hypophysis
may degenerate also in the later stages of Basedow's disease. I would sur-
mise this, because in such cases are found characteristic fat-deposits and
swellings of the skin that remind one of myxedema, while the hyperthyrosis
still continues and shows a great sensitiveness against thyroidin.

All this points to the fact of an uncommonly intimate pathological corre-
lation between hypophysis and thyroid gland, that is well adapted for the
complication of clinical pictures.

Differential Diagnosis. — The first question to be decided in the matter of
differential diagnosis is as to whether an existing adiposo-genital dystrophy is
of hypophysial origin, or whether the individual is a eunuchoid; if the latter is
the case, of course all symptoms of brain pressure are absent, and the X-ray
plate shows a sella of normal size. But it should not be forgotten that also
in hypophysial dystrophy, the sellar alterations and the pressure symptoms
may be absent, if gummata, tubercles, or sclerotic processes cause a dis-
turbance of function of the hypophysis. Perhaps also in many cases the
examination of the respiratory metabolism might be used for purposes of dif-
ferential diagnosis. Marked reduction of it would probably only occur when
the case is one of hypophysial dystrophy. Of course, many more investiga-
tions in this direction are necessary. Probably the ossification conditions are
important from the standpoint of differential diagnosis. In primary genital
dystrophy certain epiphysial junctures remain open until high age, and there
occurs tallness and growth beyond the [age] growth limits of normal. In
severe cases of hypophysial dystrophy there occurs, on the contrary, an inhibi-
tion of development in the occurrence of the bone-nuclei and also dwarfism,
and the epiphysial junctures apparently remain open less long.

The differential diagnosis from tumors of the pineal gland may be at-
tended with difficulty. In the cases of pineal gland tumor that begin in early
life the diagnosis is easy, as here is also found a premature development of
the genitalia. But even in youthful cases, the tumor of the pineal gland
may under circumstances restrict the function of the hypophysis, so that the
picture may become admixed with features of the hypophysial insufficiency
(see the case of Raymond and Claude, in the chapter on the epiphysis).

Also the distinguishing of hypophysial dystrophy from multiple ductless
glandular sclerosis may present difficulties, as there exist cases that are

HYPOPHYSIAL DYSTROPHY 325

associated with marked cachexia. This we saw, for instance, in case G
(Observation XLV). Very marked retrogression of the genitalia and of the
secondary sexual characters leads one to think of associated involvement of
the suprarenal cortex. Attention should also be especially directed to myx-
edematous skin alterations and to pigmentations, hypotonia, and reduction in
the amount of sugar in the blood. When these symptoms are present, we
should consider the associated involvement of the thyroid gland or of the
chromamn tissue. In an adiposo-genital dystrophy of hypophysial origin,
the exact differentiation of the processes that lead to an impairment of the
hypophysis is often very difficult or impossible; and yet this would be of
great practical importance for the indications for operation. Here the X-ray
examination furnishes important information.

Tumors that proceed from the hypophysial apparatus itself, deepen, when
they lie intraseliarly, the floor of the sella. If they proceed from the hypo-
physial duct they dilate chiefly the sellar introitus, but can also, if they are
large, deepen the floor of the sella. An intracranial process chiefly sharpens
the clinoid processes to a point (Erdheim, Schuller) . Later it may erode them.
Then the X-ray would readily lead to faulty conclusions; in such cases ero-
sions are mostly found, however, in other places. Exceptionally a similar
destruction — here I follow the dissertation of Schuller — may be produced by
an aneurysm of the carotid artery, by an endothelioma of the dura mater, or
by basal tumors of the middle fossa of the skull. In tuberculous caries or in
primary tumors of the body of the sphenoid bone, the infiltration of the
sphenoid bone is shown in the X-ray plate, thus enabling differentiation.
Finally the clinoid processes may be eroded and sharpened from behind by
tumors of the cerebello-pontiie angle. The finer details of the bone erosions
are alone of value for the X-ray diagnosis, for as Schuller mentions, the
tumors themselves are only visible in the X-ray picture when they calcify or
when they penetrate in one of the pneumatic cavities of the skull. Apart
from the X-ray examination, the presence of early pressure symptoms on the
part of the more distant cranial nerves or symptoms of a hydrocephalus
speak against the primary involvement of the hypophysial apparatus.

Treatment. — To-day operation stands in the mid-point of therapy.
Schlojjer and v. Eiselsberg in the cases of v. Frankl-Hochwart, O. Hirsch, and
Gushing first carried out operation in hypophysial adiposo-genitalis, with
partial good results. The methods now used are all intracranial. Sckloffer
and v. Eiselsberg made a path to the hypophysis by making a flap of the nose,
O. Ilirsch by operating endonasally. The result consisted at all events chiefly
only in the combating of the symptoms of brain pressure; the tormenting
headaches disappeared, and the visual power improved, but only in few cases
did there result in addition a recession of the dystrophic manifestations, and
did the patients lose some kg. of their fat; in certain cases hair even disap-
peared on the pubis and in the axillae; in one case erections occurred, in

326 THE DISEASES OF THE HYPOPHYSIS

another a slight menstrual hemorrhage was observed some months after the
operation. The improvement in the blood picture after operation is notice-
able in Observation XXXIV. Also the mental condition changed, and the
patient was much more impressionable. Even the combating of the pres-
sure symptoms alone and the saving from complete blindness might in
themselves be regarded as a striking result; extreme care must always be
taken in considering the indications for or against operation. Apart from
the danger of the operation we should consider that the surgeon should not
remove just that part of the hypophysis that functionates, thereby increasing
the dystrophic manifestation and eventually bringing on a cachexia. The
operation is therefore only indicated in tormenting symptoms of brain pres-
sure or in rapid increase of the visual disturbance. The tumor tissue can-
not be radically removed by any of the methods named. Therefore no case
without relapse.

The conception of dystrophia adiposo-genitalis as hypopituitarism leads
us to expect results from a therapy by administration of hypophysial sub-
stance. Levy and Rothschild, Axenfeldt and Delille, as well as Cushing, claim
to have seen good results. In one case I also saw a striking improvement.
Leman and van Wart after the administration of hypophysis tablets saw a
growth of hair on the torso. The tumor symptoms (hemianopsia, etc.) are
naturally not improved by this treatment. Thyroidin may be used with
effect against the obesity. In cases with marked tormenting symptoms of
cerebral pressure in which a radical operation is not possible or does not seem
advisable, palliative trephining or Anton's "Balkanstich" [puncture of the
corpus callosum] brings relief. Finally it should be mentioned that Beclere
saw improvement of the visual disturbance after X-ray irradiation.

Therapeutic Use of Hypophysis Extracts. — While in the treatment of hypo-
physial diseases even the use of preparations from the hypophyses of animals
has not as yet won general recognition, yet the extracts from the pars inter-
media or the posterior lobe of the hypophysis, pituitrinum (pituitrinum
infundibulare is a preferable designation) have rapidly acquired a place in
gynecology and obstetrics. The investigations of v. Frankl-Hochwart and
Frohlich have justified our using them in postpartum bleedings. Foges and
Hofstatter in Vienna and simultaneously Bell in England first reported the
favorable influence on hemorrhages after labor, in which the tendency of the
uterus to contraction was heightened by the preparation. The agent may be
used intramuscularly as well as intravenously (1—2 cc. in 20 cc. physiological
salt solution) (Hofbauer). In the numerous experiments of Foges and others,
it was found to be entirely harmless. The agent is especially valuable for
Cesarean section. Lately its use has been commended for hemorrhage from
the nongravid uterus . (Bab). It is also recommended in postoperative
paresis of the bladder (Hofstatter). The voluminous literature pertaining to
the subject is found in the works of J. Novak and of C. Heeke. Finally there

ADDENDUM 327

are statements as to the treatment of osteomalacia with pituitrinum infun-
dibulare (Bondi, Pal, Bab, Neu}. Its use as a cardiac and vascular tonic has
not as yet been tested. As when it is injected subcutaneously in man it can
increase blood-pressure not inappreciably and for a long time, tests in this
direction seem to me very desirable, the more so as disagreeable by-actions are
very much rarer than when adrenalin is used. As pituitrinum infundibulare
increases the respiratory metabolism, Bernstein and / have tried it in one case
of adiposity, without result.

Pituitrinum glandulare has been tested but little. Very interesting is
the statement of Pal that two cases of osteomalacia that were treated with
extract of anterior lobe (Parke, Davis & Co.) improved essentially.

Addendum

The subject of acromegaly, always an interesting one, has been so
thoroughly dealt with by the author, and so much has been written about
it, especially in this country, by Cushing, that the editor feels he has nothing
to add. The author is perhaps a trifle misleading in the portion of the
chapter that deals with hypophysial dystrophy, conveying the impression
that all cases of pituitary tumor that cause this affection are associated
with the characteristic fat distribution. Whether this is so is "questionable,
although authors who have reported such cases do not always take pains
to deny that such a distribution is present, v. Frankl-Hochwart himself
did not find it in the case reports that he reviewed, and in some of these
reports an emaciation was spoken of. In eleven of his own cases it was
present pronouncedly in eight, and was only suggested or indicated in three.
v. Frankl-Hochwart points out that the cases more nearly approach the
classic types the earlier in life the disease sets in.

Wolf stein in reporting a case of hypophysial tumor calls attention to the
importance of bitemporal hemichromatopsia in the early diagnosis. In this
author's case the pubic and axillary hair did not fall out, although there
was a sudden cessation of menstruation.

Sweet and Allen have done apparent total hypophysectomy in dogs, with
characteristic changes in the animals but not death. They believe that in
the dog the entire gland can be removed without danger to life.

Recent experiments of Herring make it appear as though there are two
separate active principles in the posterior lobe of the hypophysis. It is
probable that the active principle of the posterior lobe is a product of the
epithelial cells of the pars intermedia, and that there are in the pars nervosa
certain products of the breaking down of these cells. The substance acting
upon the uterus is formed at an early stage in the cells of the pars intermedia,
but the substance acting on the blood pressure and kidney is a later product

328 THE DISEASES OF THE HYPOPHYSIS

resulting from the breaking down in the pars nervosa, of the hyaline bodies,
or the disintegrating pars intermedia cells.

Gcetsch has recently ascertained, as the result of numerous experiments,
that extract of anterior lobe of pituitary body (representing pituitrinum
glandulare), when fed to young rats, has a stimulating effect upon the growth
of the animal and upon its sexual development and activity. Posterior lobe
extract (representing pituitrinum infundibulare), when given in the same
manner, has a retarding influence.

Oppenheim calls attention to the fact that both tabes and general paralysis
may be closely simulated by pathological processes affecting the hypophysis.
Among the effects of such processes may be a simple optic atrophy and
evidences of true posterior column degeneration. These symptoms have
nothing to do with the presence of the tumor per se, that is, they are not due
to pressure, for instance, nor are they due to a true tabetic or paretic process,
but are due to the alteration (quantitative or qualitative) of function of the
ductless glands.

REFERENCES

Gushing (H.}. Pituitary body and its disorders. Phila. and London, J. B. Lippincott
Co., 1912.

Gushing (H.). Concerning the symptomatic differentiation between disorders of the
two lobes of the pituitary body; with notes on a syndrome accredited to hyperplasia of the
anterior and secretory stasis or insufficiency of the posterior lobe. Am. J. M. Sc., March,

1913, PP- 313, 328.

v. Frankl-Hochwart (L.}. Die Diagnostik der Hypophysistumoren ohne Akrome-
galie. Wien. med. Wcnsch., 1909, 37, p. 2127, 38, p. 2297, 39, p. 2326, 1909, 37, p.
2127, 38, p. 2257.

Wolf stein (D. J.}. Tumor and clinical pathology of the hypophysis. Lancet-
Clinic, Vol. CVIII, Oct. 5, 1912, pp. 365-373.

Sweet (J. E.} and Allen (A. R.}. The effect of removal of the hypophysis in the
dog. Annals of Surgery, 58, 1913, p. 485.

Herring (P. T.). The physiological activity of the pars intermedia and pars nervosa
of the ox pituitary quantitatively compared. Quarterly journal of Physiology, Vol. VIII,
19, pp. 267-274.

GcEtsch (.E.). The influence of pituitary feeding upon growth and sexual develop-
ment. An experimental study. Bulletin of the Johns Hopkins Hospital, Vol. XXVII,
No. 300, Feb. 1916, p. 29-50.

Oppenheim (H.). Uber Vortaiischung von Tabes und Paralyse durch Hypophysis-
tumoren (Pseudotabes pituitaria, etc.). Ztschr. f. d. ges. neurol. u. psychiat., i, 1914,

xxv, pp. 527-535-

CHAPTER VII

THE DISEASES OF THE EPIPHYSIS (GLANDULA PINEALIS,
"ZIKBELDRUSE") [CONARIUM]

Anatomy and Embryology. — The epiphysis originates from an extrusion
from the roof of the third ventricle. About the fifth month of fetal life there
develops between the posterior commissure and the habenular commissure
a thin epithelial extrusion that later thickens and penetrates the mesodermal
tissue. The epiphysis in many of the animal classes, for instance the reptiles,
is very well developed, and in the developed human being it constitutes a

..•
• %,- -* • ^- '^-v-i. *-_ : /•:•

: - \'\ .• ./" \- f •>•• >;:*..;:«: v:;; ;-^:

r- -- •• : - • •-*' - "

. .,

'..'• -:OVv-:^'; ••!*.-.:.. . '*V::.!.'v:?.

•; . .' ••'•.-:.-» '•..'••.. XV^- • /"v.-'--

*'. ..." "".'..•*•';'*••. •-.••' • ','.'•'-"".:':

v* • • .*. .•*•'.'*. -.'*•.*"/.'•;. '.'••'•"."'

FIG. 63. — Epiphysis of rrtan.

flat body that arches forward, about i cm. long and 0.5 cm. broad, which by
the dorsal lip comes into connection with the habenular commissure and by
the ventral with the posterior commissure. Between the two lips the recessus
pinealis extends from the third ventricle into the gland. In the new-born it
is more spherical, and contains regular follicles with polygonal cells, and,
toward the recess, glial tissue. Commencing with the seventeenth year there
begin signs of involution, increase of the connective tissue and glia; the fol-
licles sometimes form cysts or contain concrements, the so-called brain sand.

329

330 THE DISEASES OF THE EPIPHYSIS

Pathological Anatomy. — The diseases of the epiphysis known up to the
present time consist chiefly in cyst formations, gummata, and tumors.
Neumann has collected twenty tumors from the literature and adds two of his
own; they were sarcomata, carcinomata, teratomata, gliomata, psammomata,
and cysts. The individuals affected were chiefly youthful so that, as Neumann
supposes, the underlying factors might well be chiefly developmental an-
omalies; these are very much more frequent in the male sex. The terato-
mata contain hair follicles, sebaceous glands, cartilage, fat, smooth muscle
fibers, etc. (Weigert and others).

Symptomatology/ — The symptoms that are produced by these lesions
of the epiphysis are on the one hand local symptoms, on the other hand char-
acteristic trophic disturbances. The first are caused by the pressure of the
enlarged organ on the neighboring brain structures (thalamic and subthala-
mic regions, pulvinar, pons, cerebellum, corpus callosum, etc.), and through
congestion in the brain ventricle. If the tumor grows backward, congestion
in the fourth ventricle occurs on account of closure of the aqueduct of
Sylvius; if it grows forward, there occurs hydrocephalus of the third and
lateral ventricles. The pressure symptoms consist in motor symptoms of
irritation or paralysis, ophthalmoplegias, conjugate deviation, alteration of
the pupillary reactions, nystagmus, ataxia, epileptiform convulsions (mostly
bilateral) , pareses, rigidity of the neck, choked disc, or more rarely genuine
atrophy, difficulty in hearing, vertigo, headaches, vomiting and eventually
slowing of the pulse, lethargy, symptoms that are common also to all the
tumors of the quadrigemina.

In addition to these symptoms there occur, if the tumor develops in early
childhood, characteristic trophic disturbances that consist in an abnormally
rapid bodily development and in a premature development of the genitalia,
and are uncommonly similar to those which we shall consider under adeno-
mata of the suprarenal cortex. To this group belong the cases of Ostreich-
Slavyk, Ogle, Marburg, v. Frankl-Hochwart, and Raymond and Claude.
Throughout the cases were those of children under ten years of age.

In the case of Ogle, the premature development of the genitalia was very
considerable. It was the case of a six-year-old boy who died with the mani-
festations of a brain tumor. Lately the boy had masturbated. The penis
was developed h'ke that of a seventeen-year-old youth. There was an abun-
dance of hair on the mons veneris. The testicles were apparently not en-
larged. Autopsy showed an alveolar sarcoma of the pineal body. The case
of Ostreich-Slavyk was that of a four-year-old boy who from the third year of
life had shown a striking body development; the penis was 9 cm. long, the
genitals were covered with hair i cm. long. The boy was 108 cm. tall and
weighed 20 kg.; these measurements correspond with those of a seven- to
eight-year-old boy. The mammae were hypertrophic and contained colos-
trum. At the beginning also voracious hunger existed, but later this

SYMPTOMATOLOGY 331

disappeared. The case was also described by Heubner. The case of v.
Frankl-Hochwart was that of a fi ve-and-one-half-year-old child, whose body
length corresponded to that of a nine-year-old boy; the development of the
penis and of the entire genitalia and the secondary sexual characters cor-
responded with those of a fifteen-year-old boy; frequently erections oc-
curred. The voice was deep, and in addition there was a premature mental
development (thoughts about the immortality of the soul); also Ostreich-
Slavyk designated the four-year-old boy described by him as "old- wise"
[altklug].

In most cases the conditions of nutrition were started to be very good. In
other cases — apparently in those which develop later — there occurred an
excessive adiposity. So for example is the case of O. Marburg; here we are
dealing with a nine-year-old girl, in whom
right at the beginning of the disease (eight
months ago) obesity developed, that finally
became excessive, especially on the breast
and abdomen. Autopsy showed a complex
tumor of the epiphysis consisting of tissue of
the pineal gland, the ependyma, the choroid
plexus, and of glia. In addition to this was
found a slight colloid thyroid gland struma,
and a slight status lymphaticus; the genital
glands and the hypophysis were normal.

Also in the case recently described by Bailey

J J ^ ternal genitalia ot a lour-and-one-

and Jelli/e, that of a twelve-year-old boy, half-year-old boy, 123 cm. tall (penis
there was obesity; the genitalia were normal. 6 cm. long, hair on the mons
Autopsy showed a teratoma of the pineal y/nfris)' accor*incs*° »•/'"'**•

Hochwart, Ztsch. f. Nervenh., 1900.

gland.

In the epiphysial tumors that up to the present have been observed in
adults and adolescents there occurred either no especial trophic manifesta-
tions (for example in the case of Neumann, twenty-seven-year-old man, or in
the case of Askanazy, nineteen-year-old man) or the trophic manifestions
were quite of a different kind. Here there occurred either adiposity, which,
as in M tiller's case may attain an excessive degree (increase of 55 to 79.5
kg. in weight) ; other cases of adiposity in pineal gland tumor or of tumors
that destroyed the pineal gland have been described by Coats, Daly, Falckson,
Kny, Konig, Nothnagel, and others. Or in other cases there develops a strik-
ing cachexia in which the skin may show a pasty consistency. In certain
cases polyuria has been observed, in others persistence of the thymus gland,
in the case of Neumann formation of a goiter. There may also occur atrophy
of the genitalia and of the mammae.

The significance of all these trophic manifestations is not yet clear. As far as the pre-
mature development that occurs in childhood is concerned, the great morphological

332 THE DISEASES OF THE EPIPHYSIS

difference in the tumors may be explained by the fact that they represent the failure or
insufficiency [of function] of the epiphysis. We should therefore understand that nor-
mally in childhood inhibitory influences on development proceed from the pineal gland,
which gradually fall away or become slighter with the partial involution.

This view has been especially developed by Marburg. Marburg believed
that hypopinealism leads to premature development of the genitalia, hyper-
pinealism to universal obesity and apinealism to cachexia. The interpre-
tation of adiposity as hyperpinealism is no longer held to be correct, even
by Marburg. It may very well come about through disturbance of the hypo-
physial function; one may see very well that the pineal gland tumors may
behave in this respect just like other processes that increase cerebral pressure,
the more so because on account of their position they lead to stagnation in
and dilatation of the third ventricle. The interpretation of the premature
development as hypopinealism has recently been supported by animal ex-
perimentation. Exner and Boese could not indeed observe a premature
development after extirpation of the epiphysis in young animals. C. Fod,
however, saw after extirpation of the epiphysis in young fowls a premature
and extraordinary development of the testicles and some of the secondary
sexual characters. Extirpation of the sexual glands in youth produces in
male and female animals atrophy of the epiphysis (Black and Hulles).
Askanazy believes that every embryonal teratoma is to be regarded as a
sort of pseudopregnancy that should lead to a premature maturation and a
premature development of the genital sphere, a view that Hart accepts, while
Pappenheimer opposes it. I do not regard it as impossible that the trophic
influences of the pineal glandular tumors in early life go over the suprarenal
cortical system, [hyperplastic development of] which also leads to premature
maturation and premature development of the genitals (see the following
chapter) .

At least it should be noticed that in one case Raymond and Claude found
hyperplasia of the suprarenal cortex. I will quote this interesting case in
greater detail. It was that of a ten-year-old boy. The disease began in the
seventh year of life with gradual blindness and increasing adiposity. The boy
at the age of ten years was 138 cm. tall (about corresponding to a thirteen-
year-old boy) and weighed 39 kg. Much fat had accumulated, especially on
the abdomen and on the hips. The pubic hairs were well developed and there
was a foreshadowing of a beard on the upper lip. Penis and testicles were
small. Histologically the testicles showed no spermatogenesis, but the inter-
stitial glands were very well developed. The less strong predominance of
the premature genital development could in this case have been brought
about through a restriction in the function of the hypophysis; for the epiphy-
sial tumor, which was the size of an apple, had led to a marked dilatation
of the lateral and the third ventricles and to a marked flattening of the
hypophysis.

ADDENDUM 333

The diagnosis of epiphysial tumors in adults is hardly possible, as the
symptoms produced are hardly to be distinguished from the tumors of
the neighborhood of the corpora quadrigemina.

According to Marburg the possibility of an epiphysial tumor should be
thought of when there occurs associated symptoms of initial headaches —
especially of the occipital region — early choked disc, vertigo, sleeplessness,
convulsions, later, somnolence, paralysis of the eye muscles associated with
ataxia (Nothnagel) , and disturbances in hearing. What makes the diagnosis
the more difficult is that epiphysial tumors, as above mentioned, also lead to
dystrophia adiposo-genitalis, probably through limitation of the function of
the hypophysis. On the contrary, the diagnosis in childhood is possible,
through the combination of general brain tumor symptoms and those of
quadrigeminal lesion with those of premature development of the body, the
psyche, and the genital sphere, and was first made in vivo by v. Frankl-
Hochwart. The treatment by operation has not as yet been tried.

Addendum

Jordan finds no clear histological evidence indicative of a glandular func-
tion of the pineal body, and that if the pineal body in the sheep subserves an
important physiological function, this is probably active only 'during the first
eight months of postnatal life. Pineal bodies of sheep older than one year
present much variation and degeneration.

An editorial in the Journal of the American Medical Society, Vol. LXVI, No. 5,
Jan. 29, 1916, p. 361, calls attention to the stimulating effects of pineal gland extracts
when administered to young animals, and to negative results following extirpation of
the pineal gland. The literature dealing with the material of this apparent incon-
gruence will be found in conjunction with Walter E. Dandy's article : Extirpation of the
pineal gland, Journal of Experimental Medicine, Vol. XXII, No. 2, Aug. i, 1915, p.
237-247.

Jordan (H. £.). The histogenesis of the pineal body of the sheep. Am. J. Anat.,
Vol. XII, 1911-12, pp. 249-270.

Anatomy and Embryology. — The suprarenals are paired organs, that rest
hook-like on the upper pole of the kidneys. Their breadth according to
i). Neusser and Weisel, is about 40-50 mm., their height 30-35 mm., their
thickness 2-8 mm., their weight averages 10.6 gm. in women and n.6 gm. in

Z.gi.

Cor.

Z.r.

FIG. 65. — Suprarenal gland of man. C. = capsule, Cor. = cortex, M. = medulla, Z.gl. = zona
glomerulosa, Z.f. = zona fasciculata, Z.r. = zona reticularis.

men. They are made up of two embryologically independent parts, the cor-
tex and the medulla. The so-called intermediary zone belongs to the cortex.
The cortex is made of columns of cells, which cells are filled with glistening
granules, most doubly refractile, of a lipoid character. The medulla con-
tains numerous nerves and multipolar ganglion cells, and in addition nests

334

ANATOMY AND EMBRYOLOGY 335

of cells, which take a brown color when they are stained with chromic acid,
and a green stain with iron chloride. They are termed chromaffin cells.

From the arteries of the diaphragm, from the aorta, and also from the renal artery, re-
spectively, are given off a branch to the suprarenal glands. These form subcapsularly an
anastomosis, frorn which the cell columns of the cortex are surrounded by a fine capillary
network, and which also continues into the medulla; moreover there are the so-called
arteriae perforantes, which run through the cortex and first form a capillary network in
the medulla. The suprarenal veins empty into the vena cava.

True accessory suprarenals that are made up of cortex and medulla are
rare. On the contrary accumulations of chromaffin tissue may exist outside
the suprarenals. The larger have been termed " par aganglia " by Kohn.
Such cell accumulations are found on the carotid artery, in the ganglia of the
sympathetic trunks and in the solar plexus, in the left stellate ganglion, on
the site of giving off of the left coronary artery and superior mesenteric, at
the hilus of the kidney, and along the course of the sympathetic nerves
(Zuckerkandl, Kohn). In the adult the total amount of the extramedullary
chromaffin tissue is not smaller than the medullary part; in the new-born
it is greater. Accumulations of cortical substance can be found at the hilus
of the kidney, in the renal substance itself, along the suprarenal veins, and
in the internal genitalia. Schmorl found them in 92 per cent, of cases, Weisel
in the genitalia of new-born boys in 76.5 per cent. Aichel found them never
absent in the broad ligament of new-born girls. Some of these, also, later
retrogress.

Embryological and phylogenetic studies agree with the anatomical that
the suprarenal apparatus consists of two independent systems which in the
lower classes of animals are arranged segmentally and remain separated per-
manently. The chromaffin or adrenal system is of ectodermal origin and is
part of the sympathetic.

Already at a very early period the primitive cells separate into two differ-
ent forms, into the primitive form of the sympathetic nerve cells and into the
so-called phaeochromoblasts, from which the chromaffin cells originate. The
cortical tissue — the so-called interrenal system — develops from the ventral
part of the mesoderm and indeed quite in the neighborhood of that place of
the celomic epithelium from which the sexual glands originate; suprarenal
cortex and sexual glands are laid out in the Wolffian duct, which explains the
topography of accessory suprarenals consisting in cortex alone along the
entire way that the sexual glands travel, indeed even in the sexual glands and
kidneys themselves (Soulie). During fetal life the suprarenal is at first
larger than the kidney, and at birth is about the same size. Already at an
early period some of the chromaffin cells have broken through the complex of
cortical cells to form the medulla. Through the descent of the genital
organs small parts of both systems are displaced. This shows that the
former complete physiological independence of both systems later gives place

336 THE DISEASES OF THE SUPRARENAL APPARATUS

to a common function, at least in part (Biedl), which fact is also indicated by
the previously mentioned relations of the blood-vessels. It is indispensable
for the comprehension of diseases of the suprarenals to consider that the two
systems for a great part are functionally independent. The higher we go in
the classes of animals, the greater become the complexes of the two systems
that finally unite to form a single organ, the suprarenal.

a. Conditions of Hypofunction of the Suprarenal Apparatus
i. Addison's Disease

Definition. — In the year 1855 Thomas Addison described the disease that
bears his name. The disease mostly develops in the third or fourth decades of
life, usually quite insidiously, with adynamia and apathy. To these are added
disturbances of the digestive tract (constipation, often alternating with diarrheas)
and pigmenting of the skin and the mucous membranes; the patients succumb
under a gradually increasing cachexia, not rarely with stormy terminal mani-
festations; autopsy almost always shows disease of both suprarenals, mostly
tuberculous caseation. Addison's description embraces all the essential
features.

Symptomatology. — The disease affects mostly individuals, often heredi-
tarily inclined to tuberculosis, who have been weakly from youth. Mostly
it is individuals of middle age who are affected, rarely are children or old
people affected. Almost always the disease manifests itself in ready fatiga-
bility, disinclination for work, and apathy; to these symptoms are sometimes
added headaches, poor sleep, sometimes obstinate insomnia, psychical ill-
humor and depression, often too, abnormal irritability; further, diminution
in memory, noises in the ears, vertigo and commonly fainting attacks,
singultus, and rheumatoid pains in the back and in the extremities, sometimes
also epileptiform convulsions. Extremely stormy manifestations on the
part of the nervous system may, especially in the later stages, make their
appearance — violent delirium, acute confusion, convulsions, deep stupor, and
coma. The symptoms on the part of the digestive tract are very various.
The patients complain about pressure in the stomach, eructation, nausea,
pyrosis, sometimes vomiting and epigastric pains. In the later stages there
are mostly lessening or absence of the hydrochloric acid and ferment produc-
tion. Often diarrheas alternate with constipation. The diarrheas may
occur in crises with great violence, may be associated with spasms of the
calves and may simulate the picture in cholera nostras. In the terminal
stages there is often immitigable vomiting. To this may be added ab-
dominal pains and constipation; the abdomen is retracted, the abdominal
walls are tense, the pulse becomes small, in short, there exists the picture of
peritonitis (Ebstein).

In the later stages the adynamia becomes prominent. Early the pulse is
strikingly small and soft, the blood-pressure reduced, the force of the pulse

ADDISON S DISEASE 337

lowered (Munzer). Dyspnea ensues on slight physical exertion. Edema is
almost never observed, even later. Arteriosclerosis is extremely rare; when
it is present, the rise in blood-pressure does not occur.

The blood picture always shows changes. The count of erythrocytes
and the hemoglobin contents are almost always reduced, the leucocyte count
is mostly normal. Lymphocytosis was first observed by v. Neusser. In
the cases from the literature in which the leucocytic formula is given, espe-
cially in the cases of Bittorf and Munzer and in those described by myself,
lymphocytosis was always present. Hypereosinophilia is not constant.
Moreover the number of large mononuclear cells is often increased, and the
number of neutrophilic cells relatively and absolutely much diminished, some-
times to 40 per cent. Commonly there are found in additionsigns of a status
lymphaticus; swelling of the glands, the tonsils, the papillae at the base of the
tongue, etc. Also hyperplasia of the thymus was observed in some cases
(Weisel, Kahn, Hedinger).

Of alterations of the metabolism should be mentioned especially the
falling off in weight. . In very rare cases only is observed corpulency lasting
until death (Bittorf). Investigations as to the fundamental exchange are
not known to me. The gastrointestinal disturbances may very well cause
the emaciation. The few investigations as to the protein metabolism are
too short as to time. Wolf and Thacher found the endogeneous uric-acid
elimination very low. In three cases of Addison's disease, Eppinger, Rudin-
ger, and / found very high tolerance for grape-sugar and absence of glycosuria
after injection of adrenalin. Also in a case of Pollack's there was no sugar
after 2 mg. adrenalin. Later O. Forges found pronounced hypoglycemia (up
to 0.033 Per cent.) while in other cachexias the blood-sugar picture lay nor-
mally high. The finding of Forges that was corroborated by Bernstein in
several cases, has therefore come to have a diagnostic value attached to it.
The body temperature is often reduced, but when the manifestations become
violent there may be found sudden increases in temperature, even to hyper-
pyretic values.

The making use of the diet is, so far as there are no diarrheas, normal;
frequently there is indicanuria. In the later stages are found very frequently
disturbances of the genital function, deficiency or absence of menstruation,
in men diminution or loss of sexual power.

The pigmentations that are so important from a diagnostic point of view
mostly begin on the uncovered parts of the body, or on parts where the
clothing presses, or on parts on which certain irritants, for instance plaster,
have exerted their action. Sites of especial predilection are the borders of
the lids, the areoke of the nipples, the linea alba, the genitalia, the anal folds,
the folds of the palm; otherwise the palms, the soles and the nail beds usually
remain free. In many cases too the hairs become darker. The pigmented
places are light brown to dark brown, and in many cases the entire body may

338 THE DISEASES OF THE SUPRARENAL APPARATUS

assume a bronze tint. Pigment displacements are less frequent. The pig-
mentations of the mucous membranes are almost always spot-like and
blackish-blue. They are found on the borders of the lips, on the mucous
membranes of the cheeks, on the soft palate and on the border of the tongue.
Pigmentations of the vaginal and rectal mucous membranes are also observed.
The skin pigment lies in the deeper layers of the rete Malpighii and is iron-
free. In rare cases there is observed also a combination of Addison's disease
with hemochromatosis (Fod, Bittorf, and others). The pigmentation is ex-
traordinarily frequent. In the statistics of Lewin, based on five hundred
sixty-one autopsied cases, it was found in 72 per cent., and Bittorf believes
that these figures are too low.

The course of Addison's disease is very manifold. There are peracute
cases in which destruction of suprarenal is brought about by hemorrhages,
thrombosis, etc.; in these cases death may occur in a few days with stormy
cerebral and intestinal manifestations. Pigmentation is absent.

A short time ago Brodnitz reported an interesting case which I shall repeat
in detail. It was that of a thirty-six-year-old, strongly built, markedly fat
man, previously healthy. Two and four years ago there suddenly occurred
violent intestinal colics, which ceased after a few hours, and were followed
only by a marked loss of strength. Also at present such a colic has come on
quite suddenly. The facial expression is anxious, the pulse hard and full,
50-60 beats per minute, the temperature normal or slightly subnormal. No
improvement on injection of morphine. This condition lasted two days and
was then followed by an operation. On the jejunum and ileum were found
columnar contractions of 10-20 cm. of the intestine at three places. Other-
wise conditions were normal. In the course of the fourth day manifestations
of peritonitis made their appearance. Tympanites appeared, the pulse was
soft, thread-like, very rapid. Vomiting, temperature increased to 39°C.
Death on the fifth day. At autopsy was found marked inflation of the
stomach and duodenum, the small intestines, and the colon. No peritonitis.
Complete destruction of the right suprarenal, partial destruction of the left.
On microscopical examination the left suprarenal at one place showed marked
development of the connective tissue, with hemorrhagic pigment, in brief
signs of a previous hemorrhage.

As a further example I cite the case of Karakaschejf. A young man of
eighteen years became sick suddenly with pains in the head and abdomen
and felt very ill, but nevertheless went about. The manifestations became
stronger only after three days, when vomiting ensued, and finally loss of con-
sciousness. Autopsy showed old total destruction of the right suprarenal,
apparently through thrombosis and a quite fresh infarction of the left supra-
renal. Death had occurred five days after the beginning of the illness.

In other cases the affection lasts for weeks. Here the adynamia comes
more in the foreground. In the case of Straub there developed within two

ADDISON S DISEASE 339

weeks asthenia, adynamia, pigmentations that were iron-free, and only a
slight depression of the blood-pressure. Also psychic disturbances (at first
more excitement, then apathy) made their appearance. Autopsy showed
a scirrhous carcinoma of the pylorus with metastases into the retroperitoneal
tissue, especially at the hilus of the left kidney, into the lungs and pleura, and
bilateral thrombosis of the suprarenal. The older of these could very well
have occurred simultaneous with the beginning of the Addison's disease.

Moreover, sometimes in the subacute cases there is observed graded
[schubweises] occurrence of the stormy manifestations. Chronic Addi-
son's disease mostly shows remissions, in which also the pigmentation may
retrogress. Cases that have lasted ten years are on record. As the remis-
sions may have lasted for years, we must be cautious as to our assertions
that an individual case has been cured.

Such individuals with chronic Addison's disease are for the most part
very labile; physical exertion, excitements or slight complicating affections
may lead to a fatal collapse.

As an example of the chronic course, I cite the following case:

Observation XLVI. — H. K., forty-two years. Entered the clinic Nov., 1911. No
tuberculous taint; the family, however, shows the presence of gout. The illness began
ten years ago, when a gradually increasing brown coloration of the skin became ap-
parent; during the first years the coloration was extraordinarily intense, the greater part
of the skin, but especially that of the face, the neck, hands and forearms being deep
brown — a bronze color. Since that time the brown coloration has persisted in varying
intensity. At that time the patient spent a year at Davos, as the lungs had become
affected. Ten years ago an attack of articular rheumatism that affected especially the
joints of the feet and toes. Since that time several attacks, two or three times a year,
in which the most different joints are involved. At present such an attack is in prog-
ress after an interval of some years. Loss of 12 kg. weight during the last half year.

On examination, it was found that the skin of the whole body shows a brown colora-
tion, which is especially intense on the extensor surface of the forearm, on the backs of
the hands, on the face and neck, and on the genitalia and inguinal region. The brown
coloration is partly diffuse, partly more circumscribed in spots, the individual spots at-
taining the size of a lentil. Mucous membranes of the lips, mouth, and throat show
numerous mustard-seed-sized, irregularly limited brownish-black spots, which are espe-
cially distinct on the mucous membrane of the cheeks. The mucous membranes are
pale, the skin is dry, the percussion sound over the left pulmonary apex is shortened, the
vesicular murmur weakened; no rales. The cardiac dulness is rather small, the heart-
sounds are clear, the blood-pressure, according to Gartner, 60, liver and spleen not enlarged.

Several joints are reddened, swollen and painful, especially both knee-joints, right
great toe-joint, left ankle-joint, left shoulder-joint, right elbow-joint and left hand-joint.

No uric acid demonstrable in blood.

Traces only of albumin in the urine.

Temperature up to over 38°.

Estimation of sugar in the blood (Bernstein} 0.067 per cent.

Leucocyte count normal (8 per cent, eosinophiles). We are here dealing with the
chronic Addison's disease, that has existed for ten years and that shows long remissions.
During the last years the condition is apparently rather stationary, lately a new exacer-

340 THE DISEASES OF THE SUPRARENAL APPARATUS

bation (reduction in weight). With this there exists complications with frequently
recurring articular rheumatism.

Pathological Anatomy. — Congenital errors of development of the supra-
renal are often found combined with other malformations. Zander quotes
forty-two cases of hemicephaly in which the suprarenals were always small.
This finding is also constant with other malformations, if there is an absence of
the anterior cerebral hemispheres. There apparently exists in such cases
aplasia of the cortical system. At least Elliott and Armour in a case of anen-
cephalus found the suprarenal medulla and the paraganglia normal, while
the cortex was entirely absent. Czerny found the medullary substance
entirely absent in five cases of congenital hydrocephalus. Ulrich observed
in an adult complete aplasia of the suprarenal medulla; here the paraganglia
must have been especially well developed.

Important practically is the hypoplasia of the chromamn tissue described
by Wiesel, Hedinger, Goldzieher, and others, which is mostly associated with
status lymphaticus and sometimes with great parenchymal value of the
thymus gland. According to Wiesel such individuals are especially predis-
posed to Addison's disease. Acute destruction of the suprarenals may occur
as a result of hemorrhage of thrombosis of the suprarenal veins (Virchow,
Carrington, Karakaschejf, Goldzieher, [Lavenson, Hektoen, Ellis]) and others or
through suppuration (Janowsky). Much more frequent are simple atrophy
or sclerosis (Rolojf, Simmonds, Bittorf, Goldzieher).

Bittorf collected forty-seven cases of true atrophy or cirrhosis of the supra-
renal glands, adding to these three cases of his own. In such cases the supra-
renals are much decreased in size or entirely shrunken and often grown
together with the surrounding tissue. Microscopical examination usually
shows a very considerable reduction of the parenchyma, fattening and
eventually necrosis of the cells. With the cirrhosis, one finds thickening
or obliteration of the vessels, and growing together with the surround-
ings. Sometimes the sclerosis exists on a luetic basis (Schwyzer, Esser}.
Esser found gummata in connection with symptoms resembling Addison's
disease in a new-born. According to Lichtwitz, pigmentations occur in all
these cases. This author found the condition complicated with scleroderma
in four cases in the literature, adding a fifth case. Most commonly, how-
ever, tuberculosis of the suprarenals is found bilateral, not rarely isolated.
Often, however, other tuberculous foci in the body are found. Among five
hundred forty-nine cases from the literature, Elsdsser found isolated tuber-
culosis of the suprarenals in 17 per cent., in 48 per cent, combination with
pulmonary tuberculosis, and tuberculous foci in other parts of the body in
the rest of the cases.

In four hundred seventy-two cases the lesion of the suprarenal was bi-
lateral. The suprarenals may be destroyed also by tumors. Bittorf re-
ports two cases of hypernephromata with symptoms of Addison's disease.

ADDISON S DISEASE 341

There are also cases of Addison's disease in which the suprarenals are
found to be healthy. Nieszkowski, and Virchow, first reported such cases.
Lewin found them in 12 per cent, of five hundred sixty-one cases. There are,
further, cases in which clinically no signs of Addison's disease are present,
but at autopsy show destruction of both suprarenals. v. Neusser hence
expressed the thought that a lesion in the splanchnic itself or at some other
point of the sympathetic system could lead to Addison's disease. There are
but few cases, however (Jurgens, Bramwell), that are adapted for such an
explanation; otherwise changes in the sympathetic are rare and mostly slight
(v. Kahlden, Martineau}. An explanation of the above-mentioned exceptions
would be possible only on the recognition that the suprarenals represent only
a part of the chromaffin or interrenal system, and on the consideration of the
presence of accessory suprarenals.

Whether the complete or partial destruction of the suprarenals will in a
given case lead to Addison's disease, depends upon the fact whether the por-
tion of the suprarenal apparatus lying outside the glands proper is sufficiently
well developed to assume the function of the destroyed tissue, apparently
also on whether the destruction has progressed slowly enough to give time
for vicarious hypertrophy.

There has taken place a lively discussion as to whether Addison's disease
should be referred to a lesion of the chromaffin tissue or the interrenal system.
Wiesel in five cases of Addison's disease observed that the entire chromaffin
tissue was destroyed, while the cortex seemed to be less affected. He thought
that the destructive process began primarily in the chromaffin tissue, and
involved the cortex only secondarily. On the other hand, Karakaschejj
reported cases in which chiefly the cortex was affected, and in which he
regarded the cortical lesion as the sole course of the symptom-complex. The
question is not as yet fully cleared up, although the pathologico-anatomical
investigations of latter times and the physiological researches tend to show
that in Addison's disease a disturbance of function of both suprarenal systems
is present, a standpoint that is upheld in the new monographs (Bittorf,
v. Neusser and Wiesel, Biedl). Of other pathologico-anatomical findings I
mention only the known atrophy of the heart, and the atrophy of the
sexual glands that is almost regularly present. Kyrle has made exact in-
vestigations as to the testicles. He found a deficient spermatogenesis and
also changes in the interstitial glands.

It is very noteworthy that the suprarenal often becomes affected espe-
cially in severely infectious diseases and intoxications. Diphtheria toxin has
an especial affinity for the suprarenals. In animals after the injection of
diphtheria toxin, the suprarenals are always found to be markedly hyperemic
and suffused with hemorrhages (Roux and Yersin). Necroses, hemorrhages,
and edema of the suprarenals are found in the various infectious diseases
(Oppenheim and Loeper). In many cases, an acute insufficiency of the supra-

342 THE DISEASES OF THE SUPRARENAL APPARATUS

renal apparatus and especially the chromaffin tissue is well an important cause
of the cardiac insufficiency. In such cases the suprarenals show an essential
reduction in their adrenalin content (Comessati, Schmorl, Goldzieher) .

Finally we must mention a rare finding of v. Recklinghausen's. In an
eighteen-year-old dwarf who died in convulsions, he found what was apparently
a very chronic tuberculous change of both suprarenals. I shall have occasion
to refer to this case later.

Pathological Physiology of the Suprarenals. — The thesis established by
Brown-Sequard that the extirpation of both suprarenals led to the death of
the animal experimented on has met with much contradiction. The sure
knowledge that the cortical system and chromaffin tissue are in like manner
important for life was first mentioned by later investigators (I mention only
Biedl, Hultgren, and Anderson) who took into consideration the presence of
accessory suprarenals.

Biedl could at the same time furnish important demonstration that the
death of the animal was not to be blamed on the operative shock due to
injury of the sympathetic nerve plexus, as the operation also ended fatally
after transplantation of the suprarenals under the skin. After extirpation
of both suprarenals, the animals, after a latent period, showed increasing
apathy, adynamia, paresis, and emaciation. Blood-pressure and bodily
temperature gradually sank, so did also the amount of blood sugar (Forges,
Bierri, and Malloisel). Injection of phloridzin would now produce no
glycosuria or only minimal glycosuria (Eppinger, Falta, and Rudinger) ; the
glycogen rapidly disappeared from the liver and muscles (Forges), there
existed a higher sensitivity for poisons (O. Schwarz), the blood seemed to act
toxic, death occurring in convulsions. The symptom picture shows great
similarity with the peracute case of Addison's disease. We have not as
yet a sufficient explanation as to the question as to which symptoms of
Addison's disease are to be referred to the absence of the medullary system
and which to that of the cortical system. Before I enter into this question,
I will briefly mention the most important facts we know as to the physio-
logical significance of these systems.

The active constituent of the chromaffin tissue is adrenalin. After the
important preliminary researches of v. Furth, it was first isolated in a crystal-
line form by Takamine and Aldrich.

Later investigations of Aldrich, v. Furth, Pauli, et al., then led to the
establishment of its chemical formula. It is a methylaminoethanol pyro-
catechin, with the formula CgHuNOs.

Stolz first succeeded in making optically inactive adrenalin synthetically,
and Fldcher then obtained the separation into the dextro- and sinistro-
adrenalins. The sinistro-adrenalin is far the more active and is identical
with that produced in the body (A bderhalden) . Probably the organism

ADDISON S DISEASE 343

forms adrenalin from the aromatic split products of albumin, tyrosin, and
phenylalanin or oxyphenylserin (Halle, Frankel, Friedmann).

Of the chemical methods for demonstrating adrenalin we will mention
only the iron chloride test (Vulpian), the sublimate test (Comesatti), the
iodine reaction (Vulpian, Schur, Frankel, and Alters}, the potassium perman-
ganate lactic acid test (Zanfrognini).

I shall limit myself to sketching briefly the most important of adrenalin's
physiological actions. It acts as a powerful increaser of the blood-pressure
through narrowing of the peripheral vessels, it mostly acts first by slowing
the pulse, then accelerating the pulse; it slows the pulse by reflex excitation
of the vagus center, this action belonging to the so-called by-activities
[Nebeneinwirkungen] of adrenalin (Biedl) . Other by-activities are the shal-
lowing of respiration, and, according to Biedl perhaps also the increase of
the excitability of the striated muscles. It acts in a relaxing manner on the
stomach and intestines, as a contracting agent on the three sphincters (the
pyloric, and ileo-colic, and the internal sphincter of the anus). The uterine
muscle is contracted or relaxed by adrenalin, according to whether the
pressor [fordernden] or the inhibitory fibers predominate or are excitable
(Falta and Fleming). Probably the bladder behaves in the same manner.
Under circumstances mydriasis occurs. The vessels of the kidneys react to
minimal doses by dilatation and diuresis (Jonescu). Under circumstances
adrenalin may produce salivation and secretion of tears, indeed in large
doses (in guinea-pigs) , also secretion of sweat (Falta and Ivcovic) . Adrenalin
produces hyperglycemia and glycosuria (F. Blum, Metzger, and Zultzer) . The
hyperglycemia comes about by mobilization of the glycogen and probably
also by secondarily increased carbohydrate formation in the liver (Eppinger,
Falta, and Rudinger, L. Pollak). It increases the protein decomposition
during hunger. At the same time the respiratory quotient is temporarily
increased (Bernstein and Falta) . In large doses it produces in dogs increased
elimination of uric acid and allantoin. Often it leads to increase of tem-
perature. Further it brings about a neutrophilic hyperleucocytosis, during
which the eosinophiles vanish from the circulating blood. The simultaneous
increase of the mononuclear cells is a by-action, as this remains absent
after the administration of atropine. Finally adrenalin produces hyper-
globulia (Bertelli, Falta, and Schweeger), chiefly through transudation of
plasma.

Apart from the accessory actions mentioned, adrenalin acts only on the
purely sympathetic nerve-endings, and indeed on the so-called musculo-
neural junction (Langley, Elliott). It is therefore a purely sympathetic
hormone. The giving-off of adrenalin to the blood of the vena cava is con-
tinuous. The blood of the suprarenal vein should contain about one-half
part per million of adrenalin per cc. (Ehrmann). Biedl estimates that in
twenty-four hours about 4.3 mg. are given off to the blood. This amount

344 THE DISEASES OF THE SUPRARENAL APPAR ATI'S

of adrenalin may be increased by stimulation of the suprarenal nerves (Biedl,
A sher) .

The assumption that the activity of the chromamn tissue and the excita-
bility of the myoneural junction (Bayliss and Starling) is regulated by cen-
ters lying in the medulla oblongata is essentially based on the knowledge
that "puncture glycosuria" is brought about by dissemination of adrenalin
by means of the chromafhn tissue. Already Blum had supposed this. Ep-
pinger, Falta, and Rudinger further pointed out concerning this that in the dog
without a thyroid, "piqure" may remain as ineffective as injection of adrena-
lin. After A . Mayer had established the fact that " piqure " remains ineffect-
ive in rabbits after bilateral removal of the suprarenals. Waterman and
Smith tried to demonstrate an adrenalinemia by means of the insufficient
Ehrmann's reaction. The question was first entirely cleared up by the inves-
tigations of R. Kahn. This author could show that after the sugar-puncture,
the tingibility of the suprarenals to chrome stains in great part disappears
and the contents of adrenalin markedly diminish. Cutting of the splanch-
nic nerves not only prevents the occurrence of " piqure" glycosuria, as Claude
Bernard had shown, but also the coming about of any change in the suprarenal
medulla. It should be noted that in rabbits the right suprarenal is supplied
by the right and left splanchnic, the left by the right splanchnic only.

We will now consider the path that adrenalin takes in the body. The
blood in the cava, containing the adrenalin, first reaches the right heart and
then the lungs. The pulmonary vessels act refractory to it; hardly any
adrenalin is consumed here (Brodie and Dixon). From the lungs it reaches
the left heart and from this the greater circulation. The coronary vessels
of both sides of the heart are dilated by it, hence the heart is better permeated
with blood (Langendorf) . That part of the adrenalin-containing blood which
flows through the brain, also hardly loses in its adrenalin contents; the
cerebral vessels are dilated (Gerhardt) . On the contrary there occurs a marked
consumption of adrenalin in the other peripheral capillary territories of the
body, especially the muscles and the intestines (Elliott, Carnot and Josserand,
Falta and Priestly) . It therefore is to be assumed that the blood proceeding
from these organs (veins of the extremities, portal veins) is adrenalin-free
or at least poor in adrenalin. Therefore it is very striking that the test of the
arterial and venous blood as to its adrenalin contents by means of the known
biological methods (frog eyes, strips of vessel, uterus method) in the experi-
ment of Falta and Fleming showed just as strong an action, if indeed not
stronger, of the venous blood (extremity). On the contrary, after the subcu-
taneous injection of adrenalin, the arterial blood showed stronger action.
We must therefore be very cautious in the interpretation of the biological
methods mentioned, as the pressor action of the blood serum must depend
on other, as yet unknown, factors, a view that is also upheld by O'Connor.
I shall have something to say later as to the value of the biological methods

ADDISON S DISEASE 345

that we use for demonstrating adrenalin in the blood serum. However this
may be, a stronger unloading of the chromamn tissue must lead to a quite
definite distribution of blood. We find slight hyperemia of the lungs, the
heart, the brain, the kidneys, marked hyperemia of the peripheral venous
system and above all that of the liver and the roots of the portal vein, while
the other capillary systems are poor in blood. The purpose of this arrange-
ment is evident. It means the forcing of a greater amount of blood into
those organs which are the seat of life-maintaining centers and of the regula-
tion of metabolism, thus heightening the activity of these organs. The liver
occupies an especial position: It receives adrenalin-poor or adrenalin-free
blood through the portal vein arid thus becomes markedly hyperemic, and
blood containing adrenalin through the hepatic arteries; by this means
especially favorable conditions are, it seems, provided for the action of
adrenalin on the metabolism (Falta and Priestley). AlsoE. Neubauer found
by oncometric methods a hyperemia of the liver after the injection of
adrenalin.

The physiological significance of the chromaffin tissue may be adduced
from what has just been said with regard to adrenalin's intensive and mani-
fold actions. We may assume that it maintains the normal excitability
of the sympathetic nerves and that by means of graduation of the secretion
it is concerned in the regulation of the blood-pressure, the distribution of
blood, and the tonus of all other organs innervated by the sympathetic; fur-
ther that it maintains constant the amount of sugar in the blood and enters in
a regulatory manner into other factors of the metabolism ; further that it
influences muscular power (whether directly or through carbohydrate meta-
bolism is questionable) ; and finally it exercises an influence on the production
of neutrophilic leucocytes and on the plasma contents of the circulating blood.

As to the function of the cortical system, we as yet know very little. Ac-
cording to Jacoby, it contains an oxydase. Lohmann obtained cholin from
the cortex. Cholin acts as a toning agent on the autonomous nerves and it
is also found, however, in many other organs, and we do not know whether
it is given off from the cortical system in the blood paths. The assumption
of a "systeme cholinogene" (Gautrelet) as an antagonistic regulator against
the chromaffin system has not as yet received sufficient support. Also the
experiments of Goldzieher do not seem to me conclusive enough with respect
to the significance of this question.

It is assumed rather generally that the cortical system possesses a detoxi-
cating function (Brown-Sequard}. The blood of animals without their supra-
renals seems to be poisonous. As has been mentioned previously these
animals show a greater susceptibility for certain poisons; this does not, how-
ever, furnish absolute evidence for the detoxicating activity of the supra-
renals, as we may assume with Theiroloix that the withdrawal of the regula-
tory function lessens the general resistance. It is supposed by many authors

346 THE DISEASES OF THE SUPRARENAL APPARATUS

that the symptoms on the part of the intestinal tract and the central nervous
system, which are severe and remind one of an acute poisoning, depend on the
falling out of the function of the cortex. It should further be mentioned
that in the growing organism enormous influences on sexual glands and the
general hairiness proceed from the cortical system. I shall return to these
in detail later.

Pathogenesis of Addison's Disease. — Also the results of the pathologico-
physiological investigations just cited justify the dictum that Addison's disease
depends on an acute or chronic more or less complete loss of the function of the
suprarenal apparatus.

Probably from youth up there exists in individuals who acquire an Addi-
son's disease a certain weakness of the suprarenal function (Wiesel). Almost
always we find pathological processes which have affected the suprarenal
apparatus itself, but we cannot on this account rule out the assumption that
an affection of the nervous apparatus regulating the activity of the suprarenal
apparatus cannot lead to a (after a fashion) purely functional Addison's
disease.

Very difficult is the comprehension of the rare cases of Addison's disease
with unilateral affection of the suprarenal apparatus that become healed
after extirpation of the affected suprarenal, v. Neusser has supposed a
reflex influencing of the healthy suprarenal after the manner of reflex anuria,
and Bittorf a damaging of the same through abnormal metabolic products of
the diseased gland.

Among the symptoms of Addison's disease depending on the lessening
of function of the chromaffin tissue probably are the low blood-pressure, the
low sugar contents of the blood, the abnormally high tolerance for grape-
sugar, the adynamia, and the mononucleosis or the status lymphaticus,
although in the explanation of the alterations in the hematopoietic apparatus
we must not forget what is frequently present — tuberculosis. To the defi-
ciency of the cortical system are referred by most authors the manifestations
on the part of the gastrointestinal tract, vomiting, diarrheas, etc., and the
psychical alterations, the convulsions, delirium, coma, etc. No certain justi-
fication for these views have as yet been adduced (see later) .

Very difficult is the interpretation of the coming into existence of the
pigmentations in Addison's disease. The pigment is always iron-free.
On reduction with hydriodic acid it yields no hemopyrrol and on oxidation
no hematinic acid. We have, therefore, discarded any relationship with
blood pigment, and have found the mother substances in the aromatic split
products of albumin (tryptophan, tyrosin, and also adrenalin) (S. Franket).
Further, Zuzer and Lichtwitz saw the occurrence of pigmentation of the
skin and mucous membranes after the injection of adrenalin in rabbits. As
according to Eppinger the melanogen in melanocarcinoma is an N-methy-
pyrrolidinoxycarbonic acid and its elimination is increased through the

ADDISON S DISEASE 347

administration of tryptophan, so it would not be unlikely that an increased
production of tryptophan has been brought about in the body by the ad-
ministration of adrenalin. Further it should be mentioned that Neuberg
demonstrated in the tumors of the cases of melanoma of the suprarenal
cortex a ferment which let a pigment formation be recognized after the addi-
tion of adrenalin or oxyphenylethylamin. Further Jaeger has obtained
from a melanoma an enzyme that decomposes adrenalin with pigment forma-
tion. Jaeger supposes that adrenalin is the mother substance of the iron-free
pigment of the organism. Finally, according to Meirowsky, freshly excised
pieces of skin show in the incubator an increase of pigmentation, and accord-
ing to Konigstein this increase of pigment is greater in the skin of dogs without
their suprarenals. Therefore it would not be unlikely that the cortex as well
as the chromamn takes part in the pigment formation, the first furnishing the
mother substance of the melanogen (tryptophan), the latter the further de-
composition. Increased formation of pigment may occur under the most
diverse circumstances, as in Basedow's disease, when the production of ad-
renalin is increased, or in Addison's disease when the production of adrenalin
is absolutely lessened, or perhaps less disturbed than the function of the corti-
cal system. Thus may also be seen why pigment formation often remains
away entirely in acute destruction of the entire suprarenal apparatus. This
should, however, be regarded merely as a hypothesis that still requires
experimental support.

Differential Diagnosis. — For differential diagnosis, of great importance
are the pigmentations. The number of cases of Addison's disease without
melanoderma is, as Bittorf has emphasized, less than the older statistics
would lead one to expect. Similar pigmentations are found, however, in
normal individuals. Also in itching skin affections and [those due] to ver-
min, during the use of arsenic, in pregnancy ,fin chronic heart affections and in
phthisis pulmonalis; in slight grades of the latter the thought of Addison's
disease may be erroneously awakened on account of the emaciation and the
slighter hypotonia; it is hence important to remember that in all conditions
enumerated the mucous membranes remain free. In persons cachectically
tuberculous the pigmentations may become quite similar to those of Addison's
disease. Here indeed it is questionable whether the pigmentations might
not be referred directly to a damaging of the suprarenal function, an opinion
that is upheld by Lavignel-Lavastine.

In cirrhose bronzee the coloration of the skin is more blue-gray; here also,
the mucous membranes are affected only rarely and more in a diffuse form
(Heller). Here we should consider the liver lesion and the eventual compli-
cation with pancreatic disease (diabetes). Naturally it should be taken into
consideration that combinations of cirrhose bronzee and Addison's disease
may occur, if the sclerosing process in cirrhose bronzee also involves in strong
degree the suprarenal apparatus (Fod, Bittorf}. As is known, pigmentations

348 THE DISEASES OF THE SUPRARENAL APPARATUS

are also frequent in scleroderma. From this we must not conclude that a
complication of scleroderma with Addison's disease is present in the indi-
vidual cases as pigmentations belong to scleroderma as such. Also similar
pigmentations are observed in pellagra (v. Neusser). Statements as to the
characteristic erythema in the warm seasons of the year clinch the diagnosis
in this case. Arsenic melanosis and argyrosis show another tint. Pigmen-
tations are also observed in leucemia. v. Neusser thought that there were
leucemic infiltrations of the suprarenals, which opinion a case of Zeigler's
later corroborated. Pigmentations in Basedow's disease are very common.
The complication with Addison's disease is very rare. However, such
cases in which the diagnosis was confirmed by autopsy have been reported
by Fletcher, and by Greenhow. Such a diagnosis should be made in vivo with
great caution, as markedly pigmented cases of Basedow's disease with
cachectic symptoms — such as occur in the latter stages — can easily give rise
to the impression of a concomitant Addison's disease.

Very difficult is the delimitation from cachectic conditions associated with
occult carcinomas and diseases of the liver, in which diseases melanoplakia
of the oral mucous membrane may occur also (Schultze) . In these cases and
in the case of Addisonoid anemias described by Grawitz, the demonstration
of a hypoglycemia and of a mononucleosis. with hypereosinophilia is very
important.

The diagnosis of acute Addison's disease may be very difficult. Brodnitz
points out the importance of the following syndrome: Extraordinary slow-
ing of the fully tense pulse with normal temperature; violent intestinal colics
occurring in attacks; failure of the peristalsis and isolated intestinal disten-
tion. Brodnitz believes that thrombosis of the suprarenal vein occurs in
many cases of postoperative spastic occlusion of the intestine.

The prognosis of Addison's disease is always very dubious. The few
certain cases of cure concern mostly luetic disease of the suprarenal, some
with and some without specific treatment (Merckel and Birch-Hirschfeld)',
in a case of Oesterreicti 's the extirpation of the one tuberculous suprarenal led
to cure. Cure has also been observed in cases of hypernephroma with
Addisonian manifestations (Bittorf).

Treatment. — It remains to be said that treatment is very ineffective.
The statements as to improvement after subcutaneous or peroral adminis-
tration of suprarenal substance are more sparse than those concerning results
that are negative. The administration of small doses of adrenalin per os is
ineffective, as might be gathered from our researches, which show that even
more than 20 mg. per day do not call forth any especial manifestations.
Only when the doses are very much larger did we see in animals after admin-
istration for days the occurrence of hyperglycemia (Falta and Turin}. I
quote one of our experiments:

ADDISON S DISEASE 349

8.3 kg. dog, Mar. 5, sugar in blood 0.1008 per cent.

On March 8, the dog received daily 25 cc. of a i per cent, solution of adrenalin
through the stomach tube.

From March 9 to 16, inclusive, 25 cc. adrenalin twice.

Mar. 1 6, sugar in blood, 0.1552 per cent.

From Mar. 19 to 30, inclusive, 25 cm. adrenalin twice.

From Mar. 13 to 17, a trace of sugar was demonstrable in urine, later the urine was
always sugar-free, but contained traces of protein.

Subcutaneous injection of adrenalin is not advisable for any length of
time. Boinet saw manifestations of collapse. Also after the injection of
the glycerine extract of the whole suprarenal there occurred in Boinet's case,
after a time, conditions of excitement, tremor, and insomnia. Perhaps,
however, a slight result is to be obtained by the peroral administration of
tablets made from the whole gland. According to Magnus-Levy, the pigmen-
tations have become lighter in color after the administration of these
tablets, under certain circumstances.

The beautiful investigations of v. Haberer and Stoerck as to the healing-in
of pedunculated suprarenal glands [transplanted] into the kidney scarcely
give hopes for a practical application, as apart from the necessary peduncula-
tion, probably only autotransplantations of the suprarenals are possible.

Only the symptomatological treatment remains. Grawitz recommends
washing the stomach with sodium chloride solution, predomination of vege-
tative diet, avoidance of alcohol, and hydrochloric acid medication. Grawitz
saw a case that presented all the symptoms of Addison's disease which
benefited under this treatment. Also the pigmentations of the skin disap-
peared. The case was observed for a period of three years after this success-
ful result. Very important in Addison's disease is the avoidance of every
severe exertion. Boinet reports seven cases of sudden death in Addison's
disease, immediately after a marked fatigue.

Proceeding from the observation that dogs after the extirpation of their
suprarenals, lose all their glycogen except traces, O. Forges combated the
adynamia in several cases of Addison's disease by the administration of
large amounts of carbohydrates (especially of levulose) with good results.
Also Gautrelet reports favorable results.

Here might also be mentioned the favorable results of adrenalin in other
diseases. Very widespread is the employment of adrenalin in the stilling of
hemorrhage. Proceeding from the observation that animals bear enormous
amounts of adrenalin, Turin and / in ulcus ventriculi increased administra-
tion of adrenalin per os up to 7 mg., thrice daily, and up to the present have
seen good results. Many authors report the excellent action of adrenalin in
condition of collapse (John and others), especially in the infectious diseases
(for example, Heubner, in diphtheria). According to our observations
adrenalin given subcutaneously, too, in man increases the blood-pressure,

350 THE DISEASES OF THE SUPRARENAL APPARATUS

often for a long time. According to our experiment the subcutaneous in-
jection is to be preferred in not too urgent cases.

Several times we saw, too, an astonishing result from subcutaneous admin-
istration (thrice 5 mg., each in one-fourth glass of water) in obstructing car-
cinoma of the esophagus, in which the passage was reestablished probably by
subsidence of the tumefaction of the inflamed mucous membrane, but such
results only last for a few days. Further, adrenalin was introduced by Xeu
into obstetrical practice. After the injection of adrenalin the uterus was
brought to a condition of tetanoid contraction. The drug has been especially
serviceable in Cesarean section. It may be injected either subcutaneously
or directly into the uterus. Probably pituitrin will supplant adrenalin in this
respect, as it has the same action and is less deleterious.

The employment of adrenalin is also useful in phosphorus poisoning. E.
Neubauer and Forges observed that in animals poisoned with phosphorus,
the stainability of the chromafnn tissue to chromic acid disappeared; both
these authors attribute the vanishing of carbohydrates from the liver, the
subsequent fattening of the liver and the hypoglycemia (E. Neubauer, and
Frank and Isaac) to the falling out of the chromaffin tissue and in most cases
could actually prevent these symptoms by the administration of adrenalin.

As to the treatment of osteomalacia with adrenalin, see chapter on sexual
glands (appendix).

2. Isolated Symptoms due to Failure of Function of the
Suprarenal Cortex

In the consideration of the pathogenesis of Addison's disease, it has been
pointed out that we as yet know nothing certain concerning that group of
cases which has as the basis of the symptom-complex the destruction of the
suprarenal cortex. It is true that many authors regard the manifestations of
intoxication that tend to enter into acute cases and in the terminal stages of
Addison's disease as due to deficiency or absence of the suprarenal cortex.
But as yet experimental pathology has furnished no certain foundation for
this assumption. Nor does clinical observation, as will be seen from the fol-
lowing, seem to me to substantiate this assumption.

First let us consider the malformations. In anencephalus is found, as
has already been mentioned, in addition to anomalies in the genital organs,
also aplasia of the suprarenals. A pert points out that in aplasia of the supra-
renals the cortical defect seems to play the most important role. I mention
again the case of anencephalus reported by Elliott and Armour, in which the
suprarenal medulla and the paraganglia were intact. Again, in cases in which
the suprarenals are entirely absent the paraganglia may be normal, as in the
case of A pert. The aplasia of the cortex in the new-born is the more remark-
able because here the suprarenals, as is known, are especially well developed.

ISOLATED SYMPTOMS DUE TO SUPRARENAL CORTICAL FAILURE 351

An indication as to the direction in which are to be found manifestations
of deficiency of the suprarenal cortex is found, under certain circumstances,
in adenomata of the suprarenal cortex. We shall see later that in such
hyperplasia of the cortex there occurs in youth abnormally rapid growth of
the organism and premature development of the secondary sexual characters
and the genitalia, and in adults a tendency to abnormal hairiness. Hence
arises the thought that when manifestations of the opposite kind are present
there may exist a cortical insufficiency.

Moreover, in the chapter on the hypophysis I have reported a case of
hypophysial dystrophy in which the disease first developed in later life and led
to a marked retrogression of the hairiness on the trunk and on the face. In
this case both suprarenals were found to be highly sclerosed and we shall see
later in the consideration of the multiple ductless glandular sclerosis that in
man a retrogression of the secondary sexual characters may indeed set in as
the result of the failure of the function of the sexual glands, but that in
woman the mere loss of the function of the sexual glands is not usually fol-
lowed by distinct retrogression. First in cases in which the sclerosing process
involves numerous ductless glands does there seem to be in women a distinct,
and in men a marked retrogression of the hairiness and the genital organs.

In the cases of multiple ductless glandular sclerosis in which there have
been autopsies there is always to be found a marked sclerosis of the supra-
renal cortex. Further there should be observed in eunuchoidism whether in
rare cases there does not exist, in addition to the hypoplasia of the sexual
glands, a hypoplasia of the suprarenal cortex.

Finally Variot and Pironneau have described a case which was character-
ized by marked disturbance in growth, absence of any hairiness at all (eye-
brows, lashes, and almost complete baldness of the head). They have desig-
nated this case "nanisme type senile" and refer to two entirely analogous
observations by Gilford Hastings and Sir [Jonathan} Hutchinson. In the
last case the suprarenals were found to be sclerosed. Variot therefore con-
cludes that these vegetative disturbances depend on a loss of the function
of the suprarenal cortex. It seems to me, however, that in the case of Hutch-
inson there was an insufficient examination of the other ductless glands. Also
Gilford Hastings points this out, and I hold that it is not impossible that
this case constitutes multiple ductless glandular sclerosis in childhood, al-
though I am not in a position to prove this. Perhaps some objections may
be made against this view. At least I shall speak again of these cases under
the consideration of multiple ductless glandular sclerosis.

It is also doubtful whether the dwarf described by v. Recklinghausen
should be grouped under cortical insufficiency. In a dwarf eighteen years
old who had died in convulsions, v. Recklinghausen found an apparently
chronic tuberculous caseation of both suprarenals. The individual was 95
cm. tall and weighed 10)^ kilograms. The measurements correspond to about

352 THE DISEASES OF THE SUPRARENAL APPARATUS

those of a three- or four-year-old child. The body dimensions were well
proportioned. The epiphysial junctures were retained, the penis and the
testicles were rather small. If we were already disposed to regard a loss
of the suprarenal function as the cause of the disturbance in growth, we
would have to hold responsible the suprarenal cortex, as hypoplasia of the
chromaffin tissue rather produces a tall, weak, individual. I regard as more
likely that here we are dealing with a true dwarfism and that the supra-
renal caseation constitutes an accidental complication.

On reviewing the preceding material, we find that it is a question if
the observations are to be referred to an isolated withdrawal of the cortical
function. The observations seem rather to suggest that from the cortex
there proceeds a furthering influence on the genital sphere and especially on
the hairiness, an assumption, as we shall see later receives essential support
through corresponding manifestations in hyperplastic conditions of the cortex.
These observations furnish no support for the assumption that loss of the
function of the suprarenal cortex leads to manifestations of intoxication.

b. Conditions of Hyperf unction of the Suprarenal Apparatus

Here we are interested especially in tumors of the suprarenal appara-
tus, which usually, but not always, are associated with conditions of hyper-
function.

I. Tumors that Proceed from the Chromaffin Tissue

These seem to be very rare. Kuster describes two cases of glioma of the
suprarenals, one affecting a fourteen-month child whose entire right supra-
renal had been converted into a tumor, while in the left suprarenal was
found a tumor occupying the site of the medulla. Numerous metastases were
present.

In the second case the findings were accidental. Kuster regarded these
tumors as a glioma, Wiesel as a growth made up of formative cells of the
sympathetic, although Schilder has lately described a certain glioma of the
sympathetic and regards Kuster' s case as glioma. More recently there have
been described chromaffin tumors, in part too proceeding from the paragan-
glia, by Weichselbaum, Manasse, Stangl, Monckeberg, and Kolisko. Kolisko's
case (reported by v. Neusser and Wiesel) was that of a vigorous, otherwise
healthy, man who suddenly died during cocaine anesthetization on account
of the extraction of a tooth. Here was found a bilateral suprarenal tumor
made up of chromaffin tissue, and very rich in adrenalin. v. Neusser and
Wiesel regard this case as adrenalin intoxication. Very interesting is the
case of Wiesel, a tumor of the sympathetic in a two-year-old child with arterio-
sclerosis which resembled histologically the sclerosis produced experimentally
in animals by adrenalin. Hence it seems that these tumors can be associated

CONDITIONS OF HYPERFUNCTION OF THE SUPRARENAL APPARATUS 353

with hyperf unction of the chromaffin tissue. For this also speaks the
associated cardiac hypertrophy that is so frequently found.

Moreover, there should be mentioned here the case of Kawashima. In
this case were found multiple skin fibromata proceeding from the con-
nective-tissue sheath of the nerves, and also tumors of the suprarenal medulla.
Kawashima discusses the association of neurofibromata with diseases of the
nervous system. He points out that neurofibromata are very frequently
associated with general symptoms (disturbances of nutrition, intellectual dis-
turbances, gastrointestinal affections, certain visual disturbances, headaches,
spasms, depressed states, and alterations in the sexual sphere) and believes
that these as well as the general symptoms are the expression of an affection of
the nervous system. There should also be mentioned two cases of paragangli-
oma reported by M. Herde. Both cases were those of chromaffin tumors.
In one case there existed arteriosclerosis, in the other genuine "Schrumpf-
niere." Finally I mention a case of Sazuki's (chromaffin tumor of the
suprarenal medulla) and of E. Hedinger's (struma medullaris cystica supra-
renalis) .

The question as to whether there exist conditions of hyperfunction of the
chromaffin otherwise than when due to tumor has been recently discussed.
It is noteworthy that numerous authors take the negative attitude concerning
this question, at least as far as chromaffin tissue is concerned. In tumors of
the chromaffin tissue we have learned to recognize a group of clinical condi-
tions, which we may regard as due, with great probability, to an increased
function of the chromaffin tissue.

Are we then justified in regarding similar clinical conditions as the ex-
pression of a hyperfunction of the chromaffin tissue, even where a patho-
logico-anatomical substratum has not as yet been found for them?

Originally French authors (Pilliet, V agues, Aubertin and Ambard) en-
deavored to explain the increase of blood-pressure in interstitial nephritis
by an increase in the function of the suprarenal cortex, as they often met with
strikingly large supra,renals in cases with hypertonia. Josue has assumed such
in the atheromatosis associated with hypertonia. After, however, we had
recognized the significance of the chromaffin tissue for the regulation of blood-
pressure, Beaujard regarded it as regulative against increased circulation of
toxic products in the organism, which would be conditioned on the lessened
eliminatory capabilities of the kidney. Apparently the chromaffin tissue
alone seems to be significant for the pathogenesis of this condition, in so far
as we might wish to bring it into correlation with the suprarenal apparatus.
The question should, however, be formulated as to whether secondary hyper-
functional conditions of the chromaffin tissue occur as the reaction to other
processes in the body, processes that are released eventually by a permanent
reflex condition of over-excitement of the centers of this system lying in the
medulla oblongata or in the brain stem; also we should consider the possibility
23

354 THE DISEASES OF THE SUPRARENAL APPARATUS

as we have discussed in Basedow's disease, that these centers are primarily
in a state of hyperirritability on grounds that are not at all clear. If this
were so, we could speak of a true neurosis.

Wiesel was the first who referred the disease process associated with
hypertonia to a condition of hyperfunction of the chromafnn system. He
found hyperplasia of the chromaffm tissue in twenty-two chronic and some
acute cases of nephritis, and in a case of aortic insufficiency — all cases
showed cardiac hypertrophy — the hyperplasia affecting the suprarenal me-
dulla as well as the paraganglia. Later Schur and Wiesel tried to demonstrate
in such cases the increased amount of adrenalin in the blood, by means of the
Ehrmann-Meltzer reaction. The hyperplasia of the chromafrin tissue was cor-
roborated by numerous authors, of whom are named Schmorl, Goldzieher, and
Molnar and Comisatti. Both Schmorl and Goldzieher also found an increase in
the adrenalin content of the suprarenals. Other authors, as Bittorf, found no
such hyperplasia. Certain negative cases do not seem to me to mean very
much, as not every case of hyperplasia need be distinct. The statements as
to the increased adrenalin content of the serum have met with more contra-
diction. It is certain — with the following my own experiences agree — that
in numerous cases with hypertonia the frog's-eye method fails. But also
other fine biological methods give negative results, for Schlayen, using Meier's
vessel-strip method, and A . Frankel, using the myographic method, found the
serum of nephritics even less active than normal serum. These behaviors
were complicated by the foreign serum, as Schlayer ascertained, in a manner
that could not be overlooked. The myographic method is, however, from its
very nature hard to interpret, for Fleming and /, also on the use of an adrenalin
Ringer-solution, saw inhibition of the movements and the tonus of a rabbit's
uterus. O'Connor, using the Laewin-Trendelenburg frog muscle method came
to like results. He found that the activity of the serum was conditioned not
only by its adrenalin content but also by other substances, that first get into
the serum on coagulation. We therefore can say only that up to the present
the biological methods do not furnish a certain evidence for the increased
adrenalin content of the serum. On the strength of this, however, I do not
feel justified in denying the teaching of Schur and Wiesel. In favor of it
speaks in addition to the hyperplasia of the chromafnn tissue the increased
diuresis, which agrees with the increased amount of sugar in the blood as
shown by E. Neubauer and also, as I believe, with alterations in the distri-
bution of the blood as seen in experimental hyperadrenalinemia. Very
frequently we see congestive conditions in the lungs, in the brain (retinal
hemorrhages, apoplexies), and in the liver. In beginning decompensation
very often the swelling of the liver is the- first to appear. Again, in such
conditions, very often at the beginning, we see a slight grade of hyper-
globulia; later the count of red blood cells is very often reduced (destructive
effect of chronic adrenalinizing on the ery thropoiesis) . Finally we find the

CONDITIONS OF HYPERFUNCTION OF THE SUPRARENAL APPARATUS 355

count of neutrophilic cells mostly at the upper limits of the normal or even
slightly exceeding these.

As to the question why interstitial nephritis is associated with an increase
of function of the chromaffin tissue I shall not enter into here more inti-
mately. In many cases, for instance, in the nephritis of scarlet fever, the
disease of the kidney is primary, in other cases the contracted kidney can only
be a partial manifestation of the general arteriosclerosis of the small blood-
vessels. Such a general arteriosclerosis must lead reflexly to a hypertonia
through lowering of the resistance, if the accessory amount of blood should
be driven through the capillary system of the muscles, etc. Finally it is
conceivable that the increase of function of chromaffin tissue (as for instance
in tumors of the sympathetic, perhaps also in premature arteriosclerosis of
diabetics, or in transition of diabetes into contracted kidney) is the primary
factor (Frank's hypertonic diathesis).

Still less clear is the significance of the chromaffin tissue for the coming
into existence of the atheromatosis. As is known, chronic adrenalizing of
rabbits can produce sclerosis of the great vessels (Josue, Erb, and others).
This is an affection of the media. The vascular lesions in tumors of the sym-
pathetic are also affections of the media. Braun, however, by the intraven-
ous injection of minimal doses of adrenalin could produce atheromatosis of
the small vessels. The ordinary arteriosclerosis of the large vessels, that
occurs without increase of blood-pressure, has nothing at all to do with
the chromaffin tissue; it depends on a primary degeneration of the elastic
elements.

Finally, some observations as to the influence of hyperf unction of the chrom-
affin tissue on the carbohydrate metabolism. In hypertonics we find, as already
mentioned, hyperglycemia. The kidneys adapt themselves to a very gradual
increasing amount of sugar in the blood, without glycosuria (v. Noorden).
In many cases of diabetes mellitus, and especially in advanced cases, much
speaks for the view that here also there is a slight overproduction of adrenalin
(Falta, Newburgh, and Nobel). That the administration of this escapes
detection by the known biological methods is not to be wondered at, when on
the one hand we take into consideration the unreliability of the biological
methods (see above) and on the other, consider what monstrous dilution,
i gm. of adrenalin, which under circumstances may produce much sugar in the
urine, must experience when injected subcutaneously in man. Such a slight
increase in adrenalin production may very well be overshadowed by the
counter-regulations without leading to increase in blood-pressure. On the
contrary the toxic components seem to dissociate, as is shown by the prema-
ture arteriosclerosis so frequently observed in diabetes. An exact histological
study of the same has not as yet been made. Finally we should point out the
frequent transition of diabetes into contracted kidney. On the grounds de-
tailed the negative standpoint that G. Bayer, and Broking and Trendelenburg

356 THE DISEASES OF THE SUPRARENAL APPARATUS

have taken against the assumption of a functional increase of the chromaffin
tissue in certain forms of diabetes mellitus, does not seem to me a priori to
be justified.

2. Tumors that Proceed from the Cortex

These appear to possess greater clinical interest than the tumors of the
chromamn tissue. The knowledge that they may be associated with hyper-
function of the cortical system is one of the achievements of recent years. In
a clinical respect we can distinguish two groups of cortical tumors. In one
of the groups belong chiefly the sarcomata, lymphosarcomata, carcinomata,
alveolar sarcomata, endotheliomata, the melanotic carcinomata, and the cysts
(literature in Bullock and Sequeira, Frew, Glynn, Tilestone, Winkler, Hanschen,
and Arnaud}. These seem to bring forth only the usual symptoms of a
benign or malignant tumor. We shall not discuss this group any further.
The other group embraces the numerous cases of adenomata of the cortical
substance.

These show great diversity in their point of departure. They may pro-
ceed from the cortex itself, or may originate in the separated germs of the
cortical system in the kidney, or in the genitalia, etc. The process concerned
in such adenomata may be that of a simple hyperplasia, that may either run
its course without symptoms or give rise simply to the local manifestations of
tumor, or may assume malignant character, and then show great inclination
for the formation of metastases. Finally these tumors may, without the men-
tioned tumor symptoms, lead to profound alterations of the organism, that
with a certain probability may be regarded as the expression of a hyperfunc-
tion of the cortex. Before I enter into the consideration of the clinical mani-
festations, I should like to refer to the demonstration of Bournemlle that in
idiots with "sclerose tubereause du cerveau" there are regularly found in the
cortex of the suprarenals lumps that Pellizzi regards as adenomata of the
suprarenals.

The hypernephromata consist in round, oval, or polygonal cells, of an epi-
thelial character. The cells are often of many shapes. As the suprarenals
are of mesodermal origin, it is readily intelligible that the cells often assume a
mesodermal character, and in their histological structure approach primitive
sarcomata (Glynn). They are different, however, from the suprarenal sar-
comata proper; true lumina are never observed in them (Woolley).

The simplest form clinically is represented by so-called Grawitz tumors.
These may originate in the kidneys (Grawitz) or the ovaries (Vonwiller) or in
the tail of the pancreas (R. Mohr). Lately their origin from separated germs
of the suprarenals has been combated by Stoerck and Zehbe, while R. Mohr
has again arrayed himself for this genesis. In the clinical respect it is signifi-
cant that they are never associated with alterations in the genital sphere.
This without doubt speaks for the view of Stoerck and Zehbe. At most we

CONDITIONS OF HYPERFUNCTION OF THE SUPRARENAL APPARATUS 357

must assume that the Grawitz's tumors are strumas of the suprarenals that
analogously to strumas of the thyroid do not tend to be associated with
manifestations of hyperfunction.

When the Grawitz's tumors are of large growth they may lead to local
oppressions (pains in the lumbar region, intercostal or femoral neuralgias,
and when there is pressure on the kidneys to hematuria, albuminuria, cysturia,
etc.), or they degenerate malignantly and lead to metastases and cachexia.
Westphal has gathered twenty-four cases from the literature, and has added
seven cases from his own statistics.

In Grawitz's tumor there is frequently a tendency to formation of cysts
due to softening, with characteristic chocolate-colored content, which is
eventually demonstrable on puncture.

It is true that Westphal adduces symptoms that indicate a hyperfunction
of the chromaffin tissue. In two of seven cases he found temporary glyco-
suria, in three cases a relative increase in the neutrophilic cells and a distinct
increase in blood-pressure in the early stages. I believe that these symptoms
are only of a secondary nature, called forth by an initial irritation of the
medullary substances by the growing tumor. It is worth mentioning that
Bittorf in two cases of unilateral hypernephroma also found symptoms of an
Addison's disease, emaciation, lassitude, pigmentations, and low blood-pres-
sure. These cases also showed a lymphocytosis. It seems to me that this
furnishes a corroboration of my view that the manifestations on the part
of the chromaffin tissue (irritation or deficiency) are only of a secondary
nature. Bittorf also observed slight psychical- symptoms in his case and
believes that they are of diagnostic importance and they do not occur in
tumors of the kidneys (v. Strumpell}. Both Bittorf 's cases were cured on
operation, only the pigmentations remaining unaltered.

Perhaps the following two cases also belong to this group, v. Neusser
mentioned a twenty-five-year-old man with very tense pulse, multiple hemor-
rhages in the brain. The section showed a carcinoma of one suprarenal.
Vascular system and kidneys were normal.

In addition v. Neusser cites a case of Frankel's, an eighteen-year-old girl
with headaches, vomiting, and high pulse tension. Section showed a vas-
cular neoplasm of the left suprarenal; the kidneys were normal. Here, too,
can the hyperfunction of the chromaffin tissue be regarded as an irritative
symptom. Conversely in rapidly growing cortical tumors symptoms of de-
ficiency of the chromaffin tissue may occur.

Of very great interest for the knowledge of the internal secretions are
those adenomata of the suprarenal cortex that are associated with hyper-
function of the cortex. In the clinical picture of these cases there seems to be
an appreciable difference according to whether they develop in the entirely
childish, or in the juvenile, or in the adult organism.

I. With the development of such hyperfunctionating cortical tumors in

358 THE DISEASES OF THE SUPRARENAL APPARATUS

the childish organism there occurs an enormously accelerated development of
the body, a premature development of the genitalia. Such cases are described
by Cooke, a seven-year-old female ; Tilesius, a 'four-year-old female ; Ogle, a
three-year-old female; Calcott-Fox, a five-year-old female; Orth, two and
one-half-year-old female ; Dobbertin, four-month-old female ; Ritsche, four-year-
old female; Bullock and Sequeira, eleven-year-old female; Linser, five-and-
one-half-year-old male; Adams, fourteen-and-three-fourth-year-old male.
In the case of Adams, puberty set in at the age of ten years. The boy was
large and strong muscularly. Autopsy showed tumor of the left suprarenal
proceeding from the cortex. A careful compilation of the literature has been
made by Neurath, and more recently by Glynn. Further cases are reported
by Guthrie and W. d'Este Emery (four-and-one-half-year-old boy, fat, large
tumor of the suprarenal cortex) , by Richards (seven-year-old girl) , by Glynn
and by French (reported by Glynn) ; and perhaps also the case of Guinon
Bijou belongs here (no autopsy).

Some cases I shall quote more exactly. The case of Linser was that of a
five-and-one-half-year-old boy, who looked like a youth and therefore was
admitted into the men's department of the hospital. He was 138 cm. tall,
the penis was 8-9 cm. long, the testicles as large as pigeon's eggs, the pros-
tate like that of a fifteen-year-old boy, the musculature was well-developed.
The size of the body, the ossification, the almost complete set of permanent
teeth, corresponded fully to those of a fifteen-year-old boy. The upper
length was larger than lower length, hence childish dimensions were present
in a potentized form. The hypophysis was normal and there was adiposity.

The case of Bullock and Sequeira was of an eleven-year-old female who
looked like a forty-year-old woman. Menstruation had set in at the age of
nine and three-fourth years and from this time on there developed an in-
creasing adiposity. The girl was 4 ft. 6 in. high and weighed 6 stones, 3 Ib.
[87 Ib.]. The breasts were fully developed. Long hairs were present on the
genitalia. Autopsy showed a large tumor of the left suprarenal consisting
in cells of zona fasciculata, with numerous metastases, hyperplasia of the
thyroid and the parathyroids, fully developed uterus and large ovaries with
corpora lutea of recent date.

The case of Richards was that of a seven-year-old girl. At the age of
five she developed pubic hair and hair on the face. At seven years old she
looked like a woman twenty years old, the hairs on the genitalia were fully
developed, and hairs were present on the side of the face and on the site of
the mustache.

The case of Glynn was that of a girl five years old. In the third year of
life she began with pains in the abdomen and the head, later apathy. She
was as large as a girl fourteen years old, and fat. Hairs were present on
the upper lip, on the pubis and on the back. The sexual organs were espe-
cially well developed. There was found a large tumor of the suprarenal

CONDITIONS OF HYPERFUNCTION OF THE SUPRARENAL APPARATUS 359

cortex, ovaries and hypophysis were normal. In the case of French (seven-
year-old girl) the abnormal hairiness began to develop as early as the
eighteenth month; the genital organs were very large; here also was found
a suprarenal tumor.

It will be seen that the condition nearly always affects girls. Of
seventeen cases offered by Glynn, fourteen were of the female sex. What
is common to all in the clinical picture of these cases is, as Neurath empha-
sizes, the premature excessive development of the secondary sexual characters
and of the external genitalia. Neurath mentions that in this category of pre-
mature sexual development, the function of the generative portion is on the
contrary not prematurely developed. This does not always point to an espe-
cially intimate relation between the suprarenal cortex and the interstitial
glands. Moreover, common to almost all cases is adiposity, furthermore the
accelerated growth, probably with retention of the infantile dimensions,
and the accelerated ossification and dentition. The development of the
psyche in such children as a rule does not keep pace with the bodily develop-
ment. Also the development of the sexual instinct is usually slow.

II. The manifestations that occur on the development of hypernephro-
mata in the juvenile or mature organism are likewise characterized by an enor-
mous influencing of the sexual sphere. . Here also I would enter more fully in
the case reports. The case of Bortz and Thumim was that of a sixteen-and-
three-fourth-year-old girl. At first she had developed quite normally, then
the menses ceased, and there developed a luxuriant deep black beard and
a sparse mustache. Hairs developed on the chest and on the linea alba, the
voice became deeper and universal obesity developed. Death occurred as
the result of an intercurrent illness. Section revealed atrophy of the ovaries,
enormous enlargement of the thyroid gland, normal hypophysis; on both
sides there existed a suprarenal tumor rich in blood-vessels that had ap-
parently developed only from the cortex.

Case of Winkler. — Sixteen-year-old girl. Abundant black hair on the
upper lip. Uterus small. Tumor of the right suprarenal with metastases.

Case of Bovin. — Twenty-eight-year-old woman. Two labors, then cessa-
tion of menses at the age of twenty-one. Development of the beard. There
is also an abundant growth of hair on the abdomen. Simultaneously, the de-
velopment of an abdominal tumor. Operation showed a large ovarian tumor
proceeding from separated suprarenal germs. The patient recovered from
the operation, the uterus became larger again, menstruation reappeared, and
the abnormal hairiness disappeared. However, the observation after opera-
tion was for a short period of time only.

The case of Hegar perhaps belongs to this group (abnormal hairiness,
uterus duplex, cystic tumor of the ovary). Moreover, perhaps also the case
of Alberti. In this case menstruation was normal up to the nineteenth year.
Development otherwise normal. Then set in hypertrichosis, development of a

360 THE DISEASES OF THE SUPRARENAL APPARATUS

beard, mustache, and hair on the trunk. At the same time a tumor developed
in the abdomen. Death occurred. Autopsy showed a cystoma pseudomu-
cinosum proceeding from the right ovary. The clitoris was appreciably
enlarged (autopsy only partial, no statement as to the suprarenals) .

Case of Goldschwend. — Thirty-nine-year-old woman, had five children.
Cessation of menses three years ago. For four months pains in abdomen,
development of an abdominal tumor, development of a mustache and
beard, and hair on the abdomen, malignant adenoma of the left supra-
renal, uterus and ovaries small, epiphysis and hypophysis normal.

Case of Launois, Pinard, and Gallais.- — Nineteen-year-old girl. Men-
struated first at the age of thirteen years. At seventeen violent vomiting,
gradually colossal obesity, mental changes. Cessation of menstruation,
emaciation, then diffuse depilation, and only then hypertrichosis and
myasthenia. The girl appeared to be much older than she was, black beard
and mustache. Tumor of the right suprarenal.

Possibly also the following case of Dalche belongs here; twenty-eight-year-
old woman, body quite feminine, for five years development of a mustache
and beard and (after miscarriage) cessation of menstruation. Breasts well
developed, voice feminine, uterus small, atrophy of the inner genitalia, hyper-
trichosis on abdomen, slight manifestations of hyperthyrosis, there were no
other symptoms of a suprarenal tumor.

Also a case has been reported that began at the menopause.

Case of Santi. — Fifty-three-year-old woman, two normal pregnancies,
menstruation always regular until six years ago. Then the periods became
more frequent, until the woman lost blood almost constantly. Enlargement
of the abdomen, enormous obesity. Autopsy showed a tumor of the kidney
proceeding from separated suprarenal germs, and a similar tumor of the
ovary. No statement as to hairiness.

Under this category may well belong the case of Vollbracht, mentioned
by v. Neusser and Wiesel. The case was designated by the last named
authors as Addison's disease with contrasexual sexual characters.

Let us look over the cases I have mentioned. In women simultaneously
with the development of a hypernephroma there occur cessation of the
menses, hypertrichosis of a definite localization (linea alba, growth of beard)
and obesity. The development of hypernephroma at the menopause ap-
parently gives rise only to obesity.

III. Cases of Pseudohermaphroditism. — Marchand first reported the
autopsy findings in a fifty-year-old individual who in life was always
regarded as a man.

The individual showed masculine body conformation and masculine hairi-
ness of the face; autopsy showed a hermaphroditismus spurius femininus, a
very large penis-like clitoris, a distinct scrotum and a rather large prostate;
there was also a vagina with the traces of a hymen, a uterus, and atrophic

CONDITIONS OF HYPERFUNCTION OF THE SUPRARENAL APPARATUS 361

ovaries. Finally colossal hypertrophy of the suprarenal cortex and a large
accessory suprarenal. A similar case had previously been reported by
Crecchio.

Three cases of pseudohermaphroditismus femininus by Fiebiger: Habitus
and hairiness quite masculine, larynx masculine, penis and prostate present,
no vasa deferentia, vagina, uterus, and ovaries. The last showed the
follicle formation. No menstruation; capable of cohabitation. Masculine
sexual sense. Very large suprarenals, apparently hyperplasia of the cortex.
Fiebiger regards these cases as an especial teratological type.

Case of Engelhardt. — Fifty-nine years. Married a woman at the age of
twenty-seven years. Erections were present, but only weak and very rare.
Questionable whether ejaculations were present. Beard and mustache.
Facial features masculine. Breasts feminine, hands and feet slender. Penis
embedded in a cushion of fat. Hypospadia, corpora cavernosa present.
Scrotum only indicated by tissue rich in fat, testicles, buttocks, hips and
thighs are feminine. Prostate feebly developed. Autopsy showed an
aberrant suprarenal struma at the lower pole of the right kidney. The
ovaries were small and dense, with sparse, poorly developed, follicles.

Here also belongs the case of Hepner and Ogston and furthermore the very
interesting case of Meixner (case III). This was the case of a new-born
child with pseudohermaphroditismus masculinus, bilateral cryptorchidism,
with separated and enlarged suprarenal glandular tissue in the neighborhood
of the testicles.

v. Neugebauer mentions in his large work thirteen cases of pseudo-
hermaphroditism with suprarenal tumors.

Summarizing the cases cited : only one case was that of pseudohermaph-
roditismus masculinus. The other cases were pseudohermaphroditismus
femininus. All cases showed a bilateral swelling of the suprarenal cortex.

IV. Finally it should be remembered that also in acromegaly there occur
certain cases in which hyperplasia of the suprarenals is observed (Delille,
Fischer, and Fischer and Schultze}. Fischer and Schultze find the entire
suprarenals, cortex as well as medulla hyperplastic, while Delille observed
only a hyperplasia of the cortex. It is very probable that in the future when
we pay more exact attention to these relations we will find hyperplasia of
the suprarenals, and especially of the cortex, in many cases of acromegaly. I
would also call attention to the fact that in many cases of acromegaly, there
occurs both in men and women abnormally abundant hairiness. In women
the hairiness may assume quite the masculine type.

Surveying the entire field of facts, one is surprised by the wealth of
clinical observations that properly classified demonstrate that from the su-
prarenal cortex there proceeds an enormous influence on the growth of the
body, and the genital sphere, and on the hairiness, therefore on an important
secondary sexual character. Until a short time ago these connections were

362 THE DISEASES OF THE SUPRARENAL APPARATUS

scarcely suspected. In the books of Neusser and Wiesel on the diseases of the
suprarenal glands they are hardly taken up. As to what concerns the al-
terations in the organisms that occur in hyperplasia of the suprarenals, that
is in conditions of hyperfunction, it is worthy of note that they are different
according to the age at which such hyperplasia develops. Their action occurs
earliest in pseudohermaphroditism. Here their development occurs in fetal
life. That the development of such cortical hyperplasias stands in a causal
relationship with the development of pseudohermaphroditism is hardly at
all probable; when one considers that up to the present insufficient attention
has been paid to such relationship, it would not do to assume that the hyper-
plasias occur constantly in pseudohermaphroditism. It is much more likely
that they are only a partial manifestation of the malformation, which would
lend to them at all events a definite expression. It has already been men-
tioned, they occur almost exclusively in pseudohermaphroditismus femininus.

In the age of childhood we see with development of the tumors of the
suprarenal cortex a premature development of the entire organism, a sort
of transient gigantism associated with potentized childish dimensions and
premature development of the genital organs, a clinical picture that in
almost all respects is similar to that observed in the development of tumors
of the pineal gland in childhood. Whether hyperplasia of the suprarenal
cortex is frequently present with tumors of the pineal in childhood is as yet
not certain. Up to the present it has been observed in one case only. As we
shall see later in the development of tumors of the sexual glands in childhood
there occur the same clinical pictures, even, if possible, better pronounced.
Here also future studies must decide as to the behavior of the suprarenal
cortex. Apparently there exists an intimate connection between these three
forms of premature development and it would not be unlikely that the bond
of union is the suprarenal cortex. At any rate, a certain influence of the supra-
renal cortex on the growth is evident; with this agrees also the occurrence of
cortical hyperplasia in acromegaly. Just as evident is a certain stimulating
influence on the development of the sexual glands. Apparently there exists
here a reciprocal correlation, as hyperplastic changes in the suprarenal cortex
occur during rut in animals and in pregnancy (Guiyesse, Stoerck and v. Haberer) .
In this also can be seen a certain relation of the suprarenal cortex to growth.
As is known, women who are pregnant and whose epiphysial junctures are still
open often take on a renewed growth during the pregnancy. And finally there
can be seen on it a relation to the growth of the fetus, if it be not forgotten that
the hyperplastic alterations in the anterior lobe of the hypophysis may also
produce and maintain the tendency to increased growth.

When the cortical tumors develop in the fully developed organs the mani-
festations are quite different. Thus far the cases have been favorable.
Here there comes about a pronounced disturbance of the functions of the
sexual glands with involution of the uterus and in addition a tendency to

ADDENDUM 363

obesity and to the development of hairiness, both of which with respect to
abundance and localization are entirely masculine. The influence of the
suprarenal cortex on the hairiness is especially unmistakable in all the con-
ditions mentioned. We find abnormal hairiness in pseudohermaphroditismus
femininus, in the premature development in childhood, in the cortical tumors
that develop in the adult organism, perhaps just in the cases of acromegaly
with hyperplasia of the cortex, and finally, as is known, in pregnancy, in
which hair begins to grow in places that otherwise represent the virile type.
Therefore it seems necessary that in future, when the question is asked as to
which influences the secondary sexual characters have to thank for their
origin, attention should also be paid to the suprarenal cortex. The near re-
lationship that the suprarenal cortex and the substances of the sexual glands
show embryologically and morphologically seems also to exist in tfie function
of these parts.

Treatment. — Up to the present, only the operative treatment of hyper-
nephromata has been tried. In every case an early diagnosis is important, as
the tumors are often malignant. That result may be expected from operation
is shown by the previously mentioned case of Bovin. Perhaps in certain
cases a result may be expected from the use of the X-rays.

3. Tumors of the Suprarenals that Apparently Consist in Cortex and

Medulla

Damdsohn has reported a case of melanoma of the suprarenals with nu-
merous melanotic metastases. Histologically he found cells of the zona
fasciculata and glomerulosa, and also cells of the medulla. The metastases,
on chemical examination and on blood-pressure tests, were found to contain
adrenalin. Moreover, perhaps here belongs the case of Neuberg, in which in-
deed no adrenalin could be demonstrated, but in which an enzyme was found
which could change adrenalin into a black pigment. Neuberg believed that
the adrenalin further produced in the metastases was the mother substance of
the melanin found there. These cases were not accompanied with disturb-
ances of the sexual sphere.

Addendum

%

Glynn, from a review of the literature, arrives at about the same opinions
as the author with reference to the relation of the suprarenal cortex to the
other ductless glands and to sex. He adduces as a further argument for the
view that renal hypernephromata arise from suprarenal rests the fact that
such rests are rare in the kidney, while hypernephromata are common kidney
tumors; and that suprarenal rests in other localities, though comparatively
common, especially in early life, rarely produce tumors at all.

364 THE DISEASES OF THE SUPRARENAL APPARATUS

Cannon, Shohl, and Wright subjected cats to fright, and uniformly ob-
tained glycosuria. This glycosuria was not present after adrenalectomy.

Glynn (E. £.)• The adrenal cortex, its rests and tumors; its relation to other ductless
glands and especially to sex. The Quarterly Journal of Medicine, Vol. V, 1911-1912,

P- 157-

Cannon (W.), Shohl (A. T.), and Wright (W. S.}. Emotional glycosuria. Am. J.
Physiol., 1911-1912, pp. 280-287.

CHAPTER IX

STATUS LYMPHATICUS AND STATUS HYPOPLASTICUS
A. Status Lymphaticus

Here at the conclusion of the discussion of the suprarenal apparatus we
might add some remarks on the so-called status lymphaticus, because recent
investigations have shown that it possesses a close relation to conditions of
hypofunction of the chromaffin tissue. As I have already mentioned in the
chapter on the thymus gland, the tendency among many authors is for the
separation of status thymicus from status lymphaticus. The frequent co-
incidence of a large thymus gland and status lymphaticus can perhaps be
explained by the increase in the lymphoid elements in the thymus gland.
The great interest that clinicians and pathological anatomists have turned on
status lymphaticus depends on the fact that it is associated with cases of
sudden, quite inexplicable, death. It is the great service of A. Paltauf to
have recognized that here there is an underlying profound constitutional
alteration, which is always associated with lymphatism.

How, now, is status lymphaticus characterized? Here it seems that I
must give vent to a conception that has forced itself upon me especially in the
study of the diseases of the ductless glands. I am forced to distinguish a
primary and a secondary lymphatism. The first develops in earliest youth,
and has on this account a profound influence on the development of the whole
organism. It is characterized by the following earmarks (in this I follow the
description of A. Paltauf and especially the new excellent description by
Kolisko). Under normal circumstances we find that in childhood the lym-
phatic apparatus is essentially more strongly developed than in adults.
Hence it comes about that the leucocytic formula of the child shows a greater
content of lymphocytes. The years of childhood are those in which lymphat-
ism is especially prone to develop. The involution of the lymphatic appara-
tus follows, chiefly at puberty. In true status lymphaticus the involution of
an already abnormally developed lymphatic apparatus remains absent.
We find enlarged follicles at the base of the tongue, hyperplasia of the entire
pharyngeal lymphatic ring, lymphoid growth in the nose, enlargement of the
lymphatic glands in the neck, in the axillary and inguinal regions, hyperplasia
of Peyer's patches, red bone marrow, large spleen, and more or less large
thymus gland. Very frequently we found hypoplasia and narrowness of the
aorta and the whole arterial vascular tract. The heart likewise is often ab-
normally small, although it can also be hypertrophic. Commonly there is

365

366 STATUS LYMPH ATICUS AND STATUS HYPOPLASTICUS

dilatation of the left ventricle with diffuse clouding of the endocardium, and
not rarely remaining behind in the development of the genitals, slight de-
velopment of the secondary sexual characters, retarded onset of menstruation,
and retarded, lessened, sexual instinct.

According to the new researches of Wiesel and Hedinger there is regularly
associated with these characteristics an abnormally slight development of the
chromamn tissue. The medullary substance of the suprarenals is essentially
lessened, and the paraganglia are illy developed. According to v. Sury this
underdevelopment of the chromamn tissue mostly sets in after birth.

In status lymphaticus there occurs in the blood picture a relative or ab-
solute reduction of the neutrophilic leucocytes and a corresponding increase
in the mononuclear cells, eventually also a hypereosinophilia (v. Neusser).
This fact is readily intelligible when the experiments of Bertelli, Schweeger,
and myself are considered. On the one hand it is possible that the giving off
of mononuclear cells of the blood is increased in hyperplasia of the lymphatic
apparatus, and on the other hand we must assume that an enormous trophic
influence is exerted on the production of the neutrophilic elements of the bone
marrow, this influence proceeding from the chromamn tissue by mediation of
the sympathetic; here the production of neutrophilic elements by the bone
marrow is probably diminished.

It is very possible that this anomaly of constitution is the cause of the
sudden death. If the chromamn tissue is underdeveloped and not attained
to a great functional breadth, it may, if especial demands are made on it
especially by a cold bath or by the effects of narcosis of the sympathetic
nervous system, suddenly give out. This form of status lymphaticus may well
be designated an "entite morbide." The opinion has been expressed that
substances are given off from the lymph-glandular system to the blood path,
substances that in their action are in a certain way antagonists of adrenalin
(v. Neusser) . Also in this sense can we consider this form of status lymphati-
cus under the diseases of internal secretion. Such individuals, as Eppinger and
Hess point out, not rarely show symptoms of the relatively increased vagal
tonus (inclination to sweats, certain anomalies of the pulse and respiration,
etc.). The slight functional breadth of the chromamn tissue is, however,
especially important for the fate of such individuals. Often the blood-pres-
sure lies near the lower limits of normal, as Munzer emphasizes, the pulse
shows a slight force [Wurfkraft]. According to Wiesel such individuals are
especially predisposed to Addison's disease, in that tuberculous and other
processes become established in the hypoplastic suprarenal medulla, and by
spreading to the cortex call forth the typical picture of Addison's disease.

The secondary form of status lymphaticus is characterized by the fact
that the signs of lymphatism predominate only later, the development origi-
nally being normal. According to the age of the individual, according to
whether the lymphatism is only transitory or remains permanent, does the

STATUS HYPOPLASTICUS 367

development become more or less inhibited. In childhood, as already //.
Kundrat mentioned, rachitis leads to lymphatism not infrequently, as do also
tetany, the exudative diathesis, especially scrofulosis, and a series of other
infectious processes. In adolescent and adult individuals occasion is given
for a temporary or a permanent lymphatism by the vagal neurosis, bronchial
asthma, chronic infectious diseases, especially lues and tuberculosis, osteo-
malacia, and especially the affections of the ductless glands. In a great num-
ber of cases perhaps there occurs at first, through chemotactic influences, only
a slight mononucleosis of the blood, and only later a slight hyperplasia of the
lymphatic apparatus, therefore a forme fruste; in other cases, especially in
many formations of ductless glandular affections, the hyperplasia of the lym-
phatic apparatus may be fully developed. Of the ductless glandular diseases
should be mentioned especially Addison's disease, myxedema, Basedow's dis-
ease, acromegaly, tetany, and dystrophia adiposo-genitalis. Also in some
cases that we must regard as true eunuchoids we found appreciable mononu-
cleosis of the blood. It is self-evident that mononucleosis is a symptom with
many meanings, and in itself speaks nothing for the diagnosis of status lym-
phaticus. Thus we found it strikingly present also in many severe forms of
diabetes mellitus in which autopsy showed no status lymphaticus. It is very
probable that under secondary lymphatism are concealed numerous and di-
verse conditions, in part chronic inflammatory in nature, the differentiation
of which perhaps can first be made by a careful microscopical examination of
the lymphatic apparatus.

The great difficulty in the diagnosis of status lymphaticus in vivo is made
prominent in the comprehensive exposition of this subject brought out a short
time ago by V. Neusser. v. Neusser relates how important it is to have in
mind, in consideration of the minute factors, the possibilities of an existing
status lymphaticus, because the infectious diseases and especially the most
diverse noxious agents frequently take on a characteristic expression on
the ground of this constitutional anomaly and often pursue their course
unfavorably.

B. Status Hypoplasticus

In several works, Bartel has indicated a form of developmental disturbances
that he designates hypoplastic constitution. It is frequently, but not always,
associated with status lymphaticus. The body size of such individuals is on
the average normal. Often the fatty tissue is very well developed. There is
found hypoplasia and narrowness of the vascular system and poverty of the
smooth musculature of the aorta (Wiesner), and in addition faulty develop-
ment of the sexual glands and secondary sexual characters. The sexual
glands are indeed of normal size, the ovaries often even enlarged; microscop-
ically there is found, however, proliferation of the connective tissue (Herrmann
and Kyrle) . When status lymphaticus is present an atrophic stage can follow

368 STATUS LYMPH ATICUS AND STATUS HYPOPLASTICUS

the stage of hyperplasia. Bartel assumes as the cause of this condition con-
genital predisposition on the one hand, and on the other hand damaging of
the sensitive childish organism, especially by infectious diseases. The
length of life of such individuals is mostly shortened, and 56 per cent, of the
cases investigated by Bartel died between the fourteenth and twenty-fifth
years of life. The status hypoplasticus is thus not entirely identical with
status lymphaticus, but also not with true infantilism, which will be described
in another chapter.

CHAPTER X
THE DISEASES OF THE SEXUAL GLANDS

The knowledge of the internal secretion took its origin from the sexual
glands. Brown-Sequard injected himself with testicular extract and be-
lieved that thereby he could obtain a sort of rejuvenation of the organism.
The experiments on the sexual glands also first brought the knowledge that
the function of the ductless glands is in a high degree independent of the nerv-
ous system. Goltz transected the spinal cords of animals and observed that
these animals conceived, carried their young normally, gave birth, and suckled,
in spite of the fact that the ovaries were cut off from the higher nervous
centers. The later researches on transplantation of the sexual glands showed
this independence in still higher degree. Ribbert, and later Knauer, trans-
planted the ovaries under the skin in animals and observed that in such
animals there occurred no involution of the uterus such as would otherwise
tend to occur after castration. Halban showed that also in the youthful
incomplete organism transplanted ovaries could exercise their protective
influence on the development of the genital apparatus. The ovaries were
transplanted under the skin of new-born guinea-pigs. After one year
Graffian follicles and ova were present in the transplants. Uterus and
breasts developed normally, while in the castrated control animals breasts
and genitalia remained quite rudimentary. Foges and later Steinach then
showed that after transplantation of the testicles the secondary sexual char-
acters develop (although not always completely), while in the castrated
control animals the development of these characters suffer marked damage.

While not until lately has experimental pathology furnished an insight
into the function of the sexual glands, clinical observation from the very be-
ginning has stirred the interest of physicians and the laity, because the in-
stinct of procreation affects everything that lives. The influence that the
loss of the sexual glands exercises on the configuration of the body and the
development of the secondary sexual characters has been known since antiq-
uity. Just those malformations that stand in especial relations with the
sexual glands, such as hermaphroditism, or the development of the so-called
contrasexual character, belong to these curiosities that since that time have
been exhibited in show-booths [museums]. Also the problem of heredity is
intimately associated with the function of the sexual glands.

Finally this problem has always had a great significance for breeders
of animals.

24 369

37° THE DISEASES OF THE SEXUAL GLANDS

Embryological, Anatomical, and Physiological Preliminary Remarks.—
For the comprehension of the physiology and pathology of the sexual glands
it is necessary to distinguish sharply between these proper and the accessory
genital apparatus. The rudiments of the accessory apparatus (primordial
kidneys with Wolffian and Mullerian ducts) are common to both sexes.
According as to whether sexual glands develop into testicles or ovaries do
the indifferent rudiments develop into epididymis, paradidymis, vasa
deferentia, and prostate, or into epoophoron, paroophoron, Gartner's ducts,
tubes, uterus, and vagina.

Two parts of the sexual glands are to be distinguished: the interstitial
glands1 (consisting in the so-called Leydig's interstitial tissue) , and the specific
glands of generation (in man, seminiferous tubules, Sertoli's cells [?] in
wTomen, the follicular apparatus).

A. The Interstitial Glands

The Leydig's interstitial cells are epithelioid cell accumulations imbedded
in the sexual glands of the male. They are filled with acidophilic and baso-
philic granules, show great similarity to the cells of the suprarenal cortex,
and like these are of mesodermal origin (Simon, 1892, Wallart, Seitz). These
cell formations develop enormously at the time of puberty. In women we
understand by "interstitial glands" a cell complex that develops from the
atretic follicles of the theca interna. In women these cells develop very
markedly at the time of puberty, and temporarily during pregnancy (Wallart.}
I must not omit to state that the view is held by many that in the highest
female mammals, in the human species and in monkeys, the interstitial glands
are inconstant (Bucura). This has been denied on other sides, and I would
only state here that the function of the interstitial glands in man is to-day
already so sharply delimited and that it is concerned with functions so im-
portant, functions that influence the conformation of the body in such an
extensive manner, that it is hard to believe that so important an organ is
absent in women.

According to the view of some of the authors the interstitial glands govern
in man in this special field the development of the primary and secondary
sexual characters, and are hence of great importance for the formation of
the body.

The distinction between interstitial glands and generative apparatus is

1 The distinction between "internal secretory and germinative" that up to the present has
been the practice in the literature, and that was also retained by me in my article on the diseases
of ductless glands in Mehr-Staehclin's handbook, must be rejected by me, as it seems to me to
lead to the coarsest misunderstandings. Steinach designates the "innersekretorische" glands
as " Pubertatsdriise." It seems to be undoubted however that the "internal secretory" activity
of the generative apparatus is very considerable. Indeed the entire teaching of hormones has
been developed -from the influencing of the growth of mammary glands through the hormone of
the fetus or of the chorionic epithelium, that is properly speaking, the ovum.

THE INTERSTITIAL GLANDS 371

based on a series of clinical observations and experimental facts. The clinical
observations, which I shall describe first, are concerned with cryptorchidism.

Variot first pointed out the great difference between kryptorchides ab-
dominaux and kryptorchides inguinalis. The first is associated with obesity
and broadening of the pelyis; the larynx remains small, the voice remains
high and shrill, the beard and the pubic hairs do not grow; microscopical
examination shows marked connective tissue proliferation in the extremely
small testicles. I shall speak of this form later in the consideration of
eunuchoidism.

In. the adult kryptorchides inguinales, in which the testicles remain behind
in the inguinal canal, the sexual potency may be present. Such individuals
may have ejaculations without the expulsion of spermatozoa. They are
therefore potent, but sterile. These individuals have an entirely masculine
habitus, the voice changes, there occur growth of beard and normal hairiness
of the trunk, the musculature is vigorous, the dimensions of the skeletons are
normal, etc. Here the function of the interstitial glands is retained, while
that of the generative glands is not developed. In twenty cases of cryptor-
chic testicles, Tandler did not find spermatogenesis in a single case, but did find
normal interstitial substance. Therefore, in cryptorchidism the disturb-
ance in the development of the glands of generation is the rule, while the
disturbance of that of the interstitial glands is found only in severe cases.

The first experimental observations were made by Ancel and Bouin.
They ligated the vasa deferentia and found that after a time spermatogenesis
had entirely disappeared, while interstitial glands were retained. These
animals showed complete normal development of the masculine habitus.
Tandler and Grosz further showed that after intensive Rontgen irradiation
of the testicles of young Cerviden the spermatogones, on account of their
greater sensitiveness become destroyed, while the interstitial glands were
retained. In these animals the masculine sexual characters developed in
entirely normal manner. Latterly Simmonds has shown that after Rontgen
irradiation there are always found individual undamaged seminal tubules,
that can again regenerate; but the significance of this finding must not be
estimated too high. Lately Steinach has reported concerning transplanta-
tion experiments that place the matter in a secure position. If in young
sucklings the testicles are transplanted, the secondary sexual characters
proceed to develop entirely normally. The histological examination shows
that the spermatozoa are entirely absent. Clinical observation was thus
entirely corroborated by experiment.

As in such animals also the external genitalia develop entirely normally,
it is to be assumed that the interstitial glands exercise an important influence:
i. On the development of the generative glands. An isolated develop-
ment of these without the interstitial glands is not known in' the male
sex.

372 THE DISEASES OF THE SEXUAL GLANDS

2. On the accessory genital apparatus.

3. On the so-called secondary sexual characters.

Hence the question is explained in the male sex. As has been mentioned
it is hard to assume that in women such an important organ should be
absent.

Although it is now established that the interstitial glands exercise an
entirely essential influence on the development of the secondary sexual
characters, we must still regard the question of the genesis of the secondary
sexual characters and their relations to the sexual glands as one that is
much argued. There is no uniformity in the definition, even of the sec-
ondary sexual characters. Darwin understands by them any sexual char-
acters that are characteristic for the sex in question, but which have nothing
directly to do with reproduction.

R. Mutter divides the secondary sexual characters into physical and
mental, and further divides them into:

1. Such as have entered into an intimate relationship with the propaga-
tion and nurture of the young animals: for example, female pelvis,
mammary glands, temperament, sexual instinct, maternal love.

2. Such in which are shown an immediate dependence on sexual glands:
skeleton, muscular system, skin-appendages (antlers, horns, combs,
etc.), formation of the larynx, swelling of the thyroid gland, etc.

3. Such that are only mediately dependent on the sexual glands: internal
organs, different psychical activity, etc.

I wish from the beginning to limit myself to these two definitions. My
attitude toward them will be stated later.

First I shall describe more in detail the distinguishing features between
the [human] male and female bodies, following the exposition of Novak.
The female and male bodies are far more like each other up to the time of
puberty than later. Before puberty both show the infantile type, although
extensive differences exist even in the earliest period of embryonal life.
For instance the pelvis may be recognized as feminine as early as the fifth
month of embryonal existence (Fehling) . At the time of puberty the growth
in both sexes is essentially increased. In the male the larynx now enlarges,
the voice changes, the growth of the beard begins to be more evident; in the
female, the breasts develop, the characteristic form of pelvis becomes more
prominent, the figure becomes rounded and an abundant deposit of fat is
found especially on the hips. In both sexes there now occurs a growth of
pubic and axillary hairs, the former in women remaining bounded above by
a horizontal line, while in man it closes above in the form of a triangle. In
man the body size is on the average greater, the horizontal circumference of
the head is slighter in relation to the body height, in woman the capacity of
the head is less, as is also the extension of the facial part. In man the ex-
tremities are longer in relation to the length of torso, in woman this is re-

THE INTERSTITIAL GLANDS 373

versed. In women the shoulder-girdle is relatively small, the hips broader,
hairs of the head in woman are much longer, the hairiness of the body is
absent. Michaeli's quadrangle is broader in woman, the sacrum is less curved
and is shorter, the symphysis is broader and lower, the pubic angle is greater,
the iliac fossae are broader, the transverse extension of the pelvis is greater,
the pelvic entrance and exit are greater and wider. The glandular substance
in the breast is always developed even in the virgin, the nipples are more
prominent, and more easily erectile. In addition there is in woman a less
number of erythrocytes per cubic millimeter of blood. Then there are
differences in the psyche, that become more prominent from the time of
puberty.

I would now briefly sketch those problems that seem to me most im-
portant for the evaluation of the secondary sexual characters and for their
genesis.

Almost all of the distinguishing signs that have been mentioned may
be included under Darwin's definition. The mammary glands seem to me
to form an exception. Much seems to speak for the fact that the female
mammary glands are a primary sexual character, or rather that they should
be directly ascribed to the generative apparatus. We cannot say of them
that they have nothing to do directly with propagation, for in mammals
the brood would be annihilated if the mammary glands were to cease to
functionate. We can, however, go farther and suppose that the growth im-
pulse and mammary glands experience in women emanates not from the
interstitial glands, but from the generative apparatus, that there exists
no development of the glandular substances (certainly not of the fat sub-
stances) without development of the follicular apparatus, and that the
most extensive growth impulse, namely that during pregnancy, proceeds
from the generative apparatus, equally if we regard as the source of the
mammary hormone the growing fetus or the chorionic epithelium. We
shall enter more fully into this question later.

A further moot point is whether the secondary sexual characters are
performed from the ovum — as to the question whether before or after con-
ception, I shall not enter into here at all — or whether they develop in the
masculine or feminine direction under the influence of the sexual glands.
Lenhossek and Halban hold the opinion that the total sexual characters are
somewhat preexistent and that the sexual glands exercise only a protective
action on their development.1 Another view that stands rather bluntly
opposed to that just described is that the sexual glands furnish a direct
formative stimulus on the sexual characters. Recently Steinach on the

1 Also Tandler upholds the opinion that the sexual sphere of action of the secondary sexual
characters as well as those of the germinal glands are preexistent. Tandler and Grosz mention
in this connection that the so-called secondary sexual characters are only characters of species
and enter into relation to the genital sphere only secondarily.

374 THE DISEASES OF THE SEXUAL GLANDS

ground of transplantation experiments inclines to this view. Finally Biedl
supposes a hermaphroditic rudiment of the sexual glands. The secondary
sexual characters develop either in a masculine or a feminine direction
according as to whether the development of the masculine or feminine
internal secretory sexual glands predominate. The occurrence of heterolog-
ous sexual characters is explained by Biedl by the supposition that the
internal secretory portion of the sexual glands that belongs to the other sex
obtains the upper hand.

A further problem lies in the fact whether the sexual characters in their
development especially depend exclusively on the sexual glands, or whether
much more do they not rather receive decisive influences from the other
ductless glands.

The discussion of all these questions makes necessary not only the resort
to experimental pathology and physiology, but to an abundance of clinical
observations. It seems to me therefore suitable to describe first the genera-
tive apparatus, then to detail the most important clinical observations and
only later to enter into the discussion of these questions. I need hardly
emphasize that judging from the contradictory nature of the opinions, the
discussion must be strongly tinged subjectively.

B. The Generative Apparatus

As previously mentioned, the interstitial glands are of mesodermal origin.
This has also been assumed for the generative apparatus, although to me
the view seems very noteworthy that the generative apparatus (spermato-
gonia in man, follicular apparatus in women) develop out of the primordial
cells. Then the interstitial glands and generative apparatus are differenti-
ated embryologically. Primordial follicles and Sertoli's cells are demon-
strable already at an early embryological stage.

We shall first take note of the development of the generative glands and
their influence on the total organism, in woman. The development of the
follicular apparatus is quite gradual. First -at the time of puberty, together
with the beginning of maturation of the interstitial glands does it come to
full development; at the same time too with an enormous growth impulse
for the breasts and the beginning of menstruation. While now in man after
complete maturity there enters the condition of rather continuous function of
the sexual glands and especially the generative apparatus, in woman the
activity of the sexual glands and especially of the generative apparatus
is subjected to periodic variation. With the periodically recurring ovula-
tion and menstruation, there enters into the vital processes a noticeable wave
movement that has been deeply studied by Goodman, Jacobi, Rabutau,
Reinl, Ott, and others. We must distinguish a premenstrual period, a period
of menstruation and a postmenstrual interval. During the premenstrual

THE GENERATIVE APPARATUS 375

period there are found signs of a gradually increasing vitality of the internal
organism, that rapidly reduces during the bleeding. In the seven or nine
days immediately before menstruation the blood-pressure increases, it falls
rapidly with the beginning of the flow, and reaches its lowest value at the
close of the period. With this variation in blood-pressure are associated
variations in the erythrocyte count. In the premenstrual period the ery-
throcyte count may lie i to i^ millions higher than toward the end of
menstruation. It is very possible indeed that just as in tetany, these
variations in the erythrocyte count are to a great degree the expression of an
increased or diminished tonus of the vessels; for which view speaks also the
careful blood-pressure measurements. In connection with it may stand
too the strong permeation of many organs with blood. Moreover in the
premenstrual period there is found a higher level of bodily temperature that
becomes prominent especially in latent diseases (Reinl). On the day pre-
ceding and the day following menstruation the temperature is the lowest.
In many individuals there may also be demonstrable, in the premenstrual
period, a slight neutrophilic hyperleucocytosis and a slight heightening of
the coagulability of the blood. Also the respiratory volume is often raised
in the premenstrual period, while it is slightly decreased during menstrua-
tion (L. Zuntz). Many of the manifestations detailed seem to me to point
to an increased function of the chromaffin tissue. With this may be con-
nected the observation that in the premenstrual period the glycosuric ac-
tion of adrenalin is heightened. Moreover there is found an increase in
reflex excitability and often a higher mental alertness and capacity, while
during menstruation there often occurs a certain mental obtuseness. Known
for a very long time is the swelling of the thyroid gland in the premenstrual
period (struma antemenstrualis, Heidenhain). It is further stated that
before rut and in the premenstrual period the suprarenal cortex increases in
size. Also the interstitial glands show the same behavior during this period,
apparently also does this hold true for the glandular hypophysis. At least
such a conclusion seems suggested by the similar alterations of these ductless
glands during pregnancy; perhaps there is also found in the premenstrual
period an increased growth of any beard that may be present (Halban).
Finally it is known that the mammary glands often swell slightly, and in
rare cases even in the virgin may secrete a slight amount of colostrum.
Further the nipples often show an increased erectibility and are painful.

What now is the cause of this rhythmically occurring menstrual wave?
Pfluger developed a theory that monthly ovulation leads by reflex paths to a
hyperemia of the pelvic organs, thereby causing menstruation. Pfluger's
law has been made untenable by the knowledge that the influence of the
ovaries in the organism is independent of the nervous system and depends
on the giving off of substances to the blood-path. Hence it must be modified
to state that the influence of the internal secretion of the generative apparatus

376 THE DISEASES OF THE SEXUAL GLANDS

on the organism is, through the maturation of the ovum, increased in a
rhythmic manner. It is now urged against the dependence of menstruation
on ovulation that not rarely menstruation and ovulation do not occur at
the same time, but that under circumstances ovulation can take place after
menstruation (Leopold and Mironow, Ravano}. Frankel has therefore upheld
the view that the retrogression of the corpus luteum gives rise to menstrua-
tion. According to the view of most authors there can, however, be attrib-
uted to corpus luteum at most a postponing but not a releasing [auslosende]
action (Halban). Halban would principally ascribe to the ovulation, that
is to the sexual glands, only a protective but not a formative influence on
menstruation or on rut and on the cyclical menstrual phenomena, pointing
out the known fact that after even a long time after bilateral ovarectomy
the menstrual wave may reappear. Numerous extensive statistics exist as
to this question ; I mention only the statement of Pfister that in on an average
of 12 per cent, of castrated women menstruation reappeared and that among
116 castrations vicarious menstruation from the bowel or the nose occurred
for a time in cases. Finally it must be pointed out that in a great per-
centage of cases after castration there exist cyclical menstrual molimina
(backache, nausea, colics, etc.). Of course these molimina occur when the
uterus is removed and the ovaries remain behind in the body. Halban is
therefore of the opinion that the menstrual wave is released not from the
ovary itself, but by an as yet unknown agent and that much the more the
ovary itself reacts to this agent in an especially sensitive way, and this reac-
tion of the ovary first brings the menstrual wave to its complete fulfillment.
I would not subscribe unreservedly to the view of Halban. The de-
pendence of menstruation on ovulation is in any case very considerable.
Halban himself has shown that in baboons, which have a menstruation
similar to that of human beings, menstruation is retained after transplanta-
tion of the ovaries. On the other hand after ovarectomy, rut remains
away with almost every case. Lately Adler has shown that subcutaneous
injection of watery extract of ovaries calls forth in virginal animals altera-
tions in the internal genitalia, especially the uterus, that remind one of the
changes that take place during rut. In two amenorrheic women in whom
pieces of mucous membrane were obtained from the uterus by curettement
before and after injection of this extract, microscopical examinations of these
pieces showed that there were menstrual alterations of the mucous mem-
brane. As after castration the menstrual wave is recovered after a time in
an attenuated form, this does not seem to me quite inexplicable. We can
imagine that the menstrual wave that has existed for several years may under
circumstances continue for a while after castration, if the sexual life has
once been fully developed. The difficult point according to my view would
lie in the question whether, in youthful persons in whom menstruation is
mostly absent, the development of the wave would be entirely prevented

THE GENERATIVE APPARATUS 377

by castration. I believe that this would be the case, just as the sexual life
fails to develop, in those castrated in early youth. The circumstance that
ovulation and menstruation do not always occur at the same time does
not seem to me very essential. It is conceivable that the acme of the in-
ternal secretory function of the maturing follicle and the reaction of the
organism due to this in many cases occur before the extrusion of the egg, in
fashion similar to that which Halban assumes for the function of the chori-
onic epithelium in pregnancy. While therefore ovulation is independent of
menstruation, ovulation may continue to exist when menstruation is ab-
sent. This is satisfactorily demonstrated by the fact that women a long
time amenorrheic may conceive. Indeed ovulation may take place in
women who have never menstruated; then are found eventually only
cyclical swelling of the uterine mucous membranes, or cyclical leucorrhea
(Ogorek).

Pregnancy. — Even after fructification the ovulation shows certain starts
[Ansatze] (Ravano-Fellner) , then it ceases entirely, and menstruation ceases
with it. The corpus luteum persists. Probably the cessation of ovulation
is to be referred to persistence of the corpus luteum, or both manifesta-
tions are to be referred to the developing fetus or much more to the develop-
ment of the chorionic epithelium. I. cite the following from' known facts
that are important for the understanding of these relationships. In the
cow there not rarely occurs persistence and hypertrophy of the corpus lu-
teum. Then rut ceases. If the corpus luteum be removed, rut recurs.
Moreover Kleinhans and Schenk showed that extirpation of the corpus luteum
alone does not lead to interruption of pregnancy, therefore that the develop-
ment of the fertilized egg is not dependent on corpus luteum.

Pregnancy leads to profound changes in the maternal organism. Accord-
ing to Neumann and Hermann lipoidemia can always be demonstrated.
They found the lipoidemia also after castration and in the climacteric period.
I would refer it especially to the cessation of the activities of the follicular
apparatus. Further, during pregnancy, are found signs of a heightened
excitability of the vegetative nervous system. L. Pollak could show during
pregnancy heightened glycosuric action of adrenalin. The statement
as to an increased adrenolinemia in pregnant women (Neu) could not be
corroborated by Neubauer and Novak.

Very commonly in the latter stages of pregnancy is found a neutro-
philic hyperleucocytosis. Further the temperature is placed at a higher
level, and also the blood-pressure and the pulse rate are higher.

Also investigations on the metabolism have shown that there are pro-
found alterations. Folk and Hesky, and Zangemeister found relative in-
crease in the ammoniacal nitrogen, Leersum, Rebaudi, and Falk and Hesky
found increase in the amino acids, the authors last-named also an increase in
the polypeptid nitrogen, and Salamon and Saxl an increase in the elimina-

378 THE DISEASES OF THE SEXUAL GLANDS

tion of oxyproteinic acid. The tendency of pregnant women to alimentary
glycosuria and alimentary levulosuria is well known. Lately Xovak and
Forges have discovered a tendency toward ketonuria. The cause of these
metabolic alterations is seen by most of the authors cited in a disturbance of
the function of the liver, from which they have inferred degenerative proc-
esses in that organ. It would, however, be remarkable if a physiological
process such as pregnancy should regularly lead to such severe disturbances;
I would regard as the cause of these metabolic disturbances only an in-
crease in the irritability of the liver, which is a partial phenomena of the
increased vitality of the whole organism.

It is very noteworthy that numerous symptoms point to an increased
function of almost the whole ductless glandular system. Certain of the
previously mentioned symptoms may be referred with some probability
to an energetic activity of the chromaffin tissue; the regular occurrence of
iron-free pigment perhaps points also to an increased adrenalin consump-
tion.1 As is known such pigmentations develop along the linea alba, at the
navel, on the perineum, on the labia majora, on the areolae of the nipples,
and on the face (chloasma uterinum). Very noteworthy is the occurrence
of abnormal hairiness, as Halban first pointed out. Especially distinct is
the increased growth of a previously existing rudiment of the beard. Halban
cites a very interesting case of Slocum's. A woman carried three children
normally and also had an abortion at the sixth or eighth week. In each
pregnancy the beard grew on the cheeks and chin. But also the downy
hair on the entire body, especially on the abdomen and on the linea alba,
grew stronger during pregnancy. These hairs fell out again after the labor.
Halban could even demonstrate the increased growth tendencies of the hair
in animal experiment. After shaving of the abdomina of pregnant animals
the hair grows faster there than on the abdomina of nonpregnant animals
similarly treated. He refers these anomalies in the hairiness to the internal
secretory activity of the chorionic epithelium; it would also be likely, how-
ever, that this comes into relationship with the hyperplasia of the suprarenal
cortex that occurs in pregnancy, as is pointed out by Glynn. This hyper-
plasia of the suprarenal glands has been demonstrated by v. Haberer and
Stoerck.

I would attribute especial value to the fact that during pregnancy the
interstitial glands develop enormously. This fact shows that also in the
sexual glands of the female there is a certain independence of the function
of the interstitial glands from that of the generative glands. While the
activity of the follicular apparatus becomes inhibited, the interstitial glands
show histological signs of an increased activity. According to my view the
clinical symptoms correspond to those of the histological finding. As I

1 See the hypothesis as to the genesis of the pigmentation in the chapter on the suprarenal
apparatus.

THE GENERATIVE APPARATUS 379

already emphasized in the article on ductless gland diseases in Mohr-Stae-
helins handbook (Vol. IV), I cannot subscribe to the opinion upheld
especially by Tandler and Grosz that during pregnancy the "internal secre-
tory" activity of the ovary is inhibited by the persistence of the corpus
luteum. By "internal secretory" activity is understood by these authors a
function that in fact can only depend on the interstitial glands. Against
an inhibition of the interstitial glands speaks, however, the fact that during
pregnancy the secondary sexual characters throughout do not retrogress,
and on the contrary there is found, in agreement with histological findings,
strong accentuation of them. Entirely especial, however, are the views
concerning the relation of the sexual glands to the hypophysis, which had
led to the rapid entrance into the literature of what I consider an incorrect
view. Therefore I must enter into this question more in detail.

The hypophysis in woman during pregnancy enlarges considerably.
Its weight can rise to two and one-half times as much as normal. Enlarge-
ment of the anterior lobes is exclusively responsible for this increase in weight;
this lobe becomes more juicy and essentially softer. It shows the occurrence
of enormous numbers of pregnancy cells, which develop from the so-called
chief-cells. In the later stages of pregnancy more than four-fifths of the organ
may consist of the new formed cells. . Comte, and Launois and Moulon first
pointed out this enlargement of the hypophysis, and Erdheim and Stumme,
whose exposition I follow, carefully studied these alterations in a great num-
ber of cases. Then enlargement of the hypophysis during pregnancy is some-
times so considerable that in rare cases even a pressure-action on the chiasma
seems to be possible, v. Reuss described repeated temporary blindness dur-
ing pregnancy, while Bellinzona and Tritondani report bilateral narrow-
ing of the visual field. Actually there exist a series of manifestations that
point to an increase in function of the hypophysis during pregnancy. To
these may belong the osteophyte formations on the internal surface of the
skull that are associated with marked hyperemia of the dura. In addi-
tion they are found also on the upper jaw, on the nose, and on the frontal and
parietal bones (Manau), further the development of substance devoid of
calcium in the pelvis. Breus and Kolisko observed increase of the growth
of the pelvis during pregnancy. Tandler and Grosz point out that in gravid
persons there is a coarsening of the facial features, especially of the soft
parts of the nose, lips, and moreover that a thickening of the hands is not
rare, manifestations that remind pne of a slight grade of acromegaly. I
refer in the chapter on the hypophysis to the case of Marek, in which we
can indeed speak of a transitory forme fruste of acromegaly. As far as the
growth of hair on the linea alba is concerned, I should rather ascribe it to
the hyperplastic alterations of the suprarenal cortex. Into association with
increase of function of the hypophysis may be brought also the observa-
tion of Halban that in youthful persons whose epiphysial junctures are not

380 THE DISEASES OF THE SEXUAL GLANDS

yet fully closed, the growth can proceed in fits and starts during pregnancy.
I shall refer to this later.

We see therefore that in pregnancy an increase of the function of the hypo-
physis is associated with an increase of function of the interstitial glands, as;is
also the case in acromegaly. There remains only one point that also seems
very much to support the view of Tandler and Grosz. Tandler and Grosz con-
cerned themselves with the observation that the extirpation of the ovaries,
hence a removal of the internal secretory activity of these organs, leads to en-
largement of the hypophysis, and they thus regard the cause of the tall growth
in the castrated to an increase in the function of the hypophysis. Fischer
first reported that in capons and castrated male cattle the hypophysis is often
twice as large as in cocks and uncastrated male cattle. Moreover, Jutaka
Kon states that in eight castrated women the hypophysis was found enlarged
and rather heavy. The enlargement affected the glandular part alone and
on histological examination there was found the picture of true hyper-
trophy. Finally Tandler and Grosz several times observed a strikingly
large sella turcica in "skopzen." [See p. 391.] So far as the findings in the
hypophyses of castrated animals is concerned, there is found, however, the
statement that manifestations of an apparently degenerative kind (vacuole
formation) are often observed. I am very sceptical with regard to the finding
of Jutaka Kon. At least one cannot draw from it the inference as to an in-
crease of function of the hypophysis, for nobody would state that symptoms
occur in castrated women that indicate such an increase. In male late
castrates may be observed such an enlargement of the sella turcica, as in one
of the cases I reported (castration in the twenty-sixth year of life) , or in the
case of Rieger (epistolatory communication). Further Tandler and Grosz
have already stated that no enlargement of the sella was found, and further
on I shall report four cases of eunuchoidism, in which the sella was found to
be normal in size or strikingly small. Finally as far as the tallness of enunchs
and eunuchoids is concerned, I would refer it not to an increase in function
of the hypophysis, but to a persistence of the epiphysial junctures. As
we have seen in the chapter on the hypophysis early acromegaly does not
always lead to tallness, also not when the epiphysial junctures have not
closed prematurely. Nor are there to be found in eunuchs or in eunuchoids
any other signs of a hyperfunction or an increased function of the hypo-
physis; I call to mind only the so characteristic behavior of the carbohydrate
metabolism in acromegaly. The view of Launois and Roy that when the
epiphysial junctures are open, functional increase of the hypophysis leads
to tallness or to gigantism, and when closed, to acromegaly is to my mind as
untenable as the opinion that falling away of the sexual glands produces in-
crease of function of the hypophysis. If we follow both views to their ulti-
mate consequences, we arrive at the postulate that castration after
epiphysial closure must call forth acromegalic manifestations, as is evidently

THE GENERATIVE APPARATUS 381

not the case. And I believe therefore that Halban's symptom of increase of
growth in youthful gravida does not depend so much on increase of hypo-
physial function but rather much more on the periodically increased vitality
of the whole organism when the epiphysial junctures are open.

Let us now return to the behavior of the ductless glandular apparatus in
pregnancy. I must here mention the fact known already in antiquity that
during pregnancy there is increase in volume of the thyroid gland. There
develops a parenchymatous struma that feels soft on palpation. There is
indeed no doubt that this increase in volume is associated with a slight in-
crease in function, that is even a partial phenomenon of the increased
vitality.

An increase of function of the parathyroids and of the pancreas can be
inferred by us only indirectly, from the fact that the latent insufficiency of
these glands tends to be manifest during this period; we have grounds for
assuming that this occurs as a consequence of increased demands and there-
fore that normally the function of these ductless glands is increased.

We will now describe the changes undergone during pregnancy by the
mammary glands. First of all I will make some remarks as to their devel-
opment. Halban, whose important works we have to thank for our informa-
tion, distinguishes four periods of grow-th impulse separated in point of time.
The first falls about in the time between the eighth and ninth lunar months
[of embryonal life]. The second , occurs at the time of puberty, the third
always recurs at the premenstrual periods, and the fourth, especially inten-
sive, occurs during pregnancy. The ovaries constitute the trophic center for
the first three growth impulses. This may already be seen by the fact that
in disturbances in the development of the ovaries the breasts too remain
undeveloped (Foges) . The growth impulse during puberty leads as is known
to a noticeable development of the glandular parenchyma. The growth im-
pulse in the premenstrual periods can in rare cases be so strong that in virginal
individuals colostrum may be secreted, and later, during the menstruation,
milk may appear (Scanzoni, Gauthier). The most intensive impulse of
growth occurs during pregnancy. The breasts swell and toward the end
of pregnancy may yield colostrum on expression. There is no doubt but
that this impulse for growth is set free by hormones. This is shown by ob-
servations on the Siamese twins, Blazek; when the one became pregnant the
breasts of the other swelled also, and after confinement, secretion of milk
occurred in both (Schauta)', Grigori and M. Cristea could make the same
observation on parabiotic animals. For the hormone theory speaks also
the observation of Ribbert that transplanted mammae secrete milk after
birth. The ovaries are not necessary for the pregnancy-hyperplasia of
the mammae, as also in spite of castration undertaken in the early stages
of pregnancy, the development of the breasts proceeds in a normal manner,
and the women are able to suckle their children. Mainzer has collected

382 THE DISEASES OF THE SEXUAL GLANDS

sixteen such cases from the literature and Halban has added three more.
It looks very much now as though the removal of the ovary later exe'rcises
a favorable influence on milk-production, as breeders state that castrated
cows yield abundant milk. Noteworthy in this respect is the case of Foges.
After a labor a woman experienced a secretion of milk for seventeen years.
During this time constant amenorrhea existed. After seventeen years men-
struation a new conception occurred. After the labor the milk-secretion
continued again for six years.

Milk usually comes on two or four days after labor. This whether the
birth takes place at normal time or whether there has been a miscarriage.
Secretion of milk has even been observed after an abortion as early as the
second month of pregnancy. As the pregnancy-hyperplasia of the breasts
is independent of the ovaries, Starling and Lane-Claypon have regarded the
fetus as the source of the mammary gland hormone. Actually they even
succeeded in inducing growth of the mammary glands by injection of ex-
tract of embryos into the peritoneal cavity of rabbits that had not yet been
covered. Also Biedel and Konigstein lend themselves to this view, as has
also Fod who recently on the ground of his experiment has upheld the
opinion that the mammary glandular hormone was not specific in kind.
Against this, Halban has upheld the view that the pregnancy-hyperplasia of
the breasts is produced by a hormone, that proceeds from the chorionic
epithelium of the placenta. Halban bases his view on the following observa-
tions. The pregnancy-hyperplasia of the breasts can still develop if
the fetus has been dead a long time but the placenta remains living. If,
however, the placenta too dies, the further development of the mammary
glands ceases and milk begins to flow. Halban further observed two casee of
cystic mole, in which secretion of milk began after expulsion of the mole.
Halban sets forth that the chorionic villi develop from the fertilized egg
and in spite of enormous growth until the end of pregnancy undergo but
little differentiation. By the copulation of spermatozoa and ovum is ex-
plained the fact that the hormonopoietic action of chorionic epithelium is
stronger than that of the ovum alone. Hardly anything can be objected
against Halban's clinical observations. On the contrary it seems to be not
refuted that also from the fetus may mammary glandular hormones proceed,
as indeed the chorionic epithelium may live without fetus, but not the fetus
without chorionic epithelium. Hence it seems to me that the views of
Halban and of Starling are not irreconcilable.

Yet a few remarks concerning the onflow ["Einschiessen," literally a
shooting in] of the milk, which, as previously mentioned, usually occurs on the
second to fourth day after birth. It was formerly regarded that the cause of
the onflow was the act of suckling, but Halban has pointed out that suckling
during pregnancy may indeed induce the secretion of colostrum, but never
calls forth the production of milk (cases of Duval and of Hildebrand}. The

THE GENERATIVE APPARATUS 383

onflow of milk also occurs in cases in which the child has never been put to
the breast. On the other hand (apart from such cases as the case of Foges
cited above) the act of suckling or of drawing off the milk is requisite for
the continuance of the milk-secretion. From a series of clinical observa-
tions Halban draws the conclusion that the onflow of milk always coincides
with the removal or the death of the placenta. Again, the extirpation of the
ovaries at a time other than during pregnancy may increase the existing
secretion of milk, while, as is known, the occurrence of menstruation during
lactation inhibits the secretion of milk, and indeed in the premenstrual
period, and also that amount of its solid constituents, especially the casein,
the fat, and the salts, are diminished (N. Davis). Indeed even at the be-
ginning of the climacteric there may exist for a time with the introduction of
the ovarian function painful swelling of the breasts and excretion of milk.
Halban reports such a case. Halban therefore concludes that the ovary is
growth-inducing and secretion-inhibitory on the mammary glands, just as
is the placenta, only less so.

Finally there remains to be mentioned the pregnancy reactions of the
fetus described by Halban. The uteri of new-born girls regularly show
considerable hyperemia and histological alterations of the mucous mem-
brane that bear great similarity to those of menstruation. There may even
occur genital hemorrhage, that have nothing to do with menstruatio praecox,
as the latter usually set in much later, at a time that ovaries have shown signs
of maturity. The uterus of the new-born girls shows almost always a slight
involution that is usually completed three weeks postpartum. Moreover,
the mammary glands of new-born girls and boys show signs of epithelial
proliferation, indeed, even the secretion of colostrum (witch's milk) . Fur-
ther, the blood shows a slight grade of hyperleucocytosis and increased
coagulability. Finally the prostate of the new-born boy shows a slight
hyperplasia, which is then affected by involution. Halban correctly brings
all these manifestations in analogy with the pregnancy-reactions and ascribes
them to the hormonopoietic function of the chorionic epithelium.

After labor, as is known, there occurs in the mother a rapid retrogression
of all the profound alterations just described. The neutrophilic hyperleuco-
cytoses give place to a leucopenia with mononucleosis, the tachycardia
temporarily to a bradycardia. With the onset of the milk, numerous
eosinophilic cells make their appearance in the blood (Blumenthal) . Accord-
ing to Novak and Jetter there are found in the early puerperium different
irritative symptoms of the entire vegetative system; then the signs of an
increase in the functions of the ductless glandular system gradually vanish.

Surveying now the alterations described, which take place in the organ-
ism of pregnant women, we find that they are entirely analogous to those
which occur in the premenstrual period, while those of the puerperium are
analogous to those of the menstrual period. As is known, labor takes place at

384 THE DISEASES OF THE SEXUAL GLANDS

the menstrual term. Hence seems justified the dictum of W. H. Freund
that "labor is a menstruation, in which a fully developed egg is extruded."
While, however, the phenomena of the premenstrual period proceed from
the ovary, there can be no doubt at all that the similar, but potentized,
manifestations of pregnancy proceed from the developed egg. It therefore
seems to me that the conclusion lies at hand that all the manifestations of
premenstrual period are set free by the maturing follicle, which only renders
intelligible the fact that the extirpation of the ovaries during pregnancy has
no influence on this phenomenon, as the maturing ovum no longer is found
in the ovary, but in the uterus. From this we see that if we ascribe to
women an interstitial gland, it can have very little to do with the phenomenon
during pregnancy. It takes part in hyperplasia and in increase in function
only in the same manner as do the other ductless glands, and the stronger
emphasis of many of the so-called sexual characters may stand in connection
with it. The most important prevailing alterations of pregnancy are at all
events independent of it.

At the climacteric the interstitial glands show certain regressive changes;
they are, however, retained in part, while ovulation ceases entirely. The
lipoidemias that Neumann and Hermann observed in postclimacteric women
are in my opinion to be referred to the falling out of the function of the fol-
licular apparatus. As is known, libido may be retained for a still longer
time. The function of the sexual glands is usually associated with an in-
crease in the fatty layer of the abdomen and mammae. As is known there
occur during the transition period numerous nervous disturbances, that
point to extraordinary changing and manifold conditions of excitation
in the vegetative nerves. Manifold symptoms of a psychical hyperirrita-
bility are added, an existing hysteria becomes worse, and when a predisposi-
tion to a psychosis exists this may develop to a climacteric psychosis, which,
however, has no specific character (Krajjt-Ebing) .

We now have to consider the question as to whether the generative ap-
paratus in man too possesses an internal secretion. We have already seen
that there are clinical observations to the effect that the function of the
generative apparatus does not develop (the kryptochides inguinales of
Variot) , while the interstitial glands and with them also the masculine habitus
are well developed, and that on the other hand similar results have been
brought about by experiments. It would now be proper to investigate
whether such sterile but otherwise masculine individuals possess the same
libido as normal individuals. The cardinal point is the fact whether the
developmental disturbance sets in in early youth, or that experimental attack
is made on quite young animals. For experience teaches that if once the
generative apparatus has been fully developed and has functionated normally
then also after complete extirpation of the sexual glands the libido can be
retained for a long time. It seems to me important, however, that also in

THE GENERATIVE APPARATUS 385

such cases the libido is mostly released only through external influences.
On the whole it seems to me, although I can not demonstrate this with
certainty, that a normally strong sexual instinct is present only when the
function of the generative gland is normal, and in this circumstance speaks
for the hormonopoietic function of the generative glands.

The known stimulating action on the central nervous system, which
expresses itself in tendency to movement and in a heightened muscular
tonus, which comes to expression also in a spiritual sense in higher creative
activities, and which characterizes especially the period of " Sturm and
Drang," I would refer more to the hormonopoietic activity of the generative
glands. What has been done experimentally on this question does not lend
itself to the support of this view. On the whole the numerous reports as to
the stimulating action of testicular extract and of spermin Poehl have not
been written with the necessary critique; the careful investigations oiZoth and
Pregl, which showed an increase of the muscular capacity, were made with
extracts of whole testicle, so we are unable to say what part the generative
glands had in producing the effect.

While in man the function of the generative glands is a more continuous
one, there exist in the most of male animals the same cycle as in the fe-
males. As is known, the complete extirpation of the sexual glands prevents
a recurrence of rut. Although in some cases the wave of nit remains for
some time longer, I would not lay 'much stress on this fact as Halban does.
Here also must we consider that the organism had been accustomed to the
rut-wave for a long time. As certain cohabitation experiments show, how-
ever, it is possible that it is promoted psychically by the rutting female. I
believe also here the question permits of discussion as to whether many
of the rut phenomena usually grouped with secondary sexual characters,
that are necessary for the act of copulation, as for instance, the hypertrophy
of the arm musculature and the thumb callosities in frogs, are set free by
the generative glands. I have been unable to find any experimental inves-
tigations that help to clear up this question.

i. THE MALFORMATIONS

It is not my intention to enter into a comprehensive exposition of the
malformations accruing to the sexual glands. I shall only choose those
types that seem to me important for the discussion of the problems stated
above.

i. Aplasia of the Sexual Glands

Halban has collected from the literature the reports of cases of con-
genital amorphia or aplasia of the ovaries. They all come from the older
literature, so that Tandler and others have expressed doubt as to the exact-
as

386 THE DISEASES OF THE SEXUAL GLANDS

ness of the observations. It is true that this doubt does not extend to the
observations on anorchia that were made on boys shortly after birth. In such
cases are always found also anomalies of the internal genitalia — anomalies
such as lack of the epididymis or of the funiculi sperm atici or the vesiculae semi-
nales. When, however, we hear in many of the observations in old literature
as to aplasia of the sexual glands that the external and internal genitalia were
quite well developed, or that in the male individual a beard was present,
such a doubt is well justified. It is at all events very striking that no such
observations have been made in the last decade, although the number of
sections has enormously increased. From the observations on anorchia in
new-born children the most that can be mentioned is that also without
sexual glands there is possible a development, if only a disturbed develop-
ment, of the male or female accessory genital apparatus, and perhaps other
characteristics of the male sex.

Also the observations that Landau and Peck publish concerning the exist-
ence of individuals of a neutral sex do not seem to me to be free from objec-
tions. I quote the following two cases that Peck regarded as especially
important. In the case of v. Swinarski-Pfannenstiel there was a fifty-five-
year-old unmarried "woman," who had never menstruated. The general
habitus was masculine, the clitoris 3 cm. long, both ovaries were considerably
enlarged, the superficies smooth, no corpora lutea were to be seen, and on
microscopical examination the ovaries were found to be entirely "parenchy-
maless." The internal genitalia were those of the female. The case of
Houitz was that of a forty-nine-year-old unmarried "woman." The hairi-
ness and form of the pelvis were masculine; the large and small labia were
present, the clitoris was 6 cm. long and 2 cm. thick. The urogenital sinus
was smooth, and on its floor was found an opening through which one could
pass a thin sound into the 7 cm. long vagina. Between the thirtieth and for-
tieth years of life blood issued from the vagina at intervals of one to several
years. At the site of the ovaries on each side was to be found a body of the
shape and size of an almond. There was no follicle formation in the ovaries,
and the stroma was strikingly hard. In this case which had come to advanced
age one could not say with certainty that the follicular apparatus had always
been entirely absent. The absence of menstruation does not allow of the
statement that at least for a time there did not exist a tendency [start,
Ansatz] for menstruation. Also statements to the proportioning of the body
are not given. Finally an examination of the suprarenal cortex in such cases
would be very desirable. It seems to me therefore that such cases should not
enter into our discussion.

2. Hermaphroditism

We distinguish a hermaphroditismus verus and hermaphroditismus spurius
or pseudohermaphroditism. Cases of hermaphroditismus verus, in which ova-

HERMAPHRODITISM 387

ries as well as testicles are capable of functionating, are as yet unknown
in man. But there are cases of so-called ovotestis; I will cite some examples.
A case of Salen was that of a forty-three-year-old "woman." Menstruation
had existed since the seventeenth year, the clitoris was 5 cm. long, the vagina
6 cm. long, the labia majora were of normal development, the habitus was
feminine. The ovotestes show in the ovarian part Graafian follicles and
typical ovules, in the testicular part seminal tubules, Leydig's interstitial cells,
but no sperm. The case of Simon was that of a twenty-year-old "man."
The individual felt as if he were a man. The sexual inclination was mascu-
line. Menstruation had existed for three years, the secondary sexual
characters were mixed, with the feminine predominant. The labia majora
were well developed, the penis was 6.5 cm. long, the glans was not perforated.
There were found tubes, parovaries, and ligamenta lata; vasa deferentia and
epididymis were without connection with the testicular part of the ovatestis.
In the latter were found typical sexual glandular tissue of both sexes, but no
sure signs of function.

In pseudohermaphroditism there are found sexual glands of one sex and
the sexual characters of the other. We distinguish pseudohermaphroditismus
internus, if only the internal sexual passages of the other sex are present,
and a pseudohermaphroditismus externus, if only the external sexual passsages
of the opposite sex are present, and a pseudohermaphroditismus completus
when both external and internal sexual passages of the other sex are present.
Further, according to the prevalence of the sexual glands a pseudohermaphro-
ditismus Jemininus or masculinus.

As an example of the pseudohermaphroditismus completus I cite the
case of Heyn. The habitus of a forty-six-year-old individual was entirely
feminine. The person married at the age of twenty-one years, sexual inter-
course was entirely normal and was attended with orgasm and discharge.
There was found a vaginal cul-de-sac; uterus, ovaries, prostate were absent.
Testicles were present on both sides.

In pseudohermaphroditism are found all conceivable varieties. There
are cases of somatic pseudohermaphroditism in which not only the sexual
organs but all the psychical characteristics of the other sex prevail, v.
Neugebaudr has collected twenty-five such cases. Further, there are cases in
which the secondary sexual characters, such as hairiness, voice, dimensioning
of the body, belong partly to one and partly to the other sex, and there are
cases in which the sexual glands and genitalia belong to one, the secondary
sexual characters to the other sex (pseudohermaphroditismus secundarius ,
Halban) .

Finally there are observations concerning unilateral pseudohermaphro-
ditism. In man so far as is known, this has been observed in a very rudi-
mentary form only. Halban cites cases of unilateral development of the
breasts in women. There are, however, numerous such observations 011

THE DISEASES OF THE SEXUAL GLANDS

the part of zoologists. Delbet saw butterflies that possessed on the one side
an ovary, and on the other a testicle, and in which one-half of the body was
colored like that of a female, the other side like that of a male. I further
cite the known observation of Weber. A finch possessed testicle and male
plumage on one side, an ovary and female plumage on the other.

Let us now survey the rich material of facts, from which I have chosen
only a relatively few illustrative examples, but examples that are important,
and let us proceed on the basis of these to enter into the discussion of the
problems mentioned above.

Let us turn first to the relation between sexual glands and the secondary
sexual characters. I would here sketch again, in outlines, the different
views. We have seen that in this respect two views stand bluntly opposed
to each other. According to one the sexual characters exist from the be-
ginning, there exists a male, a female, and hermaphroditic predisposition,
and the sexual glands exercise only a protective stimulus on the development
of the sexual characters. According to the other, it is the sexual glands
alone that form the sexual characters. The authors that adhere to the
last opinion, show that indeed already in the first embryonal stages there
are differences to be observed between the male and female sex, but that
the sexual glands have begun to develop already at this time and begin to
exercise their influence.

It will be seen at the first glance that multiplicity of the phenomena is
not explained in a satisfactory manner by the last-named assumption. How
shall we explain the coming about of complete hermaphroditism in which
the sexual glands of one sex lead to the development of the sexual characters
of the other, if the sexual glands exert a specific sex-determining formative
stimulus? Even less explicable according to this hypothesis is the occurrence
of unilateral hermaphroditism. In this connection, no matter from which
point of view we regard the matter, we cannot circumvent the opinion of
Halban. For this opinion speaks also the circumstance that in hermaphrodit-
ism the heterosexual characters are enormously developed even at the time
of puberty, and the known fact that unioval twins are always of the same
sex. Only in the last analysis does this solution meet with great difficulties.
According to it we should suppose that the protective influence of the
sexual glands would be always active if it met with a heterosexual predispo-
sition. According to this we would expect that when the sexual glands are
extirpated in a not yet fully developed animal, and the sexual glands of the
opposite sex are implanted in this animal, the original predisposition would
come to development even then. Steinach has followed this method. He
implanted ovaries into previously castrated young males of guinea-pigs and
rats. The transplants "took," and not only the interstitial glands de-
veloped, but also the primary follicles, to large follicles with normal ova, and
there occurred in entirely normal manner the formation of atretic follicles

HERMAPHRODITISM 389

of corpora lutea. In these animals not only did the penis cease develop-
ing, but it was even set back in its development. If a tube and a piece
of the uterus were transplanted with the ovary, these developed to mature
organs. Moreover, there came about an enormous development of the
mammary glands, that in form and size were entirely like those of normal
female, and indeed even exceeded them in size. Furthermore, the animals
remained behind in growth, the body showed entirely the proportioning of
the female; also the growth of hairs and the layer of fat showed the texture
of that of the females, and there was a reversal of the psychical sexual
characters.

If Steinach's experiments were to receive full corroboration, were someone
in converse manner successful in bringing to previously castrated females the
male sexual characters by implantation of testicles, we would have to agree
that they would stand in contradiction to Halban's view. I believe, however,
that we would not be making allowance for the difficulty of the problem, if
we were to regard it as entirely solved by this view; for Steinach's experi-
ments do not explain the occurrence of heterosexual characters in the pres-
ence of the sexual glands of the other sex. The observations belonging to
this problem have led Biedl to assume an hermaphroditic mapping-out
[Anlage] of the sexual glands. The occurrence of heterogenous sexual
characters is explained by Biedl by his supposing that the internal secretory
part of the sexual glands that belongs to the opposite sex gains the upper
hand. Biedl thus explains the occurrence of certain masculine characters
in old women after the menopause.

On cessation of the activity of the female sexual glands, there can occur,
according to Biedl, a reversal of the sexual characters in that the existent
male sexual glands continue to functionate. I would here agree with
Novak in not considering the illustration that Biedl employs as convinc-
ing. The occurrence of the so-called old woman's beard is not a male
sexual character. Its occurrence is explained much more adequately by
Halban, who points out that the individual sexual characters possess very
different tendencies to growth and that the development of the beard in
women is very much delayed. In the same manner I do not regard the
localization of the deposits of fat in old men as a female sexual character,
but rather as the sign of the beginning dissolution of the activities of the
sexual glands, only as the suggestion of a symptom that in eunuchoidism is
exhibited in early years in a pronounced manner.

It therefore seems to me that the only possibility is to look for the
solution of the problem in another direction; we should not endeavor to
crowd all of the manifestations into one of the views set forth, but should
consider the question as to whether the genesis of the sexual characters is
not determined by a number of factors. We cannot discard the assump-
tion of a preexistent tendency for certain sexual characters without doing

3QO THE DISEASES OF THE SEXUAL GLANDS

away with the problem altogether. Before all, however, we should think of
the possibility that the sexual glands actually give off the formative stimulus
for many a sexual character, especially if we take the viewpoint that some of
the sexual characters come under the dominating influence of the interstitial
glands, others under those of the generative glands. I have previously set
forth that if we ascribe to women an independent function of the interstitial
and the generative glands, the development of the mammary glands seems to
stand only under the formative stimulus of the follicular apparatus or of
the ovum. From this standpoint it is worthy of note that Steinach in his
experiments transplanted not only the interstitial glands but also the follicu-
lar apparatus. We can readily imagine that the interstitial glands alike,
whether they come from man or woman, exercise the same protective stimulus
on certain preexistent masculine or feminine sexual characters; but no one
would expect the same action from the masculine as from the feminine gen-
erative glands.

Finally we should think of the possibility that the development of many
of the sexual characters comes entirely or partially under the influence of
other ductless glands. A new viewpoint has lately opened in this direction,
a viewpoint that also seems adapted for showing the occurrence of many
a heterosexual character in a new light. I refer to those observations that
were described in detail in the consideration of tumors of the suprarenal
cortex. Women who have developed entirely normally up to or beyond the
age of puberty become, on the development of such a tumor, amenorrheic;
the uterus atrophies, and there develops a hypertrichosis. Mustache and
beard grow, and hairs on the trunk become abundant; in short, the distri-
bution of hair assumes quite the masculine type. The supposition that this
heterosexual hairiness is to be referred to a hyperfunction of the suprarenal
cortex is very probable, suggesting the thought that also in the virile type
of hairiness that is observed in acromegalic -women, or even in normal women
during pregnancy there is the same cause — for hyperplasia of the suprarenal
cortex is observed in both conditions.

Why, however, do we find, in those cases in which the suprarenal tumor
develops in earliest youth, a premature development of the genitalia with
marked accentuation of the sexual characters without reversal to the hetero-
sexual type, while, when it occurs in women who are already matured, the
activity of the sexual glands fails? In explaining this fact I would refer once
more to the relations in acromegaly. Here, in addition to marked accen-
tuation of many sexual characters, in addition to the masculine type, we
find either, mostly only temporary, increase of the activity of the genera-
tive gland (even with secretion of colostrum) or, what is more frequently the
case, the failure of this from the beginning. In this there seems to me to
lie an analogy with the behavior of the generative glands in tumors of the
suprarenal cortex; we may assume that hyperfunction of the suprarenal

EUNUCHS 391

cortex always leads to a marked development of the hairiness on the trunk,
but that an increase of the activity of the generative glands enters in only
when there is an especial vitality of these glands, while in the cases in which
vitality fails, there is rapid exhaustion. In the very strong impulses in
childhood there would come about a pronounced increase (premature de-
velopment), and in already matured individuals an exhaustion. In acro-
megaly, in which this impulse is very much less feeble, a temporary increase
of function may first occur; even in late years, although in most cases the
exhaustion appears in the foreground already from the beginning.

These observations and convictions ascribe to the suprarenal cortex
an important trophic influence on a very important sexual character, namely,
the hairiness. This supposition finds a certain support in embryology and
histology. Let us recollect that the suprarenal glands as well as the inter-
stitial glands are of mesodermal origin, that both proceed from immediately
contiguous parts of the celom, and that the histological picture of cortical
cells and the interstitial cells present a great similarity. Also Glynn inclines
to the assumption that the suprarenal cortex is a trophic center for the growth
of beard and the hairiness on the body, and believes that we should properly
expect that in man the suprarenal cortex is better developed than in woman.
As is known, this is really not the case. I would not, however, ascribe any
great significance to this absence of better development in man. As we can-
not quite discard the assumption of a masculine or a feminine predisposition
[Anlage] for the body, it is explicable that with normal impulses the mascu-
line or feminine type of hair distribution will exist. When, however, the
impulse is considerably increased, then the virile type in man is potentized,
while in women the virile type is approached or attained. Even under
physiological conditions, namely, in pregnancy, is there an approach to
the virile type. This idea also includes the explanation of why in pseudo-
hermaphroditismus femininus the suprarenal cortex is usually found so
hyperplastic.

II. AGENITALISM OR HYPOGENITALISM

i. The Eunuchs

Occurrence. — The manifestations of agenitalism or hypogenitalism
occur in the form of a pure physiological experiment in eunuchs and in
skopzen. Castration, as is known, was very much practised in antiquity;
even until a short time ago it was carried out in Italy for " musical purposes,"
and in the Orient it is to-day carried out on the watchers of the harem,
and in Russia on the religious sect, the skopzen, on religious grounds. All
these forms affect male individuals. As to castration of females there
exists only a very inexact report from India by Roberts.

Symptomatology. — An excellent exposition of the symptomatology has
been given by Tandler and Grbsz, which I shall in great part follow. The

3Q2 THE DISEASES OF THE SEXUAL GLANDS

action of castration is different according to whether it has been done in
early youth or after the entrance of puberty.

We shall first pay attention to the manifestations of loss of sexual glands
in males. When the castration occurred in earliest youth, the development
of the accessory genital apparatus is extremely deficient. Penis, prostate,
and seminal vesicles remain small (Pelikan). When castration has taken
place in later years the penis becomes only slightly smaller, while the pros-
tate shrinks to a greater extent. As is known, castration has been done
for prostatic hypertrophy; I shall consider in detail later the action of late
castration.

In early castration all sexual instinct is absent, and the small penis that
remains never becomes erect. As the castration is not always complete,
it may happen some of the eunuchs may still experience a slight degree of
libido, on account of which some of the harem-watchers in the Orient had
their penis removed with the testicles. A. Marie reports the case of a forty-
year-old Egyptian eunuch who had been castrated in childhood, but who
showed illusory ideas that had an erotic content.

If castration has been carried out after development of puberty the
sexual instinct — Mobius calls it the cerebral sexual instinct — is retained
for a long time; copulation is still possible and there occurs an ejaculation
of prostatic secretion.

According to Gall, the cerebellum should atrophy, and indeed in uni-
lateral castrates the opposite half of the cerebellum. This statement has
been contradicted, although Mobius pointed out that no certain contradictory
evidence has been advanced. According to a personal communication of
Prof. Tandler, however, the statement of Gall is certainly not in accordance
with fact.

The statement as to the characters of castrated individuals varies very
much. For the most part it is stated that 'castrates lack the courage, the
passions, and the aspiration of a normal man; they are described as tricky,
revengeful, and cruel. On the contrary the intellectual capabilities are
not diminished, as many eunuchs have attained to influential positions.
It is hard to judge these statements, as in the most of the famous eunuchs,
the history lacks exact knowledge as to the time and the completeness of
the castration. Mobius points out that castrates lack the higher artistic
endowments, for the virtuosity of castrated singers cannot be regarded as
such. At any rate, animal experimentation shows that castrated animals
(oxen, geldings, capons) lack the courage, the animation, and passions of
normal male animals.

Noteworthy is the influence of castration on the skeletal formation and
the development of the secondary sexual characters. Castration in early
years leads in man and animals to increase in length (Godard, Pelikan,
Pittard, Becker, Lortet, Pirsche, Sellheim, Tandler and Grosz, and others).

EUNUCHS 393

Eunuchs of 200 cm. in height are observed often. The tallness first sets in at
the time of puberty. The closure of the epiphyses is delayed. Many
epiphysial junctures may remain open until a high age. The ossification of
the cranial sutures is also delayed. Signs of the frontal, cranial, sagittal, and
lumboid sutures are retained for a long time. Therewith the skeleton shows
especial characteristics; the head is small, the tabular part of the occipital
bone is. according to Gall, flattened. The spinal column is especially short,
the extremities are lengthened, especially in their distal parts, thus causing a
certain preponderance of the lower length over the upper length and a rela-
tively large span width. Often there is genu valgum. The breadth of the
shoulders is diminished, the pelvis shows a mid-form between masculine and
feminine type, and remains infantile. In the same cases the sella turcica is
remarkably large. I have already remarked I cannot infer from this an
increase in function of the hypophysis. In the tall eunuchoids the sella
turcica, as we shall see later, is not enlarged, but rather smaller. The larynx
remains small, does not ossify, shows childish dimensions, in which the
laminae thyroidiae encroach upon each other at a wide angle and the promi-
nentia laryngea is indistinct; the voice does not change, and the childish
soprano is retained. The bones, especially the long tubular bones remain
delicate, and the sites of the muscular insertions are only very feebly developed.
The tonus of the muscles is slight, the phenomena of movement should take
place more slowly. The muscles 'are permeated with fat. The metabolism
of the muscles must become essentially altered through the castration, for on
castration the meat of male animals takes on the characteristic odor, an
experience that is extensively made use of by breeders.

The skin is strikingly delicate and pale and in older castrates shows the
fawn-yellow coloration and wrinkling. It is very poor in pigment. The
distribution of fat is very characteristic, fully corresponding to that which will
be described under dystrophia adiposo-genitalis. Hence there are found
pads of fat in the hypogastric region, and on the mons Veneris, the latter of
which is bounded above by a horizontal fold; also on the nates, on the hips
and thighs, on the mammary glands and laterally on the upper eyelids which
may hang down like bags. In many cases there occurs pronounced adiposity.
Tandler and Grosz distinguish between a tall and a fat eunuch type, al-
though in the first the characteristic distribution of fat is always indicated.
The muscle meat is, as in the castrated animals, permeated with fat. The
tonus of the musculature is slight.

Finally the secondary sexual characters are deficient. While the hair of
the head is dense, such individuals are beardless, and show only lanugo hairs
on the face, especially on the chin and the upper lip; in later life, individual
bristly hairs may develop, similar to those that grow in old women, on the
lateral parts of the upper lips. . The trunk remains completely hairless and
the axillary hairs are absent or are sparse. The pubic hairs are absent, or

394 THE DISEASES OF THE SEXUAL GLANDS

consist in only a few sparse hairs at the root of the penis. Also the peri-
neum remains hairless. The involution of the thymus gland is slight.

We know much less concerning the results, of castration in the youthful
female organism. According to the inexact statements of Roberts the
female castrates grow to be tall, the accessory apparatus of the genitalia
remain entirely undeveloped, the secondary sexual characters and the breasts
do not develop. With this rather agree the animal experiments of Hegar,
Kehrer, and others, and the observation on female eunuchoids that will be
mentioned later.

2. Late Castrates

Castration in man after the onset of puberty is carried out but very rarely.
In the most cases the indication for it is found in tuberculosis of the testicles.
Later, in late eunuchoidism, we will learn about the group that depends on a
traumatic foundation. As, however, in most of these cases the sexual glands
remain behind in the body and are only shrunken. I classify these cases
with later eunuchoidism, as it seems to me of like significance whether the
shrinking of the testicle is the result of a traumatic action or of another
disease process.

If castration in man takes place at a relatively early age there occurs a
pronounced regressive alteration of the genital apparatus, and at least
a partial retrogression of certain secondary sexual characters, and finally a
distribution of fat that is similar to that of eunuchs. It is remarkable that
I was unable to find in the literature an exact description of such a late eu-
nuch. From the older literature I quote that of Martin: In war, a piece of
shell tore away the penis and testicles of a married man. Soon afterward
the man lost his beard and his breasts began to increase in circumference.
More frequently is found the statement that on castration in already fully
developed individuals a retrogression of an already developed accessory
genital apparatus and of the secondary sexual characters does not occur.

A short time ago I was able to observe carefully a suitable case, and I
herewith report it:

Observation XLVII. — Kr. J., forty-nine years old. Entered the clinic July, 1912.
In the eighteenth year of life he had gonorrhea and bilateral orchitis. In the nine-
teenth year of life he acquired lues. In the twenty-first year of life there began a swell-
ing of the cervical lymphatic glands and at the same time a caries of the lower jaw; the
latter continuing three years and disappearing after operative procedure. In the twenty-
sixth year of life, both testicles were removed on account of tuberculosis. A year after
the operation the patient suffered with cardiac palpitations, that later disappeared. In
the thirty-seventh year of life he developed a goiter after a trip to the Steiermark, which
goiter later receded. For several years he has had attacks of typical bronchial asthma.

Since the castration the patient has gradually gained about 30 kg. The potentia
coeundi still exists, but coitus is carried out but very rarely; ejaculation takes place,
but since the operation libido has been very slight.

LATE CASTRATES

395

The mustache, which even before was not developed very strongly, has become very
much more sparse since the operation, so that there exists on the upper lip only a small
strip of sparse hairs, as is seen in the accompanying photograph. The beard on the cheek
is now so sparse that the patient has to shave himself much less frequently than formerly.
The hairiness of the mons Veneris is very sparse, it is a little denser at the root of the penis.
Here it terminates above in a horizontal hue.

The penis is only 3 cm. long, the foreskin has become too long and, therefore, shows
numerous transverse wrinklings. In an erect condition the penis is only 4^ cm. long.

The hairiness in the axillae, on the trunk and on
the perineum and on the extremities is entirely
absent.

The patient is rather fat, the breasts are pro-
nouncedly rich in fat, and the hypogastric region and
the mons Veneris are also rather fat.

The case reported is not entirely free of
objections, as it might be supposed that the
previous gonorrhea and luetic infection and
the tuberculosis may have damaged the
sexual glands seriously even before the castra-

FIG. 66. — Late castrate.

FIG. 67. — Genitalia of a late castrate.

tion. Nevertheless the statements of the patient that the alterations de-
scribed took place only after the operation are very precise.

In the female sex castration after puberty has been carried out fre-
quently by the gynecologists. It leads regularly to atrophy of the uterus and
vagina. Menstruation remains absent. The external genitalia, especially the
clitoris, shrink, the vagina becomes narrower. In female animals the sexual
instinct ceases. Bucura experimented on rabbits. If after the castration
the female did not admit the male, this was a sure sign that the operation
had succeeded. Also after castration in women is the sexual sense reduced.
Gloevecke found this in 78 per cent., P festering per cent., Alterthum in 68
per cent. In women who have been having sexual intercourse for a long time.

396 THE DISEASES OF THE SEXUAL GLANDS

libido may be retained for a while. In rare cases (Mandl and Burger, Pfister)
the libido may be increased for a time after the castration.

After the castration the skin becomes lighter on account of loss of pig-
ment (Pfister) . The hair of the head becomes luxuriant. There is no distinct
influence on the shape of the breasts; but the nipples show a slight grade
of atrophy, and the areolae become light-rose in color through partial loss
of pigment.

As in man, there is in woman after castration a tendency to corpulency.
Considerable increase in weight was found by Alterthum in 29.5 per cent.,
by Glaevecke in 57.5 per cent.

The behavior of the respiratory metabolism after castration has become
a subject of lively discussion. Lo'wy and Richter found in female castrated
animals the fundamental exchange lowered about 20 per cent., in the males
about 14 per cent. On administration of ovarian substances it again rose
to normal. Again, Luthje has pointed out that the slight reduction of the
fundamental exchange was to be referred to the greater phlegma of the
animal, v. Noorden has subjected the experiments that exist in the literature
to a thorough criticism, and comes to the conclusion that a reduction of the
fundamental exchange has not as yet been strictly demonstrated. The
clinical observation of an increased deposit of fat after castration is ever
known "on account of the broad basis on which it rests, unquestionable."
Recently, further investigations by L. Zuntz have been made on three wromen
who were castrated on account of gynecological complaints. During the
first week Zuntz found no distinct reduction of the fundamental exchange.
In all cases there was found, after a long time, a slight fall of the oxygen con-
sumption, as much as 20 per cent. The administration of oophorin was not
able to produce a distinct addition to the oxygen consumption. We shall
see later that also in eunuchoidism, in the few investigations that have been
made up to the present, the respiratory metabolism was found to be rather
normal. There is no ground, however, for the fact that the corpulency that
develops after castration in a great majority of cases does not depend directly
on the loss of the sexual gland, as small turnings of the scale not demonstrable
by our present methods may amount to something in the course of years; and
as the disturbance in the regulation of the fat metabolism does not depend
exclusively on the fundamental exchange (see Chapter XIV).

Very little is known as to the other alterations of the metabolism that
occur after castration. Also the action of the sexual glandular substances
introduced in the organism has not been sufficiently studied up to the present.
As we have seen before, its influence on the respiratory metabolism is still
subject* to controversy. Many authors (Matthis, Neumann and Vas, and
others) found under the influence of oophorin a slight increase in the elimina-
tion of nitrogen, and an increase of the elimination of salts, especially of
the elimination of phosphorus through the intestine.

EUNUCHOIDISM 397

Cristofoletti saw after the administration of ovarian substances the glyco-
suric action of adrenalin become weaker.

In woman, the acute loss of the sexual glands leads, as is known, to a series
of manifold excitatory states of the vegetative nervous system. Drawing
pains, emotional excitements, feeling of anxiety, headache, fainting spells,
heat and feeling of cold, disturbance of the intestinal tract, weakness of
memory, and mental depression occur. The wave-movement ceases. The
manifestations become intelligible when we consider what distinct revolutions
occur in the female organism after castration.

Cristofoletti saw after castration (also in animal experiments) increase of
the glycosuric action of adrenalin. Alder found delay in the coagulation-
time of the blood and reduction of the calcium in the blood.

As is known, all these manifestations occur also at the climacteric.
" Castration produces an artificial climax, that is like the natural one, and
often transcends it in pathological manifestations" (W. H. Freund).

The treatment of eunuchoidism will be considered further on.

3. Eunuchoidism

Dystrophia adiposo-genitalis, gerodermia genito-distrofico, obesite
d'origine genitale.

Definition. — Eunuchoids we term, according to Tandler and Grosz, indi-
viduals who, without being castrated, entirely simulate in their clinical mani-
festations the true eunuch type, or at least are extraordinarily similar to it.
They are either tall, or if complications are absent, are at least not stunted in
growth; they show the typical fat distribution of eunuchs, and eventually pro-
nounced obesity; the epiphysial junctures persist abnormally long, the skeletal
dimensions are characterized by an especial length of the extremities, and fur-
thermore the individuals show a definite psychical habitus. Finally there is
found a more or less pronounced disturbance of development of the genitalia
with faulty development of the secondary sexual characters. It is probable that
in such cases we have to do with a developmental disturbance beginning primarily
in the sexual glands, and indeed especially the interstitial glands, as functional
disturbances of the generative glands alone do not lead to eunuchoidism.

Historical and Case Histories. — Such a case was first termed eunuchoid
by Griffith. A sharp delimitation of the clinical picture occurred only a
short time ago, when Tandler and Grosz first reported a series of cases and
then described the clinical picture thoroughly. Even before Tandler -and
Grosz, however, a great number of such cases had been reported in the litera-
ture under very different names.

Meige mentions a case of Reichlin's that was a pronounced eunuchoid.
Moreover Tandler and Grosz regard as an eunuchoid the case of Redlich.
Similar cases were described by Kisch. Kisch distinguishes between heredi-

398 THE DISEASES OF THE SEXUAL GLANDS

tary and acquired obesity and divides the hereditary obesity into two forms,
one of which develops in early youth and which becomes prominent later, and
in which only the predisposition to obesity is inherited. Then Kisch men-
tioned that the hereditary obesity " acquires a quite characteristic nutritive
expression of degeneration." The description of these types that Kisch
furnishes suits entirely, as Tandler and Grosz points out, the eunuchoid type.
Among two hundred thirty-eight cases of obesity, Kisch saw it twenty-four
times, seventeen of these cases developing at an early age.

Pirsche cites the case of Papillaunet and adds three observations of his
own. Other cases have been reported by Etienne, Jeandelize and Richon
(man fifty-nine years old, 174 cm. tall, preponderance of the lower length,
epiphysial junctures incompletely closed, the testicles — one cryptorchiditic —
very small and fibrous, seminal vesicles and prostate also small and fibrous,
penis 4 cm. long); and by Duckworth (thirty-seven-year-old man, 171.7 cm.
tall, 179 cm. span width, considerable preponderance of the lower length,
marked fibrosis of the testicles, the prostate, and the epididymis, already
described by Griffith} ; already Duckworth mentions the similarity to "cryptor-
chid conformation." Very worthy of mention are the cases of Sainton of five
brothers (and sisters), three were eunuchoids, and besides this an uncle and
great-uncle. The case described was 172 cm. tall. The lower length
predominated considerably. The thymus gland was not persistent. I
believe that also the case of Babonneix and Paisseau (case I) and that of
Lemos Magalhaes belong to this group ; also the case of Thibierge and Gastinel
(termed gigantism with infantilism).

Neurath furnishes the description of an eleven-year-old tall-grown girl
with typical "eunuchoid" obesity, that is very likely a case of eunuchoidism.

Also the case of Porhon and Mihaelesco described by these authors as
"cas d'infantilesme dysthyreoidique et dysorchitique " seems to me to
belong to this group, as also the case of "anorchidia" of Launois and Roy.

Also the case of " cryporchides abdominaux" Variot; also a case of Apert,
also case I of Babonneix and Paisseau would fit in this group very well.

Of special interest is the case of Josef son and Lundquist that affected a
female eunuchoid, I shall consider this in detail later on. I also mention here
briefly the case of Peritz.

During the course of the last few years, I have seen four cases, which I
shall report, before entering into the description of the symptomatology.

Observation XLVIII. — B. Sch., thirteen and one-half years. First observed Nov.,
IQIO. Father had lues at the age of twenty years. His Wassermann still positive. Asa
child the patient had an umbilical hernia, and a left-sided inguinal hernia, also slight con-
stipation. The umbilical hernia healed three months. after birth, the inguinal hernia
only after some years, three years ago operation on the tonsils.

Before this, always sore throat and snorings. For about three years gradual onset of
obesity. In addition vomiting sometimes, especially after breakfast. When the vomit-
ing has finished, appetite returns. The boy now weighs 55 >£ kg. The body build is

EUNUCHOIDISM

399

slender. The skin pale, soft, satiny, facial complexion pale, marked collection of fat
on the breasts, in the inguinal region and on the mons Veneris. The penis is quite small,
as is also the scrotum; the right testicle is about the size of a plum-kernel, the left is about
half the size and is not quite descended. Examination of the eyes shows entirely normal
relations. Likewise the X-ray examination of the skull [i.e., normal]. Sella turcica
rather small. Temperature 36.2°, circumference of the head 54 cm.

Erythrocytes, 5,290,000

Hemoglobin, 95 per cent.

Leucocytes, 10,700, of which:

Polymorphonuclear neutrophiles, 49.6 per cent.

Large mononuclears, 3 per cent.

Lymphocytes, 42.4 per cent.

Eosinophiles, 5 per cent.

Genu valgum on each side.

The boy is well developed mentally, but lazy.
He is silent, especially in intercourse with com-
panions of the same age.

Thyroid small, hardly palpable. Liver and
spleen not enlarged.

Thyroid gland treatment. Loss of about 3 kg.

June, 1911. The boy has grown, still very fat,
typical distribution of fat. The testicles are not
better developed. The right testicle has a longi-
tudinal diameter of about 25 mm., the left pf about
18 mm., the latter is fully descended.

Leucocytes, 10,800, of which:

Polymorphonuclear neutrophiles, 50.94 per cent.

Lymphocytes, 31.26 per cent.

Large mononuclears, 12.8 per cent.

Eosinophiles, 3 per cent.

Eye examination normal.

Jan., 1912. A new X-ray examination of the
skull showed that size of the sella turcica had not
essentially altered. The examination by a perime-
ter showed an entirely normal visual field. The
thyroid treatment was tried once more, which,
however, soon led to slight signs of hyperthyroid-
ism and hence had to be abandoned. The patient
was then ordered radium baths three times a week
with 100,000 Mache units per bath, which per-
haps exercised a favorable influence. At all events
there became apparent a distinct progress of the
development, as even the patient thought in June,
1912. The patient was now 174 cm. tall and still
somewhat fat. Abundant fat deposits were to be

found in the hypogastric region. The pubic hairs were now well grown, but still showed
a horizontal boundary above. The trunk was still fully bald, and only in the axillae on
both sides were a few sparse hairs to be seen. The size of the penis and the testicles
corresponded to the age of the patient. It was stated that pollutions had not as yet
occurred. The voice had changed and the patient complained only very rarely of
headaches. Some adenoid vegetations in the nose were now removed.

FIG. 68. — Case of eunuchoidism
(Observation XL VIII).

400 THE DISEASES OF THE SEXUAL GLANDS

FIG. 69. — Sella turcica in eunuchoidism (Observation XL VIII).

EUNUCHOIDISM

4OI

Summary. — Here was a typical case of eunuchoidism. The headaches and the occa-
sional vomitings at first awakened the thought of a hypophysial tumor; but the X-ray
examination of the skull and the observations, continued for three years, and especiaUy
the absence of an inhibition of growth, ruled out this possibility, the inhibition of develop-
ment seemed to be only transitory, that has re-
cently been made up for very considerably.

Observation XLIX. — Dat., from Jerusalem,
twenty years old. Entered the clinic Dec., 1905.
Typhoid fever at the age of sixteen years; since
this time chronic enteritis. Total length 159 cm.,
circumference of head 57 cm., of breast 74 cm.,
of abdomen 87 cm., anterior superior spine to in-
ternal malleolus 88 cm., acromion to styloid
process of radius 57 cm., acromion to oleocranon
35 cm.

Distantia spin, 26 cm.

Distantia crist, 27^ cm.

Distantia trochant, 29 cm.

Slender build, marked emaciation, except that
there are fat deposits on the hips and mons
Veneris. Milk-teeth in part retained. The
penis and scrotum quite small. Testicles on
both sides in the inguinal canal; very few hairs
at the root of the penis. No hairs in the axillae,
no beard. Never erections, no libido.

Marked hyperextensibility of the joints, espe-
cially the phalangeal joints of the fingers. The
fingers can be bent backward to a right angle,
and the knees can rest comfortably in the axillae.
Fingers are very long and slender.

Sexual life entirely absent.

X-ray examination shows that the distal epi-
physial junctures of the ulna and radius, the
proximal of the first metacarpal bones and proxi-
mal of the phalanges are still open; the bones
seem rarefied.

The sella turcica is rather small.

Striking is a short, round, and sharply de-
lineated calcification in the anterior part of the
sella turcica immediately beneath the clinoid
process.

Slight genua valga.

Voice high.

Indistinct prominentia laryngea.

Thyroid not palpable.

Test for alimentary glycosuria (100 and 150
gm. dextrose respectively) negative.

Observation L. — M. W., twenty-three years
old. March, 1903. Genitalia hypoplastic, as
far back as patient can remember. Deposits of fat on the mons Veneris and hips,
which during the last few years have become more strongly developed. Never libido
26

FIG. 70. — Case of eunuchoidism
(Observation XLIX).

402

THE DISEASES OF THE SEXUAL GLANDS

erections often since the eighteenth year, during which the penis becomes about 3 cm. long.
Has never had sexual intercourse. Recently, several pollutions. Patient is 169 cm. tall.
Length of lower extremities (from ant. sup. spine of ileum to int. malleolus) 87 cm.;
length of the upper extremities (from head of humerus to end of third finger) 76 cm.
Span width 184 cm., genu valga. Copious deposits of fat on the hips, on the outer sides
of the thigh and on mons Veneris. Mammae not very rich in fat. No beard hairs at all.
Abundance of hair on head. Hairs in axillae sparse; pubic hairs present, not very luxuri-
ant, bounded above by a horizontal line. No hairs on the linea alba. No hairs on the
thighs. Genitalia hypoplastic. Penis small, scarcely i% cm. long. Each testicle
about size of a bean, soft.

»#

FIG. 71. — Eunuchoidism (Obser-
vation L).

FIG. 72. — Genitalia in case M. W. (Observation L) .

X-ray. — Sella turcica normal, the distal epiphysial junctures of the radius and ulna,
and the proximal of the first metacarpal phalanges are still open.

Leucocytes, 7600 of which 46 per cent, are neutrophilic polymorphonuclear cells.
Voice higher. Prominentia laryngea not palpable. Thyroid gland not distinctly palpa-
ble. Test for alimentary glycosuria (100 and 150 gm. dextrose) negative. Character:
Silent, not communicative, somewhat shy. Intelligence normal.

Observation LI . — H. Ad., twenty-eight years. Entered clinic April, 1912. The patient
had nine brothers and sisters, five of whom died shortly after birth. One sister had chloro-
sis. One brother when a child apparently had laryngospasm. Since his sixteenth year
the patient has suffered with a gradually increasing chronic exudative articular rheuma-
tism. He states that once during an exacerbation of the joint affection, he lost much
weight. Then in the twenty-first year he was at a bath-resort and in a short time,

EUNUCHOIDISM

403

FIG. 73. — Sella in a case of eunuchoidism (Observation L).

404

THE DISEASES OF THE SEXUAL GLANDS

gained 42 to 48 kg. Later this became obesity.
Then during another attack of articular rheumatism
he again lost weight. Now the body weight is
66y2 kg.

The patient states that he has experienced sexual
sensations since the twelfth year of life. Later he
often had erections, in which the penis became quite
stiff. His inclination was always for young boys,
however, and occasionally he practised active pe-
derasty. Since his sixteenth year, his inclination
gradually turned to women, but the libido was never
very strong. He had love-episodes but he never
attempted coitus, as he knew that he was im-
potent. Later, never pollutions; the penis has
always been very small.

The patient is 176 cm. tall, of typical eunuch-
oidal form and dimensions. The span width is
185^4 cm., the lower length nearly 100 cm. The
thorax is small in relation to the pelvis, the head is
small, the prominentia laryngea is only indicated.
Bilateral genua valga.

The patient is very intelligent but very taciturn
speaking only when he is spoken to. The [mental]
attitude is often depressed.

The voice is high, the thyroid gland not distinctly
palpable. Typical distribution of fat, and a thick
pad of fat on and superior to the mons Veneris.
Marked fat collection in the hypogastric region,
which is separated from the mons Veneris by a deep
fissure, also fat on the outer sides of the thighs and
on the buttocks. The breasts are very rich in fat.
On the hips are striae (the results of former obesity).

Hair. — No beard, no axillary hairs, hairs on the
mons Veneris only sparse, forming a horizontal line
above. No perineal hair. Hair on the trunk other-
wise absent.

The penis is 3 cm. long, as in a five-year-old
boy. The testicles are palpable in the scrotum,
above the size of beans, very soft. The prostate is
very small.

The breadth of the heart as shown by X-ray
examination is only 10^ cm.

The X-ray examination of the skull shows a
small but otherwise well formed sella turcica. X-ray examination of the hand shows that
the proximal epiphysial junctures of the phalanges are still open, and that the distal are
closed. Open are the proximal of the first metacarpal and the distal of the radius and ulna.
Blood examination: Erythrocytes, 5,800,000.
Hemoglobin, 75 per cent.
Leucocytes, 5500, of which:
Neutrophiles, 59 per cent.
Lymphocytes, i6>£ per cent.
Large mononuclears, 22^ per cent.
Eosinophiles, 3 per cent.

FIG. 74. — Eunuchoidism (Observa-
tion LI).

EUNUCJIOIDISM 405

Examination of the respiratory metabolism (Dr. Bernstein}.

CO2 in cc. O2 in cc.

176.5 221.0

C02 02 RQ

2.67 3.31 o.

According to this the oxygen consumption is entirely normal.
Test as to alimentary glycosuria (100 and later 200 gm. dextrose negative).
Summary . — Typical case of eunuchoidism, in which a slight function of the sexual
glands was present at the time of puberty, which, however, soon disappeared.

Symptomatology. — The form of eunuchoids is characterized by its slender-
ness. Even in fat individuals the bony build is slender, and especially the
tubular bones are striking by their length. The head is small, the hands
are slender and long. This is well shown in the accompanying photographs.
Tallness is the rule in most of the cases. There are cases known that were

"• 1

FIG. 75. — Genitalia in Case H (Observation LI).

nearly 200 cm. tall. As far as I can judge by the literature, individuals with
eunuchoidism who are not pronouncedly tall are never, on the other hand,
small. In the case I reported the height is never below what corresponds to
the age. Only case Da is small, but here the parents are very small. Hence
there usually exists abnormal tallness and at all events never, unless especial
complications should exist, stunting of growth. We shall see later that this
is important for differential diagnosis from hypophysial dystrophy.

The dimensions of the skeleton in eunuchoidism are characterized by the
especial length of the extremities. There is almost always found an excess
of the lower length over the upper length and of the span width over the body
length. I quote some examples. In the case of Duckworth the body length

EUNUCHOIDISM 407

was 171.7 cm., the span width 179 cm. in Observation LI, H., the length
was 176 cm., the span width 185^ cm., the lower length 100 cm. In
Observation L, the height was 169, the span width 184. The tallness and
the preponderance of the length of the extremities is brought about by an
abnormally long remaining open of certain epiphysial junctures, namely,
those which usually ossify the latest. According to Tandler and Grosz they
are chiefly the following: The sternal end of the clavicle, the proximal end
of the humerus, the distal ends of the radius and ulna, the distal of the tibia
and fibula, the crista ilei, the tuber ischii. Often at the site of the coronal
and the parietooccipital sutures is found a tertiary suture formation.
The root of the nose is often deeply saddled. On the contrary the bone-
nuclei are apparently always correspondingly well-developed. At least in
Observation Sch, I could find at the fourteenth and at the sixteenth years of
his life that there was a development of the bone nuclei corresponding to his
age. Also in Observation W. M. (twenty- three years) and in Da (twenty
years) the bone nuclei are already developed very well.

At later years the junctures may be fully closed (Case Thibierger and
Gastinel) .

The sella turcica, so far as observations have been made on it is normal
in size or rather small (Tandler and-Grosz, also the author's observations).
This agrees with the observations of Eppinger, that in women with infantile
genitalia, the sella turcica is rather small. In my case a small focus of calci-
fication was found on X-ray examination (Observation Da).

Almost always there are genua valga. These were always present in my
cases. Moreover, I could often observe the hyperextensibility of the joints,
especially of the phalanges of the fingers (confer case Da). At the diaphyses
the bones are commonly rarefied.

The dentition is sometimes retarded. In Observation Da, milk-teeth
were present at the twentieth year.

The larynx remains cartilaginous and retains the dimensions of child-
hood. The angle of the laminae thyroidae remains wide. The prominentia
laryngea is only slight. In highly pronounced cases voice remains high
and is usually shrill.

All cases show the typical distribution of fat, that is, pads of fat on the
mons Veneris and the hypogastric region, which latter is separated from the
mons Veneris by a deep furrow. Moreover, there are copious fat deposits
on the buttocks and on the outer sides of the thighs, and fat deposits in the
breasts. Tandler and Grosz distinguish, as in true eunuchs, a tall and a fat
type. The tall individual always shows the eunuchoid distribution of fat,
however. Also in these individuals, who from some reason or other have lost
weight, is the distribution of fat always at least indicated by an inclination
to become fat. When the conditions are favorable, the obesity develops
surprisingly rapidly (confer Observation H). It may attain an excessive

408 THE DISEASES OF THE SEXUAL GLANDS

degree. Tandler and Grosz report a case in which a 6 kg. pad of fat was re-
moved by operation from the hypogastric region, which removal seemed to
make the patient easier.

The hair of the head is abundant. There are often lanugo hairs on the
face, especially in front of the ears and on the chin and upper lip. There are
no mustache and beard. In later years occur on the lower jaw sparse bristly
hairs, such as are seen in old women. The hair in the axillae is absent or
only sparse, that on the mons Veneris is limited to a few short hairs at the
root of the penis. When they are more abundant in this situation they are
limited above by a horizontal line. There are no hairs on the perineum; nor
on the trunk and extremities.

The skin is remarkably delicate, pale, velvety, and sometimes has a fawn-
yellowish color. The face in older individuals often shows folds and wrinkles.

As 'a rule the musculature is but little developed, and shows but slight
tonus.

In most cases the thyroid glands seem to have a slighter volume, at least
the statement is repeatedly made that the thyroid was not palpable.

The genitalia are pronouncedly hypoplastic. The penis is always very
small and sometimes quite buried in the fat pad on the mons Veneris. The
scrotum is small and smooth and hairless. The prostate is small. The
testicles are small, soft, and sometimes not larger than a pea. Sometimes
they are not or only partially descended on one or both sides. In this case
the inguinal canals are open. Autopsies were made in the case of Etienne,
Jeandelize and Richon, and in the case of Duckworth and of Tandler and Grosz.
In the case first named the testicles were very small, fibrous (3 gm.), the inter-
stitial glands were degenerated. Also the prostate was very fibrous. On
microscopical examination, Tandler and Grosz found sparse seminal canals
and sparsely developed interstitial substance. Also the seminal vesicles
were small, but the epididymis on the other hand, well developed.

Cases of female eunuchoidism seem to be rare. Josef son and Lundquist
have reported such a case, which I shall quote somewhat in detail.

Thirty-four-year-old woman who had kept on growing from the fifteenth year on
(the growth had been especially active up to the twenty-fourth year); she was 183.6
cm. tall (upper length 118 cm.), she had never menstruated and had felt only slight in-
clination for men; the mammae were small, flat, without palpable glandular substances,
the nipples very small; she had rather a mannish appearance, but a feminine voice. The
form of the pelvis was rather womanly. The epiphysial junctures were closed, the sella
turcica not enlarged. Examination of the genitalia showed very small labia minora, a
hypertrophic clitoris, the vestibule was rather narrow, the internal genitalia were not
palpable. No introitus vaginae or hymen.

In eunuchoids the genital function is always markedly reduced or entirely
absent. In many cases, however, erections are possible despite the smallness
of the penis. I refer to the Observations Da and H. In many cases libido

ETJNUCHOIDISM 409

is entirely absent, although it may be present slightly. In one of my cases
the inclination was at first contrasexual. In many cases potency can exist
for some time, but this becomes less after some years and disappears. In
other cases the inhibition of development and disturbance of function occurs
chiefly at the time of puberty and later becomes compensated (transitory
eunuchoidism). We may regard both as formes frustes. As a case of the
first form I would regard case II of Josef son and Lundquist. It was that of a
forty-five-year-old man who had been married since the thirty-sixth year and
who was entirely impotent for three years. The breasts had been very rich in
fat ever since youth and the pubic hairs ended above in a horizontal line, the
voice had not changed, the hairs of the beard and in the axillae were very
sparse, trunk hairless.

Eunuchoids of the male and female sex are always sterile. At least no
case of procreation or conception is known.

In woman, the breasts are poorly developed or fatty, but poor in glandular
substances; in man they often contain much fat.

Observations on the respiratory metabolism have as yet been confined to
Observation H and to a female eunuchoid of L. Zuntz's. The value of O2
requirements is entirely normal. Of course from which we are not justified
in concluding that in such cases we may not have had a slight degree of
endogenous obesity, as small differences may not be evident on investigation,
and yet through summation may favor deposition of fat. It is certain that in
all these cases there is present an abnormal disposition for the deposition^
fat, as was observed for example in the case of H. At all events the cause
may be due chiefly to the slight inclination for movement and to the indi-
vidual's phlegma.

Test for alimentary glycosuria was undertaken in three of my cases, with
150-200 gm. dextrose, and always resulted negative. Hence the assimilation
limits for carbohydrates seem to be high.

Guggenheimer reports a case in which at an old age diabetes developed. I
cannot see here an especial connection with eunuchoidism. In eunuchoidism
(as in normal individuals) there may very well set in a degeneration of the
pancreatic insular apparatus. Another case of eunuchoidism with diabetes
seems to be the "giant" described by Uhthojj. This. patient at the age of six-
teen years suffered an attack of pneumonia. From then an abnormal growth.
He was 194 cm. tall, hands and feet were not especially large. There existed
bilateral cryptorchidism, the pubic hairs were sparse, and he had never been
potent.

The purin metabolism has been studied (not published) in one case only,
Observation H of N ' owaczinski and myself. The endogenous uric acid
elimination was normal. Purin administered exogenously was well elimi-
nated. Perhaps this behavior is of differential diagnostic importance as
against hypophysial dystrophy.

410 THE DISEASES OF THE SEXUAL GLANDS

The blood examined in my case showed normal values for erythrocytes
and hemoglobin. The leucocyte count was near normal; in all cases there
existed a pronounced mononucleosis. Lately also Guggenheimer has found
the marked predominance of lymphocytes in several cases of eunuchoidism;
in one case he saw hyperleucocytosis with predominance of the mononuclear
cells.1

The thymus gland showed abnormally slight involution (Kolisko, and
Tandler and Grosz) .

The findings in the internal organs show no essential alterations, except
such as must be regarded as coincident. In one case the heart shadow as
shown by the X-ray was seen by me to be strikingly small.

Perhaps the excitability of the vegetative nerves in cases of eunuchoid-
ism is somewhat reduced. This was tested in some cases with pilocarpine
and adrenalin, yielding a slight, but distinct, reaction.

The development of the intelligence in such individuals is mostly entirely
normal. Feeble-mindedness, which has been observed in some cases, is to
be referred to other coincident developmental disturbances. On the
contrary, certain common traits do exist in the psyche of eunuchoids. They
are, as Tandler and Grosz notice, strikingly quiet, but little communicative,
and often but slightly independent. At any rate this mental condition is not
to be designated as infantile. The masculine quality is all that is lacking.

Occurrence and Pathogenesis. — Eunuchoidism, at least as far as its pro-
nounced forms are concerned, occurs essentially more frequently in the male
sex. Thus far the only typical incontestable case in woman has been reported
by Josef son and Lundquist. Perhaps to this may be added the previously
quoted cases of Swinarski, Pfannenstiel, and of Howitz. But here there are no
statements a.s to the proportions of the body, which would be very important
for the diagnosis. Animal experiments show us that castration in early life
produces long-legged individuals in the female also. We know very little as
to the cause of the developmental disturbances in the sexual glands. As was
mentioned previously, eunuchoidism in the male sex is very frequently asso-
ciated with cryptorchidism. This may be either abdominal or inguinal. It
may well be regarded as a partial manifestation of the developmental dis-
turbances and not as its cause. Moreover the developmental disturbance
may very well be congenital if it first manifests itself at the age of puberty.

1 Guggenheimer states that in two cases of eunuchoidism he found hyperglobulia. He mentions,
moreover, that in these cases after the injection of adrenalin there never occurred an increase of
erythrocytes, but even diminution of these. He says that he could not "corroborate" the hyper-
globulia after injection of adrenalin as observed by Bertelli, Schweiger, and myself. This expres-
sion seems to me out of place. We have never asserted that we saw hyperglobulia after the injec-
tion of the doses of adrenalin used in man. The hyperglobulia observed by us in the dog after
larger doses had already declined after twenty-four hours. Guggenheimer, however, tested very
small doses of adrenalin twenty-four hours after injection. The individual values for the ery-
throcytes in Guggenheimer 's case also varied appreciably in the days uninfluenced by adrenalin.

EUXUCHOIDISM 41 1

It is also conceivable that traumatic and infectious insults in early youth may
damage the sexual glands and thus lead to eunuchoidism. This is especially
true of mumps, perhaps also of scarlet fever, measles, etc. We shall meet
with these etiological factors again in the consideration of late eunuchoidism.
Not rarely, eunuchoidism is hereditary. The case concerned in direct repro-
duction can be only the lightest cases, those principally associated with obes-
ity in childhood. On the contrary, it is conceivable that cases that do not
reproduce may now and then crop up in a family. Such a familial occur-
rence has been reported by Sainton. Of five living brothers and sisters,
three were eunuchoids and besides this an uncle and great uncle.

Grandfather Great-uncle

Uncle Mother

99 d1 <? cf d1

Died early + + +

9

Very noteworthy is the observation that eunuchoidism and chlorosis
can occur in the same family (Tandler and v. Noorden) (see also Obser-
vation H).

Differential Diagnosis.- — Differential diagnostically, infantilism and hypo-
physial dystrophy come chiefly into consideration. The former in the
pure forms shows retention of the childish dimensions. Also the psyche
remains infantile; but the psyche of male eunuchoids although mannish,
can hardly be called childish. Peretz and Wolf are wrong in their attitude
against the delimination of the eunuchoid type. When they call eunuchoid-
ism a pure form of infantilism, they are confused as to the meaning of the
diseases. Both the female individuals that Peretz describes are to my mind
not eunuchoids, but infantiles (see Chapter XII, Infantilism). Naturally
there occur also mixed forms of infantilism and eunuchoidism, hence cases
of infantilism in which the development of the sexual glands not only remain
at a childish stage, but their function is much more seriously disturbed.
It must not be forgotten that normally the interstitial glands functionate
also in children, even if a subordinate degree only. Such cases show in
addition to the infantile features also more or less distinct eunuchoid dimen-
sions and the typical distribution of fat such as is not a feature of true in-
fantilism. The four female cases of Walk are not true eunuchoids. One
of them is apparently a true dwarf, the others are cases of infantilism, or
at least transitional cases which tend nevertheless more toward infantilism.

The differentiation from hypophysial dystrophy is on the whole not
difficult. Common to both are the genital disturbance and the association of
fat distribution or obesity. Hence there are an eunuchoid and hypophysial
form of dystrophia adiposo-genitalis. The two forms are different from each
other:

412 THE DISEASES OF THE SEXUAL GLANDS

1. By the growth in height. In the hypophysial form, so far as it sets in
in childhood, is found pronounced inhibition of growth; in the eunuch-
oidal form is found even tallness, or at least no growth disturbances.

2. Eventually through the behavior in metabolism. In the severe forms
of hypophysial dystrophy the fundamental exchange is usually dis-
tinctly reduced in the end; in the eunuchoid form the reduction is
perhaps not considerable enough to become demonstrable. The
answer to these questions will depend on further investigations.

3. Through the cerebral manifestations in hypophysial dystrophy.
Here in most cases are found signs of a hypophysial tumor or of, at
least, a tumor in the hypophysial region, or at least signs of increased
brain pressure. One should not forget, however, that cases of eunuch-
oidism at the time of puberty not at all rarely complain of headaches;
and occasional vomiting may occur (two cases under my observation) .
In such cases the X-ray examination of the sella is very important.
At all events there are also processes that may destroy the hypophysis
without distinctly altering the sella and producing symptoms of brain-
pressure; for examples gummata or chronic inflammations. Such proc-
esses indeed set in after completed development. Hence here comes
into consideration the differentiation from late eunuchoidism or from
multiple ductless glandular sclerosis.

The blood examination in the hypophysial as well as the eunuchoid form
mostly shows a pronounced mononucleosis. Hence here there is no dis-
tinguishing factor. We can at most say that in the hypophysial form, at least
in the severe cases, the hemoglobin and the erythrocyte count are often more
markedly reduced.

Prognosis and Treatment. — Very important is the observation of Tandler
and Grosz, that in the eunuchoidism that sets in early, developmental dis-
turbances of the sexual glands are often only temporary (prepubertial eunuch-
oidism). Hence such cases may be improved. One of my cases showed
such a condition. At the sixteenth year (Observation Sch) the voice had
changed, the genitalia had developed almost normally, but as yet there had
occurred no pollutions. In these cases the obesity is only improved for the
abnormal distribution of fat still exists. In such cases we would recognize
the developmental disturbances later in life by the distribution of fat, and
probably also by the hair condition. Also it is very probable that in these
cases the function of the sexual glands disappears prematurely. Case II
of Josef son and Lundquist seems to point in this direction.

Rapid improvements have been reported from the thyroidin treatment.
A pert mentions a case complicated with cryptorchidism in which arfter one-
half year's treatment with thyroidin, the penis had distinctly grown, the
testicles had lowered, and the weight had increased about 2^ kg.

Also Parhon and Mihailesko report a similar case in a fourteen-year-old

LATE EUNUCHOIDISM 413

youth with left-sided inguinal cryptorchidism and obesity; under thyroidin
treatment the genitals took on a rapid development.

There is no doubt that we are often able to improve with thyroidin the
fat types of obesity. Thus for example in Observation Sch, there occurred
without limitation of diet, after the administration of even small doses of
thyroidin, a rapid reduction of 3 kg. in weight. A considerable improvement
is also reported by Lemos Magelhaes. In a case of adipositas nimia who
weighed 160 kg. there occurred under thyroidin treatment a reduction of 32^
kg. Then intoxication symptoms appeared. I do not feel justified, however,
in referring offhand, as do Apert, Parhon and Mihailesko, the improvement
in the genital sphere to the thyroidin treatment, or in constructing, because
of the improvement, an etiological connection. To me the reports do not
seem convincing that these cases were cured by thyroidin, because as has just
been mentioned, there have been sometimes observed in this growth period
improvements that are spontaneous. But we must accept a certain stimu-
lating action of thyroidin.

Not much has been reported as to other methods of treatment. I do not
know that extracts of sexual glands have been used. As radium emanations
have a certain stimulating action on the sexual glands — Freund and / saw
several times through radium treatment an increase of the potency, a re-
currence of the periods at the climacteric or an aggravation of dysmenorrheic
complaints — in one case (Observation Sch) I used the radium emanation,
perhaps with good results. Such a result is to be expected only in youthful
cases. In another case (Observation H, twenty-eight years old), who on
account of his joint affection was treated for a long time, all action on the
sexual glands remained absent.

The transplantation of the sexual glands has not to my knowledge been
tried in the treatment.

4. Late Eunuchoidism

Historical. — The first excellent description of this disease we find in
Larrey in his " Campagne d'Egypte : de 1'atrophie des testicules." Larrey ob-
served in several soldiers who had followed the campaign in Egypt with
Napoleon and later, in soldiers of the Imperial Guard, simultaneously with
gradually occurring atrophy of the testicles with retrogression of the penis,
disappearance of the libido and the potency, falling out of the pubic and ax-
illary hairs, development of a falsetto voice, and certain alterations of intelli-
gence and psyche. Larrey sees the cause of the disease in the deleterious in-
fluences of the climate, or in sexual abuse or in alcoholism. Lately interest
has again been turned toward this subject by Gandy who described three
cases, that he termed infantilism reversif ou tardif. Of Candy's cases I
would regard two as typical cases of late eunuchoidism. The third belongs
to multiple ductless glandular sclerosis. Gandy seeks the cause of the

414 THE DISEASES OF THE SEXUAL GLANDS

affection chiefly in a dysthyroidism, while Claude and Gougerot describe a
series of cases that they refer to an insuffisance pluriglandulaire endocrinienne.
Cordier and Rebattu treat the subject in a large study of these cases; they
again uphold the designation " inf antilisme regressif type Gandy,"

Recently I have published a study on this subject in which I pointed out
that the manifestations in this disease, so far as they connected with the
genitals, are like those of eunuchoidism; and I selected from the group the
pure cases of "late eunuchoidism" [" Spateunuchoidismus "] from late eu-
nuchoidism which is only the partial manifestation of a very complex clinical
picture.

Definition. — / term "late eunuchoidism" a clinical picture that comes about
by the fact that in an already matured organism in which also the functions of the
sexual glands have attained their full development, there occurs atrophy of
the accessory genital apparatus (in man retrogression of the penis, scrotum, the
prostate, etc.; in woman the labia major a and, the uterus), and, retrogression of
the secondary sexual characters (mustache, beard, hairiness of the axillce and the
pubis, the trunk and the extremities}. Moreover there develop more or less
distinct collections of fat on the breasts, the mons Veneris, and the hips, and
often certain alterations of the psyche. The typical eunuchoidal alterations of
the skeleton can no longer go on developing, especially where the develop-
ment of the skeleton has been already closed off; that is where the epiphysial
junctures have already united.

There is regularly found a high-grade affection of the sexual glands, that must
be regarded as the cause of the manifestations described.

Case Reports. — I have already treated in my publication the case histories
of this affection somewhat in detail. Since the time I wrote my article I have
found still more cases in the older and newer literature. As I would describe
the clinical picture in detail and delimit it as precisely as possible, I will here
make a complete report of the case histories. Then I shall classify the cases
according to their etiology, as nearly as possible. Moreover, I would here
state that the position of a series of cases is still uncertain. I shall come back
to these cases in the consideration of multiple ductless glandular sclerosis,
and here set forth only those cases which I regard as pure cases of late eu-
nuchoidism or at least as cases in which the manifestations of late eunuchoid-
ism stand quite in the foreground.

A. Cases that depend on a traumatic foundation.

Observation of A chard and Demanche. — Sixty-eight-year-old man. Pale tinge, the
skin of the entire body pale and dry. Hair of head abundant, skin of the face and trunk
and extremities completely bald. Eyebrows sparse. The breasts not essentially enlarged.
The scrotum small, both the testicles small, the cremasteric reflexes very weak. Intelli-
gence normal. Easily excitable disposition; at the twenty-fifth year of life, the man had
sustained an injury, due to the tread of a foot, in the scrotal region. The testicles had be-
come swollen, as the result of the injury, and later atrophied. Beard and cranial hair,

LATE EUNUCHOIDISM 415

that previously had been abundant, became at the same time always sparser, the muscu-
lar strength decreased, a certain amount of libido was retained, but ejaculations had never
occurred.

Observations of Gallavardin and Rebattu. — Twenty-six-year-old man, 174 cm. tall,
looks like a fifteen-year-old youth. Preponderance of the lower length over the upper
length (femur + tibia = 90^ cm.). The distal epiphyses of the radius and ulna have
as yet not united. The voice that previously had been mannish, is now shrill, the skin
is white and delicate, scrotum and penis are very small (as in a six- to ten-year-old boy).

At eighteen and one-half years of age the man had received a violent knock in the
scrotal region, after which for three hours he was unconscious. After this there devel-
oped a considerable swelling of the testicles and bloody suffusion of the skin of the
scrotum; these phenomena disappeared after three months. Later the testicles became
small, the penis atrophied, the secondary sexual characters and the libido disappeared,
and complete impotence appeared. The photograph accompanying the report of the
case shows well the eunuchoidal fat distribution.

Observation of Cordier. — Twenty-nine-year-old man, looks like an eighteen-year-old
youth. Genitalia and prostate markedly atrophic, secondary sexual characters and libido
have almost disappeared. The man married at the age of twenty-five years, is the
father of one child. At twenty-five and one-half years a trauma that affected the tes-
ticles. Gardual falling out of the hairs of the mustache, the beard since then has become
very sparse, marked reduction of libido.

Observation of Stieda. — Thirty-year-old man. At the age of fifteen both testicles
bruised. From then on the testicles became gradually smaller, he first remained behind
in growth and then grew appreciably between the twentieth and thirtieth years. The
voice was only somewhat rough, and the. potentio coeundi remained, although there was
no ejaculation of semen. The mammary glands grew somewhat in circumference.
According to his statement a growth about the size of a thaler appeared at their site
on each side. The man remained beardless, there was hair on the mons Veneris but the
upper border of this hair was horizontal. Height 175 cm., the extremities were remark-
ably long, the breadth of the shoulders was slight, the pelvis broad, the larynx small,
internal and external genitalia had remained behind in development. The testicles
were about the size of beans, the epididymises were about just as large.

Observation of Riedinger. — The patient in his twenty-first year suffered a severe injury
in which the anterior perineal region was bruised and the scrotum torn, and the testicles
and prostate severely injured. The penis had previously been of normal size (examined
by Rieder). Erections were still possible the first year after the injury, but there were no
signs of ejaculations. Now erections only very seldom, no sexual intercourse any more.
The man is 163 cm. tall, the lower extremities (from the trochanters down) are 86 cm.
long, the skin is pale in color, the skin of the face lax and wrinkled. He appears much
older than he is. The skin is otherwise lax and flabby. He is very thin; the accom-
panying photograph allows one readily to recognize, however, the abundance of fat in the
breasts and on the mons Veneris. The penis is 6 cm. long, reduced in all its dimensions.
The pubic hairs are very sparse and the upper border of the pubic hairiness is horizontal.
The hairs in the axillary and anal region are also sparse. No beard (before the injury
there was a beard). The voice is' mannish, lately a goiter has developed. The sella
turcica, as the author kindly informed me in a written communication, is not enlarged.

Own Observation LII. — Forty-two-year-old man, rather corpulent, breasts very rich
in fat, mons Veneris and hips somewhat more rich in fat. Sparse hairiness of the axillae.
Genitalia rather well covered with hairs. Both the testicles as large as peas, very soft,
the scrotum small, without tension, cremasteric reflexes absent. Bilateral scars in the
inguinal regions as the result of operation.

41 6 THE DISEASES OF THE SEXUAL GLANDS

Four years ago, after operation for bilateral inguinal hernia there developed on each
side an enormous hematoma, which after some time disappeared. Only a few weeks after-
ward the patient noticed diminution of potency, which later disappeared entirely for a time.
The libido did not disappear entirely, later erections were again possible and coitus was
performed a number of times per month. According to statement, only a slight ejacula-
tion occurred.

The cause of the atrophy of the testicles in these cases may very well be regarded as a
circulatory disturbance, whether through injury of the arteries, or compression due to
shrinking of scar tissue, whereby damage was done to the nutrition of the testicles.

B. Cases that depend on an orchitis due to syphilis, gonorrhea, or mumps.

Perhaps some of the cases described by Larrey belong to this group.

Observation of Coffin. — Male individual, afte.r bilateral luetic orchitis the testicles
shrank to the size of beans. The voice became higher, obesity developed, the beard
fell out, the muscular power diminished, erections and ejaculations ceased, the penis
became smaller, finally to the size of that of a six- or seven-year-old child. The breasts
became larger.

Observation of Charcot. — Soldier. After bilateral mumps, orchitis, atrophy of the tes-
ticles to the size of beans. Libido disappeared, complete impotence, the breasts in-
creased in size.

Observation of Lereboullet. — Twenty-seven-year-old man, skin pale, eunuchoid form,
breasts well developed, penis and testicles very small, impotence. Beard absent, the
patient was formerly very potent and the beard well developed. The voice mannish.
At twenty-four years, mumps with bilateral orchitis, later gradual atrophy of the testicles.

Observation of Dalche. — Thirty-six-year-old man. Color of face pale, hair of beard
abundant. Hairs of beard, axillae and genitalia, are entirely absent. Testicles very
atrophic, libido absent, complete impotence, intelligence weak, forgetfulness, tendency
to weep, apathy; often chills. At twenty years lues, at thirty years, bilateral orchitis,
since that time development of the genital atrophy. Later also slight swelling of the
legs and the face. Polyuria. In this case the eunuchoidism is certainly in the fore-
ground. But in addition there exist symptoms (and indeed chiefly symptoms of fail-
ure) on the part of the other ductless glands.

Observation of Dupre. — Forty-five-year-old man. Abundance of hair on head. Mus-
tache much reduced, very little pubic hair, pallor of the face; penis and testicles small,
soft, libido absent, impotence. Formerly gonorrhea and syphilis. At the thirtieth
year gradual testicular atrophy and development of the symptoms described.

Observation of Gandy. — Forty-six-year-old man. Color of face pale-yellowish, sec-
ondary sexual characters very sparingly developed. Genitals markedly atrophic, some
collection of fat on the trunk. Impotence. Formerly entirely normal, lues at the thirty-
third year. About this time beginning of the retrogression of the genitalia, and secondary
sexual characters, temporary polyuria (in the thirty-sixth year), also temporary swelling
of the face.

Observation of Gandy. — Forty-two-year-old man. Face very pale, wax-like, skin of
the forehead arranged in fine parallel folds, skin of the trunk delicate, voice monotonous,
no hair at all on lips or trunk, penis and testicles very small, prepuce long and folded,
cremasteric reflexes absent, no libido; impotence, memory somewhat weakened, apathy,
blood-pressure reduced. At thirty-two years of age bilateral gonorrheal orchitis; from
about this time began atrophy of the genitalia and impotence. At the twenty-ninth
year states that he is somewhat stronger; pad-like swelling of the skin of the face, the
hands, and the back of the feet.

f

LATE EUNUCHOIDISM 417

Gaudy regards this case as " dysthyreoidie + dysorchidie." I believe, however, that,
in spite of this, late eunuchoidism stands in the foreground.

Apparently also the observation of Foges belongs here. After bilateral luetic orchitis
there developed a "gynakomastie." The mammary glands were removed, microscopical
examination showing only fat and no glandular substances. Sexual sensation was much
reduced.

C. Cases of other etiology.

Observation of Cordier and Francillon. — Thirty-five-year-old man. 175^ cm. tall,
lower length 90^ cm. hence distinctly predominating. Epiphyses united, eunuchoid
distribution of fat, skin pale, diffuse pigmentatk is. Hairs representing beard absent,
hair on cheeks sparse, atrophy of the genitals, libic'o present but coitus rare and incom-
plete. Weakness of memory. Patient is quarrelsome, easily excited, slight anemia with
hyperleucocytosis and mononucleosis (phthisis pulmonalis is present, however). Typhoid
fever at about twenty-four years of age. Before development was entirely normal and
potency was normal. Several months after the typhoid gradual development of genital
atrophy and impotence; temporarily, also, complete loss of libido. Great bodily weak-
ness, that later improved. Since that time increase in height about 3 cm.

Observation of Gougerot and Gy. — Fifty-two-year-old man, quite normal up to forty-
eighth year (except that he had had gonorrhea); about this time a hard to define acute
infectious disease, after this asthenia, polydipsia, polyuria, atrophy of the genitalia, im-
potence, loss of libido, retrogression of the secondary sexual characters, pigmentations on
the forehead, hands and feet,, cachexia.

Observation of Galliard. — Fifty-seven-year-old man, face very pale, mustache and
beard very sparse, no hair in the axillae, scrotum and penis small, testicles very small,
impotence. At fifty-three years eczema, "since that time development of the phenomena
described."

Observation of Belfield. — In a man twenty-seven years old there developed at the same
time with a polyuria a "retrograde puberty," atrophy of the testicles and the external
genitalia, retrogression of the secondary sexual characters, etc. The hair of the head
remained abundant. Examination took place when the man was thirty-nine years old.
X-ray showed sella turcica normal. Thyroidin therapy and later adrenalin were used
without results. Later was administered dried suprarenal gland, containing both cortex
and medulla. After four months the daily amount of urine had been reduced to one-
half. The body hairs had grown distinctly, the testicles were twice as large, and coitus
already had been several times performed.

I would here refer to the observation of Josef son and Lundquist (case 2). We can
regard this case as a transition between eunuchoidism and late eunuchoidism. I have
described this case in detail in a previous section.

Finally, more on account of the curiosity, I will report an observation described by
Hammond. The Pueblo Indians in New Mexico seem to have cultivated the so-called
mujaderes for purposes of pederasty. For this purpose already fully developed men are
excessively masturbated and at the same time are made to ride enormously. This treat-
ment causes an atrophy of the testicles and epididymises, the penis becomes smaller,
libido disappears, the testicles are insensitive to pressure, the mammae enlarge, the indi-
viduals become fat, the voice becomes higher and the bodily strength decreases. Ham-
mond himself has examined two such individuals. While in many respects the story
sounds fabulous (one of the mujaderes stated that he had suckled children), the agree-
ment with the picture of late eunuchoidism is so complete that I had at least to mention
the observation.
27

418 THE DISEASES OF THE SEXUAL GLANDS

Symptomatology. — Late eunuchoidism is found almost exclusively in
men. There have been individual cases reported in women but these are
not pure cases. As we shall see later they belong to the group of multiple
ductless glandular sclerosis. The cause of the disease in man is either violent
trauma effecting the testicles or their vicinity, or, as in my case, probably, a
damage to both spermatic cords through shrinking of scar tissue; or a bi-
lateral high-grade orchitis on a syphilitic or gonorrheal basis, or mumps
orchitis; or it may be due to severe infectious disease — typhoid for example —
or to an infectious process of an unknown nature, affecting the entire organ-
ism and probably also the testicles. At the close of these deleterious influ-
ences, or also in certain cases quite spontaneously, without distinct recog-
nizable cause, in individuals who previously had been entirely normally
developed, in whom especially the secondary sexual characters were com-
pletely developed and in whom the genital function has been entirely nor-
mal— there develops quite gradually an atrophy of the entire genital appa-
ratus and at the same time a retrogression of the secondary sexual characters.

Finally there seem to be cases in which there exists from youth a certain
lessened valuation of the rudiments of the sexual glands and soon an exhaus-
tion (case of Josef son and Lundquist) .

The ages of the affected individuals are very different. In the case de-
tailed the beginning of the disease fell between the eighteenth and fifty-
third years of life.

The alterations in the genitals must be regarded as manifestations of
retrogression and not, as Claude and Gougerot believe, as mere atrophy. In
this view I am entirely in accord with Gandy. The retrogression of the testi-
cles may be astounding. The testicles are estimated as at the size of hazel-
nuts, cherries, beans, and peas. The diminution of volume is naturally less
where connective tissue has formed at the site of an infectious process; and
here too there is not such a diminution in consistence; in most cases has been
emphasized an especial softness. The scrotum can be as small as that of an
eight- to ten-year-old boy; and it loses its tension and its pigments. Also the
penis can reduce in size to such an extent that it looks like that of an eight-
to ten-year-old boy. The picture is therefore entirely similar to that of early
eunuchoidism. Also the prostate takes part in the atrophy.

We have already described the manifestations that occur after castration
in the matured woman. Retrogression of the genitalia occurs, mostly an
increased fat-deposit and loss of pigment, but not a falling out of the pubic
and axillary hair. We shall consider later under ductless glandular sclerosis
those cases in which retrogression in the hairiness occurs simultaneously
with spontaneous atrophy of the ovaries.

In late eunuchoidism the function of the genitals suffers severe damage.
In man complete impotence with entire incapability of cohabitation can
occur under circumstances. Libido is here entirely lost; but in other cases

LATE EUNUCHOIDISM 419

only impotence occurs, while libido remains in enfeebled form. In the formes
frustes the capability for cohabitation still remains; except that in these cases,
as Cordier and Rebattu point out, much stronger stimuli are needed to induce
erection. The cremasteric reflexes are either weaker or entirely wanting.
Hence the functional disturbance also corresponds entirely with that of early
eunuchoidism.

The same is true for the coloration of the face. The pallor of the face
and the delicacy of the skin and body are noted in all cases. There is often
found a yellowish tinge; and (in one case) folding of the skin of the forehead
(as in eunuchs) . Puffiness of the skin of the face is very rare indeed among
the cases reported.

The hair of the head remains abundant, but as a rule is rather dry. (The
cases with patches of alopecia do not belong to pure late eunuchoidism.)

In severe cases the hair of the body falls out entirely. The mustache,
that previously may have been very luxuriant, falls out entirely or at least
thins out very much. The same is true of the beard; often is found the state-
ment that the patients who previously had to shave several times a week,
shave much less frequently. Thinning out of the lashes and the eyebrows
does not in'deed belong to the pure picture of this disease. Also the trunk
and the extremities may become entirely bald. The axillary hairs, the
hairs on the scrotum, the perineum, and on the root of the penis, may fall
out altogether.

Very important for the comprehension of the disease picture are the al-
terations of the form. ' As has previously been mentioned, it is in itself sug-
gestive that where the beginning of the disease falls at an age where the total
epiphysial junctures are closed, a development of the eunuchoidal skeletal
type is no longer possible. Of especial importance, therefore, are the observa-
tions of Gallavardin and Rebattu, of Cordin and Francillon, and of Stieda. In
the first case a youth of eighteen and one-half years old suffered a knock in the
scrotal region, and in the second the beginning of the disease lay in the twen-
tieth year. In the first case there was only a suggestion of the eunuchoidal-
skeletal type (predominance of the lower length over the upper length), and
the epiphysial junctions that close at a later period were still open at the
twenty-sixth year. In the second case there was a further growth of about
3 cm. at the twenty-fourth year. The case of Stieda's sustained a trauma in
the fifteenth year of life. He first remained behind in growth and then grew
appreciably between the twentieth and the thirtieth years. Here, therefore,
the epiphysial junctions had remained open abnormally long. Here also
there came about the development of the eunuchoidal dimensions.

The influence on the weak parts is noted more frequently. In many cases
the statement is made that there appeared at the beginning of the disease
an adiposity; in other cases that the breasts had become fatty, or the hips
rounded, or that the mons Veneris had become richer in fat. In several

420 THE DISEASES OF THE SEXUAL GLANDS

cases, in which the typical distribution had not been noted especially, it
could be recognized in the illustrations that accompany the reports.

In the majority of cases it is furthermore stated that the voice which had
previously been mannish, altered in the course of the disease. A falsetto
voice did not develop, as in eunuchs and early eunuchoids, but the voice
placement was high and the voice shrill.

In the pure cases there is no alteration of the intelligence. The apathy,
[mental] heaviness, forgetfulness, that are stated to have occurred in indi-
vidual cases, may well be referred to the general prostration following several
general infectious diseases or perhaps to a slight myxedematous component.
We shall again see such manifestations under multiple ductless glandular
sclerosis. In pure cases the statements as to alterations of the moral and
psychical attitude are on the contrary very frequent; statements that such
individuals like early eunuchoids, are psychically more easily excited, and
given to sudden anger and to lying. In two cases also has been noted tem-
porary polyuria {Gougerot and Gy, and Dalche). In the first case the late
eunuchoidism came after an acute infectious disease, in the second after lues.
We shall often meet with these symptoms in the consideration of multiple
ductless glandular sclerosis. Perhaps it is of hypophysial origin.

Are we now justified in separating out these cases as an especial clinical
formation and giving it the name "late eunuchoidism?" As has been men-
tioned, Gandy regards them as " dysthyreodie + dysorchidie." Gallavardin
and Rebattu express themselves more in favor of [in affection of] the sexual
glands, Cordier and Rebattu distinguish between an " inf antilisme regressif
myxedemateux et non myxedemateaux." Claude and Gougerot finally group
all these cases under "insuffisance pluriglandulaire." The confusion can, I
think, readily be overcome if we place in the foreground the classification of
these cases according to their etiological factor, and separate out, before
everything else, those cases which have the value of experiments, namely,
the traumatic. Where acute infectious diseases or noxi of a more general
nature have led to degeneration of the sexual glands it is very well intelligible
that also other ductless glands can suffer damage, and that other features
often hard to define become associated with the picture of a disease that is
due to falling-out of the sexual gland.

As to the significance of thyroid insufficiency in this disease picture, we
can become clear on this point, if we have recourse to the experiments. If
in an individual who has attained complete maturity, the thyroid gland is
completely extirpated, there come about disturbances of the genital function,
but never any such retrogression of the genitalia as has been just described.
The thyroprivic disturbance of the genital function can be promptly over-
come by thyroidin medication, while all statements are in accord that
thyroid medication does not improve the disturbance of sexual glandular
function in late eunuchoidism. In spontaneous myxedema of adults the

LATE EUNUCHOIDISM 421

behavior in these respects is not always as clear as in operative myxedema.
It should, however, be considered that the disease process that in this con-
dition is responsible for the sclerosis of the thyroid gland very readily and
very often involves other ductless glands, and that here we are no longer
dealing with mere action at the distance.

Can we show by experimentations the significance of the sexual glands
for this clinical picture in a clean and clear-cut fashion? To answer this we
must have recourse to the known experiments of A ncel and Bouin. In
male grown animals the ligation or transection of the vas deferens, or patho-
logical stenosis of the exit-ducts of the sperm, leads to degeneration of the
germinative part of the sexual glands, while the interstitial substance is
retained. The animals become sterile but they are not impotent, and retain
their masculine appearance. If, however, the " interstitial glands" are
brought to degeneration the animals lose their masculine appearance and
become similar to castrates. In this manner there is therefore produced an
experimental late eunuchoidism. I refer moreover to late castrates whom I
have described above. The same value for the pathogenesis is afforded by
the very numerous cases of pure traumatic late eunuchoidism; they show that
severe injuries of the male genitalia may lead to the full symptom-complex of
late eunuchoidism; also in these cases there does not exist the slightest basis
for regarding the condition as a primary affection of the other ductless
glands. The question as to whether the loss of both sexual glands leads
regularly to the development of late eunuchoidism does not seem to me en-
tirely solved by the material up to the present time, although I regard it as
very likely. Widal and Lutier have reported a case with marked testicular
atrophy, in which the manifestations of late eunuchoidism did not seem to be
present. Cordier and Rebattu discuss the possibility whether in these cases
there were still present functionally capable islands of Ley dig's interstitial
cells or ectopic sexual glandular tissue.

Much less clear are the alterations in women. That premature meno-
pause and hyperinvolution of the uterus through repeated births or pro-
longed lactation does not lead to any change in the secondary sexual char-
acters is readily intelligible, as there need not be .associated with the retro-
gression of the follicular apparatus a retrogression of the interstitial substance.

On the contrary it is really not intelligible why the loss of the whole
ovaries exercises such little influence on the axillary and pubic hair. The
few cases of pronounced regression of this hair seem to me to belong under
the caption multiple ductless glandular sclerosis.

The differential diagnosis has especially to consider the diseases of the
hypophysis that first develop in later years after the attainment of the com-
plete cessation of growth and complete maturity of the body. In this case
there is no disturbance of growth, as occurs in the differential diagnosis
between the eunuchoid and the hypophysial dystrophia adiposa-genitalis.

422 THE DISEASES OF THE SEXUAL GLANDS

Where symptoms of brain-pressure are present and the X-ray shows altera-
tions of the sella turcica, the diagnosis is at once cleared up. Sometimes
difficult, however, is the delimitation from atrophic and inflammatory
sclerotic processes in the hypophysis. Perhaps points of differential diag-
nostic value can be obtained from the examination of the respiratory gaseous
exchange and of the purin metabolism. The history also ought to be im-
portant; the fact that the patient has sustained a luetic, gonorrhea], or
mumps orchitis should at any rate lead to the suspicion of late eunuchoidism.
The differential diagnosis with respect to multiple ductless glandular sclerosis
will be considered later.

The treatment has not up to the present yielded anything reassuring.
That thyroid medication fails is indeed only too comprehensible. But also
the administration of sexual glandular substances has led to only transitory
results, or, as in the case of Dalche, led to improvement of symptoms that
probably were not to be referred to the lack of the sexual glands (forgetful-
ness, general weakness, chills). In the valuation of therapeutic results, we
should not forget that in certain cases spontaneous improvement is possible,
such as also occurs in early eunuchoidism.

5. Treatment of Sexual Glandular Insufficiency

The drug therapy of sexual glandular insufficiency has as yet had in man
no decisive results. The feeding with testicular substance is but little
carried out, and the reports as to the result of injection of sexual glandular
extracts disagree. Spermin (Poehl) may have a certain stimulating action
on the nervous system, but profound symptoms of insufficiency are hardly
improved thereby.

In want of a better treatment, thyroid treatment has been recommended
—a therapy that plays a part in the treatment of all ductless glandular affec-
tions, to a certain extent indeed, erroneously. In eunuchoid obesity, thyroid
medication has on the whole a good result and is certainly to be recom-
mended if it be employed with necessary caution. It is also conceivable
that through stimulation of metabolism often a certain furthering influence
is exerted on the sexual glands, but we cannot expect decisive results as to
this point. In such cases treatment with hypophysis tablets seems to be en-
tirely valueless. I do not know whether anybody has as yet employed
pituitrinum infundibulare. As I have mentioned already, perhaps employ-
ment of radium emanations would be of some value, but as yet no experiments
with them have been reported. I shall not go further into the question of the
other roborant and tonic treatment methods.

The organotherapy of the symptoms due to loss rest on a much broader
experience as far as is concerned with woman. The medication with ovarian
substances was introduced by Regis and has been especially recommended by

TREATMENT OF SEXUAL GLANDULAR INSUFFICIENCY 423

Jacobi, Chrobak, Landau, and others. Various preparations have come into
the market; oophorin tablets, ovaraden, ovarin, ovarial tabloids, etc. Ordi-
narily 3 to 6 tablets are administered daily. As has been mentioned, Lowy
and Richter found in their experiments a stimulation of the respiratory
metabolism; but this result seems to be inconstant, as other investigators
did not find it. Also there did not always occur an improvement in the
nervous symptoms. Bucura points out that this may be due to the unre-
liability of the preparations used. He believes that it is not a matter of
indifference whether the preparations are obtained from the ovaries of young
or old animals, and whether they are taken during the rutting season or the
interval. He mentions experiments with the milk of rutting animals. As
yet the involution of the uterus after castration cannot be prevented by the
use of ovarian substances (Jentze and Beutner) . Frankel proceeding from his
view that the corpus luteum possesses an internal secretion, has introduced
lutein tablets into therapy.

Very promising are the experiments on transplantation of the sexual
glands. Ribbert was the first who succeeded in transplanting testicles.
Foges, after autotransplantation of the testicles in young fowls, saw rather
good development of secondary sexual characters. Steinach succeeded with
the same experiment in rats and guinea-pigs. The interstitial cells and the
Sertoli's cells were retained, but seminal cells were entirely absent. I do
not know whether homiotransplantation of the testicles has succeeded. If
it were to succeed, a favorable influence on eunuchoidism would not be impos-
sible. The transplantation of the testicles, epididymis, and vas deferens, and
therewith the possibility of semen production, is still the task of the future.

Much more noteworthy are the experiments with transplantation of
the ovaries. Here also the successful experiment is that of autotransplanta-
tion which was. done by Ribbert. Knauer then showed that in grown rabbits
involution of the uterus could be prevented by the autotransplantation. An
essential progress was made by the experiment of Halban, who in new-born
guinea-pigs transplanted the ovaries under the skin. After one and one-fourth
years there was still present parenchyma capable of functionating. Graafian
follicles and even mature ova had developed and the tube that had been
transplanted at the same time had matured in normal manner. The breasts,
as well as the uterus, had developed normally. In the castrated control
animals the breasts remained rudimentary and the genitalia were markedly
hypoplastic. In woman, also, transplantation has occasionally been followed
by good results in operations on the genitalia. It is true that transplants
often show regressive manifestations, but a part of the parenchyma may,
however, still be retained, and on account of this the involution of the uterus
and the nervous symptoms due to the loss are prevented. In autotrans-
plantation in the neighborhood of the tube, even maturation of the ovum
and pregnancy have occurred.

424 THE DISEASES OF THE SEXUAL GLANDS

Still more significant are the experiments with homiotransplantation of
the ovaries. I refer to the collected statistics of Novak. It is true that in
most cases the result lasted only for a short time, but in animal experiments
numerous results of longer duration including maturation of the ovum and
conception have occurred. On experiments in man, I mention the two cases
that follow. Cranner transplanted into a twenty-one-year-old woman, who
had never menstruated and who possessed rudimentary mammae, the ovary
of an osteomalacic woman. Menstruation then set in and the breasts de-
veloped. Still more remarkable is a case of Halliday-Crom. In this case
amenorrhea had set in after labor and symptoms of absence developed.
The small cystic ovaries were removed and a foreign ovary implanted.
The woman again menstruated four months after the operation, and four
years after the operation she conceived and bore a normal child. This case
was earnestly discussed before the Edinburgh Obstetrical Society, and
cannot well be denied. There is indeed in this case no doubt that if there
has been no error of observation, this woman bore the child of another woman.
Serious objections might be raised against such procedures on ethical and
forensic grounds.

m. HYPERGENITALISM

Definition. — We have come to know hypergenitalism already in the
chapters on the hypophysis and in the consideration of suprarenal cortical
tumors. There are also cases of premature development of the genitalia
associated with temporary excessive development of the organisms, in which
the epiphysis or the suprarenal cortex do not come into consideration as
etiological factors, but in which we must assume, with great probability, a
primary disturbance of the sexual glandular function on the sense of a pre-
mature occurrence or an excessive increase.

Pathologico-anatomical Findings. — A portion of these cases show malig-
nant tumors of the sexual glands. Neurath collects five cases from the litera-
ture, four ovarian tumors (two established at autopsy, two on operation) and
one testicle tumor (operation) . In another the sexual glands were described
as only extraordinarily large. I must state that in two cases hydrocephalus
was reported. One of the cases was reported by Wetzler; also in a case of
Pellizzi's did there exist, besides pronounced hypergenitalism and excess-
ive growth, hydrocephalus with convulsions. Whether these were cases
of primary hypergenitalism cannot in the present state of our knowledge be
answered.

Symptomatology. — The premature sexual development is found in both
boys and girls. Neurath, who has written an excellent essay on this subject,
quo'tes forty-three cases of premature sexual development in boys. In
such individuals an excessive development of the genitalia may occur al-
ready in the first year of life.

HYPERGENITALISM 425

I quote the following examples. The case of Bernhardt-Ziehen was that of a three-
year-old boy in whom an enormous growth had set in at the eighteenth month. At two
years the pubic, axillary, and beard hairs were present. At two and one-half years the legs
had hair on them; he was 103 cm. tall, the circumference of the skull was 53 cm., the body
weight 49.5 kg. He looked like a seven- or eight-year-old boy. He was again examined at
the age of eight years. He was then 138 cm. tall (116 cm. is the height for this age). The
circumference of the skull was 56.5 cm. The sexual parts were developed like those of a
grown man. He looked as if he were twenty-five to thirty years old. His intelligence was
fairly well developed, he was lively, showed inclination for the female sex, but otherwise his
demeanor was childish. As another example I cite the case of Hudovernig and Popovicz.
In a later investigation of Hudovernig the boy was five and one-half years old; at one and
one-half years he sustained a febrile disease (meningitis). The abnormal growth had
existed since that time. He was 137 cm. tall and weighed 35.5 kg., this corresponding to
the age of fifteen or sixteen years. The penis is 9 cm. long, the testicles very well de-
veloped. The psyche is infantile. The intelligence is rather behindhand. Skull and
face were rather asymmetrical. The X-ray examination showed that the ossification was
as well advanced as that of a fifteen- or sixteen-year-old boy. Also the skull bones were
well developed, and the sella turcica seems to have been enlarged, although the observation
is not convincing. The boy was first treated with thyroidin tablets or with thyroidin
tablets plus potassium iodide. This did not affect the excessive growth. Later ovarian
tablets were administered. This time the growth was somewhat less (only 3.1 cm. in nine
months as compared with 5 cm. in the six months of the first period and 5 cm. in the ten
months of the second period). In the third period the boy seemed to have become psy-
chically more quiet. Hudovernig assumes that the ovarian tablets have retarded the
excessive growth. I doubt this. If we calculate the growth per month we obtain for the
first period 0.95 cm., for the second, 0.5 cm. and for the third, 0.3 cm. There is hence
found a gradual decrease of the excessive growth, which surely, as we shall see later,
is to be referred to the gradual closing of the epiphyses. Finally I would mention the
case of Stone, which is especially interesting from the fact that also the father of the boy
showed a premature development.

These cases all have in common the premature and excessive development
of the genitalia and of the secondary sexual characters, premature change of
voice, and the excessive body development. Already in the first year
there occur erections, ejaculation — Pellizzi demonstrated spermatozoa in his
cases — and eventually premature sexual instinct. The development of the
internal genitalia often hurries the development of the whole body. As far
as the latter is concerned, the osseous system and the musculature are mostly
affected in like manner. There therefore occurs a transitory gigantism;
as, however, the epiphysial closure is rather hastened, the body growth finally
attained is not abnormal, but mostly rather small. The psychic and intel-
lectual development of such individuals do not keep pace with the body
development; they for the most part show a childish demeanor, corresponding
with their age, which demeanor has a characteristic stamp only through the
premature sexual life. The assumption of such cases as primary hyper-
genitalism is often uncertain without autopsy findings, although such a pri-
mary hypergenitalism may be made secure by operation in certain cases.
I mention especially the case of Sacchi. It was that of a nine-year-old boy

426 THE DISEASES OF THE SEXUAL GLANDS

who had developed normally until his fifth year; in that year an excessive
growth and especially a premature development of the genitalia and of the
secondary sexual characters set in; at the same time there developed a tumor
of the left testicle; at nine years of age the boy weighed 44 kg. and was 143
cm. tall. The lower length was 77 cm. Hence the boy showed childish di-
mensions, and was in this respect different from other true gigantism which,
as we shall see later, shows either normal or eunuchoid dimensions. The
testicular tumor, which was an alveolar carcinoma, was removed. One
month after the operation the beard hairs fell out and the abnormal hairiness
of the extremities retrogressed; the hairs on the mons Veneris remained. The
penis became smaller, the previously low 'voice became childish, and the
pollutions and erections ceased.

In the female sex such cases are mostly described under the title men-
struatio prascox. The older literature is found in Kussmaul and v. Holler.
Neurath counts eighty-three cases from the literature. The external genitalia
develop in an abnormal manner, mostly more strongly than the internal.
The secondary sexual characters (hairiness, etc.) and the development of the
mammae are always abnormally premature. As in the male sex, excessive
growth of the body is found to be more or less pronounced. Also the den-
tition, the change of teeth, and the appearance of the bone nuclei and the
closure of the epiphysial junctures is premature.

I cite the following: The case of Geinitz was one of menstruatio praecox in an eighteen-
month-old girl. The uterus had attained the size of a twelve- to fourteen-year-old
girl. The case of Klein, of menstruatio praecox (two and one-half years), the vulva had
grown to the size of that of a fourteen-year-old girl. Stacker describes twin sisters, of
whom one had been larger since birth. In the first, menstruation began before the end
of the first year. The flow occurred regularly every four weeks, lasting three days. At
eight years of age the child had the size and appearance of a twelve-year-old girl; she
measured 139 cm. and weighed 34% kg., while the twin sister was 121 cm. tall and
weighed 20 kg. The case of Neurath was that of a six-year-old girl who exceeded in size
and weight her eight-year-old sister. The ossification conditions corresponded to those
of the tenth or eleventh year. Recently there has been reported a case of Wolf concerning
a girl four years and one month old. The size had been large since birth. The child
had menstruated since the second year. She looks like a seven-year-old girl. The hair
of the head is long. The height is 121 cm., the weight 26 kg., the span width 114.5 cm-
(hence potentized childish dimensions). The intelligence corresponds to the age. The
mammae are very well developed. The mons Veneris is covered with hair. The ossi-
fication corresponds to that of a ten-year-old child. Especially instructive is the case of
•v. Haller. In this the menstruation set in at the age of two years; at the age of eight
the girl became pregnant and shortly afterward the excessive growth stopped. She
lived to be seventy-five years old. This case shows that premature closure of the epiph-
yses may also occur in the female sex. Finally the case of Riedel shows that in certain
cases a primary hypergenitalism may be demonstrated also in females. In this case of
precocious menstruation (six-year-old child) the uterus was the size £>f a seventeen-year-
old girl. There was a sarcoma of the ovaries ; on the removal of the sarcoma, the menstrua-
tion ceased.

CHLOROSIS 427

Treatment. — Up to the present, the treatment, as far as tumors were
demonstrable, has been surgical operation. In many cases, as is shown in
the above reports, the results were remarkable. Whether X-ray, radium
irradiations, or mesothorium irradiations have been tried as yet in certain
cases, I do not know. Also in cases without demonstrable tumors it is
conceivable that injections of thorium X or actinium X might induce an
inhibition of the abnormal sexual glandular development and thus influence
the premature development of the organism.

IV. CHLOROSIS

The circumstance that the beginning of chlorosis always falls at the time
of puberty or during the time of maturation of the female organism following
puberty, together with the circumstance that in chlorosis, disturbances in
the genital sphere are found almost regularly, shows that this disease, at
least to a certain extent, belongs in the chapter on the sexual glands. Opin-
ions are at variance in regard to the nature of the functional disturbances.
Therefore I avoid placing chlorosis in one of the divisions of hypogenitalism
or hypergenitalism and give it a position by itself.

Historical. — Virchow on the ground of pathologico-anatomical findings
assumed a congenital deficient development of the vascular system. Im-
memann supposed a weakness of the blood-forming organs that is in part
congenital and associated with the hypoplasia of the vascular system, and
in part acquired and temporary, The disease begins in puberty because
at this time especial demands are made in blood-forming apparatus, v.
Bunge places in the center of the pathogenesis a disturbance in the iron
metabolism. The maternal organism gives to the child organism a very
great amount of iron. This is stored up not during pregnancy but already
at the time of puberty, whereby there occurs a poverty of the blood in hemo-
globin. Zander regards the cause of chlorosis as a disturbance of the absorp-
tion of iron, other authors as chronic constipation, and as gastroptosis through
the wearing of tight corsets, etc. . Basing his views on the theory of Immer-
mann, v. Noorden for the first time explains a disturbance of the activity of
the ductless glands as essential for the coming into existence of chlorosis.
According to v. Noorden chlorosis depends on an in part congenital, in part
acquired, weakness of the blood-forming organs, in consequence of which
there occurs in the period of sexual ripening disturbances in the blood-
formation proceeding from the female sexual organs. Normally impulses
flow from the female sexual glands to the blood-forming organs. Loss or
weakening of the internal secretion of the ovaries leads to chlorosis.

Grawitz sees the cause of chlorosis in a disturbance of the relation of liquid
interchange between blood and tissues. This depends on deficient function
of the vasomotors. He therefore regards chlorosis as a neurosis.

Very recently, Morowitz, on the ground of observations in which the rest

428 THE DISEASES OF THE SEXUAL GLANDS

of the chlorotic symptom-complex is associated with an approximately normal
blood condition, upholds the view that the blood-changes in chlorosis con-
stitute only a symptom and not the essence itself of the disease; he points
to the frequency of thyroid glandular swelling and believes the cause to be
a disturbance in the reciprocal action of the ductless glandular system.
Kottman observes that there is a deficient iron-assimilation on account of a
weakening of the internal secretion of the ovaries. Finally we mention the
theory of Charrin and Villemin that chlorosis is a menstrual autointoxication.
Villemin assumes in addition that the internal secretion of the corpus luteum
possesses hemolytic properties.

Symptomatology. — Chlorosis is a disease that inclines very much toward
relapses. The first attack of chlorosis usually occurs between the fourteenth
and twentieth years of life. Cases of so-called tardive chlorosis (Hayem,
Rieder) are extraordinarily rare. Lately also cases of infantile chlorosis have
been described (Rist, Hutinel, Stoltzner, et al.~). Because of the uncertain con-
nection with these cases with true chlorosis, v. Noordenproposed for these cases
the name chlorotoid. Also the connections of the extraordinarily rare cases
of conditions similar to chlorosis occurring in the male sex (for example,
the cases of Formanoli, Ferrari, Byrom Bramwell) are contested by most of
the later authors, v. Noorden and v. Jagic believe that in such cases we are
dealing with sexual neurasthenics who are insufficiently nourished. A great
role in chlorosis is played by heredity. Often many sicknesses are found in
the family of the patient. In rare cases there is observed in the same family
simultaneous occurrence of chlorosis and of prepubertal eunuchoidism
(Tandler, v. Noorden; confer also Observation LI) .

Chlorosis usually sets in with a series of subjective complaints; attention
is attracted to the color of the face. These symptoms consist in ready
fatigability, cardiac palpitations on slight bodily exertions, slight dyspnea,
headache, sensations of cold — especially tendency to cold hands and feet —
eventually seeing black, flickers before the eyes, ear noises, vertigo, fainting-
spells, pressure in the gastric region, nausea, etc.

Examination of the heart often shows in advanced cases slight broaden-
ing, soft systolic murmurs, the known humming-top murmur over the jugular,
furthermore in a great number of cases acceleration of the pulse, great ex-
citability of the cardiac activity and of the vasomotors. Further is found
a marked laxity of the arteries (crural double tone). According to the
investigations of Bihler and v. Noorden there is always a reduction of
blood-pressure.

Breathing is mostly somewhat accelerated and superficial, with high
position of the diaphragm.

As far as the digestive tract is concerned, should be mentioned that there
is frequently a slight degree of hyperacidity. According to v. Noorden,
constipation is not much more frequent than in normal girls. The respira-

CHLOROSIS 429

tory gas exchange is usually slightly increased. The condition of nutrition
is as a rule not bad. Investigations as to the assimilation limits for carbohy-
drates gave an increase, or at least no decrease. After the ingestion of 150
gm. of grape-sugar, there never, in the experiments of v. Noorden and v.
Jagic, occurred glycosuria except in one case that at the same time showed
symptoms of Basedow's disease. Also Chatin came to the same result. It
should further be mentioned that not rarely chlorotics show a higher level of
their body temperature.

In not very rare cases there are found pigmentations of the skin.

The examination of the urine shows no abnormal constituents. Also
the products of destruction of hemoglobin are not eliminated in abnormal
amount.

I now enter on a description of the blood findings; on account of the
poverty in hemoglobin there occurs in the severe cases a greenish-pale
facial color, that has given to the disease its name. There are, however,
numerous cases that on account of the reddening of the cheeks make a florid
impression. Here the disease is unmasked by a close examination of the
mucous membranes and careful examination of the blood. The chlorotic
blood-finding is characterized by a relatively very marked poverty of the
blood in hemoglobin and a relatively slight reduction of the erythrocyte
count. Hemoglobin amounts as low as 50 per cent, are very frequent, those
and as low as 30 per cent, not rare. When there is high-grade poverty of
the hemoglobin there is found more or less distinct poikilocytosis; and in
addition isolated nucleated erythrocytes. In the lighter forms the count of
the red blood cells is normal or only slightly reduced, only in the severe
forms do reductions as low as 60 per cent, occur. In the severe cases the
specific gravity of the blood is markedly reduced, while that of the serum is
essentially unaffected. With regard to the leucocytes there is a slight
relative mononucleosis.

Recently, as was mentioned. at the beginning, Horowitz, has called at-
tention to the fact that in rare cases that otherwise show the symptom-com-
plex of chlorosis, the blood is found to be normal or nearly normal. Already
Laache had described such cases, also several statements have been made by
O. Naegeli and Grawitz, while lately Seller, Groag, Dubnikojf, and others have
described such cases. Handmann even found twenty-three cases with normal
blood findings among forty-four cases of chlorosis.

It is furthermore very noteworthy that the investigations so far made as
to the quantity of blood in chlorosis have shown a plethora. While accord-
ing to the investigations of Smith the total amount of blood in normal in-
dividuals is about 5 per cent, of the total body weight, this author found in
chlorotics with 29-50 per cent, hemoglobin the blood amount to be 7.5
per cent, and 14.3 per cent. The lower the hemoglobin percentage, usually
that much larger the amount of blood. Plesch and Oerum using other

430 THE DISEASES OF THE SEXUAL GLANDS

methods came to a like result. It should further be noted that in pernicious
anemia Smith and Plesch found subnormal values [for the quantity of blood].

In connection with this subject it might be well to mention the altera-
tions in the water metabolism that are observed in chlorotics. v. Romberg,
v. Noorden and Rethers frequently observed in chlorotics a tendency to the
retention of water, while on the other hand we often see under the influence
of iron-therapy a rapid loss of weight with moderate polyuria. As has been
mentioned, products of decomposition of hemoglobin are not, in chlorosis,
eliminated in the urine. Therefore we cannot regard an increased destruc-
tion of the blood-coloring matter as a cause of the poverty in hemoglobin.

Not at all rarely the thyroid gland shows a swelling. Giudiceandrea,
Archangeli and Bastianelli found it in half the cases. Handmann found it
in twenty-four times among forty-four cases, three times with distinct
Basedow's symptoms, v. Noorden and v. Jagil report an interesting case in
which the development of the anemia was associated with a swelling of the
thyroid gland and on a relapse led to an acute Basedow's that lasted for
several days. As the statements as to the involvement of the thyroid increase
in so astonishing a manner (since the time that attention has been directed to
the fact) , we must ask ourselves whether the pseudochlorosis described by
Fr. 11. Mitller does not stand in an intimate relation with true chlorosis.
v. Muller states that in regions where goiters are frequent, there are not
rarely found pale, readily fatigable, girls with abnormally irritable heart-
action, in which manifestation of Basedow's disease later became more
distinctly conspicuous.

Finally I come to a description of the alterations of the genitalia, after
which I shall add some remarks as to the disease's pathogenesis. I shall
try to separate those changes that are due to an alteration of the glands of
generation and those to changes of the interstitial glands.

Disturbances of development are found in the genitalia in chlorotics not
rarely. Deficient development of the external genitalia, deficiency in the
prominence of the mons Veneris, flat nates, small labia majora, while labia
minora and clitoris are uninvolved; eventually, narrow vagina, faulty develop-
ment of the uterus, breasts, etc., are sometimes observed. The statistical
reports of Stieda, and of H. W. Freund and v. Noorden show that a relatively
larger percentage of chlorotics have such developmental disturbances in more
or less pronounced manner. There are undoubtedly a not inappreciable num-
ber of chlorotics whose genitalia are developed normally. As especially note-
worthy I would emphasize that the hairiness of the genitalia, the mons Veneris,
and the axillae corresponds to the age of the individual and further that a
delayed closure of the epiphysial junctures and corresponding eunuchoid
dimensions of the body is not to be observed in chlorosis. Tandler states
on the contrary that he has observed very frequently in chlorotics a very
frequent premature epiphysial closure, and as a result of this, an especial

CHLOROSIS 431

short leggedness and also a certain prematurity, as shown by other sexual
characters.

As far as the function of the generative glands is concerned, almost all
the statements are concerned with menstruation, while, as is intelligible,
ovulation evades observation. Disturbances of menstruation are relatively
very common. I here quote some examples from the statistics. According
to Stieda only seven chlorotics among twenty- three had menstruated regularly.
According to Otten, among four hundred forty-eight cases there were only
one hundred eighty-six who had menstruated regularly before and during
Ihe illness. In the first edition of v. N Garden's monograph, 60.7 per cent, of
one hundred seventy- three cases showed weakness of menstruation. In the
newer statistics of v. Noorden and v. Jagil that embraces two hundred
fifty cases this figure was raised even to 77.2 per cent., and twenty-six of the
cases had not menstruated before the onset of chlorosis. There are, how-
ever, cases with entirely normal menstruation, and furthermore cases with
abnormally strong menstrual hemorrhage. Trousseau has described such
cases as menorrhagic chlorosis. In such cases the ovaries were found to
be enlarged and there was a great abundance of follicles, v. Noorden and
v. Jagic on the basis of their compilation came to the conclusion that in
chlorosis menstruation shows no characteristic behavior.

Pathogenesis. — If we now survey what I have just said as to the re-
lation of the sexual glands and the primary and secondary sexual characters,
we find it hard to accept the theory that chlorosis is a functional disturbance
of the interstitial glands, especially if we compare it with those manifesta-
tions which are described in the rare cases of female eunuchoidism. There
is indeed no doubt that in chlorosis there occurs an enfeebled development
of the primary and secondary sexual characters, but in such cases this is
mostly only of a slight grade, and just the essential symptoms of failure
(deficient hairiness, delayed epiphysial closure) are absent practically al-
ways; indeed on the contrary, according to Tandler, as has been mentioned,
the development points to a degree of prematurity. Also animal experi-
mentations have as yet failed to furnish any support for the assumption of
a diminished activity of the interstitial glands. According to the investi-
gations of Monaro and of Breuer and v. Seiller the extirpation of the ovaries
in young dogs in a state of development indeed leads to a temporary com-
mensurate sinking of the amount of hemoglobin and count of erythrocytes,
never, however, to the blood picture observed in chlorosis. If I here use the
methods that I employed in the exposition of the tests of the sexual glands
for separating the symptoms that depend on the functional failure of the
interstitial glands from those to the functional failure of the generative glands,
I may suppose a slight strengthening of the function of the interstitial glands;
it is, however, a priori improbable that these stand in the mid-point of
the pathogenesis. I believe that there is applicable an hypothesis that at

432 THE DISEASES OF THE SEXUAL GLANDS

least has the advantage that it is not contradicted by any of the known facts.
In chlorosis, as has already been mentioned, the behavior of menstruation
shows nothing characteristic. We find that although in the majority of
cases there is a weakening of the menstrual process, there may be a normal
course or an essential strengthening. This is what is told to us with regard
to menstruation, but not in regard to ovulation. We know only that there
is no menstruation without ovulation. It is known, however, that under
circumstances ovulation proceeds without menstruation, and it does not seem
to me that anything stands in the way of the proposition that under circum-
stances it may go on in an increased or precipitate manner. The assumption
of precipitate ovulation in chlorosis is, however, though it seems fascinating,
not at all unconditionally necessary. To me the assumption seems enough
that the violent revolutions that go on in the feminine organism at the time
of puberty or with the setting in of a strengthened activity of the follicular
apparatus lead in nonvigorous individuals to a temporary or longer con-
tinued exhaustion of the organism. We have seen in the description of the
physiology of the sexual glandular apparatus that ripening of the follicle in
the premenstrual period leads to a heightened vitality of the whole organ-
ism. Hence there proceed impulses from the follicular apparatus that spur
on all the organs and especially the entire ductless glandular system to a
heightened activity. Would it not be conceivable that in a predisposed in-
dividual, in whom these impulses are perhaps increased by precipitate
ovulation, there may appear an exhaustion?

On the basis of this supposition I shall now proceed to analyze the
symptom-complex of chlorosis. Let us first consider the genital disturbances.
The assumption of an increased activity of ovulation does not seem to me
to stand in contradiction to the diverse behavior of menstruation. On the
one hand it explains cases with increased menstrual bleeding, and on the
other that after a time a feebler organism no longer reacts to every impulse
of the growing follicle, or at any rate not with the corresponding altera-
tions of the uterine mucous membrane. It is therefore not at all necessary
to consider that the internal secretion of the corpus luteum normally is
cast off through menstruation and that with the continued absence of men-
struation with progressive ovulation an autointoxication becomes established
(Villemin). Otherwise we would have to have a chlorosis in every case of
amenorrhea, and the cases of chlorosis with excessive hemorrhage would
not be explicable at all.1 An increased activity of the follicular apparatus
would also exercise a certain reinforcing action on the function of the in-
terstitial glands, thus explaining unforcedly the symptoms of prematurity
that are seen in certain cases.

Through my assumption, a case of childish gigantism with sexual pre-

1 The assumption of Villemin depends in addition on the incorrect hypothesis that in chlo-
rosis there is an increased blood disintegration.

CHLOROSIS 433

maturity and chlorosis, observed by Hastings Gijford, does not seem so in-
explicable. The author had observed this case between the second and
the eighteenth years. Menstruation began at the age of thirteen months and
from then on came at irregular intervals up to the eighth year of life, after
which it was regular. With the menstruation at the thirteenth month oc-
curred also a rapid growth ; at three and one-half years of age the child was
already 146 cm. tall and weighed 41)^ kg. X-ray plates of the hand showed
a development that corresponded to that of an eight-year-old girl; the sexual
development was that of a thirteen- to fourteen-year-old child. The intelli-
gence had remained somewhat behind. From the sixth to the twelfth year
the girl was always under treatment for recurring chlorosis. From then on
recovery set in.

We have further seen that in the premenstrual period the activity of the
ductless glands is increased, so that there is hence in chlorosis either an in-
crease in the activity of the ductless glands, or, in those whose activity
comes most in demand, an exhaustion. Very significant in this respect
seems to me the behavior of the thyroid gland. I refer to findings described
under symptomatology and the frequency of slight symptoms of Basedow's
disease. From this standpoint it is indeed intelligible that a newer attack
of chlorosis, that perhaps takes place with the maturation of a follicle, leads,
when a corresponding disposition is present, to temporary symptoms of
Basedow's disease (see the cases of v. Noorden and v. JagiX).

A second ductless gland whose activity seems to me to be very significant
is the chromaffin tissue. We have seen that under normal conditions there
occurs in the premenstrual period an increase of blood-pressure, and we have
expressed the opinion that impulses proceed from the ripening follicle that
increase the activity of the chromaffin tissue and raise the vascular tonus.

Plainly this organ can become relatively rapidly exhausted, the ex-
haustion leading to an influencing of the vasomotor system in the sense
of an irritable weakness. The laxity of the arteries as well as the low blood-
pressure belongs to the constant symptoms of chlorosis. We may indeed go
further and try to explain the blood alterations, at least in part, from this
point of view. Heightened tonus of the vessels leads to hyperglobulia
through transudation of the plasma into the tissue. (I refer to the dis-
cussions on the subject of tetany, and those concerning the significance of
the chromaffin tissue for the regulation and distribution of blood-pressure.)
It is therefore to be expected that on decreased vascular tonus there will be
an increase in the amount of the blood; as the blood becomes thereby poorer
in erythrocytes, it is to be assumed that erythrocytes that are then poorer
in hemoglobin are given off to the blood paths. Just these conditions ob-
tain in chlorosis, increased amount of blood, slightly reduced erythrocyte
count, more markedly reduced amount of hemoglobin. In a group of
cases the functional breadth of the bone marrow may fully suffice for this
28

434 THE DISEASES OF THE SEXUAL GLANDS

regulation, in another group it soon, according to this view, becomes ex-
hausted, the exhaustion leading to poverty in hemoglobin. In addition
to this it is possible that direct impulses go from the follicular apparatus
to the bone-marrow and on increased activity of the former favor the ex-
haustion of the latter. As according to this hypothesis we are dealing only
with an exhaustion due to the large demands, it is intelligible why in the
autopsies on cases of chlorosis the bone-marrow was found to be normal
(Birch-Hirschfield, Grawitz). Perhaps other symptoms of chlorosis point
to a lessened valuation of the chromaffin tissue, signs such as slight mono-
nucleosis, the not rare pigmentation, and indirectly the high carbohydrate
tolerance, which up to the present have been observed by all investigators.
The investigations as to the blood sugar have not as yet been made. At
all events it would not be unintelligible why chlorosis develops just in in-
dividuals with hypoplasia of the vascular system, which, as is known, is asso-
ciated with hypoplasia of the chromaffin tissue; the corroboration of our
views would be an instance of the penetrating vision of the past-master,
Virchow.

This hypothesis seems to me also to explain why chlorosis is found al-
most exclusively in the female sex. If we were to assume the insufficiency
of the interstitial glands, it would be indeed unintelligible why in eunuch-
oidism, in which the symptoms of insufficiency are so conspicuous, we meet
with no chlorosis. The interstitial glands have the same function in both
cases; the follicular apparatus is something specific for woman. The revo-
lutions that take place in the female at the time of maturity are different
from those that occur in man and are much more powerful.

The experimental basis for this view is yet to be laid. Whether the im-
plantation into young animals of ovaries taken in marked ovulation will be
able to produce a picture similar to chlorosis, is at all events questionable ;
just as castration, which according to the view set forth would bring the
chlorosis to a standstill in a short time, is impracticable. We must, however,
consider whether a very cautious X-ray irradiation of the ovaries would
not act favorably on the chlorotic process.1 Perhaps this view furnishes the
key for the solution of the problem of iron therapy. As is known, iron has
an almost specific action in chlorosis, while in the other anemic processes it
mostly fails. Morawitz has concluded that the iron does not act principally
on the bone marrow, but somewhere else in the body. From the stand-

1 1 would here call attention to the later views as to the cause of uterine hemorrhages. Pankow
pointed out that metritis and chronic endometritis could not be the cause of the profuse men-
strual hemorrhages. The chronic inflammation may very well be associated with profuse bleed-
ing, but it does not condition it. Pankow seeks the cause rather in a different functional size of
the ovaries conditioned by "disturbances in the reciprocal relations of the ductless glands to
each other." Perhaps the assumption of a deficient or increased ovulation would suffice, as the
climacteric hemorrhages have been favorably influenced by X-ray irradiation (Doderlein),
which restricts the process of ovulation.

OSTEOMALACIA 435

point mentioned, it would be well to investigate whether ovulation or the
giving-off of hormones is not inhibited by the great amount of iron ingestion.
At all events it seems to me that such a specific influence of iron on the ovaries
is not at all necessary. The difference of chlorosis from anemia consists
in the fact that the bone marrow in the former is not diseased, but simply
gives out because of increased demands, in the course of which exhaustion
the formation of the red cells is less affected than that of the hemoglobin.
It is thus readily understood why in chlorosis abundant administration of iron
works better than in the anemias. With the increase of the hemoglobin
may be exercised a favorable influence on the entire organism and indirectly
on the sexual glands.

Appendix. Osteomalacia

In way of an appendix, some remarks as to the relations between osteo-
malacia and the ductless glands might find place here. There are no doubt
a number of, in part, important facts that point to the involvement of the
ductless glandular system in the development of the osteomalacic process;
the most important of these observations are the following:

1. Osteomalacia occurs almost exclusively in women, and indeed, in the
overwhelming majority of cases, during pregnancy.

2. Castration leads very often to a rapid cure or at least a considerable
improvement of the osteomalacic process (Fehling). Also after labor
or after artificially induced abortion, Osteomalacia tends to cure or
at least to improve, just to relapse at the next pregnancy.

3. The curative or ameliorative action of castration can in such cases
enter in without the interruption of the pregnancy (cases of Cramer,
W alcher, Cristofoletto) .

4. Frequently symptoms are found in Osteomalacia that point to an in-
volvement of the other ductless glands. Thus for instance osteo-
malacia is not rarely complicated with Basedow's disease (Latzko),
or with Basedow's and tetany (Koppen, v. Recklinghausen) . Mobius
reports a case of Basedow's that later went over into myxedema, and
then later acquired puerperal Osteomalacia. Moreover, there is found
in Osteomalacia frequently, perhaps regularly, a hyperplasia of the
parathyroids (Erdheim, Strada, et al.J. This hyperplasia of the para-
thyroids does not tend to occur in senile osteoporosis.

5. In Osteomalacia the glycosuric action of adrenalin and apparently
also its action on the heart and vessels is strikingly slight (Cristo-
foletti, see also Reinhardt, Merletti, v. Neusser, Englander, et al.}. This
is also true for Osteomalacia during pregnancy, because otherwise
in pregnancy the action of adrenalin is especially powerful. Further-
more, long-continued injections of adrenalin in many cases of osteo-
malacia have exerted favorable influence (Rossi). Cristofoletti has

436 THE DISEASES OF THE SEXUAL GLANDS

collected forty-seven cases of osteomalacia that were treated with
adrenalin. Of these, eleven were gravid and thirty-five nongravid
women. Of the gravid women 45 per cent, were cured, and about 18
per cent, improved. Of the nongravid women about 17 per cent, were
cured, and 40 per cent, improved.

6. In some cases of osteomalacia improvement follows the injection of
pituitrinum infundibulare (Bondi, Pal). Lately Pal has reported
concerning excellent influencing of the osteomalacia, in two cases,
through injections of pituitrinum glandulare.

Three forms of osteomalacia are to be distinguished. The puerperal form
which is by far the most frequent. The rheumatic form, which is rare,
which mostly does not follow a severe course and which occurs also in women
independent of a preceding labor; it is also observed in man. Finally
the senile form.

The views as to the bone processes in osteomalacia are many. One
group of authors imparts the most important value to the decalcification of
the completed bones, another group to the apposition of especially calcium-
poor bones. Likewise is there division of the authors as to whether rachitis
and osteomalacia are two different disease conditions or constitute one and
the same disease process, that leads when it develops in youth, to rickets, and
when it develops in the fully developed organism to osteomalacia. Cristo-
foletti sets forth the facts that speak against the unitary theory, as well as
gross anatomical difference: the endemic occurrence of osteomalacia that
is independent of the extension of the rachitis, the occurrence in grown
people, and finally the cardinal symptom of osteomalacia, the pain, which is
absent in rachitis. The fact also seems to me noteworthy that rachitis
mostly affects persons who were not rachitic in youth.

As might be expected, investigations as to calcium metabolism in osteo-
malacia show great disturbances. Almost regularly is found negative calcium
equilibrium. Especially is the elimination of calcium through the intestine
increased. That therewith the phosphorus is also eliminated in increased
amount in the feces is not characteristic for osteomalacia, as the calcium
carries with it the phosphorus. The calcium contents of the blood in os-
teomalacia is somewhat raised (Capellani). We can see a certain relation
between pregnancy and osteomalacia in that fact that osteophytes that
normally form during pregnancy are very poor in lime.

Of the hypotheses that are at hand as to the pathogenesis of osteo-
malacia, I mention those only which concern the ductless glands. The
assumption of a specific thyrogenic disturbance cannot be accepted as
correct, nor can the view that goiter formation and the osteomalacia have
a causal connection. Among thirty-four cases of osteomalacia, Bossi saw not
one with a goiter; and I can also very well reject the supposition of a pri-
mary functional disturbance of the chromaffin tissue. The sexual glandular

OSTEOMALACIA 437

hypothesis has attracted the most adherents. Through the favorable re-
sults of castration, Fehling was furnished the occasion for regarding the cause
of osteomalacia as a hyperfunction of the ovaries. Cristofoletti modified this
hypothesis by assuming that the internal secretory function of the ovary
lasts during pregnancy, and that this leads to a hypofunction of the chrom-
afnn tissue.

For an especially functional disturbance of the interstitial glands speaks
the finding of Wallart that the interstitial substance in osteomalacia is
especially strongly developed. The assertion of Siegert and M. B. Schmidt
that infantilism and osteomalacia belong together is made scarcely plausible
by this fact alone. As, however, also in normal pregnancy the interstitial
glands are more strongly developed, it is questionable whether we may
estimate the value of the findings of Wallart as high, although I am unable
to bring anything else against them.

I would not ascribe the hypofunction of the chromafrin tissue so great
a value as does Cristofoletti. As signs of it, Cristofoletti quotes: the hyper-
eosinophilia, the absence of the adrenalin glycosuria and the eventually
present pigmentations. But why, then, do we never find osteomalacic
manifestations in Addison's disease? The combination of hypofunction
of the chromafnn tissue with pregnancy can not be such an important factor,
for there are cases of osteomalacia without pregnancy. Moreover the
relations of the chromafrin tissue to the calcium metabolism are still rather
questionable.

To my knowledge, there are no existing observations as to whether
there is in pregnancy a continuation of ovulation. After all, the assump-
tion of a hyperfunction of the ovaries is up to the present the only one that
can be supported by numerous and good observations. It is at all events
surprising that the osteomalacic process is as well influenced by both cas-
tration and by normal or artificially induced labor. We may, however,
suppose with Halban that the activity of the ovary and that of the chorionic
epithelium become summated, and that it is therefore sufficient to limit
only one of these factors. Also the hyperplasia of the parathyroids perhaps
is explained by this hypothesis. Already during normal pregnancy are
greater demands made on the parathyroid glands, still greater demands may
lead to hyperplasia (confer the chapter on the parathyroid glands) .

The observations of Pal, that extracts of the anterior lobe of the hypo-
physis influence osteomalacia favorably, turn our attention to the hypophysis.
Perhaps in osteomalacia the normal hyperplasia of the anterior lobe during
pregnancy fails to take place. Up to the present, all these theories are hy-
potheses, as between the described and the supposed alterations in the func-
tion of the ductless glands and the profound disturbance in the osseous
system there is still a very wide gap.

In a thorough monographic dissertation on osteomalacia and rachitis,

438 THE DISEASES OF THE SEXUAL GLANDS

G. Pommer has upheld the view that both diseases depend on an affection
of the central nervous system. Considering the intimate relationship
between the central nervous system and the function of the ductless glands
this supposition seems to me to deserve more attention than it has thus
far found.

Addendum

Whitehead reports the histological examination on the testicle of the
case of E. M. Prince. As Prince's case is. very interesting and apparently
forms the only case on record of true human hermaphroditism in which the
organs of both sexes were present, it will be quoted in extenso:

The patient, apparently a girl, eighteen years of age, consulted Prince
stating that she had never menstruated, and that she suffered from headaches
supposed to be due to that fact; she had withdrawn from the college she had
been attending because of the headaches which were worse about every
twenty-eight days. She appeared to be a healthy, robust girl, refined
and intelligent. There was a heavy growth of hair upon the head, the
voice was soft and feminine and the breasts well developed, rather larger than
ordinarily seen in a girl of her age. The hips were typically feminine, the
mons Veneris was rather scantily covered with hair, the labia majora were
normal; the clitoris was not enlarged and the hymen was unruptured. No
uterus could be made out by rectal examination. The vagina was about 2 in.
long, and terminated in a blind pouch. In the upper part of each labium
majus a body could be felt which was freely movable. The diagnosis made
was congenital abscess of the uterus with hernia of both ovaries. At the
operation (exploratory laparotomy) a small body the size of a pecan nut was
found at the usual site of the uterus, and to the left of this there was found an
apparently normal ovary with a rudimentary tube. At a subsequent opera-
tion the two bodies in the labia majora were removed and were found to be
testes, a diagnosis which was afterward confirmed by a pathologist.

In this case the secondary sexual characters were of the female type.
A weak point in the case is the absence of the microscopical examination of
the bodies believed to be ovaries.

Saenger reports seven cases of eunuchoidism which had come under his
personal observation, and concludes that the condition is by no means so
rare as is generally supposed. His last case is especially interesting in that
the subject was an kyphoscoliotic acromegalic individual aged thirty-three
years, who developed a late eunuchoidism in consequence of a gangrene of
the testicle; after the injury there was a failure of potency, a falling-out of
the hairs of the beard and pubic regions — and in part also of the eyebrows
— but there was no eunuchoidal distribution of fat, nor gigantism.

All references to the subject of the sexual glands would be incomplete
without mention of the name of Leo Loeb, whose researches on the function

ADDENDUM 439

of the corpus luteum are epoch-making. According to Loeb the corpus
luteum supplies to the uterus a sensitizing substance which prepares it to
respond with the production of the maternal placenta, if there is added an
external stimulus of a mechanical nature.

Seitz, Wintz, and Fingerhut have been able to isolate from the cow's
corpus luteum two bodies. One of these, a luteoproteid, has hemorrhage-
checking properties; the other, a lecithin albumin, has, in animals, a stimu-
lating influence on the genitalia. When injected subcutaneously in amenor-
rheic women, it brought about menstruation.

The knowledge of the relation of possible sexual glandular diseases to
dementia precox, as suggested by positive Abderhalden reactions when ex-
tracts of the sexual glands are tested against the sera of dementia precox
patients is as yet very obscure. The results of such tests against the sera
of chlorosis patients, would, in view of the author's views on the cause of
chlorosis, be very interesting.

Whitehead (R. H.).' The structure of a testis from a case of human hermaphroditism.
Anat. Record, Vol. VII, 1913, p. 83.

Saenger (A.). Ueber Eunuchoidismus. Deutsche Zeitschrift fur Nervenheilkunde,
Vol. LI, H. 3-6, 1914, pp. 178-197.

Loeb (L.). The experimental production of the maternal placenta and the function of
the corpus luteum. J. Am. M. Assn., Oct. 30, 1909, Vol. LIII, No. 18.

Seitz (L.), Wintz (H.), and Fingerhul (Z,.). Ueber die biologische Funktion des
Corpus luteum, seine chemischen Bestandteile, und deren therapeutische Verwendung
bei Unregelmassigkeiten der Menstruation. Miinchen. med. Wchnschr., 1914, LV.
pp. 1657-1661, 1734-1738.

CHAPTER XI

PLURIGLANDULAR DISEASES
Multiple Ductless Glandular Sclerosis. — Gigantism

Already in the first chapter we pointed out how that in recent time
there has been a growing tendency especially in the French literature to
regard individual diseases of the ductless glands as pluriglandular diseases.
The number of contributions as to pluriglandular disease has shown a steady
growth. I have already stated my opinion that I regard this tendency as
mistaken. It must have the result that the individual typical disease pic-
tures will become more and more confused and that the laborious acquisitions
[to our knowledge] will again become lost in the general chaos. In order to
make manifest my viewpoint on this question, I would again briefly capitu-
late what I have already stated in detail in the first chapter as to the physio-
logical and pathological correlations. The disease of an individual duct-
less gland regularly has as a sequel disturbance in the other ductless glands,
that eventually may be recovered from if the gland primarily affected be-
comes healthy or if, for example, its absence of function [Ausfall] has been
made good by therapy (physiological correlations). By pathological cor-
relation I mean the phenomenon that the disease that has first involved one
gland involves, in its further course, other members of the ductless glandular
system. In the majority of cases, it may readily be seen what ductless gland
was first involved; for the most part indeed the disease of that ductless
gland stands so much to the fore, that in this case also I would rather avoid
the designation pluriglandular disease. Much more do I consider it cor-
rect to reserve this term for those cases in which the clinical picture shows
that the disease process embraces the whole ductless glandular system or at
least a large part of it. Multiple ductless glandular sclerosis must be des-
ignated as such a pluriglandular affection *<"•' «£ox^v. In such cases we have
to deal with general symptoms of deficiency [of function, Ausfallerschein-
ungen] on the part of the system of ductless glands.

The question as to whether the antitype exists, that is, if there occurs a
generalized hyperplasia of the ductless glandular system with corresponding
manifestations of increased function, seems to me not yet ripe for discussion.
There is no doubt that hyperplastic changes in the thyroid gland and in the
suprarenal cortex are not rarely a concomitant of acromegaly. But in
this case there is no occasion to doubt the diagnosis acromegaly on this
account. So much is the picture dominated by symptoms on the part

440

MULTIPLE DUCTLESS GLANDULAR SCLEROSIS 441

of the hypophysis. The only disease that perhaps belongs here is gigantism.
Later I shall expound in detail that I cannot regard gigantism as simply an
acromegaly of child-life, as Launois and Roy assert. The enormously in-
creased tendency to growth of the entire body seems to signify to me much
more a rendering potent of the entire ductless glandular system, that is mostly
followed by a rapid exhaustion, in which some glands, as for example the
sexual glands, even at the beginning of the disease, show signs of a decay
[of function] or of a remaining backward in development. One aspect of
the problem seems to me not as yet explained, namely, whether we are
justified in regarding the potentizing of the ductless glandular system as
alone the cause of the increased tendency to growth or whether we must not
assume that from the beginning there was an abnormal tendency [mapping-
out, Anlage] of the entire organism, . including the ductless glands. It
seems to me, however, that the inclusion of gigantism among the pluri-
glandular diseases seems best adapted for our purpose.

Multiple Ductless Glandular Sclerosis

Historical. — A number of the cases that I shall group under this term
appear in the literature under very diverse designations. In the descrip-
tion of late eunuchoidism it was mentioned that the cases of multiple ductless
glandular sclerosis all are associated with more or less distinct symptoms of
late eunuchoidism, that however' these symptoms constitute only a partial
manifestation of the picture, far richer in symptoms, of multiple ductless
glandular sclerosis. A uniform conception of this disease picture has not
as yet permeated the French literature. Gandy describes as infantilism
reversif ou tardif a part of the cases here set forth by myself and ascribes an
important etiological factor to a disease of the thyroid gland. Cordier and
Rebattu place the sexual glands as the central figure of the pathogenesis and
distinguish between dysorchidie and dysorchidie-dysthyroidie. The works
of Claude and Gougerot mark an essential advance, these authors in 1907
having described this clinical picture under the terms insufrisance pluri-
glandulaire endocrinienne. To my mind, however, Claude and Gougerot
have lately gone too far, in that they had especially also later French authors
have included under this designation cases whose position [thereunder] have
seemed to me uncertain. I have already dealt with this in detail in the first
chapter. There I have classified together under the term multiple ductless
glandular sclerosis those cases in which a primary simultaneous disease, or
almost simultaneous disease, of several glands exist, cases that we must re-
gard as correlated to the inflammatory sclerosis and atrophy of the ductless
glands as found at autopsy.

There are, of course, cases of spontaneous myxedema or of Addison's dis-
ease that likewise depend on inflammatory sclerosis of the ductless gland con-

442 PLURIGLANDULAR DISEASES

cerned. Mostly, however, we are in a position sharply to differentiate the
disease pictures. In the cases about to be described we are dealing with a
symptom-complex that already in vivo suffices to let us refer the diagnosis
to a more or less generalized sclerosis of the ductless glands and justifies
us in picking out this disease-form as an entity.

Definition. — As multiple ductless glandular sclerosis I term that clinical
picture which is brought about by a probably infectious, for the most part not
as yet more well-defined, disease process — a disease process that involves several
ductless glands simultaneously, and leads to high-grade sclerotic atrophy and
hence to manifestations of deficiency on the part of these glands. Thyroid gland,
sexual glands, hypophysis, and suprarenals are mostly involved. Correspond-
ingly are found more or less pronounced the manifestations of hypothyrosis, of
late eunuchoidism, and hypophysial insufficiency, combined with a syndrome
similar to Addison's disease (hypotonia, pigmentations, etc.). Especially
brought into prominence is a progressive [i.e., uncontrollable] cachexia, that
develops to a high grade.

Case Histories. — Of the cases reported in the literature I regard the fol-
lowing as belonging to multiple ductless glandular sclerosis. At all events
I must mention that some of these cases are not exactly enough described,
so that their membership in the group is not quite certain.

Observation of Rumpel. — Man, thirty-six years old. Great weakness, backs of hands
and feet thick and puffy, pronounced cachexia, and considerable anemia, skin dry, weak-
ness of memory, frequent chills, temperature abnormally low, penis of normal size, scrotum
very small, testicles much atrophied, but still sensitive. Cremasteric reflex weakened,
libido absent. Scanty axillary and pubic hair; also the hair of the head is thinned out;
subcutaneous fat-tissue increased, especially on mons Veneris; polyuria and polydipsia;
gonorrhea at the age of twenty-four years. Beginning of the disease in the thirtieth
year of life with gradual loss of the sexual instinct, with thickening of the skin of the dorsa
of the hands and feet, lessening of memory, falling out of hair, etc. Thyroid treatment
without result. No autopsy.

Observation ofPonfick. — Man, forty-seven years old, cobbler, married since twenty-third
year of life, has six children. Since the thirty-second year has had a gradually-increasing
fullness of the face, working ability decreased, the cheeks become puffy, the lips swollen,
the skin rigid and pale as wax, the hair of the head thinned out, the hair on the cheeks is
entirely absent. Also the mustache is thinned out. Mimicry slow, speech scanning,
hearing diminished, skin slightly colored cyanotic, scaly, the hairiness of the trunk and
extremities has decreased markedly, the genitalia are almost entirely devoid of hair.
Hemoglobin 55 per cent. Essential improvement on thyroid medication, gain of weight,
8 kg., hemoglobin rises again to 75 per cent. In spite of continuation of the thyroidin
treatment, later much puffiness of the face, diarrheas, hemoglobin again falls, hearing be-
comes worse (sclerosis of the middle ear), body weight sinks lower, although thyroidin is
no longer given. Death from pneumonia. Thyroid 10.2 gm., therefore only a third of the
normal weight. The isthmus and the parts bordering on it well retained, however, and
show tissue that is entirely capable of functionating. Periarteritis hemorrhagica.
Suprarenals generally thinned, cortex somewhat smaller. Hypophysis: in the sella
turcica a large cavity, the posterior lobe well retained, the peduncles of the hypophysis

MULTIPLE DUCTLESS GLANDULAR SCLEROSIS 443

penetrate the cavity (hydrops ex vacuo), dura grown fast to the underlying tissue.
Destruction of the glandular lobe. Callous thickening in the retained part. Rigidity of
the fiber masses.

Observation ofGouilloud.— Woman, thirty-seven years old, mother of three children, se-
vere hemoptysis at the thirty-third year, at that time cessation of menses, which have
never been right since that time; the temperament, which was formerly very lively, has
altered, the patient is apathetic, forgetful, childish mentally. Cachexia for the last half
year. Face pale. Lashes have in part fallen out. Also the hair of the head is thinned
out and has lost its color. Also the hairs of the axilla? and on the pubis have fallen out.
The hands are cold, backs of the hands edematous. The thyroid is apparently smaller
than normal, the uterus entirely atrophic. Improvement by thyroid therapy doubtful.

Observation of Djemil Pascha.- — Man, eighteen years old, testicles began to atrophy
three years ago, the potency became lost. The mamillae began to increase in volume, also
the breasts became larger, the pitch of the voice was higher. After operative removal of
the breasts libido returned, the testicles became larger again, pollutions occurred; later,
increasing paleness and puffiness of the skin of the entire body, apathy, increasing cachexia,
dryness of the hair. Medication with thyroidin unsuccessful, death, no autopsy.

Observation of Claude and Gougerot. — Man, forty-seven years old, formerly very potent,
father of three children, alcoholism. At forty-two years, probably tetany, also perhaps
nephritis. During convalescence falling out of the hair of the head, the testicles atrophied,
complete impotence, the voice altered, and also the external genitalia became atrophic.
Hairs of the beard very scanty. Pubic hair and axillary hair absent. Skin dry, apathy,
pigmentations on the skin and mucous membranes, low blood-pressure, asthenia, gradual
diminution in the size of the thyroid gland, high-grade cachexia, tuberculosis of the lungs,
death. Autopsy showed tuberculous foci in lungs, liver and kidneys. The thyroid very
small, only 12 gm. The testicles very atrophic (22 gm.), prostate and seminal vesicles also
atrophic. Hypophysis small and sclerotic. Histological examination of the skin; atro-
phy of the epidermis; hair follicles, sweat glands and sebaceous glands atrophic.

Observation of Gandy. — Man, thirty-three years old, formerly gonorrhea, father of two
children; was very potent; at twenty-seven years, polyuria, headaches, severe sweats,
puffiness of the face, falling out of hair, nasal hydrorrhea. Later retrogression of the
secondary sexual characters and atrophy of the genitalia. Looks like an eighteen-year-
old youth. Skin of the face, pale, subicteric, skin dry, slightly scaly. Hairs of beard
very scanty. Trunk and extremities bald. Scrotum and testicles quite small, the latter
insensitive. Penis 6-7 cm. long. Complete impotence. Prostate also atrophied. Cre-
masteric reflexes absent. Perineum and genitalia have lost their pigment. Autopsy:
Inflammatory sclerosis of the thyroid (7 gm.), the testicles very small (8-10 gm.). In-
terstitial substance has disappeared entirely. Meningitic changes at the base of the
skull, with edema of the brain. No statement as to hypophysis.

Observation of Brissaud and Bauer. — Twenty-nine-year-old woman, heart failure, em-
bolism, tuberculosis, peritonitis. First menses at the age of fifteen. Birth of child at the
age of twenty. From that time has not menstruated. Infantile appearance, face very
pale, slightly swollen, breasts little developed. Hair of head dry and thinned out, likewise
the eyebrows, entire absence of pubic and axillary hair. Voice monotonous. Apathy,
headaches, anemia, and cachexia. Autopsy. Thyroid 15 gm. apparently normal. No
statement as to microscopical examination. Left side salpingitis and oophoritis. Right
ovary much sclerosed, very small. Uterus like that of a little girl. No statement as to
the pituitary.

Observation of Sainton and Rathery. — Woman, thirty-two years old, syphilis at the age
of twenty-five. Very distinct myxedema, appears very infantile, absence of pubic and ax-
illary hairs. Hair of head thinned out, dry. Apathy. Speech slow, almost complete

444 PLURIGLANDULAR DISEASES

amaurosis, pulse 66, improvement as a result of thyroidin medication. Autopsy.
Thyroid gland sclerosed, 12 gm., thymus large, suprarenals sclerosed. Genitalia
atrophic. Ovaries very small, sclerotic. Uterus infantile. Soft malignant, cystic de-
generated tumor of the hypophysis.

Observation of Josserand. — Man, thirty years old, five years ago influenza and articular
swellings, later great loss of body weight, marked weakness, the mustache fell out, also the
axillary hair and the eyebrows, the skin of the penis became thick, and inelastic, atrophy
of the testicles, loss of libido and of potency. Extreme weakness, then some improvement.
Anemia, senile appearance. Testicles the size of hazelnuts, bilateral hemianopsia,
apparent increase in size of the hands and feet.

Josserand mentions in brief a second case who at the age of thirty-five passed safely
through an attack of influenza, and later became senile.

Observation of Gougerot and Gy. — Man, fifty-two years old, formerly very strong, very
potent, at the age of forty-one years a "hard to define" infectious disease, with pains in the
limbs and in the abdomen, vomiting and numbness, lasting two and a half months.
Later asthenia, and temporary polyuria. From this time on libido and potency gradu-
ally lessened and finally disappeared. Hairs of the beard fell out, axillary and pubic
hairs are almost entirely absent. Senile appearance, testicles atrophied, sensation of cold,
tuberculosis of the apices, lupus on the nose, erysipelas, later pneumonia. Autopsy:
Thyroid gland highly sclerosed, right lobe 6 gm., left lobe 5 gm. Testicles likewise
sclerosed, right 18 gm., left 20 gm. Suprarenals sclerosed, chiefly in the cortex; pancreas
also sclerosed, likewise the hypophysis (0.3 gm.), and the parathyroids. Also liver, spleen
and kidneys sclerotic.

Personal Observation. — Observation LIII. — Forty-year-old man (history partly elicited
from the wife of the patient). Father of the patient died at the age of sixty years of
carcinoma of the stomach, mother at forty-five years, of tuberculosis. One brother also
died of tuberculosis, otherwise no tuberculosis in the family. One uncle died of diabetes.
No gout, no obesity, no Basedow's, in the family. The patient himself had in his youth
passed through measles and scarlet fever. At twenty years of age, catarrh of the pul-
monary apices, that became healed. The patient then remained healthy up to his
thirty-fifth year. Sexual life was fully normal. He married at the age of twenty-eight
years and has three healthy children. Hair of the head abundant, and there was a fair
amount of hair on the trunk and extremities. Abundant beard. Axillary and pubic
hair abundant. Potency and libido entirely normal. Had never engaged in [sexual]
excesses; at the age of twenty-two years gonorrhea and slight orchitis. He was never
especially strong muscularly, was always rather thin, but he felt well and could always
fulfill his now and then exacting duties as a tradesman. At the age of thirty-five years
he became ill rather acutely with fever, lancinating pains in the extremities, pains in
the back and neck (he cannot say whether the thyroid was swollen). The physician
diagnosed influenza and ordered aspirin. For some days later there also existed diarrhea.
The fever rose as high as 39.5°C. Later when the acute manifestations had retrograded,
there occurred edema of the legs, the face, and also the backs of the hands and feet.
Albumin was found in urine and the physician diagnosed nephritis. The patient felt
very weak, after about eight weeks improvement occurred, but the weakness persisted;
convalescence continued for an unusually long time, for several weeks still the patient
suffered from great muscular weakness, he became thin, and the edematous swellings dis-
appeared very slowly. After three months the patient had recovered, yet he never felt
entirely well since that illness. The potency gradually became lost, and about three-
quarters of a year after the illness the testicles seemed to him to be smaller. Also the
penis was smaller, the hair of the head had become thinned out immediately after the ill-
ness, so that some bald spots had formed. Now also the hair of the mustache and

MULTIPLE DUCTLESS GLANDULAR SCLEROSIS 445

beard began to fall out, and the axillary and pubic hair and the hair on the trunk gradu-
ally disappeared. Since this time the patient has been an invalid. Later, the physicians
regarded the nephritis as cured; although the puffiness of the skin never left entirely.
The patient is very apathetic, tires very easily, shivers, is never quite warm, has never
attained his former body weight, mental work exerts him very much, he sleeps poorly
at night, suffers from pressure in the head, sometimes complains of drawing pains in
the back and legs; lately the swelling of the face has again become distinct. Also the
pallor of the face has increased. He has visited different bath resorts and taken many
medicines, among them iodine and arsenic. The bowel movements often occur at inter-
vals of four to five days. Recently, albumin has again been found in the urine.

The patient came under my observation in May, 1911. Medium height, cachectic
appearance, looks very much older. Face pale with a light yellowish tinge. Distinct
puffiness of face, especially about the eyes, on the cheeks and lips. Light livid discolora-
tion of the middle of the cheeks. On the upper lips mustache hairs very scanty; chin
and cheeks bald. Hair of head thinned out, dry, and brittle, at certain places much more
scanty, especially on the occiput. The trunk is bald, there are no hairs in the axilla; at the
root of the penis a few scanty hairs only, the perineum is almost free from hair. Tongue
perhaps somewhat thickened. Teeth poor, partly carious, the crowns much worn away,
transverse folds on the forehead, skin in the supraclavicular fossse shows slight pad-like
thickening, elastic; also the skin on the backs of the hands and feet is more elastic, other-
wise skin on trunk is rather rich in fat. Several lens-shaped specks of pigment on the
mucous membrane of the cheeks. Many places, on the skin more strongly pigmented as
in the folds of the palm of the hand, also in the vicinity of the nipples, on the backs of the
hands, forearms, also about the waist. Breasts not enlarged. Mons Veneris rather rich
in fat; no especial deposition of fat on hips. Findings as to cranial nerves entirely normal,
except that Chvostek II distinctly positive. Trousseau negative. Pupils react promptly.
Eye-grounds normal. Patellar reflexes weak. Size of heart normal to percussion; faint,
weak, systolic murmur at Erb's point. Pulse 68, tension slight, blood-pressure (Riva
Rocci) 65, liver not enlarged, spleen not distinctly palpable, neighborhood of the kidneys
on each side not especially sensitive to pressure. Penis small, about 7 cm. long. Skin on
penis folded. Testicles on each side about the size of a bean, soft, epididymis also small,
somewhat hardened. Scrotum small, soft. Examination per rectum shows that the
prostate is very small. Examination of the blood: leucocytes 12,000 of which 51 per cent,
are neutrophiles and 5 per cent, eosinophiles. In the urine no sugar, traces of albumin.
Slight dulness over the right apex, very few rales. Vesicular murmur somewhat weakened.
Therapy. Thyroidin tablets o.i gm. t.i.d. After two and one-half months report
by letter that the myxedematous manifestations have improved, but the deteriora-
tion in strength has progressed.

Symptomatology. — The cases described show a very noteworthy agree-
ment with one another. It is therefore not difficult to delineate the clinical
picture of the condition. All cases show in pronounced manner the symp-
toms of late eunuchoidism, an exact description of which I need not enter into
here. This syndrome, however, constitutes only one, although one of the
most emphatic expressions in the total picture of the disease. To it is
added in all cases a most irresistibly progressive cachexia, and mostly also,
as far as investigations have determined, a pronounced anemia. Hence it
occurs that such patients in spite of the boyish beardlessness of face, do not,
as in late eunuchoidism appear younger than they really are, for the most

446 PLURIGLANDULAR DISEASES

part they rather appear prematurely old, and in some cases the face has
even a senile appearance. There never occurs the development of an adi-
posity of the type of the eunuchoids. For the most part there rather
occurs an increasing emaciation, which is associated with a feeling of weak-
ness and with chills, and which persists in spite of all attempts at
feeding up. Then there occurs more or less pronounced puffiness of the
skin of the face, especially of the cheeks, and of the skin of the backs of the
hands and feet, in many cases quite pronounced myxedema, which partially
but not entirely retrogresses on thyroidin medication. There usually are
added to the falling out of the hair on the face, trunk and extremities,
thinning out of the hair of the head, eventually falling out of the hairs
in spots, such as is seen in true myxedema, also thinning out of the eye-
brows, eyelashes, and symptoms that also do not belong to true late
eunuchoidism. Also brittleness of the nails was observed in my case.
The loosening of the teeth, and especially the marked wearing down of
the crowns, as I saw in my case, perhaps too belong to the clinical picture.
In many cases are found in addition to the puffiness of the skin, pronounced
atrophy of the rest of the skin, and marked dryness and exfoliation. There
further develops in the majority of cases pigmentations of the skin, especially
in places exposed to light or where the clothing presses, sometimes, too, dis-
tinct pigmentations of the mucous membrane as in Addison's disease; in
other cases a pigmentation that is more brownish is noticed. Almost in no
case are absent asthenia that increases to high-grade prostration of strength,
mental sluggishness and apathy, further a feeling of pressure in the head,
forgetfulness, insomnia, and eventually transitory rheumatoid pains in the
limbs. In addition there exists hypotonia. The sugar content of the blood
has not as yet been investigated. In cases in which the blood has been
examined have been found in addition to the anemia, slight leucocytosis with
mononucleosis and eosinophilia. Temporary polyuria has been reported
remarkably frequently (Rumpel, Gandy, Gougerot and Gy). Occasionally
also occur tetanic convulsions (Claude and Gougerot), or at least the symptoms
of a latent tetany.

The tracing of the relationship of the numerous symptoms to the diseases
of the individual ductless glands often meets, as will be understood, with diffi-
culties. It seems to me that the simplest to explain is the syndrome that we
learned to know in the exposition of late eunuchoidism, and that comes about
through the degeneration of the sexual glands. It should only be mentioned
in addition that in the cases that affect women, the retrogression of the
genital apparatus and of the secondary sexual characters are present in a pro-
nounced manner. At all events we cannot in the cases with pronounced retro-
gression of the genital apparatus, and especially of the hair of the mustache,
exclude the possibility that a degeneration of the suprarenal cortex does not
play a role. In male individuals, it appears to me only necessary to assume

MULTIPLE DUCTLESS GLANDULAR SCLEROSIS 447

such an involvement of the suprarenal cortex in the crassest cases, as in
traumatic late eunuchoidism, in which the etiological factor is quite clear,
quite severe manifestations of retrogression may occur. In women, however,
there may perhaps be ascribed to the suprarenal cortex a greater signifi-
cance in this direction, for we see after castration very slightly pronounced
the ordinary retrogression of such secondary sexual characters as the hairi-
ness of the axillae and of the genitalia.

The changes in the hair of the head are to be referred to a degeneration
of the thyroid gland, as are also trophic disturbances of the nails, probably
also of the teeth, and further the apathy, headache, forgetfulness, etc.,
finally the myxedema of the skin. At all events it seems to me questionable
whether the myxedematoid consistence of the skin is always of purely thyro-
genic origin, as thyroidin medication very often does not fully control it.
Such myxedematoid alteration of the skin is found not infrequently in the
hypophysial dystrophia adiposo-genitalis; further such alterations occur not
rarely if cachexia develops in Basedow's disease. I refer to the chapter
dealing with this subject, and would like only to express the conviction that
in such cases the skin changes may be brought into relationship with a
(even simultaneous) degeneration of the glandular hypophysis.

The sclerosis of the hypophysis may also very well play a part in the
rapidly progressive cachexia. . That there does not ensue a distinct develop-
ment of hypophysial obesity is intelligible when we consider the general
cachexia in multiple ductless glandular sclerosis. If individuals who are
not yet fully developed were to become the subjects of this disease, the
absence of the eunuchoidal tall height would also be intelligible, as the action
of the insufficiency of the sexual glands on the development of the skeleton
might be compensated by the insufficiency of the hypophysis. I would
bring still another symptom into relation with the hypophysis — the transi-
tory polyuria. As is known we find this symptom quite commonly in
diseases of the hypophysis, or in pathological processes at the base of the
skull. We may readily conceive that sclerosing processes that have be-
come established in the anterior lobe of the hypophysis temporarily act as
irritants on the posterior lobes or on the pars intermedia. From this stand-
point it seems to me worthy of mention that two of the cases of late eunuch-
oidism reported in the tenth chapter, in which we found transitory polyuria,
developed after an acute infectious disease or after lues. Here the polyuria
may well be regarded as hypophysial.

Hypotonia, high-grade asthenia and the pigmentations serve as mani-
festations of absence or deficiency [Ausfall] on the part of the suprarenals or,
much more, the suprarenal medulla. Finally the tetanic spasms that occur
point to an involvement of the parathyroid glands in the disease process.
Here perhaps it may be thought that the lowering of the thyroidal and
suprarenal activities can antagonize the occurrence of distinct tetanic symp-

448

PLURIGLANDULAR DISEASES

toms even where there is high insufficiency of the parathyroid glands. I

know that much that is hypothetical is bound up with these attempts at

explanation. In one point, however, I believe I can scarcely err, namely, in

Jthe supposition that the rapidly progressing cachexia that is observed so

I frequently finds its explanation not in the functional disturbance of one

ductless gland, but in the progressive degeneration of the ductless glandular

system.

The etiology of multiple ductless glandular sclerosis of the ductless glands
seems to be of diverse nature. In many of the cases acute infectious diseases

FIG. 77.— Case with insufficiency of sev-
eral ductless glands (Observation LIV).

FIG. 78. — Slightly myxedematous facial expression.

have preceded the beginning of the disease. Thus in the case of Josserand,
influenza; in the case of Gougerot and Gy a "hard to define acute" illness
occurred, as in my case also. The case of Sainton and Rathery was syphilitic.
In the case of Claude and Gougerot, and in that of Brissaud and Bauer there
existed at the same time tuberculosis. Histologically, in the cases in which
there were autopsies, there was found a simple sclerosis; except in the case
of Claude and Gougerot, where there was found in addition tubercle in the
thyroid gland. It is indeed very likely that the ductless glandular sclerosis
may depend very often on a tuberculous foundation, as Poncet and Leriche

MULTIPLE DUCTLESS GLANDULAR SCLEROSIS 449

mention, although I cannot follow the connection of ideas of these authors
when they ascribe to cases of dystrophia adiposo-genitalis, yes even to cases
of acromegaly, a tuberculous foundation.

In many cases the disease picture of multiple ductless glandular sclerosis
develops quite spontaneously, without a preceding or an accompanying
disease. The opinion of Claude and Gougerot that there exists in such cases
a congenital weakness of the ductless glandular system, so that a not well-
definable deleterious agent brings this system to degeneration, is not im-
probable. In such cases the organism, especially that which is still in a state
of development, may come to a temporary manifestation of insufficiency
on the part of the ductless glandular system.

I would regard the following as such a case:

Observation LIV. — J. K., seventeen years old (first medical clinic). One year ago
typical tetany, two months ago typical epileptic attacks for the first' time. Now tetany
again. Of medium height, pale color of face, skin somewhat dry and exfoliative. Face
distinctly myxedematoiis, especially the eyelids. On the backs of the hands slight
myxedematous swellings. Hairs of the beard and axillae are entirely absent, as is also the
hairiness of the linea alba and the calves. Scanty hairs at the root of the penis. The
testicles are very small and soft. As yet no libido, never erections nor pollutions.
Finger nails very compact, strongly curved, and ridged longitudinally. Teeth through-
out strikingly small and poorly developed, "terrace-like striations on the enamel (whether
he had tetany in childhood cannot be elicited). Ossification normal. Blood-pressure 65.
On the administration of even 200 gm. dextrose, no glycosuria. Neutrophile cells 54 per
cent. Typical tetanic attacks. Slight apathy; on thyroidin medication the myxede-
matous symptoms disappear entirely, the blood-pressure soon rises to normal, the blood
picture becomes normal.

After a year the case was examined by Redlich. There were new attacks of tetany, also
epilepsy. There was nothing to be seen of the myxedematoid symptoms, the second-
ary sexual characters had for the greater part developed, and the sexual life had begun
to assert itself.

Thus in this case there existed, in addition to typical tetany and epilepsy,
a simultaneous disturbance of the function of the thyroid gland and of the
sexual glands. Perhaps the suprarenals (pronounced hypotonia) were also
involved. Probably the inhibition of development of the sexual glands
was not occasioned directly by the disease of the thyroid. For this
speaks the fact that thyroid-gland therapy immediately brought the mani-
festations of hypothyroidism to disappearance, while the insufficiency of
the sexual glands gradually disappeared spontaneously.

Claude and Gougerot believe that also alcoholism may furnish an etiological
factor. In this respect two cases of general hemochromatosis, concerning
which Folk has reported, are of interest. As is known, there are found in
such cases pronounced sclerosis of the liver and mostly also of the pancreas.
In both the cases, as I myself had occasion to observe, there was also a pre-
mature diminution or cessation of the genital function, without the history
29

450 PLURIGLANDULAR DISEASES

furnishing a basis for a preceding disease of the genitalia. In both cases
there was found an almost complete falling-out of hair on the trunk and
the extremities, and also that in the axillae and on the pubis. The histo-
logical examination of an excised piece of skin showed, in addition to collec-
tions of pigmentation, abundant connective-tissue proliferation of the cutis;
and in places the sweat-glands and the hair follicles were replaced by
connective-tissue strands. Falk believed that this sclerosis was also the
cause of the falling-out of the hair. I incline more to the supposition that
the involvement of the sexual glands in the general sclerosis had led to a retro-
gression of the secondary sexual characters.

For this assumption I find support in the investigations of Weichselbaum
and Kyrle. In individuals, who do not as yet stand under the influence of
the senium, Weichselbaum and Kyrle found on account of alcoholism cirrhotic
alterations of the testicles, affecting interstitial cells as well as the glands of
generation.

In the broad field of multiple ductless glandular sclerosis belongs perhaps
a disease that v. Noorden has described as degeneratio genito-sclerodermica.
It affects young, previously healthy, girls, in whom after a previously normal
| development the menstrual periods suddenly cease at the termination of an
I acute infectious disease. There are marked emaciation and loss of appe-
tite, a premature senility occurs, and there develop trophic disturbances
of the skin; in some cases in which the condition was looked for, the body
of the uterus was found to be atrophic.

Further I would mention for consideration whether such a multiple duct-
less glandular sclerosis does not exist in many cases of pedatrophy. Thompson
has described a noteworthy case in which sclerotic processes were found in all
the ductless glands.

Finally I might here mention an apparently rather typical disease picture
of which Sir Jonathan Hutchinson, Hastings Gilford and recently Variot
and Pironneau have furnished examples. Hastings Gilford designates these
cases as "progeria," Variot and Pironneau as "nanisim type senile." As we
shall see directly much speaks against our classifying, without other con-
sideration, these cases with multiple ductless glandular sclerosis. I would
say here, however, that at least an indirect connection with the ductless
glandular system is here possible, and that the inclusion of the condition at
another place appears to me less to the purpose.

I will here shortly report the three cases described up to the present. In the case of
Hastings Gilford the observation extended between the fourteenth and eighteenth years
of life of the individual affected. A photograph of the individual taken at the second
year of life shows that the hair of the head was markedly thinned out already at that time;
at the later investigations the patient showed a marked remaining behind in growth and in
entire development. At fourteen years of age the boy was 113 cm. tall, weighed 16 kg.
He was extremely thin, so that the cartilages of the nose and the veins and the tendons of
the entire body were very prominent. The head was rather large, the facial skeleton

MULTIPLE DUCTLESS GLANDULAR SCLEROSIS 451

relatively small. There were on the head only a few thin hairs, the eyebrows and the
lashes were absent, almost completely, as were also the hairs of the trunk. The lower jaw
was ill-developed, and there was especially a poor development of the clavicles. The mus-
culature was poorly developed, the genitalia were about one or two years behind in their
development, the skin was thin and dry, the nails were short and the anterior fontanelle
had not as yet closed, and certain of the temporary teeth were still present. There was a
falsetto voice; the intelligence was rather well developed. The individual made quite a
senile impression. At the age of eighteen, the boy died with symptoms that gave thought
to the diagnosis of "thymic or cardiac asthma." At autopsy was found an enlarged
thymus gland and atheromatous alteration of the mitral and aortic valves; the coronary
arteries were highly sclerotic. The capsule of the spleen was thickened, the kidneys were
fibrous, the walls of the intestines and stomach were so atrophied that they were almost
transparent. The liver was relatively large, the brain normal. The long tubular bones
were rather slender, but the ends much thickened. Especially the condyles of the femurs
and the arterial ends of the clavicles were swollen up. Ossification had been premature.
Microscopically the ductless glands (thyroid, hypophysis, testicles and suprarenals) were
apparently normal, there was no microscopical examination.

Hutchinson observed a three-and-a-half-year-old-boy with the same disease. Hastings
Gilford saw this case when it was fifteen years of age and followed it to its death two years
later. There existed extreme emaciation, so that the bones and the tendons were very
prominent. The abdomen was large, the condyles of the tubular bones were rather thick-
ened, especially the distal epiphyses of the femurs, so that the patellas were pushed
forward. The fingers were short, the size of the hands corresponding to that of a three-
year-old child. The ossification represented that of a twenty-year-old youth. There
were symptoms of a mitral and aortic failure, and death occurred with symptoms of a
cardiac syncope. {There was no autopsy.

The case of Variot and Pironneau was that of a fifteen-year-old girl. She weighed only
11.65 kg.— like a two-year-old child — was 102 cm. in height, size and dimensions corre-
sponding with those of a five-year-old child. The appearance was entirely senile. Apart
from isolated hairs on the head, the hair was entirely absent, even the hairs of the eyebrows
and lashes. The skin was thin and folded, the panninculus adiposus was entirely absent.
The muscles were relatively well developed, and stood up prominently through the thin
skin. The nails were very small, the tooth formation was very bad, and second dentition
was just appearing. Many teeth have fallen out without especial pain. The develop-
ment of the genitalia had remained behind, and breasts especially had not developed.
The intelligence was rather good. Up to the fifteenth month development had been en-
tirely normal, and from this time it had remained behind. X-ray examination showed
that the lower jaw was very atrophic and that the epiphysial junctures had for the most
part closed. Gilford Hastings reports also a case of Ransom that possibly belongs here.
It was concerned with a twenty-seven-year-old girl who was 135 cm. tall and weighed 16
kg. The father had been a heavy alcoholic. The girl's intelligence was feebly developed.
Diarrhea had existed from youth, and later there had been a diabetes. The genitalia in
their development represented those of a ten-year-old girl. The ovaries were absent.
The girl was markedly emaciated and looked pronouncedly senile. At autopsy there were
found fibrous changes in the spleen, lymph glands, the pancreas, kidneys, suprarenals,
thyroid, hypophysis, etc. The heart weighed 6 oz. (about 176 gm.) and there were athero-
matous changes in the aortic and mitral valves and in the aorta.

The cases cited show the greatest similarity to one another. Already
Hastings Gilford remarked that his case and that of Hutchinson were so similar

452 PUURIGLAXDULAR DISEASES

that the father of the first when shown the photograph of the second believed
momentarily that it was that of his child. Also the case of Variot and Piron-
neau was similar to the first two, as is seen in the photographs these authors
publish; it is also remarked by them, although their case is that of a girl.
In all cases the disturbance in development began in the earliest youth. In
all the inhibition of growth was very considerable, so that we could really
speak of dwarfism. In all there was extreme emaciation, with the skin thin
folded. In all were the muscles rather prominent. The osseous system
showed the characteristic alterations. The dimensions remained childlike.
The lower jaw was rather poorly developed, apparently also the upper jaw,
causing perhaps the aquiline nose observed in all. The long bones were
relatively slender, the ends of the bones thickened, the closure of the epiphyses
was rather premature. The genitalia remained backward in development in
all cases; and finally the absence of hair is common to all, affecting not
only the hairiness belonging to the so-called secondary sexual characters,
that on the lip, chin, axillae, pubis, and trunk, but also the hair on the head,
lashes, and eyebrows. This increased the senile appearance, which in all
these cases is of high degree.

That here we are dealing with a morbid entity can in all likelihood be as-
sumed from the similarity of the cases and the course of the disease. On the
contrary the pathogenesis of this condition and the role of the ductless
glandular system in the same seem to me to be as yet but little clear. Variot
and Pironneau point out that in the case of Hastings Gilford the suprarenal
showed fibrous degeneration, and see in the disease picture the sequel of a
suprarenal insufficiency's setting-in in youth. A pert goes still further
and sees the cause in a damaging of the suprarenal cortex. On account
of the characteristic disturbances in the hairiness and in the genital sphere
he sees in this disease a countertype to that of tumors of the suprarenal
cortex. Hastings Gilford believes on the contrary that we are to ascribe
to the hypophysis a "growth center" of considerable importance. The
results of the one autopsy done on these cases up to the present are insufficient,
as there was no microscopical examination of the ductless glands. It was
mentioned only that the suprarenals were sclerosed. In the case of Ransom,
that does not belong with certainty to this group, the other ductless glands
were also apparently sclerosed. If now also the microscopical examination
in such cases would also furnish an extensive sclerosis of the several ductless
glands, it would not necessarily be shown the disease of the ductless glands
was primary; it would also be possible that we might be dealing with a diffuse
sclerotic process involving the entire body, that has also involved the ductless
glandular system, such a general process as we regarded above as possible
for hemochromatosis and which is perhaps also true for pedatrophy.

Then we would be dealing with a secondary sclerosis of the ductless
glandular system, that at all events lends to progeria many of the striking

MULTIPLE DUCTLESS GLANDULAR SCLEROSIS 453

• features of ductless glandular sclerosis, and which may play the chief role
in the enormous cachexia and the senilism of these individuals.

In the clinical picture of progeria are some features that seem to me
hardly compatible with the assumption of a ductless glandular sclerosis.
In the three typical cases the intelligence was fairly well developed, which
rules out a strong involvement of the thyroid gland. Especially, however,
does it seem to me that the premature ossification points to a sclerosing
process independent of the ductless glandular system, as otherwise we would
expect considerable retardation of ossification. The severe disturbance in
the development, or the retrogression of the hair, can indeed very well be
brought into relation with an involvement of the suprarenal cortex; it is,
however, conceivable that it has its foundation in a severe atrophy of the
skin. It was already in the first chapter pointed out that we must not re-
gard old age, as Lorand does, simply as a gradual degeneration of the ductless
glandular system; but consider that the ductless glandular system, like
the rest of the organs takes part in a general involution of old age. It
seems to me that the same thought can be applied also to premature and
to childish senility.

Differential Diagnosis of Multiple Ductless Glandular Sclerosis. — The
cases out of the literature that I have quoted show a remarkable agreement
with each other, so that for the most part the diagnosis does not meet with
difficulty, especially so in that the retrograde processes in the genitalia and
the secondary sexual characters constitute especially striking symptoms.
The delimitation from pure late eunuchoidism may indeed become difficult.
Marked puffiness of the skin, thinning of the hair of the head in patches,
and of the hair of the lashes and eyebrows, speak against late pure eunuch-
oidism, as do also marked emaciation and cachexia. For the delimita-
tion from pure myxedema I regard as important the partial or extremely
deficient results attending thyroid-gland therapy. Concerning the diagnosis
from pure Addison's disease nothing further need be said. As far as diag-
nosing it from hypophysial dystrophia adiposo-genitalis is concerned, I
do not known that in this disease such a high-grade atrophy of the genitalia
of adults occurs as was described under late eunuchoidism; naturally the
absence of symptoms of brain tumor is also important, although it must
be remembered that in the case of Sainton and Rathery there was found at the
same time a malignant cystic degenerated tumor of the hypophysis. There-
fore it seems that a combination of multiple ductless glandular sclerosis and
hypophysis tumor may occur.

Up to the present the treatment has been of little avail. In the cases of
Rumpel and of Djeinil Pascha the use of thyroid gland was negative, and in
Gouilloud's case doubtful. French authors have tried a combined ductless
gland therapy (thyroidin, hypophysis substance, sexual gland substance, and
suprarenal substance), and have sometimes seen temporary improvement of

454 PLURIGLANDULAR DISEASES

individual symptoms under the influence of these, yet the progressive
cachexia can for the most part not be essentially influenced.

Gigantism

Historical. — It can be readily understood that gigantism usurped the
interest of the laity and physician from early times. Indeed a philanthropist
even founded a prize in order that by the intermarriage of giants a larger
and stronger race would be produced. For the first valuable scientific obser-
vations concerning this interesting phenomenon we are indebted to C.
v. Langer. v. Langer distinguished between normal and pathological giants.
He described three skeletons of normal giants, one from the Berlin Patho-
logical Institute, one from Hunterian Museum, and one from Trinity College,
Dublin. These giants enjoyed good health until a high age; they showed in
general normal dimensions of their skeletons corresponding to their size,
therefore rather large skull and a relatively large upper body, the upper
length somewhat exceeding the lower length. In the other group, the
pathological giants, v. Langer first pointed out that here certain pathological
alterations of the skeletons were present, such as relatively small cranium
with enlarged sella turcica and enlargement of the facial skeleton with enor-
mous lower jaws, widening of the pneumatic spaces, increased development
of the insertions of the muscles, certain abnormalities of the pelvic girdle, fre-
quency of genu valgum, in short a series of alterations that to-day we would
designate as acromegalic. v. Langer pointed out that from illustrations also
degeneration of the soft parts, such as enlargements of. the tongue and the
lips, had existed.

Then Sternberg in a detailed work pointed out the frequency of the com-
bination of acromegaly and gigantism. According to Sternberg about 40
per cent, of all giants are acromegalics, and about 20 per cent, of all acro-
megalics giants. This question entered upon a new stage when especially
the French school sought to define the relation between acromegaly and
gigantism. After Massalongo had designated acromegaly as late gigantism,
Brissaud and Meige came forward with the teaching that acromegaly and
gigantism are one and the same disease and depend on the same cause,
namely, an alteration of function of the hypophysis, which leads in youthful
individuals to gigantism, and in older individuals, those in whom the epi-
physial junctures have already ossified, to acromegaly. These authors also
support the view that only the acromegalic giants should be termed proper
giants, and that gigantism should always be regarded as the disease. This
opinion, which was actively contradicted by Pierre Marie, Launois and Roy
have tried to support in several researches and in their monograph.
These authors show, in convincing fashion, that the greater part of the
giants thus far observed have been acromegalics, or have later become

GIGANTISM 455

acromegalic. Also Biedl has relegated the subject of gigantism to his
chapter on the hypophysis.

Symptomatology and Types of Gigantism

According to the opinions thus far existing in the literature, as to the
pathology of gigantism, it is not possible to define it uniformly. The
difficulty begins already with the question as to which individuals should be
regarded as giants. Bellinger proposed regarding as tall, human beings
whose height reached 205 cm., and only speaking of giants when the height
exceeded 205 cm. This classification is naturally quite arbitrary. Accord-
ing to it a whole group of the cases reported in the literature would no longer
be regarded as belonging to giants. Just as arbitrary seems to me the
opinion occurring in the French literature that only those giants that bear
acromegalic features should be regarded as true giants. Even though well-
proportioned, nonacromegalic giants are apparently among the greatest
rarities, yet, according to the definite statements of v. Langer and Virchow,
their existence is not to be doubted. Therefore it seems to me to the point
to adhere to the old classification of Langer and to distinguish between
normal and pathological giants. Moreover we find described in the literature
a group of cases, whose height lay between 190 and 200 cm. ; cases that showed
no acromegalic features, but on the other hand, all the signs of typical eu-
nuchoidism. Here, therefore, there lies before us all the signs of a potentized
form of eunuchoid tallness, and for this the designation eunuchoid gigantism
seems to me not without foundation. The cases coincide in part with those
cases which Launois and Roy have called infantile gigantism. Considering
the fact that I have sharply separated eunuchoidism from infantilism — I
shall come back to this differentiation in the next chapter — I must regard
the designation eunuchoid as more precise than infantile. I would here
point out that a portion of the giants described by Launois and Roy as in-
fantile are not pure eunuchoids, but already bear the acromegalic features.
Finally, as to what concerns the acromegalic giants I shall take pains to show
that here there are very diverse types, those types in which from the be-
ginning acromegalic manifestations are distinctly prominent; those types
which to use an expression of Launois and Roy " acromegalize " only later;
those types which possess the eunuchoid features or even pronounced eu-
nuchoidism from youth on; those types to whom a kind of late eunuchoidism
comes only later, and finally those types in whom the eunuchoid features are
entirely absent, in whom, moreover, the function of the sexual glands and
genitalia are entirely normal, or even perhaps temporarily abnormally
increased.

In the great multiplicity of the manifestations of gigantism a uniform
exposition of the symptomatology is scarcely possible; it seems to me more

456 PLURIGLANDULAR DISEASES

to the purpose to adduce examples of the various types from the literature,
whereby I would mention that all possible transitions between the groups
occur.

I will not enter further into the subject of normal giants. In the historical
introduction I have already mentioned the most important facts.

Of the eunuchoid giants I mention the twenty-seven-year-old man
described by Launois and Roy. (Soc. de Biol., 10 Jan., v., 1903.) In this
individual the increased growth in height apparently began after an attack
of typhoid fever.

I shall now adduce a series of cases relating to acromegalic giants, in
whom the function of the sexual glands was normal. As the first example I
communicate a case that I myself had occasion to investigate.

Observation LV. — B. O., "Bulgarian giant," born in Gross- Wenkheim near Bad
Kissingen, thirty-seven years old. The male members of the family are almost all
rather tall. The tallest was his father's brother, who measured 186 cm. His father
measures 180 cm. B. O. states that he first began to exceed his school companions in
growth at the seventh year of life. At twelve years of age he measured about 206 cm.,
and at twenty-four years of age had attained his full height (212.5 cm.). He served in the
"Bayerischer Leibregiment" and was at that time examined by the chief physician, Dr.
Seggel. At that time he was entirely well, and had grown completely used to the military
service. He says that as a young man he weighed 145 kg. Especially in his eighteenth
to nineteenth years had his appetite become enormous. He says that it was easy for him
to devour at one meal i kg. of meat with copious additional fare. The highest weight was
195 kg. He had never suffered from headache. According to his statement the sexual
development was entirely normal. In 1900 he married a woman who was 187 cm. tall.
After one year she bote an entirely normally carried child, who died after four weeks.
Then later the woman had two premature deliveries, about in the fifth month. The
potency up to this time had, according to his statement, not diminished. Six years ago
he suffered from influenza and since that time "has had to do with a cough." The apex
of the right lung is defective.

The man now measures 210 cm. as a distinct kyphosis exists, it is very probable that
his statement that he formerly measured 212.5 cm- is perfectly correct. The span width
reaches 220 cm., the breadth of the shoulders 52 cm., the circumference of the chest 118
cm., of the waist 100 cm. Distance from the anterior superior iliac spine to the floor
124 cm.

There exists, as already mentioned, distinct kyphosis, the enormous shoulder blades
project prominently. The clavicles are enormously developed. The circumference of the
upper arm measures 29 cm., formerly when the patient was very muscular it reached
68 (?) cm.

The distance of the external malleolus of the wrist-joint to the point of the middle
finger is 27 cm.

The greatest circumference of the hand is 30.5 cm. The greatest circumference over
the metacarpopharyngeal joint is 27 cm.

The middle finger, from the metacarpopharyngeal joint to the point of the finger is 14
cm., the circumference of the thumb 9 cm.

Distance between the anterior superior spine and the upper border of the patella is
57 cm.; length of foot 33.5 cm. Circumference around the ankle-joint and heel 43 cm.;
length of great toe 9.5 cm.; circumference of the same n cm. The head is enormous.

GIGANTJSM

457

FIG. 79. — Gigantism (Observation LV) and hypophysial dwarf (Observation XLIV). The

normal individual measures 183 cm.

458 PLURIGLAXDULAR DISEASES

The fronto-occipital circumference reaches 67 cm. The occipitomental circumference 73
cm. The superciliary arches project markedly, as do also the malar ones. There exists
distinct prognathia. The anterior upper incisors are 1.5 cm. from each other. The set of
teeth is normal; only one tooth is absent. The tongue is disproportionately large. The
palate is in proportion. The least circumference of the neck is 42 cm. The pomum Adami
projects markedly. The thyroid gland is palpable and is in proportion. The voice is
very deep and low. The hairiness is very abundant. The mustache is well developed,
the man must shave every two days. The chest and the linea alba are extensively pro-
vided with hair. Also the hairiness on the genitals ,and the perineum, and in the axillse is
abundant. The genitalia are proportioned to the other relations. Heart dulness; upper
border of the fifth rib, left sternal border, 7^ cm. to the left of the border of the sternum.
Heart sounds clear. Slight tachycardia (105).

The orthodiagram shows a greatest heart breadth of 13 cm., breadth of the aortic
shadow 7 cm. These measurements are relatively very small. Tuberculous affection of
both apices. The stomach is enormously large, sac-like, reaches 20 cm. below the navel.
The ordinary bismuth meal is just enough to fill the fundus of the stomach.

Blood examination: Hemoglobin (according to Sahli), 80 per cent.
Erythrocytes, 5,720,000
Leucocytes, 5600, of which:
Neutrophilic polymorphonuclear, 65 per cent.
Lymphocytes, 20 per cent.
Large mononuclears, 9 per cent.
Eosinophiles, 6 per cent.

The examination of the urine shows sugar o, albumin o, urobilin o, indican + .

Eye examination (Dr. Ulbrich). The pupillary distance is 72 mm. (normaLaroout 65
mm.). The length of the palpebral fissures 33 mm. (normal 28 mm.).

On the contrary we find that globes lie abnormally free on all sides and thatjiiie, width
of the cornea is not greater than the normal average (n mm.). Eye-ground^ normal.
Visual field and color field normal.

The X-ray plate of the hand shows entirely normal ossification. The enlargement
affects bones and soft parts rather to a like degree.

The X-ray plate of the head shows enormous relations. We see the frontal and the
maxillary sinuses considerably broadened and, further, the distinct prognathia of the lower
jaw. The bones of the cranial vault are enormously thickened, the sutures markedly
projecting, especially striking is the enormous external occipital protuberance.

The sella is markedly enlarged and deepened; the posterior clinoid processes are dis-
tinct, and the anterior less evident. The introitus of the sella is relatively not very
wide (Fig. 80).

We are hence dealing in this case with a typical acromegalic giant.
The acromegalic tendency became evident at a rather early age and seems
to have progressed very gradually. At least this man can give no sure
statement as to when the coarsening of the features and the prognathia be-
gan to develop. He states that, his hands and feet have not become essen-
tially larger in the last ten years. We have better data so far as the kyphosis
is concerned. During the military service, hence fourteen years ago, this
did not exist. Another point is furnished by the diminution of muscular
strength, which at about the twentieth year must have been enormous.
The pulmonary tuberculosis that has developed in the last year can surely be

GIGANTISM 459

held responsible for only a small portion of the decay. Signs of increased
intracranial pressure are not as yet present in this patient; with which the
X-ray findings- — these show especially a deepening of the floor of the sella,
are in accord. Especially important in this case is the behavior of the
sexual glands. The functions of the genitalia up to the present time have
been entirely normal. At all events up to his thirtieth year the patient
was capable of reproduction. At most we could say that the early death of
the first child and the two following premature deliveries on the part of his
wife point to a diminished valuation of the semen, but this assumption does
not seem to me to be well considered. In agreement with the sexual po-
tency we find the dimensions of the skeleton normal, and the hairiness even
abnormally strongly developed.

Also the giant of Hue hard and Launois had two children. In this case
the abnormal increase in growth began in the twelfth year of life. At the
age of eighteen he was 197 cm. tall. The genitalia were entirely normally
developed. He attained the age of sixty years and at that time showed typical
acromegalic manifestations. The sella turcica was the size of a nut. Sclero-
sis of the anterior lobe was found at autopsy. This case has been brought
forward as a demonstration against the hyperfunction theory of acromegaly.
Incorrectly however, for we may well imagine that in late life the acromegalic
manifestations must not necessarily retrogress when there occurs without any-
thing else a secondary sclerosis of the hypophysis.

The case c-f Buday and Jancso showed an abnormal increase of the
potency that was at all events short in duration. At seventeen years of
age this patient was very potent, and performed coitus four to six times
every night. From the twentieth year on he gradually became impotent.
It is noteworthy that this case was only 103 cm. tall when he was twenty
years old. Now he first began to grow appreciably, and at the age of thirty-
five years had attained the height of 198 cm. He now showed distinct
acromegalic symptoms; there was found a large tumor of the hypophysis,
the genitalia were atrophied, the length of the lower part of the body was
•very considerable, there existed a genu valgum, the epiphysial junctures
were ossified (the abnormal growth has ceased for two years). In this case
we have the sort of late eunuchoidism combined with acromegaly. It is
very noticeable that in spite of the increased sexual function, the epiphysial
junctures remained open between the seventeenth and twentieth years.

I would regard the case described by Gushing as one in which the late
eunuchoidism began later. This thirty-five-year-old patient came from a
healthy family. The father was six feet tall. At the age of thirteen years
the patient first began to grow enormously rapidly; at the age of nineteen
years he was 6 ft. 4 in. tall, weighed 200 Ib. and was of extraordinary strength
and he was intelligent, a good student, and "aside from an uncontrolled
libido sexualis" had good manners. Especially noteworthy seems to me

460 PLURIGLANDULAR DISEASES

the fact that only latterly did the obesity that occurred assume the eu-
nuchoid type (as far as I can see from pictures). This is true also of the
absence of beard, and the eunuchoid hairiness. "He has practically no
beard, and except for a scant pubic growth of feminine distribution, the
skin of the trunk and extremities is practically hairless." The hair of the
head was abundant.

Also in the case described by Levi and Franchini did there occur a late
eunuchoid obesity.

The abnormal growth began in this person, who was sixty-five years old, at the age of
eight to ten years, the secondary sexual characters were apparently normally developed at
the time of puberty, there were few erections, however, and there never had existed an
especial libido. The external genitalia were normal, as was also the mental development.
He was always weak muscularly, in the last few years obesity developed, the distal parts of
the extremities showed a considerable enlargement, there existed cervicodorsal kyphosis,
in short the signs of an acromegaly that had gradually developed over a long period of
time. The epiphysial junctures were closed.

I now adduce several examples of the eunuchoid type, in which the
symptoms of deficiency on the part of the sexual glands already exerted an
influence on skeletal formation in early youth. Here belongs the giant
Charles described by Launois and Roy. In the thirtieth year of his life,
his height was 204 cm. The lower length was considerably more than the
upper length. The penis was small, the testicles were very small, and the
prostate also was small. He had had on several occasions erections, but
never ejaculations. The hairiness of the trunk was typically eunuchoid.
The epiphysial junctures were entirely open. In later life, acromegalic
features made their appearance.

A pronounced case is reported by Gushing that on account of the mon-
strosity present I shall herewith adduce; thirty-six* year-old man; he was al-
ready as a boy abnormally tall, and from the fifteenth year on grew enormously.
For ten years he has been sick and weak. At autopsy the body measured
251.5 cm., the skin is delicate, hairness of the head good, no growth of beard,
no axillary hairiness, sparse hairiness of the pubic region. The genitalia are
small, the testicles atrophied. The distal epiphysial juncture of the radius
is still open, no alimentary glycosuria. Distinct symptoms of acromegaly are
present. The sella turcica is very much enlarged (2.2 to 2.7 cm.) and the
hypophysis consists, in great part, of a cyst.

Again, in such eunuchoid giants the acromegalic alterations may be very
significant. There are also known female eunuchoid giants. As example I
adduced Lady Aama, described by Woods Hutchinson. She was about
seventeen to nineteen years old, 244 cm. tall, and trie lower length far ex-
ceeded the upper length ; hands and lower jaw were very large. The genitalia
were infantile, the mons Veneris was poorly developed, the labia majora were
flat, the clitoris was well developed and resembled a poorly developed penis.

GIGANTISM 461

»

The ovary on each side was very small, and changed into glandular masses.
The hypophysis was enlarged, the sella turcica was destroyed, the mammae
were entirely hypoplastic.

I believe that the examples I have furnished suffice to show the enormous
multiplicity of the manifestations of the pathological forms of giant growth.
The symptoms of eunuchoidism or late eunuchoidism are combined with
those of acromegaly in the most diverse ways. If we disregard, however,
the quite rare cases of pure eunuchoid gigantism, we find indeed that the mani-
festations of eunuchoidism and late eunuchoidism, are very common, while
the manifestations of acromegaly are present almost always regularly, or
that they develop later. In this connection the classification of pathological
giants of Launois and Roy is very correct, even if it is not just to the uncom-
monly numerous types. .

Pathogenesis. — If we now turn to a pathogenesis of gigantism, our
first task will be to test whether the formula of Brissaud-Meige, which also
has been adopted by Launois and Roy, is in the position to explain the mani-
fold types of gigantism. Brissaud and Meige have expressed the opinion
that gigantism is nothing other than an acromegaly beginning in early
youth, that is, before the closure of the epiphyses. A great difference be-
tween acromegaly and pathological gigantism exists, first of all, in the be-
havior of the sexual glands. I must here again point out the fundamental
difference in the relation of the glands of generation and the interstitial
glands in typical acromegaly. The first show temporary increase of their
function, but then there very commonly occurs very premature disturb-
ances or entire loss of their function, whereas the function of the interstitial
glands is rather more emphasized, or at all events, apart from very rare cases,
shows no disturbance in the course of the disease. In gigantism we see this
behavior in but a few cases. In the majority of cases the manifestations of
eunuchoidism are prominent from the beginning, or later there occur mani-
festations of late eunuchoidism. In the description of early acromegaly a
similar behavior of the sexual glands has been noted.

There cases were described in which also the interstitial glands showed dis-
turbances of their function, in this respect lending countenance to the Brissaud-
Meige' s formula. There also we learned about sure cases of acromegaly, that
came to manifestations of acromegaly while the epiphysial junctures were still
open. Increase of function of the hypophysis alone, hence, does not lead to
gigantism. We must assume in addition to it a potential tendency to growth,
that may be either proportionate (normal giants) , or as it is mostly, dispro-
portionate, partly through a preponderance of the function of the hypophysis,
partly through an insufficiency of the interstitial glands and probably also
through many other factors. While in acromegaly we certainly find a
tendency to hyperf unction and hyperplasia of other ductless glands in which,
however, always the increase in function of the hypophysis remains quite in

462 PLTJRIGLANDULAR DISEASES

the foreground, in gigantism the tendency to increase in function of the whole
ductless glandular system seems to belong quite to the essence of the disease.
It would seem that in addition to the hypophysis all the ductless glands are
involved in a predominant manner in the hyperplasia — the suprarenal cortex,
probably also the chromamn tissue, etc. How enormous the pancreas may
become is shown by the autopsies of the giants Bassoe Peter and of the Tam-
bourmajor. The pancreas of the former weighed 275 gm., that of the latter
250 gm. Also the sexual glands may be involved in this hyperplasia. In
addition to this tendency to hyperplasia there exists, however, a lability, a
ready exhaustibility of the hyperplastic ductless glandular system; this
seems to affect the most readily the sexual glands, in which degenerative
processes may be established prematurely, indeed under circumstances the
sexual glands (and especially the interstitial glands which, indeed differ from
the other ductless glands in that they attain full maturity not until the time
of puberty) may be disturbed in their development from the beginning.
Also the development of the nervous system may suffer damage from this fact.
The monstrous eunuchoid giants are the most deficient mentally. In addi-
tion to the sexual glands the other ductless glands mostly rapidly show signs
of decay. The frequency of diabetes in youthful giants is known. In
the great decrepitude and muscular weakness perhaps there is involved a
degeneration of the chromaffin tissue. Even in the hypophysis, such de-
generative processes frequently occur, if the individuals attain a high enough
age. I refer to the case of Huchard and Launois in which the hypophysis
was found to be sclerotic, or to that of Gushing in which the hypophysis
was in great part converted into a cyst. How rapidly the decay can enter
in just these monstrous giants is shown by numerous cases in the literature.
The enormous muscular power of which these individuals were wont to be so
proud gives place in a few years to a great weakness. The ductless glandular
system has exhausted itself and the organism fades rapidly like a plant
driven to rapid growth by artificial means. Mostly the invalidism is rapidly
made an end to by an intercurrent disease. Woods Hutchinson tells of
eight giants that died on the average in their twenty-first year of life.

Investigations of the respiratory metabolism of giants, as well in the
time of bloom as in that of decay, would be very important. I do not know
of any of them. With regard to the other metabolism investigations, there
are only the statements of Lem and Franchini, who in one case found increase
of the elimination of amino-acids, ammonia, and neutral sulphur.

On the basis of what has been said above, I would assume in gigantism
an abnormal mapping-out [Anlage] of the whole ductless glandular system,
and would not, as have other authors, simply include it in the chapter on
acromegaly. We know indeed that there are other forms of gigantism
setting in in early life in which not the hypophysis, but other ductless glands
(the epiphysis, the suprarenal cortex, the sexual glands) occupy the chief

GIGANTISM 463

role in the pathogenesis. In such cases there may indeed appear even
simultaneous manifestations of hypophysial insufficiency (confer the case
of Raymond and Claude}. But as I mentioned already at the beginning
the conception does not seem to me established as yet. I must leave open
the question as to whether the hyperplastic mapping out of the entire duct-
less glandular system is only a partial phenomenon of an abnormal mapping
out of the entire organism. We know indeed of a gigantism of individual
extremity masses. I refer to the communications of Fischer, Manasse,
Wiedenmann, Grunfeld, et al. We cannot hold the ductless glandular system
responsible for such an abnormal growth tendency, even though there are
found, also not rarely, certain anomalies of this system, e.g., cryptorchidism
on the same side.

Addendum

Parhon and Parhon would add paralysis agitans to the list of pluriglan-
dular diseases on the strength of certain Abderhalden tests in which the duct-
less glandular extracts in general, but especially those of thyroids and para-
thyroids, reacted positive to the sera of paralysis agitans patients.

REFERENCE

Parhon (C.S.), and Parhon (M.) : Untersuchungun iiber die Abderhaldensche Reaktion
bei der Parkinsonschen Krankheit. Fermentforschung, Vol. i, No. 3., p. 311-314.

CHAPTER XII

VEGETATIVE DISTURBANCES, NOT DIRECTLY DEPENDENT ON
DISEASES OF THE DUCTLESS GLANDS

The words "vegetative disturbance" [Vegetationstorung] to my knowl-
edge originated with Kundrat. By them we understand any inhibition of de-
velopment. Since the time it was known that the growth, and especially
the normal development of the organism was guaranteed only by a normal
development of the ductless glandular system, modern investigation has
been directed toward seeking the cause of the different vegetative disturb-
ances in the ductless glandular system. In the foregoing chapters an entire
series of vegetative disturbances were comprehended, which to-day we are
justified in regarding as referable to a functional disturbance of individual
ductless glands. It seems important for the following exposition, again
briefly to sketch what these are:

1 . Absence of the thyroid leads to dwarfism ; in this is found characteristic
disturbances of ossification, consisting in a high-grade remaining behind in
development of the bone nuclei, and in the closure of the epiphyses, further
in a disturbance in development of the bone marrow; what, however, has
already been formed of the bones is of abnormal hardness; further there are
found disturbances in the dentition, and in development of the central
nervous system, whereby the development of the intelligence suffers.
Further there are found the characteristic myxedematous alterations of the
skin, and disturbances in the development of the genitalia.

2. The vegetative disturbances in endemic cretinism is not dependent
alone on the goitrous degeneration of the thyroid gland. It is far more
likely that the deleterious agent acts also directly on the central nervous
system and on other ductless glands, for instance, the hypophysis. Thereby
the vegetative disturbances are extremely manifold, the individuals remain
very much behind in growth, but the disturbance in ossification is not
disproportionate; one time the developmental disturbances of the central
nervous system may stand in the foreground, another time the inhibition in
growth, and another time perhaps the disturbances in the development of
the hypophysis.

3. Pronounced inhibition of development is found also in diseases of the
hypophysis that develop in early youth. In this case there occur, at least
in a suggestive manner, eunuchoid dimensions on account of a prominent
developmental inhibition of the sexual glands, and further there occurs
eunuchoid distribution of fat. Disturbances in the development of the bone

464

INFANTILISM 465

nuclei and of the epiphysial junctures occur distinctly only in most severe
cases. The intelligence develops normal, although these individuals show
the characteristic temperamental attitude.

4. Again, disturbances in the development of the suprarenal cortices per-
haps also lead to definite vegetative disturbances; very little clearness as to
this point exists, however.

5. Isolated disturbances in the development of the sexual glands leads to
eunuchoidism with characteristic distribution of fat, characteristic dimensions
of the skeletons, remaining open of the epiphysial junctures, especially those
that close latest under normal conditions, and a characteristic psychic
attitude with normal development of the intelligence.

There remains now a group of vegetative disturbances that of late have
frequently been brought into association with the diseases of the ductless
glands. In some of these the relation to the ductless glandular system is not
yet sure, in others, the disturbances on the part of the ductless glands consti-
tute only one component of the clinical picture. Finally in others I would
deny the connection. In this great group of vegetative disturbances I would
include true infantilism, true dwarfism, chondrodystrophy, rachitic dwarfism,
and Mongolism. In the exposition of each disease, its relation to the
ductless glandular system will be especially considered. We shall not enter
further into the subject of dwarfism in microcephalus and porencephalus.
I have described dwarfism with hydrocephalus in the chapter on hypophysial
dystrophy.

I. INFANTILISM

Historical. — The first cases of human beings who for their life time re-
mained in a childish stage of development [pathologically] were described
by Dancel and Baillarger. The case of Dancel was that of a woman twenty-
four years old who was 94 cm. tall and showed a mental and physical develop-
ment of a four- to five-year-old child. Lasegue coined the name infantilism
[-us]. He understood by it a condition of persistence in the adult of the psy-
chical and physical characteristics of a child. The first exact description was
made by Lorain. He describes a form of infantilism that he describes as
" Characterisee par la debilite, la gracilite et la petitesse du corps, par une
sorte d'arret de developpement, qui porterait plutot sur la masse de 1'individu
que sur un appareil speciale: en un mot des subjets atteint d'une juvenilite
persistente qui retarde indefiniment chez eux I'establissement integral de
la puberite." Lorain and his pupil Faneau de la Cour already stated that
the different harmful influences that may affect the juvenile organism
may lead to infantilism.

The 'question has been especially discussed in the French and Italian
literature, ever since Brissaud set forth a form of infantilism that he referred
to as insufficiency of the thyroid gland in child life. Brissaud considers that

3°

466 VEGETATIVE DISTURBANCES

the type Lorain constitutes a dystrophic condition, and is brought about and
maintained by a chronic congenital or inherited disease during the period of
growth.

The views of Brissaud have been adopted in recent time by Bauer. Bauer
regards only the type Brissaud as true infantilism and separates all other
forms from the type Brissaud as "chetivisme." Hertoghe and Ausset-
Breton go still further than Brissaud; they see in all forms of infantilism an
expression of a congenital damaging of the function of the thyroid gland and
thus seek to establish all forms on a uniform basis.

Ferranini was the first to oppose this view. Ferranini separates the
two forms of infantilism, and regard the type Lorain as the sequel of a
developmental deformity, and the type Brissaud as the sequel to the stand-
still of development. Ferranini sets forward the significance of the con-
genital or early inherited heart defect in the pathogenesis of infantilism
(cardiodystrophic infantilism). Carre and Gilbert and Rathery hold similar
views. In recent time, especially E. Levi has opposed the views of Brissaud,
in that he mentions that not all the true infantilisms are to be referred to an
insufficiency of the thyroid gland. The type Lorain should also be regarded
as true infantilism. Before this Sante de Sanctis had already again sharply
separated the two types and emphasized the significance of various factors for
the genesis of the type Lorain, factors such as hypoplasia of the vessels,
chlorosis, disposition to tuberculosis, hereditary syphilis, malaria acquired
in early youth, pellagra of the parents (Agostini), etc.; furthermore, de
Sanctis separated the true form of psychic infantilism from idiocy. Then,
too, de Sanctis was the first to attempt to explain the genesis of the type
Lorain through alterations in the ductless glandular system. The delay in
the physical and psychical development is never the result of isolated
alteration of an individual ductless gland, but is produced by a "deviation
de la fonction harmonique formative-rjrotectrice de toute les glandes a
secretion interne." In an interesting study, R. Anton has described the
psychic side of infantilism. General infantilism was defined by Anton as
"a developmental disturbance, that causes the entire organism to remain
behind at the child type, but prevents the reproduction of the individual in
the sense of this species. Thereby not only the physical earmarks, but often
also the psychical characteristics of the child persist."

With general infantilism Anton includes:

A. The infantilism with myxedema and cretinism.

B. Mongolism.

C. Infantilism through absence or atrophy of the genitalia.

D. Infantilism with primary lesion of the visceral glands, especially the
suprarenals, the thymus gland, and the pancreas.

E. Infantilismus dystrophicus, with the following etiological variation:
Infantilism in vascular aplasia.

INFANTILISM 467

in primary brain lesions, unilateral or bilateral;

in hereditary syphilis;

in alcoholism or other poisonings (lead, mercury, etc.) of the parents;

in other diseases and metabolic disturbances that are acquired early,
such as tuberculosis, chlorosis, and cardiac defects;

through deformities due to bad hygienic surroundings and to insuffi-
cient nourishing of the child.

Of partial infantilism, I mention especially the infantilism consisting in
an atrophy of the genitalia, and the pure psychical infantilism.

I would finally especially emphasize here the excellent studies of di
Gasperos. Here we find five cases described in detail, which, as we shall see
later, are fine examples of true infantilism. Di Gasperos handles with special
care the psychical side of the problem.

Schuller divides infantilism into two forms: He distinguishes a dys-
trophic form conditioned by hereditary diseases, or diseases acquired in
early youth, and a form whose pathogenesis is seen to depend on a lesion of a
definite ductless gland (thyroid, hypophysis, etc.).

The regular undevelopment of the genitals in the type described by Lorain
has induced many authors to term "infantilism" the most varying patho-
logic states in which the genitalia remain more or less hypoplastic. Thus
we find in the literature numerous cases of true gigantism published under
the title infantilism plus gigantism. Further we find published numerous
cases of infantilism whose description would correspond to that which in a
former chapter we have regarded as eunuchoids, or cases that at all events
must be regarded as transition forms between eunuchoids and true in-
fantiles. This is especially the case in the new expositions of the subject
by Peretz and by Pende. In the work of Peretz we find nearly all the duct-
less glandular diseases associated with developmental disturbances classified
as infantilism. Even infantile features are ascribed to hypergenitalism.
Candy terms "infantilism reversif ou tardif" cases in which after com-
pleted development a retrogression of the genitalia and the secondary
sexual characters begins (confer "late eunuchoidism," Chapter X). The
ductless glandular theory has found an especially ardent advocate in Pende,
who assumes as the cause of infantilism a disease of the ductless glandular
system. He bluntly calls infantilism a disease of the ductless glandular
system, and arrays himself against the opinions advocated by Anton and
others, that there is also an infantilism that is dystrophic ectoglandular,
and independent of a disease of the endocrine glands.

We see then, that there is hardly an idea in the medical literature con-
cerning which there is more confusion than that pertaining to infantilism.

The name infantilism can surely readily give occasion to misunder-
standings because in any kind of inhibition of development, infantile features
may be retained. I believe, however, that a clear definition is possible if we

468

VEGETATIVE DISTURBANCES

limit ourself to the thought that the childish organism is characterized not
only by the still undeveloped genitalia and the childish mentality, but, as
already Breus and Kolisko mention, by definite childish dimensions.

Definition.— We may therefore
briefly define a pure infantilism as a
standing still at the infantile stages of
development, considering especially the
following factors: the genitalia and the
vita sexualis remain undeveloped, or de-
velop deficiently; and the same is true
of the secondary sexual characters; the
involution of the lymphatic apparatus is
deficient, the growth is deficient, ossifi-
cation, that is, the appearance of the
bone-nuclei and the closure of the epiphy-
ses is delayed, and the childish di-
mensions of the body are retained
wholly or in part ; that is the lower length
of the body equals the upper length or,
what is commoner, exceeds it only a
little, the form of the pelvis is neither
[of the] masculine or feminine [type],
but infantile, and finally the psyche,
remains behind [in development]. Such
individuals show throughout no gross
defect in intelligence, but their minds
remain childish.

Important for the definition of in-
fantilism are the following considera-
tions, which serve to render precise the
position of the ductless glandular sys-
tem in the pathogenesis of infantilism.
If the infantilism comes about through
a standstill of the entire organism at a
child stage of development, then it is
intelligible that also the sexual glands
do not develop further. Up to the
present however we have not sufficiently

FIG. 8i.-True infantilism (Observation LVI). considered that the sexual glands occupy

• a separate position in the ductless glandu-
lar system, in that, though they functionate from early youth and influence
the development of the organism, yet they attain their complete maturity
only at the age of puberty; the other ductless glands are already fully de-

INFANTILISM 469

veloped in the new-born. At the same time, the remaining behind of the
development of the sexual glands in infantilism is only a subordinate symp-
tom of the entire clinical picture. We therefore do not find in infantilism
such profound developmental disturbances as in eunuchoidism. The
genitalia are quite childish and the sexual glands functionate like the sexual
glands of children, while in eunuchoidism the sexual glands eventually do
not functionate at all or slight islands of the sexual gland tissue have
developed further, corresponding with the age, whereby there occurs an en-
tirely insufficient function, a function that, on account of the faulty develop-
ment of the accessory apparatus, is lacking; thus we see that the sexual glands
onnfantilism or the infantile genitalia are essentially different from those of
eunuchoidism.

Thus if true infantilism comers about through the standing-still of the
whole organism at a juvenile stage of development, the ductless glandular
system remains Justus childish as the skeleton or the hematopoietic apparatus
or the central nervous system; therefore the inhibition of the ductless glandu-
lar system is only coordinated with that of the entire organism; as, if these
premises hold good, we are not justified in classing infantilism with the
primary ductless glandular diseases; on the other hand, it does not then seem
to me justifiable to designate as infantilism sharply delimited clinical pictures
that depend on a primary disease or developmental disturbance of a definite
ductless gland, pictures such as juvenile myxedema, juvenile hypophysial
dystrophy, or eunuchoidism.

Before I enter into the symptomatology of true infantilism and the basis
of the view just expressed, I would like to report some typical cases of true

infantilism.

«

Observation LVI. — J. H., twenty years old. At the age of seven years, commotio
cerebri through fall from a tree. Present manifestations of a benign pyloric stenosis with
dilatation of the stomach and hypersecretion. For one-half year tetany.

Total length, 142^ cm.; lower length, 69 cm.; span width, 143 cm.

The patient looks like a boy thirteen years old. Facial expression and psychical at-
titude entirely childish. Abundance of hair on head. Beard hair absent, hair in the
axillae and on the mons Veneris absent, soft downy hair on face. Penis small. Both
testicles small. No libido, rarely weak erections which have appeared only recently, no
ejaculations. The epiphysial junctures of the skeleton of the hand are almost all still open.
For two years tetany, at the close of which slight manifestations of hyperthyrosis.

Observation LVII. — W. K., eight years old. Entrance into the clinic Nov., 1910. At
the age of four years gradual deterioration of the gait. The child also remained backward
mentally, and repeated for the third time his first class in school.

Typical progressive muscular atrophy, the description of which we may omit here.

Typical length, 117 cm. Circumference of head, 51 cm. Circumference of breast, 57
cm. Circumference of abdomen, 55 cm. From coracoid process to olecranon 25.5 cm.
From iliac spine to internal malleolus 56 cm.

Both lobes of the thyroid distinctly palpable.

The tongue is large, always is seen to a certain extent between the teeth. Root of

470

VEGETATIVE DISTURBANCES

nose not retracted, skin everywhere elastic, feels moist. Cryptorchidism. Pilocarpine
o.oi gm. elicits minimal sweats, minimal salivation.

o.ooi gm. adrenalin shows strong action on the pulse and on the blood-pressure, distinct
diuretic action, no glycosuria.

Leucocytes, 9400, of which:

Neutrophiles, 55.1 per cent.

Large mononuclears, 8.3 per cent.

Lymphocytes, 33.3 per cent.

Eosinophiles, 3.3 per cent.

FIG. 82. — X-ray picture of the hand in true infantilism (Observation LVI).
closure of the epiphysial junctures.

Delav of the

From Nov. 14 on, one thyroidin tablet a day. On Dec. 18, o.ooi gm. adrenalin.
Strong action on the pulse and blood-pressure; now 1.43 gm. sugar in the urine.

Under the influence of the thyroidin medication which now has lasted about six weeks,
the pulse increases hardly at all, no manifestations of intoxication.

On entrance the X-ray examination of the skeleton of the hand showed the following:
The distal epiphysis of the ulna, which should be deposited normally at seventh year, is
here entirely absent.

The bone nuclei of the skeleton of the wrist are abnormally small.

INFANTILISM

471

At the end of a six weeks' thyroidin medication X-ray examination was again made,
without showing any change worthy of mention.

In this case we are dealing with a typical progressive muscular atrophy,
setting in early and associated with an inhibition of development. This is
both physical (abnormal smallness, cryptorchidism, etc.) and mental. The
large tongue gives rise to a thought of myxedema, but on careful searching
no other signs of myxedema were found. Six
weeks of the thyroidin medication causes no
acceleration of ossification.

Observation LVIII. — R. R., twenty years old.
Entered May, 1912. Several cases of tuberculosis
in the family. The girl learned to walk only three
years ago. Since childhood conjunctivitis eczema-
tosa. From youth she has remained behind in
growth and in mental development; at present she
has the psyche of an eight- to ten-year-old child.
Although, on account of her eyes, she never went
to school, she can read and write and takes an in-
terest in household affairs.

127 cm. tall. Span width, 128 cm. Lower length
(ant. superior spine to ext. malleolus) 63^ cm.

Very sparse growth of hair in axillae and on the
genitalia.

Adenoids in nasopharyngeal space. Glands of
the neck, the elbow, and the groins somewhat en-
larged. Slight horizontal furrowing of the teeth.
Since sabre-sheath form of the bones, but otherwise
no signs of severe rachitis.

* The mammae on both sides developed distinctly,
little glandular substance palpable. First menstrua-
tion two days ago, weak.

Leucocytes, 7700, of which:

Neutrophiles, 61 per cent.

Lymphocytes, 32 per cent.

Large mononuclear, 5 per cent.

Eosinophiles, 2 per cent.

X-ray examination. Sella turcica normal, no
peribronchial lymph glands.

Coarse nystagmus on. both sides, the eye grounds
show medullated nerve fibers, otherwise they are
normal.

X-ray examination of the skeleton of the hand.
The ossification corresponds to about that of a fif-
teen- to sixteen-year-old individual.

Observation LIX. — B. B., fourteen years old. Entered May, 1912. It was stated that
in the first year the head and abdomen were very large, later good development, could
walk at two years, speak at three. Remaining behind in corporeal development, es-
pecially since the first year of life. Mental development fairly good. Psyche childish.

FIG. 83. — Infantilism in progressive
muscular atrophy.

472

VEGETATIVE DISTURBANCES

Length of body, in cm., lower length, 62 cm., span breadth, 113.5 cm-> length of arm,
38 cm.

Slender, weakly child, thin, looks like a child eight years old. Pallid. The head, rela-
tively large (circumference, 54 cm.). Frontal protuberances somewhat prominent.

Adenoid vegetations in nasopharyngeal space, tonsils enlarged; in the neck, in the
groins, everywhere, are palpable glands up to the size of a bean.

Distinct parallel furrows on the incisor teeth of the lower jaw. Slight form of pectus

carinatus. Some lordosis of the lumbar spine.
Slight affection of the apices of the lungs on both
sides.

Erythrocytes, 2,800,000,
Hemoglobin, 60 per cent.
Leucocytes, 10,400, of which:
Neutrophiles, 52.0 per cent.
Lymphocytes, 41.1 per cent. •
Large mononuclears, 2.5 per cent.
Eosinophiles, 4.0 per cent.
Mast cells, 0.5 per cent.

Slight poikilocytosis. X-ray examination. Vault
of cranium thin. Sella turcica normal. No basis for
thymus-rest. Right divergent strabismus, both pa-
pillae somewhat Washed out and pale, otherwise eye
grounds and vision normal.

X-ray examination of the hand; the skeleton of
the hand about corresponds with that of a ten-yea"r-
old boy.

Symptomatology. — Ordinarily the dis-
turbance in growth in true infantilism is very
significant. .The skeleton shows a reten-
tion of the childish dimensions, that is the
lower length does not exceed the upper
length, or exceeds it only a little. The head
is relatively large, the bones are slender, the
navel is low, the pelvis is neither masculine
nor feminine, but infantile. The occurrence
of the bone-nuclei and the closures of epiphy-
ses are delayed.

The genitalia remain at a child's stage
of development, they have the size and di-
mensions of a child's genitalia; we are not
dealing here with a falling away of the
genital function, but with a function which
corresponds with that of the years of child-
hood. Correspondingly there is a remaining behind of the secondary sexual
characters. Also the vita sexualis is that of a child.

The lymphatic apparatus shows deficient involution. We find there-
fore commonly a relatively great count of lymphocytes in the blood, on

FIG. 84. — Infantilism (Observation
LIX).

INFANTILISM 473

which account there is not necessarily present a status lymphaticus, al-
though it is not improbable that the damaging that produces the infantilism
also often leads to a status lymphaticus. Moreover, the anemia that is not
rarely found in infantilism can be regarded as a direct consequence of this
deleterious influence.

The hair of the head is usually abundant, the hair on the trunk is usually
absent, but not always entirely absent. The hairiness of the pubis and the
perineum is usually, very' sparse or is absent. The same holds good for the
hak in the axillae.

The internal organs are as a rule normal, so far as illnesses, occurring in
early years, have not led them to infantilism. The vascular system seems
in the most cases to show a slight grade of hypoplasia. Also the blood-
pressure often lies on' the lower borders of the normal.

I am not aware as to the existence of investigations as to the respira-
tory metabolism. In the cases that I investigated the tolerance limits for
carbohydrates approximate the normal. Functional testing of the vegeta-
tive nervous system sometimes showed slight diminution of the excitability.
Not much importance can be attached to this.

Characteristic for true infantilism is the retention of the childish features.
We find the childish logic, the childish instinct for imitating, a certain anx-
iety and non-independence. For example the case reported by me (Observa-
tion LVI), acted like a boy when at his visits he was scolded for not having
collected his urine. By the grown people of the clinic he was treated like
a child. Ziehen points out in this regard that in infantilism the individual-
izing association characteristic of children is retained. Also the psychical
inhibitory apparatus is only deficiently developed. Di Gas per o attaches
especial value to the retention of the childish ideas of value, and of the sug-
gestibility of children. A careful description of the psyche of infantilism is
furnished by G. Anton. "The mimicry, gesticulations, physiognomy, cor-
respond to childish age phases, as do the pitch and the modulation of the
voice. For the most part there is absent the childish gaiety and freedom,
often there comes to expression feelings of insufficiency, timidity, and peevish-
ness." For the most part the attention may be readily drawn, but is readily
deviable. Constant concentration is not to be attained. Complicated sense
impressions produce a feeling of unpleasantness. " Often therefore they have
acquired a routine in which complicated impressions and tasks are slipped
by; their selection tends to the primitive, the simple." I have attached
value to reproducing the description of Anton, because it is enough to show
that the psyche of persons with infantilism is essentially different from that
of eunuchoids.

Forms.— According to the intensity of the noxious agent that is to
blame for infantilism, do different forms of this condition occur, from tin-
quite excessive forms which in their corporeal and mental development

474 VEGETATIVE DISTURBANCES

remain little children all their lives, to the poorly pronounced formes frustes.
Very important for the differentiation of the forms is also the consideration
of the phase of development at which the noxus set in. "Every age period
has its infantilism" (di Gasperd). When the noxus sets in relatively late
.there results a form which has been termed "juvenilism." In this the skele-
ton is no longer purely childish. The genitalia are relatively well developed,
etc. We find very commonly the juvenile form of psychic infantilism in
ordinary life (Anton). According to whether the inhibition of develop-
ment has affected the more the skeleton, the psyche, or the genitalia, etc.,
we may speak of partial infantilism. An instructive example of a juvenil-
ism furnished by a case briefly reported by A pert and Rouillard. In a
thirty-eight-year-old man who had developed normally up to his sixteenth
year, there occurred in the wake of a typhoid fever a remaining behind in
corporeal and sexual respects, at this developmental period. There were
present no signs of eunuchoidism. A pert and Rouillard attribute this in-
hibition in development to the thyroid gland. As no signs of myxedema
were present, I would dissent from this view.

The excessive form of infantilism might well coincide with the hypo-
plastic dwarf of Breuss and Kolisko. Breuss and Kolisko indeed state that
in the hypoplastic dwarf only the height is childish, the other dimensions
only in part childish. Probably in such individuals the disturbance Mas its
onset in fetal life or in early youth.

Etiology. — The etiology of infantilism is very manifold. The most
divergent toxic and infectious deleterious agents are blamed. Alcoholism,
saturnism, nicotine-poisoning — agents that may also have affected the
parents — further malaria, pellagra, syphilis (a fine example is furnished by
Perelz), tuberculosis, abdominal typhoid in early youth (see the case of
A pert and Rouillard); polyserositis (v. Neusser), deficient development of the
cardiovascular apparatus (Hb'dlmoser has communicated "a pronounced
pertinent case that was only 125 cm. tall with a lower length of 66 cm.),
and further cardiac defects acquired in early youth (Gilbert and Rathery)
(and in this nanisme cardiaque the genital disturbance may eventually be-
come less pronounced) , and the traumata that may affect the children in early
youth (the case J. H., Observation LVI, suffered a commotio cerebri at the
age of seven years) . Joffroy described two cases of paralysis generale juvenile
with pronounced infantilism. I have reported such a case above (see
Observation LVII, W), further it has been supposed that unfavorable condi-
tions of life, and conditions of nourishment in early life are causal factors,
and also disturbances of nutrition, chronic diarrheas, etc., existing since
early life (see later concerning pancreatic infantilism). The position of
the cases with hydrocephalus does not seem to me assured as yet, in these
cases consideration must be given especially to signs of hypophysial in-
sufficiency, especially the distribution of fat.

INFANTILISM 475

Also the liver diseases acquired in early life may lead to infantilism.
Lereboullet described a case in which he ascribed hypertrophic biliary cirrhosis
of the liver as the cause of the infantilism. The following case also perhaps
belongs in this group.

Observation LX. — G. A., twenty-one years old. Entered Nov., 1909. Since early-
youth strong imbiber of alcoholic liquors. In 1906, he fell in the water, after which
pneumonia, later pleurisy. Since that time has not grown much. For about two
years, swelling of the abdomen, edema of the legs, and enlargement of the liver. The
ascites subsided, the liver remained large and painful.

According to his statement, for about three years after the time of puberty the patient
had libido and erections, that later ceased. Never pollutions, never cohabitation.

Very considerably enlarged liver, painful to pressure, pole of the spleen palpable,
heart dullness somewhat enlarged to left and to the right. Extra-systoles, no ascites,
no albumin.

The physiognomy is juvenile, no beard, no axillary hair, sparse growth on mons Ven-
eris. Testicles and penis of normal size.

Differential Diagnosis. — If we confine ourselves to the symptoms just
described, the delimitation of true infantilism from the diseases of the ductless
glands associated with infantile features is not difficult.

And yet on closer examination of the individual cases described under the
same infantilism we find that very frequently later authors confuse in-
fantilism with diseases of the ductless glands. Thus I would hold that in the
communication of Richon and Jeandelize the first of the cases described was
probably an eunuchoid, the second a cretinoid, and the third perhaps a
true case of infantilism. Another example: In the communication of E.
Levi, I regard the first case as one of hypophysial dystrophy, the second is
difficult to classify,' the third is perhaps a typical case of true infantilism.

I would detail somewhat more exactly the most important differential
diagnostic features:

Let us begin with the delimitation from infantile myxedema. In the
French school two types of infantilism are distinguished, the Lorain's type,
which on the whole is true infantilism, and second, myxinfantilism. When
however we go back to Brissaud's original publication, we find that the char-
acterization of myxinfantilism is very inexact. Here begins an error that
has continued until the present and that may be regarded as the chief
cause of the prevailing confusion. Brissaud describes myxinfantilism in the
following manner: The face is round, the lips are thick, the nose small, the
cheeks are thick, the genitalia infantile, the thyroid gland small, the ossifica-
tion is delayed, dentition is retarded or fails, the neck is short, and there
often exists lordosis of the lumbar spine; among the individuals belonging to
this type there are also those whose health may be very good. Brissaud held
the opinion that in the majority of cases myxinfantilism is not an etat morbide
and he refers also partial infantilism to an insufficiency of the thyroid
gland. As an example he quotes the cases of two sisters of whom the

476 VEGETATIVE DISTURBANCES

elder looked to be about three years younger than the other and showed
an entirely childish habitus. He also quotes the case of a boy of sixteen
years, who looked as if he were eleven years old, and whose psychical attri-
butes corresponded with that of the latter age. At the age of ten years of life
he had sustained an inflammation of the throat and a swelling of all lymph
glands; Brissaud here regards it as established that at that time the thyroid
gland was affected. The third case that Brissaud cites is, on account of the
inaccurate description, hard to classify. I need hardly detail more intimately
that the belonging of the cases cited to infantile myxedema is at least un-
certain, even unlikely. A priori we may withdraw from consideration, how-
ever, the classification on the etiological basis, according to Brissaud' s assump-
tion that a severe disturbance of development could depend on a thyroid
insufficiency without other symptoms of myxedema being present. The in-
hibition of ossification alone, on which some stress has been laid, is no certain
sign of thyroid insufficiency. Meige and Allard point out, it is true, as the
foundation of this assumption, a case of typical Lorain's infantilism in which
ossification had advanced much further than in a case of myxinfantilism.
E. Levi showed, however, that in the type Lorain the ossification is much de-
layed as compared with that of a normal individual of this age. It is certain
that also in true infantilism there exists a certain inhibition of ossification,
and that even a certain acceleration of ossification may follow thyroid gland
therapy. But this does not furnish a certain demonstration of the thyrogenic
pathogenesis of such cases, for, as Ferranini already mentions, the stimulation
of the metabolism through the administration of the thyroid gland may help
somewhat. To-day, when the manifestations of thyroid gland insufficiency
in childhood are so carefully studied, we would require unconditionally sure
signs of childish myxedema if we were to call a case myxinfantilism. The
delimitation of true infantilism from severe forms of childish myxedema is
indeed readily made. The mitigated forms may be distinguished from it by
the presence of myxedematous alterations of the skin, thickening of the
tongue and lips, the umbilical hernia, disturbances of intelligence, apathy, and
especially the result of thyroid gland therapy.

Naturally there also occur mixed cases. Signs of thyroid gland insuf-
ficiency may be added to those of true infantilism, temporarily or perma-
nently. Perhaps such a case is described by Dupre and Pagniez. Here a
myxedema began at the fifteenth year of life in a case of true infantilism.

Again, the delimitation of true infantilism from eunuchoidism is not diffi-
cult in most cases. It is quite unintelligible how Peritz can regard eunuchoid-
ism as the purest form of infantilism. In eunuchoidism we have an isolated
severe disturbance of the development of the sexual glands, and here the
analogy with eunuchoidism ends, the dimensioning of the body [in eunu-
choidism] has nothing in common with the childish dimensions. (There is
significant predominance of the length of the extremities and small head

INFANTILISM

477

[in eunuchoidism].) Also the psyche of typical eunuchoids is not childish
throughout. The feeling of absent virility here often leads to timidity and
eventually to deep mental depression, while the childish features [of the dis-
ease] are absent. Woljf, just as has Peritz, has spoken against the designation
eunuchoid, with incorrectness. Of the four cases that Woljf communicates,
case 3 probably belongs to true dwarfism, associated with genital disturbance
(Paltaufs type). He is certainly not an eunuchoid, but a mixed form be-
tween true dwarfism and infantilism. The other three cases are however
typical infantilism, distinguished from true eunu-
choids by their childish psyche and by the pro-
portioning of their bodies.

The delimitation of true infantilism from
typical juvenile hypophysial dystrophy is easy.
In this too is found the disturbance in growth,
but to the disturbance is added the typical dis-
tribution of. fat, and the disturbance of develop-
ment of the genitalia is much more severe and is
eventually retrogressive. There are also present
symptoms of increased intracranial pressure. I
would here point out, as I have already in the
chapter on -the hypophysis, that it is quite un-
justifiable to refer off-hand to the hypophysis a
disturbance of growth, if other manifestations of
hypophysial insufficiency are not otherwise pres-
ent. Aschner has described a sixteen-year-old
dwarf girl, 132 cm. tall; the ossification and den-
tition were delayed, her proportions were childish,
and psychically and intellectually she was child-
ish. She became pregnant in consequence of a
rape. This indeed does not speak much against
existing infantilism of the genitalia, as under cir-
cumstances children may become pregnant before
the onset of menstruation. Aschner rejects the
expression infantilism as indefinite, and regards
the cause of the disturbance of growth as hypo-
physial without furnishing any evidence for his
opinion. I regard this case as true infantilism or
as a hypoplastic dwarf.

Naturally there are numerous cases that con-
stitute transitional cases between true infantilism and the hypophysial or
eunuchoid form of dystrophia adiposo-genitalis. As example I cite the
following:

Observation LXI. — B. A., sixteen years old; entered the clinic February, 1911. Father

FIG. 85. — Mixed form between
true infantilism and dystrophia
adiposo-genitalis.

478 VEGETATIVE DISTURBANCES

dead. Moher had had lues before the child's birth. Wassermann reaction is still posi-
tive. The boy, too, gives a positive Wassermann. The boy learned to speak and walk as
late as three years old. At the age of eight, a fall from a second story. Unconsciousness
for ten minutes, and, according to statements, no after effects.

The boy is small, length of body 142.5 cm. Lower length 82% cm. Psyche
childish, corresponding to that of a boy thirteen years old.

Slight sinking-in of the bridge of the nose: Hiitchinson's teeth. No hair at all in the
axilla and on the pubis. On the breasts slight collections of fat, collection of fat on the
mons Veneris. Penis very small, testicle small, in the scrotum on both sides.

Scoliosis of the thoracic spine to the left; left pupil twice the size of the right; both fail
to react to light, patellar and Achilles reflexes very lively. Hyperesthesia of the whole left
side of the body, sharply cut off at the median line. No other nervous condition found.
Fundus normal; to X-ray examination sella turcica normal.

The epiphysial joints of the hand-skeleton are wide open, and the sesamoid bones as yet
show no bone-nuclei.

Diagnosis. — Infantilism + dystrophia of adiposo-genitalis of a slight grade, in heredi-
tary lues.

In this case of hereditary lues the excess of the lower length over the upper
length militates against pure infantilism. Further, the eunuchoid distri-
bution of fat is plainly indicated. The developmental disturbance of
the sexual glands is somewhat more pronounced, and is perhaps of hypophysial
origin (congenital lues, different symptoms on the part of the nervous
system); on the other hand these symptoms are slight in comparison' with
the inhibition of growth, and the psyche is decisively childish.

Just a few words concerning the so-called pancreatic infantilism. Bram-
well and later Rentoul have described such cases. In the case of Rentoul
we are dealing with a girl eighteen years old, who from youth, suffered with
diarrheas (fat stools?). She grew slowly up to the eleventh year, and then,
with regard to growth, remained at a standstill to the age of eighteen. She
looked like an eight-year-old girl. The stools improved very much on the
administration of pancreatin; she now increased rapidly in weight and grew in
four months about 2 in. I do not regard as appropriate the term "pancre-
atic infantilism." Thereby we might be induced to attribute infantilism to a
disturbance of the internal secretion of the pancreas, although in these
cases we may be dealing with true infantilism brought about through
nutritional disturbances. When the nutritional disturbance improves, the
retardation of the development may in part be mitigated. Disturbance
of the internal secretion of the pancreas does not lead as far as is known
to infantilism. Youthful diabetics do not show infantile features. In several
cases of juvenile diabetes I have convinced myself that ossification does
not remain behind.

The vegetational disturbances in early childhood through damaging of
the suprarenal cortex are as yet too little investigated that we can delimit
them from infantilism. I refer to the chapter on this subject. Apparently
hypoplasia of the chromaffin tissue likewise does not lead to true infantilism.

INFANTILISM 479

Probably such cases belong to the so-called hypoplastics of Bartels or to
true status lymphaticus.

Pathogenesis. — As I already mentioned at the beginning, the tendency
is coming more and more to the fore to regard the cause of infantilism as a
disturbance of the ductless glands, or as a disturbance of ductless gland-
ular correlations; the disturbances of the correlations is a favorite modern
catchword. This opinion I cannot share. I regard true infantilism as the
vegetative disturbance dependent on an inhibition of development of the
whole organism. But the developmental retardation of the ductless
glands is coordinated with that of the entire organism. Hence there is
found no disturbance of correlation among the ductless glands, but a func-
tion of them graduated for an organism that remains childish, a function
fully suited for the childish conditions. In true infantilism, also the sexual
glands functionate — for signs of eunuchoidism are absent — but they function-
ate like those of children. According as the damage has occurred in the
fetal, the infantile, or the juvenile organism, do there occur fetalism, in-
fantilism, or juvenilism.

A damaging that in youth acts electively on the ductless glandular system,
and injures it severely must, according to my view, lead to a vegetational
disturbance that is similar to multiple ductless glandular sclerosis. It
would condition cachexia and premature senility, but not infantilism.

The conception of infantilism agrees with that of Anton, who rules out
dystrophic -infantilism from the true ductless glandular diseases. The
difference consists only in the fact that I limit the idea of infantilism still
more and do not class with it the true ductless glandular diseases of childhood.

I need hardly mention again that this view holds only for the typical
forms of infantilism. There are perhaps as many transitional forms as
typical forms that pass over into the ductless glandular diseases. These
transitional forms may exist between infantilism and various other diseases —
hypophysial or eunuchoid dystrophia adiposo-genitalis, or pronounced
status lymphaticus, with marked hypoplasia of the chromaffin tissue, or
true myxedema or cretinism, or other vegetative disturbances yet to be
described (true dwarfism, mongolism, etc.). I believe it is better to be pre-
cise in the delimitation of true infantilism as in this way the transitory forms
that are so frequent, are made easier to recognize and easier to analyze.

Prognosis. — The later fate of true infantilism has not as yet been thor-
oughly studied. It is known, however, that the patients show an especial
disposition for various diseases and mostly die prematurely (di Gaspero,
W, A . Freund, Hegar, et al.) . Especially does tuberculosis reap a rich harvest
among them. Also their mentality seems to suffer under the rough in-
fluences of life and its severe conflicts.

Treatment. — The treatment in the true forms as yet is almost hopeless.
Thyroid gland medication, hypophysis medication, etc., may yield slight re-

480 VEGETATIVE DISTURBANCES

suits in the mixed forms. True infantilism usually shows a lower tolerance
for thyroid preparations.

II. TRUE DWARFISM

True dwarfism as a proportioned nanism may be rather well delimited
from the other vegetative disturbances that I have thus far described or
will hereafter describe in this chapter; as all of these with the exception of
true infantilism are disproportioned nanisms, while in true infantilism the
childish dimensions are retained. In spite of the fact that we are consider-
ing true dwarfism in this connection, it constitutes no uniform affection. In-
deed attempts have been made to distinguish two different types of true
dwarfism that differ from each other in important points and perhaps are
also to be separated etiologically. There exists, however, as we shall see,
all possible transitions between these types. As long as we do not know
anything certain concerning the etiology of true dwarfism a satisfactory
terminology for all the cases that belong in this group is not possible.

Historical. — In this short exposition I would not enter into the de-
scriptions that exist in the old literature. It is to be supposed that among the
numerous dwarfs that in former times were retained at the courts of no-
bility on account of curiosity or that were exhibited in the show booths
[as freaks] there were some that were true dwarfs. The descriptions of
these are, however, very inexact. Therefore I shall limit myself to the
fewer and more careful communications in the later literature. The first
exact description of the skeleton of a true dwarf originates with A. Paltauf
in the year 1891, while v. Hansemann was the first to separate the two
types of true dwarfism. v. Hansemann distinguished a nanosomia pri-
mordalis and a nanosomia infantalis. In the latter at the time of birth the
individual is 'of normal size. Growth ceases only later, the epiphysial junc-
tures remaining open; often the individual remains infantile. This form is
identical with that described by Paltauf. The primordial dwarf is small
from the beginning, although his development, apart from the smallness,
proceeds in the normal manner. He is, therefore, a veritable diminutive
human being; Sainton and Launois distinguish this true dwarfism from the
other vegetative disturbances, without, however, considering the other type.
Also E. Levi who has published a thorough study of this form of dwarfism,
has considered Paltauf 's form insufficiently.

A. The Primordial Nanosomia. — An excellent example of this form is
the case described by Virchow and later by v. Hansemann. It was that of
an individual twenty-two years old (who at the age of eleven years was
investigated by Virchow) who was 114 cm. tall. He was entirely well pro-
portioned, the intelligence was well developed, the genitalia were well de-
veloped, except that cryptorchidism was present. The epiphysial junctures
had ossified. At birth he had weighed only 500 gm. This was doubted

TRUE DWARFISM 481

by v. Hansemann although it is certain that at the birth the parents were
impressed with the abnormal smallness. He was the fifth child of twelve,
and the first dwarf. Later three dwarf children followed, but they did not
attain a high age. Between them there were births of normal-sized children,
that later also developed normally.

To the primordial dwarfs belong also the dwarf family Magri, studied by
various Italian authors and exactly described by Taruffi. The husband and
wife Magri were entirely normally developed; of thirteen children eight
survived, five were of entirely normal size, three extraordinarily small. Of
these there was a girl 102 cm. tall, in whom menstruation occurred late but
who was otherwise normal. A boy of no cm. of bright temperament, but
bad character, married in his twenty-sixth year a woman of normal size and
had by her two children — a boy who was of normal size and a girl who was
apparently a dwarf. The third dwarf child of the Magri husband and wife
was 109 cm. tall. All three Magris grew taller very slowly.

Very exactly studied are also the cases of Levi. These I shall now de-
scribe more in detail. The first was a forty-nine-year-old man, 109 cm.
tall. The lower length was shorter than the upper length. The individual
was small already at birth; the genitalia, the secondary sexual characters,
and the intelligence developed fully. At the age of twenty, he married a
woman of normal size, who after eight years bore a child of extraordinary
smallness. Two years later there followed a still smaller child, who died at
the age of ten years. At the age of forty-nine years the man was still
sexually active. The second case of Levi was that of a twelve and one-
half-year-old son of case I. He was 77 cm. tall, and very intelligent. The
third case was that of a thirty- three-year-old man, in cm. tall, weighing
25 kg. The lower length was 64 cm.; the father was very small, the mother
of normal size. The stunting of growth became prominent especially
between the eighth and the tenth year. At the age of twenty-eight he
married, and his child at two years old of extraordinary diminutiveness.
In all cases the ossification and the closure of the epiphyses corresponded to
the age. Levi also emphasizes the fact that these cases, like the dwarf
described by v. Hansemann, showed a slight retraction of the bridge of the
nose and a slight degree of drum-stick fingers.

The primordial dwarf is hence characterized by the fact that the dwarfism
exists already at birth, that apart from the smallness the development pro-
ceeds normally, and that the genitalia, the ossification and the epiphysial
junctures, and the intelligence develop rather normally. According to
Hansemann "infantile" features are found only here and there, for example,
cryptorchidism, or in the case of v. Hansemann enlarged thymus, or retention
of the lobules of the kidney, abnormal length of mesocolon, funnel-shaped
proximal end of the appendix, etc. Levi points out the slight retraction of
the root of the nose and the slight degree of drum-stick fingers.
31

482 VEGETATIVE DISTURBANCES

B. Paltauf s Du'arf. — A . Paltauf described the skeleton of a dwari who died
at the age of forty-nine years; all the epiphyses were open. The individual
was 112.5 cm. tall; he came from an entirely normal family; the intelli-
gence was normal (he had taken part in two campaigns). He had twenty-
eight erupted teeth; the thyroid gland was normal: A . Paltauf believes that
in this case he was dealing with a nanosomia sui generis that depended
on an earlier stage of the formation-age on account of the bones remain-
ing at a standstill in development. Also the deformed cartilaginous base
of the skull had ceased its growth, while the bones laid down in mem-
brane grew further, thus allowing the normal development of the brain;
although a slight cretinoid facial expression was thereby brought about.
The skeleton is proportioned, but shows childish dimensions, the upper
and lower lengths approximating those of a child (Breus and Kolisko).
Such individuals may suddenly begin to grow again. A. Paltauf cites two
instances, the English dwarf Jeffery, who began to grow again at the age of
thirty years, and the Polish dwarf Borwilawski. The brothers and sisters
of the latter were also dwarfish, but his children developed perfectly normal.
I shall limit myself to the citation of the well-observed cases.

The case of Schaafhausen was a sixty-one-year-old man, 94 cm. tall;
several members of the family were also dwarfish, the genitalia were infantile,
the facial expression childish. The sutures of the skull were all ununit'ed, the
epiphyses nearly all. The observations of Schauta, Ranke, and von Voit
perhaps belong here also.1 Hitschmann describes a thirty-five-year-old man
who came of normal family and who developed normally up to the age of
five years. Then growth was retarded, although up to the twenty-fifth and
twenty-sixth years he did grow somewhat. He was 108 cm. tall, beardless,
the voice did not change, the thyroid gland was normal. X-ray examination
showed epiphysial junctures open i^ cm.; the intelligence was normal. He
was an actor with a Lilliputian troup.

A second case of Hitschmann was that of a twenty-two and one-half-
year-old singer; the inhibition of growth began at the tenth year. She was
125 cm. tall, slender, the intelligence was normal, the epiphyses were for
the most part ununited.

Joachimsthal describes several members of a Lilliputian troup, among
whom was an individual thirty years old, in whom the stunting of growth had
begun in the third year; at fifteen years of age, she was 90 cm. tall, and at
thirty years 100 cm. tall. The facial expression was childish, the voice had
not changed and the axillary hair was absent. All epiphysial junctures
were open. The bone nuclei were about as well developed as those of a ten-
year-old child. In an individual thirty-six years old the inhibition had
begun at the age of seven. At the age of twenty-two he was 105 cm. tall,

1 The case of His, quoted by Paltauf, belongs to the endemic cretins, that of Dalega to the spor-
adic cretins.

TRUE DWARFISM 483

and at the age of thirty-six, 128 cm. tall, the epiphysial junctures were open,
the" bone nuclei had developed further. In an individual thirty-three years
old the inhibition had begun at the age of ten years, at twenty years he was
109 cm. tall, at thirty- three years 134 cm. tall; in a woman thirty years old
the inhibition had begun at the age of eight years, at nineteen years she
was 103 cm. tall, now 132 cm. tall. To the Paltaufs type belongs probably
the celebrated dwarf Helen Giibler called the "Puppenfee" [doll fairy]. At
birth she was normal. She ceased growing at the age of six years, and at
twenty years was 106 cm. tall.

If we survey the cases quoted, we find that the Paltaufs type may be
characterized thus: At birth the individuals are of normal size, and at first
show a normal development. Only later, but at all events mostly in early youth,
they suddenly cease growing. The epiphysial junctures remain open, and
in all cases there occurs a quite slow further growth, the inhibition being
broken through in exceptional cases only. The development of the bone
nuclei is in nearly all cases delayed only a little, the development of the
intelligence is normal. On the contrary the genitalia and the secondary
sexual characters remain behind almost always. The cause of this growth
disturbance is as yet not known.

The typical Paltaufs dwarf differs essentially from an individual with true
infantilism. In the latter condition not all the epiphysial junctures remain
open, but the ossification is highly retarded, so that we find ununited only
those junctures that tend to close the latest otherwise. Then too the
psyche of Paltaufs dwarf is ordinarily not childish. I have therefore dis-
carded v. Hansemann's expression "infantile dwarf" and have chosen the
expression " Paltaufs type."

The distinction between the primordial dwarf and Paltaufs dwarf, on
the one hand, and high-grade infantilism on the other hand serves only for
the typical cases. It will readily be seen that transitional forms between the
two varieties of dwarf and true infantilism occur. To quote some examples:
.Joachimsthal describes among his cases two thirty-six-year-old individ-
uals of 1 14. cm. and 116 cm. heights respectively. With these, growth
has remained at a standstill at about the tenth year. We can therefore not
classify them with the primordial dwarfs. The epiphysial junctures were,
however, closed, and both menstruated regularly since their twentieth year.
In a female dwarf with retained epiphysial cartilages the sexual organs were
developed quite normally. She conceived, and at Cesarean section was
delivered of a child above the normal in weight and size.

The circumstance that there are transitions between the primordial and
the Paltaufs type does not mean that they both rest on the same etiological
basis. It would be very easy to assume that in the primordial dwarf the
noxus took its effect in fetal life, in Paltaufs dwarf, in postfetal life. This
does not, however, explain the great difference in the relation of the genitalia.

484 VEGETATIVE DISTURBANCES

As will be seen by the example quoted, the familial hereditary occurrence is
common to both types. In both types, too, the children of the person affected
may develop normally.

There therefore does not seem to me to lie at hand any basis for con-
sidering true dwarfism as an affection of the ductless glandular system. I
need hardly point out that there is no involvement of the thyroid gland.
Aschner would indeed make the hypophysis answerable for dwarfism — cer-
tainly incorrectly — for all the symptoms characteristic of hypophysial
dystrophy are absent.

in. THE RACHITIC DWARF

Dwarfism may be the result of a high-grade rachitis developing in
children. According to Breus and Kolisko, in addition to the inhibition of
growth in height, there are found regularly also curvatures — under circum-
stances the bones are weak and flexible. "The disturbance of the periosteal
ossification, in contradistinction of endochondral ossification, comes into the
foreground." Breus and Kolisko also state that in such cases the epiphysial
junctures can often remain ununited; Gulecke, however, reports three cases
of dwarfism who had suffered severe rachitis in early life and yet f showed on
X-ray examination premature synostosis of the epiphysial junctures. Gulecke
assumes that the epiphysial cartilages were severely damaged by the rachitis,
and that then reparatory processes set in which led to premature ossification.
In fresh cases the X-rays show washing out of the boundaries between the
bone nuclei and cartilage, and at the site of the epiphyses broad light zones
apparently representing excessively proliferated cartilage (Joachimsthat).
The behavior of the epiphysial junctures and the bone nuclei thus vary
according to the intensity of the process, according to the liveliness of the
proliferation of the abnormal cartilage, and the reparatory processes.
Rachitic dwarfism is characterized by the never-absent signs of a previous
rachitis and by the normal development of the intelligence and of genital sphere.

TV. CHONDRODYSTROPHY

(A chondroplasia)

Historical. — Chondrodystrophic dwarfs were known already in antiquity.
Cestan and Meige, who have concerned themselves with the historical study
of this disease, refer to the pictures of the Egyptian god Ptah and the goddess
Bes, in which typical cases of chondrodystrophy are exhibited. Also the
statue of Karakalla and several pictures by Velasquez show typical chondro-
dystrophics. Formerly chondrodystrophy was regarded as congenital or fetal
rickets (Sommering, H. Muller, Langer, and others). Virchoiv described a
chondrodystrophic dwarf that he regarded as a case of endemic cretinism.
In France, Porak denied the assumption of achondroplasia as fetal rachitis and

CHONDRODYSTROPHY 485

•

set forth that it was concerned with an affection of the epiphysial cartilages
that sets in in fetal life. Kaufmann in his known monograph lines himself
against Virchow's explanation, Kaufmann and later Diederle have done away
for good with the conception of a thyrogenic disturbance, until Kaufmann
originated the name chondrodystrophy, by which the condition is known in
Germany. Kassowitz calls the disease " Mikromelie." But this designa-
tion is not precise, as. ihere are different kinds of micromelie (shortness of the
extremities) that have nothing to do with chondrodystrophy (osteogenesis
imperfecta [Vrolik], phokomelie, etc.), and chondrodystrophy constitutes
only one of these types. I refer the reader to the excellent dissertation of
Sieger t.

Definition. — Chondrodystrophy is characterized by a growth disturbance
of the cartilages at the ossification boundary of the cartilages, especially, those
of the long bones setting in the earliest fetal life. Microscopically there is
found, according to Kaufmann, either mucoid softening of the cartilages
(malacic form) , or only cessation of growth (hypoplastic form) , or even con-
siderable, but entirely disorderly, proliferation, which takes place in all
directions instead of iri the longitudinal direction, and thus leads to a mod-
erate swelling out of the epiphyses (hyper plastic form). In older individuals,
the cartilaginous zone of proliferation is bounded at the periphery by strips
of connective tissue (Diederle) . Thereby the periosteal bone formation is not
inhibited, and may even be excessive, as is also the formation of bone nuclei
in the epiphyses, which may even show acceleration. The disturbance affects
also the bones of (he skull that are preformed in cartilage, and the vertebral
column, while the growth of the bones preformed in membrane is not inhibited.

Symptomatology. — From this growth disturbance there results a skeletal
formation characterized by the following points: The base of the skull is
markedly shortened by the inhibition of growth and the premature synos-
tosis of the os tribasilare occipitalis and the os basilare occipitalis, as first
described by Virchow. There is thus brought about a marked retraction
of the root of the nose, such as is not observed in any other growth dis-
turbance. There are, however, rare cases of chondrodystrophy without
this retraction. Eichholz has described three such cases belonging to one
family. Then again the retraction of the root of the nose may exist, without
there having taken place a coalescence at the synchondrosis (a case of E.
Langenbach). The clivus is shortened — I here am following the description
of Breus and Kolisko — the foramen magnum is very small; the base of the
skull is usually supernormally large; there occur also hydrocephalic skulls in
which ossification is rather retarded so that the f ontanelles persist abnormally
long. The form of the sella turcica may be quite abnormal (confer Ob-
servation LXIII). If the subject lives after the period of childhood, the
development of the brain and the intelligence is normal. The upper jaws
are broad, spread far apart, and the upper jaws project markedly. Dentition

486 VEGETATIVE DISTURBANCES

is entirely normal. The vertebral canal is narrowed, usually in the frontal
diameter on account of premature coalescence of the nuclei of the arches and
the bodies, but sometimes generally.

There exists lordosis of the lumbar spine and kyphosis of the thoracic
spine. The thorax is narrowed in the sagittal diameter. In five skeletons
of grown chondrodystrophic dwarfs, Breus and Kolisko found frontal stenosis1
of the vertebral canal in every case. According to Diederle the narrowing
may also be conditioned by hyperplasia of the cartilage. This was true in
pronounced manner in both of Lampe's cases. In one of these the spinal
medulla was markedly compressed on this account.

In chondrodystrophy the ribs are broad and coarse, and at the junctions
of the ribs the cartilages are often swollen-up (pseudo-rosary), in such a
manner that the bony part embraces the cartilaginous. Siegeri describes a
marked swelling-out at the part of the rib bordering on the capitulum costis,
with sharp-angled bowing and fungus-h'ke swelling out of the epiphysis; the
sternum is broad and thick, body and xiphoid process are synostosed; the
clavicles are short, and bent in the form of an S; the scapulae very small,
their borders coarse, the pelvis generally narrowed, its inlet kidney-shaped.
The promontory [of the sacrum] projects markedly, the ilia are thickened,
shovel-shaped with thickened borders. Most characteristic of the micro-
melic growth disturbance is the inhibition in growth of length of the extremi-
ties, which is the proper cause of the dwarfism of the individual. Under
normal conditions the lower length begins to exceed the upper length already
toward the end of the first year of life, and the difference becomes more
marked as the years pass. In the disease under consideration however the
growth in length of the extremities remain so far behind that the relation of the
upper length and lower length may reach 2:1. As the periosteal bone-forma-
tion is not inhibited, the cortex of the diaphyses is very thick and very
marked places for the insertions of the muscles develop; the muscles themselves
are entirely normal, so that the chondrodystrophic dwarfs are very strong with
regards to muscular force and are clever acrobats. According to Breus
and Kolisko the fibula is less shortened than the tibia, so that it projects
markedly below the lower end of the tibia, thus producing a varus position
of the foot; the feet are shortened, also the upper extremities are essentially
shortened, likewise the hand, the breadth of which is however normal; the
shortened fingers stand apart from one another (main a trident, Radspeichen-
form). The ossification of the epiphyses proceeds very irregularly. The
epiphyses themselves may, as Siegeri mentions, sometimes be more hyper-
plastic, sometimes more hypoplastic, in the latter case embracing the di-
aphyses. The closure of the epiphysial junctures may occur prematurely,
especially those of the metacarpal bones of the hands and feet; at other places,

1 In German edition "sclerosis," according to the original article of Breus and Kolisok
"stenosis." — Editor.

CHONDRODYSTROPHY

487

however, the epiphyses may close abnormally late. In the seventeen-year-
old case I shall report later, the distal epiphysial junctures of the radius
and ulna, and the proximal of the
first metacarpal and phalanges are
as yet wide open, so that exami-
nation of the accompanying X-ray
picture will show that the head of
the metacarpal bone is swollen
out, extremely coarse, and that
the epiphyses are well developed,

FIG. 8<>. — Chondrodystrophy (Observation
LXII).

FIG. 87. — Chondrodystrophy (Observation
LXIII).

and in part — for example those of the radius misplaced. Hyperplastic and
hypoplastic processes may often be seen in the same skeleton.

There have also been described cases of partial Chondrodystrophy.

VEGETATIVE DISTURBANCES

Dufour describes such a case, in which the upper extremities were hardly
shortened, and also the trident form of the hands was not pronounced,
while the lower extremities showed marked chondrodystrophic alterations.

FIG. 88. — X-ray picture of the hand in chondrodystrophy (Observation LXIII).

Especially noteworthy is the case of unilateral chondrodystrophy described
by Siegert in his monograph.

The malacic form of chondrodystrophy is not capable of maintaining its

CHONDRODYSTROPHY

489

life; both other forms may attain a high age. The aplastic form is recogniz-
able by the absence of the vertebral and cranial synostoses described, and
further by a characteristic position of the joints by which the extremities

Jt
Tu

C/2

maintain a curved appearance (Breus and Kolisko). The dwarfs are for
the most part especially small.

For the characterization of the chondrodystrophic dwarf, it is also men-
tioned that they all show a great family likeness (Porak) ; that the gait in all

490 VEGETATIVE DISTURBANCES

is waddling, that the intelligence develops normally, and that finally the sexual
glands and the genitalia develop and functionate normally. Indeed in many
cases the genitalia are developed remarkably well.

Here are set forth two cases observed at the first medical clinic. The
notes concerning the first case, four years old (Observation LXII) , have un-
fortunately been mislaid. I can only show the characteristic illustration,
that shows the characteristics of chondrodystrophic dwarf in pronounced
manner. The root of the nose is markedly retracted; the extremities are
enormously shortened, the skin has become too wide for its extremities,
lying in thick folds.

Observation LXIII. — U. W., seventeen years old. Father of the patient normally
developed. The same is true of the father's parents and three brothers and sisters (except
that one sister has a syndactylism of three fingers). The mother of the patient seems to
have had rickets in early life, but is of normal development. Of brothers and sisters of
the patient only the youngest, a girl one year old, is living; she is entirely normal. The
eldest child died at the age of fourteen years of tuberculosis, was normally developed.
The second child died at three-fourth year, the third at one-fourth year, the fourth is the
patient. The fifth and sixth died at one-fourth and one-half years, the seventh im-
mediately after birth.

The patient, like the rest of the children, was, acpording to statement, normal at birth.
At six months of age he seems to have had pain in passing urine, and soon after the father
observed that the child remained behind in growth, and only the head was much too large.
The increase in the size of the head lasted until about the seventh year. He learned to
speak at two years, the intelligence developed entirely normally. At about one-half
year he has had paresthesia and fatigue in the legs. He began to walk with knees pressed
together and for some weeks sitting down has been difficult too.

Height 125 cm., span width 126 cm., acromion to points of finger 47 cm.; upper border
of trochanter major to the heel 53 cm. Length of hands, 15 cm., breadth 10 cm.; length
of feet 21 cm.

The cranial skull is much larger than the facial skull, is somewhat quadrangular; root
of nose deeply retracted. On looking to the left 'or upward, horizontal or vertical nystag-
mus respectively. ChwsteWs phenomenon present on both sides. Slight dextroscoliosis of
the thoracic spine. The hands are short and broad, the fingers alike in length, typical
mains a trident. X-ray shows that the epiphysial junctures of the fingers are not as yet
united. The sella turcica is pressed together in the vertical diameter, broadened in the
horizontal.

The musculature is normally developed, the genitalia hyperplastic. There is no axil-
lary hair, nor hair on the linea alba. There exists a moderately large struma of rather soft
consistency.

There are spasms of the lower extremities. Legs adducted when at rest, with slight
equinus position. Patellar and foot-clonus present, Babinski positive. Hypalgesia and
hyperesthesia from about the height of the arch of the ribs downward, becoming less from
the fossae of the ilia down; very slight on the feet.

Summary: Typical Chondrodystrophy. — At first we thought of a hydro-
cephalus, descending degeneration of the pyramidal tracts and spastic paresis
of the extremities. Yet there were no other points for our adhering to the
diagnosis hydrocephalus. It is possible that the spastic paresis was produced

CHONDRODYSTROPHY

49 1

by narrowing of the vertebral canal by the chondrodystrophic process. I
refer to the case of Lampe mentioned above.

Occurrence. — Chondrodystrophy does not belong to exceedingly rare
affections. According to Katolicky about 70 cases are known in adults.
Siegert counts 53 females and 50 male cases. Several cases of familial or
hereditary occurrence of chondrodystrophy are found reported in the litera-
ture. Porak mentioned a chondrodystrophic female dwarf who was de-
livered of a chondrodystrophic child through Cesarean section. Porak also
cites a case of Charpentier, a twenty-three-year-old chondrodystrophic
female dwarf, whose sister, father and great-grandfather had been chon-
drodystrophic dwarfs. Poncet and Leriche observed two chondrodystrophic

FIG. 90. — Chondrodystrophic family (Father — Observation LXIV).

•

sisters, Decroly saw chondrodystrophy in grandfather, father, and child.
Also Eichholtz saw familial occurrence of chondrodystrophy. He saw two
chondrodystrophic sisters, of whom one was a childless widow forty-two
years old. The other, about forty years old, had an eighteen-year-old
chondrodystrophic child. She was delivered through Cesarean section.
Also the father of both women seems to have had chondrodystrophy.
Siegert mentions that beyond these cases he could find no others of in-
heritance of the disease among the more than 100 cases reported in the
literature. However, there are later observations. Franchini and Zanasi
observed a chondrodystrophic man and wife. The woman became gravid
and was delivered through Cesarean section. The child, which indeed

492

VEGETATIVE DISTURBANCES

FIG. 91.

FIG. 92.
FIGS. 91 and 92. — Chondrodys trophic family (Son — Observation LXV and daughter — Observation LXV1).

CHONDRODYSTROPHY 493

the authors did not themselves see, was 80 cm. tall at the age of twelve years,
and had an enlarged head and shortened extremities. It seems thus also to
have been a chondrodystrophy, as the authors suppose with entire correct-
ness. Glaessner showed two cases of chondrodystrophy at the Wiener
Gesellschaft. der Ar-zte. They were father and son, fifty-six and twenty
years old, 101 and 108 cm. tall respectively. It was elicited that for four
generations, dwarfism always existed in the male members of the family,
while the women were, entirely normal. A fine example of inheritance of
the disease was also observed in the first medical clinic. It concerned a
father, son, and daughter. I here reproduce the photographs. The father
was forty-nine years old, the son nineteen, the daughter twelve years old.
The wife of the father was of normal height. (Observation LXIV, LXV,
andLXVI).

Etiology. — As I already mentioned at the beginning chondrodystrophy
was first regarded as fetal rickets, an assumption that was already the experi-
ments of Parrot and Porak showed unfounded. Virchow regarded as typical
for endemic cretinism the premature synostosis of the os tribasilaris that
'occurs in chondrodystrophy and on this supposition turned attention to
the thyroid gland etiologically. The assumption of insufficiency of the
thyroid gland is recognized as incorrect, as the result of the works of
Kaufmann and, later, Diederle, in spite of which Hertoghe, Stotzner and Moro
again adopted the thyrogenic origin of chondrodystrophy. In all accurately
investigated cases the thyroid gland is entirely normal, however (Diederle,
Breus and Kolisko, Kassowitz, etc.). The supposition of Moro that in his
case there had occurred previously a dysplasia of the thyroid gland is not
justified by anything. Also in the case reported by me, there was not a
single symptom that belonged to the symptom-complex of hypothyrosis.
Then again thyroid therapy is entirely without results, even in young
individuals. Recently Sumita has set forth the untenability of thyroid-
gland therapy.

Lauze points out that the buffoons of kings were chondrodystrophic dwarfs
who have been described as talented, loquacious, quick at repartee, "fond of
everything that glitters," and sometimes also as maniacal. Lauze regards
this mental condition as the result of hypersecretion of the interstitial glands.
Euziere and Delmas describe a case of chondrodystrophy with psychical
characteristics such as Lauze has described; they regard these however as an
expression of degeneration and do not believe that such psychical earmarks
stand in causal associationship with chondrodystrophy. In the cases of
chondrodystrophy observed by me I could not observe any of the mental
characteristics described by Lauze. The hypothesis of Lauze should hardly
gain adherents.

Differential Diagnosis. — Nowadays we ought not to waste words con-
sidering the differential diagnosis from cretinism.

494

VEGETATIVE DISTURBANCES

Another form of micromelic growth disturbance, osteoporosis congenita
(Kundraf), is characterized by a disturbance of the epiphysial as well as peri-
osteal bone formation. Clinically, it has up to the present been without
significance as the infants have never been capable of maintaining life; ex-
cept that Hagenbach described a dwarf with tumor of the hypophysis,
whose bone alterations Hagenbach regarded as osteoporosis. Up to the pres-
ent there are no tenable relationships between this disease and the ductless
glandular system.

V. MONGOLISM

(Mongoloid Idiocy}

Mongolism was first recognized as a disease sui generis by Langdon-Down.
I shall here limit myself to a short delineation, paying especial attention to

FIG. 93. — Six and one-half-year old girl (Mongolism) with three-year-old healthy sister.

the differential diagnosis from infantile myxedema, in the course of which

I follow the excellent descriptions of Bourneville, Kassowitz, Scholtz, and Siegert.

Symptomatology.-— The Mongoloid children show a great family likeness.

The term Mongolism is used because the physiognomy of these children shows

MONGOLISM

495

great similarity to that of the Mongolian races. While in infantile myx-
edema the skull is mostly large and pronouncedly brachycephalic, in Mongol-
ism it is small and round, the palpebral fissures are small and lack myxedema-
tous swelling, they are placed oblique, are slit-like and show epicanthus;
the nose is small and sits like a button on the broadened and somewhat
sunken nose-root (Kq&owitz) , while in infantile myxedema the root of the nose
is strongly retracted, so that the nasal cavities become apparent. Mongo-
loids often show a conjunctivitis. The zygomatic arches protrude somewhat,

FIG. 94. — Same case after thyroid treatment.

the forehead is low and flat, the mouth is small but becomes broad-
ened when the patient laughs, the tongue is not enlarged, or not essentially
so, is fissured, is always somewhat between the separated rows of teeth, the
lower jaw as a ruk projects beyond the upper jaw. The palatal arches are
high, the cephalic hairs are soft and silk-like, while in myxedema they are
rough and dry and are here and there absent. The ears are small and
stand back, the lobules have developed in the form of a triangle (oreille
mongolienne) , the facial expression is morose and unintelligent, in Mongol-
ism it is vacant and expressionless only in the first years of life. Later it

496 VEGETATIVE DISTURBANCES

is gay, comical, imbecile. I refer to the accompanying illustration. The
cheeks lack the thickness of myxedema and usually show a macular red-
ness. While in infantile myxedema or thyroaplasia the condition becomes
recognizable only some time after birth, Mongolism may be recognized
immediately "c'est un petit chinois." The fontanelles and sutures are open
abnormally long, dentition is somewhat delayed and somewhat irregular.
The teeth are defective, and the set of teeth mostly shows numerous ab-
normalities. (Degenerationsgebiss-F0g/); growth in height is usually
somewhat stunted, but there exists a difference from infantile myxedema
in that all these manifestations are very much less pronounced, and the
bone nuclei usually appear at the normal time or just a little later. In
many a case only isolated bone nuclei appear late (Vogt). Sieger t even
observed premature ossification of the epiphysial nuclei. Later there often
occurs a stunting of growth, and even a case of Mongoloid dwarfism has
been observed by Bourneville. The skin is smooth and moist; the pseudo-
lipomata of infantile myxedema are absent, and there often exists marked
obesity. The neck is regular, not shortened as in infantile myxedema.
The thyroid is present. Very commonly the abdomen is thickened, obstipa-
tion exists, and umbilical hernias are not rare. Kassowitz found umbilical
hernias forty-four times among fifty-five cases, and three times a hernia in
the linea alba below the umbilicus. Both the accompanying illustrations,
(Observation LXVII) for which I thank Dr. L. Mohr (Halle a. S), show the
Mongolian expression of the face.

The skeleton is proportioned, slender, the children learn to sit and stand
late, the hands are rather small, awkward, the middle phalanx of the little
finger is often shortened, the end phalanx atrophic; also the thumb is often
very short (main mongolienne) . Very commonly the joints are extra-
ordinarily low, especially the joints of the hands and feet, but also the hip-
joints. The musculature is often hypotonic. Often other anomalies of
formation occur, such as congenital cardiac defects, and not rarely slight
strabismus or nystagmus. The genitalia are different from those of in-
fantile myxedema, in that they remain only a little behind in development.
In males, the penis and scrotum are often strikingly small, as Kassowitz found
nineteen times in thirty-nine cases, and Siegert in half the cases. Also there
may be delay in descent of the testicles. Later the genital functions are for
the most part normal, although libido may be very slight. The Mongoloids
are usually short-lived, and very sensitive to tuberculosis. The mental
development is most only delayed, or there may be slight imbecility — and
but rarely pronounced idiocy. The children are rather lively, but their
attention is fixed with difficulty; they have considerable imitability and pose
readily.

Hence there are very few features of infantile myxedema mixed in with
Mongolism. These are eventually a slight degree of dwarfism, the delay of

, ADDENDUM 497

the dentition and closure of the fontanelles, the distention of the abdomen,
the umbilical hernias, the constipation, the remaining behind in mental
development, the anemia. There are, however, cases of Mongolism in which
myxedematous symptoms are more prominent; Vogt, Neurath, and others
have described such cases.

Pathogenesis and .Treatment. — From what has been said, we should
expect that thyroid-gland treatment would have only a slight influence.
Sometimes not even acceleration of the dentition and closure of the fonta-
nelles follow. Only the umbilical hernia and constipation are improved
rapidly. Kassowitz says that in young children treatment with thyroid
gland will only anticipate the improvement that later occurs spontaneously.
In the case shown above, the results of its use may be regarded as extraor-
dinarily good.

Although according to what has been said there tends to be present in
cases of Mongolism a slight temporary component of athyrosis, which may be
more strongly pronounced in certain rare cases, yet there is not doubt that
the clinical picture of this disease cannot be attributed to any disease of
the thyroid. This is confirmed by the fact that in the few autopsies thus
far recorded the thyroid for the most part was found to be normal (Neumann,
Comby, Bourneville) . Only Phillippe and Oberthur found in four cases
inflammatory sclerosis and Lange slight inflammatory changes. Bourneville
in five cases, and Siegert in one case saw a persistent thymus. The findings
in Mongolism do not present anything characteristic, and resemble those of
idiocy (Scholz). Kassowitz considers the simultaneous affection of many
ductless glands; which assumption lacks all objective evidence. Most
worthy of remark in an etiological direction seems to me the oft repeated
observation that Mongoloids are the last born in a family numerous in
children, or that the mother was very old or her strength had been reduced
.through illness. Shuttleworth therefore terms the Mongoloids the "products
of exhaustion."

In the differential diagnosis from infantile myxedema, the X-ray examina-
tion, in addition to the Mongoloid expression of the face, is of importance.

Addendum

It is true that no term in medicine has been more abused than that
of "infantilism," and that any special work done on the individuals affected
with infantilism must be accepted with caution if the type of infantilism
and exact description of the individual be not clearly stated. The author's
attempt to delimit the affection is indeed very laudable; but it is true that the
determination of the fine shades of distinction is often very difficult. Thus
certain of the cases of pituitary tumor without apparent abnormal distribu-
tion of fat have been classed under the general term "infantilism." It is
32

498 VEGETATIVE DISTURBANCES

not at all certain that these cases would be included under any of the types
mentioned by the author, although some do possess features that resemble
closely the infantile types. Among these may be mentioned the type of
"fat boy" described by Cushing, which Gushing regards as on the whole a
hypopituitarism.

The various types of dwarfism present fairly well-defined characteristics.

McKee, who has had an extensive experience with Mongoloids, claims
to have attained very good results from the use of thyroid-gland extracts.

REFERENCES

Cushing, (H.). Concerning the symptomatic differentiation between disorders of the
two lobes of the pituitary body: with notes on a syndrome accredited to hyperplasia of the
anterior and secretory stasis or insufficiency of the posterior lobe. Am. J. M. Sc., March,
1913, PP- 313-328.

McKee and Wells. Practical Pediatrics. Vol. II, p. 625, Philadelphia, P. Blakiston's
Son & Co.

CHAPTER XIII

THE DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS
AND THEIR RELATION TO DIABETES MELLITUS

A description of the pathology of the inner secretion of the pancreas
offers beforehand many greater difficulties than that of other ductless glands,
especially if the clinical manifestations are chiefly considered. The pancreas
is not, like the other ductless glands, exclusively a gland with internal se-
cretion. It belongs to the most important glands of external secretion; and
anatomically shows chiefly the structure of one of these. Actually the
physiology and pathology of the external secretion of the pancreas was for a
long time the subject of investigation, before clinical observations, and then
the experiments on the total extirpation of the pancreas, led us to think of
the possibility that the pancreas might have an internal as well as an external
secretion.

Historical Development. — Already Bouchardat had observed sclerotic
alterations of the pancreas in some cases of diabetes mellitus, and on the
ground of these observations had expressed the opinion that the cause of
human diabetes depended on a disease of the pancreas. A secure experi-
mental foundation1 for this view was first created by the celebrated ex-
periments'of v. Mering and Minkowski. These investigations showed that
total extirpation of the pancreas in dogs, in addition to the disturbances
of absorption due to the absence of the pancreatic juice, leads regularly to
an excretion of sugar, indeed even to a severe, fatally ending, diabetes.

First through this discovery was the interest of pathological anatomists
turned in general toward the pancreas. In the course of the next decade there
followed numerous statments as to various alterations of the pancreas in
diabetes mellitus, sclerotic changes, inflammatory processes, etc. ; yet in spite
.of the weight of the experimental finding, we could not overlook the fact that
in many cases of severe diabetes mellitus the pancreas showed no demon-
strable pathologico-anatomical alteration and that, on the other hand, in
many cases of high-grade destruction of the pancreatic tissue, diabetes was
entirely absent. The question assumed another aspect when attempts were
made to bring the islands formerly described by Langerhans into relation
with the inner secretion of the pancreas. While the glandular acini furnish
the external secretion, the islands of Langerhans might constitute an em-
bryologically independent tissue element distributed throughout the entire
pancreas, which might give off directly into the blood path a hormone im-
portant for carbohydrate metabolism. Especially important for this view

499

500 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

was the observation of Ssobolew and of Schulze, that after ligation of the
excretory duct of the pancreas, the acinous tissue gradually undergoes atro-
phy while the islands remain intact. Also the observations of the patho-
logical anatomists show that the islands are much more refractory toward
the action of various noxious agents than is the acinous tissue. This furnishes
the explanation of the numerous cases of severe disease of the pancreas without
glycosuria; on the other hand statements that in diabetes mellitus chiefly the
islands diseased were constantly increasing, a direction that was first inau-
gurated by Opie and quite particularly upheld by Weichselbaum. Up to the
present the insular theory has not, however, won general recognition, as it is
found on the pathological anatomical side that there are constantly occurring
cases in which in spite of an existing diabetes the insular tissue remains intact
and even in certain cases, is especially well developed. This finding has led
many authors to the view that both tissue elements of the pancreas, acinous
and insular apparatus, produce the hormone. In recent years the problem
of the internal secretion of the pancreas has experienced further complication;
the view has been expressed that the significant influence that the pancreas
exercises over digestion in the intestine depends not alone on the enzymatic
properties of the intestinal juice but in part on the internal-secretory activity
of the pancreas (Lombroso). Both tissue elements of the pancreas, according
to this, are involved in both the external as well as the internal-secretory
activities. This teaching has obviously caused much confusion.

Another aspect of the problem is the question how the pancreas takes
part in the carbohydrate metabolism. Claude Bernard assumed that in dia-
betes there was increased sugar production. Minowski first expressed the
opinion that on the absence of the pancreatic hormone the consumption of
the sugar molecule in the body suffers -harm. Naunyn inclines more to the
view of a disturbance in glycogenesis (dyszoamylie). Luthje first furnished
the certain demonstration that in addition to the carbohydrates also the
protein is to be considered as a sugar builder. The increase in the sugar
production has been more discussed again since the investigation of O. Lbwi;
Eppinger, Falta, and Rudinger assume in experimental pancreatic diabetes
both reduction in the sugar consumption (removal of the specific internal
secretion) as well as increase in the mobilization of sugar (consecutive
increase of function of the chromaffin tissue), a view that / promulgated for
human diabetes. On the ground of the investigations of Forges and Salomon,
i). Noorden brought the increased sugar production again into the foreground,
while lately Starling and Knouthon have advocated the exclusive disturbance
of sugar combustion.

As to what finally is the significance of the pancreas for the pathogenesis
of human diabetes views diverge greatly. The discovery of sugar puncture
by Claude Bernard led to the viewing of each case of diabetes as neurogenic.
After the discovery of experimental pancreatic diabetes, attention was drawn

ANATOMY AND EMBRYOLOGY 501

on the contrary to the pancreas. Of course between the experimental pan-
creatic diabetes and the genuine human diabetes there exist considerable dif-
ferences. The intensity of the glycosuria is much higher in the latter.
In association with Grote and Staehelin, I have pointed to the enormous in-
crease in the decomposition of protein and the respiratory exchange of gases
in experimental pancreatic diabetes. In genuine human diabetes on the
other hand the demand for protein as well as the demand for calories is not
increased. The supposition of Benedict and Joslin that the heat production
in human diabetes is increased I cannot subscribe to, the reason for which I
shall detail later. In consideration of these essential differences 7 have taken
position as regards the pathogenesis of human diabetes in a direction contrary
to the pancreatocentric; as also v. Noorden, on the ground of his clinical ex-
perience and the investigations carried out in his clinic, has upheld the view
that in addition to the pancreas, a high value must be ascribed to the chromaf-
.fin tissue or the nervous system.

In addition to the pancreas and the chromaffin tissue, the thyroid gland
is certainly of importance in the genesis of many diabetic glycosurias.

The manner of procedure in the following dissertations must, in order to
render possible a condensed exposition of the manifold and complex questions
deviate in some points the scheme followed thus far. After some introduc-
tory remarks as to the anatomy and embryology of the pancreas the results
of the experimental investigation will be given more space than has been the
case in the other chapters. Especially will I treat in detail the metabolic
disturbances that occur in animals after total extirpation of the pancreas.
Also experimental nervous diabetes, so far as it has not already been con-
sidered in the chapter on 'the suprarenals, will be dwelt on. In the clinical
part, I shall first describe the gross anatomical disturbances of the pancreas
simultaneously with the accompanying alterations of metabolism. Then will
follow a short exposition of the clinical manifestations of genuine diabetes as
far as this is necessary in order to emphasize the points of difference from the
changes in metabolism in experimental pancreatic diabetes. The patho-
logical anatomy of genuine diabetes mellitus will be treated more in detail,
however, including a consideration of the alterations of the pancreas, as well
as those of the central nervous system. Only then will I enter into the
question as to what role the inner secretion of the pancreas, or the patho-
logico-anatomical alterations of the insular apparatus, play in the pathogene-
sis of diabetes mellitus.

Anatomy and Embryology. — The pancreas is a long-drawn-out cylindrical
organ, situated behind the stomach just in front of the pars lumbalis of the
diaphragm. We distinguish from right to left, the broad head lodged in the
loop of the duodenum, the neck, the body, and the tail. The head is inti-
mately adherent to the loop of the duodenum, while the left end (processus
uncinatus) is more movable. On its anterior surface, the pancreas is covered
with peritoneum. The length of the organ is about 19-22 cm., the weight,

502 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

according to Vierordt varies between 85 gm. and 105 gm., according to Orth
between 90 gm. and 120 gm. The pancreas is extraordinarily well vas-
cularized. It receives a large branch (arteria pancreatico-duodenalis supe-
rior) from the ramus gastroduodenalis of the hepatic artery, further several
branches from the splenic artery, and one branch (arteria pancreatico-duo-
denalis inferior) from the superior mesenteric artery. The pancreas is sup-
plied by an abundant nerve plexus of branches from the vagus and from the
sympathetic fibers that emanate from the sympathetic trunks or from the
great sympathetic ganglia.

The glandular acini of the pancreas form large lobes bound together by
loose connective tissue that are in turn made up of smaller lobules. The
excretory ducts of the acini unite in the pancreatic duct or duct of Wirsung,
which empties in common with the ductus choledochus into the papilla of
Vater in the duodenum. A large excretory du'ctus pancreaticus accessorius,
emanating from the head, unites with the duct of Wirsung. From the acces-
sory duct there usually branches a duct uniting with the duodenum (ductus
Santorini). Opie found this duct obliterated or markedly narrowed in
numerous cases. Only in such cases was the secretion of the pancreas fully
cut off from the intestine by closure of the principal duct. The closure of
the accessory duct may lead to isolated sclerosis of the head of the pancreas.
Further, we should consider that not infrequently accessory lobules of the
pancreas are found in the duodenum.

In the lobules of the glandular parenchyma are found imbedded between
the individual acini cell groups that consist in polygonal cells with large round
nuclei. These cells stain less distinctly than the cells of the acini. The pro-
toplasm is lighter, it does not show the Distinct zymogen-granules as does the
glandular tissue. These cell groups, which occur in very different number
and size, are named after their discoverer, the island of Langerhans. They
are found in all kinds of animals (Diamare) , and in some they are very large
and even visible macroscopically. They show an especial abundance of
blood-vessels. The capillaries form a dense network interlarding the ceU
groups similar to what we see in the renal glomerules (Kuhne and Lea} . The
cell accumulations have no connection with the excretory ducts of the gland.
They are never filled after the injection of the excretory ducts (v. Ebner).
Many histologists state that the islands of Langerhans are surrounded by a
capsule (Renaut, Opie, Flint, and others}. Others combat the existence of a
capsule (Diamore, Hansemann, and others) . At any rate it should be men-
tioned that in many species of animals (for example in the cartilaginous fishes)
the capsules are found constantly (Rennie).

Very different views have been expressed as to the nature of these pic-
tures. Langerhans regarded them as nervous structures, later authors as
lymph follicles. Finally the view was promulgated that they constitute a
gland with internal secretion distributed throughout the entire pancreas,
that gives off an internal secretion to the interlarding capillary network.

DIABETES AFTER EXTIRPATION OF THE PANCREAS 503

According to the views of these authors the islands of Langerhans are com-
pletely independent. On the other hand authors state that the insular tissue
may shade off into the glandular tissue and vice versa. Laguesse first de-
scribed intermediary forms between the gland cells and the island cells, and
assumed that on certain functional demands there was a transition from the
one kind of tissue into the other (balancement) . Karakaschejf is of the opin-
ion that the islands constitute only a sort of reserve material, and that under
certain conditions, for examples, in the giving-out of gland tissue, there enters
into play a regeneration of the parenchyma from the islands. On the other
hand, Gutmann would see a changing of the parenchyma into insular tissue.
Also Swale Vincent and Thompson suppose transitions between the gland
cells and the island cells. The recent embryological studies and investiga-
tions as to the regeneration processes in the pancreas do not seem to confirm
the opinion of these authors.

The pancreas is of entodermal origin. There are present three rudiments,
a dorsal, made up of the epithelium of the primitive duodenum, and two ven-
tral proceeding from the groove-shaped rudiment of the ductus choledochus.
Laguesse first showed that the islands as well as the glandular parenchyma is
of epithelial origin, and also showed that the islands separate out from the
primitive cell columns at the same time as the glandular tissue. The newer
investigations on human fetuses (Pearce, Weichselbaum and Kyrle, Mironescu)
leave room for no doubt that the island tissue already in earliest fetal life
develops from the epithelial cell columns just as do the acini.

The youngest fetus in which the islands of Langerhans were observed was
54 mm. long (Pearce). Weichselbaum and Kyrle did not find them present
as yet in a fetus 50 mm. long. The islands are first found in the distal part
of the pancreas. Also in adults they are more frequent in the tail of the pan-
creas (Opie). v. Hansemann assumed that the islands were of mesenchy-
mal origin, but Weichselbaum and Kyrle found them also later still in asso-
ciation with the excretory duct of the pancreas, and hence regarded them as
entodermal. Moreover, also the observations as to the regenerative processes
in the pancreas after abundant destruction of glandular tissue show that the
islands always develop from the excretory duct (Ssobolew, Kyrle) ; especially
beautifully do the investigations of Kyrle show that on implantation of pieces
of pancreas into the spleen, in the regenerative processes that soon make their
appearance, the island and acinous tissue develop independently out of the
epithelium of the excretory duct.

I. EXPERIMENTAL PART

A. Diabetes after Extirpation of the Pancreas

We shall first describe carbohydrate metabolism after extirpation of the pan-
creas. The complete extirpation of the pancreas causes in all kinds of ani-

504 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

mals disturbances in the metabolism of sugar. It is true that in certain
species of birds this does not go as far as glycosuria, but there results a hyper-
glycemia. The significance of the pancreas for the metabolism of sugars is
therefore universal. The extirpation of the organ in dogs has been studied
the most exactly; I shall therefore make especially the observations in the
experiments on dogs the foundation of the following dissertation. The
complete removal of the pancreas in dogs always causes a diabetes. The
negative results that were obtained by certain investigators, especially those
who preceded Mering and Minkowski, and referred to the facts that total ex-
tirpation of the pancreas is very difficult, and that sometimes slight remnants
suffice to prevent the outbreak of the disease. Luthje has contributed still
later reports in which in spite of complete extirpation, the glycosuria remained
absent. There occurred, however, as Luthje himself stated, hyperglycemia
after the operation, and later histological examinations of the duodenum
showed that remnants of pancreatic tissue were present. In more than forty
experiments that we ourselves have instituted in the course of the last year,
like Minkowski we never missed the occurrence of a severe diabetes. When
about a third of the organ is left behind, diabetes usually remains absent, but
can, however, develop later if the piece left behind undergoes inflammatory
processes. If a still smaller piece of the pancreas is left behind, there occurs
a light diabetes, that is, excretion of sugar occurs only when the carbohydrate
metabolism is overstrained by the administration of a diet rich in amylaceous
material (Sandmeyer's diabetes).

The sugar that is excreted in the urine after the total extirpation of the
pancreas is grape-sugar. The sugar elimination usually starts only a few
hours after the operation and in about forty-eight hours the diabetes is at
its height. Before the death of the animal the excretion of sugar usually
gradually sinks. The duration of life after the operation is at the most
fourteen days. Exact information as to the intensity of the excretion of sugar
is furnished by the excellent work of Minkowski. This author showed that
administration of sugar raises the existing glycosuria by the amount ad-
ministered, and further that at the height of the disturbance in metabolism
the amount of excreted sugar bears a definite relation to the amount of ex-
creted nitrogen. This quotient, D:N, remains 2.8 to 3 [:i], just as well
when the dog is fasting as when it is fed with meat or other albuminous body.
Minkowski hence drew the conclusion that in this quotient is expressed the
extent to which the animal organism is enabled to form sugar out of protein.
The animals become poor in glycogen extraordinarily rapidly. After forty-
eight hours the liver is almost free of glycogen and later becomes highly
fatty. The glycogen is retained in the muscles for a long time, however.
Even the leucocytes are strikingly rich in glycogen. Administration of
grape-sugar cannot halt the disappearance of glycogen. The power of form-
ing glycogen does not however disappear entirely, for on the administration

DIABETES AFTER EXTIRPATION OF THE PANCREAS 505

of levulose a part of the same may be deposited as glycogen, in which case, as
Eppinger and / observed, also the fattening of the liver is halted. A part
of the levulose is excreted as levulose, another part as glucose. The ques-
tion as to whether the increase in elimination of sugar conditioned by the
administration of protein, depends on the direct formation of sugar from
protein was discussed very energetically, especially through the numerous
objections of Pftuger, until Luthje ascertained that after abundant adminis-
tration of casein the total amount of the excreted sugar far exceeds the pos-
sible amount of stored glycogen. The administration of fat does not increase
the excretion of sugar, yet it is to be considered that as a result of the absence
.of pancreatic juice, fat is very poorly absorbed. On the simultaneous ad-
ministration of pancreatin we have seen, however, in individual experiments
appreciable, although only transitory increase in the D:N quotient (to 7).

In addition to the glycosuria there exists polyuria and ketonuria. The
occurrence of the latter is combated by many authors, although the experi-
ments of Embden and Lattes let it be expected that in the pancreas-diabetic
dog there exists a predisposition to ketonuria. If the blood of normal cattle
was allowed to flow through the liver of a pancreasless dog, there was found
as great an amount of diacetic acid as the liver of normal animals lets be
produced only on the addition of the strongest acetone formers. Allard
saw in addition to this, in pancreasless dogs, the occurrence of a not inap-
preciable amount of diacetic acid and betaoxybutyric acid, especially when
pieces of pancreas were placed under the skin of the abdomen and only later
extirpated; when therefore the development of the diabetic disturbance of
metabolism was retarded. In such animals ketonuria then develops rather
rapidly and eventually leads to coma.

Also the protein metabolism in pancreatic diabetes shows definite dis-
turbances. Already Minkowski had shown that after removal of the pan-
creas there occurs an increase of the protein decomposition. In collaboration
with Grote and Staehelin, I showed that this increase is constant and its
intensity conformable to law. The hunger protein exchange after complete
extirpation attains to three or three and a half times the hunger protein ex-
change before the extirpation. Mohr found less values; however, Eppinger,
Rudinger, and /, in the later investigations confirmed our former statements.

Also the excretion of salt is appreciably increased, according to the in-
vestigations of Whitney and myself.

Finally the respiratory metabolism is essentially increased, according
to the investigations of Grote, Staehelin and me, and of Mohr. Our investiga-
tions were carried out in Jaquet's respiratory apparatus. Already the ap-
preciable increase of the protein destruction would lead one to expect an
increase of the caloric production, on account of the specific dynamic energy
of protein. According to our investigations, however, the increase of the
exchange (about 42 per cent, in the experiments not complicated with fever)

506 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

was higher than could be calculated from the destruction of albumin. An
increased exchange might be anticipated also from the rapid losses of body
weight, such as were ascertained in the later experiments I carried out with
Eppinger and Rudinger.

For the reason that bodies very rich in oxygen (sugar and ketone bodies)
are excreted, the respiratory quotient is very low. In our experiments it
averaged about 0.73.

In the pancreasless dog the excitability of certain sympathetic nerves is
increased. O. Lb'wi showed that the instillation of atropine into the eye of
a pancreasless dog would produce mydriasis, a stimulus that had been below
the threshold thus becoming operative. With this agrees the fact that sub-
cutaneous or subperitoneal injection of adrenalin, increases, according to
Eppinger, Rudinger, and my experiments, the D : N quotient. The amounts
of sugar that raised the quotient to more than 2.8 were greater than those
which under like conditions could be obtained by the injection of adrenalin
into normal fasting dogs. Therefore the glycosuric action of adrenalin in
pancreasless dogs is increased. As these experiments with adrenalin were
undertaken at the height of the metabolic disturbance, therefore at a time
when the glycogen constituent was already reduced to a minimal, it may be
supposed that this increase is brought about, not only through the increased
consumption of glycogen, or through a washing-out of circulating sugar, but
also through an increased formation of sugar.

Then, too, other ductless glands influence the intensity of the pancreatic
diabetes. The experiments on simultaneous extirpation of the thyroid gland
or the parathyroid glands [together with the pancreas] show this. It is
known that after thyroid extirpation the hunger protein exchange is lowered.
When the pancreas is simultaneously extirpated the hunger protein exchange
is about three to three and one-half times that of a thyroidectomized dog
the same size, is therefore absolutely lower than after extirpation of the pan-
creas alone. The excretion of sugar is, however, the same, so that the
quotient of dextrose to nitrogen (D : N) is higher. In experiments in which,
together with the pancreas, a large part of the parathyroid glands was
extirpated, we found further that the intensity of the diabetes was essentially
increased. We observed quotients of 3.6, although the hunger protein
destruction (in relation to the body weight) was greater than was to have been
expected in dogs of the same size after extirpation of the pancreas alone.
Further, worthy of mention is the statement of Zulzer that in an experiment
on a dog in which the pancreas was extirpated and simultaneously the renal
vein was ligated, the intensity of the excretion of sugar was very slight and
transitory.

We shall now enter further into the question as to how we may explain
the occurrence of glycosuria after extirpation of the pancreas, or the regula-
tory influence of the pancreas on sugar metabolism under normal relations.

DIABETES AFTER EXTIRPATION OF THE PANCREAS 507

It is generally recognized that in the present state of our knowledge, the as-
sumption of an internal secretion of the pancreas is not to be avoided.
Opinions of former authors, that the irritation or injuries to the sympathetic
nerve plexuses in the course of the severe operations determined the glyco-
suria, are contradicted by the transplantation experiments of Minkowski
and Hedon. If the part of the pancreas lying in the mesentery of the duo-
denum is transplanted with its vascular peduncle, under the skin, and later
the rest of the pancreas removed, diabetes does not occur. A minimal
[operative] attack then suffices to remove the transplanted piece and to call
forth a diabetes in its fullest intensity. That the presence of pancreatic
juice in the intestine is not necessary for the normal course of the carbohy-
drate metabolism is readily seen in the fact that administration of pancreatin
essentially improves the absorptive disturbances, but rather increases the
intensity of the excretion of sugar.

The experiments detailed lead us to assume, as already mentioned, an
inner secretion of the pancreas. We have not as yet succeeded, however, in
isolating the internal secretion and defining it chemically. We are not even
certain as to the path of the giving off of the same. Biedl showed in his
interesting experiments on dogs that after leading off the lymph of the tho-
racic duct to the exterior, glycosuria can occur. Biedl concluded from that
that the inner secretion of the pancreas is carried off by the lymph. Later
Biedl and Ojjer stated that adrenalin glycosuria can be prevented by the simul-
taneous injection of duct lymph. If the internal secretion of the pancreas
were carried off by the lymph we would expect that on the administration of
the lymph of normal dogs to pancreasless dogs the intensity of the metabolic
disturbances would be essentially reduced, or that the excretion of sugar
would completely disappear, at least for some time. In numerous investiga-
tions as to this point we could not find these things. In large dogs that were
fed abundantly with carbohydrates, the lymph from the thoracic duct was
collected for some hours, and this lymph administered to pancreasless dogs
either subcutaneously or by the drop-by-drop method into an exposed vein,
without producing an essential influence on the quotient of dextrose to nitro-
gen (D : N) , although the experiments were conducted for hours only. When
Biedl more recently 'states that he succeeded in similar experiments in de-
pressing the D : N ratio from 1.8 per cent, to 1.5-1.2 per cent., it seems to me
that the difference is much too small to decide as to this important question.
Recently an attempt has been made by Tuckett to explain the glycosuria oc-
curring in dogs with a lymph fistula, by the operative injury to the sympa-
thetic nerve in the neck and also by the narcosis. This explanation, it seems
to me, in consideration of the high percentage of sugar found by Biedl, does
not appear satisfactory. If the internal secretion of pancreas is not carried
off by the lymphatics — I leave this question open — there remains its trans-
ference by the pancreatic veins.

508 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

We have for this reason collected the blood of the pancreatic veins of
large dogs and injected subcutaneously the serum of pancreasless dogs.
Also in these experiments were the results negative. V. Ehrmann has carried
out the same sort of experiments with similar negative results. Not much
can be concluded from these experiments. The pancreas is extraordinarily
well vascularized; it may be that the amount of blood collected in a half
hour does not contain enough internal secretion to produce distinct evidence.
It should also be considered that under normal relations the blood of the pan-
creatic vein is carried directly to the liver, whereas in our experiments it
entered directly into the greater circulation. Finally we should consider
the possibility that the internal secretion is bound in the blood corpuscles.
The excellent vascularization of the pancreas may also furnish the founda-
tion for the fact that we have not as yet succeeded in obtaining an extract
of the pancreas that is active in influencing metabolism. The relations here
seem to be similar to those affecting the likewise well-vascularized parathy-
roid glands. The pancreas is also in respect to its internal secretion no stor-
age gland as, for example, the thyroid is. Probably the internal secretion
is carried off as it is formed. Zulzer, acting on similar considerations, has
ligated the veins of the pancreas, thus producing a stasis, and claims to have
seen a favorable influence of the extract obtained from such a gland on the
glycosuria of pancreasless dogs and on the ketonuria of human diabetes. It
is true that the statements of Zulzer are not very convincing. The results
in pancreasless dogs are very slight, and on the injection of the extracts into
human beings shiverings are produced that influence the metabolism in a
non-negligible way.

The question as to which tissue element of the pancreas is to be referred
the production of the hypothetical internal secretion has, since the discovery
of the islands, been much discussed, especially with respect to human dia-
betes. I regard it as suitable to consider quite separately the results ob-
tained in animal experimentation, as much speaks for the assumption that
human diabetes is not of a single nature and as the disturbances of absorp-
tion, observed after shutting-off of the pancreatic juice in the animals ex-
perimented on seem to deviate in many respects from those in man. Soon
after the discovery of Langerhans' islands the view was expressed that these
pictures, which in their histological structure show a certain similarity to
certain ductless glands, especially the suprarenal cortex and the parathy-
roids, produce the internal secretion of the pancreas, while the glandular
parenchyma is concerned exclusively with the production of the external
secretion. The view that was later upheld by several authors, namely, that
the Langerhans' islands could pass over into glandular parenchyma, or
reversely; I have mentioned this in speaking of the anatomy and embryology
of the pancreas; in which exposition, in consideration of all the data as to
the histological and embryological observations, I have accepted the views

DIABETES AFTER EXTIRPATION OF THE PANCREAS 509

of those authors who ascribe to the insular apparatus a morphological and
embryological independence. Of especial importance for the insular theory,
were, more recently, experiments that make a functional independence in high
degree possible.

Already Katz and W inkier had made the observation that after ligation of a larger ex-
cretory duct the islands hast for a while, while the glandular parenchyma in the part of the
pancreas affected goes to pieces. The general attention was first, however, attracted to this
subject by the mutually independent observations of v. Ssobolew and Schulze. Schulze
ligated in guinea-pigs a large lobe of the pancreas and found that even after eighty days the
islands were retained, while in the sclerotic tissue were found only traces of the acini.
Furthermore, it should be mentioned that according to Schulze' s investigation the islands
undergo no alteration during fasting, while the pancreatic acini show alterations con-
ditioned by the reduced function. Schulze came to the conclusion that the islands are en-
tirely independent structures. Ssobolew experimented in rabbits, cats, and dogs. The
results in rabbits were the clearest. The pancreas in rabbits, which lies flattened-out
between the two layers of the mesentery possesses one excretory duct only. When this is
ligated the pancreas shrinks markedly, owing to atrophy of the glandular parenchyma. It
is true that Ssobolew found, between the thirtieth and the one hundred and twentieth day
after the operation, slight sclerotic alterations of the islands in their clump of sclerotic tis-
sue, but later the islands partially recovered; and they were retained even four hundred
days after the operation. They also survived after analogous operations in dogs and cats.
In dogs, Ssobolew found the atrophy of the glandular tissue less marked, as he supposes
that it forms new excretory ducts. Tiberti found, after ligation of the excretory duct in
rabbits, at first increased formation of zymogen-granules in the acini, that he regarded as
hypersecretion, then hyposecretion, and finally complete cessation of granule formation.
Later slight regeneration of the excretory duct made its appearance. In later investiga-
tions Tiberti found that the great part of the acini disappeared, and that pictures
remain behind whose significance as remaining islands is not clear. In two rabbits,
Tiberti found slight glycosuria five months after the operation. In dogs, according to
Tiberti's investigations, the sclerosis of the pancreas is less distinct than in rabbits, as
islands as well as acini are in part retained.

Visentini ligated the excretory ducts of the pancreas in twenty-four dogs; he examined
the pancreas two hundred and twelve days after the operation and found a gradually pro-
gressing sclerosis. Even one hundred and twenty days after the operation individual
gland-lobules were found; in two experiments after two hundred and sixty and two hundred
and twelve days (respectively) the glandular tissue had entirely gone to pieces. In the
dog that survived two hundred and twelve days there was found a slight glycosuria.

Sauerbeck found after ligation of the excretory duct in rabbits gradually progressing
sclerosis of the glandular parenchyma, the islands as in the investigations of Ssobolew
showed transitory damages to their structure, owing to the sclerosing process. In
this stage, Sauerbeck, in agreement with the older experiments of Hedon often observed
glycosuria, sometimes considerable; in later stages the islands again showed their normal
structure, and then no glycosuria existed. Lombroso found in forty-one pancreases of dogs
that the ligation of the pancreatic duct did not lead unconditionally to sclerosis. Islands
as well as acini could be in part retained.

In ligation of the duct in rabbits, Lombroso and Sacerdote found that the islands \vt-rc-
indeed retained, but that their number and size were diminished.

Finally we should mention the investigations of Zuntz and Mayer. After ligation of
the excretory duct of the pancreas, these authors found abundant retention of gland-
acini in certain cases, showing more or less alterations of their structure. Very excep-

510 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

tionally indeed did the acini seem to have changed their structure. The islands of Lan-
gcrlians likewise showed alterations of structure, "perhaps they seem smaller, but their
number does not seem to have been diminished." A portion of the island cells showed
alterations even already after a few days; in every case the alterations of the islands
developed much more slowly than those of the acini.

Lombroso in his works and in a detailed review has subjected to criticism
the experiments just referred to, and has come to the conclusion that the
functional independence of the islands of Langerhans has not as yet been
demonstrated. In this conclusion Lombroso's own views that to the external
secretion of the pancreas must not be ascribed that freedom and independ-
ence of the internal secretion that we for a long time tended to ascribe to it,
has had a great influence. Before I discuss the question of the independence
of the insular apparatus, I must enter first into an account of the disturb-
ances of absorption after extirpation of the pancreas or after ligation of its duct.

Already Abelmann, whom we have to thank for the fundamental absorption experi-
ments after extirpation of the pancreas, stated that it is true after total extirpation, the
absorption of fat in the intestine almost completely ceases, although fat-splitting may be
very good; that, however, the disturbance of absorption never reaches to this extreme
grade when a part of the pancreas is left behind, even when its connection with the intes-
tine is entirely broken up. Also after ligation of the excretory duct is the disturbance of
absorption never intense. It has been attempted to explain this by the statement that in
this case the pancreatic juice is in part absorbed, and reaches the intestine by way of the
blood-vessels or that the dogs with pancreatic fistula lapped up the secretion that flowed
out. (Sinn, Hess, Burckhardt, et al.)

Besides this it is mentioned that in dogs, there often occur accessory pancreases, and
that in such cases therefore the complete cutting-off of the pancreatic juice from the intes-
tine is very difficult. Sinn, and Hess found almost regularly in dogs a third excretory duct
of the pancreas. According to these authors the ligation of all ducts is especially difficult
intra vitam. When it really succeeds, there occurs within some weeks an almost complete
necrosis of the pancreatic tissue. In these cases Hess, and Sinn, found no diabetes, in most
cases, however, an appreciable temporary disturbance of protein and fat absorption. In
some cases indeed the absorption was quite good. Lombroso in his numerous experi-
ments has ascertained the following: The absorption of fat in dogs is rather good when the
entire number of ducts are ligated, or when after a part of the pancreas has been trans-
planted and a fistula from this to the outside has been made, the other part of the pancreas
has been extirpated. This also occurred, according to Lombroso, when the re-ingestion of
the secretion was entirely prevented.

In an experiment carried out in Minkowski's laboratory the disturbance of the absorp-
tion of fat was indeed not inappreciable (up to 60 per cent.). When later the vascular
nervous pedicle of the transplanted part of the pancreas was ligated and cut, a transitory
glycosuria occurred, and the fistula secreted further. Only after extirpation of the remain-
ing part of the pancreas did the diabetes and the disturbance in fat absorption reach its full
height. In a second analogous experiment, glycosuria was present from the first, but the
disturbance of absorption in this case was less (38.7 per cent.). Lombroso further showed
that bile, saliva, and intestinal juice show no alterations in their enzymatic characteristic,
and that therefore an excretion of absorbed pancreatic juice into the intestine was there-
fore improbable. This was also confirmed by Zuntz and Mayer. Lombroso concluded
from his experiments that the influence of the pancreas on the absorption of fat was also

DIABETES AFTER EXTIRPATION OF THE PANCREAS 51 1

conditioned through an internal secretion. Fleckseder has instituted analogous experi-
ments. He observed that the using up of fat and albumin is somewhat diminished in
the fistula animals, whether the secretion is let flow free from the fistula, or is let stagnate,
whether it is re-ingested or not. Very interesting is an experiment of Fleckseder' 's in which
gradually, through increasing sclerosis of the piece of pancreas left behind, a diabetes
developed to full height, the secretion from the fistula stopped, but the absorption of fat
was, however, better than before.

Lombroso in his review has, as before mentioned, doubted the significance
of the ligation experiments for the functional independence of the pancreas.
He uses the just mentioned disturbances of absorption in a like sense, and
comes to the conclusion that islands as well as gland parenchyma take part
in the production of the external secretion of the pancreas, and that this is of
importance for the carbohydrate metabolism as well as for fat absorption.

The amalgamation of both questions seem to be rather unhappy. From
the experiments just cited it seems that the two disturbances do not run a
parallel course throughout. Thus we found, for instance, in one of Lombroso' s
experiments relatively, good absorption in spite of existing glycosuria, and in
an experiment of Fleckseder's right good absorption in spite of a fully de-
veloped diabetes. On the other hand we find in an experiment of Lombroso's
a not inappreciable disturbance of absorption in spite of absence of a dis-
turbance in carbohydrate metabolism. So much is therefore certain that, if
an internal secretion of the pancreas actually essentially influences the absorption
of fat, it is not identical with the pancreatic hormone regulating carbohydrate
metabolism. As we shall see later, the same is true of the observations on
human diabetes.

In men the relations are on the whole much clearer than in the dog. Here
we find cases with severe lethal diabetes and high-grade isolated disease of
the insular apparatus; in spite of this, in these cases the characteristic, not-to-
be-overlooked, fat stools are absent. On the other hand, when the pancreatic
juice is completely cut off, fat stools occur, as we shall see later, which im-
prove considerably on the administration of pancreatin. Characteristic of
these pancreas stools in men is the deficiency of the splitting of neutral fat,
whereas in the dog, according to the statements of all investigators the split-
ting of fats is not essentially disturbed even after the total extirpation of the
pancreas.

In reviewing the information at hand up to the present time, we find,
according to my opinion that we can thus far say with certainty, only that
the absorptive activity of the intestinal mucosa is somehow influenced by
the pancreas even when the pancreas is entirely separated from the intestine,
that, however, this influence is independent within wide limits of that of the
carbohydrate metabolism through the pancreatic hormone. At all events, I do
not regard it as proper that these not at all negligible relations should be used
as a basis against the teaching of the functional independence of the glandular

512 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

and the insular apparatus. For this independence speak the known trans-
plantation experiments of Minkowski, Gley, Thiroloix and Hedon. When we
pass these in review from the standpoints above mentioned, we see that the
production of pancreatic juice, therefore the function of the glandular
parenchyma, is quite independent of the disturbance in carbohydrate me-
tabolism. The glandular parenchyma of the transplanted piece may atrophy,
the secretion from the fistula may stop flowing, and yet the diabetes remain
absent. Only after extirpation of the sclerotic piece (with the retained
islands) does the diabetes set in. On the other hand, there is known the ex-
periments of Thiroloix in which diabetes set in after the transplantation, in
which case therefore the islands probably suffered harm, while the secretion
continued to flow from the fistula.

I do not subscribe to the critical remarks of Lombroso directed against the
remaining refractory of the insular apparatus after duct ligation. It seems
to be intelligible that the chronic inflammatory processes that occur after
ligation of the duct, may under certain circumstances damage also the insular
apparatus and on account of this lead transitorily to glycosuria. There is
no longer doubt as to the fact, now communicated from all sides, that also a
long time after the ligation of the duct the entire glandular apparatus becomes
sclerotic, the insular apparatus remains entirely or largely retained, and that
on this account disturbances in carbohydrate metabolism remain absent.
The experiments on pigeons that Lombroso quotes as support of his position
are not convincing. In these experiments although the insular apparatus
was apparently markedly damaged, the glycosuria remained absent. As
Biedl has already pointed out, however, in many species of birds, the total
extirpation of the pancreas does not lead to glycosuria, but only to hypergly-
cemia. The experiments on transplantation of the pancreas and the institu-
tion of a pancreatic fistula seem to me to be especially poorly adapted for the
decision of this question. If the healing follows by primary intention the
carbohydrate metabolism and also the insular apparatus do not alter. If,
however, infection occurs and on account of this infection sclerosis of the
pancreas sets in, naturally the insular apparatus can also be damaged, and
often it would be very hard to estimate in such an altered pancreas the
functional integrity of the tissue constituents still present. I have carried
on some experiments that in spite of the unfavorable relations seem to me to
point to the functional independence of the two apparati.

Zuntz and Mayer found in their pretty experiments that the ligation of
the excretory duct led in the dog first to a more or less well-expressed loss of
body weight. Mostly the dogs rapidly regain their body weight and then
live from then on like normal dogs. In other cases, however, the body weight
falls still further, the emaciation terminating in death. Now Zuntz and
Mayer found an almost complete disappearance of the glandular acini in
these dogs, while in the dogs that recovered the disappearance of the glandu-

DIABETES AFTER EXTIRPATION OF THE PANCREAS 513

lar parenchyma proceeds much more slowly. Zuntz and Mayer conclude
from this that in addition to the production of the pancreatic juice and, of the
still hypothetical hormone regulating carbohydrate metabolism the pancreas
has still another function, by which it becomes concerned with general me-
tabolism. Cannot fat necroses, that are known to be difficult to avoid in the
operation on the pancreas, have played a part in the sudden death of the dogs?

I should like to summarize the results of the experimental investigation
up to the present in the following propositions. There is probably produced
from the insular apparatus of the pancreas a hormone that is given principally
to the venous blood and carried to the liver. When this hormone is absent,
marked excretion of sugar and disturbance of glycogenesis occurs. Further,
there occurs elimination of ketone bodies. The decomposition of protein
and the excretion of salts, and again the production of calories is highly
increased, and finally there occurs an increased excitability of the sympa-
thetic nerves.

According to my view, there speaks for a disturbance of glycogenesis, in
addition to the marked poverty in glycogen, especially the fact that we have
in partial extirpation of the pancreas (Sandmeyer's diabetes) the occurrence
of a glycosuria only on alimentary overfeeding. In the severest forms,
at the height of the metabolic disturbance the glycogen formation in the
liver seems markedly reduced. For this speaks the observation, as already
Minkowski found, that the administration of dextrose raises the sugar-
elimination to about the amount administered, and also the demonstration
furnished by Grote, S(aehelin and myself, that administration of sugar does not
'increase the respiratory quotient. That glycogen formation is not entirely
in abeyance is spoken for, among other circumstances, by the fact that we
may still obtain it on the administration of levulose.

In my opinion there speaks for an overproduction of sugar the fact that
also in fasting, when the alimentary influences are entirely ruled out, sugar
production proceeds in the liver with the intensity that it does.

Finally there remains for discussion the question as to whether the over-
production in the liver is alone the cause of the sugar elimination, or whether
also the combustion of sugar in pancreatic diabetes is diminished or increased.
An attempt has been made to reach nearer the solution of this question by
investigating whether muscular work will reduce the elimination of sugar.
The basic investigations of Seo have shown that after incomplete extirpation
of the pancreas sugar elimination as well as the quotient D:N diminishes
under the influence of muscular work. After complete extirpation of the
pancreas no such diminution occurs. If a shorter period be investigated,
there rather occurs an increase in the quotient. If in such an animal the
elimination of sugar at a later stage has started to fall, there occurs as a result
of muscular work an increase in the quotient even above that regarded as
the maximal boundary. From this Seo concludes that the increase in the

33

514 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

consumption of sugar on account of muscular work is only possible when
pancreatic tissue is still present in the organism. This conclusion is not,
however, very convincing, v. Noorden explained analogous observation in
human diabetes by the fact that as a consequence of oversensitiveness of
the sugar-forming apparatus the steady appeal of which to the liver for
much sugar during muscular work is answered in an excessive manner.

The fact that the respiratory quotient after total extirpation of the pan-
creas is maintained at a very low level, and, as previously mentioned,
remains at this level in spite of administration of carbohydrates, was formerly
regarded as a chief argument for the disturbance of carbohydrate combustion.
v. Noorden mentions, however, that it has not as yet been shown that the
substance that undergoes combustion in muscle is not a sugar. What it has
been shown is only that the excretory product is not a nutritional carbohy-
drate; it may, however, be a fat.

Also other authors express themselves as against a disturbance in sugar
combustion. Chauveau and Kaufman investigated the sugar contents in
the arterial and venous blood of pancreasless dogs, and found that of the
arterial blood higher. Investigations on the "sugar puncture" hypergly-
cemia yielded the same result. Forges and Salomon found in their experiments
that on exclusion of the entire portion of the body lying below the diaphragm,
the respiratory quotient in the pancreasless dog rose as high or as even higher
than in normal animals under the same conditions. As the combustion
under these conditions takes place chiefly in the muscles, they assume that
after removal of the pancreas, the muscles are in a condition to burn up sugar.

Recently Knouthon and Starling have again entered the lists for a dis-
turbance of the sugar combustion in the pancreasless dog. If a heart-lung
preparation of a normal dog is transfused with normal blood, there occurs a
strong consumption of sugar. If, however, the heart-lung preparation of a
pancreasless dog is transfused with the normal blood, the consumption of
sugar straightway becomes o. If dealbuminized pancreas extract be ad-
ded to this blood, consumption of sugar reappears. Knouthon and Starling
conclude from this that tissue and blood contain a substance ordinarily
coming from the pancreas that is necessary for the sugar consumption in the
tissues.

The experiments of Knouthon and Starling may be interpreted in two
ways: Either in normal dogs the sugar is burned, or it is polymerized and
assimilated. According to the interesting experiments of Levene and Meyer
the latter is not at all unlikely. For these authors showed that through
the combined action of muscle-plasma and pancreas extract, the power of
reduction of a sugar solution becomes reduced, but may be regained on
cooking with acids.

The experiments also make necessary a revision of the important investi-
gations of Lepine on glycolysis.

EXPERIMENTAL NERVOUS DIABETES 515

It is very unlikely that the combustion of sugar in the pancreasless dog
ceases entirely. It must not be forgotten, that very intense grades of glyco-
suria occur not only in human beings, but that forms of diabetes may also
be produced in dogs, that are associated with a more intense elimination of
sugar than is the case'in pancreas diabetes. I refer to investigations of Lusk
on phloridzin diabetes, in which the quotient 3.6 was regularly attained.
Also in our investigations on simultaneous extirpation of the pancreas and
thyroid gland, and especially of pancreas and parathyroid glands were the
quotients high. Therefore in ordinary pancreatic diabetes it must either be
that less sugar is formed, or that sugar is still consumed.

If we adopt the standpoint that the combustion of sugar in the muscles
is only possible after preceding assimilation, the experiments of Starling
would show that the glycogenesis in the muscles and probably also in other
cells that otherwise contain glycogen is, without the pancreatic hormone,
highly reduced. A certain grade of glycogenesis is always found remaining
in the pancreatic diabetic dog, as already mentioned. If we assume that in
the experiments of Forges and Salomon that only the carbohydrates just
assimilated is consumed to the last traces, we may readily bring it in harmony
with the assumption that the assimilation of carbohydrates in the muscles of
pancreasless dogs is diminished. It seems to me therefore that the two series
of experiments do not unconditionally contradict each other, if the fact is
emphasized that in the pancreasless dog the formation of glycogen is dis-
turbed not only in the muscles but also in the liver.

It is very hard to explain the enormous increase of the protein decomposi-
tion, the salt- elimination, and especially also the caloric production, in the
dog with pancreatic diabetes. I shall return to this in the theoretical con-
siderations, later on.

I might summarize what I have just detailed in the following hypo-
thesis: The pancreatic hormone is an exquisitely assimilatory hormone,
and governs glycogenesis in the liver and muscles. In the light grades of
insufficiency the disturbance in carbohydrate metabolism occurs only when
there are instituted great demands on glycogenesis in the liver (alimentary over-
loading with carbohydrates). In the severer disturbances there occurs, in addi-
tion to the disturbance in anabolism, a marked increase in catabolic processes
and thereby a faulty decomposition of higher and lower fatty acids (ketonuria) .

B. Experimental Nervous Diabetes

The experimental nervous diabetes will be mentioned here only briefly.
Many important facts have already been mentioned in the chapter on the
suprarenals. We have to thank Claude Bernard for the fundamental ex-
periment. A puncture at a definite place in the fourth ventricle leads in
many animals to a glycosuria lasting several hours. Recently Aschner has

516 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

shown that a similar sugar center lies also further centrally, in the subtha-
lamic region. In sugar puncture the stimulus travels over the paths of the
sympathetic, and leads to an unburdening of liver glycogen and to hypergly-
cemia. If the conduction is interrupted in the spinal cord above the giving-
off of the splanchnics, or if the liver is previously rendered sugar-free, as for
instance, by strychnine, the puncture is of no avail. Until up to a few years
ago this is as far as the mechanism of sugar puncture had been explained,
nor did we know how the impulse was carried over from the splanchnics to
the liver. The investigations of the last few years have shown that the chro-
maffin tissue is to be regarded as the governing device. Already Blum had
expressed the opinion that sugar puncture acted by way of the suprarenals.
In common with Eppinger and Rudinger, I showed that in thyroidless dogs
adrenalin glycosuria as well as " sugar puncture" glycosuria were not induced.
Both were therefore prevented by the same factor. Waterman and Smith
found after puncture a mydriatic substance in the serum. But to-day we
must consider the methods used by these authors for the demonstration of
adrenalin as insufficient. A further analogy between adrenalin glycosuria
and sugar puncture lies in the appreciable hyperemia of the liver that occurs
after each procedure, as Priestly and / have pointed out. After each pro-
cedure there occurs an increase in blood-pressure (E. Neubauer) . For the con-
vincing experiment we have to thank R. H. Kahn. He showed that after
sugar puncture the staining of the suprarenals to chrome dyes as well as the
pressor power of the suprarenal extract decreases. If the puncture is done
after previous section of both splanchnics the glycosuria remains absent,
as is known, and the staining of the suprarenals to chrome dyes is retained.
It was shown therewith, in confirmation of the experiments of Nishi, that
the left splanchnic supplies both suprarenals, while the right splanchnic gives
off fibers only to the right suprarenal; for on action of the right splanchnic
the puncture makes both suprarenals poorer in adrenalin, while on section
of the left splanchnic only the right suprarenal suffers somewhat in its adrena-
lin contents. Electrical stimulation of the splanchnic (section of the nerves
and stimulation of the peripheral stump) elicits glycosuria. Tschebokraroff
had previously shown that the adrenalin contents of the blood of the supra-
renal veins is increased by electrical stimulation of the splanchnics.

Therefore the action of sugar puncture may be explained by an afferent
impulse conducted along the splanchnics, which leads to an unloading of the
chromaffln. How adrenalin occasions a dissemination of the sugar from the
liver is not as yet clear. E\ Neubauer thought that the hyperemia of the
liver was alone the cause of the dissemination of glycogen. I think, however,
that against this speaks the fact that there are agents that bring about dis-
tinct hyperemia of the liver without producing glycosuria. Such an action
has pituitrinum infundibulare, for instance. The hyperemia of the liver
may, however, very well favor the development of a glycosuric action, as has

EXPERIMENTAL NERVOUS DIABETES 517

already been dealt with in the chapter on the suprarenals. We might sup-
pose an activation of the diastatic ferment in the liver. Hofmeister reports
recently that after the puncture, the glycogen for the most part is no longer
found in the liver-cells, but in the efferent lymph and blood-vessels. Zulzer
first propounded the view that adrenalin and the pancreatic hormone have an
antagonistic action. > The poisonous action of adrenalin would be neutralized
by the pancreas hormone in the liver, v. Noorden expressed the view that
both pancreas and chromaffin tissue influence the diastatic process in a con-
trary manner — the pancreas inhibits, the chromaffin tissue accelerates it.
v. Furth and Schwarz have taken justified exception to the experiment of
Zulzer. A certain opposition in the action of the pancreatic hormone and of
adrenalin is, however, unmistakable. The former works assimilatorily, govern-
ing the building up of glycogen, and the latter is dissimilatory, occasioning
melting down of glycogen and decomposition in sugar. At all events we shall
see later that the alimentary factor governed by the pancreas and the
nervous factpr working by way of the chromaffin tissue may be highly inde-
pendent of each other!

According to later investigations of Bernstein and myself, I might assume
that as in the liver so also in the muscular system the same regulating powers
that govern assimilation and dissimilation are opposed to each other. In a
large series of experiments we saw the respiratory quotient rise in human be-
ings after the injection of adrenalin (previously Roth and Fuchs had already
reported on two experiments on patients with Addison's disease). The rise
in the respiratory quotient may be so appreciable that from it we may infer
a combustion-of an additional 30-40 gm. of sugar in the course of from half
to three-quarters of an hour. As after injection of adrenalin there occurs
also an impoverishment of the muscles in glycogen; I would consider most
likely that under the influence of adrenalin the glycogen is everywhere mobil-
ized and burnt1 in a precipitate manner, whereby a greater part of the sugar
is furnished precipitately to the blood from the liver, producing hyper-
glycemia and glycosuria. Now it is very noteworthy that in severe cases of
diabetes mellitus, that had been made sugar-free, we saw after injection of
adrenalin considerable glycosuria, but no rise in the respiratory quotient.
Hence there is absent in the severe diabetic the power to take into combustion
precipitately mobilized sugar; of course the possibility should be considered
that the sugar mobilized on account of adrenalin in the severe diabetic ema-

1 Such an increased combustion of carbohydrate seems moreover to be able to occur isolated
in the muscles. I refer to the experiments with "pituitrinum glandulare" already quoted in
the chapter on the hypophysis, in which there occurred a rise in the respiratory quotient, while
all other actions were quite opposed to those of adrenalin (lessening of the volume of the liver,
sinking of blood-pressure, no rise in blood sugar, but more often slight reduction, and finally
reduction in the total caloric exchange). Also in two experiments on severe diabetics was there
a rise in the respiratory quotients, while the reduction of the total gas exchange, showed with
certainty that the agent was active.

518 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

nates not from glycogen, but from fat; in such a case the respiratory quotient
should, however, sink.

II. CLINICAL PARTS

Although we are informed as yet only by hypotheses as to the intimate
process by which the pancreas enters into the regulation of the carbohydrate
metabolism, we have no reason for doubting the fact that the pancreas be-
longs to the most important regulators of the carbohydrate metabolism and
plays a leading role in its disturbances. If now we try to enter further into
the question as to what role the pancreas or its inner secretory function plays
in human pathology, we find that it is more to our purpose to view the
problem from two different sides. On the one hand it will be necessary to
pass in review the clinical pictures in which gross anatomical alterations of
the pancreas have been observed, and tq analyze which symptoms of the
total symptom-complex can be referred eventually to the disturbance of the
internal-secretory activity. A thorough description of these disease pictures
does not lie within the province of the task I have set for myself, and is also
not necessary for the purpose I am striving for; yet it seems tome desirable
to delineate them, at least in coarse outlines. For as we have already
mentioned in the consideration of the experimental physiology, there have
been attempts to bring many symptoms that were formerly referred to as
the external secretion of the pancreas into connection with the internal
secretion. On the other hand I shall draw the essential features of the
metabolic disturbance that we designate diabetes mellitus, describe the
pathologico-anatomical alterations found in the condition, and discuss what
role the pancreas plays in it.

It will be evident that there are a number of cases the analysis of which
we can approach as well the one way as the other.

A. Gross Anatomical Disturbances

An etiological classification of the diseases of the pancreas is not possible
to-day. As yet we know far too little in this respect. At any rate, the role
played by infection is important. This may occur hematogenously, or by
contiguity, in which case infectious processes of the neighboring parts affect
the pancreas; and finally especially in gall-stone affections (Hirschfeld} in
which infection reaches it from the intestines through the ducts. The route
last mentioned is by far the most frequent. An important role is played by
diseases of the vessels of the'pancreas and by cirrhotic process that depend
on the chronic action of poisons (alcoholism, etc.). Also trauma may come
into consideration as an etiological factor, especially in existing arterio-
sclerosis of the pancreas. Further we recognize a series of tumors of the
pancreas under which carcinoma is by far the most common; further cyst
formation, the genesis of which may be of various nature, and finally a con-

GROSS ANATOMICAL DISTURBANCES 519

genital failure of development especially of the insular apparatus (see genuine
diabetes).

An acute attack of the function of the entire pancreas may be -observed
under circumstances in apoplexy of the pancreas or in acute hemorrhagic
pancreatitis. The first occurs chiefly in old corpulent drunkards with ad-
vanced arteriosclerosis. In association with suddenly onsetting abdominal
pains there occurs distention of the abdomen in the epigastrium, retention of
feces, vomiting, and finally, with distinctly pronounced manifestations of
ileus, death in the course of a few hours or days. Section shows enormous
blood effusions in the pancreas, and eventually into the abdominal cavity, as
the consequence of hemorrhage from the pancreatic vessels. The course of
the disease is for the most part so fulminant, that glycosuria mostly does
not occur even on complete destruction of the pancreas.

Acute hemorrhagic pancreatitis usually sets in with acute gastric dis-
turbances after indefinite prodromal symptoms that have lasted for some
time; to the gastric disturbances are rapidly added distention of the epigas-
trium, violent pressure pains in the pancreatic region and high fever; either
death follows rapidly under the manifestations of acute ileus and perforation
peritonitis, or the case comes to remissions; then usually the disease lasts a
longer time. Symptoms, that depend on falling away of function of the
pancreas are not rarely observed. In a case that proceeded rather acutely,
I found 12 per cent, of sugar in the urine. In this case the reduction of the
copper sulphate took place even in the cold. An interesting case with a
chronic course is described by Albu. In a twenty-nine-year-old woman who
had formerly 'of ten suffered with violent pains in the gastric region there
gradually developed in association with rise in temperature a resistance in
the epigastrium, fat-stools, and glycosuria. After a transitory improvement,
the manifestations grew worse again, and a piece of necrotic pancreas tissue
was removed on operation. A second operation was necessary on account of
suppuration of the gall-bladder, after which the febrile process ceased, the
fat-stools and the glycosuria disappeared; after some time there was a
recurrence of the fat-stools, and of the sugar up to 5 per cent.

Acute hemorrhagic pancreatitis was first described by Balser. Later the
clinical picture was accurately described chiefly by Korte. According to
the recent experimental investigations it is to be assumed that there first
occurs necrosis of the pancreatic tissue through infection from the intestine
or through the pancreatic duct (Korte, Opie) on account of nutritive disturb-
ances, and then this goes on to fat necrosis through the action of the pancre-
atic juice. The fat necrosis probably travels further by way of the lymph
channels, and then the pancreatic secretion gets into the circulation and
acts toxic (Gulecke and v. Bergmami). Disturbances in sugar metabolism
are lo be expected, only if the process involves the greater part of the gland
and is not too fulminant.

520 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

It is very probable the chronic inflammatory processes of the pancreas
occur more frequently from infection through the pancreatic duct than we
had previously supposed. Hirschfeld described three cases in which at the
end of an influenza or of febrile angina there occurred either swelling of the
liver and gastric distress, or colicky pains and glycosuria of 2 to 6 per cent.
After lasting one to five months the pains disappeared. Sometimes chronic
pancreatitis occurs in cholelithiasis, although here the insular apparatus
is affected only rarely. Mayo Robson found only four cases of diabetes
(0.2 per cent, of 0.4 per cent, sugar) among sixty-five cases with stones in
the ductus choledochus and with hard enlarged pancreas. In three cases
the sugar vanished after the operation. Later one case passed into severe
diabetes.

Before I enter more intimately into chronic pancreatitis and pancreatic
cirrhosis, I would mention a special form of "it, namely, the luetic. The heredi-
tary syphilitic form is apparently chiefly interstitial, and avoids the insular
apparatus, on which account it almost always pursues its course without
glycosuria. The syphilitic pancreatitis of adults is either gummatous
(Hernheimer, Hirschfeld} , or interstitial. The latter form, if it progresses, may
also temporarily damage the insular apparatus and thus lead to glycosuria.
Chrelitzer, Ehrmann, Albu et al., report such cases. In the case of Chrelitzer, a
relapse of lues occurred ten years after the primary affection. Simultaneously
with the exanthema occurred abdominal pains radiating toward the back,
vomiting, meteorism, jaundice, swelling of the liver and rise of temperature.
A hard tumor was palpable deep between the navel and the xiphoid process.
In the urine was found 2.2 per cent, of sugar. Cure occurred spontaneously.
In Ehrmann's case an extremely severe diabetes (8 per cent, of sugar, acetone)
developed at the time of the outbreak of a syphilitic exanthema. The
inunction cure was interrupted and an antidiabetic regimen introduced. All
symptoms disappeared within eight days. Albu's case was very chronic.
In a forty-four-year old man (primary affection fourteen years previous)
there developed gastric disturbances, emaciation, jaundice, and enlargement
of the liver; after a longer time, fat stools and glycosuria (0.9 per cent.);
also a tumor was palpable deeply. Under enemas of potassium iodide, and
pancreatin, improvement occurred; and after several months tumor and
glycosuria disappeared and the case was cured. In general, lues does not
play a great role in the etiology of diabetes, v. Noorden found syphilis in
the history of 1.2 per cent, in male individuals under twenty years of age,
7.1 per cent, in males over twenty, and 2.3 per cent, of female diabetics of
all ages.

Chronic indurative pancreatitis is a very common disease. It may proceed
from the vessels (arteriosclerosis, endarteritis obliterans) or from the excre-
tory ducts. It may be diffuse or circumscribed. In gall-stone affections
there may sometimes occur isolated sclerosis of the head of the pancreas

GROSS ANATOMICAL DISTURBANCES 521

(Riedel). Chronic indurative pancreatitis often occurs simultaneously with
atrophic cirrhosis of the liver, especially in alcoholics. Weintraud, Bence,
and others have described such cases, in which as a result of high-grade de-
ficiency of pancreatic function there occurred pronounced disturbances of
fat absorption. In Btnce's case severe diabetes existed. The section showed
a marked disappearance of the pancreas and sclerosis; the islands of Langer-
Jians were entirely destroyed, and only remnants of the acinous tissue were
present. In very severe alcoholism there exists simultaneously sclerosis of
the liver and pancreas (and suprarenals) , sometimes associated with the
deposition of iron-containing pigment in the liver, pancreas, skin, etc. (cir-
rhose bronzee or diabete bronzee). Atrophy of the pancreas with sclerosis
is a common finding in diabetes mellitus. When it occurs the insular appa-
ratus is mostly rather severely damaged. We shall come back later to the
consideration of v. Hansemann's granular atrophy of the pancreas and the
interacinous sclerosis of Opie, and the sclerosis periacinous of Lepine, and
Lemoine and Launois. In severe damaging of the glandular parenchyma,
there may in such cases occur disturbances of absorption. In the case of
Keuthe, that had previously been described by Glassner and Siegel, there
existed a moderate disturbance of the fat absorption (the fat in the diet was
slight only) and several times transitory glycosuria (of 0.3 per cent, to 0.7 per
cent.). The autopsy showed marked atrophy of the pancreas, the duct of
Wirsung was not to be found, the islands of Langerhans were in part retained
or were hypertrophied. Sometimes the marked sclerosis of the pancreas is
the result of a lithiasis pancreatitis. Lithiasis of the pancreas may occur
isolated; but not rarely it is combined with cholelithiasis. In certain cases
kidney stones were also found. In this event, we may speak of a general
stone diathesis, that not rarely is familial. The pancreas stones are whitish,
brittle, crumbly, unlike gall-stones they contain no pigment, but on the con-
trary are rich in lime-salts, so that under circumstances they can be demon-
strated by the X-rays. Probably they usually originate (as do gall-stones)
after a chronic catarrh has established in the duct system of the pancreas.
Often the larger and smaller pancreatic passages are plugged up with stones.
In other cases there are found one or more larger stones, which pass with
severe colic, and may temporarily or permanently block up the larger ducts
of the pancreas, or even the principal excretory duct. Behind the place where
the stone lodges there often occurs a dilatation of the passage in question and
an indurative pancreatitis, which at the beginning affects the islands but little,
but no longer duration damages them severely. The pancreatic colics that
Minnich first intimately described commence with severe girdle-like pains
radiating to the back and even to the shoulder. In a case that I saw, the
girdle-like pains associated with symmetrical hyperesthetic zones over
the iliac crests led me to think of a spinal affection, until on the next day the
occurrence of very voluminous stools with creatorrhea and steatorrhea made

522 DISKASKS OF THE INSULAR APPARATUS OF THE PANCREAS

possible the diagnosis of occlusion of the duct of Wirsung by a pancreatic
stone. The impaction of a pancreatic stone can also take place without pains.
This was the case in a patient observed by Gigon and me. Also here there
recurred from one day to another all the acute absorptive disturbances
characteristic of impaction of a pancreatic stone, without, however, the exist-
ence of colic. At autopsy there was found in addition to numerous small
stones in the pancreas a stone the size of a cherry stone which fully occluded
the place of opening of the pancreatic duct into the ampulla of Vater.

The high-grade indurative pancreatitis that so frequently complicates
stone of the pancreas, especially on the occlusion of the chief excretory duct
by a stone, makes intelligible the fact that lithiasis of the pancreas is so fre-
quently associated with disturbances of the sugar metabolism. Oser reports
that among seventy cases, diabetes or at least temporary glycosuria was
observed in twenty-four, that is, in more than 34 per cent, of the cases.
Lazarus indeed found it in 45 per cent. Albu mentions an interesting case.
The test for alimentary glycosuria had previously resulted negative. There
existed a tumor in the region of the. pancreas which distinctly enlarged during
a severe attack of colic. On test for alimentary glycosuria, 2.9 per cent, of
sugar was found in the urine. In the' case of mine previously mentioned a
slight diabetes existed before the colic. The patient could easily be made
sugar-free by a strict diet. After the colic and the occurrence of the fat
stools, the diabetic metabolic disturbances became essentially worse; after
about eight days the voluminous stools disappeared; after another two weeks
the stools were entirely normal, even after heavy overloading with fat;
simultaneously with this there was also observed a retrogression of the dia-
betic metabolic disturbances, so that the patient again became temporarily
sugar-free. Apparently as a sequel of severe inflammatory processes in the
ducts, the islands of Langerhans do not, in occlusion of the duct of Wirsung
by stone, behave so refractory as in animal experimentation after ligation
of the excretory ducts. It is also of importance for the occurrence of dis-
turbances in sugar metabolism, whether the second pancreatic duct is ob-
literated or is likewise closed by a stone, or whether numerous intrapancreatic
passages are rendered impassable; as the intensity and the extensiveness of
the sclerotic processes are in part dependent on these factors.

These circumstances are also important for the occurrence of disturbances
of absorption. It is without other considerations to be expected that these
only become manifest in a pronounced manner when the flow of pancreatic
juice into the intestine either fs fully interrupted, or at least almost completely
ceases. I would like to enter here upon the question as to the relationship
that exists between the disturbances of absorption that occur on cessation
of the pancreatic juice in man, and the internal secretion of the pancreas.
At the beginning, when the animal experiments of Abelmann were regarded
as indicative, the question seems to have become entirely cleared. We

GROSS ANATOMICAL DISTURBANCES 523

referred the occurrence of absorptive disturbances to the absence of the pan-
creatic juice, the occurrence of glycosuria to insufficiency of the internal
secretory activity of the pancreas. In more recent times this question has
encountered confusion in the literature. Naturally there occur disturbances
of fat and albumin absorption when the production of pancreatic juice is
normal, as in profuse diarrheas of different origin, amyloidosis of the intestine,
etc. We know further the disturbances of fat absorption in complete cutting
off of the bile from the intestine and also the fat stools in certain forms of
Basedow's disease; as important differential criteria against both the last-
mentioned forms are, since Friedrich v. M tiller's investigations and the
observations of v. Nporden's clinic as to Basedow's disease, the disturbance
in fat decomposition that occurs on the cutting-off of the pancreatic juice
and again the slight holdings in soaps. To this should be added the fact
that in typical pancreatic stools, the creatorrhea, that is the more prominent
occurrence of striped muscular fibers, dominates the microscopical picture.
With this is associated a more distinct loss of nitrogen by way of the feces
than is observed in other disturbances of absorption. Finally there have been
worked out a series of methods for demonstrating the absence of a proteolytic
or amylolytic ferment in the feces obtained after purgation. Many authors
have raised objections to these diagnostic postulates, as they have observed
cases of disease of the pancreas in which the characteristic disturbances of
absorption were absent, in spite of complete cutting-off of the pancreatic
•juice from the intestine. Thus Deucher, Albu, Ury, Alexander, Keuthe and
Brugsch saw normal fat splitting in pancreatic diseases. Also creatorrhea
is sometimes absent. We might suppose that in these cases the other diges-
tive ferments have entirely taken over the role of the pancreatic secretion.
Brugsch explains that on simple occlusion of the excretory duct of the pan-
creas there occur no, or only temporary, absorptive disturbances, but more
intense disturbances only when the pancreas is completely degenerated,
or the gland tissue is for greater part destroyed through carcinoma or ab-
scesses, etc. Then only would loss of fat occur up to 60 per cent, and the
nitrogen loss up to 20 per cent. This hypothesis, which has indeed not been
based on the examination of a definite case, but has been influenced by the
views of Lombroso which we have already criticised, is not decisive. I refer
only to the previously mentioned case of Gigon, in which the absorptive
disturbances set in suddenly on occlusion by stone and lasted until death.
The pancreas cannot degenerate in a day; if, however, it has already been
markedly degenerated, we cannot readily see how it can have furnished
sufficient secretion up to the day on which the occlusion occurred. Too, it
seems especially inappropriate to apply off-hand to human pathology the re-
sults of animal experiments, which as we have seen are not as yet fully ex-
plained. It would indeed be conceivable that the other digestive secretions
in the dogs render the pancreatic secretion less indispensable than in man.

524 DISEASES OF THE INSULAR APAPARTUS OF THE PANCREAS

In human pathology, the conditions seem to me to be clearer and to justify
a single standpoint, v. Noorden and Salomon have pointed out in this re-
gard that in cases of absence or insufficiency of the pancreatic juice, the ab-
sorptive disturbances become manifest, if the intestine is overloaded with
fat; if in this functional test, butter stools occur we may take it for granted
that there is certainly a disease of the pancreas or absence of the pancreatic
juice. Also this is true if creatorrhea makes its appearance. It should
not be forgotten that in many of the cases of pancreatic disease in the litera-
ture (especially in carcinoma, in which fat stools are absent, on account of
the increasing cachexia), the intake of diet was very slight at the time of the
observation. We must here again refer to the anatomical relations of the
duct system. We must consider that if the second duct of the pancreas is
not obliterated or occluded, enough pancreatic juice may still reach the in-
testine, even if the principal duct be completely occluded, that the disturb-
ance does not become manifest even on heavy overloading. As far as the
fat splitting is concerned, Salomon has pointed out that during the tedious
procedure of drying the stools on. the water-bath, always more fatty acids
occur. If we do not take this into account, we may arrive at entirely false
values for fat splitting. We may summarize by saying that markedly
lessened or absent production of pancreatic juice, or cutting-off of the
pancreatic juice from the intestine, leads in man to characteristic absorptive
disturbances.

I have entered into detail into these conditions, because we require a
clear formularization if we wish to enter into the question as to how far the
internal secretory activity of the pancreas is independent of the external
secretory activity, and whether these disturbances occur isolated in the
gross anatomical diseases of the pancreas. In the acutely onsetting, severe,
damagings of the organ (suppurative or acute hemorrhagic pancreatitis,
necrosis of the pancreas or apoplexy of the pancreas) it is intelligible that we
do not see much of the disturbance of the external or internal secretory
activity of the pancreas. Often, too, in complete extirpation of the pancreas
in animal experimentation, the sugar does not occur immediately if septic
processes are present at the same time. When diet is low or not ingested
at all, of course the absorptive disturbances do not occur either. If the course
is subacute, as a rule both disturbances are present. In tumors of the pan-
creas, the behavior of the disturbances varies very much. Cysts may leave
behind sufficient functionating pancreatic parenchyma and hence may pursue
their course without any disturbance whatsoever. If the greater part
of the pancreas takes part in the process sympathetically, a latent in-
sufficiency of both functions may develop that may eventually become
evident only on overloading; although it is intelligible that in individual cases
on account of especial anatomical relation the absorptive disturbances may
become more distinct through compression of the duct system. In carcinoma

GROSS ANATOMICAL DISTURBANCES 525

of the pancreas it seems that the islands of Langerhans hold out longer against
the carcinomatous infiltration than do the acini. As the carcinoma usually
is seated in the head of the pancreas it not infrequently happens that there
is. complete shutting of! of secretion through compression of the chief duct,
and hence a distinct prominence of absorptive disturbances. We should
consider, of course, that the ingestion of food in such a case is very slight on
account of the cachexia.

In carcinoma we not rarely observe, in addition to this that the intensity
of the glycosuria diminishes with increase in the cachexia, or the sugar en-
tirely disappears. This is entirely comprehensible. We see even in the
pancreasless dog the glycosuria diminish, if with the weakening of the liver
processes the mobilization of sugar is also less. In slight grades of chronic
indurative or more atrophic pancreatitis no disturbances in carbohydrate
metabolism need necessarily be present. In advanced cases it may very well
be assumed that the function of the insular apparatus has often suffered
previous damage and has thus led to disturbances in the sugar metabolism.
We shall see later that this form of pancreatitis not rarely forms the patho-
logico-anatomical stratum for the "genuine" diabetes mellitus. In this,
as is well known, no absorptive disturbances occur, although the antidia-
betic diet mostly means a considerable and permanent overloading of the
fat absorption. In former times this was associated with a heavy overload-
ing of the intestines with meat. Thus can the production of pancreatic juice
be strongly limited without disturbances of absorption becoming manifest.
These occur only with the higher grades of atrophy of the pancreas. The
most important are the cases with occlusion by stone, and those of consecutive
sclerosis. In stoppage of the duct by stone we have in addition the suddenly
appearing characteristic absorptive disturbances, which are fully developed,
and most often the latent or manifest disturbances in carbohydrate me-
tabolism that had already been present, perhaps because the catarrh of the
duct system has for a long time led to incrustation of the ducts and to in-
durative pancreatitis. There are, however, cases in which, at least at the
beginning, there exist fully developed disturbances of absorption, but only
minimal latent disturbances of carbohydrate metabolism. These cases are
entirely intelligible, if through impaction of a gall-stone or through other
factors leaving the pancreas for greater part intact, the supply of pancreatic
juice is interrupted. Ehrmann and others, have described such cases. As
example I submit the following:

Observation LXVIII. — R. M., thirty-five years. Entrance into the clinic Nov., 1911.
Until one and one-half years ago the patient was entirely well. Then obstipation that
often lasted four or five days set in, and also slight headache. For about seven months
severe colicky pains in the right hypochondrium, about ten days after this jaundice, that
has lasted until to-day. Since this time four or five bowel movements daily that were
very voluminous, " more than he ingested as food." The stools are clay-colored. In spite

526 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

of this fact the appetite remained very good, the patient fell off rapidly. The patient is
almost entirely impotent. More severe jaundice, hair on head very much thinned out,
that in the axillae almost entirely absent, sparse on the pubis. Colossal hydrops of the
gall-bla-dder. In addition, in the middle line, very deep, is a resistance hard to outline.
Ascites.

Rontgen examination: diffuse aortic extension of a moderate degree. Wassermann
negative. Increased peristalsis of the stomach, although emptying of the stomach is not
essentially slowed. Urine deeply jaundiced, no sugar. Chemical examination of the
stomach contents normal.

The stools (3-4 daily) are very massive and are acholic; urobilin test constantly nega-
tive; minimal, quantitatively not estimable amounts of urobilogen (Dr. Charnas). The
stools are of gray-white color, glittering with fat, of very foul odor, microscopically show
much neutral fat, soap and fatty acid needles and striated muscle fibers. By loading with
fat (250 gm. oats, oatmeal, and 300 gm. butter) there occur typical butter stools. The
test was repeated five times always with positive results.

The chemical examination of the stools (with the overloading test) showed 38.5 per
cent, unsplit fat and 64.2 per cent, fat in the form of fat acids and soaps. The chemical
examination of the butter-stools showed 71.7 per cent, neutral fat.

The examination of the stool for tryptic ferment according to Gross, and also for dia-
static ferment according to Wolgemut showed only traces. In one examination, however,
there was found slight, but distinct tryptic and diastatic action.

Five tests for alimentary glycosuria (100 gm. of dextrose, fasting) were always negative.

During the stay at the hospital there often occurred colicky pains in the gall-
bladder region.

The ascitic fluid had a specific gravity of 1012, 8 per cent, albumin. The albumin
bodies precipitated by acetic acid were present only in traces.

The Salomon-SaxVs carcinoma reaction was positive.

Although the Salomon-SaxVs test as well as the ascites spoke for a new growth, yet the
possibility of an occlusion of the ductus choledochus by stone could not be excluded; so that
the patient was operated on. There was found at operation, deep down in the abdominal
cavity, a tumor whose situation was not quite clear. Cholecystogastrostomy was done.
Death occurred some weeks afterward. Section showed a scirrhous carcinoma of the
head of the pancreas, with closure of the pancreatic duct, marked dilatation of the passages
in the body and tail of the pancreas. The ducts were filled with a milky yellowish fluid.
The ductus choledochus was occluded about ij^ cm. above the papilla of Vater, and
there was marked dilatation of the bile ducts above it.

The case described fulfills all the conditions that we could establish
at a physiological experiment. There are present all symptoms that are
characteristic for the cutting-ojf of the pancreatic juice (and the bile) , while
the carbohydrate metabolism was entirely normal even on heavy overloading.
Such cases have an important significance. They show us that in human
beings the internal secretory and the external secretory activity of the pancreas
are fully independent of each other within wide limits.

B. Genuine Diabetes Mellitus

It is not my intention here to depict the symptomatology of diabetes
mellitus in exhaustive fashion. Much more will I limit myself merely to
sketching the clinical picture, assigning only somewhat more space to the

GENUINE DIABETES MELLITUS 527

metabolic disturbances in order to discuss later the position of the pancreas
in the pathogenesis of diabetes mellitus.

The Carbohydrate Metabolism. — Among the symptoms of diabetes
mellitus, glycosuria is the most striking for physician and laity. Theoretically
and also more practically important, certainly, is hyperglycemia, for glycosuria
is only a result of this. There is in diabetes mellitus an excretion of sugar
without hyperglycemia, but not rarely does there occur hyperglycemia
without excretion of sugar. If the diabetes has existed for a long time, the
kidneys lose their finer sensitiveness for the heightening of the blood-sugar
contents, they gain in sugar-imperviousness (v. Noor den, Lief mann, and Stern}.
There is also in such cases no proportion between the degree of the hypergly-
cemia and the intensity of the glycosuria. Especially is this true for the dia-
betes of old age. The fact is also very important, as may be expected, that
the tolerance only rises when the sugar in the blood has been for a long time
normal, and that a series of symptoms, that we regard as the sequel of a long-
continuing hyperglycemia (furunculosis, impotence, diabetic gangrene,
rheumatoid pains, etc:) only vanish when the hyperglycemia is combated.

For the assumption of diabetic disturbance of metabolism there is neces-
sary the demonstration that the sugar excreted in the urine is grape-sugar.
Further, there must be excluded a series of conditions that according to
experience are associated with a temporary excretion of sugar, or at least
appreciably reduce the tolerance for carbohydrates. Of such conditions I
mention acute febrile diseases, intoxication with carbon monoxide or mor-
phine, and asphyxic conditions, etc.

It should further be considered that after copious ingestion of sugar,
sometimes slight amounts of sugar are found in the urine of even normal
human beings. The glycosurias in certain ductless diseases especially in
Basedow's disease and in acromegaly are considered in detail in the chapters
on the subject. We shall consider later the matter of nervous glycosurias
(in traumatic neurosis, hysteria, neurasthenia, and in certain nervous diseases,
such as tabes and [general] paralysis).

I might here mention the laws that the excretion of sugar follows. In the
great majority of cases of diabetes we can observe a narrow relation between
intake of food and excretion of sugar. If we place such a diabetic on a diet
of a constant composition, the excretion of sugar sets in at a definite level and
maintains it for a long time. In cases that have not advanced entirely too far,
it is known that the tolerance may be influenced by a corresponding dietetic
regime. If the patient on account of the limitation of the sugar-forming
material becomes sugar-free, and if the amount of sugar in the blood remains
for a long time normal, a reparation occurs, so that later a diet without gly-
cosuria may be borne that formerly led to sugar-excretion. On the other
hand the tolerance is depressed when a high sugar-content of the blood has
existed for a long time.

528 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

It is known that the individual food-stuffs are not equivalent in their
action on the glycosuria. Carbohydrates and protein act more positively
on the glycosuria than fat, while alcohol, for instance, does not influence the
glycosuria. Also the individual carbohydrate and albuminous bodies show
differences in their action. Of the kinds of sugar, maltose, for example, acts
more glycosuric than glucose, and this again acts more strongly than levulose.
However, the individual diabetics do not behave the same throughout. For
example, milk-sugar is borne very well by many, others react to it with a
severe excretion of sugar.

Also the individual protein bodies influence the glycosuria in different
manners. To mention only a few examples, casein and meat-albumin act
more on the glycosuria than plant-albumin and egg-albumin, the latter acts
less glycosuric when it is ingested in its. native condition. The founda-
tion for this lies partly in the fact that the individual albuminous bodies are
drawn into decomposition at different rates. In very severe cases of diabetes
the differences vanish, however. Otherwise the individual diabetics act
differently with regard to the administration of protein. Especially severe
cases often react to increase of the ingestion of protein with a sugar elimina-
tion relatively stronger than on the administration of carbohydrates — "pro-
tein sensitive cases."

The question whether in human diabetes sugar can be built out of pro-
tein has been energetically discussed. On the clinical side it has been shown
that severe cases of diabetes mellitus that have been kept for months on
exclusively meat-fat-diets, constantly excrete so much sugar that it is hardly
possible to refer this to the slight carbohydrate-content of the diet and to the
original glycogen-content of the organism. It is further known that in
especially severe diabetics the excretion of sugar varies simultaneously with
the ingestion of protein. The question of sugar-formation out of protein
can to-day be answered with a "yes." On the contrary the question as to
what extent the normal or the diabetic organism can build sugar out of pro-
tein cannot be safely decided with the methods of investigations of me-
tabolism to-day at our disposal. We cannot in this manner make sure as to the
origin, as far as ingested food material is concerned, of the sugar eliminated
in the urine. It is very probable that the sugar also appearing in the urine
in slight cases does not only depend on the change in carbohydrates, but also
on that of the protein. Theoretical considerations that I shall not enter into
here, speak for the fact that from 100 gm. of protein (about 16 per cent,
nitrogen) not more than 80 g'm. of sugar can be formed. From i gm. of N.
therefore would come about 5 gm. sugar.

The question is much more complicated by the fact that we have, too, to
regard fat as a sugar-former. At all events, however, the administration of
fat does not ordinarily increase the excretion of sugar. On these facts the
dietetic treatment of diabetes is for most part built. This is readily under-

GENUINE DIABETES MELLITUS 529

stood when we consider, that, as v. Noorden emphasizes, that fat is transmitted
to the blood and the tissues especially by the lymphatic paths, and from there
is transported to the liver only in accordance with needs, while carbohydrates
and protein directly flow to the liver through the portal vein and increase
the condition of irritability of the liver. The facts that, apart from theoret-
ical considerations, speak for the formation of sugar from fat: In severe cases
of diabetes mellitus we sometimes observe a not inappreciable increase of
sugar elimination when we administer large quantities of fat during a hunger
period. In such cases the dextrose to nitrogen quotient sometimes raises to
10. Further cases are known in which on abundant ingestion of fat the dex-
trose to nitrogen quotient is found higher than in the period of less fat in-
gestion. Finally, we have the results of exact metabolism investigations in
cases of very severe diabetes, which show that for long protracted periods
so great quantities of sugar eliminated that these cannot be explained by
the changes in protein and carbohydrates, v. Noorden has therefore men-
tioned that the conclusions drawn from the dextrose to nitrogen quotient as
to the extent of the formation of sugar out of protein in human diabetes, are
faulty, as we do not know the source of the sugar.

In one group of diabetics this regularity, as just described, between the
sugar-value of the food and sugar eliminations exists in much less well ex-
pressed manner; indeed it may even happen that this law may be broken
down by other factors. I shall describe in detail later the nervous glycosurias
dependent on organic foundations. I shall cite here only the psychical fac-
tor. Any psychical agitation, a fright, a great excitation on account of a
case of death in the family, or business cares, can suddenly lead to an out-
break of the diabetes. The glycosuria may attain a high grade; lassitude,
great thirst, polyuria, induce the patient to consult the physician, who then
finds sugar.

Often a slight limitation of the diet suffices to bring about a disappearance
of the sugar, or the sugar disappears spontaneously. In a short time, normal
tolerance is reestablished. At all events such cases as just mentioned are
exceptional. Ordinarily, also in this group of cases is the alimentary factor
plainly to be recognized; but this is small in comparison with the psychical
factors. In such cases we see not rarely that painful affections of any sort
at all may serve to increase the excretion of sugar. I naturally will not say,
concerning the category of cases in which the alimentary factor dominated
the scene, that also psychical excitements may not temporarily lower the
tolerance. In the nervous cases, however, the nervous factor predominates.

The Protein Metabolism. — The question of protein need in diabetes has
been studied in numerous metabolism investigations. In light and mod-
erately severe diabetics the protein need is certainly not increased; and even
in severe diabetics, as long as they are nourished rationally, we cannot speak
of an increased need for protein. This has long been shown by the protracted

34

53° DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

investigations of Wcintraud. In a series of severe cases, I have investigated
the nitrogen elimination of the " hunger" day and found values that do not
differ from those furnished by normal individuals under like conditions. The
severe diabetic, he who rationally fed, remains constantly on a diet rather
poor in protein, can indeed enter upon a striking low protein need, and shows,
when abundant protein is now administered, a striking tendency to reten-
tion of nitrogen. Only in the severest cases, before the fatal coma, does the
melting down of protein seem to raise to a high degree.

Benedict and Joslin calculate the nitrogen elimination per kilogram of
body weight in their fasting-experiments, and find that the average of all in
these experiments is higher than in normal individuals; yet much might be
said in objection to the calculation per kilogram of body weight, as the rela-
tion between protoplasm and body-mass becomes disarranged in severe dia-
betics on account of the extreme poverty in fat.

In the severest cases also the high elimination of endogenous uric acid
indicates a marked melting-down of muscle albumin (v. Noorden).

The qualitative alterations of the protein metabolism are, apart from the
high ammonia values dependent on the becoming acid, not appreciable.

We shall here say only a few words about the ketonuria of diabetics. The
ketone bodies originate kfrom the change in protein and fat substance on
diminished carbohydrate combustion. The cause of this origination should
not be otherwise than in a normal man when he has been fasting or has eaten
meat and fat exclusively. Also in this case they are due to the lack of
assimilation of carbohydrates. That in the diabetic such considerably
high degrees are attained is comprehensible because in him is absent also the
sugar originating from the protein, and because they develop so very gradu-
ally. If the ketonuria lasts longer and attains higher grades, it gives rise to
lipoidemia and to fattening of the liver. In the most severe grades of lip-
oidemia the blood may assume a light rose-red color and on standing may
express a cream-like dense layer to the surface.

The alterations in the salt metabolism to be observed in diabetics are
associated in part with the formation or the elimination of ketone bodies.
Through the formation of large amounts of the ketone acids, alkalies are
withdrawn from the body, and as is known, later the alkalescence of the
blood sinks and then the calcium equilibrium is minus (Gerhardt and W.
Schlesinger) .

The equilibrium of water in diabetics often shows significant variations
on alterations of the diet. If diabetics who formerly had fed without
purpose are placed on a diet poor in carbohydrates and protein, they often
gain in weight in a short time. It is very probable that this depends not so
much on the filling up of the fat deposits and partly also of the glycogen
deposits, but much more on the retention of water. In more fully advanced
cases the water-contents of the tissues is much reduced. Rumpf found the

GENUINE DIABETES MELLITUS 53!

Water-contents of the tissues of diabetics who had died in coma
per cent, lower than in normal individuals.

The Respiratory Metabolism.— The first experiments as to the caloric
exchange in diabetics are those of Pettenkofer and Volt. At the beginning,
these investigators misinterpreted their experiments. They overlooked on
the one hand the loss in oxygen that the diabetic suffers through the elimina-
tion of sugar rich in oxygen, and on the other hand they committed the error
of comparing the change in an emaciated diabetic weighing 54 kilograms
with a healthy individual weighing 71 kilograms. These objections have been
set forth especially by Leo; Pettenkofer and Voit later modified their opinion;
Fr. Voit again discussed the experiments in detail and came to the conclusion
that in severe diabetics the demand for calories is not increased. This
result is entirely in agreement of the long-protracted metabolism experiments
of Wientraud carried out at Naunyn's clinic. H. Leo, R. Stiive, Nehring and
Schmoll, and Magnus-Levy and Salomon have further instituted experiments
with the Zuntz-Geppert apparatus. They found that in severe diabetics
the oxygen requirements were increased. I shall not enter into the question
of the experiments of Livierato and of Robin and Binet, as the methods used
are not reliable.

The interest in this question was reawakened through the demonstra-
tion that there was an increase in the production of calories in the dog
without a pancreas. Since this is true a series of experiments have been pub-
lished. Of especial interest is a great number of experiments that were
carried out in, Atwater-Benedict' 's respiration calorimeter. Finally I men-
tion a series of experiments carried out by Eugene DuBois and Borden 5.
Veeder with Pettenkofer's apparatus at Kraus's clinic, and finally experi-
ments with the Zuntz-Geppert apparatus by Leimdorfer. I shall discuss
later the experiments last mentioned. The experiments of Eugene DuBois
and Borden S. Veeder showed no increase in heat production. These authors
arrived at the same results as did Pettenkofer and Voit.

A more exact exposition is demanded by the first-mentioned experi-
ments carried out in the respiration calorimeter. They were begun by
Benedict, Dr. Joslin and myself in collaboration, when I had gone to Boston
for the study of the respiration calorimeter. Our work in common concerned
itself with the first twelve experiments. I reported briefly concerning
these experiments at the Congress for Internal Medicine, 1909; and there, on
the ground of the comparison of the figures obtained with those obtained
with a normal subject, whom I had especially selected for comparison on
account of his low body weight, came to the conclusion that the resting-
exchange of the three diabetics investigated by us, and especially that of one
very severe case, was not essentially raised. Later Benedict and Joslin on
the ground of their more numerous experiments came to another assump-
tion. Since that time I have let the matter rest on account of other work.

532

DISEASES OF THE INSl LAR APPARATUS OF THE PANCREAS

Only now at the preparation of this chapter have I received the experiments,
and also the large experimental material of Benedict and Joslin. and have
attained the conviction that I must hold fast to my original opinion. As
the question is of importance, I shall contribute the first twelve experi-
ments, that Prof. Benedict has in praiseworthy manner allowed me to pub-
lish separately in extenso. There will be found in them some details that
seem to me to warrant an exact exposition.

First, a few remarks concerning method. The experiments herewith published were
carried out in a so-called calorimeter. Therefore in the fasting experiments we were
concerned with estimation of the exchange in a quiet, comfortable, sitting-position. It is
to be expected that the values obtained in the fasting-experiments do not fully represent
the fundamental exchange, but lie somewhat higher. The figures republished by me
differ somewhat here and there from those in the corresponding experiments of Benedict
and Joslin. I cannot state the reason for this, the differences are however so slight that
they do not influence the total result in any way. As concerns the exact details of the
arrangement of the experiments, I refer to the work of Benedict and Joslin. In the tables
will be found the heat-production as well as the heat-elimination. The values for the
heat-elimination were estimated, by adding to the value shown by the calorimeter, also the
vaporization heat of the water produced (amount of produced water 0.568). The cal-
culation of the heat production was based on the behavior of the body-temperature.

If, for example, the body temperature during an experiment rose, there was added to
the amount representing the elimination of heat an amount that would be necessary to
warm the person under experimentation the corresponding tenths of a degree. If the
temperature fell, the loss of heat had to be subtracted from the figures representing heat
elimination. Ideal values for the heat production we do not find, however, as the indi-
vidual organs may possess different temperatures, and, for example, after ingestion of food
the fall of heat from the liver to the mouth or rectum, where the temperatures are taken,
ought to be greater than during fasting. Perhaps this is the reason that Benedict and
Joslin do not give values for heat-production in their experiments.

EXPERIMENT No. I. — PERSON UNDER EXPERIMENTATION A

0

Dextrose

i£ i |fl

Date

Period

!|

Pola-

Titra-

N

D:\

CO5

Oi

R.Q.

HiO

a

R If ^1

<a

tion

tion

0,

•-Z £= =-

.
Nov. 4, 1908

Preceding period

7- 8 o'clock ....

84.5

2.19

2.430.51 4-77

r

8-10 o'clock1

I86.J 4.8

5.32 i .08 4.92

Fasting. . . . -j

10-12 o'clock

169.7 1.2

4.901.044.71 38.7

40.2

0.701

58.0

80

.... U5.8

I

12-2 o'clock

118.3

3.2

3.36

0.81

4-iS

38.5

40.1

0.699

41-4

81

U7.6

288.0

8.26 1 .85

77.2 80.3 •

1 The first period of 8 to 10 o'clock I have omitted, as the values in comparison with those in the later
fasting-experiments were non-serial. Probably the patient, who was in the apparatus for the first time, was
restless.

1 Calculated for six hours, 409.1.

GENUINE DIABETES MELLITUS

533

KXPKKIMKNT NO. II. PERSON UNDER EXPERIMENTATION A

"o

Dextrose

i

4

•

Date

Period

3 o
o a

N

D:N

COz

Oi

R.Q.

HjO

g

E £

!•!

£2

Pola-

Titra-

£ U

*£

£ a

S cfl

^ 3

< fl

tion

£

n5

a c

K-d

Nov. 5, 1908

Preceding period

220 gm.

7.24- 9. 22 o'clock

303. i

7.9 8.01

1.46

6 T

meat

8.22-10.28 o'clock

2IO. I

6.7

7.0

i . i

6.33

42.9

28.6

R/t

10.28-12.28 o'clock

328.6

10.6

9.78

1.49

5-04

43-9

44-3

0.721

42.4 82

148.8

10.22 gm. [

12.28- 2.28 o'clock

184.2

5-2

5-65

1.39 4-04

41.0

43-9

0.680

35-1

81

140.9

Sum (urine from about 5 hours) . .

22.5

22.43

3.98

127.8

435.4

1

EXPERIMENT No. III. — PERSON UNDER EXPERIMENTATION A

Date

Period

Amount of
urine

Dextrose

N

D:N

COz

Oz

R.Q.

HzO

0)

0*

Tempera-
ture (P.)

Heat elimi-
nation

2c
ao

II

E"0

Pola-
riza-
tion

Titra-
tion

Nov. 1 8, '08

Preceding period
7 - 8.52 o'clock
8.52-10.52 o'clock

IO2.2

97-9

3.88
2.94

3.87
3-45

0.80
0.80

4.84
4-31

38.5

47-9

69

98.1
98.1

138.6

139

Fasting. . .

10.52-12.52 o'clock 58.7

1.29

1.36

0.55

3-00

37.8

38.2

0.721

36.3

6?

US-9

134

J

98.0

12.52- 2.52 o'clock

50.2

O.6o

0.96

0.55

1.74

37-9

40.7

0.677

45.8

65

I3I-S

127

.

97-8

Sum

206.8

4-83

5-77

1.90

114.2

406.0

400

EXPERIMENT No. IV. — PERSON UNDER EXPERIMENTATION A

Date

Period

Amount of
urine

Dex

Pola-
riza-
tion

-rose

Titra-
tion

N

D:.\

COz

Oz

R.Q.

HzO

1
I

Tempera-
ture (F.)

Heat elimi-
nation

o
5§

11

•U-o

Nov. 19, '08

Preceding period
7 - 8 . 50 o'clock

117.0

3-74

3-90

0.85

4-59

98.3

237 gm.

8. 50-10. 50 o'clock

297-3

10.01

10.23

1.87

5-47

44-8

43-3

0-753

50.8

7-'

ISS-8

169

meat =

98.5

9.91 gm.

10 . 50-1 2 . 50 o'clock

193-5

6.19

6.70

1.58

4.24

45-4

46.5

0.709

53-3

(,S

IS6.9

151

N

98.6

1 2 . 50- 2 . 50 o'clock

134-4

3.76

4-25

1.38

3-08

42.2

44-0

0.698

45-7

M,

I5I-3

140

132.4

98.1

Sum

625.2

19.96

21.18

4-83

133.8

0.719'

464.0

460

1 Average.

534 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

EXPERIMENT No. V. — PERSON UNDER EXPERIMENTATION A

Date

Period

Amount of
urine

Dextrose

N

I):X

CO2

0;

R.Q.

H20

CJ

1

Tempera-
ture (P.)

Heat elim-
ination

!l

cfl o

0 3

= •3

Pola-
riza-
tion

Titra-
tion

!

Nov. 23, '08

Preceding period
7 — 9.20 o'clock

68.4

3-42

4-03

0.59

6.7

97.8

9 . 20-1 1 . 20 o'clock

231.8

17.62

18.45

1. 13

42.4 41.40.745 58.87298.0153-7

154

75 gm.

98.0

roll + 25

1 1 . 20- i . 20 o'clock

189.5

14-59

15-44

0.99

38.3 38.70.720

52.9

68

141.8

137

gm.

97.8

dextrose

1 . 20- 3 . 20 o'clock

99-5

7.17

7-90

0.64

. . ..

37-3

37.1 0.730

48.5

64

132.1

128

97.6

419

Sum

520.8

39.38

41.79

2.76

118.0

117.2

0.732'

427.6

EXPERIMENT No. VI. — PERSON UNDER EXPERIMENTATION A

Date

Period

Amount of
urine

Dextrose

N

D:N

CO2

02

R.Q.

HzO

£

Tempera-
ture (P.)

Heat elim-
ination

!i

Pola-
riza-
tion

Titra-
tion

Nov. 24, '08

Preceding period
7 - 9 . 20 o'clock

175-6

5.27

7.46

1.23

6.06

97-9

75 gm.

9 . 20-1 1 . 20 o'clock

237.6 16.63

17.73

i. ii

39.8

42.2

0.687

58.8

72 98.0

146.1

147

roll + 25

,

98.05

gm. dex-

ii. 20- i. 20 o'clock 214.2 15.85

16.32 1.04

37-8

37-3

0.735

53-9

67

135-7

133

trose

97-95

i . 20- 3 . 20 o'clock 108.5 7.27

7-92

0.67

37-5

37-5

0.726

49.1

63

135-5

132

97-8

Sum

560.3

39-75

41-97

2.82

US- 1

117.1

0.7I51

161.8

417.3

412

EXPERIMENT No. VII. — PERSON UNDER EXPERIMENTATION B

Date

Period

Amount of
urine

Dextrose

N

D:N

C02

Os

R.Q.

H2O

0

1

Tempera-
ture (P.)

Heat elim-
ination

§•§

-t->'*3
a! o

a> 3

M*

Pola-
riza-
tion

Titra-
tion

Nov. 9, '08

Preceding period
7 - 9.02 o'clock

241.3 10. 13

11.49

1.87

6.13

99.2

9.02-11.02 o'clock 136.6

•5.46

6. 02

1.24

4-83

51.0

50.9

0.729

46.5

77

176.3

167

98.7

Fasting. .

1 1. 02- i. 02 o'clock 91.5

2.74

3-81

I.OO

3.82

47-5

49-4

0.699

59. i

77

171.7

167

98.45

i. 02- 3. 02 o'clock 62.9 1.31

2.14

0.90

2.43

45-9

46.6

0.717

53.7

77

160. i

170

•

3.14

98.95

504

Sum .

291.0

9-51

11-97

144.4

146.9

0.7I51

508.1

1 Average.

GENUINE DIABETES MELLITUS
EXPERIMENT No. VIII. — PERSON UNDER EXPERIMENTATION B

535

Date

Period

Amount of
urine

Dextrose

N

D:N

COj

Oz

R.Q.

HiO

a.

a ~

fe>

II

Heat elim-
ination

o
*g

•s'ti

o 3
B-3

Pola-
riza-
tion

Titra-
tion

Nov. 10. '08

Meat
13.9 gm.

>
Preceding period
8 - 8.54 o'clock

8 . 54-10 . 54 o'clock
10.54-12.54 o'clock
12.54- 2.54 o'clock

214-7
218.0
268.8
168.2

8 . <i6

i .03

8 i

7.42
9-95
7.01

1.07

2. 12
2.14

7-0
4-7
3.23

53-7
54-2
58.3

57-3
57-7
59-3

0.682
0.683
0.715

41.9
67.2
45-9

77
77
77

98.85

194-3
190.1
193-6

196
193
169

98.9

99-0

98.2

Sum

655.9 24.38

5-33

.... 166.2

174-3 0.6931

iSS.o

578.0

558

EXPERIMENT No. IX. — PERSON UNDER EXPERIMENTATION B

Date Period

Amount of
urine

Dextrose

N

D:X

COz

Oi

R.Q.

H,0

m

i

Tempera-
ture (F.)

Heat elim-
ination

o

5§

sl

K-o

Pola-
riza-
tion

Titra-
tion

Nov. 16, 'o

8 Preceding period
7 - 9.21 o'clock
9.21-1 1 .21 o'clock

266.2
152.6

15-17
7.02

14-iS
7-32

2.26
1-49

6.26
4.88

82

46.4

80 99-0
98.5

162.0

Fasting. .

ii. 21— i. 21 o'clock

105.4

4.22

4-75 1-25

3-80

44.2

79

159-9

98.3

i. 2 1- 3.21 o%'clock

I6I.2 2.IO

2-53 0.85 2.98

46.4

80

156.7

•

98.6

Sum

4 1 9-' 2

13-34

14.603.59 137-0

478.6

EXPERIMENT No. X. — PERSON UNDER EXPERIMENTATION B

Date

Period

Amount of
urine

Dextrose

X

D:N

COj

Oi

R.Q.

H,0

£

Tempera-
ture (F.)

Heat elim-
ination

i§
11

Pola-
riza-
tion

Titra-
tion

Nov. 17, '08

Preceding period

I. Chief

I
7 - 8 . 07 o'clock
II
8.07- 9.26 o'clock
7.26-11.26 o'clock

127.0

165.4
275-3

7. ii

8.93
19.15

7.19

9-57
14-37

0.92

1.26
2.26

7.82

7.60
6.36

90

52.0

54-1

0.699

60.0

8399.0

174-3

160

period

98.5

meat.

;ii. 26— i. 26 o'clock 215.7

10.04

11.04

2.20

5.0

52.0

53-7

0.705

58.4

76

173-7

168

16.9 gm.

98.3

N

i . 26- 3 . 26 o'clock

165.0

8.13

8.48

3-10

2.74

55-2

57-6

0.697

60.2

80

173-8

177

178.6

—

98.4

Sum 656.0 37.32

33-89

7-56 ....

159-2

i6s.4O.7OO1

521.8505

1 Average.

536 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

EXPERIMENT No. XI. — PERSON UNDER EXPERIMENTATION C

Date

Period

Amount of
urine

Dextrose

N

D:N

C02

02

R.Q.

HjO

y

Tempera-
ture (F.)

Heat elimi-
nation

!•!

s tj

« 3

K-o

Pola-
riza-
tion

Titra-
tion

Nov. ii-u
1908.

Fasting. .

.

Preceding period

7 - 8 . 30 o'clock
8. 50-10.50 o'clock

10 . 50-1 2 . 50 o'clock
12.50- 2.50 o'clock

86.8
95-4

69.7
55-2

2.34
1.72

0.56

0. II

2.66
1.94

0.84
0.28

1. 19

1.38

i .09
0.93

2.23
1.4

0.76
0.29

48.9
47-5
47-4

46.8O.759 46.8

4S.8o.753 43-8
52. i 0.661 52. i

82
81

So

98.6
98.2

181.7
161.7

IS7-I

172
162
165

98.2

98.5

Sum

220.3

2.39

3.06

3-400.91

143.8 144.7 0.722*

500 . 5 499

EXPERIMENT No. XII.— PERSON UNDER EXPERIMENTATION C

Date

Period

Amount of
urine

Dextrose

N

D:N

CO2

02

R.Q.

H2O

V

•f.

s.

Tempera-
ture (F.)

Heat elimi-
nation

:

51

a o

£3

£?=•

Nov. 12-13,
1008.

Meat
17-39
gm. N.

Preceding period

7 - 8.58 o'clock
8.58-10.58 o'clock

10.58-12.58 o'clock
12.58- 2.58 o'clock

142.4
272.5

244.0
157-2

5-13
10.90

9.76
5.66

•;

5-40
9.81

IO.22
5-81

•

1.95
3- ii

3-58
3.07

2.7

3-l6
2.56
1-9

59.7

59-8
57-4

59-2
58.4
57.8

0.734
0.744
0.722

42-3
66.6
46.1

88
8u
87

99.2
98.6

199-9
196.5
191-8

184
207
176

99-0

98.4

Sum

25.84

9.76

176.9

I75-40.7331

588.2

567

The Fasting Experiments

The rest-fasting experiments are summarized in an easily reviewed
manner in the following table :

REST-FASTING EXPERIMENTS

Person under ex-
periment

Date

Age

i

»

£

«

D:N

COZ

Oj

R.Q.

Calories

Per
hr.

Per

kg-
and

min.

Per

kgA

and
min.

Per
hr.

Per

kgn
and

hour

No. LA

Nov. 4... 47

49.1

171

(4-77)-4-92 3-34 4-76

0.688

1-39

Diabetes mellitus
No. III. A

Nov. 1 8.
Nov. o..

47

52.8
60.0
60.0
59-2

171
173

176

-4.71-4.15

-3.0 -1.74
(6.i3)-4.83
-3.82-2.43
(6.24)-4.88
-3.80-2.98
(2. 23)-!. 40
— 'o. 76-0. 29

19-37
24.07
22.52
23-93

3.06
3-36
3-14
3-40
326

4-34
4.76

4-33
4.76

A ^Q

66.6
84.0
'77-8
83.17

I. 26
1.40
1.30
i-45

i-35

No. VII. B

Diabetes mellitus
No. IX. B
Diabetes mellitus
No. XL C.. . .

Nov. 1 6. ...
Nov. it.. 23

o. 722

Diabetes mellitus
Average

A. W. W. normal Mar. 21..
A. W. W. normal Mar. 15..

57-0

C7 O .

3-65
3-65

4-38

4. 10

0.832

0.840

76.55
76.55

1 Average.

GENUINE DIABETES MELLITUS 537

I laid these tables before the congress in my communication. It will
readily be understood why I on the data of these experiments believed that
there was an essential increase in the production of calories in diabetes
mellitus.

The production of calories per kg. per hr. is on the average in the diabetics, 1.34, in the
normal person, 1.345; the oxygen consumed is in the diabetic greater throughout. It is
on the average, 4.59, in the normal person, 4.24.

I shall speak later as to the cause of the greater oxygen consumption in
diabetics.

The carbonic acid production is on the average in diabetics 3.26, in the normal person,
3-65.

Hence the production of carbonic acid is somewhat less in the diabetics.

The respiratory quotient is very low throughout in the diabetics, cor-
responding to the circumstance that all the cases investigated were moder-
ately severe cases. Also the person C may be counted with the moderately
severe cases.

The question that I asked myself at the reworking-up of the experiments
was the following: Do there exist severe cases of diabetes mellitus that in
spite of the copious elimination of sugar show no increase in heat production
during fasting? As there were only a relatively few experiments at my
disposal for the solution of this, conclusions as to the question were merely
tentative. The diet which the persons tested received on the days be-
fore the experiments were mixed. It contained, however, neither abun-
dant carbohydrate or protein. As all experiments began fourteen hours after
the latest ingestion of food and lasted six hours, so that the experiment lasted
for the fourteenth to twentieth hours after the latest ingestion of food, the
quotient D :N observed must be regarded as high. Only in person C did the
quotient D : N fall almost to o during the period of experimentation. In the
first persons under experimentation the ammonia value was also raised very
high. In person A the /3-oxybutyric acid in the urine was also estimated
and found in not inappreciable quantity. I have not included these figures
in the tables and refer to the detailed works on Benedict and Joslin. In such
severe cases, as persons A and B are, one must expect under conditions of
experimentation that there would have been an appreciable result, if the
heat production in severe diabetes is really increased. It was not the case,
however. We have already seen previously that the chemical observations
allow this result to be anticipated.

On the study of the extensive and carefully detailed experimental material
contributed later by Benedict and Joslin I have arrived at the conviction
that an increase of heat production in diabetes mellitus cannot be inferred
also from this material. The explanation of the deviating conclusions of
Benedict and Joslin is to be sought, I think, in the fact that they did not take

538 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

into account the difference in body weights of the normal persons and
diabetics they investigated. I here quote in descending series the body
weights of the normal individuals and the diabetics.

Normal individuals: 83.5-79.7-74.4-67.6-66.5-66.0-59.6-48.5.

Severe diabetics (weight during the experiment): 67.1-59.0-54.9-52.7-
51.8-48.8-48.0-40.5.

A glance at this summary shows the great difference in body weight
between the normal and the diabetic individuals.

When we compare with one another the heat production of those cases
that have the same body weight, we obtain the same result that I found in
the preceding experiments. This is seen in the following summary:

Mrs. B. Diabetic G

Weight 67.0 67.0

Height 161.0 178.0

Calories per kg. per hr i .09 1.15 (bed calorimeter)

L.E.E. Diabetic F

Weight 59.6 59.0

Height I79-Q 176.0

Calories per kg. per hr i-47 I-39

Dr. R. Diabetic A

Weight 48.5 48.8

Height 167.0 171.0

Calories per kg. per hr i .39 i .34

The heights of the persons under experimentation are not entirely alike.
In the cases of Mrs. B. and diabetic G the difference is indeed appreciable.
In the other two pairs the difference would not signify much. In addition,
in one case the difference favors the normal individual, in the other it favors
the diabetic. We see from this summary that the heat production in cases of
severe diabetics does not differ essentially from that of the equally heavy normal
individual.

Benedict and Joslin themselves made the objection that their material
is not uniform in respect to body weights. They sought to rule out this
objection in the following experiment (Case C. S., 227). The first investiga-
tions were undertaken at a time that the patient weighed 62.4 to 65.4 kg.
They found at that time a heat production between 1.23 and 1.40 per kilo-
gram per hour. As the patient had later fallen away to 54.9 kg., the heat pro-
duction (in one experiment) was 1.26 per kilogram per hour. I can ascribe
to this one experiment no demonstrative value. It is a known law that in
normal individuals the exchange lies higher the smaller and lighter the indi-
vidual is. This is readily seen [from the figures that Benedict and Joslin
themselves have summarized.

GENUINE DIABETES MELLITUS 539

Investigations with Zuntz-Geppart apparatus (p. 168):

Individuals between 65 and 43.2 kg. Oz requirements per

kg. per minute 4 . 08 c.c.

Individuals between 66 and 88.3 kg 3.5 c.c.

Investigations with the respiration calorimeter, during sleep (p. 168) :

Individuals between 64.1 and 55 kg 4.04 c.c.

Individuals between 66.1 and 84.7 kg 3 . 56 c.c.

There does occur in severe diabetes a circumstance moreover that must
be considered especially. It is known that in the obese the fundamental
exchange is relatively low, as the obese person possesses little respiring proto-
plasm in relation with body weight. The severe diabetic is, however, always
strongly drained of water (as is shown in investigation on the water-con-
tents of the organs of those dying in coma) . Moreover, in severe diabetics
almost every -trace of fat has disappeared from the ordinary sites of fat-de-
position, as can be seen at almost every autopsy. If now in addition the
albuminous constituent suffers severe damage in the later stages, the mass of
respiring protoplasm in severe diabetes will be still greater in proportion
to body weight. I believe, therefore, that even if on calculation per kilo-
gram of body weight there is found in severe diabetics a slight increase of
heat production, this would not mean much.

Already Lusk has pointed out the dissimilarity of the material compared
by Benedict and Joslin, and from this has drawn the conclusion that the in-
crease of heat production found by Benedict and Joslin is less high than these
authors suppose. From the calculations and discussions cited I must, however,
conclude that the demonstrations of an increase of heat production in severe
diabetes, has with the material at hand, not been supplied.1

Now as concerns the oxygen requirements, this in severe cases of diabetes
is undoubtedly increased. This may be seen in my tables. I find that the
oxygen requirements with otherwise similar heat production average in the
diabetics 4.59, in the normal individuals 4.24.

i. This is also to be seen in the figures of Benedict and Joslin:^ That there
is an increased heat production, however, cannot be inferred from the in-
creased demand for oxygen. Already Leimdorfer mentioned that in the
severe diabetic through the loss of bodies very rich in oxygen, in the urine

1 Remark on Correction. — Also in a second publication that Benedict and Joslin made a short
time ago concerning this subject (A Study of Metabolism in Severe Diabetics, Carnegie Institu-
tion of Washington, Publication No. 476, 1912), this is shown in an indubitable manner. Here
are found statements only as to the carbonic acid production and the oxygen requirements;
in the severe diabetics there was a COz elimination :(Per kg. per min.) of 3.13 c.c. (according
to my calculation 3.25); in the normal individual of like weight this was 3.13.

2 In the second publication, 4.54 O2 per kilogram per minute in the severe diabetics as against
3.75 in normal individuals of the same weight.

540 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

(sugar, ketone bodies), the relation between oxygen consumption and car-
bonic acid production is disarranged. Direct calorimetry actually shows in
the experiments made at the Boston Institute, that in diabetics with normal
heat production, the oxygen consumption is increased.

2. In the experiments with the administration of meat the specific dynamic
energy of the protein and the time consumed in the decomposition of this
in severe diabetes was investigated. The question can, however, scarcely
be discussed, because the number of experiments is too small.

3. The experiments with the administration of carbohydrates seem on
the contrary to be worthy of mention. In these investigations there was
sought to be determined whether in short periods (two hours) the respira-
tory quotient did not temporarily rise. The two experiments on this
subject agree very prettily. In normal individuals, on the administration
of just as much carbohydrates, we would expect an increase of the respira-
tory quotient to nearly i.o. In the two experiments on the diabetic the
respiratory quotient was hardly influenced, however. In the severe diabetic,
therefore, the administration of carbohydrates does not suffice to increase the
combustion of sugar. These experiments agree very prettily with the ex-
periment of Falta, Grote, and Staehelin on the dog without a pancreas. Also
here the respiratory quotient was not increased on the administration of
sugar. In both experiments on the diabetic the heat production rose some-
what in the first two-hour periods. This rise is perhaps to be referred to the
increased work of digestion.

The manifestations on the part of the vegetative nervous system in
diabetics has only recently been made the subject of study. I have already
in the discussion of the experimental physiology mentioned Lowi's reaction.
Its absence shows an increased excitability of the dilator pupillae (innervated
by the sympathetic). We have tested this reaction in human diabetes on
a large amount of material and have found it positive in a number of cases.
We could not demonstrate that it is connected with the intensity of the
glycosuria or ketonuria. We sometimes found it positive in cases in an
aglycosuric condition, and in other severe cases; even in the presence of
coma, it was negative. The glycosuric action of adrenalin in diabetes has
been studied by Newburgh, Nobel, and myself. It was found that in cases in
the aglycosuric state, adrenalin in almost all cases leads to a distinct increase
in the elimination of sugar. On the contrary, in a certain number of these
aglycosuric cases, the action was negative. There were among these cases
that had to be regarded as severe, cases that only on the complete withdrawal
of the carbohydrate and strong limitation of the protein would be main-
tained sugar-free, and that on the administration of slight amounts of
carbohydrates responded with glycosuria. These investigations show the
independence of the nervous and alimentary factors at least in the aglycosuric
state. An especially intense action of the adrenalin on the heart and

GENUINE DIABETES MELLITUS 541

vascular system in diabetes could not be shown. On the contrary, among the
cases investigated were a number in which enormous adrenalin-diuresis
supervened. Among the numerous non-diabetes cases on whom we tested
the diuretic action of adrenalin, we never saw an action so intense. It is
especially worthy of remark that among the diabetics who resisted so in-
tensely, were also cases in an aglycosuric condition. Therefore in many a
diabetic the vessels of the kidneys are in an abnormally irritable state, [a fact]
which was not known before. I might take advantage of this opportunity to
add some remarks concerning the diuresis in diabetes mellitus. Ordinarily we
find a parallelism between the intensity of the elimination of sugar and the
amount of the urine. It has been known for a long time that there are ex-
ceptions to this rule. There are cases in which a long period of increased
diuresis precedes the occurrence of diuresis (v. Noorden}. There are further
cases in which, as v. Noorden likewise emphasizes, the polyuria outlasts the
glycosuria for a long period. Then there are cases in which, in spite of high
•percentage of .sugar, the amount of urine is very slight. Naunyn reports, for
example, a case in which about 8-9 per cent, of sugar was excreted, with 2
liters of urine. In another case there was just as much sugar, and a specific
gravity of 1040, with urine amounting to only 1200-1400 c.c. We designate
these cases diabetes decipiens. On the other hand there are cases with con-
siderable polyuria with relatively little elimination of sugar, especially if
the diabetes came as a result of head injury. Naunyn reports, indeed, a case
of pure uncomplicated diabetes who constantly, with a diuresis of 5-6 liters
eliminated only 1.2^2 per cent, of sugar. Hence the elimination of sugar
is certainly not the only cause of the increased diuresis, and perhaps not
the principal cause. According to the experiments previously mentioned the
increased diuresis has its foundation in an especial sensitiveness of the
kidney vessels to an irritant circulating in the blood. We can summarize
the observation set forth in the statement that in many cases of diabetes
mellitus a heightened excitability of certain organs innervated by the sympathetic
(dilator papilla, liver, kidney, etc.), may eventually also exist in the aglycosuric
condition.

The excitability of the autonomous nerves in diabetes mellitus is not
diminished throughout. We have even in numerous experiments in the
advanced stage of diabetes found strikingly intense actions of pilocarpine
on the secretion of sweat and saliva. Also the miotic action of pilocarpine
is very distinctly pronounced. That the diabetic glycosuria is not diminished
by pilocarpine, is here mentioned because the fact again illustrates the in-
dependence of the nervous and alimentary factors. In advanced cases there
are found many kinds of manifestations that perhaps may even point to a
heightened irritability in many territories of the autonomous nervous
system. We observed in almost all very severe cases high-grade obstipation,
whose spastic nature was shown on the palpation of the sigmoid flexure and

^4- DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

through the appearance of the stools. Up to the present I have not seen
similar statements in the literature. Purgative measures are of service
in such cases only when they are given in rather large doses, and then defe-
cation is rather painful. Such patients prefer enemas to purgatives.
The spastic nature of this obstipation is demonstrated too by the prompt
action of a subcutaneous injection of atropine (i mg.). On what ground
there occurs the development of such a spastic obstipation is difficult to say ;
it can hardly be due to the lack of bread in the diet, as these cases on account
of considerable ketonuria could not long have been kept on a carbohydrate-
free diet, and the diet was in addition always very rich in cellulose (vegetables) .

I would further mention here an observation which I have likewise not
been able to find in the literature. We found in all severe cases of diabetes
in which the examination was made, a relative or absolute increase in the
mononuclear cells in the blood. As the total count of the leucocytes was
always normal, there always existed, then, a relative and absolute diminution
in the number of neutrophilic cells. It is possible that chemotactic influences
lie at the basis of this. If we regard -this as in connection with the spastic
obstipation, we could consider it as the expression of a high tonus of the
autonomous nerves.

I would not leave the description of the manifestations of the vegetative
nervous system without mentioning a finding that probably belongs here.
In investigations carried out together with Newburgh and Nobel, we found on
the administration of thyroidin to nondiabetic individuals a reduction of
the fall of blood-pressure from heart to periphery. Investigations on the
blood-pressure in the brachial artery with Riva-Rocci's apparatus showed no
change, while the investigation at the finger with Gartner's instrument showed
in many cases a distinct fall of the blood-pressure. In the diabetics we foundr
however, after the use of thyroidin a distinct, and in many cases, an appreci-
able increase in blood-pressure with both methods; this increase often out-
lasted the thyroidin medication for days. We could also observe this in
cases in the aglycosuric condition. It is very well likely that this increase
of blood-pressure is brought about through an enormously increased activity
of the chromafrin tissue. If this is so, it must be assumed that in diabetes
there exists an enormously increased excitability of this organ or of the nervous
centers regulating its activity.

Also the erethism of the vessels of the skin speaks for an increased ex-
citability of the vegetative nerves. The red face of the diabetic; lending as
it does such a characteristic appearance to the advanced case, is well known.
Also there mostly exists distinct dermographism. On exposure the skin
often reddens to far over the trunk. It is known that the skin of the severe
diabetic is often very dry on account of the severe draining of the dry body of
its water, yet there do not rarely occur sweats, even in cases that show no
manifestations of a complicating tuberculosis of the lungs.

GENUINE DIABETES MELLITUS 543

Finally I would mention a group of diabetics in whom the conditions
of hyperexcitability and hyperirritability of the sympathetic nervous system
are still more prominent. These are for the most part diabetics in middle
life, who overwork much and who in their occupations are exposed to great
excitements and cares; moreover, they may have sustained traumas. Psychic
excitements are here an important factor in the influencing of the glycosuria.
The blood-pressure is often raised not inappreciably, but in spite of this,
traces of albumin are found only transitorily, and here and there is seen an
entirely isolated cast. In such cases, adrenalin acted glycosuric in the
aglycosuric state; the Lowi's reaction was positive. We may perhaps desig-
nate these cases as hypertonic diabetes.

As example I cite the following case:

Observation LXIX. — G. K., forty-eight years old, conductor; entrance into the first
medical clinic on Sept. 6, 1912. In the year 1904 the patient suffered a train injury.
In it he was thrown to the floor, and the right thigh was contused. In July, 1910, he fell
from a wagon, immediately after which he had the sensation as if something internal had
torn. Since this time, always sensitiveness to pressure in this region, and very nervous.
In 191 1 unquenchable thirst with decrease of the previous appetite. The skin was dry, the
potentia coeundi fell off very much. On entrance there was found 3.7 per cent, sugar and
a distinctly positive acetone reaction. The sugar-elimination after the ingestion of 75 gm.
of roll and a third of a liter of cream was about 80 gm. dextrose, the excretion of acetone
was about 3 gm. On withdrawal of carbohydrates the sugar sank rapidly, the oat-meal
treatment that was instituted brought about only traces of sugar, the acetone disappeared.
The tolerance rose very quickly, so that after six weeks the patient bore 60 gm. roll, 30 gm.
rice, and 60 gm. potato Without excretion of sugar.

The amount of urine during the sugar-free period was also appreciably increased.
Mostly there were values of 2000. At the beginning also values between 3000 and 4000.
The specific gravity was raised only in the first day. Then it sank quickly to about 1010,
and later showed great variations; it mostly lay low, around or lower than ioio,and tem-
porarily would increase to 1020.

The patient was very excitable, the patellar reflexes were lively, the blood-pressure was
high, varying according to measurements by the Riva-Rocci apparatus between 130 and
150. Correspondingly the arteries showed increased tension, but there were no signs of
arteriosclerosis. The heart dulness was broadened to a slight extent toward the left. In
the urine was found on repeated examinations at most minimal traces of albumin. No
casts were found in the centrifugated fluid. Lowi's reaction was positive.

In the aglycosuric condition i mg. of adrenalin was injected many times. Regularly
there occurred a not inappreciable elimination of sugar, once to 6 gm., in the hours after
the injection. One of these experiments took place at the time that the tolerance of
the patient was already essentially increased. Further the diuretic action and especially
the action on the heart and vessels was strongly marked. In the experiment mentioned
the blood-pressure rose to 180.

The investigation of the respiratory gas-exchange (Dr. Bernstein) always showed nor-
mal COz production, and mostly an increased Oz consumption. The gas-exchange after
an adrenalin injection was investigated twice. Both times the oxygen consumption and
carbonic-acid production rose strongly, but the respiratory quotient was not influenced.
I cite the following experiment as an example:

544

DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

C02

Per kg. per min.

0*

Per kg. per min.

RQ

Before

217.6

2. 7<

?I7 7

4. O2

o 685

20 min. after injection of i
mg. adrenalin

2=;o.o

172 . <

06/1

In this experiment the injection led to an elimination of 6 gm. of sugar. The action of
adrenalin was therefore intensive in all respects, only the raising of the respiratory quotient
was wanting.

I would here mention quite briefly the complications of diabetes mellitus.
In diabetes in men, impotence is one of the most frequent complications;
only very rarely does there occur increased sexual desire. With the former is
often found an atrophy of the testicles. In the diabetic women, men-
struation is disturbed only in the severest cases, but on the contrary, con-
ception is rare. In men, there is never observed a retrogression of the
secondary sexual characters. The deleterious influence affects therefore
only the generative part of the function of the sexual glands. The vulnera-
bility of the tissues, the falling out of the teeth, the suppurations, diabetic
cataract, the furunculosis, the xanthelasma, the pruritus, the rheumatoid
pains, the diminution of the reflexes, and the degenerations of the posterior
column are here merely briefly indicated. These symptoms are for the
most part brought into a relation of cause and effect with the constant
hyperglycemia, yet this explanation is for very many of the cases as yet very
uncertain. This is also true for the premature arteriosclerosis of the dia-
betic with its sequel, diabetic gangrene, which is perhaps the result of the
hypertonic condition we have described.

Let us survey now the alterations of the metabolism in genuine diabetes!
First, I would again point out that according to investigations up to the
present there are demonstrable neither an increase of the protein decom-
position nor an increase of heat production. Why then does a severe case
of diabetes become thin? The basis lies apparently in the devaluation of his
diet through the limitation of sugar and of ketone-bodies. This is especially
true of the omnivorous, irrationally fed, severe diabetic. Such a person loses
flesh in spite of the abundant ingestion of the food because a certain part
of the material ingested leaves the body unused. In such an individual the
heat production can be raised at most by the increased work of digestion,
and because he must warm the large amounts of fluids of which he partakes
to body temperature. The polyuria conditions a slight loss of heat. This
is however an ectogenous raising of the heat production. In the light and the
moderately severe diabetic, he who can be made sugar-free very early by a
relatively slight restriction of the ingestion of protein and carbohydrate
and thus again uses his diet to its full value, there lies no basis for emaciation.
The severe diabetic can only be made sugar-free through great limitation of

GENUINE DIABETES MELLITUS 545

the proteids and carbohydrates. Also this individual may, as Weintraud
has already shown, be maintained at body weight for a long time, on this
just adequate diet, indeed it seems as though through the chronic under-
feeding he may become established on a lower requirement for calories, as
we can observe also in chronically underfed nondiabetic individuals. In
still further advanced .stages of the disease, the adequate diet does not serve
any longer to maintain freedom from sugar in the urine; indeed in very severe
cases it is no longer possible to limit the glycosuria to a low figure, as now
on account of the strong formation of ketone bodies, carbohydrates must be
administered unconditionally. That in such cases the carbohydrates are
in a position to limit the formation of ketone bodies, at least to some degree,
indicates that a part of the carbohydrates goes over the glycogen stage,
although on account of the rapid re-combination this cannot be demon-
strated with certainty in respiration experiments. The most marked effects
are in such cases produced by the exclusive administration of carbohydrates,
especially of oat-meal (v. Noorden), perhaps because other simultaneous
administration of protein favors the re-combination of the formed glycogen.
In such cases, too, we then see the body weight rapidly increase, a phenom-
enon that is certainly not explained by the inhibition of water alone. In
the very highly advanced cases these carbohydrate treatments are, as is
known, also of no use. The severe diabetic loses weight and uses up
his protein constituent, because he can be maintained sugar-free and
ke tone-body-free only on an extremely just adequate diet; as soon, how-
ever, as the diet becqmes more abundant, the elimination of sugar and ketone
bodies is increased, by which the value of the diet is detracted from. That
the fattening of severe diabetics presents great difficulties is intelligible as it
is known that a fattening is only possible when abundant assimilation of
carbohydrates goes on at the same time.

To me it seems that very much seems to speak for the fact that the
metabolic disturbance that is present in genuine diabetes mellitus is made
up of two different factors. The one factor consists of a disturbance in
anabolism. This disturbance in the building up of glycogen is usually first
to appear. The alimentary influence is here predominant. In the initial
stages a disturbance becomes manifest only on overstraining of the carbo-
hydrate assimilation. If we adopt the viewpoint that the disturbance of
glycogenesis affects both liver and muscle and that combustion of the carbo-
hydrates in the muscles is only possible after preceding assimilation, we may
in this sense speak also of a disturbance in sugar-combustion. On account
of the lessened formation of glycogen, there gradually develops a deficient
splitting up of protein and fat, and the formation of ketone bodies.

The other factor consists in a disturbance of catabolism. This is most
evident, when in spite of the ruling out of alimentary influences sugar is
continually formed from albuminous and fatty substances and eliminated

35

546 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

(increased sugar-production). This increase of the catabolism must there-
fore be regarded as endogenous; it leads, if the lack cannot longer be made
up through ingestion of food, to a melting down of albuminous and fatty
substance. We can therefore very well speak of an increased exchange in
severe diabetics, whether this is due to the devaluation of the food adminis-
tered in excess, or to a melting down of the body substance. This increased
transformation is expressed in the experiments on respiration only by increased
oxygen requirements not by increased carbonic acid production or heat production.

These two disturbances show a certain independence of each other; in
the initial stages of diabetes the disturbance in anabolism tends to come to
the front, as the predominance of the alimentary factor would indicate.
There do, however, exist cases in which the catabolic factor predominates
already at the commencement (neurogenic diabetes). In the later stages
both factors are present at the same time, although they are not always just
as strong as each other.

If we review once more the alterations of metabolism that characterize
the diabetes after extirpation of the pancreas, and compare these with those
of genuine human diabetes, it is not hard to recognize a distinct difference ;
to both are common the anabolic as well as the catabolic disturbances. They
differ from each other, however, in the behavior of the protein exchange and
the heat production. In the dog with pancreatic diabetes the decomposition
of protein and the heat-production are much increased; in genuine diabetes
these are not essentially altered. Before we discuss this fundamental dif-
ference, I must first tell about the results of pathologico-anatomical research
in genuine diabetes.

Pathological Anatomy of Diabetes Mellitus

Bouchardat first in 1845 expressed the opinion that diabetes came about
through a disease of the pancreas, at all events Bouchardat was forced to the
assumption that under circumstances only a functional disturbance may
exist, as in many cases of diabetes mellitus he found the pancreas normal.

After Bouchardat, Lapirre, Frerchs, Cantani, Seegan, and Lanceraux
drew attention to the pancreas in autopsies on diabetics, and found that
in addition to cases with the most varied alterations of the pancreas there
were also cases of diabete maigre in which the pancreas was apparently
normal. In 1891 Lemoine and Launois described the sclerosis of the blood
and lymph vessels in diabetes. In 1893 Laguesse first expressed the view
that in diabetes the islands oiLangerhans were diseased. In 1894 v. Hanse-
mann described a specific atrophy of the glandular parenchyma in diabetes
mellitus, associated with proliferation of the connective tissue about the
acini, which, on account of the similarity to granular atrophy of the kidney
he designated granular atrophy of the pancreas. In a later work v. Hanse-

PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 547

mann reported on investigations in thirty-four cases of diabetes mellitus.
In the majority of these this granular atrophy was found, in six cases was
found hyaline degeneration of numerous islands, to which, however v. Hanse-
mann attributed no great significance. Dieckhojj examined the islands espe-
cially and among seven cases found three times diminution in the number of
islands, once disappearance of the islands, once the insular tissue qualita-
tively altered, and twice no alterations. He also found that the glandular
parenchyma for the most .part showed changes. In 1898 Schlesinger first
reported that he found in cases of pancreatic disease without diabetes that
the islands were remarkably well preserved. In several interesting studies,
Opie advocated the opinion that the disease of the islands of Langerhans
was the cause of the diabetes.

Opie distinguished two types of chronic inflammation of the pancreas;
an interlobar pancreatitis (twenty-one cases) brought about by occlusion
of the excretory duct by pancreatic stone or gall-stone, or by compression
of the duct by tumors, or as the result of an acute inflammation of the
pancreas on account of infection of it from the intestine, or by generalized
tuberculosis, or as an accompaniment of atrophic cirrhosis of the liver. Here
the islands are only a little altered, and indeed only altered if the cirrhosis is
of a very high degree. On the contrary we find in interacinous pancreatitis
the islands markedly affected and on marked changes in these also, for the most
part, diabetes. Opie describes among the cases here observed also one of
generalized hyaline degeneration of the islands of Langerhans. Ssobolew, into
a consideration -of wfrose experimental studies I have already entered, de-
scribed alterations of the pancreas without diabetes in which the glandular
parenchyma was in part highly altered, while the islands seemed to be very
much more resistant. In primary or metastatic carcinoma of the pancreas
the islands are often retained in the midst of the tumor tissue; only in one
case of primary tuberculosis of the pancreas were traces of sugar present,
there being present in this case also an extensive dense formation. In
sixteen cases of diabetes he found, on the contrary, mostly disappearance
of the islands or diminution of their numbers, or signs of degeneration. He
comes to the conclusion that in diabetes, the islands seem to be the least resist-
ant. As enemies of the insular theory appeared Gutmann, Karakaschejf ,
Herxheimer, and others. Herxheimer found in a majority of these cases v.
Hansemann's granular atrophy, and in addition in five cases found changes
with the strong predominance of the regenerative new formation of excretory
ducts, and he designates this form cirrhosis of the pancreas on account of its
similarity to cirrhosis of the liver. He did not regard as significant the
changes he found in the islands. Also Schmidt maintains a sceptical atti-
tude. These authors show that in diabetes mellitus also the glandular paren-
chyma may be very much diseased, and that the islands throughout do not
have to be the only part diseased; in many cases the islands are remarkably

548 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

well preserved or show distinct signs of regeneration; and in many cases
they appear entirely normal. KarakaschejJ upholds, as already mentioned
previously, the opinion that the islands constitute only reserve material,
and under circumstances can form new glandular parenchyma, while
Gut maun assumes a new formation of islands from glandular parenchyma.
MacCallum describes a case of juvenile diabetes in a child, in which the
islands showed a high-grade hypertrophy. Before the appearance of a
part of the work directed against the insular theory, Sauerbeck had treated the
subject in a "Referat" [collection of references] and in a monograph. He
collected one hundred and fifty-seven of diabetes from the literature. The
islands found normal in 40 per cent, of which there were twenty-six cases
with alterations of the glandular parenchyma. Changes in the islands.
were noted in one hundred and seventeen cases. In these the islands were
not found at all, or only scars marked their places in seven. In twelve more
cases the number of the islands was diminished whereby the glandular par-
enchyma was rendered in part atrophic. In ninety-eight cases the islands
were altered qualitatively, there occurring hemorrhages, simple atrophy,
hyaline or fatty or hydropic degeneration, sclerosis, or acute or chronic in-
flammatory alterations. In seventeen of his own cases of diabetes mellitus
Sauerbeck found mostly that alterations of the glandular parenchyma ran
parallel with those of the islands, and usually that in severe cases of
diabetes mellitus distinct alterations of the islands were present. Sauerbeck
inclines more to the insular theory; he believes that diabetes cannot originate
from the parenchyma, as in cases of severe alterations of the parenchyma
the diabetes may remain absent entirely.

Recent times have brought a series of important studies on this subject.
v. Halasz investigated twenty-nine cases of diabetes mellitus. He found
90-95 per cent, of the islands normal eight times; six times in 60-90 per cent,
of the islands, seven times in 30-40 per cent, of the islands, he found al-
terations that consisted in hemorrhages, sclerosis, atrophy, hyaline degen-
eration and in atheroma of the blood-vessels. Signs of regeneration were
found only twice. Alteration of the parenchyma was found by Halasz chiefly
in old diabetics, and the weight of the pancreas was for the most diminished,
often distinctly, v. Halasz comes to the conclusion that not every diabetes
is a pancreatic diabetes. Heiberg investigated six cases of diabetes mellitus
and found the islands either qualitatively altered or the number of them
diminished. Heiberg attributes this defect in the islands to their destruction
by inflammatory processes, in which residues of the inflammation were not
always necessarily present. In one case the islands showed in part the round-
cell infiltration described -by M. B. Schmidt, Halasz, and Cecil Russell.
There was found in addition in this case islands with necrotic cells, without
[round cell] infiltration; Heiberg regards these alterations as the later stage
of the inflammatory processes.

PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 549

In a later publication in which Heiberg reports on investigations of the
pancreases of two diabetic children, he again mentions that the number of
the islands must be considered as well as their quality. Saltykow examined
twenty-one cases with pathologically altered pancreas without diabetes;
of these four cases show insignificant alterations in the islands, which were
otherwise well preserved. In many cases, especially in sclerosis and diffuse
carcinomatous infiltration of the pancreas, the islands were indeed very well
preserved. In nine cases of diabetes Saltykow found always alterations in
the islands. Among 'these was a case of isolated hyaline degeneration of
the insular apparatus with diabetes, as it had already been described by
Opie, Wright and Joslin, and others.

A far-reaching confirmation of Opie's findings was contributed by Russel
L. Cecil; he found among ninety cases of diabetes alterations of the pancreas
in seven, and among these regularly alterations of the islands, such as
sclerosis, hyaline degeneration, leucocytic infiltration. In seventy-six cases
were found fibrosis, in twenty-seven hyaline degeneration, etc. In twelve
cases the alterations affected the islands exclusively; and among the cases
without qualitative alteration of the pancreas was found striking smallness
of the organs, or decreased number of islands.

The question has been studied the most thoroughly by Weichselbaum.
Weichselbaum had previously reported with Stangl thirty-three cases of
diabetes mellitus in which striking alterations in the islands, but not essen-
tial changes in the parenchyma had been found. The latest communication
of Weichselbaum is based on the whole on one hundred and eighty-three
cases of diabetes mellitus. The number of control experiments and pan-
creases of nondiabetics is still greater. Microscopically the pancreases of
diabetics often showed distinct atrophy and decrease in size, and fatty
degeneration; often they were entirely normal. Microscopically constant
alterations in the islands were found. In addition to diminution in the
number of islands and decrease of their extent (Neumann), Weichselbaum
described a hydropic degeneration of the island cells; in this the protoplasm
of the cells loses its structure, becomes transparent, shows characteristic
granular inclusions and eventually are decreased in size (transition into
atrophy). This hydropic degeneration was found in 53 per cent, of the
cases and indeed almost exclusively in younger individuals. In 43 per cent,
of the cases, mostly in persons over fifty years of age, Weichselbaum found
sclerosis of the islands, proliferation of the connective tissue in and about
the islands, and mostly interlobar and intralobar proliferation. There was
found also sclerosis of the arteries. In 28 per cent, of the cases there was
found hyaline degeneration of the island cells together with the sclerosis
above mentioned. Manifestations of regeneration of the islands were
found chiefly in the head of the pancreas, and indeed in young individuals.
Hypertrophy of the islands were found only in some cases of insular sclerosis.

DISEASES OF THE IXSTLAR APPARATUS OF THE PANCREAS

While therefore the insular apparatus regularly showed alterations, high-
grade degeneration of the glandular parenchyma was found only in closure
of the pancreatic duct or in carcinoma of the pancreas. In the control
investigations on the pancreases of non-diabetic individuals these changes
were almost always absent, but on the contrary there existed high-grade
atrophy of the glandular parenchyma, whereby the weight of the pancreas
was very much diminished; in chronic tuberculosis even to 20 gm. Weich-
selbaum mentions that in diabetes mellitus the relation between regeneration
and destruction of the islands must be considered; and not only the structure
but also the number of islands.

On the basis of his investigations Weichselbaum distinguished from the
pathologico-anatomical standpoint three forms of human diabetes; first a
youthful form, the proper diabete maigre, in which is found the hydropic
degeneration of the islands; this is hereditary and would seem to depend
on congenital weakness or on failure of formation of the insular apparatus.
Then he distinguished the form dependent on chronic interstitial pancreatitis,
that occurs in the later years of life and is commonly associated with lipoma-
tosis of the pancreas and general adiposis (diabete gras). This form is hence
lipogenous or depends on a chronic catarrh of the excretory ducts and chronic
alcoholism and is often complicated with cirrhosis of the liver. Finally
the third form, which, depending on the hyaline degeneration of the islands,
occurs in the later years of life, apparently is a subvariety of the second
form, and is usually associated with sclerosis of the arteries.

I have reproduced rather in detail the numerous labors as to the patho-
logical anatomy of the pancreas in "genuine diabetes," and have purposely
confined myself strictly to the words of the various authors, because it seemed
to me that an intimate penetration into the development of the question
makes its solution essentially easier. On reviewing once again the entire
material detailed, we see that with increasing exactness the microscopical
investigation and also the findings of the pathologico-anatomical alterations
in the islands have become essentially commoner, so that the later authors
almost all belong to the adherents of the insular theory. It is further per-
fectly clear that pathologico-anatomical alterations found in so-called genuine
diabetes mellitus are not of a uniform nature, a conception that is upheld
in the larger and more thorough of the works cited. A large group possesses
well-defined characteristics, although the names given to it by different
authors are different. It is the form of interacinous pancreatitis occurring
in later life, that v. Hansemann calls granular atrophy of the pancreas, Opie,
interacinous sclerosis, Lepine, and Lemoine and Launois, sclerose periacineuse,
and which Weichselbaum regards as dependent on interstitial pancreatitis.
The causes of it are probably very different. In part they are sclerotic
changes similar to those of cirrhosis of the liver, often occurring in common
with hepatic cirrhosis and like it dependent on alcoholism. Commonly

PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 551

the cause can be ascribed to high-grade arteriosclerosis of the vessels of
the pancreas; in other cases an ascending catarrh of the duct system might
be the cause. The latter cases go over without sharp boundary into that
large group of high-grade atrophies of the pancreas, which we previously
treated under the gross anatomical alterations of the pancreas. In all
these cases are found in addition to changes in the insular apparatus more or
less pronounced alterations of the glandular acini, which is true of the cases
that proceed from catarrhs of the excretory ducts only when the process is
more advanced. It is comprehensible why these cases do not lead to absorp-
tive disturbances, for there is still enough functionating parenchyma present,
and it is to be expected that such disturbances became manifest only on high-
grade diminution of pancreatic juice production. The decision as to whether
the alterations in the insular apparatus observed in this form suffice to explain
the disturbance in carbohydrate metabolism is certainly very difficult, and
is further complicated by the occurrence, commonly observed, of regenera-
tive manifestations in the islands. It is indeed very questionable whether
these new-formed islands have the same functional integrity. We see, how-
ever, in many forms of cirrhosis of the liver often strongly developed and wide-
spread regeneration of the liver tissue, and yet we find in these cases signs
of deficiency of liver function. Also the occurrence of individual hyper-
trophic islands and adenomatous proliferations of islands does not furnish a
certain conclusion as to the function of the entire insular apparatus. Like-
wise, as Saltykow points out, just as little does the finding of partially normal
islands speak against the island theory; for example, we have in cases
of nephritis, large amounts of normal renal parenchyma visible micro-
scopically, without casting doubt as to the insufficiency of the renal tissue.
That also in this group are found cases in which the insular apparatus has
suffered relatively severe damage need cause no wonderment. Weichselbaum
emphasizes the fact that the cases with isolated hyaline sclerosis of the insular
apparatus probably form only a subdivision of this group; also here is
commonly found a sclerosis of the vessels of the organ; it seems to me very
likely, however, that in these cases of isolated sclerosis of the insular ap-
paratus there is expressed a certain undervaluation in the rudiments of the
insular apparatus, that becomes manifest only on the additional occurrence of
further damaging influences.

For the judgment of the role that the pancreas plays in the pathogenesis
of diabetes mellitus, no doubt the second group — that which affects youthful
individuals — is the more significant. Most important for us are those cases
in which the diabetes commences at an early age, and, ceaselessly progressing,
leads to fatal coma. It is these cases that up to the present have furnished so
unsatisfactory pathologico-anatomical findings. The monographs on dia-
betes by Naunyn and by von Noorden state likewise that in the rich experi-
ence of these authors numerous cases are met with, in which even the most

552 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

careful microscopical examination of the pathological anatomists did not show
anything certain. In one of these cases the count of the islands has furnished
inferences worthy of remark. It is shown in this group that the number of
islands and also their size is markedly diminished, and indeed there are
statements that the islands are entirely wanting. The supposition of
Heiberg that in such cases the defect in islands can be referred to a preceding
inflammation with the formation of scars has much in its favor. In many
cases of juvenile severe diabetes, however, the number and size of the islands
is insignificantly and perhaps not even at all diminished. In these cases
Weichselbaum constantly found the hydropic degeneration. This statement
of W 'eichselbaum 's has up to the present time not been recognized by all
pathological anatomists. If, however, the hydropic degeneration in such
cases is found to be constant, we must also ask the question if the alterations
are not of a secondary nature, brought into existence by the long duration
of the hyperglycemia and acidosis, and if. these relatively slight alterations
suffice to explain the high-grade functional deficiency. This form of diabetes
always commences with heavy elimination of sugar. In the majority of
cases there is found in the later stages an intensity of glycosuria, that comes
up to that seen in pancreasless dogs, and in the most of cases even exceeds
this. On the whole we can hardly be mistaken if we were always to assume a
participation of the pancreas in such cases. The hereditary element so
conspicuous in the pathology of this form of diabetes points to a weakness
in the "Anlage" of the insular apparatus, as a result of which any toxic or
infectious deleterious influence at all finds a locus resistentiae minoris. In
spite of all this we cannot reconcile the incongruity of the pathologico-
anatomical findings and the intensity of the metabolic disturbance and must
ask ourselves the question whether if in this form of human diabetes, and
perhaps in the most cases of severe human diabetes, there is not present, in
addition to the insufficiency of the pancreas, also another disturbance that
we have essentially to regard as an increase of sugar production dependent on
a nervous basis.

Before we enter into this question, it is necessary to observe more care-
fully those forms of diabetes in which the clinical observation or the patho-
logical anatomy points toward a prominent participation of the nervous
system in the coming about of the diabetic disturbance of metabolism.

The question as to whether we are justified in recognizing a "nervous
form" of diabetes has been discussed in a lively manner for a long time.
The discovery of the "piqure" happened before that of diabetes after extir-
pation of the pancreas. Since the time that the discovery of pancreatic
diabetes turned the general1 attention toward the pancreas, the interest in
nervous diabetes has fallen behind. The greater part of the clinical observa-
tions of "nervous" diabetes come from earlier times, thus making critical
observations not less difficult.

PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 553

I shall first select from the observations at hand those which seem to me
the most important, and describe them more exactly.

Glycosuria occurs not infrequently in brain-hemorrhages and encephalo-
malacias. This was first described by Leudet. They may be associated with
acute hemorrhages as well as the chronic encephalomalacias. A case of the
latter sort is described by Naunyn in which the diabetes gradually developed
during a slowly progressing encephalomalacia. For the most part there
exists in addition to the glycosuria, polyuria, and also even albuminuria.
Cases of the first kind are communicated by Dutrait, Frerichs, and others.
The seat of the hemorrhage or softening in such cases associated with
glycosuria is mostly the pons or its vicinity. Especially interesting is the
case of Reinhold. In a sixty-three and one-half-year-old woman with
melancholia, ten days before death there developed a marked edema of the
feet and strong glycosuria. Section showed a hemorrhage on the floor of
the fourth ventricle (serial sections), slight hydrocephalus, and a strong
hyperemia of the liver. It should not remain unmentioned that glycosuria
is sometimes observed in the parts of the brain that lie further off, and that
cases occur in which there is no glycosuria in spite of hemorrhages in the
neighborhood of the pons. Such a case is reported by Lemcke. In this
case there was an enormous lowering of the body temperature to 23°C.
There was found neither glycosuria nor albuminuria. Section showed a
fresh focus of hemorrhage beneath the floor of the fourth ventricle.

It is an interesting fact that H. Strauss in tests for alimentary glycosuria
in cases with fresh apoplectic attack, several times found them positive im-
mediately after the attacks but they were negative later. In this category
belong too the cases of brain hemorrhage after trauma to the head. The
first case was described, by Claude Bernard (Physiol. experim., Tom. i,
1855). Glycosuria disappears at the same time as does the wound.

Here also belongs the case of Drummond. A seventy-six-year-old man
suffered a blow on the head. Since that time increasing weakness, thirst,
and glycosuria. Autopsy showed besides an extreme dilatation of the
lateral ventricle and the aqueduct of Sylvius, a small blood effusion in the
fourth ventricle.

I mention further the case of Kammitz. A seventeen-year-old girl, pre-
viously well, caught her head in a cutting machine. Loss of consciousness,
later vomiting, and copious bleeding from the nose, and downflow of blood
along the posterior wall of the pharynx pointed with certainty to fracture
of the base of the skull. The temperature at first was 35°C. After two days
an abducens paralysis became evident. A week after the trauma there de-
veloped increased thirst, polyuria, and glycosuria (about i per cent, sugar).
The sugar-contents gradually rose to 2.3 per cent. There now existed excess-
ive polyuria. About three weeks after the trauma the somnolent condition
had disappeared, the diplopia still existed, and a unilateral hypoglossus

554 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

paralysis had developed. During the next few weeks, the sugar following
exclusive meat diet fell to i per cent., but the polyuria had decreased but
little. Two months after the trauma traces of sugar were still present, one
month later the urine in spite of abundant ingestion of food was entirely
free of sugar, but there still existed a diuresis of 4-6 liters, with a specific
gravity of 1005. Nothing was noted, unfortunately, as to the further
course. The supposition of a hemorrhage in the medulla oblongata, that
became still more marked some time after the trauma, is very probable in
this case.

Entirely similar is the case of Plagge. A sixteen-year-old boy suffered
a head injury, after which amblyopia and strong glycosuria commenced.
The glycosuria disappeared after two or three weeks, while the polyuria
remained for two or three months.

Further I might still mention the case, of Loeb. In the first case (pontile
hemorrhage with rupture into the fourth ventricle and with general arterio-
sclerosis) sugar and albumin were found in the urine. The urine had been
examined previously and found to be free of sugar. In the second case
there occurred after an apoplexy (probably small hemorrhage of the pons)
sugar and albumin in the urine. 'All manifestations later vanished leaving
not a trace behind. Loeb regards the albuminuria as conditioned centrally.

In addition to the hemorrhages, it is chiefly tumors and abscesses in this
region that can lead to glycosuria. The case of Iwan Michael is much cited.
In a twenty-five-year-old man there occurred, together with increasing weak-
ness and tormenting headache, polyuria, polydipsia, and glycosuria. The
amount of urine reached over 6100 cubic centimeters, the elimination of
sugar reached to 25 mg. Death in coma followed later. Autopsy showed a
cysticercus racemosus of the floor of the fourth ventricle. Steida reports on
the contrary a case of cysticercus racemosus of the fourth ventricle which,
in spite of changes in the floor of the ventricle, did not call forth glycosuria.

Of the other changes in the floor of the fourth ventricle associated with
glycosuria have been observed tubercle (de Jonge) sclerosis, abscesses and
tumors (especially gliomata). The changes may also affect the vicinity of
the cerebellum. The first glioma was reported by Nevrat-Perrotton; other
cases are described by Reimer, Catola and others. Especially worthy of
remark is the case of van Ordt. It concerned an eight-and-one-half-year-old
girl in whom no sugar was found at the beginning of the illness. The test
for alimentary glycosuria was first positive on the aggravation of the tumor
symptoms, then 3^ per cent, of sugar occurred in the urine, then on limita-
tion of the carbohydrates in the diet the sugar disappeared, later to reap-
pear also on a strict diet to' the extent of % per cent. The autopsy, in addi-
tion to showing several miliary tubercles on the floor of the fourth ventricle,
revealed a tumor in the territory of the posterior corpora quadrigemina, the
pes cerebri, and the tegmentum of the pons, which also involved the floor of

PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 555

the fourth ventricle. According to the judgment of van Ordt, this could have
been present only in the course of the last weeks. The pancreas was found
to be normal. According to van Ordfs statistics, glycosuria has been found
up to the present in

Cerebral tumors i time

Cerebellar tumors i time

Basal ganglionic .tumors.

Thalamic tumors 3 times

Tumors of the corpora quadrigemina 3 times

Dorsal pontile tumors 5 times

Basal pontile tumors

Tumors of the floor of the fourth ventricle 18 times

If we take only those cases in which the floor of the fourth ventricle was
destroyed to a greater or less extent, we find that 70 per cent, of all these
cases are associated with glycosuria. Tests for alimentary glycosuria were
found positive five times in eleven cases of tumors of the interior of the skull,
three times in sixteen cases of other diseases of the brain (among them one
case of lues) . . It should be mentioned that abscesses of the cerebellum
very commonly lead to increase of temperature and glycosuria (Hammond).

I believe that among the cases detailed as well as among numerous
analogous cases there are those which fulfill all the requisitions of a diabetes
conditioned nervously. It is true, as Naunyn says, that he has seen many
cases of apoplexy with glycosuria but that he could not exclude in these the
possibility that a slight diabetes did not exist beforehand. It must further
be said that exact examinations of the pancreas especially with reference to
the insular apparatus are scarcely at hand. We can, however, only with
difficulty conceive how in individuals with previously perfectly normal sugar-
metabolism, and especially in the youthful cases, so high grade a damage
to the pancreas can develop so suddenly. The parallelism in the develop-
ment of the glycosuria and the brain symptoms points much the more to
the fact that alterations in the nervous system have a decisive significance.
According to the experimental experience up to the present only the assump-
tion of an irritation of the nervous centers and paths as cause of the "nervous"
glycosuria is possible. It is therefore intelligible that pathological [altera-
tions in the neighborhood of the floor of the ventricle or the sub thai amic
region do not always necessarily lead to glycosuria. Irritation would
the sooner follow if tumors or apoplexies gradually encroach upon the
corresponding centers; rapid destruction of these centers on account of hemor-
rhage or softening would much rather lead to symptoms that are the opposite
of irritative symptoms. The case of Lemcke with considerable hypothermia
may be perhaps explained in the above way. I should like to point out
one point further, namely, the strong hyperemia of the liver in Reinhold's
case, which is seen regularly too after the piqure.

556 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

The cases of diabetes after trauma here need a more exact analysis. We
have to consider the following points:

1. Whether the diabetes began immediately or at least a short time after
the trauma, or after an interval of several months or years.

2. Whether the trauma affected the head and whether other brain symp-
toms existed in addition to the glycosuria, or whether other parts of the
body were affected by the trauma.

3. Whether the diabetes healed again, or whether it existed further or
relapsed; in short, whether a chronic diabetes developed.

Concerning the frequency of these different factors several statistics are
at hand. Jodry (cited by Lepine} collected one hundred and forty-five cases
of diabetes after trauma. The trauma affected the head in seventy-two
cases — 50 per cent. ; the vertebral column in twenty-seven cases — 20 per cent.;
the abdomen in twelve cases — 8 per cent.; the seat of the trauma was not
defined in 1.7 per cent.

In a third of the cases, the diabetes became manifest during the first
days after the trauma.

Lepine analyzed twenty-nine well observed cases from the literature and
added five cases of his own. The symptoms of diabetes appeared in the
first three days — ten times; in the first week — five times; in the first three
months — twelve times; later seven times.

Asher found among one hundred and twenty-nine cases of diabetes after
trauma fifty-four cases of injuries of the head; sixty-two cases of injuries
of other parts of the body; nine cases after injuries of an undefined kind.

Higgins and Ogden among two hundred and twelve cases of head-injury,
found sugar in 9.3 per cent. If only the severest cases were considered, the
percentage rose to 23.4 per cent.

Among eighty-four cases of simple wound of the scalp, sugar was found
in 5.95 per cent.

Among forty-three cases of wounds of the scalp that laid bare [freilegten]
the bone, in 9.3 per cent.

Among forty cases of concussion of the brain with loss of consciousness,
but without fracture, in 2.5 per cent.

Among twenty-four cases with fracture of the vault of the skull, in 20.8
per cent.

Among twenty-one cases with fracture of the base of the skull in 23.8 per
cent.

The question as to the connection between trauma and diabetes has been
discussed in a lively manner. Ebstein and later Kausch collected the cases of
traumatic diabetes from tHe literature. While Ebstein inclines to the view
that also cases of chronic diabetes, eventually diabetes first occurring a long
time after the trauma may be ascribed to the trauma, Kausch is very
sceptical. He would hold as valid only the ephemeral or transitory glyco-

PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 557

surias occurring immediately after, or only a short time after the trauma,
and denies the connection between trauma and chronic diabetes, especially
when the latter first occurs a long time after [the accident]. I believe
that we must consider Kausch right in many points, even if perhaps he goes
too far, in the separation of the ephemeral or transitory glycosurias and
chronic diabetes. It seems to me appropriate to go a little further into the
points [just] previously sketched. I am not regarding the responsibility
serving for the law for accidents. Naunyn and v. Noorden mention that one
must not be too narrow-minded, as considering the obscurity of the condi-
tions, individuals should not suffer harm on account of theoretical considera-
tions. The scientific side of the question, however, demands a much stricter
criticism.

Now as regards what concerns the first point, we can ascribe, with con-
siderable justification, diabetes after head injury to the injuries of the nervous
centers regarding sugar-metabolism, when the elimination of sugar occurs
within the first eight to fourteen days and especially when, too, other symptoms
are present that indicate an injury to the brain stem and medulla oblongata.
I have mentioned in brief several such cases on page 553. As further examples
I would cite both cases of Bouchard. In a seventeen-year-old and twenty-
one-year-old man respectively there occurred, after fracture of the base of the
skull glycosuria to 1.5 per cent, and 1.75 per cent., and albuminuria and cylin-
druria. The first case healed entirely, but the second case died after some
days. If no brain symptoms are otherwise present, we cannot, however,
deny without anything further the connection with the trauma. Very in-
teresting is the observation of Honiger that new-born infants whose heads have
been strongly squeezed by the artificially induced birth, can show glycosuria
for several days, while the long duration of a spontaneous birth never leads
in itself to glycosuria.

If the glycosuria starts in a longer time after the trauma, we can here also
not deny the connection with trauma in every case without anything further.
It is conceivable that blood effusions that are undergoing absorption in organi-
zation, may exercise an irritation in the corresponding centers through shrink-
age and the action of traction (Rosenberger) . Of course this would hold only
for very few cases. We may regard that of Schaper as such a one. In a duel,
a dagger thrust penetrated the orbit and went deep into the cranial cavity.
There developed a right-sided paralysis and gradually a high-grade diabetes.
Death occurred after three and a half months; it was found that the path of
the stab reached to the left border of the medulla oblongata and was filled
with pus and coagulated blood. There should finally still be thought of, in
such cases of later glycosuria, the spontaneous glycosuria of the traumatic
neurosis. We shall consider this latter in the discussion of the connection of
psychoses or psychic excitements with glycosuria. The fact whether there
is polyuria is important in the solution of the question as to whether the late

558 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

glycosuria is associated in any way with the trauma. In many cases of
head injury the glycosuria starts in simultaneously with pronounced polyuria.
Usually both develop at the same time. If the glycosuria later disappears,
the polyuria often lasts for many months, in other cases the polyuria develops
first, and the glycosuria accompanies it only after weeks or even months.
The central origin of such polyuria is very probable. On it is based the hy-
pothesis of a central origin of the glycosuria. In any case the similarity
with the sugar and polyuria puncture is worthy of notice.

The second question concerns itself with whether glycosurias after
trauma that does not affect the head, but other parts of the body, can be
referred to the trauma and can be regarded as nervous glycosurias. Kausch
himself has furnished noteworthy contributions to this subject. He described
twelve cases of fractures of the pelvis, thigh, leg, patella, or toes, that showed
ephemeral glycosuria. This glycosuria continued for at most ten days and
under circumstances, on the ingestion of grape-sugar, would be increased to
30 gm. It is worthy of remark that these cases later did not show any alimen-
tary glycosurias and therefore presented an entirely normal carbohydrate
metabolism. Before Kausch, Haedke has already pointed out that after
traumata of different kinds alimentary glycosurias would be obtained in a
large percentage. The connection of such transitory glycosurias with trauma,
in cases that are not narcotized, is doubtless. Experimental pathology (gly-
cosuria after injury to the sciatic, etc.) gives us an idea as to the kind of con-
nection. Very much severer is the significance in a series of cases, of which I
shall quote the following cases of Scheuplein more exactly.

A young soldier who was not hereditarily predisposed to diabetes fell
about 12 meters from a third-story window. He fell on his buttocks.
There was found a luxation of the first lumbar vertebra, without there being
symptoms that pointed to an injury of the spinal cord. Reposition was suc-
cessful; complete cure resulted, so that later the patient could again ride and
carry on severe bodily labor as menial servant [in the army]. Fourteen days
after the fall it occurred that the urine was much thinned and pale, and that
the feeling of thirst was distinctly increased. The urine contained sugar.
Ten days later the sugar-content of the urine was very great, and the amount
of urine reached about 13 liters. The patient was placed on a meat diet.
After fourteen days the sugar had disappeared, but the polyuria remained
for a while longer. Two years after the trauma the patient was entirely
free of sugar, although his diet consisted chiefly of cereals. The body weight,
that at the time of the sugar elimination had sunk very low, raised again so
that in short the patient could be regarded as cured in every respect. The
significance of this case is indeed not easy [to determine]. We could perhaps
think of an apoplexy of the pancreas, but against this speaks the simultaneous
diabetes insipidus. Against a hemorrhage in the medulla oblongata speaks
the absence of any other brain symptoms. Scheuplein discussed the possi-

PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 559

bility of an injury of the solar ganglion. To me the possibility seems in any
case to be thought of that on account of the great swelling formed by the
injured vertebra there followed an irritation of the sympathetic paths in
their course from the sugar center to the suprarenals. By this means can
be explained even the polyuria. Scheuplein also refers to a case of Braun.
In a twelve-year-old boy there existed a spondylitis of the twelfth thoracic
and first lumbar vertebrae with an acute-angled kyphosis. When the boy
was placed in a horizontal position, symptoms of collapse, with polyuria
and glycosuria, developed. Comfortable lying on roll pillows brought about
a cessation of all manifestations. Also I must not leave unmentioned the
case of Schwenkendick. A man sustained a tread of a foot in the vicinity of
the navel. After some hours great thirst and polyuria started. Two days
afterward there occurred stormy manifestations, marked pallor of the face,
coldness of the extremities, distention of the abdomen, frequent vomiting.
The urine was at first free of albumin and sugar, after two days more there
was found 4.75 per cent, of sugar and abundant acetone. Later the patient
evacuated black stools that contained blood, and death soon followed under
manifestations of coma. The author thinks of apoplexy of the pancreas
or necrosis of the pancreas as an affection of the splanchnic nerves.

It is possible that in the setting free of this glycosuria, pain plays a con-
siderable role. For instance, it has been known for a long time that in severe
neuralgias there exists inclination to alimentary glycosuria. Frerichs reports
such a case; in a forty-eight-year-old man there occurred, after a cataract
operation, at the same time as severe neuralgic pains of the right half of the
face, sugar in the urine up to 2% per cent. As the pains ameliorated, the
sugar disappeared and ten years later the man was still sugar-free. It is also
known that cases of sciatica, especially those with frequent attacks, frequently
show alimentary glycosuria. H. Strauss found [urines tested for alimentary
glycosuria] in three cases positive, and then when the painful attacks were
over, negative in the same patients. Much cited is also the case of Frerichs,
concerning a shot injury of the sciatic nerve with severe attacks of pain,
during which sugar always appeared in the urine. As the suffering amelio-
rated the sugar disappeared entirely. It might be possible that in such cases
the irritation passes away along the sympathetic nervous system through
irradiation. We do not know certainly as yet as to whether longer con-
tinuing glycosuria may originate through involvement of the splanchnics
or the great ganglia of the sympathetic as the result of chronic inflammatory
processes — impaction in hard tissue, hemorrhages, etc. In the cases of long
continuing glycosurias of high grade known up to the present time, and
previously detailed, the associated involvement of the pancreas or the centers
in the brain stem through the violent concussion cannot be excluded entirely.

I now turn, finally, to the third question, whether in the wake of a trauma
a chronic or eventually a later recurring diabetes on a nervous foundation,

560 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

is conceivable. It seems to me that the possibility that a scar formation
exercising irritation on the centers regulating sugar metabolism cannot
entirely be ruled out, as I have already signified. But at all events severe
diabetes of year-long duration, that is progressive and eventually ends in a
coma, cannot be explained by it. If the diabetes after the trauma is chronic,
it is indeed very probable that a predisposition [Anlage] for diabetes has
existed beforehand.

Although we, in the previously detailed cases of organic alterations of the
brain, must regard it as extremely unlikely that an acute alteration of the
pancreas should exist at the same time, this (factor) cannot be excluded in
those cases of brain syphilis which are also designated "nervous." The
cases are so interesting that I would like to discuss them. In 1860, Lendet
first described such a case. It was that of a thirty-two-year-old woman, who
four years previously had progressed as f-ar as the development of a "saddle
nose." In her there developed rather suddenly polyuria and polydipsia, un-
consciousness, paralysis of the eye-muscles, left-sided anesthesia, etc. In the
urine was abundance of sugar. On the institution of a potassium iodide treat-
ment the diabetes insipidus and glycosuria disappeared, and also the brain
symptoms ameliorated. Later, with a more recent aggravation of the brain
symptoms, polyuria occurred again, but not sugar. Autopsy showed that
the choroid plexus was adherent to the left border of the calamus scriptorius,
and the brain substance of this was "eroded." In the book by French
are reported three cases of lues with brain symptoms and in part associated
with very severe diabetes, in which diabetes disappeared under antiluetic
treatment, or, as in one case, improved considerably. Very instructive
cases are reported by Dub and Lemonier. I would like to mention more in
detail the case of Hemptenmacher. In a forty-two-year-old woman who had
been infected with syphilis thirteen years previous there developed, at the
same time with a polydipsia and pollakisuria, a left-sided hemiplegia with
severe headache. In the urine was found 3.6 per cent, of sugar. Under the
inunction treatment and potassium iodide the glycosuria gradually disap-
peared without the retention of an antidiabetic regime. Also the brain
symptoms gradually ameliorated, and later complete cure was obtained.

In this and in other cases there without doubt exists a causal connection
between lues and diabetes. The occurrence of diabetes simultaneously
with tertiary luetic symptoms, the cure of diabetes by antiluetic treatment
without alteration of the diet alone allows of no other conclusion. On the
other hand the interpretation of the condition as nervous diabetes is entirely
uncertain, as a simultaneous alteration of the pancreas is not to be excluded.
It is true that never was the occurrence of absorptive disturbances mentioned,
but the fact cannot be excluded that the insular apparatus may alone have
been damaged in its function; the case of Manchot, moreover, that ran along
without brain symptoms showed likewise no absorptive disturbances.

THEORETICAL CONCLUSIVE CONSIDERATIONS 561

Theoretical Conclusive Considerations

Before I finally turn to the question as to what signification the internal
secretion of the pancreas has for the pathogenesis of human diabetes, I
should like briefly to summarize the most important points that were touched
upon in the course of the exposition.

1. Embryology, anatomy, experimental pathology, and clinical observa-
tion point to a certain independence of the insular apparatus. The em-
bryological investigations showed that the insular apparatus and the acini
developed separately. The anatomical investigation showed a different struc-
ture of these two apparatus; a transition of the one tissue-element into the
other has not up to the present been demonstrated with certainty. The ex-
perimental pathological investigations showed that after ligation of the excre-
tory ducts the acini become destroyed, while the insular apparatus for the most
part behaves refractorily. The pathological-anatomical observation likewise
showed that on the one hand the insular apparatus ordinarily is more resistant
to certain destructive processes and that on the other, isolated alterations of
the insular apparatus occur; finally clinical observations showed that dis-
turbances in the function of the glandular apparatus and the insular appara-
tus occur entirely apart from each other, and that to such isolated disturb-
ances a corresponding pathological-anatomical finding can with probability
be ascribed.

2. After the complete extirpation of the pancreas always occurs (in the
dog) a characteristic disturbance of metabolism; there always develops a
severe diabetes Jeading to death, in the course of which affection the glyco-
genesis is to a high degree, but not entirely, prevented in the liver and
muscles; the disturbances in the assimilation of sugar might lead immediately
to a disturbance in the combustion of sugar. In addition to this disturbance
in anabolism exists a severe disturbance in catabolism, that affects not only
the carbohydrate metabolism (increased sugar production), but also the
protein, fat, and salt, metabolism. The catabolic disturbance shows, on
extirpation of the pancreas, great regularity; there further exists regularly a
certain hyperexcitability of the sympathetic nerves.

3. The investigation of the metabolism in human diabetes shows disturb-
ances in both anabolism and catabolism; the latter, however, confine them-
selves only to the sugar metabolism, while quantitatively increased breaking
up of albumin and fat are not demonstrated even in the severer cases. On
the contrary, catabolic disturbances in the sugar metabolism are much
more severe in the graver cases, as the glycosuria attains a much greater
intensity than in the dog without a pancreas.

4. Concerning the nervous manifestations in human diabetes, we can
distinguish two types, between which we find all possible transitions. In the
first, rarer, type, to which v. Noorden has lately directed attention, the nerv-

36

562 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

ous manifestations are strongly in the foreground from the beginning. Be-
fore everything is the psychic factor, that under circumstances dominates
the elimination of sugar from the beginning up to even years, or at least
influences it to a marked degree. Especially accentuated does the nervous
factor enter into certain psychoses, into traumatic neuroses, into severe
attacks of pain, etc. But this can be the case in even uncomplicated cases of
human diabetes. In such cases it would perhaps be possible to demonstrate
regularly a hyperexcitability of a certain part of the sympathetic system;
especially does the glycosuric action of adrenalin always seem in such cases
to be distinctly present, indeed under circumstances the entire complex of
adrenalin action (vascular and cardiac manifestations, etc.), seems to be very
decidedly pronounced. There are all the transitions between this and hyper-
tonic diabetes, in which in addition to the hyperexcitability of the sympathetic
nervous system, there also occur conditions of permanent hyperexcitability.

In the much more frequent second type the alimentary factor is in the fore-
ground from the beginning. It governs the intensity of the elimination of
the sugar, whereas psychical factors have no distinct influence on this.
Especially are there no manifestations of hyperexcitability of the sympathetic
system, especially that apparatus which has to do with the regulation of
sugar metabolism. In the later stages of this type, when it has developed
to severe diabetes, there occur a series of symptoms that point to a hyper-
excitability of the sympathetic system. Then adrenalin can make the
glycosuria distinctly more intense or, if the patient has been rendered sugar-
free, may call forth glycosuria. Further there then begins an especial
sensitiveness of the renal vessels, in that adrenalin, or similar agents, like
pituitrin, then act diuretically. Finally there now shows itself the note-
worthy phenomenon that long continued administration of thyroidin raises
the blood-pressure, without eliciting any stronger manifestations of hyper-
thyroidism than when it is used in non-diabetic individuals. This phenome-
non seems to indicate an especial lability of the sympathetic nervous system.
To this is added in severe diabetes the known erethism of the vessels, the
genesis of which is hard to account for; finally I would like to point out a
symptom that seems to me to belong at this place; it is the extraordinary
richness in blood of the liver, which we see, as already Klebs mentioned,
in the individuals dead from severe diabetes.

All these manifestations are common to the later stages of both types;
I would believe that they are more markedly pronounced in the later stages
of the first type. Yet for the corroboration of this is necessary a greater
material than has been observed up to the present.

Let us now investigate how far the pathologico-anatomical findings suffice
to explain the clinical observations. No doubt there are cases with gross
anatomical disturbances of the pancreas and especially of the insular appara-
tus, that without anything else explain a severe disturbance of function of the

THEORETICAL CONCLUSIVE CONSIDERATIONS 563

same. Such cases rightly deserve the name pancrcatogenic diabetes. There
are further described in detail cases of alterations of the central nervous sys-
tem, whose seat makes appear intelligible long continuing irritative mani-
festations on the part of the sympathetic centers, which have to do with the
regulation of metabolism, or perhaps on the part of the paths that bind these
with the chromamn tissue. It is doubtful whether a permanent diabetes
may become manifest through such gross anatomical disturbances. In
addition there exists' a great many cases in which nothing certain is found in
the nervous system and the insular apparatus shows only relatively slight
alterations. If we accept the viewpoint of Weichselbaum, however, it seems
to me that up to the present there has been in such cases an insufficient agree-
ment between the pathologico-anatomical findings and the intensity and
acuteness of the clinical manifestations. Especially would this hold true for
the juvenile uncontrollably progressive cases of diabetes mellitus. In such
cases there lies close the thought of a congenital weakness in the rudiment
[Anlage] of the insular apparatus, whereby the hereditary and familial occur-
rence may become more intelligible. We can also suppose that in such
individuals various deleterious influences— infections and intoxications,
etc. — find a locus resistentiae minoris and damage the insular apparatus;
and we can further suppose that the same alterations of the insular apparatus
may recuperate, especially if by reason of a corresponding dietetic treatment
or prophylaxis the damaged organ is given time and rest for recovery.

It appears, however, that through these means of consideration alone the
problem of human diabetes will not become solved. The nervous factor that,
as clinical observation teaches, often occupies the foreground, assigns to the
nervous system a much more important role. A disturbance of the regulation
of sugar metabolism through the central nervous system is especially to be
thought of in two directions. Either the activity of the insular apparatus
may be deficient thereby, so that the nervous impulses necessary for a normal
function are too weak — an insufficiency on a nervous basis, such as we know
in the glands with an external secretion in achylia gastrica, for instance. It
appears to me, however, that according to that which I have previously set
forth concerning the nervous type, this assumption has little a priori to
recommend it. Or in the metabolism of sugar there may be an increase in
catabolism through an enormous excitation of those centers which regulate
the activity of the chromaffin tissue. We can designate this type, then, as
nervous or adrenalinogenic. I would only point out especially that in this
type the insular apparatus is entirely intact. That such an excitation of the
nervous centers leads to a continuous and strong glycosuria, brings into relief
a certain weakness of the insular apparatus. In individuals with completely
normal pancreas, such excitations as increase the catabolic processes are
neutralized by the corresponding counter-regulations. The difficult feature
of the question seems much more to lie in the fact that in the nervous type

564 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

this condition of hyperexcitability seems to occur primarily and that it in-
creases the disturbance in metabolism in a manner that is hardly possible
through failure of the insular apparatus alone, while it accompanies the pure
pancreogenic type only secondarily and perhaps in a less intense form. That
also in the nervous type an increased adrenalin-contents of the blood could
not up to the present be demonstrated, seems to me to signify nothing against
this assumption; on the one hand, the biological methods up to the present
have been insufficient for the demonstration of adrenalin in the serum (I refer
to the work of O'Connor, Priestly, Fleming, Kahn and myself] and on the other
hand we can conceive that on insufficient contraregulation also minimal sur-
plus production of adrenalin already produces a significant effect on sugar
metabolism.

As to the cause of such an abnormal excitation in the nervous system we
know as yet nothing. We have, however, met with similar conceptions in the
diseases of the other ductless glands. I refer to Basedow's disease where
especially in the peracute cases, the increase of function of the thyroid gland is
ascribed by many authors to a central excitation; and indeed they regard
many symptoms as coordinate with hyper thyroidism, and conditioned cen-
trally. We could designate the entire disease picture as hyperthyrosis, and
the important syndrome conditioned by the hyperfunction of the thyroid
gland we could designate hyperthyroidism. According to this hypothesis we
could regard these hyperfunctional conditions of the ductless glands as neu-
roses. So far as this theory of diabetes is concerned, we are unmistakably
approaching again the view first propounded by the genial investigator of
diabetes, Claude Bernard, although in a considerably modified form.

If we now on the basis of the developed view, finally turn to the question
as to why the diabetes of dogs without their pancreas deviates in some essen-
tial points from that of the genuine human diabetic it seems to be that as yet a
satisfactory explanation has not been possible. The principal difference lies
in the fact that in the dog without a pancreas the catabolic factor of the car-
bohydrate metabolism is less strong, that of the fat and protein metabolism
more strong, while in genuine human diabetes the first is more strongly de-
veloped, and the latter factors fail almost entirely. Perhaps there may after
all be elicited some grounds for the explanation of this considerable difference.
On the one hand it might not be impossible that in the carnivorous dog the
significance of the inner secretion of the pancreas is not quite the same for the
metabolism as in the omnivorous human being.

We must then assume that in the dog the pancreatic hormone exercises
also a direct inhibiting influence on the splitting up of protein and fat. A
certain decision of this question if exact observations of sudden and complete
absence of pancreas [function] in man were at hand, which up to the present
has not been the case.

On the other hand the following idea might very well be elicited from what

THEORETICAL CONCLUSIVE CONSIDERATIONS 565

has been said: In experimental pancreatic diabetes, only the pancreas is absent,
all the rest of the manifestations are secondary; in genuine human diabetes there
exists, however, a disease of the whole apparatus regulating sugar metabolism
(nervous centers in the medulla and brain stem, connecting paths, pancreas, and
chromaffin tissue} with insufficiency, but not complete absence, of one part and
more or less independent hyper excitability in the other part.

Through this view, which has been the product of v. Noorden's clinic in
recent years, the problem of the pathogenesis of diabetes mellitus has been
broadened, but the solution of it seems only to have been thrust back one
step further.

As far as the other glands are concerned in the bringing about of diabetic
glycosuria, we may off-hand ascribe with certainty an important role in this
direction to only two other glands, the thyroid and the hypophysis. There
exists, however, but littler clearness in which way these ductless glands enter
into the regulative mechanism of sugar metabolism, and whether they exer-
cise this influence chiefly or exclusively by way of the pancreas. In the chap-
ter on Basedow's disease we found that hyperthyroidism was not rarely
associated with a reduction of the assimilation limits for carbohydrates; in-
deed, under circumstances, it could lead to spontaneous glycosuria. The
circumstance that the alimentary factor is so prominent in these cases,
speaks for the fact that through the hyperthyroidism there is called forth an
insufficiency of the pancreas; further, the circumstance that with the suppres-
sion of the hyperthyroidism the glycosuria again disappears and eventually
there come about normal relations, shows that this insufficiency is actually the
result of hyperthyroidism. It appears therefore as has already been amplified
in the chapter on Basedow's disease, that hyperthyroidism seems to signify a
functional overloading of the pancreas; it is intelligible, from this standpoint,
that glycosuria sets in only in individuals predisposed to it. As without such
a functional overloading glycosuria would never occur, we are well justified
in speaking of a thyrogenic glycosuria in such cases. This also is mostly
easily delimited from true diabetes complicated with Basedow's disease.

As far as the diabetic glycosurias that occur so frequently in acromegaly
and gigantism are concerned, it has already been set forth in the correspond-
ing chapter that there is present in the great majority of cases an organic
disease of the insular apparatus. It was mentioned there that in all conditions
of hyperfunction of the glandular hypophysis a period of an abnormal tend-
ency to growth is followed by a period of decay, and that the entrance of this
decline is different in the various organs and especially so in the various duct-
less glands. The insular apparatus appears to be especially sensitive. Be-
sides these true diabetic glycosurias there is present in rare cases of acromegaly
a similar condition to that observed in true thyrogenic glycosurias; in these
cases right at the beginning of the disease there develops a glycosuria, which
later disappears and gives place to a normal assimilative ability. Whether

566

DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

ffland

this glycosuria is of thyrogenic origin or whether the hypophysis enters
not in some other manner directly into the regulatory mechanism of the
carbohydrate metabolism, I shall not touch upon.

i). Noorden has portrayed the influence of the ductless glands upon the
regulation of the carbohydrate metabolism in the following scheme. I have
modified it in that I have added to it two connecting lines — -one between
the chromaffin tissue and the tissue at the periphery (chiefly the muscular
system) and one between pancreas and tissue. This lends expression to the
opinion that pancreas and chromaffin tissue directly regulate the assimila-
tion and dissimilation of carbohydrates. Let me call attention to the
fact that, the line of connection between thyroid gland and pancreas is
meant to express only the fact that increased thyroid activity disturbs the
equilibrium to the disadvantage of the pancreas. Whether this happens

Thyroid- through the influencing of the activity
of the insular apparatus or through in-
fluencing the ultimate organs affected
is still uncertain.

"The line of dashes represents nerve
paths; the solid lines represent blood paths.
The arrows show the direction of the ex-
citation; the signs + or — behind them
mean whether the stimulus transmitted by
the respective path increases or diminishes
the specific activity of the organ in ques-
tion," whether it acts assimilatorily or
dissimilatorily.

Differential Diagnosis. — A sharp
separation of the ephemeral or transi-
tory glycosurias from true diabetes is not practical. There are fleeting tran-
sitions between these forms. We would naturally not regard every individual
who has one time eliminated grape-sugar in his urine as a diabetic; otherwise
if investigations as to alimentary glycosuria (100 gm. grape-sugar) carried out
at great intervals result always negatively, we could with justification speak
of the cure of the diabetes.

We would think in general of a pancreatogenic diabetes when the alimen-
tary factor comes strongly in the foreground; especially if pancreatogenic
resorptive disturbances are present; further in all those conditions, which
according to experience favor infection of the pancreas; hence in cholelithia-
sis, pancreatic stones, also in lues, cirrhosis of liver, and arteriosclerosis,
etc. Hirschfeld regards also the behavior of diuresis as a differential diag-
nostic factor. It is not unlikely that in true pancreatic diabetes there is
at the beginning no polyuria.

In glycosurias that occur during the course of infectious diseases, there
is indeed much that speaks for the involvement of the pancreas in the infec-

Chromaffin
tissue

Pancreas

THEORETICAL CONCLUSIVE CONSIDERATIONS 567

tion; there is much for the thought, however, that the violent conditions of
excitation in the vegetative nervous system may be of significance for the
genesis of a nervous glycosuria.

For the assumption of a nervous glycosuria there are brought about
symptoms that indicate a disease of the pons, cerebellum, and medulla ob-
longata, perhaps also Circumstances that can bring about an irritation of the
splanchnics or the great sympathetic ganglia either directly or by circuitous
routes; especially, trien, severe neuralgias. Further we have to turn our
especial attention to the behavior of the vegetative nervous system and the
influencing of the glycosuria through the psyche. In many cases we can
perhaps carry out the test for adrenalin glycosurias (in the aglycosuric con-
dition) or Lowi's reaction; high-grade polyuria as well as simultaneously
existing hypertonia speak for the nervous form or for a marked associated
involvement of the nervous system.

Finally, as to the thyrogenic form, naturally we must take pains to
detect synchronous systems of hyperthyroidism. I would mention that in
all the cases of true thyrogenic glycosuria that I have seen, the eye symptoms
were at most indicated. But tremor, sweats, and mononucleosis of the blood
were always present. A higher degree of glycosuria speaks well against the
purely thyrogenic origin. Fat stools with strikingly good splitting of the fat
and abundant soap-contents speak for the thyrogenic glycosuria. The diag-
nosis would be assured, if with the retrogression of the hyperthyroidism
(spontaneously or by means of Rontgen illumination, etc.), the glycosuria
disappeared altogether, and if now strong loading of the carbohydrate
metabolism no longer led to elimination of sugar.

To close with some therapeutic points of view. In pancreatogenic dia-
betes the difficult feature of 'the treatment up to the present lies in the diet,
which purposes to avoid [the functionating of] the diseased organ. This
is brought about by limitation, or even by temporary complete withdrawal
of the supply of carbohydrates and by simultaneous limitation of the supply
of proteins. Also in cases with ketonuria, an abundant supply of fat should
be avoided. The patient should be made free of sugar, and when possible,
maintained sugar-free. There often occurs in such cases a restoration of
the insular apparatus; if later than the investigation shows that the assim-
ilatory ability has significantly increased, carbohydrates should again be
administered at times in order to avoid permanent poverty in glycogen. The
great significance of v. Noot -den's oat-meal treatment lies in the fact that in
an individual under-nourished with carbohydrates large quantities of gly-
cogen are administered as an increment. Thus is often explained the wonder-
ful action on the ketonuria. The catabolism becomes limited. In the severe
forms the complete withdrawal of carbohydrates is not possible perma-
nently, as the complete absence of glycogen increases the formation of
ketone bodies entirely too markedly. Here we must try to restrict the gly-

568 DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS

cosuria at least as much as possible, and counteract the overloading with acids
by alkali therapy.

Much indeed speaks for the fact that in the nervous form too vigorous
dietetic measures act unfavorably, although v. Noorden points out that in
such cases a weakness of the insular apparatus may always be supposed, which
tends to come to the fore in the further course, and therefore that a complete
disregard for prophylactic dietary prescriptions may be disastrous for the
patients. In the pure thyrogenic form the treatment of the hyperthyrosis
occupies the foreground, in the pursual of which, however, vigilance in a
dietetic respect is not excluded. The treatment of diabetes in acromegaly
should coincide with that of genuine diabetes.

Addendum

Allen, in his book on "Glycosuria and Diabetes," draws an essential
distinction between these two conditions, pointing out that in nondiabetic
animals the limits of tolerance are apparent, not real, and that in these ani-
mals there is no real limit to the power of utilization of the sugar except death.
Also that in the various forms of glycosuria dextrose always produces a
limitation of the amount of urine, never a diuresis as in diabetes. He divides
diabetes by pancreatic operation into a diabetes gravis and a diabetes levis,
according to whether dextrose is or is not excreted on meat diet, and each
of these into a permanent and a transient form. Permanent diabetes gravis
and transient diabetes levis are absolute terms; but transient diabetes gravis
and permanent diabetes levis are relative, the two conditions passing into
each other. These various types depend on the condition of the pancreatic
remnant. The ways that diabetes could be produced when the pancreas
remnant is of more than ordinary size are by an irritative nervous lesion, such
as the Bernard puncture, and by circulatory disturbances in the pancreas.
The fact that the nervous system can influence the pancreatic hormone, as is
practically also Falta's conclusion, seems to the editor to speak in favor
of Crile's contention that diabetes may be conditioned centrally, the nerve
cells showing chromatolytic changes. At all events the intermediation of
the islands of Langerhans of the pancreas remain unquestioned, this bringing
about a deficiency of what Allen terms "pancreatic amboceptor." Accord-
ing to Allen's experiments there occurs in diabetes not a change in the hepatic
cells that cause them no longer to fix dextrose, but a change in the physical
state of dextrose itself. Instead of combining with a colloidal "pancreatic
amboceptor" to be in a condition to be utilized, it maintains its ordinary
crystalloidal properties, thus causing diuresis. Whether there is any dis-
tinction between pancreatic hormone and the pancreatic amboceptor does
not seem very clear in a cursory review of Allen's voluminous work. Allen
seems to call the substance an amboceptor because it acts as an intermediary
body between the dextrose and various body cells. It has in common with
hormones, at all events, the fact that it is an internal secretion, dependent

ADDENDUM . 569

on the integrity of the insular apparatus of the pancreas. Evidence is brought
forward that at least one form of diabetes insipidus is associated with cir-
culatory disturbances of the pancreas (how is this diabetes insipidus to be
correlated with the polyuria approaching a diabetes insipidus that occurs in
certain hypophysial affections?), but that is not associated, as is diabetes
mellitus, with any evidence of insular involvement.

It is probable that the good results of oats on diabetes are due to the fact
that rest is provided for 'the pancreas. According to Allen: by reason of
freedom from harmful stimuli from the intestine, also perhaps by reason of a
diminished labor of external secretion, and possibly by reason of a mild
beneficial stimulation in a positive sense, the pancreas is able to perform
its function of internal secretion more efficiently, and the diabetic condi-
tion is correspondingly benefited. This explanation agrees with facts in the
literature.

On the strength of his experiments, Allen has recently advocated and
practised with good results a method of treatment, which consists in absti-
nence from food and drink, doses of alcohol (not absolutely essential), and
the administration of sodium bicarbonate. This regime is continued for
twenty-four to forty-eight hours after the absolute disappearance of sugar
from the urine (which occurs in from one to eight days), when it is replaced
with 10-40 gm. of carbohydrates in the form of steamed green vegetables
(gradually increased), together with fats and proteins (which are also in-
creased gradually). As soon as sugar reappears in the urine, another fast
day is instituted. Stengel, Jonas and Austin while advocating Allen's treat-
ment for severe .cases of diabetes showing high ketonuria, have had good
results in the milder cases, those in which Allen's treatment is perhaps too
severe, by placing the patient on a carbohydrate-free diet, then adding green
vegetables to this diet, and later allowing carbohydrates, below the limits of
tolerance. The days of the carbohydrate-free diet are to be spent in bed,
at rest.

A recent study of the hypophysis in diabetes mellitus by Fry has shown
that it exhibits definite histological changes. It contains adenomatous
masses of eosinophile cells, and there is colloid invasion of the anterior lobe,
together with area of cellular degeneration in this part of the gland.

REFERENCES

Allen (F. M.). Studies concerning glycosuria and diabetes. Boston, 1913, N. M.
Leonard.

Allen (F. M.). Studies concerning diabetes. Jr. Am. M. Ass., Vol. LXIII, No.
n, Sept. 12, 1914, p. 939-943-

Stengel (A.), Jonas (L.), and Austin (J. //.). The treatment of diabetes mellitus
with special reference to Allen's method. Pennsylvania Medical Journal. Vol. XIX.
No. 4, Jan. 1916, p. 283—287.

Fry (H. J.B.). The pituitary gland in diabetes mellitus and disorders of the glands of
internal secretion. The Quarterly Journal of Medicine, Vol. VIII, No. 32, July, 1915,
pp. 277-299.

CHAPTER XIV

THE DIFFERENT FORMS OF OBESITY AND ADIPOSITAS

DOLOROSA

We have already spoken of obesity in other chapters. It seems to me
appropriate, however, to describe the relations of the ductless glands to the
pathogenesis of obesity, even though I do not tell anything new. Further,
it would be appropriate to discuss the relations between obesity and lipomato-
sis, as also the origin of lipomatosis has been brought into relation with
disturbances of the ductless glandular system.

A. THE DIFFERENT FORMS OF OBESITY

Two. different principal types of obesity have been distinguished
(v. Noorden, Lor and], exogenous obesity and endogenous obesity. By exogen-
ous obesity, Lorand understands the obesity of big eaters — that which later
becomes combined with diabetes; endogenous obesity he refers to a disease
of the ductless glandular system. Such individuals are for the most part
anemic, have an ''unhealthy fat," and the combination of the disease con-
dition with diabetes belongs to the great rarities. The separation and char-
acterization of both forms has been carried on exhaustively by v. Noorden
in his monograph on obesity.

According to v. Noorden exogenous obesity is either an overfeeding obesity
or a laziness obesity, or the result of both overfeeding and laziness combined.
Exogenous obesity often occurs familially or hereditarily, although v. Noorden
points out that in many of these cases there has been much more the heredi-
tary transmission of a habit of living than that of a definite constitution.
Naturally, cases occur that must be regarded as transition forms between
exogenous and endogenous obesity. A further entrance into the subject of
exogenous obesity does not lie within the confines of my theme; I shall refer
to the exhaustive exposition of v. Noorden.

In endogenous obesity much value has been laid on the demonstration of
a diminution of the fundamental exchange and great pains have been taken
in the demonstration. While such a diminution may be demonstrated in
myxedema with certainty and ease, the attempts to demonstrate it in en-
dogenous obesity have met with great difficulties. As the fat tissue only takes
part in internal respiration to a limited degree, the fundamental exchange
must fall very strongly in each fat individual if we wish to calculate it per
kilo of body weight. But we possess no method of estimating the fat con-

570

THE DIFFERENT FORMS OF OBESITY 571

tents of an individual, but must rely on coarse, insufficient estimations.
The investigations up to the present on the fasting and rest values of corpu-
lent individuals (v. Noorden, Thiele and Nehring, Stuve, Magnus-Levy,
Rubner, Jacquet and Svenson, Salomon, Reach, Staehelin, and v. Bergmann)
have been subjected to an analytical criticism by v. Noorden; the calculation
of the exchange per kilo of body weight, must, as already mentioned, be

C>2 consumption
rejected as of no use. The calculation of the quotient

body height

shows in corpulent individuals higher values sooner than in normal indi-
viduals. This is perhaps due to the fact that in heavy accumulations of fat
the work of the heart and of the respiratory muscles is perhaps made more
difficult, v. Noorden arrived at the result that the estimation of the respira-
tory exchange at rest has up to the present furnished no sure decision in this
question. This is true apparently of the estimations up to the present of the
factors influencing the exogenous respiration gaseous exchange. The
opinion has been held that in the corpulent the ingestion of food should
call forth a slighter increase of the exchange. Herein lies a tendency to
saving. The experiments that have been made up to the present, however,
do not bear strict criticism. Up to the present only the determination of
the calorie requirements has led to reliable results in some cases. The supply
of heat was estimated in a very careful manner and for a long period, and it
was determined that corpulent persons either take on fat or do not lose it
under conditions under which normal persons either would not become corpu-
lent or would lose in body weight. In this method care should be taken that
exogenous factors are not allowed to take a part. The corpulent individual,
to whom every movement is attended with exertion and is disagreeable,
has often learned to get along with the minimum of movement, otherwise
he sits and stands as a normal individual. To this must be added also the
phlegm of such individuals. These methods can thus furnish a certain
conclusion as to the diminution of the fundamental exchange, if extremely
low values are found. This is actually so in the cases reported. Such cases
are, however, as v. Noorden has pointed out, quite rare.

We must now consider the question as to whether a diminution in the
fundamental exchange characterizes endogenous obesity, and whether this is
necessary for the assumption of a case as such. In a typical myxedema it is
true that simultaneously with the reduction in the fundamental exchange
there occurs an increase of the body weight, but this does not always progress
to obesity. It is much more probable that the increase in weight can de-
pend solely or in great part on the accumulation of myxedematous tis-
sue and the water accumulation. In normal grown individuals the ingestion
of food rises or falls with the greater or lesser need for it. The body weight,
.apart from slight variations, often remains the same for years at a time.
This depends on a fine regulatory mechanism that as yet has not been investi-

572 OBESITY AND ADIPOSITAS DOLOROSA

gated sufficiently. The most important element in the same is the appetite,
although at times we eat very much more than the appetite really craves
for, and then follows a period not of lessened appetite, but perhaps of in-
creased demand for movement, the cause of which is not known. May
not. perhaps on the occasion of too great demand on the assimilation, sub-
stances arise which give occasion to this desire for movement? If now the
diminution of the fundamental exchange increases the body weight, that is,
the need for food does not keep pace with the exchange, it seems to me that a
diminution of the fundamental exchange is less to blame for this increase in
body weight than a disturbance of the regulatory mechanism; and it is per-
haps not inconceivable that there are forms of endogenous obesity without
diminution in the fundamental exchange. In exogenous obesity, according to
this point of view, the regulatory mechanism is disturbed voluntarily or
on account of bad habits (v. Noorden) ; in endogenous obesity, involuntarily
through an alteration in the working together of the factors governing assimi-
lation. If now I investigate how far such factors depend on the function of
the ductless glands, it is known to me that I trespass into the territory of
speculation, yet I see no other way of bringing into association the few cer-
tain observations that we possess on this question. At first I must again call
to mind that the ductless glands exert an influence on both the endogenous
and the exogenous factors of the total exchange. Upon the endogenous
through diminution of the vegetative functions, for example; on the exogen-
ous by their influence on the temperament, the psyche, the desire for move-
ments, etc.

i. Pancreatogenic Obesity

We shall consider in the first place a form of obesity, whose genesis
has yet not been furnished to us. It is observations from the physiology
and pathology of metabolism that makes the supposition of such a form possi-
ble; if this supposition, however, suffices, many other forms of endogenous
obesity may be made the more readily intelligible from this standpoint. The
complete extirpation of the pancreas in the dog leads to an appreciable in-
crease in the gaseous exchange. High-grade insufficiency of the insular
apparatus in man is not, however, associated with an essential raising of the
heat-production. Therefore, if although up to the present there has not
been demonstrated by gaseous-exchange experiments concordant results as
to a quenching of the heat production through the function of the insular
apparatus, other considerations, however, seem to ascribe to the pancreas an
important role in the calofie economy.

v. Noorden first adhered to such an opinion, in that he indicated the possi-
bility "that fixing of glycogen and sugar-production can be disturbed, while
fat formation from carbohydrate still functionates. The fat tissue then
takes up the excessively formed carbohydrate (as fat) ; there already exists a

THYROGENIC OBESITY 573

true diabetic disturbance of metabolism, but without glycosuria" (diabeto-
genic obesity).

I would consider in the following consideration a further possibility:
It is known that carbohydrates have the ability to save protein to a much
larger extent than fat, and that an individual can hardly maintain his nutri-
tion on protein and fat alone. An abundant feeding, especially when there
is a simultaneous raising of the protein constituent, succeeds only when there
is abundant carbohydrate in the diet. Hence carbohydrate diminishes the
decomposition of the protein. As the specific dynamic energy of protein is
very much higher than that of fat and of carbohydrate the increase of the
calorie production associated with the more abundant ingestion of nutrition
is restricted. Now to-day there is not a particle of doubt that the ac-
cumulation of carbohydrates is under the governing power of the insular
apparatus. There must also accrue to the pancreas a direct influence on the
assimilation of fat, not only because on the ingestion of abundant carbo-
hydrates a portion of these is converted into fats, but because in severe dia-
betes the elimination of ketone bodies increases enormously on the adminis-
tration of abundant fat. For fattening, therefore, is necessary a functionally in-
tact pancreas. That we so often see diabetes supervene in fat people is per-
haps due to the fact that the long overstrained pancreas becomes insufficient,
apart from the circumstance that chronic overfeeding is often associated
with other factors deleterious to the pancreas (alcoholism, continual hypere-
mia of the abdominal organs, etc.).

The considerations up to the present are concerned chiefly with exogenous
obesity. We can- conceive, however, that the origin of obesity may receive
an impetus through a primarily strengthened function of the insular apparatus,
in that the assimilation of larger amounts of food goes on abnormally easily,
and hence there does not occur the setting free of the reactions that in
normal individuals work against an ingestion of food which for a long time
supersedes the need.

2. Thyrogenic Obesity

The idea of thyrogenic obesity was first set forth by von Hertoghe, v.
Noorden, Lorand, Ewald, and others. Occasion for it was given by observations
of rather rapidly developing obesity with slight symptoms of hypothyrosis,
slight puffiness of the face, apathy, diminution of memory, insomnia, etc.
To it is often added a slight grade of anemia. Such individuals often bear
reducing treatment very badly, v. Noorden mentions especially that in such
cases reducing treatment often leads to conditions of cardiac weakness, while
a thyroid-gland treatment is often accompanied by rapid results, the manifold
oppressive symptoms disappear, the individuals become livelier, fresher, and,
although they eat with appetite and do not essentially restrict the intake of
food, they now gain in weight rapidly. There appear to be very different

574 OBESITY AND ADIPOSITAS DOLOROSA

etiological factors that lead to such a slight functional disturbance of the
thyroid gland. In many cases there had been numerous parturitions fol-
lowing each other at short intervals. In others the obesity develops imme-
diately at the close of a protracted infectious disease, v. Noorden mentions
for instance cases in which the obesity developed progressively after an
abdominal typhoid, and refers to similar examples from the French literature.
The diagnosis of this form of obesity is often difficult, because the symp-
toms of hypothyrosis are only suggested. The justification for one's regard-
ing the hypothyroidism as the cause of the obesity can, however, in many
such cases, indeed not be doubted. It is found in the entire course of the dis-
ease and in the excellent action of the thyroid treatment, which we may re-
gard as a sort of functional test. Of course thyroid gland acts as an agent
that reduces weight also in the cases of ordinary exogenous obesity. The
essential point lies, however, as v. Noorden mentions, in the difference between
the complete action of the thyroid cure and the intolerance against much
withdrawal of food, and, as I would attach especial value to, in the high
tolerance for thyroid-gland preparations. From the theoretical standpoint
the assumption of such a thyrogenic obesity is well founded. We can con-
ceive that just in such slight degrees of thyroid-gland insufficiency, the bal-
ance between thyroid-gland function and the function of the pancreas is dis-
turbed in favor of the latter, and that thus is furnished the impulse for the
origin of an obesity, while with a severe disturbance of the function of the
thyroid often all vegetative functions are highly diminished, and therewith
the ingestion of food and the appetite are restricted. The very general
observation that in such cases of thyrogenic obesity the assimilation limits
for carbohydrates lie abnormally high, indicates with the greatest probability
a preponderance of the pancreatic function.

3. Dystrophia Adiposo-genitalis

In this form, whether it be of primary genital or hypophysial origin, there
is found a characteristic distribution of fat such as has been described in detail
in the corresponding chapters. It depends on the withdrawal or the weaken-
ing of the protective influence of the interstitial glands on body formation.
The distribution of fat has per se nothing to do with obesity, as it is re-
tained in such individuals when they otherwise become very thin on any
other basis, and for the reason that sure cases of hypophysial dystrophy and
also many eunuchoids do npt come to the development of a pronounced obes-
ity, while the abnormal distribution of fat is always present. Also a certain
degree of fatty infiltration of the muscles may be peculiar to this dystrophy,
independently of obesity, as well as a weak, velvety texture of the skin, and
the behavior of the hair. The fact is, however, that in both forms, obesity
develops very commonly, even to excessive degree. The factors that give

ADIPOSITAS DOLOROSA 575

occasion to this are as yet not entirely clear. We must consider that eu-
nuchoids have another temperament than normal individuals; they are less
lively, have less energy, the muscular tonus is slighter; in hypophysial dys-
trophy there also happens that in the severer cases the vegetative functions
seem to course more slowly, and the fundamental exchange therefore is
established at a low level, as experimental investigations on animals have
shown. Also in these forms the function of the insular apparatus seems
to have a certain preponderance, at least, as has already been set forth in
detail, in almost all cases there is a strikingly high tolerance for carbohy-
drates. In the intimate pathological correlations between glandular hypo-
physis and thyroid, also a thyrogenic factor can, in many cases of hypo-
physial dystrophy, very well play a part. Ordinarily this does not seem the
case, at least the result of a thyroid treatment in such cases is not so excel-
lent as in the ordinary obese individuals, and the tolerance for the admin-
istration of thyroid gland is not essentially higher. There are numerous
statements in the literature that in such cases of hypophysial dystrophy
the peroral administration of hypophysis tablets or eventually a combina-
tion [of these] with sexual gland substance was followed by results.

4. Epiphysial Obesity

It is as yet doubtful whether we are justified in recognizing such a form.
At all events it is remarkable that commonly with the development of pineal
tumors in adults, obesity also develops. This may attain an excessive
degree. We may readily conceive that the obesity may be brought about
on account of limitation of function of the neighboring hypophysis. Actu-
ally, in the case of Raymond and Claude, the hypophysis was very much
flattened. One would then expect the other characteristic symptoms of
hypophysial dystrophy in all cases. From the cases in the literature, which,
however, have not been described very exactly, I have not succeeded in
eliciting a safe basis for this.

B. ADIPOSITAS DOLOROSA

In the years 1882 and 1892 respectively, Dercum described a disease
picture which is characterized by the peculiar form of fattening and by the
painfulness of the fat masses. Later Vitaut called attention to two additional
cardinal symptoms, namely the asthenia and certain psychical alterations.
Dercum considered the disease as due to an especial form of dysthroidia; since
that time numerous appropriate cases have been reported; most authors
adhere to the ductless glandular pathogenesis of this disease, although others,
especially French authors, oppose the setting up of this syndrome as a
disease sui generis, advocating the opinion that from this syndrome there

OBESITY AND ADIPOSITAS DOLOROSA

are transitions to the different forms of lipomatosis and to the trophic edemas.
Lately Lyon is even of the opinion that also the different forms of obesity
and those of lipomatosis go over into each other without sharp boundaries.
Many authors assume a nervous trophic origin for this syndrome. Before
I enter into the description of the syndrome, I would like to report an appro-
priate case.

Observation LXX. — Fr. B., fifty-six years old. Entered the first medical clinic Sept. 3,
1912. The parents of the patient were both corpulent. Of five brothers three are very
corpulent, and of four sisters, two. According to the statement of the son the localization

FIG. 96. — Case of adipositas dolorosa (Observation LXX).

of the fat in the corpulent relatives is not just the same as in the patient. The four chil-
dren are not adipose. There is no diabetes or gout in the family, so far as is known. As
a child and youth the patient was healthy. The obesity began to develop during his mili-
tary service, especially later, however, when the patient adopted a sedentary life; he was
landlord of an inn and ate and drank very much, consuming 4^ liters of wine daily and
smoking very much. The obesity was especially heavy from the thirty-fifth year of life
on. The fat developed in cushions on the shoulders, on the upper arm, on the thorax, and
on the pelvic girdle, while forearms and hands and [lower] legs and feet remained thin.
For about ten years there often occurred oppressions of respiration and vertigo, especially
on going up stairs and on long marches. Lately he can hardly walk on this account. The
appetite became slight, and he ingests practically only liquid nutrition. In the spring of
1912 he weighed as much as 140 kg. Since that time he lost about 30 kg. Foralongtime
there has existed pains in the hepatic region; during the last weeks he vomited several
times daily, independently of the ingestion of food, also belches. For the last year there

ADIPOSITAS DOLOROSA 577

has been entire impotence and failure of libido which for a long time has been developed
only very moderately.

The patient now weighs 105 kg. and by Nov. 9 had lost 3 kg. more. The body length is
170 cm., the span width, 169 cm., the greatest circumference of the abdomen, 124 cm.
There are enormous accumulations of fat on the upper arms and on the outer sides of the
shoulders, also on the inner side of the upper arm, also a thick cushion of fat over the verte-
bra prominens (a true fat neck), also on the outer sides of the buttocks and of the thighs;
the thin forearms and [lower] legs stand in characteristic contrast to the heavy fat accu-
mulations on the shoulder and pelvic girdle. In consequence of these the patient presents
the appearance of an athlete. On closer examination, however, it is noted that the body
build is slender, and that thorax and pelvic girdle are not abnormally broad. The cir-
cumference about the shoulders is, in consequence of the enormous cushions of fat, 128 cm.

FIG. 97. — Inflammatory alteration of the feet-tissue in a case of adipositas dolorosa

(Observation LXX).

The circumference of the abdomen a hand's breadth under the xiphoid process is 122 cm.,
the greatest circumference of the thorax, 123 cm., the greatest circumference of the upper
arm on both sides, 40 cm. On the inner side of the forearm may be felt on both sides sev-
eral symmetrical fat nodules, the size of a nut; the fat has accumulated more abundantly
on the upper part of the thorax, in the vicinity of the nipples, so that it drapes forward
in two enormous folds, directed obliquely outward and downward, and drapes backward
in several oblique and horizontal folds. From the waist on the fat again begins to be
enormous, so that it hangs below like an apron over the symphysis and half conceals the
genitalia.

Also laterally over both iliac bones are enormous fat nodules that are bounded below

37

578

OHKSITV \\D ADII'OSI I'AS Di >!.< >R()SA

by folds. On tin- outer side of the tVmur palpation reveals a more diffuse embedding of
dense nodular fat. On the inner side is found on rarh side an mormons fat nodule.
The distribution of fat b everywhere Strictly symmetrical. At some places a re found thick
symmetrically disposed fat nodules of the si/.e of a lien's c-gg to that of an apple, often
the nodules are smaller, seeming to the palpating linger like small nodules. Everywhere
over the fat cushions are to be seen ectatic veins, around which are plainly evident in the

FIG. 98. — Thyroid in a case of adipositas dolo%sa (Observation LXX).

whole course of the veins fat disposed like bunches of grapes. Here the fat is especially
painful.

The left lobe of the thyroid gland shows a struma about the size of a goose egg.

The border of the liver is palpable three finger-breadths below the border of the ribs,
and is hard. The urine shows urobilin and traces of albumin.

Test as to alimentary glycosuria (100 gm. dextrose) negative.

AUIPOSITAS DOLOROSA

579

After injection of 3 c.c. pituitrinum glandulare, and later 5 c.c., there was no increase
of temperature.

The blood sugar-contents is normal.
Blood count: Leucocytes, 12,000, of which:

Neutrophiles, 50 per .cent.

Lymphocytes, 42 per cent.

FIG. 99. — Hypophysis in a case of adipositas dolorosa.

Large mononuclears, 6 per cent.
Eosinophiles, 2 per cent.

X-ray shows that the aorta is 7 cm., the heart 13.5 cm. broad. The genitals show
nothing especial.

The sella turcica is seen (by X-ray) to be of normal size.

Nerve status: The fundus is normal. The pupils react promptly. Patellar reflexes
are weak on both sides, superficial abdominal and cremasteric reflexes normal. No
Babinski, no Romberg. Slight paresis of the right facial nerve. Distinct alcoholic
tremor. Gross strength of the muscles reduced. Gait sonu-what in sec lire. Sensibility
not essentially disturbed.

The microscopical examination of an excised piece of fat showed pronounced peri-

58o

OBESITY AND ADIPOSITAS DOLOROSA

vascular infiltration consisting especially of mononuclear. and partially of polynuclear
cells. Especially distinct is this infiltration in the interstitial connective tissue between
the individual fat lobules, although the smallest perivascular infiltrations are found also
around the capillaries between the fat cells themselves.

The patient went down very rapidly, soon he was not oriented any more as to time and
space; there occurred hallucinations of faces, he spoke confusedly, believed himself to be
on a journey, whistled and made a noise, especially at night. Apparently there was diplo-
pia on looking toward the left. Slight paresis of the left abducens. The ingestion of
food became always slighter; nutritive enemas were not retained. At times vomiting.
The pulse accelerated, small, soft cardiac remedies were without effect. At the close there
developed an ulcerous pharyngitis, later bronchitic murmurs; death occurred with in-
creased cardiac weakness.

Autopsy (Assistant Dr. Schopper). Hypertrophic cirrhosis of the liver with moderate
enlargement of the organ and uniformly granulated superficial and cut surface. Marked

(•»», \ *s< *
^VxM^v..

^ -»# ~ *v j** j »•••«• £«.

FIG. 100. — Anterior lobe of hypophysis in a case of adipositas dolorosa (Observation LXX).

fat infiltration of the heart in the form of nodular fat lobules with penetration of the fat
until up to the endocardium. Concretio cardio cum pericardio. Increase of the fat also
in the pericardium, hypostasis- of the lungs, etc. Chronic internal hydrocephalus with
granular thickening of the ependyma. Slight fatty degeneration of the kidneys and of
the myocardium. Acute splenic tumor. Ulcerative pharyngitis. Marked atheromatosis
of the aorta. Slight sclerosis of the peripheral arteries.

The distribution of fat corresponds to the clinical description. The fat is of a yellow-
ish gray color, firm consistence with individual stripes and spots of white-gray color that
are appreciable even macroscopically.

The hypophysis is rather small, otherwise macroscopically normal.

The thyroid gland is macroscopically for greatest part quite normal, in the left lobe is
found a goose-egg-sized strumous nodule.

ADIPOSITAS DOLOROSA 581

The suprarenals are microscopically normal.

Also in the sexual glands is found nothing especial. The pancreas is macroscopically
normal.

The microscopical examination of -the pancreas and the suprarenals showed fully nor-
mal conditions. The microscopical examination of the thyroid gland showed, as the
adjoining illustration shows, a colloid struma, yet there is still found every where abundant
thyroid glandular tissue of normal consistency (Fig. 98).

Also the microscopical examination of the hypophysis showed normal relations, as well
in the glandular lobe as in the nervous lobe and in the pars intermedia.

FIG. 101. — Perivascular infiltration in a case of adipositas dolorosa (Observation LXX).

Fig. 99 shows a general view.

Fig. 100 shows a portion of the glandular part on higher magnification.

Also another piece of fat tissue was examined microscopically; in this
section there was a perivascular infiltration, more distinctly developed about
the large vessels. See Fig. 101.

Symptomatology. — Adipositas dolorosa or adiposis dolorosa is found more
commonly in women than in men. It usually begins between the forty-fifth
and the sixtieth years of life. In women the disease often sets in with
the menopause. There are, however, individual cases in which the beginning
occurred at the eleventh year of life. As cardinal symptoms of the disease
are regarded the fat tumors, the tenderness of the fat to pressure or its pain-
fulness spontaneously (Dercum) , the asthenic and the psychical alterations

582 OBESITY AND ADIPOSITAS DOLOROSA

(Vitaiit'i. In addition there have been described, however, a series of ac-
cessory symptoms, that consist especially in disturbances on the part of the
motor, sensory, and vegetative nerves.

The distribution of the fat tumors may vary. Vitaut first distinguished :

(a) Nodular, asymmetrical fat tumors, disposed asymmetrically in and
under the skin — lipomatose nodulaire.

(b) Circumscribed, diffuse, not sharply delimitable fat growths, lipo-
matose diffuse localisee.

(c) General diffuse fat growths, lipomatose diffuse generale; this is the
most frequent form, and in it the fat is not uniformly distributed as in ordi-
nary adiposity, the skin shows much more an uneven texture. The fat
masses feel lump-like, like a bundle of worms (Dercum), and at those places
especially where a pressure is exerted, for instance in the waist, or where the
garters press, they are separated from each other by deep furrows.

In lipomatose diffuse localisee the accumulations of fat are mostly found
only on the trunk and on the proximal third of the extremities. In such
cases the fat deposits may be quite excessive and hang down like an apron,
as for instance in a case of Dercum and McCarthy's, in which the fat masses
hung laterally over the hips and backward over the buttocks in thick folds,
or in a case oiLdning and Fuss's in which the fat masses hung from the abdo-
men and the inguinal region almost to the lower third of the thigh.

In the nodular form the throat and face, as well as hands and feet, eventu-
ally also the forearms and [lower] legs are entirely free; the latter are
often very thin. In a case of Debove's there was found, especially on the
outer side of the upper arm, symmetrically disposed masses up to the size
of a pigeon's egg. The hands were entirely free. These fat nodules may
be arranged in a multiple manner, or symmetrically.

On careful observation of the reported cases we may see that all transi-
tions between these three types occur. This was already observed by
Weiss; the classification has but little value. I refer to the case detailed
above, which constitutes a combination of lipomatosis nodulaire and lipo-
matosis diffuse localisee.

The second cardinal symptom consists in the painfulness of the fat.
In many cases there is a sensation of violent burning " as if a dog were tear-
ing the flesh from the body" (HaSkovec); in other cases the pains occur in
attacks, under circumstances before the fat infiltrates become visible. In
other cases vesicles appear during the attacks of pain. In other cases spon-
taneous pains are absent, the fat infiltrates are painful only on pressure; in
my case the painfulness of the fat infiltrate was bound chiefly to the vicinity
of the dilated veins. There are also cases described, otherwise typical,
in which the tenderness to pressure was but very slight.

In all cases the asthenia is more or less distinctly pronounced. In the case

ADIPOSITAS DOLOROSA 583

described above, the muscular weakness was so great that the patient could
scarcely walk.

Psychical alterations are indeed very common, but not constant. The
case of L'dning and Fuss, a sixty-six-year-old woman in whom the disease had
existed for about twelve years was mentally entirely normal and active. The
psychical alterations are very various. In many cases hallucinations and
conditions of excitement are observed, in others, as for instance Ballet's case,
depressive melancholic conditions. Also the accessory symptoms are very
diverse and not constant. On the part of the motor nerves are observed
tremor (alcoholism), slowing of the speech, alterations of the reflexes, es-
pecially reduction. On the part of the sensory nerves there are hyper-
esthesias and paresthesias, disturbances of the sensibility, etc., on the part
of the vegetative nerves often vasomotor symptoms such as dermographism,
tachycardia, dyspnea, anidrosis, and hyperidrosis. There occurs in addition,
trophic disturbances, such as premature turning gray of the hair, and on the
part of the vascular system hemorrhages, inclination to nose-bleed, purpura,
etc. As may be seen, very diverse symptoms are collected together in this
group. As we are mostly dealing with elderly people with fatty heart and
severe alcoholism, many of these symptoms are readily intelligible without
anything further.

Investigations as to the metabolism are as yet very sparse. Schwenck-
enbecher observed two cases in which the body weight only began to fall
when the administration of calories was as low as 19 calories per kilogram.
In many cases polydipsia is asserted, in others reduction of the body
temperature.

Pathological Anatomy. — There are already a series of autopsies, into a
consideration of which I shall enter somewhat exactly, as it is necessary for
the discussion of the pathogenesis.

Dercum described two cases, in which were found macroscopically en-
largement and calcareous infiltration of the thyroid gland. In a case of
Dercum '5 was found uniform atrophy of the thyroid gland, and widespread
interstitial neuritis of the peripheral nerves in the depositions of fat. In a
case of Burr's was found degenerative alterations in many lobules of the thy-
roid gland, also a glioma of the hypophysis, and in addition interstitial
neuritis, sclerosis of the liver, and atrophy of the ovaries. In a case of Dercum
and McCarthy's the thyroid gland was normal, there was found an adeno-
carcinoma of the hypophysis, enlargement of the right suprarenal, hemo-
lymph glands in the fat tissue, interstitial neuritis, hypoplasia of the
testicles, and acute parenchymatous nephritis. In a case of Guillain and
Alquier's the thyroid gland was found to be enlarged and the connective tissue
in it increased. The hypophysis was likewise enlarged, the connective tissue
in the glandular portion was increased, in association with which the eosino-
philic and basophilic cells were increased, alterations that reminded both

584 OBESITY AND ADIPOSITAS DOLOROSA

these authors of an alveolar carcinoma. In a case of Price's there were
found inflammatory alterations in the thyroid gland as well as in the hypo-
physis (alveolar or glandular carcinoma?) and interstitial neuritis. In a
second case there was found in the thyroid gland much interstitial tissue,
the acini were dilated, the hypophysis showed similar but not essential al-
terations. In the fat tissue no especial alterations were found. In a case of
Lbning and Fuss's the thyroid gland was dense, changed into a whitish-yellow
callous tissue; microscopically was found smallness of the gland cells and
round-cell infiltrate, the hypophysis was small, soft, unaltered. Finally,
in my case there were no essential alterations in the ductless glands. We
can hardly ascribe any especial significance to the colloid struma, there
were found perivascular infiltrates in the fat tissue, and cirrhosis of the
liver.

Summing up the autopsy findings we find the following: Among eleven
cases, there were found nine times alterations of the thyroid gland, especially
of a chronic inflammatory nature. The hypophysis was examined micro-
scopically in seven cases. Among these were found alterations five times,
and these indeed of a very diverse nature (round-cell infiltration, sclerosis,
adenocarcinoma, glioma). Also in the sexual glands was sometimes found
sclerosis, in addition to which was found ovarian cysts, and once hypoplasia
of the testicles. Liver and spleen often show cirrhotic changes, the kidneys
sometimes interstitial changes. The microscopical examination of the
fat often showed, as well in the diffusely distributed fat as in the encapsu-
lated lipomata, abundant connective tissue; and in some cases newly formed
hemolymph nodules or perivascular inflammatory infiltration. In other
cases there were found no inflammatory alterations. Very frequently, there
was found interstitial neuritis (six times among seven cases investigated) , as
well in the fine nerve trunks in the fat tissue itself, as in the nerves of the
muscles. In one case there was degeneration of GolVs column.

Pathogenesis. — The views of the authors as to the pathogenesis of
adipositas dolorosa are very different. Dercum considered the cause of
the affection as a sort of dysthyroidia, through which came about a re-
duction of fat combustion and inflammatory alterations of the nerves.
Vitaut expresses himself similarly. Most of the authors assume a chronic
intoxication, the cause of which they see in a disturbance of the function of
the ductless glands (Price, Ballet, Miquet); but they are not agreed as to
which ductless gland is at fault. For example, Price believes that in addi-
tion to the thyroid, the hypophysis plays an especial part, Ballet regards
the involvement of the thyroid gland as unlikely and thinks of disturbances
of the other ductless glands, etc. Debove places the nervous system as
the central figure of the pathogenesis. Strubing and Thimm regard the
disease as a trophoneurosis, Haskovec as a central trophoneurosis. Sicard
and Roussky think of an involvement of the ovary, as they saw the disease

ADIPOSITAS DOLOROSA 585

develop after ovariotomy in two relatively youthful cases. Schwenken-
becher believes in an endogenous obesity, with a pressure of the fat growth
on the small vessels and nerves, causing circumscribed circulatory disturb-
ances and paresthesias. We thus see that the views as to the pathogenesis
of this disease diverge greatly.

Before I discuss the significance of the ductless glandular system for this
disease, I would like to say a few words concerning the relationship of these
to lipomatosis. The view has been adopted by French and German authors
that adiposis dolorosa is no disease sui generis, but only a syndrome that
belongs to the great group of lipomatoses and of trophedema. To my
knowledge, Kottnitz was the first to point out that in the symmetrical lipo-
mata there frequently occur constitutional symptoms, such as nervous
symptoms, rheumatoid pains, etc. He describes a case, in which the meno-
pause set in prematurely, and at the time of the failing menses, symmetrical
lipomata several times developed, the eruption of which was attended with
pain in the part of the body in question. Kottnitz regards adipositas
dolorosa as a trophoneurosis and believes that all transitions to the painful
symmetrical lipomata occur. Also Cheinisse and Fulconis maintain the iden-
tity of the two diseases.. After Potain and Mathieu had assumed transitions
from neuropathic edemas to pseudolipomata and even to true lipomata,
especially Strubing, and after him Thimm, advocated the view that neuro-
pathic edema (oedeme blanc and bleu), multiple lipomatoses, symmetrical
diffuse lipomata, and finally the painful lipomata all belonged to a great
group of diseases that "had at their foundation the same basic process."
Also Miguel sought to establish in detail that the oedeme neuropathique of
Mathieu, the oedeme segmentaire of Debove, the chronic trophedema of
Meige and the pseudooedeme catatonique of Dide formed with adipositas
dolorosa a great group, the cause of which was to be sought in alterations of
the nervous system and of the ductless glands. Lately Lyon after a careful
compilation of the literature and the addition of new material, has advo-
cated a similar view.

The view that fleeting transitions exist between painful symmetrical
lipomata and adiposis dolorosa has received much support from the works
of the last years. Among the circumscribed lipomata that are often dis-
tributed in great number over the entire body are those, as Launois and
Bensaude point out, that are painful to pressure and are associated with
spontaneous neuralgiform pains. In the symmetrical lipomata the consti-
tutional factor mostly comes still more strongly into the foreground. Here
are frequently found manifestations of asthenia, also vasomotor disturb-
ances, especially bluish-red coloration of the skin over the nodes, paresthesias,
even psychic disturbances. Also in such cases the hereditary and familial
element is often well pronounced. As an example I cite a case of Lyon's
(case 2). In two sisters painful symmetrical lipomata set in at the time

586 OBESITY AND ADIPOSITAS DOLOROSA

of puberty and attained their full development at maturity. They were
associated with rheumatoid pains, dysmenorrhea, and psychic impairment.
According to Lyon there may be also found in such lipomata lymph nodules
similar to those which are found in adipositas dolorosa. That in adipositas
dolorosa the distribution of fat may be rigidly symmetrical is shown by the
case quoted in detail above. A quite similar distribution of fat was found in
a case of Dercum and McCarthy's. In my case, there were, in addition, lipo-
mata up to the size of a goose egg, with a rigidly symmetrical distribution.
This type of fat distribution was also present in a case of Bock-rock's.

I will not venture to pass judgment on the question whether there are
also transitions between lipomatosis and trophedema. I shall only register
some important findings. In a case of trophedema, Strubing found on
microscopical examination, no edema at' all, but only fat with strikingly
large fat cells. Haskovec describes a case in which there set in at the meno-
pause pains in the back and in the limbs, attacks of weakness, and then
edema, which, recurring constantly, closed with attacks of violent pains.
At the site of the edema there then gradually developed a painful hyperplasia
of the subcutaneous fat tissue. Haskovec regards this case as a transition of
a vasomotor neurosis or an acute edema to a trophoneurosis. We must
remember, however, that the acute edema usually shows quite another
localization from that of the symmetrical lipomata. Also combination of
adiposis dolorosa with other diseases that are regarded as trophoneuroses,
for example, xanthelasma, are known. Debove has described such a case.

Finally, as far as the ductless glands are concerned in the pathogenesis
of adiposis dolorosa, this seems to me very doubtful. The pathologico-
anatomical alterations in the ductless glands are very diverse. As we have
previously seen, there have been found rather frequently degenerative
changes and especially chronic inflammatory changes in some of the ductless
glands, especially in the thyroid gland and in the hypophysis. (The findings
of adenocarcinoma or glioma of the hypophysis might very well be an acci-
dental coincidence).

These chronic inflammatory alterations seem to me throughout not re-
markable, as in this disease we find them otherwise in many organs. Cir-
rhotic alterations in the liver and spleen, chronic inflammations in the nerves,
etc., belong to the commonest findings, and may in part be explained by the
alcoholism that is present. Thyrogenic obesity, a mild form of myxedema,
is widely distinguished in its clinical behavior from the picture of adiposis
dolorosa. Simultaneous sclerosis of the thyroid gland and of the hypophysis
leads to a combination of myxedema and cachexia, a disease picture that
has nothing to do with adipositas dolorosa. There does not appear to me
to be any grounds for assuming the involvement of any of the other ductless
glands. The assumption of Lyon that all forms of obesity and of lipomatosis
have their origin in a disturbance of correlation of the ductless glands, I can-

ADDENDUM 587

not subscribe to. Here too many things are thrown together. The sup-
position of the disturbance of correlation of the ductless glands as the cause
of a disease is, without corresponding pathologico-anatomical correlate a
vague idea, which only obstructs a deeper penetration into the pathogenesis
of such a disease. So that there remains only the supposition of a tropho-
neurosis, although I cannot conceal the fact that not much has been gained
by this assumption.

There have been described still other trophic disturbances of the fat tissue
of which I shall here briefly refer to one only, although probably it has less
to do with the ductless glandular system than adipositas dolorosa. Pic and
Gardere first pointed out a trophic disturbance which Simons has lately desig-
nated lipodystrophia progressiva. It is concerned with disappearance of
the fat on the face and arms, simultaneously with a gradually increasing
adiposity in the region of the buttocks and on the thigh. Sensory and vaso-
motor disturbances are absent. The investigation of the fundamental ex-
change in Simon's case showed normal relations.

In the differential diagnosis of adipositas dolorosa from myxedema we
should consider that in the latter the swellings are especially in the face;
from trophedema that this mostly sets in at an early age, that the edema
is mostly unilateral and that hands, feet, forearms and [lower] legs are
usually involved; from neurofibromatosis of Recklinghausen that the nodules
in this affection are much harder and also smaller, that they are more
confluent, that they do not avoid hands and feet, and that the psychic dis-
turbances are more pronounced, also that there are often marked pig-
mentations of the skin (Debove). The differential diagnosis from alcoholic
polyneuritis in the obese, concerning which diagnosis Umber and Schwenken-
becker have written, is often very difficult, if the characteristic distribution
of fat is absent.

In the treatment of adipositas dolorosa a great role is played by thyroidin.
In many cases the results are indeed undoubted, but this does not furnish
evidence for the thyrogenic nature of the disease. It has been stated that
cases have been cured by thyroidin medication (Price). Also the psychic
disturbances have retrogressed, v. Noorden has seen good results from
systematic bath-treatments. X-ray irradiation and iodine have been
recommended.

Addendum

The type of obesity described by Anders under the name adiposis tuberosa
simplex is apparently nothing more than a transitional stage between simple
diffuse obesity and adipositas dolorosa. It is doubtful whether even the
latter will long maintain its position as a disease sui generis. It is probable
that many of the cases described under it could very well be classed under

588 OBESITY AND ADIPOSITAS DOLOROSA

the other varieties of obesity. In adipositas dolorosa we have the additional
factor of pain, which may very well be explained as a neuritis of the small
nerve filaments. In many of the histories there is quite enough to account
for the existence of such a neuritis and also the mental changes; nor is the
asthenia of sufficient importance to delimit this condition as a pathogenic
entity, although for clinical purposes adiposis dolorosa does constitute one
of the recognizable types of obesity.

This being the case, the question as to which ductless glands are at fault
in adiposis dolorosa seems to me entirely misplaced. We may very well con-
ceive that certain of the cases might (just as ordinary obesity) show no changes
in the ductless glands at all, and that others might show changes in individual
glands or in several, as in the varying types of obesity in general. In no case,
or perhaps only very rarely, is the condition to be regarded as pluriglandular
in the author's conception of the term, but rather as a result of a patho-
logical or a physiological correlation.

Price has recently contributed a case that suggests to him the possibility
that, in addition to the thyroid condition, there were some disturbances in
function of the parathyroids— the woman showed alternating, long periods
of apparent hypothyroidism and hyperthyroidism (without exophthal-
mus) and in 'addition, during or just before the periods of hyperthyroidism
flexor cramps of the extremities, especially of the hands and the feet.
Whether in this case these cramps would be considered a sign of hyperexcita-
bility of the nerves such as would presage tetany, or constitute an attack of
tetany, cannot be decided from the case report alone.

McCarthy and Karsner have recently reported a case of adenocarcinoma
of the thyroid, with metastases to the cervical glands and pituitary, which
they regard as linking together three of the groups of pathological fat —
adiposis cerebralis, symmetrical adenolipomatosis (a predominence cervicale)
of Launois and Bensaude, and adiposis dolorosa. McCarthy regards another
case reported by him with Dercum as an intermediate type between adipo-
sis dolorosa and adenolipomatose symmetrique a predominance cervicale.
A third case mentioned by McCarthy in the report was evidently a case of
eunuchoidism.

In the treatment mention should be made of the various "degrassators"
that bring about a reduction of the fat by electrical means, also of hot steam
or electrical light baths. It is needless to state that these measures should
be employed in those weakened and debilitated individuals affected with
adiposis dolorosa only with extreme caution, if at all.

REFERENCES

Anders (H. S.). Adiposis tuberosa simplex. Am. J. M. Sc., 1908, CXXXV, 325-333.
Price (G. £.). Clinical types of adiposis and lipomatosis. Report of a case of adiposis

ADDENDUM 589

dolorosa presenting unusual symptoms. N. York M. J., Vol. C, No. 8, Aug. 22, 1914, pp.

355-357-

McCarthy (D. J.) and K'arsner (H. T.). Adenocarcinoma of the thyroid with meta-
stasis to the cervical glands and pituitary, a contribution to the pathology of abnormal fat
formation. Am. J. M. Sc., 1912, CXLIV, 834-847.

Dercum (F. X.) and McCarthy (D. J.). Autopsy in a case of adiposis dolorosa.
Am. J. M. Sc., 124, 994, 1902.

LITERATURE

CHAPTER I
GENERAL PART

Addison, Thomas, On the constitutional and local effects of disease of the suprarenal

bodies. London, 1855.
Adler, Zur Physiologic und Pathologie der Ovarialfunktion. Arch. f. Gynaek., 95, 349,

1912.
Aschner, Uber die Funktion der Hypophyse. Arch. f. d. ges. Physiol., 146, 1912, u.

Zur Physiologic des Zwischenhirns. Wien. klin. Wchenschr., 1912, Nr. 27, 1042.
Asher and Flack, Die innere Sekretion der Schilddriise. Ztschr. f. Biol., 60, 1910.
Balint, R. and B. Molnar, Experimented Untersuchungen iiber gegenseitige Wechsel-

wirkung innerer Sekretionsprodukte. Berl. klin. Wchenschr., 1911, 289.
Bauer, Neuere Untersuchungen iiber die Beziehungen einiger Blutdriisen zu Erkrank-

ungen des Nervensystems, etc. Ztschr. f. d. ges. Neurol. u. Psychiat., 3, 195,

1911.
Baumann, E., Uber den Jodgehalt der Schilddrtise von Mensch und Tier. Ztschr.

f. physiol. Chem., 22, i, 1896.
Bayliss and Starling, The mechanism of pancreatic secretion. J. Physiol., 28, 325-353,

1902, u. ibid., 29, 1903.

Bernard, Claude, Vorlesungen uber Diabetes, 1878.
Bertelli, Falla, and Schweeger, Uber die Wechselwirkung der Driisen mit innerer Sekretion.

III. Uber Chemotaxis. Ztschr. f. klin. Med., 71.

Biedl, Innere Sekretion. Urban u. Schwarzenberg, 1910. Berlin, Wien.
Bircher, E., Fortfall und Anderung der Schilddriisenfunktion als Krankheitsursache.

Lubarsch-Ostertag, Ergebn. d. Pathol.
Block, Br., Diathesen in der Dermatologie. Ref. Kongr. f. inn. Med., 1911, u. Bezei-

hungen zwischen Hautkrankheiten und Stoffwechsel. Ergebn. d. inn. Med. u.

Kinderheilk. 2, 521, 1908.
Blum, F., Uber Nebennierendiabetes. Deutsches Arch. f. klin. Med., 1910, 71. Weitere

Mitteilungen zur Lehre von dem Nebennierendiabetes. Arch. f. d. ges. Physiol.,

90, 617, 1902.
Brown-Sequard, Des effets produits chez 1'homme par des injections souscoutanees d'un

liquide retire des testicules frais de cobaye et de chien. Compt. rend. soc. de

biol., 1889, 415, 420, 430, et 451. Experience demontrant la puissance dynamo-

genique chez 1'homme d'un liquide extrait des testicules animaux. Arch, de

Physiol. norm. u. path., 1889, 651.

Cassirer, Die vasomotorisch trophischen Neurosen. S. Karger, Berlin, 1912.
Charcot, Myxoedeme, cachexie pachydermique en etat cretinoide. Gaz. d. hop., 1891,

Nr. 10.

Chvostek, F., Konstitutiqn und Blutdriisen. Wien. klin. Wchenschr., 1912, Nr. i, 6.
— Xanthelasma und Ikterus. Wien. klin. Wchenschr., 1910, Nr. 46, 1630.
Claude, H., Syndromes d'hyperfonctionnement, etc. Compt. rend. soc. de biol., 59, 362,

1905.
Claude and Gougerot, Delimitation des syndromes d'insuffisance et d'hyperfonctionnement

pluriglandulaire. Gaz. d. hop., 1912, Nr. 57, 849.

GENERAL PART 59!

Curschmann, In Handbuch der inneren Medizin v. Mohr-Staehelin, 5, 1913. Verl. v.

Springer.

Dehu, see Cassirer.
Dupuy, R., Arrieration infantile et opotherapies endocriniennes. Rev. de med., 32,

307, 1912.
Dupre and Guillain, Association des syndromes basedowien, sclerodermique et tetanique.

Bull, et mem. soc. med. d. hop. de Par., Paris, 45, 1900.
Dupre and Kahn, Sclerodermie et maladie de Raynaud syndrome polyglandulaire. Gaz.

d. hop., 1909, 866.
Egger, F., Fieber bei vasomotorischen Neurosen. Schweizer Neurologische Gesellschaft

Reference in Neurol. Centralbl., 30, 1911, 218.
Elliot, The action of adrenalin. J. Physiol., 32, 1905.
Eppinger, Falta, and Rudinger, Wechselwirkung der Driisen mit innerer Sekretion.

I. Mittlg. Ztschr. f. klin. Med., 66, 1908.
Eppinger and Hess, Zur Pathologic des vegetativen Nervensystems I. Ztschr. f. klin.

Med., 67.
Erdheim, Hypophysengangsgeschwiilste. Sitzungsb. d. k. Akad. d. Wissensch. Math.-

natunv. Cl. Wien. Abt., Ill, 113, 1904.
Ewald, Die Erkrankungen der Schilddriise, etc. Nothnagel, II Auflage Leipzig u.

Wien, 1909. Holder.
Falta, W., Spateunuchoidismus und multiple Blutdriisensklerose. Berl. klin. Wchenschr.,

1912, Nr. 30 u. 31.

— tjber die Gesetze der Zuckerausscheidung, beim Diabetes mellitus. X. Mitteilung

(Theorie). Ztschr. f. klin. Med. Berl., 66, 1908.

— Die Krankheiten der Driisen mit innerer Sekretion. Handbuch der inneren Med.

von Mohr-Staehelin, IV, 1913.
Falta, Newburgh, and Nobel, Wechselwirkung der Driisen mit innerer Sekretion, IV,

tiberfunktion und Konstitution. Ztschr. f. klin. Med. Berl., 72, 1911.
Falta and Priestley, Beitrage zur Regulation von Blutdruck- und Kohlehydratstoffwechsel

durch das chromafnne System. Berl. klin. Wchenschr., 1911, Nr. 47.
•o. Frankl-Hochwart, Die Diagnostik der Hypophysentumoren ohne Akromegalie. 16.

International med. Kongress, Budapest, 1909. liber den Einfluss der inneren

Sekretion auf die Psyche. Med. klin., 1912, Nr. 48. Zur Diagnostik der Zirbel-

driisentumoren. Deutsche Ztschr. f. Nervenheilk., 37, 1909.
Frohlich, A., Tumor der Hypophyse ohne Akromegalie. Wien. klin. Rundschau., 1901,

Nr. 47, 48.
Gley, Des effects de 1'extirpation des glandules parathyreoides chez le chien et le lapin.

Arch. de. Physiol. norm, et path., 1897, 18.

Gougerot, Syndromes pluriglandulaires. Paris med., 24 Juin, 1911.
Grasset, Traite elementaire de physio-pathologique, I, 629, 1910.
Grasset, see Cassirer.
Gull, A., A cretinoid state supervening in adult life in women. Tr. Clin. Soc. Lond.,

7, 180, 1874 and Brit. M. J., Nov., 1873.
Hi'dinger, Uber Beziehungen zwischen Status lymphaticus und Morb. Add. Deutsche

path. Gesellsch., Dresden, 1907.
Hectoen, Ein Fall von Sklerodermie diff. in Verbindung mit chronisch-fibrosen Verander-

ungen der Schilddriise, etc. Centralbl. f. allg. Path. u. path. Anat., 1897, Nr. 17.
Hess and Konigstcin, Uber Neurosen der Hautgefasse. Wien. klin. Wchenschr., Nr. 42,

1911.
His, W., Geschichitliches und Diathesen in der inneren Medizin. Referat. Kongr.

f. inn. Med., 1911.

592 LITERATURE

Horsley, Die Funktion der Schilddriise, etc., Festschr. f. Virchow, i, Berlin, 1891.
Jeandellze, Insuffisance thyreoidienne et parathyreoidienne. These de Nancy, 1902.
Jeanselme, Sur la coexistance du goitre exophth. et de la sclerodermie. Mercredi med.,

I, 1895.
Kaufmann, M., Uber hysterisches Fieber. Ztschr. f. Neurol. u. Psychiat., 5, 706, 1911.

Nervensystem and Stoffwechsel. Handb. d. Neurol., i, 1157.
Kepinow, Uber Synergismus von Hypophysenextrakt und Adrenalin. Arch. f. exper.

Path. u. Pharmakol., 67, 247, 1912.
Klinger, Citation in Hess and Konigstein.

Kocher, Th., Uber Kropfexstirpation und ihre Folgen. Arch. f. klin. Chir., 1883, 29.
Kraepelin, Lehrbuch d. Psychiatric., 1896, 5, Aufl.
Kraus, Fr., tjber das Kropfherz. Wien. klin. Wchenschr., 1899, 416 u. Deutsche med.

Wchenschr., 1906, 1889.

Krehl, L., Uber die Storungen chemischer Korrelationen im Organismus. Deutsches
Arch. f. klin. Med., 88, 351-384, 1907, and Verhand. deutsch. Naturf. u. Arzte
Stuttgart.

Kren, Uber Sklerodermie der Mundschleimhaut. Arch. f. Derm. u. Syph., 95, 163.
Laignel-Lavastine, La correlation des glandes a secretion interne et leurs syndromes

pluriglandulaires. Gaz. d. hop., 1563, 1908.
Langley, J. N., Observations on the physiological action of extracts of the suprarenal

bodies. J. Physiol., 27, 237, 1901.
Leredde and Thomas, Sclerodermie generalisee. Arch. d. med. exper. et d'anat. path.,

1898, 665.

v. Leube, Klin. Bericht von der Abteilung des Landeskrankenhauses Erlangen, 1875, 28.
Lichtwitz, Uber einen Fall von Sklerodermie und Morbus Addisonii. Deutsches Arch.

f. klin. Med., 94, 1908.
Loewe, S., Uber Phosphorstoffwechsel bei Psychosen und Neurosen. Ztschr. f. Neurol. u.

Psychiat., 5, 445, 1911.
Lowi, 0., Eine neue Funktion des Pankreas, etc. Arch. f. exper. Path. u. Pharmakol.,

59, 1908.

Lorand, Das Altern. Verlag v. Klinkhardt, 1910, III, Aufl.
Marburg, Die Epiphyse. Ergebn. d. Neurol., Springer, 1913.
Marchand, Des Testicules et des Ovaires dans la Paralysie generale. Compt. rend.

Soc. de BioL, Paris, Mai, 1903. Reference in Rev. neurol., Par., 1904, 848.
Marie, Pierre, Sur deux cas d'acromegalie, etc. Rev. d. med., Par., 6, 297, 1886.
Markeloff, G. J., Uber die Myasthenie. Arch. f. Psychiat., Berl., 49.
Martins, Pathogenese innerer Krankheiten, 1899.
Mering and Minkowski, Diabetes nach Pankreasexstirpation. Arch. f. exper. Path.

u. Pharmakol., 26, 374, 1889.

Mobius, Schilddriisentheorie. Schmidt's Jahrb., 210, 237, 1886.
Miiller, J., Lehrbuch der Physiologic. I. Koblenz, 1844.
v. Nottha/i, Neuere Arbeiten und Ansichten iiber Sklerodermie. Reference Centralbl.

f. allg. Path. u. path. Anat., 9, 870, 1898.
Novak, Die Bedeutung des weiblichen Genitales fur den Gesamtorganismus. Nothnagel,

Supplbd., 1912.
Opie, E. L., On the relation of chronic interstitial pancreatitis to the islands of Langer-

hans and to diabetes mellitus. Exper. Med., 1901, V, 397, 527.
Ord, W. W., On myxedema, a term proposed, etc. Med.-Chir. Tr., 1879, 61. Some

cases of sporadic cretinism, Lancet, 1893.
Osier, see Cassirer.

GENERAL PART 593

Oswald, Zur Chemie und Physiologic des Kropfes. Arch. f. path. Anat. [etc.] Berl., 169,

1902.

Paghini, II ricambio organico nella demenza precoce. Riv. sper. di. freniat., 32 u. 33.
Paltauf, R., Discussion on 'Aschner's demonstration. K. k. Gesellsch. d. Arzte in Wien.

Wien. klin. Wchenschr. Dez., 1909.
Pfanndler, Uber Wesen und Behandlung der Diathesen im Kindesalter. Referat.

Kongr. f. inn. Med., 1911.
Pineles, F., Uber Thyreoaplasie,. etc. Wien. klin. Wchenschr., 1902, Nr. 43. Zur Patho-

genese der Tetanic. Deutsches Arch. f. klin. Med., 85, 1906.
— Die Beziehungen der Akromegalie, zum Myxodem und zu anderen Blutdriisener-

krankungen. Volkm. Samml. N. F., 1899, 242.
Poetzl, Eppinger, and Hess, Uber Funktionspriifungen der vegetativen Nervensysteme

bei einigen Gruppen von Psychosen. Wien. klin. Wchenschr., 1910, Nr. 51.
Pollitzer, H., Uber neurogene Galektosurie. Wien. klin. Wchenschr., 25, 1159, 1912.
Rapin, E., Des angioneuroses familiales. Rev. med. de la Suisse Rom., 1907.
Rasch, C., Sklerodermie mil Affektion der Mundschleimhaut und Basedow mit Addison-

Symptomen. Dermat. Ztschr., 19, 244, 1912.

Raymond, Soc. neurol. d. Par., 5 Febr., 1903. Rev. neurol., 1903, 245.
Renon, Les syndromes polyglandulares et 1'opotherapie associee. J. d. Practiciens,

1908, Nr. 30, 25 Juillet., 465.
Renon, Z,., and Delille, A., Insuffisance thyreo-ovarienne et hyperactivite hypophysaire,

etc. Soc. med. des hop., 1908., 19 Juin., 973. De 1'utilite d'associer les medi-
cations opotherapeutiques. Soc. de therap., 1907, 12 Juin, 289.
Reverdin, J. and A., Notes sur 22 operations du goitre. Rev. med. de la Suisse Rom.,

1883.
Rosen/eld, Uber den Einfluss psychischer Vorgange auf den Stoffwechsel. Allg. Zeitschr.

f. Psychiat., etc., Berl., 63, H. 3 u. 4 p., 367.

Roussy, Les glandes a secretion interne. Paris med., 1911, 8 Juillet.
Roux, Sclerodermie et corps pituitaire. Rev. neurol., 1902, 721.
Saltier, Die Basedowsche Krankheit. Leipzig, 1909 and 1910, Englemann.
Sauerbeck, Die Langerhansschen Inseln im normalen und kranken Pankreas des Men-

schen. Arch. f. path. Anat. [etc.] Berl. 177. Supplementary volume, 1904.
Scholz, W., Klinische und experimentelle Untersuchungen iiber den Kretinismus. Berlin,

1906.
Schultze, W., Die Bedeutung der Langerhansschen Inseln im Pankreas. Arch. f. mikr.

Anat., 56, 491, 1900.
Seige, cited by Kaufmann.

Sicard and Roussy (and Berkowitsch) , cited by Gougerot.
Singer, Zur Pathologic der Sklerodermie. Ber. klin. Wchenschr., 1895, 260.
Ssobolew, L. W ., Beitrage zur Pankreaspathologie. Beitr. z. path. Anat. u. z. allg. Path.,

47, IQIO.
Stern, R., Uber korperliche Kennzeichen der Disposition zur Tabes. Fr. Deuticke

Leipzig und Wien, 1912.

Stiller, Asthenische Konstitutionskrankheit. Stuttgart, 1907.
v. Strilmpell, Ein Beitrag zur Pathologic und pathologischen Anatomic der Akromegalie.

Deutsche Ztschr. f. Nervenh., II, 87.
Takamine, The isolation of the active principles of the suprarenal gland. J. Physiol., 29,

1901.
Tandler and Grosz, Die Eunuchoide. Arch. f. Entwicklungsmechanik d. Organ., Leipz.,

29, 1910.

Tobias, E., Uber myasthenische Paralyse, etc. Neurol. Centralbl., 31, p. 551, 1912.
38

594 LITERATURE

Vassale and Generali, Sur les effets de 1'exstirpation des glandes parathyreoides. Arch.

ital. de biol., 25, 459, 26, 61. 1896 u. 33, 1906.
v. Wagner, Uber endemischen und sporadischen Kretinismus. Wien. klin. Wchenschr.,

1900, Nr. 19.
Weichselbaum, tlber Veranderungen des Pankreas bei Diabetes. Wien. klin. Wchenschr.,

1911, Nr. 5.
Wiesel, Zur Pathologie des chromaffinen Systems. Arch. f. path. Anat. [etc.], Berl.,

176, 1904.

Wunderlich, Spec. Pathol. und Therap., 4; 1856.
Ziilzer, Untersuchungen iiber den experimentellen Diabetes. 24. Kongr. f. inn. Med.,

1907.

CHAPTER II

THYROID GLAND

Abadie, Traitement chir. du-goitre exophthalmique. Congr. fran?. chir., Oct., 1906.
Abrikosojj, Anatomischer Befund in einem Fall von Myxodem. Arch. f. path. Anat.

[etc.], Berl., 177, 426, 1904.
Andersson and Bergmann, t)ber den Einfluss der Schilddriisenfiitterung, etc. Skandin.

Arch. f. Physiol., 8, 326, 1908.
A pelt, Ein Fall von Basedowscher Krankheit im Anschluss an nicht eitrige Thyreoiditis

acuta. Miinchen. med. Wchenschr., 41, 1908.
Appert, Myxoedeme fruste, croissance tardif, diabete. N. iconog. de la Salpetriere,

1904, 174.

Argudinsky, P., Ein Beitrag zur Kenntnis des kongenitalen Myxodems und der Skelett-

wachstumsverhaltnisse bei demselben. Berl. klin. Wchenschr., 1906, 1209.
— Abnormer Tiefstand des Nabels bei angeborenem Myxodem. Berl. klin. Wchenschr.,

1905, Nr. 35.

Aschojf, Uber einen Fall von angeborenem Schilddrusenmangel. Deutsche med. Wchen-
schr., 1899, 203, Beil.

Asher, Kongr. innere Med., 1906. Discussion, article otFr. Kraus.

Asher and Flack, Die innere Sekretion der Schilddriise. Ztschr. f. Biol., 60, 1910.

Askanazy, Pathologisch-anatomische Beitrage zur Kenntnis des Morbus Basedowi usw.
Deutsches Arch. f. klin. Med., 65, 118, 1898.

Ballet, Gigantisme et goitre exophthalmique. Arch, de neurol., 19, 1905.

Ballet and Enriques, Des effets de 1'hyperthyroidisation experimentale. Med. mod., 28,
Dec., 1895.

Balini and Molnar, Durchfalle bei Basedowscher Krankheit. Deutsche med. Wchen-
schr., 1910, 2211.

Baruch, Zur experimentellen Erzeugung des Morbus Basedowi. Centralbl. f. Chir.,
39, 316, 1912.

v. Basedow, Exophthalmus durch Hypertrophie des Zellgewebes in der Augenhohle.

Wchenschr. f. d ges. Heilk, 13, 14, 1840.
— Die Glotzaugen. Ibidem, 49, 1848.

Bay on, Uber die Atiologie des Schilddriisenschwundes, etc. Neurol. Centralbl., 1906,
792.

Becker, Uber spontanen Arterienpuls in der Netzhaut etc. bei Morbus Basedowi. Wien.
med. Wchenschr., 1873, Nr. 23.

Beclere, Un nouveau cas de myxoedeme gueri par 1'alimentation thyreoide, etc. Bull.
et mem. Soc. med. d. H6p. de Par., 12, Sept., 1894, 931.

Bence, J., and Engel, K., Uber Veranderung des Blutbildes beim Myxodema. Wien.
klin. Wchenschr., 1908, Nr. 25.

Berard, Corps thyreoides. Paris, Baillere freres, 1908.

Bergeat, Uber 300 Kropfexstirpationen an der Brunsschew Klinik, 1884-1894. Beitr.
z. klin. Chir., 15, 1890.

v. Bergmann, Der Stoff- und Energieumsatz beim infantilen Myxodem. Ztschr. f. exper.
Path. u. Pharmakol., 5, page 646, 1909.

Bernheim-Karrer, Uber zwei atypische Myxodemfalle. Ztschr. f. Kinderheilk. 64.

595

596 LITERATURE

BcrteUi, Falta, and Schiceegcr, Wechselwirkung der Driisen mit inncrer Sckretion, III.

Chemotaxis. Ztschr. f. klin. Med., 71, 1910.
Bcrtoye, Etude clinique sur la fievre, etc. These de Lyon, 1888.
Bctlmann, J. S., t)ber den Einfluss der Schilddriisenbehandlung auf den Kohlehydrat-

stoffwechsel. Berl. klin. Wchenschr., 1897, Nr. 24.
Biedl, see chapter on parathyroids.
Bcinfait, A., Contribution a 1'etude de la pathogenic du goitre exophthalm. Bull, de

Facad. beige, 8, 1890. Semaine med., 1890, 267; Schmidt's Jahrb. 22, 247.
Bircher, E., Fortfall und Anderung de Schilddriisenfunktion als Krankheitsursache.

Lubarsch-Ostertag, Ergebn. Pathol., 15, 1911. See also chapter on cretinic degen-
erations.

Bircher, H., see chapter on cretinic degeneration.
Birch-Hirschfeld and Nombuo Ynvuye, Experimentelle Untersuchungen iiber die Path.

der Thyreoidamblyopie. Arch. f. Ophth., 61, 1905.
Bittorf, A., Fettstiihle bei Morbus Basedowi. Deutsche med. Wchenschr., 1912, Nr. 38,

1034.
Bleibtreu and Wendelstadt Stofifwechselversuch bei Schilddriisenfiitterung. Deutsche

med. Wchenschr., 1895, 374-

Block, E., Die dysthyre Schwerhorigkeit. ' Deutsches Arch. f. klin. Med., 87, 178, 1906.
Blum, Die Schilddriise als entgiftendes Organ. Berl. klin. Wchenschr., 1898. Arch.

f. path. Anat. [etc.], Berl., 188, 1899.

Boinet, Ed., Maladie de Basedow avec troubles psychiques, etc. Revue neurol., 7> 1899.
Bolaffio, Tedesco, s. Falta, weitere Mitteilungen iiber die Wechselwirkungen der Driisen

mit innerer Sekretion. Wien. klin. Wchenschr., Nr. 30, 1909.
Bonnet, Thymus et mort subite. Province med., 36, 37, 38, 1899.
Borchardt, see Chapter IX.

Bourneville and Bord, Cas d'idiotie mongolinne. Rev. d'hyg. et med. inf. [etc.[, 5» 1906.
Bourneville and Bricon, De 1'idiotie compliquee de cachexie pachydermique. Arch, de

Neurol., 12, 1886.

Bourneville, Fin de 1'histoire d'un idiot myxoedemateux. Arch, de neurol., 16, 1903.
Boyce and Beadle, cited by v. Eiselsberg.
Bramann, Uber Schilddriisenimplantation bei Myxodem und Kretinismus. Deutsche

med. Wchenschr., 1909, Nr. 40.
Bramwett, Production of symptoms of thyroidism in a child at the breasts, etc. Lancet,

March 18, 1899.
Breuer, Beitrag zur Atiologie der Basedowschen Krankheit, etc. Wien. klin. Wchenschr.,

1900, 28, 29.
Bryson, Preliminary note on the study of exophthalmic goiter. New York M. J., 24,

1898.

Brunei, Degenerescence mentale et goitre exophthalmique. These de Paris, 1893.
Bilhelr, M., Uber die Lymphocytose bei Basedowscher Krankheit. Miinchen. med.

Wchenschr., 1910, Nr. 19.
Bultschenko and Drinkmann, Blutunttrsuchungen nach Exstirpation der Schilddriise.

Allg. med. Central Ztg., 60, 1897.
Burghart and Blumenthal, Uber eine spezifische Behandlung des Morbus Basedowi.

Fstschr. f. Leyden, II, 1902.

Buschan, Die Basedowsche Krankheit. Wien and Leipzig, 1894, Fr. Deuticke.
Capelle, Ein neuer Beitrag zur Basedowthymus. Beitr. z. klin. Chir., 58, 1908, Munchen.

med. Wchenschr., 1908, 35.
Capelle and Bayer. Thymektomie bei Morbus Basedowi. Beitr. klin. Chir., 72, 214,

1911.

THYROID GLAND • 597

Caro, L., Blutbefunde bei Morbus Basedowi und bei Thyreoidismus. Bcrl. klin. Wchen-

schr., 1908, No. 39, 1755.

Cassirer, Die vasomotorisch-trophischen Xeurosen., S. Karger, Berlin, 1912.
Chamisso, Uber einen Fall von Struma accessoria baseos linguae. Beitr. z. klin. Chir.,

19, 281, 1897.

Charcot, Gaz. hebd de med., 44, 1859 et 36, 1862; Gaz. d Hop., 13, 15, 1885, et 34, 1889.
— Myxoedeme, cachexie pachydermique en etat cretinoide. Gaz. d. Hop., 1881, Xr. 10.
Cheadle, Exophthalmic goitre.. Lancet i, June, 1869 and Brit. M. J., Jan. 4, 1890, 19.
Cholmogorojf, tjber den Einfluss der Schwangerschaft auf den Morbus Basedowi.

Monatschr. f. Geburtsh, u. Gynaek, 5, 313, 1897.
Comte, Contribution a 1'etude de 1'hypophyse humaine et de ses relations avec le corps

thyreoide. These de Lausanne, 1898.

Chvostek, F. Sr., Morbus Basedowi. Wien. med. Presse, 1869, 1872 und 1875.
Chvostek, Fr., Jr., Uber alimentare Glykosurie bei Morbus Basedowi. Wien. klin.

Wchenschr., 1892, 17, 18, 22.

- Diagnose und Therapie des Morbus Basedowi. Wien. klin. Wchenschr., 1910, 191.
Ciuffini, Contribute alia patologia del morbo di Basedow. Policlinico, Roma; sez.

med., 18, 1906.
O'Connor, Uber Adrenalinbestimmung im Blute. Miinchen. med. Wchenschr., 1911,

1439-

v. Cyon, Physiologic der Schilddriise und des Herzens. Arch. f. d. ges. Physiol., 70, 1898.
•o. Cyon and Oswald, Uber die physiologischen Wirkungen einiger aus der Schilddriise

gewonnener Produkte. Arch. f. d. ges. Physiol., 43, 1901.

Dale, James, Glycosuria from taking thyroid extract. Brit. J. Dermat., June, 1894.
Dauscher, Ein hochgradiger Fall von Morbus Basedowi. Wien. med. Presse, 1889, Xr. 7.
Dennig, A., Miinchen. med. Wchenschr., Nr. 17, u. 20, 1895.
Dercum, see forms of obesity, Chapter XIV.
Dieder' Die Athyreosis und die Skelettveranderungen. Arch. f. path. Anat., [etc.

BeJ.], 184, 1906.

- Uber endemischen Kr'etinismus. Jahrb. f. Kinderh., 64, 1906.

Donitli, J., Beitrage zur Pathologic und Therapie der Basedowkrankheit. Ztschr. f. klin.

Med., 48, 1903.

Dourdoufi, Deutsche med. Wchenschr., 1887, 21.

Dunger, Uber akute, nicht eitrige Thyreoiditis. Miinchen. med. Wchenschr., 36, 1908.
Dunlop, Edinb. M. J., May, 1896.
v. Eiselsberg, Fall von Thyreoaplasie. K. k. Gesellsch. d. Arzte Wiens., 7, Juni, 1912,

ref. in Wien. klin. Wchenschr.

- Zur Behandlung des Kropfes mit Rontgenstrahlen. Wien. klin. Wchenschr., 1909,

1585-

- Die Krankheiten der Schilddriise. Stuttgart, 1901, Enke.

- Uber vegetative Storungen im Wachstum von Tieren nach friih/eitiger Schilddriisen-

exstirpation. Arch. f. klin. Chir., 49, 1895.

Enderlen and Borst, Beitrage zur Gefasschirurgie und zur Organtransplantation. Miin-
chen. med. Wchenschr., 1910, 1865.

Engelreimers, Uber Schilddriisenschwellung in der Friihperiode der Syphilis. Zntralbl.
f. Chir., 1895.

Eppinger and Hess, Zur Pathologic des vegetativen Nervensystems. Ill, Ztschr. f. klin.
Med., 68, 1909.

Eppinger, Falta, and Rudinger, Wechselwirkung der Driisen mit innerer Sekretion. I,
Ztschr. f. klin. Med., 66, 1908.

- Wechselwirkung der Driisen, etc. II, ibidem, 1909, 67.

598 LITERATURE

Erb, It"., t'hcr Myxodem. Berl. klin. Wchenschr., 1887.

Erdheim. tjber Schilddriisenaplasie bei Kretinismus, etc. Beitr. z. path. Anat. u. z. allg.

Path., 35, 366, 1904.
d'Espine, cited by Breuer.
Esser, Blut und Knochenmark nach Ausfall der Schilddriisenfunktion. Deutsches

Arch. f. klin. Med., 89, p. 576, 1907.
Ewald, tJber einen durch die Schilddriisehtherapie geheilten Fall von Myxodem, etc.

Berl. klin. Wchenschr., 1895, Nr. 2.

- Die Erkrankungen der Schilddriise, Myxodem und Kretinismus. II. Aufl. Leipzig

u. Wien., 1909, A. Holder.

— Adenokarzinom der Schilddriise. Wien. klin. Wchenschr., 1896.

Falckenberg, Zur Exstirpation der Schilddriise. X. Kongr. inn. Med., p. 502, 1891.
Falta, W., tiber die Korrelationen der Driisen mit inner Sekretion. Ergebn. d. wissenschu.,
Med., 1910.

- tiber Glykosurie und Fettstiihle bei Morbus Basedowi, etc. Ztschr. f. klin., Med.,

71, 1910.

- Weitere Mitteilungen iiber die Wechselwirkung der Drusen mit innerer Sekretion.

Wien. klin. Wchenschr., 1909, Nr. 30.
Falta, W., and G. B. Fleming, tiber die Wirkung des Adrenalins und Pituitrins, etc.

Miinchen. med. Wchenschr., 1911, Nr. 50.

Falta and Kahn, Studien iiber die Tetanic, etc. Ztschr. f. klin. Med., 74, 1911.
Falta, Newburgh, and Nobel, Wechselwirkung der Drusen mit innerer Sekretion. IV.

Uberfunktion und Konstitution. Ztschr. f. klin. Med., 72, 1911.
Falta and Rudinger, Studien iiber Tetanic. Kongr. f. innere Med., 1909.
Farner, E., Beitrage zur pathologischen Anatomic des Morbus Basedowi, etc. V. Arch.

f. path. Anat. [etc.], Berl., 118, 509, 1896.
v. Fenyvessy, tiber die Wirkung des Schilddrusensaftes auf Zirkulation und Atmung.

Wien. klin. Wchenschr., 1900, 6.
Filehne, Zur Pathogenese der Basedowschen Krankheit. Sitzungsb. der phys. med. Soc.

zn. Erlang., 14, Juli, 1878.
Fleischmann, Sitzungsber. d. physiol. Gesellsch. Berlin. Atropinentgiftung durch Blut.

Centralbl. f. Physiol., 1910.

— Zur Frage der regionar verschiedenen Empfindlichkeit gegen Jod. Miinchen. med.,

Wchenschr., 1911, 4.
Fletcher-Beach, J. Ment. Sc., 1876, 22.
Fonio, A., tiber den Einfluss von Basedowstruma und Kolloidstrumapraparate und

Thyreoidin auf den Stickstoffwechsel, etc. Mitt. a. d. Grenzgeb. d. Med. u. Chir.,

24, 123, 1911.
Formanek and Haskowez, Beitrage z. Lehre iiber die Funktion der Schilddriise. Wien,

1896.
Forschbach, Kreatininausscheidung bei Krankheiten. Arch. f. exper. Path. u. Pharma-

kol., 58, p. 113, 1907.
Fox, E. L., A case of myxedema treated by extract of thyreoid by the mouth. Brit.

Med. J., 29, Oct., 1892.
Frankel, A., tiber den Gehalt des Blutes an Adrenalin bei chronischer Nephritis und

Morbus Basedowi. Arch. f. exper. Path. u. Pharmakol., 60, 1909.
Frey, Ernst, Familiare Basedowsche Krankheit. Neurol. Centralbl., 1911, 197.
Frohlich and Chiari, Arch. f. experim. Path. u. Pharmakol., 66, 1911.
v. Filrth and Schwartz, tiber die Wirkung des Jodothyrins auf den Zirkulationsapparat.

Arch. f. d. ges. Physiol., 124, 1908.

THYROID GLAND ' 599

Gamier and Lebret, Explorat. des fonctions renales intestinales et hepatiques d'un myx-

oedeme. Soc. med. d. Hop. de Par., 1905.

Garre, Discussion on Kocher's lecture. Surgical Congress, Berlin, 1911.
Gautier, L., Symptomes de myxoedeme a debut chez une femme anterieurement atteinte

de goitre exophtalmiques. Rev. med. de la Suisse rom., n. (Reference in

Jahresb. f. Neurol. u. Psychiat., 1899, 899.)
Gebele, Zur Frage der Thymuspersistenz bei Morbus Basedowi. Arch. f. klin. Chir.,

93, 1910.

- Uber experimentelle Versuche mit Basedowthymus. Beitr. z. klin. Chir., 76, 823,

1911.
Georgjewsky, K., Uber die Wirkung der Schilddriisenpraparate auf den tierischen Organis-

mus. Ztschr. f. klin. Med., 33, 1897.
Gerhardt, C., tJber das Verhalten der Korperarterien bei Basedowscher Krankheit.

Mitt. a. d. Grenzgeb. d. Med. u. Chir., i, 1896.

Gibson, The function of the thyroid gland, etc. Brit. M. J., Jan., 14, 1893.
Gibson, Notes on some pathological appearances in three fatal cases of Graves' disease.

Brit. M. J., Sept., 1893.
Gierke, Die Persistenz und Hypertrophie der Thymusdriise bei Basedowscher Krankheit.

Mvinchen med. Wchenschr., 1909, Nr. 116.

- Uber Knochentumoren mit Schilddriisenbau. Arch. f. path. Anat. [etc.], Berl., 170.
Gilbert and Casteigne, Infection thyroidienne et goitre exophthalmique. Compt. rend.

soc. de biol., 1899, 463.
Gley, Sur les effets de 1'extirpation du corps thyreoide. Compt. rend. soc. de biol., 1891,

5°9-
Gluzinski, Einige Bemerkungen zum klinischen Bild des Klimakteriums. Wien. klin.

Wchenschr., 1909, 48.

Goldflam, S., Zur Frage des Jodbasedow. Berl. klin. Wchenschr., 1911, Nr. 10.
Gordon and v. Jagic, t)ber das Blutbild bei Morbus Basedowi und Basedowoid. Wien.

klin. Wchenschr., 1908, 1589.
Grasset, see Cassirer.

Graves, Lectures. London M. & Surg. J., 7, 173, 1835.
Grawitz, Morbus Basedowi, kompliziert mit Diabetes mellitus, etc. Fortsch d. Med.,

1897, 15.

Grienfieldt, Brit. M. J., Dec. 9, 1893.
Grober, J., Zum erblichen Auftreten der Basedowschen Krankheit. Med. Klinik, Nr.

33, 1912.

Gultl, W., Tr. Clin. Soc. Lond., 7, 1873.

Guzmann, Discussion the Referat of Kraus-Kocher. Kongr. f. innere Med., 1906.
Halliburton, Report on chemical investigation of the tissues and organs from cases of

myxoedema in man and animals. Reports on Myxoedema. London, 1888.
H aisled, W. S., An experimental study on the thyroid glands of dogs, etc. Baltimore,

1896.

Hanau, see Cretinism.
Hannemann, 0., Uber Glykos. und Diabet. mell. bei Basedowscher Krankheit. Inaug.-

Diss., Berlin, 1895.
v. Hansemann, Schilddriise und Thymus bei der Basedowschen Krankheit. Berl.

klin. Wchenschr., 1905.

Hart, H., Uber Thymuspersistenz, etc. Munchen. med. Wchenschr., 1908.
Haskovec, L., Einwirkung des Schilddrusensaftes auf den Kreislauf. Wien., med. Bl.,

1896.
Haugardy and Langstein, Jahrb. f. Kinderh., 61, 1905.

6<DO LITERATURE

Hectoen, Ein Fall von Scleroderma diffusum. Centralbl. f. allg. Path. u. path. Anat.,

1897, Nr. 17.
Heintzheimer, Entwicklung und gegenwartiger Stand der Schilddriisenbehandlung.

Miinchen, 1895.
Hertoghe, Influence des produits thyreoidiens, etc. Bull. Acad. roy. de med. de Belg.

X, 1896, p. 381.
Hertoghe-Spiegelberg, Die Rolle der Schilddruse bei Stillstand und Hemmung des Wach-

stums, etc. Miinchen, 1900, Lehmann.

Herz, A., Verhandl. d. Gesellsch. f. innere Med., 4, Juni, 1908.
Himmelheber, Akute Thyreoiditis als Komplikation nach einer Operation. Centralbl.

f. Gynak., 35, 1909.
Hirsch, R., Glykosurie nach Schilddriisenexstirpation bei Hunden. Ztschr. f. exper.

Pathol. u. Therap., 3, 1906.
Hirschl, J. A., Osteomalacie bei Morbus Basedowi und Myxodem. Jahrb. f. Psychiat.

u. Neurol., 20, 406, 1901, und Wien. klin. Wchenschr., 1901, 333.

- tiber Geistesstorungen bei Morbus Basedowi. Jahrb. f. Psychiat. u. Neurol., 1894,

p. 52.
Hirschlaf, W., Zur Pathologic und Klinik des Morbus Basedowi. Ztschr. f. klin. Med.,

36, 200, 1899.
Hofbauer, Typische Atemstorungen bei Morbus Basedowi. Mitt. a. d. Grenzgeb. d.

Med. u. Chir., Nr. n, 531.
Hofmeister, Experimentelle Untersuchungen iiber die Folgen des Schilddriisenverlustes.

Beitr. z. klin. Chir., u, 1894 "und Deutsche med. Wchenschr., 1896, Nr. 22.
Honnicke, Discussion on Kocher's lecture. Kongr. f. inn. Med., 1906, 108.
Holmgren, J., tlber das Langenwachstum bei Hyperthyreose. Med. Klin., 1910. Uber

den Einfluss der Basedowschen Krankheit, etc., auf das Langenwachstum.

Leipzig, 1909.

Holzknecht, Gesellschaft der Arzte. Wien. klin. Wchenschr., 1909, Nr. 47.
Horsley, Die Funktion der Schilddruse, eine historisch-kritische Studie. Fstschr. f.

Virchow, i, Berlin, 1891.

Hotz, Die Ursache des Thymustodes. Beitr. z. klin. Chir., 55, p. 509, 1907.
Huchard, Nature et traitement du goitre exophthalmique. J. des praticiens, 1900, 157.
Hunt, Reid, Influence of thyroid feeding and of various foods and of small amount of food

upon poisoning by acetonitril. J. Biol. Chem., i, 33, 1905.

- The relation of iodin to the thyroid gland. J. Am. M. Ass., 1907.

— The probable demonstration of thyroid secretion in the blood in exophthalmic goiter.

Ibidem, 1907.
Hunt, Reid, and Atherton Siedell, Studies of thyroid. Hyg. laborat. Bull. 47, 1908,

Treasury Department.
Jaboulay, Resection bilaterale du sympathique cervical dans le goitre exophtalmique.

Bull. Acad. de med., 38, 1897.
v. Jaksch and H. Rotky, t)ber eigenartige Knochenveranderungen im Verlauf des Morbus

Basedowi. Fortschr. a. d. Geb. d. Rontgenstrahlen, 13, 1908.
Jaquet and Svenson, Stoffwechsel fettsiichtiger Individuen. Ztschr. f. klin. Med., 41, 375,

1900.

Jeanselme, Thyreoidite et Strumite infectieuse. Gaz. d. Hop., 1895.
J of roy, A., and Ch. Achard, Contribution a 1'anatomie pathologique de la maladie de

basedow. Arch, de med, exper. et d'anat. path., 5, 807, 1893.
Jones, Exophthalmic goiter and rheumatoid arthritis. Lancet, 16, Jan., 1909.
Jonescu, cited in Jahresb. f. Fortschr. a. d. Geb. d. Chir., 1901, p. 454.

THYROID GLAND' 6oi

Kahler, 0., Dber den Leittingswiderstand der HautlDei Morbus Basedowi. Prag. Ztschr.

f. Heilk., 9, 1888.
Kappis, M., IJber Hirnnervcnlahmungen bei der Basedowschen Krankheit. Mitt. a. d.

Grenzgeb. d. Med. u. Chir., 22, 1912, Heft, 4.
Kappis, liber Lymphocytose des Blutes bei Basedow und Struma. Mitt. a. d. Grenzgeb.

d. Med. u. Chir., 21, 1910, p. 729.
Kashiwamura, Die Schilddruse bei Infektionskrankheiten. Arch. f. path. Anat. [etc.],

Berl., 166, 373.
Kassowitz, Infantiles Mxyodem, Mongolismus und Mikromelie. Wien. med. Wchenschr.,

Nr. 22 u. Fortsetzung, 1902.

Kaufmann, E., Untersuchungen uber die sog. fotale Rachitis. Berlin, 1892.
Kirk, Notes on cases of myxodema. Lancet, 2, 743, 1893.
Kishi, Beitrage zur Physiologic der Schilddruse. Arch. f. Path. Anat. [etc.], Berl., 176,

p. 260.
Kleinwachter ', Wie ist der Genitalbefund bei Morbus Basedowii? Ztschr. f. Geburtsh.

u. Gynaek., 16, 144, 1889.

- Das Verhalten des Genitales bei Morbus Basedowi. Centralbl. f. Gynak., 1889, Nr.

10, 181.

Klemm, Die operative Therapie des Morbus Basedowi. Arch. f. klin. Chir., 86.
Knopf elmacher, Alimentare Glykosurie und Myxoedem. Wien. klin. Wchenschrift.,

1904, 224,

- Wien. klin. Wchenschr., 1902, Nr. 28, p. 712.

— Zwei Falle von Myxb'dem, etc. Wien. klin. Wchenschr., 1905, 296.
Kocher, A., Uber Jodbasedow. Arch. f. klin. Chir., 92, Heft, 5.

- liber Morbus Basedowi. Mitt. a. d. Grenzgeb. d. Med. u. Chir., 9, 1902.

— liber die Ausschiedung des Jods im menschlichen Organismus, etc. Ibidem, 14, 1905.

- Blutuntersuchungen bei Morbus Basedowi, etc. Arch. f. klin. Chir., 87, 1908.

- Die Behandlung der Basedowschen Krankheit. Munchen. med. Wchenschr., 1910,

677-
Kocher, Th., Surgical Congress. Berlin, 1912.

- Die Pathologie der Schilddruse. Kongr. f. inn. Med., 1906.

- Blutuntersuchungen bei Morbus Basedowi. Arch. f. klin. Chir., 87, 1908.

- liber Kropfexstirpation und ihre Folgen. Arch. f. klin. Chir., 29, 1883.

- Uber Kropf und seine Behandlung. Deutsche med. Wchenschr., 38, 1265, 1912.
Kocher-Langhans, Deutsche Ztschr. f. Chir., 34, 1892, and Arch. f. Path. Anat. [etc. ], Berl.,

128, 318.
Kohler, R., Myxodem auf Syphilis beruhend. Berl. klin. Wchenschr., 1892, 743, and 1894,

41.
v. Korczynski, Einige Bemerkungen uber das Myxodem. Wien. med. Presse, 1898, Nr.

36-37-
Kostlivy, Uber chronische Thyreotoxikosen. Mitt. a. d. Grenzgeb. d. Med. u. Chir., 21,

1910.
Kottmann, A ., and Lidsky, Beitr. zur Physiologic und Pathologie der Schilddruse. Ztschr.

f. klin. Med., 71, 344, 1910.
Kowalewsky, P., Myxoedeme ou Cachexie pachydermique. Arch, de Neurol., 18, 422,

1889.
Kraus, Fr., Handbuch d. inn. Medic. Ebstein-Schwalbe, 1899.

- Die Pathologie der Schilddruse. Referat kongr. f. inn. Med., 1006.

- Uber das Kropfherz. Wien. klin. Wchenschr., 1899, 416, und Deutsche med. Wchen-

schr., 1906, 1889.

602 LITERATURE

Kratis, Fr., and Fricdcnthal, Uber die Wirkung der Schilddriisenstoffe. Berl. klin. Wchen-
schr., 1908, 1709.

Kraus and Ludwlg, Klinische Beitrage zur alimentaren Glykosurie. Wien. klin. Wchen-
schr., 1891, 898.

Krehl, Miirichen. med. Wchenschr., 1910, Nr. 47.
Krong, E., cited by Saltier. Lit. Nr. 2700.
Lampe, Liesegang, and Klose, Die Basedowische Krankheit, etc. Beitr. z. klin. Chir., 77,

1912.

Landstrom, /., Uber Morbus Basedowi, etc. Stockholm, 1907.
Lange, Die Beziehungen der Schilddriise zur Schwangerschaft. Ztschr. f. Geburtsh. u.

Gynaek., 14, 1899.
Langhans, Uber Veranderungen in den peripheren Nerven bei Cachexia thyreopriva des

Menschen und Affen, etc. Arch. f. Path. Anat. [etc.], Berl., 128, 318, 1892.
Lanz, Uber Schilddriisenfieber und Schilddriisenintoxikation. Mitt. a. d. Grenzgebiet

d. Med. u. Chir., 8, 1901.
- Ein Vorschlag zur diatetischen Behandlung Basedowkranker. Cor.-Bl. f. schweiz.

Aerzte, 1899, u. Weitere Mitteilungen uber serotherapeutische Behandlung des

Morbus Basedowii. Munchen. med. Wchenschr., 1903.
Lawson, Tail, Reference in Schmidt's Jahrb., 168, 34, 1875.
Lebert, cited by Breuer.

Leichtenstern, Uber Myxodem und Entfettungskuren mit Schilddriisenfutterung. Deut-
sche med. Wchenschr., 1894, Nr. 50.
Leischner und Marburg, Zur Frage der chirugischen Behandlung des Morbus Basedowi.

Mitt. a. d. Grenzgeb. d. Med. u. Chir., 21, 761, 1910.
Lepine, Lyon Med., 1903, 101.
Leredde and Thomas, Sclerodermie generalisee. Arch, de med. exper. et d'anat. path.,

1898, 665.
v. Leube, Klinischer Bericht von der Abteilung des Landeskrankenhauses Erlangen, 1875,

28.

Lewin, Zur Kasuistik des Morbus Basedowi. Inaug.-Diss. Berlin, 1888.
van Lier, Blutuntersuchung bei Morbus Basedowi. Beitr. z. klin. Chir., 69.
Lorand, Uber das Altern, Verl. v. Klinkhardt., 1910, 3, Aufl.
Loeb, J '., in Oppenheimers Handbuch der Biochemie, 2, i, 1910.
Loew, J., tiber das Auftreten von Odemen beim Morbus Basedowi. Wien. med. Presse,

38, 721, 1897.
Loewi, O., Eine neue Funktipn des Pankreas, etc. Arch. f. exper. Path. u. Pharmakol.,

59, 1908.
Lowy, J., Uber Basedowsymptome bei Schilddriisenneoplasmen. Wien. klin. Wchenschr.,

1909, 1671.
Lubarsch, Schilddriisenveranderung bei Basedowscher Krankheit. Centralbl. f. allg.

Path. u. path. Anat., 6, 716, 1895.
Mabille, De I'efficacite de 1'arsene centre 1'accident de la medication thyreoide. Paris,

1899.
MacCallum and Fabyan, On the anatomy of a myxedematous idiot. Johns Hopkins

Hosp. Bull., 18, 198, Sept., 1907.
Maccone, L., Beitrag zum Studium der histologischen Veranderungen beim kindlichen

Myxodem. Pediatria, 6.
Macfie Campbell, cited by Bouchan.

Maclllwine, Myxedema in mother and child. Brit. M. J., May, 24, 1902, 1261.
Mackenzie, H., A lecture on Graves' disease. Brit. M. J., 1905, 1077.
Macpherson, Thyreoid grafting in myxedema. Edinb. M. J., May, 1892.

THYROID GLAND ' 603

Magnus-Levy, A., Untersuehungen zur Schilddrusenfrage. Zschr. f. klin. Med., 33 u. 60,
1897-

— tJber Myxodem. Ztschr. f. klin. Med., 52, 1904.

Maranon, G., La Hiperchlorhidria en el Hiperthiroidismo. Rev. Ibero. Am. de cien. med.

Junio, 1912.
Maresch, Kongenitaler Defekt der Schilddruse bei einem n jahrigen Madchen, etc.

Ztschr. f. Heilk., 19, 1898.
Marfand, Thyreoi'dite rheumatismale avec myxoedeme et vitiligo. Bull, de med., Paris,

33, 1900.
Marie, Pierre, Contribution a 1'etude et au diagnostic des formes frustes de la maladie de

Basedow. These de Paris, 1883.
Marinesco and Minea, Nouvelles recherches sur 1'influence qu'exerce 1'ablation du corps

thyro'ide, etc. Compt. rend. Soc. d. biol., 1910, Nr. 4.

Matthes, Zum Stoffwechsel bei Morbus Basedowi. Kongr. f. innere Med., 1897, 232.
Maurer, Die Entwicklung des Darmsystems. Hertwigs Handb. d. vgl. Entwicklungs-

gesch., 2, i, 1906.
Mayerle, Beitr. zur Kenntnis des Stoffwechsels bei kunstlicher Hyperthyreoiditis. Ztschr.

f. klin. Med., 71.
Mayo, A consideration on the mortality in one thousand operations for goiter, etc. Surg.

Gynec. and Obst., March, 1909, 8.
McCarisson, Lancet 2, p. 1570, 1906.

Meltzer, Uber Myxodem. New Yorker med. Monatschr., April, 1894.
Mendel, Zur pathologischen Anatomic des Morbus Basedowi. Deutsche med. Wchen-

schr., 1892, 5, und ein Fall von Myxodem ibidem, 1893, 25.

Meunacher, Blutbefund beim Myxodem. Monatschr. f. Kinderheilk., 6, 666, 1907.
v. Mikulicz, Die Thymusfiitterung bei Kropf, etc. Berl. klin. Wchenschr., 1895, 16.
v. Mikulicz and Reinbach, tJber Thyreoidismus. Mitt. a. d. Grenzgeb. d. Med. u. Chir., 8,

1901.

M hunch, W., Das Kropfherz, etc. Leipzig u. Wien, 1904, Fr. Deuticke.
Mobius, P. J., Schmidt's Jahrb., 210, 237, 1886.

— Die Basedowsche Krankheit. Wien, 1906, Holder.

— Munchen. med. Wchenschr., 1903, Nr. 4.

Moszkowicz, Protokoll der k. k. Gesellsch. der Artze in Wien, 1908. Wien. klin. Wchen-
schr., 304, 1908.

Miiller, Charlotte, Uber morphologische Blutveranderungen bei Struma. Med. Klin.,
1910, Nr. 34.

Mutter, Fr., Beitrage zur Kenntnis der Basedowschen Krankheit. Deutsches Arch. f.
klin. Med., 51, 335, 1893.

- Discussion on Referat of Fr. Kraus. Kongr. f. innere Med., 1906.

v. Miiller, A . and P. Saxl, tlber Kalziumgelatineinjektionen. Therap. Monatsh., 26, 1912.
Munk, H., Zur Lehre von der Schilddruse. Arch. f. path. Anat. [etc.], Berl., 115, 1897,

u. 154, 1898.

Muratov, Zur Pathologic des Myxodems. Neurol. Centralbl., 1898, 20.
Murray, G. R. The diagnosis of early thyreoidal fibrosis. Transact, of the Roy. med. a.

chir. Soc., 1902, 141. (Ref. Brit. M. J., 1898, 942.)
Mygind, Thyreoiditis acuta simplex. J. Laryngol., 1895, 181.
v. Noorden, Die Zuckerkrankheit. V. Aufl. Hirschwald, 1910.

- Discussion on Morbus Basedowi. K. k. Gesellsch. d. Arzte Wiens, 1909, 1769.

— Sammlung klinischer Abhandlungen, Berlin, 1909, 48, Hirschwald.

- Die Fettsucht. II. Aufl., Holder, 1910.

604 LITERATURE

v. Noorden, Jr., Zur Kenntnis der vagotonischen und sympathikotonischen Falle von

Morbus Basedowii. Inaug.-Diss., Kiel. IQII.
t\ Xotthafft, Neuere Arbeiten und Ansichten uber Sklerodermie. Centralbl. f. allg.

Path. u. path. Anat., 9, 870, 1898.

— Ein Fall von artifiziellem akut thyreogenem Morbus Basedowi, etc. Centralbl. f.

innere. Med., 1898. Nr. 15.
Notki, Beitrag zur Schilddriisenpathologie. Wien. med. Wchenschr., 1896. Arch. f.

path. Anat. [etc.], Berl., 144, Suppl.
Novak, J., Die Erkrankungen des weiblichen Genitales in ihrer Bedeutung fur den

Gesamtorganismus und die Wechselbeziehungen seiner innersekretorischen

Elemente zu den anderen Blutdriisen. Suppl. to Nothnagel's Pathol. u. Therap.

A. Holder, Wien u. Leipzig, 1912.
Oliver and Schafer, The physiological effects of extracts of the suprarenal capsules. J.

Physiol., 18, 231, 1895 und On the physiological action of extracts of pituitary

body, etc., ibidem, 18, 277, 1895.

Oppenheim, H., Lehrb. d. Nervenkrankh. 1908, 1550 u. 1911, 183.
Ord, Med. Chir. Tr., 61, 1878.

Ortner, Vorlesungen uber spezialle Therapie innere Krankheiten, etc.
Osier, W., An acute myxoedematous condition with tachycardia, glycosuria, melaena,

mania and death. J. Nerv. Ment. Dis., 26, 68, 1899.

— Cited by Cassirer.

Oswald, Der Morbus Basedowi im Lichte neuerer klinischer und experimenteller For-

schung. Wien. klin. Wchenschr., 1900.
Oswald, Die Chemie und Physiologic des Kropfes. Arch. f. path. Anat. [etc.], Berl., 169,

1902.

— Zur Klarung der Jodothyrinfrage. Arch. f. d. ges. Physiol., 129, 1909.
Passler, Erfahrungen uber die Basedowsche Krankheit. Deutsche Zschr. f. Nervenh.,

6, 1895.
Pari, G. .4., Uber den Einfluss der Schilddriise auf den zeitlichen Ablauf der Zersetzungen.

Biochem. Ztschr., 13, 1908.
Parhon and Marbe, Contribution a 1'etude des troubles mentaux de la maladie de Base-

dow. Encephale, 5, 1906.
Parhon and Papinian, Ein Fall von chronischem dysthyreoid. Rheumatismus. Buka-

rester med. Gesellsch., 1904.

Paterson, Notes on the etiology of Graves' disease. Lancet, June, 1894, 1370.
Payr, E., Transplantation der Schilddruse in die Milz. Arch. f. klin. Chir., 80, 1906, 730.
Peucker, Uber einen Fall von kongenitalem Defekt der Schilddruse, etc. Ztschr. f. Heilk,

20, 341, 1899.

Pick and Pineles, Untersuchungen uber die physiologisch wirksame Substanz der Schild-
druse. Ztschr. f. exper. Path. u. Therap., 1909, Nr. 7.

Pilcz, Zur Frage des myxodematosen Irreseins. Jahrb. f. Psychiat., 1901, 77.
Pineles, Uber die Empfindlichkeit des Kropfes gegen Jod. Wien. klin. Wchenschr., 1910,

Nr. 10.

— Uber Thyreoaplasie, etc. Wien. klin. Wchenschr., 1902 u. Wien. klin. Wchenschr.,

1912, Nr. 43.

- Volkmann's Vortr., 1899, Nr. 242.

Ponfick, see multiple ductless glandular sclerosis, Chapter XI.
Porges and Pribram, Uber den Einfluss verschiedenartiger Diatformen auf den Grundum*

satz bei Morbus Basedowii. Wien. klin. Wchenschr., 1584, 1908.
Pribram, Basedowsche Krankheit. Prag. med. Wchenschr., 438, 1882.

THYROID GLAND ' 605

de Quervain, Die akute nicht eitrige Thyreoiditis. Mitt. a. d. Grenzegeb. d. Med. u. Chir.

Suppl., 2, 1904.

Quine, Medical treatment of exophthalmic goiter J. Am. M. Ass., 1907, 350.
Quincke, Uber Athyreosis im Kindesalter. Deutsche med. Wchenschr., 1900, 787.
Reinbac/i, Uber das Verhalten der Temperatur nach Kropfoperationen. Mitt. a. d.

Grenzgeb. d. Med. u. Chir., 4, 606, 1899.
Reinhold, Zur Pathologic der Basedowschen Krankheit. Munchen. med. Wchenschr.,

1894, Nr. 23.

Reinlinger, Cited by de Quervain.
Reverdin, J. and A., Notes sur 22 operation de goitre. Rev. med. de la Suisse Romain,

1883.

Revilliod, L., Le thyreoidisme, etc. Rev. med. de la. Suisse Romain, 15, 413, 1895.
Rillier, F., Memoire sur 1'iotisme constitutionelle. Paris, 1860.
Roasenda, G., Contribute allo studio ed all interpretazione del Morbo diFlagani-Basedow.

Rev. neuropat., 3, 1909.

Rocaz and Cruchet, Myxoedeme congenitale. Arch, de med. d. enf., 6, 97, 1905.
Roger and Gamier, La glande thyreoidea dans les malad. infect. Presse med., 1899, 181.
Rogo-witsch, Die Veranderungen der Hypophyse nach Entfernung der Schilddriise.

Beitr. z. path. Anat. u. z. allg. Path., 4, 453, 1898.
Roos, Uber die Einwirkung der Schilddriise auf den Stoffwechsel. Ztschr. f. physiol.

Chem., 21, 1895.
Rossin and Jellinek, Uber Farbekraft und Eisengehalt des menschlichen Blutes. Ztschr.

f. klin. Med., 39, 109, 1900.
Rossle, Uber Hypertrophie und Organkorrelationen. Munchen. med. Wchenschr., 1908,

Nr. 8.

Roth, Das Blutbild beim Morbus Basedowi. Deutsche med. Wchenschr., Februar, 1910.
Rothschild and Lewi, Etude sur la physiopathologie du corps thyreoi'de, etc. Paris, 1908.
Roux, Sclerodermie et corps pituitaire. Rev. neurol., 1902, 721.
Rudinger, Uber Eiv^eissumsatz bei Morbus Basedowi. Wien. klin. Wchenschr., 1908.
Sainton and Rathery, see multiple ductless glandular sclerosis, Chapter XI.
Salomon, H., Gaswechseluntersuchungen bei Morbus Basedowi. Berl. klin. Wchenschr.,

1904, Nr. 24.
Salomon and Amalgia, Uber Durchfalle bei Morbus Basedowi. Wien. klin. Wchenschr.,

1908, 870.
Saltykow, Sarkom und Karzinom in der Schilddriise. Centralbl. f. allg. Path. u. Anat.,

16, 547, 1905.
Sarbach, Das Verhalten der Schilddruse bei Infektionen und Intoxikationen. Mitt. a. d.

Grenzgeb. d. Med. u. Chir., 15, 1905.

Saltier, Die Basedowsche Krankheit. Leipzig, 1909 u. 1910, Engelmann.
Schilder, P., Uber Missbildungen der Schilddruse. Arch. f. path. Anat. [etc.], Berl., 203,

246, 1911.

Schkarine, Reference in Rev. neurol., 20, 1908 (Russian).
Schlesinger, H., Meine Erfahrungen iiber den akuten Morbus Basedowii. Therapie der

Gegenwart, 488, 1912.
Schmidt, Adolf, Discussion on the lecture on " Fettstuhle " by H. Salomon. 20 Kongr. f.

innere Med., 1902.

Scholz, W., See Cretinism, Chapter III.
Schotten, Uber Myxodem und seine Behandlung mit innerlicher Darreichung von Schild-

driisensubstanz. Munchen. med. Wochenschr., 1893, Nr. 51, 52.
v. Schrotter, L., Zum Symptomenkomplex des Morbus Basedowi. Ztschr. f. klin. Med.,

48, i, 1903.

606 LITERATURE

Scliultzc, K., Experimentelle Untersuchungen iiber das Fieber nach Kropfoperationen.
Mitt. a. d. Grenzgeb. d. Med. u. Chir., 17, 655, 1907.

— Zur Chirurgie des Morbus Basedowi. Mitt. a. d. Grenzgeb. d. Med. u. Chir., 16,

161, 1906.
Schwarz, G., Rontgentherapie der Based"o\vschen Krankheit. Wien. klin. Wchenschr.,

1908, 1332.
Seltowitsch, Ein Fall von Struma accessoria der Zungenbasis. Entstehung eines Myxo-

dems nach Entfernung desselben. Centralbl. f. Chir., 24.
Schiff, Bericht iiber eine Versuchsreihe betr. die Exstirpation der Schilddriise. Arch. f.

exper. Path. u. Pharmakol., 18, 1884.

Short, lodoform and thyroidism. Bristol M. Chir. J., June, 1910.
Siebenmann, Uber die Funktion und die mikroskopische Anatomic des Gehororgans bei

totaler Aplasie der Schilddriise. Arch. f. Ohrenh., 70, 1907.

— See Diederle.

Siegert, F., Myxodem im Kindersalter. Ergebn. d. innere Med. u. Kinderh., 6, 1910, 601.
Singer, Zur Pathologic der Sklerodermie. Berl. klin. Wchenschr., 1895, 266.
Sollier, P., Maladie de Basedow avec myxoedeme. Rev. de med., n, 1000, 1891.
Spietho/, B., Blutdruckmessung bei Morbus Basedowi. Centralbl. f. innere. Med., 34,

1892.
Spolverini, L. M., De 1'influence nocive sur le nourissant, etc. Rev. de 1'hygiene et de

med. inf. [etc.], 8, i, 1909.
Starr, Allen, A contribution to the. subject of myxedema. N. York Med. Rec., June,

1893.
Stern, R., Differentialdiagnose und Verlauf des Morbus Basedowii, etc. Jahrb. f.

Psychiat. u. Neurol., 29, 1909.

Steyrer, A., Ztschr. f. exper. Path. u. Therap., 4, 1907.
Stick and Makkas, Zur Transplantation der Schilddriise mittelst Gefassnaht. Beitr. z.

klin. Chir., 60.
Strauss, H., Zur Lehre von der neurogenen und thyreogenen Glykosurie. Deutsche med.

Wchenschr., 1897, Nr. 18 u. 20.
. Stubenrauch, Knochenveranderungen beim Myxodem. Berl. klin. Wchenschr., 76,

860, 1911.

Stiive, Festschr. d. stadt. Krankenhauses Frankfurt a. M., 1896.
Syllaba, L., Uber die Prognose bei der Basedowschen Krankheit. Wien. med. Blr., 1909,

322.
Thiele and Nehring, Untersuchungen des respiratorischen Gaswechsels unter dem Einfluss

von Thyroideapraparaten, etc. Ztschr. f. klin. Med., 30, 41, 1895.
Thomas, Erwin, Zur Einteilung der Myxodemformen. Deutsche med. Wchenschr., 1912,

461.

Thorbecke, Dissertation. Heidelberg, 1905.
Trousseau, Du goitre exophtalm. Union med., Par., 1860. Gaz. hebd. de med., Par.

1860, Gaz. d. hop, Par., 1860.
Turin, Blutuntersuchungen unter dem Einfluss der Schilddriise und Schilddriisen-sub-

stanzen. Deutsche Ztschr. f. Chir., 107, 1910.

Ulrich, Chr., Uber Morbus Basedowi Myxodem. Therap. Monatsh, 1909, 291..
Ungermann, Uber einen Fall von Athyreosis und vikariierender Zungenstruma. Arch. f.

path. Anat. [etc.], Berl.

Unna, Miinchen, med. Wchenschr., 1896, 602.
Vassale and Generali, see Chapter on Parathyroids.
Vermehren, Stoffwechseluntersuchungen nach Behandlung mit Glandula thyreoidea, etc.

Deutsche med. Wchenschr., 255, 1893.

THYROID GLAND' 607

Vermorel, De 1'origine thyreoidiennc. de certaines tachycardies ou palpations nerveuses de

la puberte et de la menopause. Centralbl. f. Gynak., 1909, 1720.
Vigour oux, R., Uber das Verhalten des galvanischen Leitungswiderstandes bei der Base-

dowschen Krankheit. Centralbl. f. Nervenh., 10, 1887.
Virchow, Uber Myxodema, Berl. klin. Wchenschr., 1887, 121.
Voit, Fritz, Stoffwechseluntersuchungen am Hund mit frischer Schilddriise undjodo-

thyrin Ztschr. f. Biol., 35, 116, 1897.
Vollmann, Uber einen Fall -von geheiltem Myxodem nach Schilddriisenexstirpation.

Inaugural Dissertation, Wiirzburg, 1893.
v. Wagner, see Cretinism.

i). Wagner and v. Schlagenhaufer, see Endemic Cretinismus.
Walter, Uber den Einfluss der Schilddriise auf die Regeneration der peripheren mark-

haltigen Nerven. Deutsche Ztschr. f. Nervenh., 38, i, 1909.
Weygandt, Uber Virchows Kretinentheorie. Neurol. Centralbl., 1904, 290.
White, Clifford, A fetus with congenital hereditary Graves' disease. Proc. Roy. Soc. Med.,

5, obstr. sec., 1912, 247.
Wiener, H., Uber den Thyreoglobulingehalt der Schilddriise, etc. Arch. f. exper. Path. u.

Pharmakol., 61, 1909.

Worms and Hamant, De 1'exophthalmie unilaterale, etc. Gaz. d. Hop., 1912, Nr. 70, 1639.
Wyss, R. i)., see Endemic Cretinism.
Zitschmann, Beitrag zum Studium der Folgen der Schilddriisenextirpation. Mitt. a. d.

Grenzgeb. d. Med..u. Chir., 19 u. Arch. f. wissensch. u. prakt. Theirp., 93, 1907.

CHAPTER III
CRETINIC DEGENERATION

Alexander, G., Das Gehororgan der Kretinen. Arch. f. Ohrenh., 78, 1908, 54.

Bay on, Neurol. Centralbl., 792.

Bircher, E., Ein Beitrag zur Kenntnis der Schilddriise and Nebenschilddriise bei Kretinoi-

den, Kretinen und endemisch Taubstummen. Frankf. Ztschr. f. Path., II, 262,

1912.

— Fortfall und Anderung der Schilddriisenfunktion, etc. Ergebn. d. Path. Lubarsch-

Ostertag., 15, 1911.

— Die Entwicklung und der Bau des kretinen Skelettes im Rontgenogramm. Erg., 21,

Fortschr., a. d. Geb. d. Rb'ntgenstrahlen.

— Zur Pathogenese der Kretinoiden Degeneration. Berlin, 1908. Urban und Schwar-

zenberg.

— Zur experimentellen Erzeugung der Struma, etc. Deutsche Ztschr. f. Chir., 103,

1910.

— Zur Pathogenese der kretinischen Degeneration. Med. Klin., 1908, Beiheft 6. Exper.

Beitr. z. Kropfherz. Med. Klin., 10, 1910.

— Zur Implantation von Schilddriisengewebe bei Kretinen. Deutsche Ztschr. f. Chir.,

98, 1909.

Bircher, H., Der endemische Kropf und seine Beziehungen zur Taubstummheit und zum
Kretinismus. Basel, 1893.

— Das Myxodem und die kretinoide Degeneration. Volkmanns klin. Vortrage, 1890,

Nr. 3, 5, 7.

Blum, see Thyroid Gland.
Bourneville, see Thyroid Gland.

Breitner, Uber Ursache und Wesen des Kropfes. Wien. klin. Wchenschr., 1912, 82.
Breus and Kolisko, Die pathologischen Beckenformen. I. Leipzig und Wien., 1904,

Deuticke.
Coulon, de, Uber Tyreoidea und Hypophysis der Kretinen, etc. Arch. f. path. Anat.

[etc.], Berl., 147, 1897, p. 53-99-
Cyan, v. see Thyroid Gland.
Danziger, Cited by Ewaldt.
Dexler, H., liber endemischen Kretinismus bei Tieren. Berl. thierarztl. Wchenschr.,

1909, Nr. 21-24.
Dieterle, Uber endemischen Kretinismus. Jahrb f. Kinderh., 64, 1906.

— See also chapter on Thyroid Gland.

Eiselsberg, v. Die Krankheiten der Schilddriise. Stuttgart, 1901, Encke.

Eller, Familiarer Kretinismus in Wien. Jahrb. f. Kinderh., 71, 1910.

Eppinger, Sr., cited by Scholz.

Ewald, Die Erkrankungen der Schilddriise, Myxodem und Kretinismus. II. Aufl. A.

Holder, Leipzig u. Wien, 1909.
Eysselt, v., Ein Jahr Kretinenbehandlung mit Schilddriisensubstanz. Wien. med.

Wchenschr., 1907, Nr. 1-3.

608

CRETINIC DEGENERATION 609

Froschels, E., Uber die Griinde der Hor- und Sprachstorung beim Kretinismus, etc.

Monatschr. f. Ohrenh., 45, 1912.
Getzowa, tJber die Thyreoidea von Kretinen, etc. Arch. f. path. Anat. [etc.], Berl., 180,

1905.
Gnlzmann, Uber die Storungen der Stimme und Sprache. Ergebn. d. innere. Med. u.

Kinderh., 3, 1909, 327.
Habermann, J., Zur Lehre der Ohrenerkrankungen infolge von Kretinismus. Arch. f.

Ohrenh., 79, 1909, 23.

Hanau, X international Congress at Berlin, 2, 128.
Hitschmann, Augenuntersuchungen bei Kretinismus und Zwergwuchs, etc. Wien. klin.

Wchenschr., 1898, Nr. 27.
Johannesen, Verbreitung und Atiologie des Kropfes in Norwegen. Ztschr. f. klin. Med.,

24, 1891.
Kocher, Th., Zur Verhiitung des Kretinismus und kretinoider Zustande. Deutsche

Ztschr. f. Chir., 34, 1892. (Ref. from dem Kongress f. innere Medizin, 1906.)
Kranz, P., Schilddriise und Zahne. Deutsche Monatschr. f. Zahnheilk., 30, i, 1912.
Kraus, Fr., Die Pathologic der Schilddruse. Kongress f. innere. Med., 1906.
— Uber das Kropfherz. Wien. klin. Wchenschr., 1899, 416.
— tiber Kropfherz. Deutsche med. Wchenschr., 1906, 1889.
Kutschera, Das Grossenwachstum bei Schilddriisenbehandlung. Wien. klin. Wchenschr.,

1901, 771.

Lager, St., cited by Bircher.
Langhans, Anatomische Beitrage zur Kenntnis der Kretinen. Arch. f. path. Anat. [etc.],

Berl., 149, 155, 1897.
Lobenho/er, Die Verbreitung des Kropfes in Unterfranken. Mitt. a. d. Grenzgeb. d.

Med. u. Chir., 24, 505, 1912.
Lombroso, cited by Bircher.

Magnus-Levy, Uber Myxodem. Ztschr. f. klin. Med., 52, 1904.
Mikulicz, i). and Reinbach, Uber Thyreoidismus. Mitt. a. d. Grenzgeb. d. Med. u. Chir.,

8, 1901.

Minnich, Das Kropfherz. Leipzig u. Wien., Deuticke, 1904.
Moos and Steinbriigge, cited by Ewald.

Nager, Die Taubstummen der Luzerner Anstalt Hohenrain. Ztschr. f. Ohrenh., 43, 234.
Ottolenghi, II campo visivo nei cretini. Arch, di Lombroso, 1893, 256. Giornale d. r.

Acad. med. de Torino, 12, 1893.
Paltauf, A., see Dwarfism, Chapter XII.
Revilliod, see Thyroid Gland.

Rose, E., Der Kropftod und die Radikalkur der Kropfe. Arch. f. klin. Chir., 22, 1878.
Scholz, W., Klinische und experimentelle Untersuchungen Uber den Kretinismus. Berlin,

1906.

—Uber Behandlung des Kretins mit Schilddrusensubstanz. Kongr. f. innere. Med., 1902.
— Uber das Kropfherz. Berl. klin. Wchenschr., 9, 381, 1909.
—Uber den Stoffwechsel der Kretinen. Ztschr. f. exper. Path. u. Pharmakol., 1905,

Nr. 2.

—Uber Kretinismus. Ergebn. d. innere. Med. u. Kinderh., 3, 1909.
Scholz und Zingerle, Beitrag zur pathologischen Anatomic der Kretinengehirne. Ztschr.

f. Heilk., 1906, 57.

Schranz, I., Beitrag zur Theorie des Kropfes. Arch. klin. Chir., 34, 92.
Schroder, Beitrag zur Kenntnis des Myxodems. Psychiat.-neurol. Wchenschr., 3-5, 1907.
Safer, Die Bekampfung des Kretinismus in Osterreich. Neurol. Central., 1910, 320.
39

6 10 LITERATURE

I'llmann, E., Uber Beziehungen zwischen dem Utersusmyom und dem Kropf. Wien.

klin. Wchenschr., 1910, Nr. 16.

Wagner, v. Mittl. d. Ver. der Aerzte in Steiermark, 1893.
— Uber endemischen und sporadischen K-retinismus. Wien. klin. Wchenschr., 1900, Nr.

19.
Wagner, v., Zur Behandlung des endemischen Kretinismus. Wien. klin. Wchenschrift,

1902, Nr. 25.
— Uber Myxodem und sporadischen Kretinismus. Wien. med. Wchenschr., 1903,

Nr. 2-4.

— Uber marinen Kretinismus. Wien. klin. Wchenschr., 1906, 1273.
Wagner v. and v. Schlagenhaufer, Beitrag zum endemischen Kretinismus. Deuticke, 1910.
Werdt, v. Uber Lymphfollikelbildung in Struen. Frankf. Ztschr. f. Path., 8, Heft 3.
Wolfler, Chirurgische Behandlung des Kropfes. Berlin, 1890.
Wyss, R. v., Beitrag zur Entwicklung des Skeletts von Kretinen, und Kretinoiden. Fort-

schr. a. d. Geb. d. Rontgenstrahlen, 1899-1900, Heft 5.

CHAPTER IV

.PARATHYROID GLANDS

Adler, S., and H. Thaler, Experimentelle and klinische Studien zur Graviditatstetanie.

Ztschr. f. Geburtsh. u. Gynaek., 62, 194, 1909.

Albu, Die Tetanic Magenkranker. Volkm. Sammlung klin. Votr., 1899, Nr. 254.
— Zur Frage der Tetanic bei Magendilatation. Arch. f. Verdauungskr., 4, 466, 1896.
Aran and Rabaitd, cited by v. Frankl-Hochwart.
Aschenheim, E., t)ber den Aschengehalt in den Gehirnen Spasmophiler. Monatschr. f.

Kinderheilk., 9, Nr. 7.

A st. Fr., tiber zwei Falle von Tetanic. Deutsches Arch. f. klin. Med., 63, 193.
Auerbach, P., Epithelkorperchenblutung und ihre Beziehungen zur Tetanic der Kinder.

Ztschr. f. Kinderh., 73, Erganzungsband.

Bartels, Ein Beitrag zur Tetaniekatarakt. Klin. Monatschr. f. Augenh., 1906, 374.
Bauer, Th., Das Verhalten der Epithelkorperchen bei der Osteomalazie. Frankf. Ztschr.

f. Path., 7, 1911.

Bechterew, v. Die Tetanic. Ztschr. f. Nervenh., 6, 477, 1895.
— Die Funktionen der Nervenzentra. I. Heft, 1908, 42.
Benedikt, Elektrotherapie. II. Aufl., 1886, 612.

Benjamins, Uber die Glandula parathyr. Beitr. z. path. Anat. u. Physiol., 1902, 143.
Berkeley and Beebe, Extract of parathyroids. Med. Research, Feb., 1909.
Berlelli, Falta, and Schweeger. Uber die Wechselwirkung der Driisen mit innerer Sekre-

tion. III. Mitt. Ztschr. f. klin. Med., 71, Heft i und 2.
Bettmann, Ein Fall Von Thomsenscher Krankheit mit Tetanic. Ztschr. f. Nervenh., 9,

33i, 1897.
Biedl, Zur Atiologie der parathyreogenen Tetanic. Zentralbl. f. d. ges. Physiol. u.

Path. d. Stoffwechs, n, 1911.

— Innere Sekretion. Vorlesungen, 1902. Wien. Klin., Nr. 29, 1903.
— Innere Sekretion. Wien, 1910, Urban und Schwarzenberg.

Blazicek, Uber einige seltene Formen der Tetanic. Wien. klin. Wchenschr., 1894, 826.
— Pseudotetanie, vorgetauscht durch Hysteric. Ibidem, 1896, 373.
Bliss, Raymond W., Die Untersuchungen der Epithelkorperchen mit besonderer Beruck-

sichtigung ihrer Beziehungen zur Sauglingstetanie. Ztschr. f. Kinderh., 2, 549.
Boese and Lorenz, Kropf, Kropfoperation und Tetanic. Wien. med. Wchenschr., 38, 1909.
Bouveret and Devic, Recherches cliniques et experim. sur la tetanic d'origine gastrique.

Rev. de med., 12, 48, 1892.
Canal, Augm. influenza della parathyroidei sul decorso di guariguone delle fratture.

Arch, per le sc. med., 4, 1910.
Carnot and Delion, Parathyreoiditis tuberculeuse. Compt.-rend. soc. d. biol., 59, 321, 21.

Oct.

Cattaneo, Sul contenuto in Calcio del sangue nella spasmofilia la pediatria, 1909.
Ceni und Besta, Proprieta terapeutiche specifiche del siero di sangue di animali immunicati,

etc. Riv. sper. di freniat., 1903.
Cheadle, U., Pathology and treatment of laryngismus, tetany, and convulsions. Lancet,

1877, 919.

611

6l2 LITERATURE

C'/iiari, R. and .1. Fro/ilich, Erregbarkcitsanderung des vegetativen Xervensystems

durch Kalkentziehung. Arch. f. exp. Path. u. Pharmakol., 64, 214, 1911.
Chvostek, sr., Beitrage zur Tetanic. Wien. med. Presse, 1876, 1201; weitere Beitrage

zur Tetanic, ibid., 1878, 821 ff. u. 1879, 1201 ff.
Chvostek, Z., Bemerkungen zur Atiologie der Tetanic. Wien. klin. Wchenschr., 1905,

969.

— Beitrage zur Lehre von der Tetanic. Ibidem, 1907, 487.
— Myasthenia gravis und Epithelkorperchen. Ibidem, 1908, 37.
— Diagnose und Therapie der Tetanic. Deutsche med. Wchenschr., 1909.
— tiber das Verhalten der sensiblen Nerven, etc., bei Tetanic. Ztschr. f. klin. Med., 19,

489, 1891.
Claude and Schmiergeld, Les glands a secretion interne dans 1'epilepsie. Compt.-rend.

soc. de biol., 65, 138, 1908.

Curschmann, H., Tetanic, Pseudotetanie, etc. Deutsche Zschr. f. Nervenh., 27, 239 1904.
— tiber einige ungewohnliche Ursachen und Syndrome der Tetanic, etc. Ztschr. f.

Nervenh., 39, 1910.

— tiber die idiomuskulare Ubererregbarkeit. Ibidem, 28, 361.
Danielsen, Erfolgreiche Epitheltransplantation, etc. Beitr. z. Chir., 66, 85, 1910.
Eggers, Tr. Chicago Path. Soc., 1907.

v. Eiselsberg, Die Krankheiten der Schilddriise. Deutsche Chir., 38, 1901.
— tiber Tetanic im Anschluss an Kropfexstirpation. Wien, 1890.
— Weitere Beitrage zur Lehre von. den Folgezustanden der Kropfoperationen. Beitr. z

Chir. .BiWro^-Festschr., Stuttgart, 1892.
Enderlen, Untersuchungen iiber die Transplantation der Schilddriisen, etc. Mitt. a. d.

Grenzgeb. d. Med. u. Chir., 3, 474, 1898.
Eppinger,Falta, and Rudinger, Uberdie Wechselwirkung der Driisen mit innerer Sekretion.

II. Ztschr. f. klin. Med., 67, 1900.

Erb, Zur Lehre von der Tetanic. Arch. f. Psychiat., 4, 271, 1874.
Erdheim, J., Morphologische Studien iiber die Beziehung der Epithelkorperchen zum

Kalkstoffwechsel. V. Frankf. Ztschr. f. Pathol., 7, 295, 1911.
— Tetania parathyreopriva. Mitt. a. d. Grenzgeb. d. Med. u. Chir., 16, 632, 1906.
— tiber Epithelkorperchenbefunde bei Osteomalazie. Sitzungsb. d. k. Akad. d. Wissensch.

Wien, 1907, 311. • Math.-naturw. Cl.

— Morphologische Studien iiber die Beziehungen der Epithelkorperchen zum Kalk-
stoffwechsel. I. Frankf. Ztschr. f. Path., 7, 176, 1911.
Escherich, Th., Die Tetanic der Kinder. Holder, Wien, 1909.
Escherich, Th. and v. Wagner, see Escherich.

Ewald-Jacobson, tiber Tetanic. 12. Kongr. f. innere Med. S., 298.
Falkenberg, Zur Exstirpation der Schilddriise. X-Kongress f. innere Med. Wiesbaden,

1891, 502.
Falta, Weitere Mitteilungen iiber die Wechselwirkung der Driisen mit innerer Sekretion.

Wien. klin. Wchenschr., 30, 1909.
— Ein Fall von Insufficience pluriglandulaire. Mitt. d. Gesellsch. f. innere Med. u.

Kinderh. Wien, 1910, 24.

Falta and Kahn, Studien iiber Tetanic, etc. Ztschr. f. klin. Med., 1911.
Falta, Newburgh, and Nobel, tiber die Wechselwirkung, etc. IV. Ztschr. f. klin. Med., 72,

191 1.
Falta and Rudinger, Klinische und experimentelle Studie iiber Tetanic., 226. Kongr. f.

innere Med. Wiesbaden, 1909.
Peer, Die idiopathischen Krampfe (Spasmophilie) des friihen Kindesalters. Cor.-Bl. f.

schweiz. Aerzte, 1908, Nr. 22, 714.

PARATHYROID GLANDS 613

Fellner, Uber die BeziehUngen innerer Krankheiten zu Schwangerschaft, Geburt und

Wochenbett. Deuticke, Leipzig u. Wien., 1903.
Ferranini, Histologische Veranderungen des Zentralnervensystems und des Magens bei

Tetanic des Magens. Zentralbl. 2. innere Med., 1901, i.
Finkclstcin, //., Jahrb. d. Sauglingskr., I., 2., Teil. S., 239.
Fleiner, Uber Neurosis gastrischen Ursprungs. Arch. f. Verdauungskr., i, u. 5.
— Neue Beitrage zu der Tetanic gastrischen Ursprungs. Deutsche Ztschr. f. Nervenh.,

18, 243, 1900.

— Uber Tetania gastrica. Miinchen. med. Wchenschr., 1903, Nr. 10 u. n.
Fleischmann, L., Die Ursache der Schmelzhypoplasien. Oesterr.-ungar. Vrtljschr. f.

Zahn., 25, 1909.

Fraisseix, Goitre exopht. et Tetanic. These de Paris, 1900.
Frankl-Hochivart, v., Die Tetanic. II. Aufl. Wien, 1907, Holder.
— Die Prognose der Tetanic der Erwachsenen. Neurol. Centralbl., 14, u. 15, 1906.
Freund, E., Uber die Beziehungen der Tetanic zur Epilepsie und Hysteric, etc. Deutsches

Arch. f. klin. Med., 76, 1903.

Freund, H., Zwei seltene Falle von Tetanic. Miinchen med. Wchenschr., 1898, Nr. 39.
Fries, Wien. klin. Wchenschr., 1907, 150.
Frohlich, A . and O. Loewi, Scheinbare Speisung der Nervenfaser mit mechanischer Erreg-

barkeit seitens ihrer Nervenzelle. Centralbl. f. Physiol., 21, Nr. 9.
Fucks, A., Wien.. med. Wchenschr., 1911, Nr. 29-31.
— Die Messung der Pupillengrosse. Wien, 1904, 120.
Ganghofner, Ztschr. f. Kinderh., 12, 1891, u. 1901.

Garre, Epithelkorperchentransplantation. Verhandl. d. deutsch. Gesellsch. f. Chir., 1908.
Gerhardt, Mitteil. in der Gesellsch. der Charitearzte. Berl. klin. Wchenschr., 36, 1886.
Gley, Sur les effets de 1'extirpation du corps thyreoid. Compt. rend. soc. de biol., 1891, u.

Arch. d. Physiol. norm. u. path., 1892, 1893 u. 1897.
Grosser, P. and R. Petke, Epithelkorperchenuntersuchungen mit besonderer Beriicksichti-

gung der Tetania infantum. Ztschr. f. Kinderh., i, 458.
Haberfeld, Die Epithelkor'perchen bei Tetanic, etc. Arch. f. path. Anat. [etc.], Berl., 203,

283, 1911.
Haberfeld, W. and P. Schilder, Die Tetanic des Kaninchens. Mitt. a. d. Grenzgeb. d.

Med. u. Chir., 20, 1909.
Hagenbach, Exper. Studie liber die Funktion der Schilddriise und der Epithelkorperchen.

Mitt. a. d. Grenzgeb. d. Med. u. Chir., 18, 1907.
Halstead, W. S., The transplantation of parathyroid glands in dogs. Proc. Path. Soc.,

Phila., und J. Exper. M., 5, 74, 1908, and Auto- and iso-transplantation in dogs

of the parathyroid glandules. J. Exper. M., n, 175, 1909.
Hanke, V., Cataract, Neuritis optica, Degeneration des Pigmentepithels der Irishinter-

flache bei Tetanic. 24. Versannul d. Ophthalm. Gesellsch. Heidelberg, 1908, 329.
Becker, Gesellsch. f. Naturheilk. in Dresden. Miinchen. med. Wchenschr., 1906, 2225.
Hirsch, R., Glykosurie nach Schilddriisenextirpation bei Hunden. Ztschr. f. exper.

Path. u. Therap., 3.

Hirschl, Wien. klin. Wchenschr., 1904, 608.

Ho/mann, Deutscher. Arch. f. klin. Med., 43, 109, 1888. (Fall 13.)
— Zur Lehre von der Tetanic. Arch. f. path Anat. [etc.], Berl., 43, 53, 1888.
Horsley, V., Die Funktion der Schilddriise, etc. Festschr. f. Yirchow I., Berlin, 1891.
Hulst, Ein Tumor der Gland, parathyr. Centralbl. f. allg. Path. u. path. Anat., 16, 103.
Ibrahim I., Uber Tetanic der Sphinkteren der glatten Muskeln und des Herzens bei

Sauglingen. Deutsche. Ztschr. f. Nervenh., 41, 1911.
Iddo and Sarles, cited by Mac Callum und Vogtlin.

6 14 LITERATURE

Iscliii, II.. Tetanic jugendlicher Ratten, etc. Deutsche Zeitschr. f. Chir., 93, 397, 1908.
Jacobi, Struma und Tetanic. Wien. klin. Wchenschr., 768, 1904 und Ztschr. f. Nerven-

heilk, 32, 1907.

Jaksch, v., Klinische Beitrage zur Tetanic. Ztschr. f. klin. Med., 1890.
Jeandelize, Insuffisance thyre'iodienne et parathyreiodienne. These de Nancy, 1902.
Jorgensen, G., Uber die Bedeutung der pathologisch-anatomischen Yeranderungen der

Glandulae parathyreoidae. Monatschr. f. Kinderh., 10.
Kashida, A'., Uber Tetanic. Mitth. a. d. med. Fac. d. k. jap. Univ., Tokio, 5, 1904,

Heft 3.
Kasparek, Ein Fall von Tetanic mit Intentionskrampfen. Wien. klin. Wochenschr.,

1890, 850.
Kassowitz, Uber Stimmritzenkrampf und Tetanic im Kindesalter. Wein. med. Wchensch,

13, 1893-

—Tetanic und Autointoxikation. Wien. med. Presse, 5, 1897.
Kinnicutt, E. P., A clinic study of the therap. value of the calc. salts in gastr. tet. Am.

J. M. Sc., July, 1910.

Kocher, Cor.-Bl. f. schweiz. Aerzte., 19, 1909.

Kocher, Th., Referat on die Schilddriise. Kongr. f. innere Med., 1906.
Konigstein, Wien. klin. Wchenschr., I9o6t 779.
Koeppe, Monatschr. f. Kinderh., 6, 510.

Kohn, Die Epithelkorperchen. Ergebn. d. Anat. u. Entwicklungsgesch. 1899 u., 1900.
Krabbel, Zur Behandlung der Tet: parathyreopr., etc. Beitr. z. klin. Chir., 72, 505,

1911.

Kraepdin, Zur Myxodemfrage. Neurol. Centralbl., 3, 71, 1890.
Krajewska, La tetanic des femmes osteomalac. 16. Internal, med. Congr. n, Budapest,

1910, 418.
Kukein, Ein Fall von latenter Tetanic bei hochgradiger Erweiterung des Magens infolge

karzinomatoser Pylorusstenose. Berl. klin. Wchenschr., 1898, 989.
Kunn, Uber Augenmuskelkrampfe bei Tetanic. Deutsche med. Wchenschr., 1897,

Nr. 26.
Kussmaul, Uber die Behandlung der Magenerweiterung durch eine neue Methode mittelst

der Magenpumpe. Deutsches Arch. f. klin. Med., 6, 481, 1869.
Lanz, Cachexia und Tetania thyreopriva. Centralbl. f. Chir., 1905, 339 und Volkmanns

klin. Vortrage, 87.
Leischner and Kdhler, Uber homoioplastische Epithelkorperchen- und Schilddriisen-

verpflanzung. Arch. f. klin. Chir., 94, 169, 1910.
Leopold and v. Reuss, Uber die Beziehungen der Epithelkorperchen zum Kalkbestand

des Organismus. Wien. klin. Wchenschr., 1908, 1343.
Levi, Riv. crit. de med., 1906, Nr. 39.
Loeb, Arch. f. d. ges. Physiol., 91, 248, 1902.
Lowental and Wiebrecht, Uber die Behandlung der Tetanic mittels Nebenschilddriisen-

praparaten. Deutsche Ztschr. f. Nervenh., 31, 414, 1906.
Lundborg, Spielen die Glandulae parathyreoideae in der menschlichen Pathologic eine

Rolle? Deutsche Ztschr. f. Nervenh., 27, 217, 1904 und Centralbl. f. Nervenh.

in Psychiat., 1905.
MacCallum, Die Beziehung der Parathyroiddriisen zur Tetanic. Centralbl. f . allg. Path.,

76, 385, 1905.
MacCallum and Voegtlin, On the relation of tetany to the parathyroid glands and to

calcium metabolism. J. exper. M., n, 1909.
Mader, Uber die Beziehung der Beschaftigungskrampfe zur Tetanic. Wien. med. Bl., 16,

1883.

PARATHYROID GLANDS 615

Mager, tlber das Fazialisphanomen bei der Enteroptose. Wien. klin. Wchenschr., 1906,

1434-

Marburg, 0., Zur Path, der Myasthenia gravis. Ztschr. f. Heilk., 28, no, 1907.
Marinesco, Tetanic d'origine parathyroid. Semaine med., 25, 289, 1905.
Mattauschek, E., Zur Epidemiologie der Tetanic. Wien. klin. Wchenschr., 1907, 470.
McCarrison, R., Epidemic Tetany in the Gilgit valley. Lancet 10, June, 1911.
Meltzer, S., Inhibition. N. York M. J., 13, 20, 27, 1899.
Meinert, Tetanic in der Schwangerschaft. Arch. f. Gynaek., 30, 444, 1887.
Meyer, E., Uber die Behandlung der Graviditatstetanie mit Kalksalzen. Therap.

Monatsh., 7, 1911.
Miller, J., Mitteilungen aus der Klinik des Prof. Seitz in Munchen. Schuster-krampf

Deutsche Klin., 28, 1858.

Morel, Les parathyroi'des dans 1'osteogenese. Compt. rend. soc. de. biol., 68, 163, 1910.
Moussy, Recherches sur le function thyreoidienne et parathyreoidienne. Paris, 1887,

s. a. Compt. rend. soc. de. biol., 1892 u. 1897, 271.

Miiller, F., Tetanic bei Dilatatio ventriculi. Charite.-Ann., 13, 273, 1886.
Munk, H., Untersuchungen iiber die Schilddruse. Ber. Preuss. Akad., 1887 u. 1888.
Murdoch, Consideration sur le retraction spasmodique. J. univ. et hebd. de m6d. et

chir. prat., 8, 417, 1842.
Narbut, Ein durch Lumbalpunktion geheilter Fall von Tetanic. Cited in Centralbl. f.

Chir., 1907, 1147.

Neumann, Zwei Falle von.Tetania gravidarum. Arch. f. Gynaek., 48, 499, 1895.
Neurath, R., IJber die Bedeutung der Kalziumsalze fiir den Organismus des Kindes, etc.

Ztschr. f. Kinderh., i, 1910.
Novak, I., Die Bedeutung des weiblichen Genitales fiir den Gesamtorganismus. Noth-

nagel's Suppl. Deuticke, Wien u. Leipzig, 1912.
Orzechowski, Die Tetanic mit myoton. Symptomen. Jahrb. f. Psychiat. u. Neurol., 29,

1909..
Palliard, Ulcere sample avcc dilatation de 1'estomac. Tetanie intense. Rev. de med.,

1888, 46.
Parhon and Urechie, Recherches sur 1'influence exercee par les selles de calcium et de

sodium sur Involution de la tetanic experimentale. Revista stiin^elor Medicale,

1907, Nr. 7-8.
Payr, E., Transplantation von Schilddrusengewebe in die Milz, etc. Arch. f. klin. Chir.,

80, 730, 1906.

Pepere, Le ghiandole parathyr. Turin, 1906.
— Reference Centralbl. f. Path., 17, 313, 1906.
Peters, A., Tetanie und Starbildung. Bonn, 1898.
— Weitere Beitrage iiber Tetanie und Starbildung. Zschr. f. Augenh., 5, 89, 1901;

see also Pathologic der Linse, Lubarsch-Ostertag. Ergebnisse. Morph. u. Path.

der Sinnesorgane, 1906, 502.
Pfei/er, H. and 0. Meier, Experimentelle Beitrage zur Kenntnis der Epithelkorperchen-

funktion. Mitt. a. d. Grenzgeb. d. Med. u. Chir., 18, 377, 1907.
Pick, Tetanie and Graviditat. Gynaek. Gesellsch. in Wien., reference in Centralbl. f.

Gynak., 1902, 1312.

• — Beitrage zur Pathogenese der Tetanie. Neurol. Centralbl., 1903, 754.
Pineles, F., Klinische und experimentclle Beitrage zur Physiologic der Schilddruse und der

Epithelkb'rperchen. Mitt. a. d. Grenzegeb. f. Med. u. Chir., 14, 1904.
— Uber die Funktion der Epithelkorperchen. Sitzungsbr. d. k. Akad. d. Wissensch.

113, 1904 und 117, 1908.

616 LITERATURE

— Zur Pathogenese der Tetanic. Deutsches Arch. f. klin. Med., 85, 1906.
— Tetaniestar, etc. Wien. klin. Wchenschr., 1906, 691.
— Zur Pathogenese der Kindertetanie. Jahrb. f. Kinderh., 66, 1907.
— Behandlung der Tetanic mit Epithelkorperchenpraparaten. Arb. a. d. neurol. Inst.

Wien, 1907.

— t)ber parathyreogenen Laryngospasmus. Wien. klin. Wchenschr., 1908, 643.
Pirquet, v., Die anodische Ubererregbarkeit der Sauglinge. Wien. med. Wchenschr.,

1907, Nr. i.

Pool, Tetany parathyreopriva. Ann. Surg., Oct., 1907.
Popper, Dyspnoe bei Tetanic. Arch. f. Kinderh., 18, 198, 1895.
Popetschnigg, Cited by Escherich.

Proescher, F. and Th. Diller, A fatal case of tetany with autopsy findings showing hemor-
rhages in the parathyreoid glands. Am. J. Med. Sc., 143, 696, 1912.
Quervain, F. de, Uber Veranderungen des Nervensystems bei experimenteller Cachexia

thyreopriva. Arch. f. path. Anat. [etc.], Berl., 133, 1893.

Quest, Jahrb. f. Kinderh., 61, 114. 1905 und Wien. klin. Wochenschr., 1906, 830.
Redlich, E., Tetanic und Epilepsie. Monatschr. f. Psychiat. u. Neurol., 30, 4, 39. 1911.
Rosenstern, Kalzium und Spasmophilie. Jahrb. f. Kinderh., 72, 2.
Roussy and Clunet, Les parathyreoides dans 4 cas de M. de Parkinson. Compt. rend. soc.

de biol., 7, 1910.
Rudinger, C., Zur Atiologie und Pathologic der Tetanic. Ztschr. f. exper. Path. u.

Pharmakol., 5, 1908.
— Physiologic und Pathologic der Epithelkorperchen. Ergebn. d. innere Med. u. Kinderh.,

1909.
Rudinger and Jonas, "Dber das Verhaltnis der Tetanic zur Dilatatio ventriculi, 1904.

Wien. klin. therap. Wchenschr.
Sabbatani, Riv. sper. di freniat. 27, 946, 1901.
Sachs, B., Lehrbuch der Nervenkrankheiten des Kindesalters. Leipzig u. Wien., 1897,

132.
Saiz, Giov, Beitrag zum Vorkommen und zur Behandlung der Tetanic. Wien. klin.

Wchenschr., 1908, Nr. 38.
Sandstrom, Uber eine rieue Druse beim Menschen, etc. Reference in Jahresb. ii. d.

Fortschr. d. Anat. u. PhysioL, 9, i, Abt.

de Santi, Parathyr. Geschwulst. Centralbl. f. Laryngol. u. Rhinol., 1900, 546.
Schieferdecker and Schultze, Beitr. zur. Kenntnis der Myotonia congenita, etc. Deutsche

Ztschr. f. Nervenh., 25, i, 1904.
Schiff, M., Bericht iiber eine Versuchsreihe betr. die Wirkungen der Exstirpation der

Schilddriise. Arch. f. exper. Path. u. Pharmakol., 18, 1884.
Schlesinger, H., Ein bisher unbekanntes Symptom bei der Tetanic (Beinphanomen).

Wien. klin. Wochenschr., 1910, 315; see also Neurol, Centralbl., 1910, 626.
Schlesinger, Versuch einer Theorie der Tetanic. Neurol. Centralbl., 1892, 66.
Schmiedlechner, Ein Fall von Tetania gravidarum. Centralbl. f. Gynak., 1905, 100.
Schmorl, Miinchen. med. Wchenschr., 1907, 497.
Schonborn, Klinisches zur menschlichen Tetanic, etc. Deutsche Ztschr. f. Nervenh.,

40, 1910.
Schreiber, L., Beitrage zur Kenntnis der Entwicklung und des Baues der Gl. parathyr.

Arch. f. mikr. Anat., 52, 1908.

Schuller, Rachitis tarda and Tetanic. Wien. med. Wchenschr., 1909.
Schultze, Uber Tetanic und mechanische Erregbarkeit der peripheren Nervenstamme.

Deutsche med. Wchenschr., 1882, 276.

PARATHYROID GLANDS 617

Segale, M., Sull' ablazione delle thyrioidie delle parathyroidi. Arch, per le sc. med., 30,

1906.

Sperber, E., Tetaniecatar,act. Arch. f. Augenh., 54, 386, 1906.
Spiegler, Protokol, Gesellsch. d. Aertze. Wien. klin. Wchenschr., 1909, 357.
Steinlechner, Uber das gleichzeitige Vorkommen von Morbus Basedowi und Tetanic bei

einem Individuum. Wien. klin. Wchenschr., 1896, 5.
Stewart, Tetany. Tr. Ass. Am. Physicians, 1889, 33.

Strada, Le Paratyroidi nell' ostomalacia e nell' osteoporosi Patologica., 17, 1909.
—Tetanic und Epithelkorperchen. Riv. di clinica Pat., Dec., 1909.
Stumme, Ein Fall von Basedow mit Tuberkulose einer Glandula parathyreoidea. Deutsche

Ztschr. f. Chir., 90, 1907.
Thiemich and Birk, cited by Escherich.
Todyo, R., Uber das Verhalten der Epithelkorperchen bei Osteomalazie und Osteoporose.

Frankf. Ztschr. f. Path., 10, 219, 1912.
Ujffenheimer, Ein neues Symptom bei latenter und manifester Tetanic des Kindesalters,

das Tetaniegesicht. Jahrb. d. Kinderh., III. F., 12, 1895.
Underhill, Frank P. and Tadasu Saiki, The influence of complete thyreoidectomy, etc.

J. Biol. Chem., 5, 1908.
Vassale and Generali, Sur les effets de 1'extirpation des Glandes parathyreoides. Arch.

ital. de biol., 25, 459, 26, 61, 1896, 33, 1906.
Vassale, Tetania da allattamento in una cagna pazialmente parathireoidectomizzata.

Riv. sper. di freniat, 27, 1901.
Verdun, Contribution a l'6tude des derives "branchiaux, etc. These de doctorat des

sciences, Paris, 1898.
v. Verebely, Beitrage zur Pathologic der branchialen Epithelkorperchen. Arch. f. path.

Anat. [etc.], Berl., 187, 1907.
Voegtlin, C. and Mac Callum, On the influence of various salts upon tetany following

parathyroidectomy. J. of Pharmak. and exper. Therap., 2, Nr. 5, 1911.
Voss, v., Tetanic und myotonische Storungen. Monatschr. f. Psychiat. u. Neurol., 8,

85, 1903.

v. Wagner, cited by Escherich. . \
Weber, Miinchen med. Wochenschr., 1905, 1608; Rheinisch-westphal. Gesellsch. f. innere

Med. u. Nervenh.

Weiss, Natan, Uber Tetanic. Volkmanns Vortrage VII, 1881, 189.
Welsh, R., On the parathyroid glands, etc. J. Path, and Bacteriol., 5, 1898.
Westphal, Zur Lehre von der Tetanic. Berl. klin. Wchenschr., 1901, 849.
Wiener, H., Uber die Art der Funktion der Epithelkorperchen. Arch. f. d. ges. Physiol.,

136, 107, 1910.
Wirtk, K., Die Tetanie und ihre Bedeutung fur die Chirurgie. Centralbl. f. d. Grenzgeb.

d. Med. u. Chir., Novemb., 1910.
Yanasse, Uber Epithelkorperchenbefunde bei galvanischer Ubererregbarkeit der Kinder.

Wien. klin. Wchenschr., 1907, Nr. 39, u. Jahrb. d. Kinderh., 67, 1907.
Zanfrognini, Eclampsia e anomalia parathyreoidea congenita. 1st. ostet. d. r. Univ. di

Geneva, 1905.
Zirm, E., Zur Tetaniecatarakt. Arch. f. Augenh., 52, 183, 1905.

CHAPTER V

THYMUS

Anton, G., Uber den Thymustod. Wien. klin. Wchenschr., 1912, Nr. 27.

Bang, Ivar, Chemische Untersuchungen der lymphatischen Organe. Beitr. z. chem. Phy-

siol., 4 u. 5, 1904.

Basch, Die Beziehung der Thymus zum Nervensystem. Jahrb. f. Kinderh., 58, 1908.
— Beitrage zur Physiologic und Pathologic der Thymus. Jahrb. f. Kinderh., 64, 1906.
Biedl, Innere Sekretion. Wien, Urban u. Schwarzenberg, 1910.
Bircher, Fortfall und Anderung der Schilddriisenfunktion als Krankheitsursache. Lub-

arsch-Ostertags Ergebn., 15, 82, 1911.

Bischof, Th., Entwicklungsgeschichte der Saugetiere und des Menschen. Leipzig, 1842.
Bournemlle, Comparaison entre les enfants normaux et les enfants anormaux au point de

vue de la persistance ou de 1'absence du thymus. Progres med., 29, 389, 1900.
Bramwell, A case of intrathoracic tumor (lymphosarcoma) with secondary deposit in the

suprarenal capsule. Brit. M. J., i, 8, 1877.
Calzolari, Recherches experiment, sur un rapport probable entre la fonction du thymus et

celle des testicules. Arch. itai. de biol., 30, 1898.

Clark, A case of absence of the thymus gland in an infant. Lancet, 74, 1077, 1896.
Cozzolino, Intorno agli effeti dell'estirpazione del timo nei giovani conigli. Pediatria.

Anno, n, 144, 1903.

Farret, Contribution a 1'etude du thymus chez 1'enfant. These de Paris, 1896.
Friedlander, Status lymphaticus and enlargement of the thymus with report of a case

successfully treated by the X-rays. Arch. Paediat., 24, 490, 1907.
Friedleben, Die Physiologic der Thymusdriise. Frankfurt a. M., 1858.
v. Ghika, Etude sur le thymus. These de Paris, 1901.
Grawitz, Uber plotzliche Todesfalle im Sauglingsalter. Deutsch. med. Wchenschr.,

188, Nr. 22.
Hammar, Zur grb'beren Morphologic und Morphogenie der Menschenthymus. Anat.

Hefte, 43, 203, 1911.
— Uber Gewichtsinvolution und Persistenz der Thymus im postfotalen Leben. Arch. f.

Anat. u. Physiol. Suppl., 1906, 91.
— 50 Jahre Thymusforschung. Kritische Ubersicht der normalen Morphologic. Ergebn.

d. Anat. u. Entwicklungsgesch., 19, i, 1910.

Hammer, Uber Thymuserkrankungen und Thymustod. Inaug.-Diss. Freiburg, 1903.
Hart, Uber Thymuspersistenz und apoplektiformen Thymustod, etc., Miinchen. med.

Wchenschr., 1908, 669 u. 744.
—Thymuspersistenz und Thy mush yperplasie. Mitt. a. d. Grenzgeb. d. Med. u. Chir.,

12, 321 u. f., 1909.
Hart and Nordmann, Experimented Studien iiber die Bedeutung der Thymus, etc. Berl.

klin. Wchenschr., 1910, 814.

Hendersson, On the relationship of the thymus to the sexual organs. J. Physiol., 31, 1904.
Hedinger, E., Mors thymica bei Neugeborenen. Jahrb. f. Kinderh., 63, 1906 and Deutsches

Arch. f. klin. Med., 85, 1905 u. 86, 1906.
Hinrichs, Behinderung der Atmung und der Nahrungsaufnahme durch eine zu grosse

Thymus bei einem 10 jahrigen Kinde, Operation, Heilung. Inaug.-Diss., Leipzig,

1907.

618

THYMUS 619

His, Uber den Sinus praecervicalis und iiber die Thymusanlage. Arch. f. Anat. u. Phy-

siol., 1886. Anat. Abt., 421.
Jonson, Studien iiber die Thymusinvolution; die akzidentelle Involution bei Hunger.

Arch. f. mikr., Anat., 73, 390, 1909.

Katz, Quelques recherches sur le thymus chez 1'enfant. Progres med., 29, 385, 1900.
Klose and Vogt, Klinik und Biologic der Thymusdriise. Tubingen, 1910.
Konig, Teilweise Exstirpation der Thymusdriise, etc. Centralbl. f. Chir., 1897, Nr. 24.
Kopp, Denkwiirdigkeiten der arztlichen Praxis. Frankfurt a. M., 1838.
v. Kundrat, Zur Kenntnis des Chloroformtodes. Wien. klin. Wchenschr., 1895, Nr. 1-4.
Langerhans and Saveliew, Beitrage zur Physiologic der Thymusdriise. Arch. f. path.

Anat. [etc.], Berl., 134, 344, 1893.
Maximow, Untersuchungen iiber Blut und Bindegewebe. II. Uber die Histogenese der

Thymus bei Saugetieren. Arch. f. mikr. Anat., 7 u. 74, 1909.

Marburg, Zur Pathologic der Myasthenia gravis. Ztschr. f. Kinderheilk., 28, no, 1907.
Matti, H., Untersuchungen iiber die Wirkung experimenteller Ausschaltung der Thymus-
driise, etc. Mitt. a. d. Grenzgeb. d. Med. u. Chir., 24, 665, 1912.
Myers, Congenital laryngeal stridor apparently due to an enlarged thymus gland, etc.

Arch. Pediat., 25, 607, 1908.
Ndgeli, Blutkrankheiten. Leipzig, 1907.
v. Neusser, Zur Diagnose des Status thymico-lymphaticus. Klin. Symptomatol. u.,

Diagn., 1911, Heft 4.

Ortner, Zur Klinik der Angiosklerose, etc. Wien. klin. Wchenschr., 1902.
Paltauf, A., Uber die Beziehungen der Thymus zum plotzlichen Tod. Wien. klin.

Wchenschr., 1889, Nr. 46 u. 1980, Nr. 9.
Pappenheimer, A contribution to the normal and pathological histology of the thymus

gland. J. med. Research, 22, i, 1910.

Paton, The relationship of the thymus to the sexual organs. J. Physiol., 32, 1904.
Paton and Goodall, Contribution to the physiology of the thymus. J. Physiol., 31, 49,

1904.

Perrin, Mort brusque de'neuf,fils d' un alcoholique. Ann. de med. and chir. in., 1903, 217.
Popper, Uber die Wirkungen des Thymusextraktes. Sitzungsbr. d. k. Akad. d. Wissench.

in Wien, math.-naturw. cl., 114, 539, 1905 und 115, 201, 1906.
Pott, Uber Thymusdriisenhyperplasie und die dadurch bedingte Lebensgefahr. Jahrb.

f. Kinderh., 34, 118, 1892.

Purrucker, Zur Pathologic der Thymusdriise. Miinchen. med. Wchenschr., 1899, 943.
Rachjord. The X-ray treatment of Status lymphaticus, etc. Am. J. M. Sc., 140, 550,

1910.

Ranzi and Tandler, Uber Thymusexstirpation. Wien. klin. Wchenschr., 27, 1909.
Rehn, L., Trachealstenose und Thymustod. Arch. f. klin. Med., 80, 468, 1906.
Ribadeau and Weil, Sur un cas d'hypertrophie du thymus. Bull, et mem. Soc. med d. hop.

de Par., 28, 431, 1912.
Ronconi, Comportamento del timo nell'uomo nelle varie eta della vita, etc. Path. Riv.

quindicin. Geneva anno, i, 595, 1909.
Schnitzler, Wien. klin. Wchenschr., 1894, 371.

Schriddle, Thymus. Handb. d. path. Anat., issued by Aschoff, 2, 139, 1909.
Sommer and Florcken, Uber die Funktion der Thymus. Sitzungsbr. d. physiol.-med.,

Gesellsch., Wiirzburg, 1908, 45.

Stieda, Untersuchungen iiber die Entwicklung der Glandula thymus. Leipzig, 1881.
Stohr, Uber die Natur der Thymuselemente. Anat. Hefte, 31, 409, 1906.
v. Sury, Uber die fraglichen Beziehungen der sog. Mors thymica zu den plotzlichen

62O LIJERATURE

Todesfallen im Kindesalter. Vrtljschr. f. d. ges. Med., 36, 1908, Anat. Hefte,
95, 1906.
Svehla, Uber die Einwirkung des Thymussaftes, etc. Wien. med. Bl., 1896.

— Rolle der Thymusdriise und innere Sekretion der Thymus. Miinchen. med. Wchen-

schr., 1900.
Tarulli and Lo Monacco, Sulli effeti dell' estirpatione del timo. IX. Congr. intern, med.,

Roma Fisiol., 2, 19, 1894.
Wiesel, J., Zur Pathologic des chromamnen Systems. Arch. f. path. Anat. [etc.], Berl.,

176, 103, 1904.

— Pathologic der Thymus. Lubarsch-Ostertag Ergebnisse, 15, 416, 1912.
Winslow, Exposition anatomique de la structure du corps humain. Amsterdam, 1732.

CHAPTER VI
HYPOPHYSIS

Arnold, I., Beitr. zur Akromegaliefrage. Arch. f. path. Anat. [etc.], Berl., 135, i, 1894.
Aschner and Forges, Uber den respiratorischen Stoffwechsel hypophysipriver Tiere.

Biochem. Ztschr., 39, 200, 1912.
Aschner, B., tiber einen Fall von hypoplastischem Zwergwuchs mit Graviditat nebst

Bemerkungen iiber die Atiologie des Zwergwuchs. Monatschr. f. Geburtsh. u.

Gynaek, 32, 644, 1910.

— tiber die Funktion der Hypophyse. Arch. f. d. ges. Physiol., 146, 1912 und Wien.

klin. Wchenschr., 1912.

— Demonstration hypophysektomierter Hunde. Wien. klin. Wchenschr. Dez., 1909.
Axenfeldt, Sehnervenatrophie undMenstruationsstorung. Deutsche med. Wchenschr.,

1903; Neurol. Centralbl., 1903, 608.

Bab, Pituitrin als gynakologisches Styptikum. Miinchen. med. Wchenschr., 1911, 1554.
Bab, tiber die Behandlung der Osteomalazie mit Hypophysenextrakten. Wien. klin.

Wchenschr., 191, Nr. 27, 997.

Babinski and Onanofl, Tumeur du corps pituitair. Rev. neurol., 8, 531, 1900.
Babonneix, Deformations du type acromegalique chez un jeune homme de 17 ans. Gaz.

d. Hop., 1911, Nr. 70, 1077.
Babonneix, L. and Paisseau, G., Sur quelque cas d'obesite, infantile. Gaz. d. Hop., 13,

Sept., 1910.
Bartels, M., tiber Plattengeschwiilste der Hypophyse ngegend. Ztschr. f. Augenh., 16,

1906.

Becker, Vorstellung von Nervenkranken. Neurol. Centralbl., i, 505, 1894.
Beclere, Le Radio-Diagnostic de 1'Acromegalie. Presse med. Paris, 98, 845, 1903.
Benda, C., Beitrage zur normalen und pathologischen Histologie der menschlichen

Hypophysis cerebri. Berl. klin. Wchenschr., 1900, 1205.

— tiber vier Falle von Akromegalie, Deutsche med. Wchenschr., 1901.

— Die Akromegalie. Deutsche Klinik III, 1903.

— Path. Anat. der Hypophyse. Handb. d. Path. Anat. des Nervensy stems. Berlin,

1904.
Benedict, G. and John Homans, The metabolism of the hypophysectomized dog. J. Med.

Research, 25, Nr. 3, 1912.
Bernstein and Falta, tiber die Einwirkung von Adrenalin, Pituitrinum infundibulare und

Pituitrinum glandulare auf den resp. Stoffwechsel. Kongr. f. innere Med., 1912.

(Work in detail not yet published.)
Berger, A., Ein Fall von Tumor der Hypophysengegend mit Obduktionsbefund. Ztschr.

f. klin. Med., 54, 1904.
Bertclli, Falta, and Schweeger, tiber die Wechselwirkung der Driisen mit innerer Sekre-

tion III. tiber Chemotaxis. Ztschr. f. klin. Med., Nr. 71.
Biedl, Innere Sekretion. Urban u. Schwarzenberg, Wien, 1910.
Bolaffio and Tedescho, see Falta, Wietere Beitrage Uber die Wechselwirkung der Drusen

mit innerer Sekretion. Wien. klin. Wchenschr., 1909, Nr. 30.

Bonnes, L. J., Consideration sur deux cas d' acromegalie. These de Bordeaux, 1007.

621

622 LITERATURE

Bondi. 5., Ein Fall von Ostcomalazie beim Manne. Gesellsch. f. innere Med. u. Kinderh.,

Nov., 1910.
Borchardt, L., Uber das Blutbild bei Erkrankungen der Driisen mit innerer Sekretion,

etc. Deutsches Arch. f. klin. Med., 106, 182, 1912.

— Funktion und funktionelle Erkrankungen der Hypophyse. Ergebn. f. inneren Med.

u. Kinderh., 3, 1909.

— Die Hypophysenglykosurie und ihre Beziehung zum Diabetes bei der Akromegalie.

Ztschr. f. klin. Med., 1908, Nr. 66, 332.

Bournier, R., Tumeur der 1'hypophyse, etc. Presse med. 25, Nov., 1911, 973.
Bregmann and Steinhaus, Zur Kenntnis der Geschwiilste der Hypophyse und der Hypo-

physengegend. Arch. f. path. Anat. [etc.], Bed., 188, 360, 1907.
Breuning, Wiirzburger Abhandlungen, 1909.

Breus and Kolisko, Die pathologischen Beckenformen. Wien, 1900.
Brisseau, see Launois and Roy.
Buday and Jancso, Ein Fall von pathologischem Riesenwuchs. Deutsches Arch. f.

klin. Med., 60, 1898.

Bychowski, Deutsche med. Wchenschr., 1909, 1561.
Cagnetto, G., Zur Frage der anatomischen Beziehung zwischen Akromegalie und Hypop-

hysistumor. Arch. f. path. Anat. [etc.], Berl., 176, 115, 1904, u. 187, 197, 1907.
Claude, H., Syndromes d'hyperfonctionnerhent des glandes vascularies sanguines dans

les acromegalies. Compt. rend. soc. d. biol., 57, 362, 1905.
Claude and Gougerot, Sur Finsumsance simultanee de plusieurs glandes a secretion interne.

Compt. rend. soc. de biol., 63, 785, 1907.
Cushing, Harvey, The pituitary body and its disorders. J. B. Lippincott, Philadelphia

and London, 1910.

— Die Hypophysis cerebri, etc. J. Am. M. Ass., Nr. 53, 1909, 249.

Cushing and Goetsch, Concerning the secretion of the infundibular lobe, etc. Am. J.
Physiol.

v. Cyan, Gefassdrusen, 1910, 124.

v. Dallemagne, 3 cas d'acromegalie. Arch, de med. exp. et d'anat. path, [etc.], 7, 589, 1895.

Dalton, Tr. Path. Soc., London, 1897, 1106.

Delille, A., L'hypophyse et la medication d'hypophyse, Paris, 1909.

Demmer, Demonstration Gesellsch. d. Aerzte Wiens. Wien. klin. Wchenschr., 1911, 8.

Dercum and MacCarthy, Autopsy in a case of adiposis dolorosa. Am. J. M. Sc., 1902,
994.

Dietrich, Knochen und Gelenkveranderungen bei Akromegalie. Verhandl. d. deutsch.
path. Gesellsch., 1909, 78.

Doebbelin, Pseudoakromegalie und Akromegalie. Inaug.-Diss., Konigsberg, 1895.

v. Eiselsberg, Uber operative Behandlung der Hypophysentumoren. Wien. klin. Wchen-
schr., 1907.

v. Eiselsberg and v. Frankl-Hochwart, Operative Behandlung der Tumoren der Hypophy-

sisgegend. Neurol. Centralbl., 1907, Nr. 21.

— Neuer Fall von Hypophysisoperation bei Degeneratio adiposo-genitalis. Wien.
klin. Wchenschr., 1908.

Eppinger, Falta, and Rudinger, Uber die Wechselwirkung der Driisen mit innerer Sekre-
tion. I. Ztschr. f. klin. Med., 66, i, 1908.

Erb, cited by Pel.

Erdheim, Hypophysengangsgeschwiilste. Sitzungsbr. k. Akad. d. Wissensch. Wien.
Mat.-natur. Cl. Abt., Ill, 113, 1904.

— Uber einen Hypophysentumor von ungewohnlichem Sitz. Beitr. z. path. Anat. u.

Physiol., 46, 233, 1909.

HYPOPHYSIS 623

Erdheim and Stumme, Uber die Schwangerschaftsveranderung der Hypophyse. Beitr.

2. path. Anat. u. Physiol., 46, 1909.
Exner, Beitrage zur Pathologic und Pathogenese der Akromegalie. Mitt. a. d. Grenz-

geb. d. Med. u. Cnir., 20, 1909.

— Operation bei Akromegalie. Gesellsch. d. Aertze in Wien. Wien. klin. Wchenschr.,

1909, Nr. 3.
Falta, Mitteil. d. Gesellsch. f. inn. Med. u. Kinderh. Wien, 2, 24, 1910.

— Concerning diseases that depend on disturbances of internal secretion. Am. J. M.

Sc., April, 1909.
Falta and Kahn, Klinische Studien iiber Tetanic mit besondcrer Beriicksichtigung des

vegetativen Nervensystems. Ztschr. f. klin. Med., 74, Heft i u. 2.
Falta, W., and Priestley, G. B., Beitrage zur Regulation von Blutdruck und Kohlehydrat-

stoffwechsel durch das chromaffine System. Berl. klin. Wchenschr., 1911, Nr.

47-
Falta and Nowaczynski, T., Uber die Harnsaureausscheidung bei Erkrankungen der

Hypophyse. Berl. klin. Wchenschr., 1909, Nr. 38.
Falta, Newburgh, and Nobel, Uber Beziehungen der Uberfunktion zur Konstitution.

Ztschr. f. klin. Med., 72, Heft i u. 2.
Falta and locovic, Protokoll der k. k. Gesellsch. d. Aertze Wien. Wien. klin. Wchenschr.,

17, Dez., 1909.

Fazio, Sopra un caso d'acromegalie. Riforma med. II, 1896, 399.
Fischer, B., Hypophyse, Akromegalie und Fettsucht. Wiesbaden, Bergmann, 1910.
Foges, A. L., and Hofstatter, R., Uber Pituitrinbehandlung bei post-partum Blutungen.

Centralbl. f. Gynak., 1910, Nr. 46.
Formanek, Zur Kasuistik der Hypophysengangsgeschwiilste. Wien. klin. Wchenschr.,

1909, 603.
Forschbach and Weber, Beobachtungen iiber die Harn- und Salzausscheidung im Diabetes

insipidus. Ztschr. f. klin. Med., 73, 221.
Franchini, G., Beitrag zum chemischen und histologischen Studium des Blutes bei

Akromegalie'. Berl. klin. Wchenschr., 1908, Nr. 36.
Franchini and Giglioli, Encore sur 1'acromegalie. N. Iconog. de la Salpetriere, 21, 325,

1908.
Frank, E,, Uber Beziehungen der Hypophyse zum Diabetes insipidus. Berl. klin.

Wchenschr., 1912, 393.
Frankl-Hochwart v., Die Diagnostik der Hypophysentumoren ohne Akromegalie. 16

intern, med. Kongr. Budapest, 1909.
Frankl-Hochwart v., and Frohlich, Zur Kenntnis der Wirkung des Hypophysins auf

das sympathische und autonome Nervesystem. Arch, f . exper. Path. u. Pharmakol.,

63, 347. iQio-
Frankel, Stadelmann, and Benda, Klinische und anatomische Beitrage zur Lehre von der

Akromegalie. Deutsche med. Wchenschr., 1901, 513.
Frdntzel, Uber Akromegalie. Deutsche med. Wchenschr., 1888, 32.
Freund, H. W., Uber Akromegalie. Volkmanns klin. Vortrage, 1889, Nr. 329.
Fritsche and Klebs, Beitrage zur Pathologic des Riesenwuchses. Leipzig, 1884.
Frohlich, A., Tumor der Hypophyse ohne Akromegalie. Wien. klin. Rundschau, 1901,

Nr. 47, 48.

Fuchs, Zur Friihdiagnose der Hypophysentumoren. Wien. klin. Wchenschr., 1903, 151.
Gajkiewicz, cited by Sternberg.
Gallais, A ., Gigantisme acromegalique sans elargissement de la selle turcique. Inversin

sexuelle. Feminisme mental. N. iconog. de la Salpe'triere, 1912, 124.
Candy, citation in Claude and Gougerot.

624 LITERATURE

Goetsc/i, dishing and Jacobsohn, Carbohydrate tolerance and the posterior lobe of the

hypophysis cerebri. Johns Hopkins Hosp. Bull., 22, Baltimore, June, 1911.
Goetzl and Erdheim, Zur Kasuistik der trophischen Storungen bei Hirntumoren. Ztschr.

f. Heilk, 1905.
Goldstein, Die Meningitis serosa unter dem Bild hypophysarer Erkrankung. Arch. f.

Psychiat., 47, 129, 1910.
Growe, Gushing, and Romans, Experimental hypophysectomy. Johns Hopkins Hosp.

Bull., Baltimore, May, 1910.
Haberfeld, W., Die Rachendachhypophyse. Beitr. z. path. Anat. u. Physiol., 46, 133,

1909.

Hagenbach, Osteogenesis imperfecta tarda. Frankf. Ztschr. f. Path., 6, 398.
Hahl, C., Die Verwendbarkeit des Pituitrins in der Geburtshilfe. Arb. a. d. geburtsh.-

gynaekol. Univ.-Klin. Helsingfors, 1912, Verlag Bergmann.
Halliburton, W. D., Candler, J. P., and Sikes, J. P. The human pituitary body. J.

Physiol., 38, 1909, and Proc. Physiol. Soc. Lond., 1908-9, p. xxxvii.
Hamburger, W. W., Action of extracts of the anterior lobe of the pituitary gland upon

the blood-pressure. Am. J. Physiol., 26, 178, 1910.
Hanau, A., Verhandl. des X. internat. Kongr. Berlin, 2, 128.
Hansemann, Uber Akromegalie. Berl. klin. Wchenschr., 1897, 417.
Hirsch, 0., Uber Methoden der operativen Behandlung von Hypophysistumoren auf

endonasalem Wege. Arch. f. Laryngol., 24, 1910. Also: Die operative Behand-
lung von Hypophysentumoren. Arch. f. Laryngol u. Rhinol., 26, 1912.
Hochenegg, Zur Therapie von Hypophysistumoren. 37 Kongr. d. Gesellsch. f. Chir.,

1908, 80. Wien. klin. Wchenschr., 1908, 891. Ztschr. f. Chir., Nr. 100, 317.
Hofbauer, Hypophysenextrakt als Wehenmittel. Ztschr. f. Gynak., 1910, 137.
Hof st&tter, Pituitrin als Blasentonicum. Wien. klin. Wchenschr., 1911, 1702.
Howell, W. H., The physiological effects of extracts of the hypophysis cerebri, etc. J.

exper. M., 3, 1898.
Hueter, C., Hypophysistuberkulose bei einer Zwergin. Arch. f. path. Anat. [etc.], Berl.,

182, 1905.

Humphrey, A case of acromegaly with hypertrophical heart. Brit. Med. J., 8, Oct., 1910.
Hutchinson, Woods, A case of acromegaly in a giantess. Am. J. M. Sc., 1895, II, p.

190.

Hutinel, L'acromegalie chez 1'enfant. Clinique. 15 Fevr., 1910, Nr. 8, 113.
Josef sohn, Studier ofver Akromegalie och hypophysistumorer. Neurol. Centralbl., 1904,

727. _
Kepinow, Uber Synergismus von Hypophysisextrakt und Adrenalin. Arch. f. exp.

Path, und Pharmakol., 67, 247, 1912.
Klebs, Allg. Path. 2, Jena, 559, 1897.
Kocher, T., Ein Fall von Hypophysistumor mit operativer Heilung. Ztschr. f. Chir.,

100, 13, 1909.
Kollarits, Hypophysentumor ohne Akromegalie. Deutsche Ztschr. f. Nervenh., 28, 88,

1905.

Kon, Jutaka, Hypophysenstudien. Beitr. z. path. Anat. u. Physiol., 44, 233, 1908.
Konig, Fr., Beschreibung eines kindlichen Beckens und kindlicher Geschlechtsteile.

Inaug.-Diss. Marburg, 1855.
Kumett, R., Zur Kenntnis der Geschwiilste der Hypophysengegend. Munchen med.

Wchenschr., 1911, 1293.
Launois and Cleret, Le syndrome hypophysaire adiposo-genital. Gaz. d. Hop., 1910,

Nr. 5 and 7.
Launois and Roy, Etudes biologiques sur les geants. Paris, 1909, Masson.

HYPOPHYSIS 62$

Glycosurie et hypophyse. Arch. gen. de med., 5 Mai, 1903.

Lecene, M. P., Intervention chirurgicale sur 1'Hypophyse. Presse med., 1909, Nr. 85.

Lemann and van Wart, A case of infantilism with absence of thyreoid and tumor of pit-
uitary. Arch. Int. Med., May, 5, 519, 1910.

Levi, E., Contribution a 1'etude de Pinfantilisme du type Lorain. N. Iconogr. de la

Salpetriere, 21, 297 et 421, 1908.
— Rivist. crit. di din. med., 10, 1909.

Levi and Rothschild, Contribution and 1'opotherapie hypophysaire. Soc. de neurol. 7
Fevr., 1907.

Loeb, Beitrage zur Lehre vom Diabetes mellitus. Centralbl. f. innere Med., 1898, 893.

Lorand, Pathogenic du diabete dans 1'acromegalie. Compt. rend. soc. de biol., Nr. 56,
554-

Madelung, Uber Verletzungen der Hypophysis. Centralbl. f. klin. Chir., 1904, 1067.

Magnus-Levy, Der Einfluss von Krankheiten auf den Energiehaushalt im Ruhezustand.
Ztschr. f. klin. Med., 60, 1906.

Magnus and Schafer, The actions of pituitary extract upon the kidney. J. Physiol.,
27, 1901, 1902.

Mar anon, G., Lesiones della Hypofisis en un caso de obesidad a hipoplasia genital. Bol.
Soc. espan. de Biol., 1911, Nr. 6.

Marburg, Die Adipositas cerebralis, etc. Deutsche Ztschr. f. Nervenh., 36, 114, 1004.

Marek, cited by /. Novak.

Marinesco and Goldstein, Deux cas d'hydrocephalie avec adipos. generalisee. N. iconogr.
de la Salpetriere, etc., 22, 1909.

Marie, Pierre, Sur deux cas, d'acromegalie, etc. Rev. d. med., 6, 297, 1886 and L'acromS-
galie. N. iconogr. de la Salpetriere I, 173, 229, 1888 und 2, 45, 96, 139, 188, 224,
327, 1889 und Sur deux types de deformation des mains de 1'acromeg. Arch, de
med. exper. et anat. path, [etc.], 1891, 539.

Marie and Marinesco, Sur Panat. path, de 1'acromegalie. Arch. d. med. exper. et d'anat.
path, [etc.], 1891.

Massalongo, R., Hyperfuriktion der Hypophyse, Riesenwuchs und Akromegalie. Cen-
tralbl. f. Nervenh. u. Psychiat., 1895, 281.

Mayer, E., Uber Beziehungen zwischen Keimdriise und Hypophyse. Arch. f. Gynaek.,
90, 600, 1910.

Mendel, reference in Deutsche med. Wchenschr., 1906, 1975.

Meyer, E., Uber Diabetes insipidus, etc. Deutsches Arch. f. klin. Med., 83, i.

Messedaglia, Studio sulla akromegalia. Padova, 1908.

Mihalkovics, Arch. f. mikr. Anat. u. Embryol., II, 1875.

Miller and Dean Lewis, The frequency of experimental glycosuria following injections of
extracts of the hypophysis. Arch. Int. Med., May, 1912, 601.

Mixter and Quacqenboss, Tumor of the hypophysis with infantilism. J. Surg., 52,
July 15, 1910.

v. Moraczewski, Stoffwechsel bei Akromegalie, etc. Ztschr. f. klin. Med., 43, 336, 1901.

Mosse, G., Deformations acromegaloides. Soc. de Neurol., Mai, 1911, 646.

Moskowicz, Wien. klin. Wchenschr., 1909, 474.

Miiller, E., Uber die Beeinflussung der Menstruation durch zerebrale Herderkrankungen.
Neurol. Centralbl., 1905, 790.

Naunyn, Der Diabetes mellitus. Holder, Wien, 1896.

Nazari, Contribute allo studio anatomic-patologico delle ciste dell' ipofisi cerebrale
e dell' infantilismo. Policlino, 1906, 445.

Neu, Uber einen durch Pituitrin giinstig beinflussten Fall von Osteomalazie. Cen-
tralbl. f. Gyna'k., 1911, 12.
40

626 LITERATURE

\cnrath, R., tJber Fettkinder, etc. Wien. klin. Wchenschr., 2, 1911.
v. Noorden, Die Zuckerkrankheit. Y. Aufl. Hirschwald, Berlin, 1910.
— Die Fettsucht. II. Aufl. Holder, Wien, 1910.
Novak, J., Die Bedeutung des weiblichen Genitales fiir den Gesamtorganismus. Noth-

nagel Suppl.-Bd., 1912.
Olliver and Schafer, On the physiol. action of extracts of pituitary body. J. Physiol., 18,

277, 1895.
Oppenheim, Diskussion zum Vortrag von Cassierer in Berl. Gesellsch. f. Neurol. u.

Psychiat., 13, Nov., 1899. Arch. f. Psychiat., 34, 303, 1901.
Oft and Scctt, The action of infundibulin on the mammary secretion. Proc. soc. exper.

Biol. and Med., 8, 48, 1911.
Pal, J., Diskussion in der k. k. Gesellsch. d. Aerzte Wien. Sitz. vom 9, Juni, Wien.,

klin. Wchenschr., 1912, Nr. 24, 938.

— tiber die Gefasswirkung des Hypophysenextraktes. Wien. med. Wchenschr., 1909, 3.
Paltauf, A., Der Zwergwuchs in gerichtlicher und anatomischer Beiziehung. Wien,

1891.
Paltauf, R., Discussion on Aschner's Lecture before the Wien. Gesellsch. der Aerzte, Dec.,

1909.

Paulesco, L'hypophyse du cerveau. Paris, 1908. Vigot freres.
Pechkrantz, Zur Kasuistik der Hypophysentumoren. Neurol. Centralbl., 1899, Heft

5 u. 6.

Pel, Acromegalie partielle avec infantilisme. N. icongr. de la Salpetriere, 19, 76, 1906.
Pineles, F., Die Beziehungen der. Akromegalie zum Myxodem und anderen Blutdrii-

senerkrankungen. Volkmann's klin. Beitr. N. F., 1899, Nr. 422.
Pirie, A case of acromegaly. Lancet, 5, Oct., 1901, 904.
Pontick, Myxodem und Hypophyse. Ztschr. f. klin. Med., 1899, 38, i.
Rath, Beitrag zur Symptomenlehre der Geschwiilste der Hypophysis cerebri. Arch. f.

Ophth., 34, 81.
Rennie, G. E., Endotfielioma of the pituitary gland with infantilisme. Brit. M. J., June,

1912, 150.

Rose, Ref. am. 39, Kongr. d. deutsch. Gesellch. f. Chir., 1910.
Rosenhaupt, Beitr. zur Klinik der Tumoren, etc. Berl. klin. Wchenschr., 1903.
Rotky, Klinische und radiologische Beobachtungen bei einem Fall von Akromegalie.

Fortschr. a. d. Geb. d. Rontgenstrahlen, 323, 1910.
Rumpel, Fall von myxodemartiger Erkrankung bei Hodenatrophie. Neurol. Centralbl.,

1896, 428.
Sabrazes and Bonnes, Examins du sang dans Pacromegalie. Compt. rend. soc. de biol.,

57> iQ°5-

Salbey, cited by Sternberg.
v. Salle, Uber einem Fall von angeborener abnormer Grosse der Extremitaten mit einem

an Akromegalie erinnernden Symptomenkomplex. Jahrb. f. Kinderh., 75, 540,

1912.

Salomon, H., Gaswechsel bei Morbus Basedowii und Akromegalie. Berl. klin. Wchen-
schr., 1904, Nr. 24.

Schafer, E. A., Die Funktionen des Gehirnanhanges. Bern. M. Drechsler, 1911.
Schafer and Mackenzie, The action of animal extracts on milk secretion. Proc. Roy.

Soc. Lond., 24, 16, 1911.
Schlesinger, W., tiber die Beziehung der Akromegalie zum Diabetes mellitus. Wien.

klin. Rundschau, 1908, Nr. 15.
Schlojfer, Erfolgreiche Operation eines Hypophysentumors auf nasalem Wege. Wien,

klin. Wchenschr., 1907, 621 u. 1075.

HYPOPHYSIS 627

Schonemann, Hypophyse und Thyreoidea. Arch. f. path. Anat. [etc.], Berl., 129, 310,

1892.
Schiiller, Die Schadelbasis im Rontgenbild. Fortschr. a. d. Gebiet d. Rontgenstrahlen

Erganz.-Bd., n.
Schultze, F., and Fischer, B., ZurLehre von der Akromegalie und Osteoarthropathie hyper-

trophiante. Mitt. a. d. Grenzgeb., d. Med. u. Chir., 24, 607, 1912.
Schultze, W., Fall von Akromegalie. Deutsche med. Wchenschr., 1904.
Schuster, Psychische Storurigen bei Hirntumoren, 1902.

Schwoner, Uber hereditare Akromegalie. Ztschr. klin. Med. Suppl.-Heft, 32.
Sokolojf, Ein Fall von Gumma der Hypophysis cerebri. Arch. f. path. Anat. [etc.], Berl.,

143, 333, 1896.
Sprinzels, Protokoll d. k. k. Gesellsch. d. Aerzte in Wien, 7, Juni. Wien. klin. Wchenschr.,

1912, Nr. 24.

Sternberg, Die Akromegalie. Nothnagel's Handb. VII, 1897.
Strauss, Diabetes insipidus und Entwickelungshemmung, etc. Folia urologica 6, 389,

1912.
Striimpell, Ein Beitrag zur Pathologic und pathologischen Anatomie der Hypophyse.

Deutsche Ztschr. f. Nervenh., n, 51, 1897.

Stumme, Akromegalie und Hypophyse. Arch. f. klin. Chir., 87, 1908.
Souza Leithe, De 1'acromegalie. Paris, 1890.
Talquist, cited by E. Meyer.
Tamburini, Beitrag zur Pathogenese der Akromegalie. Centralbl. f. Nervenheilk. u.

Psychiat., 894, 612.
Uthojf, Wachstumsanomalien bei der temporalen Hemianopsie bzw. den Hypophysen-

affektionen. Deutsch. med. Wchenschr., 1907, 1563.
Verstraeten, L'acromegalie. Rev. de med., 1889, 377 u. 493.
Widal, Roy, and Froin, Un cas d'acromegalie. Rev. de med., 4, 1906, 313.
Zak, E., Uber Hypophysentumoren. Wien. klin. Rundschau., 1904, 165.
Zollner, Tumor der Schadelbasis, ausgehend von der Hypophyse. Arch. f. Psychiat.,

44> 1908,

CHAPTER VII
EPIPHYSIS

Askanazy, cited by Pappenheimer.

Bailey and Jelliffe, S. E., Tumors of the pineal body. Arch. Int. Med., 8, 851, 1911.

Biach, P., and Hulles, E., Uber die Beziehungen der Zirbeldriise (Glandula pinealis)

zum Genitale. Wien. klin. Wchenschr., 1912, 373.
Coats, /., An adenoid sarcoma with cartilage originating in the pineal gland. Tr. Path.

Soc. Lond., 38, 44, 1887.

Daly, A case of tumor of the pineal gland. Brain, 10, 234, 1887.
Exner and Boese, tJber experimentelle Exstirpation der Glandula pinealis. Deutsche.

Ztschr. f. Chir., 107, 182, 1910.
Falckson, R., Ein Chondrocystosarkom im dritten Ventrikel. Arch. f. path. Anat. [etc.],

Berl., 75, 550, 1879.
Fod, C., Hypertrophie des Testicules et de la crete apres 1'exstirpation de la pineale chez le

coq. Arch. ital. de biolog., 57, 233, 1912.
v. Frankl-Hochwart, Zur Diagnose der Zirbeldriisentumoren. Deutsche Ztschr. f. Ner-

venh., 37, 1909.
Hart, Ein Fall von Angiosarkoma der Glandula pinealis. Berl. klin. Wchenschr., 1909,

2298.
Heubner, Tumor der Glandula pinealis. Deutsche med. Wchenschr., 1898, Vereins-

Beil., 29.

Kny, Ein Fall von isoliertem Tumor der Zirbeldriise. Neurol. Centralbl., 8, 281, 1889.
Konig, tiber ein Pseudosarkom der Zirbeldriise. Inaug.-Diss., Miinchen, 1894.
Marburg, 0., Die Adipositas cerebralis, etc. Deutsche med. Wchenschr., 1908, 2009.

Deutsche Ztschr. f. Nervenh., 36, 1909, u. Wien. med. Wchenschr., 1907, 2512.
— Die Epiphyse, Ergebn. d. Neurol. Springer, 1912.
Mutter, citation in Marburg.
Neumann, M., Zur Kenntnis der Zirbeldriisengeschwiilste. Monatschr. f. Psychiat. u.

Neurol., 9, 337, 1901.

Nothnagel, Geschwiilste der Vierhiigel. Wien. med. BL, 1888, 162.
Oestreich-Slavyk, Riesenwuchs und Zirbeldriisengeschwiilste. Arch. f. path. Anat. [etc.],

Berl., 157, 475, 1899; see also Heubner, Tumor der Glandula pinealis. Deutsche

med. Wchenschr., 1898, Vereins-Beil., 29.

Ogle, C., Sarcoma of pineal body. Tr. Path. Soc. Lond., I, 4, 1899.
Pappenheimer, Uber Geschwiilste des Corpus pineale. Arch. f. Path. Anat. [etc.], Berl.,

200, 122, 1910.
Raymond and Claude, Les tumeurs de la glande pineale chez 1'enfant. Bull. Acad. de

med. 15 Mars, 1910.
Weigert, Zur Lehre von den Tumoren der Hirnanhange, Teratom der Zirbeldriise. Arch.

f. path. Anat. [etc.], Berl., 65, 212, 1875.

628

CHAPTER VIII

SUPRARENALS

Abderhalden, Ztschr. f. physiol. Chem., 59, 61, u. 62, igog.

Adams, A case of precocious development associated with a tumor of the left suprarenal

body. Tr. path. Soc. Lond., 56, igo5.

Addison, On the effects of disease of the suprarenal bodies. London, 1855.
Aichel, O., Zur Kenntnis der. Nebennieren. Munch, med. Wchenschr., igoo and Anat.

Anz., 17, 30, igoo.
Alberti, Kasuistik zur Hypertrichosis universalis. Beitr. z. Geburtsh. u. Gynaek., 9,

33g, igos.
Aldrich, A preliminary report on the active principle of the suprarenal gland. Am. J.

Physiol., 5, 457, igoi.
A pert, Dystrophies en relation avec des lesions des capsules surrenales et progeria. Bull.

Soc. de pediat., Paris, Dec., igio, 501.
— La portion corticale de la capsule surrenale, ses relations physiol. et path, avec le

cerveau et les glandes genitales. Presse med., 28 Oct., 1911, 865.
Arnaud, Les hemorrhagies des capsules surrenales. Arch. gen. de med., 77, i, igoo, 5.
Aubertin and Ambard, Lesions des capsules surrenales dans les nephrites avec hyperten-
sion. Bull, et mem. soc. med. d hop. de Par. seance du ig Fevr., 1904; Semaine

med., 24, 63, igo4-
Bayliss, W. M., and Starling, E. H., Die chemische Koordination der Funktionen des

Korpers. Ergebn. d. Physiol. (Asher-Spiro), 5, igo6.

Beaujard, E., Les lesions surrenales dans les nephrites. Semaine med., igoy.
Bernstein and Folia, Uber die Einwirkung von Adrenalin, Pituitrin, etc., auf den respira-

torischen Stoffwechsd. 2g. Kongr. innere. Med., igi2.
Bernstein, S., Uber den Blutzuckergehalt bei Addisonscher Krankheit. Berl. klin.

Wchenschr., Nr. 40, 1911.
Bertelli, Falta, and Schweeger, tlber die Wechselwirkung der Driisen mit innerer Sekretion

III. Ztschr. f. klin. Med., Nr. 71.

Biedl, Beitrage zur Physiologic der Nebenniere. Arch. f. d. ges. Physiol., 67, 1897.
— Innere Sekretion. Vorlesungen, 1902. Wien, igo3- Wien. Klin., Nr. 29, 1903.
— Innere Sekretion. Urban u. Schwarzenberg, 1910.
Biedl and Braun, Zur Pathogenese der experimentellen Arteriosklerose. Wien. klin.

Wchenschr., igog, p. 7og.
Biedl and Wiesel, Uber die funktionelle Bedeutung der Nebenorgane des Sympathikus

(Zuckerandl) und der chromaffinen Zellgruppen. Arch. f. d. ges. Physiol., 91,

1903-
Bierry and Malloizel, Hypoglycemie apres decapsulation. Compt. rend. soc. de biol., 65,

232, igo8.

Bittorf, Die Pathologic der Nebennieren und des Morb. Addisoni. Jena, 1908.
Blum, Uber Nebennierendiabetes. Deutsches Arch. f. klin. Med., 71, 1901 and Arch. f.

d. ges Physiol., 90, 1902.
Bftinet, Troubles nerveux et tremblements observes chez un addisonien ;\ la suite de trop

frequentes injections de capsules surrenales de veau. Compt. rend. soc. de biol.,

51, 8gi, i8gg.

— De 1'addisonisme. Arch. gen. de med., 13 Sept., 1904.

629

630 LITERATURE

— La mort dans la maladie bronzee de 1'addison. Arch. gen. de med., 1903, 321.
Bortz, Xebennieren und Geschlechtscharaktere., Arch. f. Gynaek., 88, 444.
Bouniei'illc et Bonnaire, Sclerose tubereuse. Progres med., 1881, 667 et 1007.
Bin-in, Les tumeurs hypernephorides primitives des organs genitaux feminins. Nord.

med. Arch. p. chirurg., 41, 4, 1909.
Bramwcll, Anemia and some of the diseases of blood-forming organs and ductless glands.

Edinburgh, 1899.
Braun, t)ber Adrenalinarteriosklerose. Wien klin. Wchenschr., 1905, u. Sitzungsb.

Akad. Gesellsch., Wien, 1907, Nr. 116 u. Med. Klin., 1908, p. 9.

Brodie and Dixon, Contribution to the physiology of the lungs. J. Physiol., 30, 476, 1904.
Brodnitz, Die Apoplexie der Nebennieren. Miinchen. med. Wchenschr., 1910, 1591.
Broking, E. und Trendelenburg, P., Adrenalinnachweis und Adrenalingehalt des mensch-

lichen Blutes. Deutsches Arch. f. klin. Med., 103, 168, 1911.
Brown-Sequard, Influence heureux de la transfusion du sang normal apres 1'exstirpation

des capsules surrenales chex le cobbaye. Compt. rend. soc. de biol., 1893, 448.
Bulloch, W., and Sequeira, G. H., On the relation of the suprarenal capsules to the sexual

organs. Tr. Path. Soc. Lond., 56, 1905.
Carnot and Josserand, Des differences d'action de Padrenaline sur la pression sanguine

suivant les voies de penetration. Compt. rend. soc. de biol., 54, 1472, 1902.
Carrington, On cancer in a cirrhotic liver and adrenals with pigmentation of skin and

viscera. Lancet, 1885, 251.
Comessatti, Beitrag zum chemischen Nachweis des Adrenalins im Blutserum. Berl. klin.

, Wchenschr., 1909, p. 356.

O'Connor, Uber Adrenalinbestimmung im Blut. Miinchen med. Wchenschr., 1911, 1439.
— tiber den Adrenalingehalt des Blutes. Arch. f. exper. Path. u. Pharmakol., 67, 195,

1912.

Cooke, W., Philos. transact., 1756.

Crecchio, Ein Fall von Hermaphroditismus. Wien. med. Presse, 1866, 761.
Czerny, A., Hydrocephalus und Hypoplasie der Nebennieren. Centralbl. f. allg. Path.,

10, 281, 1899.
Dalche, P., Amenorrhoe recente, masculinisme regressif. Bull, et mem. soc. med. d.

Hop. de Par., Mars, 1912, 303.

Davidsohn, 13. Tagung d. path. Gesellsch., 1909, 287.
Delille, see chapter on the hypophysis.
Dobbertin, Beitrage zur Kasuistik der Geschwulste. Beitr. z. path. Anat. u. Physiol., 28,

42, 1900.
Ebstein, Peritonitisartiger Symptomenkomplex im Endstadium des Morbus Addisoni.

Deutsche med. Wchenschr., 1897, Nr. 46.

Ehrmann, Die Biologie der Nebennierensysteme. Berl. klin. Wchenschr., 41, 1909.
— Uber eine physiologische Wertbestimmung des Adrenalins und seinen Nachweis im

Blut. Arch. f. exper. Path. u. Pharmakol., 53, 97, 1905 and Deutsche med.

Wchenschr., 1909.
Elliot, J. Physiol., 1905, Nr. 32.
Elliot F. and Armour, G., J. Path., Bact., April, 1911.

Ellis, W. M. E., Hemmorrhagic infarction of the adrenals, with report of a case. Cleve-
land M. J., vol. xi., No. i, Jan., 1912, pp. 22-25.
Elsasser, Arbeiten a. d. Gebiet d. path. Anat. u. Bakt. Path.-anat. Inst. Tubingen 5,

45, 1906.
Engelhardt, A., Uber einen Fall von Pseudohermaphroditismus femininus mit Karzinom

des Uterus. Monatschr. f. Geburtsh. u. Gynaek, 12, 729, 1900.
Eppinger, Falta, and Rudinger, Wechselwirkung der Driisen mit innerer Sekretion.

I. u. II., Ztschr. f. klin. Med., 66 u. 67.

SUPRARENALS 63!

Eppinger, Uber Melanurie. Ztschr. f. Biol., 28, 181, 1910.

Erb, W., Jr., Arch. f. exper. Path. u. Pharmakol, 53, 1905.

Esser, Miinchen med. Wchenschr., 1908.

Falta, Weitere Mitteilungen uber die Wechselwirkung der Drusen mil innerer Sekretion.

\\ "it-n. klin. Wchenschr., 1909, Nr. 30.
Falta and Fleming, Uber die Wirkung des Adrenalins und des Pituitrins auf den iiberle-

benden Kaninchenuterus, etc. Miinchen med. Wchenschr., 1911, Nr. 50.
Falta and Ivcovic, Uber die Wirkungsweise des Adrenalins bei verschidener Applikation,

etc. Wien. klin. Wchenschr., 1909, Nr. 51.
Falta, Newburgh, and Nobel, Wechselwirkung der Drusen mit innerer Sekretion, IV.

Ztschr. f. klin. Med., 72, 1911.
Falta and Priestley, Beitrage zur Regulation von Blutdruck und Kohlehydratstoffwechsel

durch das chromaffine System. Berl. klin. Wchenschr., 1911, Nr. 47.
Fibiger, J., Beitrage zur Kenntnis des weiblichen Scheinzwittertums. Arch. f. path. Anat.

[etc.], Berl., 181.

Fischer, B., see chapter on hypophysis.
Fischer, B., and Schultze, see chapter on hypophysis.
Flacher, Ztschr. f. physiol. Chem., 58, 1908.

Fod, Verhandlungen d. deutsch. patholog, Gesellsch. Aachen, 1900.
Fox, Calcott, Tr. Path. Soc. Lond., 36, 460, 1885.
Frank, E., Uber die Beziehung zwischen Niere, Nebenniere und hohem Blutdruck, etc.

Berl. klin. Wchenschr., 609, 1911.
Frank and Isaac, Uber das Wesen des gestorten Stoffwechsels bei der Phosphorvergiftung.

Arch. f. exper. Path. u. Pharmakol., 64, 274, 1911.
Frankel, Uber den Gehalt des Blutes an Adrenalin bei chronischer Nephritis und Morbus

Basedowi. Arch. f. exper. Path. u. Pharmakol., 60, 1909, 395.
Friedmann, E., Zur Kenntnis des Adrenalins. Hofmeisters Beitr., 6, 92 und die Konstitu-

tion des Adrenalins, ibidem, 8, 95.
v. Fiirth, Zur Kenntnis der Brenzkatechin ahnlichen Substanz in den Nebennieren.

Ztschr. f. physiol. Chem., 1897, 1898, 1900.
Gautrelet, Compt. rend. soc. de biol., 1910, 201 u. 443.

- La choline, son role hypotonseur dans Porganisme, etc. Journ. de physiol.

path, gen., 2 Mars., 1909.
Gerhardt, Uber die Wirkungsweise der blutdrucksteigernden Substanz der Nebenniere.

Arch. f. exper. Path. u. Pharmakol., 44, 161, 1909.
Gilford, Hastings, The disorders of postnatal growth and development. London, Adlard

and Son, 1911.
Glynn, The adrenal cortex, its rests and tumors, its relation to other ductless glands

and especially to sex. Quart. J. of Med., 5, 157, Jan., 1912.
Goldschwendt, Symptomatologie und Diagnose der Nebennierentumoren. Prag. med.

Wchenschr., 1910, Nr. 37 u. 38.
Goldzieher, Beitrage zur Pathologic de Nebennieren. Wien. klin. Wchenschr., 1910,

Nr. 22.

— Die Nebennieren. J. F. Bergmann, Wiesbaden, 1911.
Goldzieher and Molnar, Beitrage zur Frage der Adrenalinamie. Wien. klin. Wchenschr.,

1908, 7.
Grawitz, P., Die Entstehung von Nierentumoren aus Nebennierengeweben. Arch. f.

klin. Chir., 30, 1884.
Guieyesse, La Capsule surrenale du cobaye. J. de 1'anat. et de la physiol., 37, 312, 435,

1901.

632 . LITERATURE

Guignou and Bijou, Deviation du type sexuelle chez une jeune fille, etc. Bull, de soc.

paed. de Paris, Mars, 1906, 129.

Guthrie, L., and Emery, W. d'Este, Clin. soc. trans., 40, 175.
v. Haberer and Stoerk, Beitrag zur Markeskretion der Nebenniere. Wien. klin. Wchenschr.,

1908, 305 u. 338.
Halle, W. L., Uber die Bildung des Adrenalin im Organismus Beitr. z. Chem. Phys. u.

Path., 8, 276.
Hedinger, Uber familiares Vorkommen plotzlicher Todesfalle bedingt durch Status

lymphaticus. Deutsches. Arch. f. klin. Med., 86, 248, 1905.
— Uber Beziehungen zwischen Status lymph, und Morb. Add. Deutsche path. Gesellsch.,

Dresden, 1907.
Hegar, Abnorme Behaarung und Uterusduplex. Beitr. z. Geburtsh. u. Gynaek., I, in,

1898.
[Hektoen, L., Death from hemorrhage into the suprarenal bodies in a boy of eighteen.

Tr. Chicago Path. Soc., 1910, viii, 87.]
Heller, Uber Hautveranderungen beim Diabete bronze. Deutsche med. Wchenschr.,

1907, 1216.
Henschen, Uber Struma suprarenalis cystica haemorrhagica. Beitr. z. klin. Chir., 49,

217, 1906.

Hepner, cited by Glynn.
Huldgren and A ndersson, Studien zur Physiologic und Anatomic der Nebennieren, Skandin.

Arch. f. Physiol., 9, 73.
Jacoby, Uber das Aldehyde oxydierende Ferment der Leber und Nebenniere. Ztschrift

f. physiol. Chem., 30, 135.
Jager, A., Die Entstehung des Melaninfarbstoffes. Arch. f. path. Anat. [etc.], Berl., 198,

62, 1909.

Janowsky, citation in Bittorf.
John, Klinische Erfahrungen Uber inravenose Suprarenininjektionen bei schweren Herz-

und Gefasskollapsen. Miinchen. med. Wchenschr., 1909, Nr. 24.
Jonescu, Notiz liber eine besondere Affinitat der Nierengefasse zum Adrenalin. Wien.

klin. Wchenschr., 1908.

Josue, Atherom. experim., etc. Compt. rend. soc. de biol., 55, 1374, 1903.
Jurgens, Demonstration in der Berl. med. Gesellsch. Berl. klin. Wchenschr. 1885, 222.
v. Kahlden, Addisonsche Krankheit und Funktion der Nebenniere. Centralbl. f. allg.

Path., 1896, 7, 464.
Kahn, F., Thymushyperplasie bei Morbus Addisoni. Arch. f. path. Anat. [etc.], Berl.,

200, 1910.
v. Karakaschejff, Beitr. z. path. Anat. d. Nebennieren usw. Beitr. z. path. Anat. u.

Physiol., 36, 401, 1904, u. 39, 373, 1906.
Kawashima, K., Uber einen Fall von Hautfibromen mit Nebennierengeschwiilsten

(Morbus Recklinghausen) . Arch. f. path. Anat. [etc.], Berl., 203, 66, 1911.
Kohn, Das chromaffine Gewebe. Ergebn. d. Anat. u. Entwicklungsgesch., 12, 254, 1903.
Konigstein, H., Uber die Beziehung gesteigerter Pigmentbildung zu den Nebennieren.

Wien. klin. Wchenschr., 1910, 17.
Kilster, H., Uber Gliome der Nebennieren. Arch. f. path. Anat. [etc.], Berl., 180, 117,

1904.

Kyrle, Verhandl. d. physiol. u. morph. Gesellsch. Wien, 5, 4, 1909.
Laignel-Lavastine, La melanodermie chez les tuberculeux. Arch. gen. de med., 2, 2497,

1903.
Langendorff, Uber die Innervation der Koronargefasse. Centralbl. f. Physiol., 1907, 551.

SUPRARENALS 633

Langley, J. N., Observations on the physiological action of extracts of the suprarenal

bodies. J. Physiol., 27, 237-256, 1901 and 1902.
Launois, Pinard, and -Gallais, Syndromes adiposo-genitale avec hypertrichose troubles

nerveux et mentaux d'origine surrenale. Gaz. d. Hop. de Par, 1911, Nr. 43.
[Lavenson, R., Acute insufficiency of the suprarenals. Arch. Int. Med., 1900, ii, p. 62.]
La-wen, A ., Quantitative Untersuchungen iiber die Gefasswirkung von Suprarenin. Arch.

f. exper. Path. u. Pharmakol., 51, 415, 1904.
Lewin, Uber Morbus Addisoni. Charite-Ann., 1892.
Lichtwitz, tiber einen Fall von Sklerodermie und Morbus Addisoni usw. Deutsches

Arch. f. klin. Med., 94, 1908.
Linser, P., Uber die Beziehungen zwischen Nebennieren und Korperwachstum, besonders

Riesenwuchs. Beitr. z. klin. Chir., 37, 282, 1903.
Lohmann, A., Cholin, die den Blutdruck erniedrigende Substanz der Nebenniere. Arch.

f. d. ges. Physiol., 118, 215, 1907.
— Uber die antagonistischen Wirkungen der in den Nebennieren enthaltenen Substanzen

usw. Arch. f. d. ges. Physiol., 122, 1908.
Magnus-Levy, Der Stoffwechsel bei Erkrankungen einiger Driisen ohne Ausfiihrungsgang

in v. Noorden's Handb. d. Path. d. Stoffwechs., 2. Aufl., 1907, 352.
Manasse, Uber die Beziehungen der Nebennieren zu den Venen und dem venosen Kreis-

lauf. Arch. f. path. Anat. [etc.], fieri., 135, 263, 1894.
Marchand, Beitrage zur norm. u. path. Anat. d. Gland, carot. u. der Nebennieren. Fest-

schr. f. Virchow, 1891, 557.
Martineau, cited by Bittorf. I
Mayer, A., Sur le mode d'action de la piqure diabetique. Compt. rend. soc. de biol.,

1906, 1123.
Meirowsky, cited by Konigstein.

Meixner, Zur Frage des Hermaphroditismus verus. Ztschr. f. Heilk., 26, 318, 1905.
Merckel, Krankheiten der Nebennieren. v. Ziemssen's Handb., VIII, 2, 281-314, 1875.
Metzger, L., Zur. Kenntnis der wirksamen Substanzen in den Nebennieren. Inaug.-

Diss., Wiirzburg, 1897.

— Zur Frage vom Nebennierendiabetes. Miinchen. med. Wchenschr., 1902.
Monckeberg, Die Tumoren der Glandula carotica. Beitr. z. path. Anat. u. Physiol., 38,

1905.
Mohr, R., Uber einen Nebennierentumor der rechten Niere mit gleichzeitigen hyper-

plastischen akzessorischen Nebennieren im Schwanz des Pankreas. Beitr. z.

path. Anat. u. Physiol., 47, 202, 1910.
Milnzer, E., Zur Lehre von den vaskularen Hypotonien. Wien. klin. Wchenschr., 1910,

Nr. 38.
Neu, M., Untersuchungen uber die Bedeutung des Suprarenins fur die Geburtshilfe.

Arch. f. Gynaek., 85, 617, 1908.
— Experimentelles zur Anwendung des Suprarenins in der Geburtshilfe. Gynak. Rundsch.,

1907. 5°7-

— Verwendbarkeit des Suprarenins in der geburtshilflichen Therapie. Therap. d.

Gegenw., 1907.
Neubauer, E., Uber das Schicksal der Milchsaure bei normalen und phosphorvergifteten

Tieren. Arch. f. exper. Path. u. Pharmakol., 61, 387, 1909.
— Ueber die Wirkung antiglykosurischer Mittel und uber Leberglykosurie. Biochem.

Ztschr., 43, 335, 1912.
—Uber Hyperglykamie bei Hochdrucknephritis und die Beziehungen zwischen Glykamie

und Glykosurie beim Diabetes mellitus. Biochem. Ztschr., 25, 284, 1910.

634 LITERATURE

Neubauer, E., and E. Forges, Uber Xebenniereninsuffizienz bei Phosphorvergiftung.

Biochem. Ztschr., 32, 290, 1911.
y either g, Zur chemischen Kenntnis der Melanome. Arch. f. path. Anat. [etc.], Berl., 192,

514, 1908.

v. Neugebaner, Hermaphroditismus beim Menschen, Leipzig, 1906, 688.
Neurath, Die vorzeitige Geschlechtsentwicklung. Ergebn. d. innere Med. u. Kinderheilk,

1909, Nr. 4.
v. Neusser, Ausgewahlte Kapitel der klinischen Symptomatologie und Diagnostik.

Braumiiller, 1911, 4, Heft.

— Die Erkrankungen der Nebennieren. NothnageVs Handb., 1899.
v. Neusser and Wiesel, Die Erkrankungen der Nebennieren. A. Holder, 1910.
Oesterreich, Operative Heilung eines Falles von Morbus Addisoni. Ztschr. f. klin. Med.,

31, 123, 1897.
Ogston, Ein Beitrag zur Kasuistik abnormer geschlechtlicher Entwickelung. Oster-

reichisches Jahrb. f. Padiatrie. Wien., i, 180, 1872.
Oppenheim and Loeper, Insuffisance surrenale chronique experimentale, etc. Compt. rend.

soc. de. biol., 1903, 330.

Orth, Arbeiten a. d. path. Inst. in Gottingen. Berlin, 1893, 75.
Pauli, Ber. d. chem. Gesellsch., 1909, 42.
Pellizzi, Studi clinichi ed anatomo-pathologichi sull'idioza. Ann. di freniat [etc.], 1900

and 1901.

Pittiet, Bull. Soc. anat. de Par., 1888, 416, 1889, 199.

Pollack, L., Untersuchungen bei Morbus Addisoni. Wien. med. Wchenschr., 1910.
Porges, 0., tiber Hyppglykamie bei Morbus Addisoni usw. Ztschr. f. klin. Med., 1909,

Nr. 69, 341.

v. Recklinghausen, Deutsche med. Wchenschr., 1890, mo.
Richards, Guy's Hosp. Rep. 59, 217.
Ritsche, cited by Bullock and Sequeria.
Roloff, Ein Fall von Morbus Addisoni mit atrophischen Nebennieren. Beitr. z. path.

Anat. u. Physiol., 9, 629, 1891.
Santi, Ipernefrome del rene e dell'ovario. Atti d. soc. ital. di ostet. e ginec., 1906 and

1907, 478.
Schilder, P., Ueber das maligne Gliom des sympathischen Nervensystems. Frankf.

Ztschr. f. Path., 3, 1909.
Schlayer, Zur Frage drucksteigernder Substanzen im Blut bei chronischer Nephritis.

Deutsche med. Wchenschr., 1907, 1897 and Zur Frage der drucksteigernden

Substanzen im Blut bei Nephritis. Miinchen med. Wchenschr., 1908, 2604.
Schmorl, Zur Kenntnis der akzessorischen Nebennieren. Beitr. z. path. Anat. u. allg.

Pathol., 9, 523, 1891.
Schultze, tJber die Melanoplaquie der Mundschleimhaut, etc. Deutsche med. Wchenschr.,

1898, 46.
Schur and Wiesel, tiber eine der Adrenalinwirkung analoge Wirkung des Blutserums von

Nephritikern auf des Froschauge. Wien. klin. Wchenschr., 1907, Nr. 23 u. 27.
Schivarz, 0., tiber einige Ausfallserscheinungen nach Exstirpation beider Nebennieren.

Wien. klin. Wchenschr., 1909.

Schwyzer, Zur Atiologie des Morbus Addisoni. N. York med. Wchenschr., Nr. 10, i, 1898.
Simmonds, tiber Nebennierenschrumpfung bei Morbus Addisoni. Arch. f. path. Anat.

[etc.], Berl., 172, 480, 1903.
Soullier, A., Sur les premiers states du developpement de la capsule surrenale chez quel-

ques mammiferes. Compt. rend. soc. d. Anat. de Montpel., 4, 1902.
Stangl, Verhandl. d. deutsche Path. Gesellsch., 1902.

SUPRARENALS 635

Stoerk, Zur Histogenese der Grawitzschen Nierengeschwulste. Beitr. z. path. Anat. u.

Physiol., 43, 393, 1908.

Stolz, Ber. d. deutsch. chem. Gesellsch., 1904, 4149.

Straub, H., Akuter Morbus Addisoni usw. Deutsches Arch. f. klin. Med., 97, 1909.
Strehl und Weiss, Beitr. z. Physiol. d. Nebenniere. Arch. f. d. ges. Physiol., 86, 107, 1901.
Suzuki, Chromaffiner Tumor des Nebennierenmarkes. Berl. klin. Wchenschr., 1908.
Takamine, /., The blood-pressure raising principle of the suprarenal gland. J. Am. M.

Ass., 38, i, Jan. 18, 1902, p. 153; also Therapeutic Gazette, Apr. 15, 1901, p. 221.
Tilesius, Voigt's Magazine, 1803.
Thumim, Geschlechtscharaktere und Nebennierenrinde in Korrelation. Berl. klin.

Wchenschr., 1909, Nr. 3.
Trcndelenburg, P., Bestimmungen des Adrenalingehaltes im normalen Blut, etc. Arch. f.

exper. Path. u. Pharmak., 63, 161, 1910.
Ulrich, Anatomische Untersuchungen tiber ganz und partiell verlagerte und akzessorische

Nebennieren, etc. Inaug.-Diss., Zurich, 1895.
Vaquez, Semaine med., 24, 45, 1901, ibidem, 25, 369, 1905.
Variot and Pironneau, Nanisme avec dystrophie osseuse et cutanee speciales, etc. Bull.

Soc. de pediat. de Par., June, 1910, 307 et Clinique infantile, 8, 705, 1910.
Vollbracht, cited by v. Neusser, and Wiesel.
Vonwiller, Grawitzsche Nebennierengeschwulst des Ovariums. Beitr. z. path Anat. u.

Physiol., 50, 161, 1911.
Watermann and Smit, Nebenniere and Sympathikus. Arch. f. d. ges. Physiol., 124, 198,

1908.
Weichselbaum, Beitrage zur Geschwulstlehre. Arch. f. path. Anat. [etc.], Berl., 75, 554,

1881.

Westphal, Fr., Die klinische Diagnose der Grawitztumoren. Inaug.-Diss. Miinchen, 1910.
Wiesel, J., tiber die akzessorischen Nebennieren am Nebenhoden des Menschen, etc.

Sitzungsbr. d. k. Akad. d. Wissensch. Math.-naturw. Cl. Wien., 108, 1898.
— Mitth. d. Gesellsch. f. innere Med. u. Kinderh. Wien., 1904, Nr. 3, 144.
— Zur pathologischen Anatomic der Addisonschen Krankheit. Ztschr. f. Heilk., 24,

1903.
— Bemerkungen zu der Arbeit H. Kilsters tiber Gliome der Nebennieren. Arch. f. path.

Anat. [etc.], Berl., 180, 553, 1905.

— Zur Pathologic des chromaffinen Systems. Arch. fur. path. Anat. [etc.], Berl., 176, 1904.
— Hemicephalie. Mitt. d. Gesellsch. f. innere Med. Wien., 1907, 144.
W inkier, Die Gewachse der Nebenniere. Fischer, Jena, 1909.
Wolf, Ch. G. H., and Thacher, H. C., Protein metabolism in Addison's disease. Arch.

Int. Med., June, 1909.

Wooley, Adrenal tumors. Am. J. Med. Soc., 1903, 33.
Zanfrognini, Eine neue kolorimetrische Methode zur Adrenalinbestimmung. Deutsche.

med. Wchenschr., 1909.
Zander, Uber funktionelle und kinetische Beziehungen der Nebennieren zu anderen

Organen, speziell zum Grosshirn. Beitr. z. Path. Anat. u. Physiol., 7, 439, 1890.
Ziegler, K., Experimentelle und klinische Untersuchungen iiber die Histogenese der myel.

Leukamie, Jena, 1906.
Zehbe, Untersuchungen iiber Nierengeschwiilste. Arch. f. path Anat. [etc.], Berl., 201,

150.
Zuckerkandl, Die Nebenorgane des Sympathikus im Retroperitonealraum des Menschen.

Verhandl. d. anat. Gesellsch. 15. Versamml. in Bonn. 1910, 96.
Zultzer, G., Zur Frage des Nebennierendiabetes. Berl. klin. Wchenschr., 1901, 28.

CHAPTER IX
STATUS LYMPHATICUS AND STATUS HYPOPLASTICUS

Bartel, J., Uber die hypoplastische Konstitution, etc. Wien. klin. Wchenschr., 1907,
Xr. 38 u. 1908, Xr. 22.

Bertelli, Falta, and Schweeger, tlber die Wechselwirkung d.er Drxisen mit innerer Sekretion.
III. tlber Chemotaxis. Ztschr. f. klin. Med., 71.

Borchardt, tlber das Blutbild bei Erkrankungen der Drtisen mit innerer Sekretion, etc.
Deutsches Arch. f. klin. Med., 1912.

Eppinger and Hess, Die Vagotonie. Sammlung klin. Abhandlungen von v. Noorden,
1910, Heft, 9 u. 10.

Falta, W., Die Erkrankungen der Driisen mit innerer Sekretion. Mohr-Staehelinsches
Handbuch der inneren Medizin, 4, 1912.

Hedinger, tlber Beziehungen zwischen Status lymphaticus und Morbus Addisoni. Deut-
sche path. Gesellsch. Dresden, 1907.

Hermann and Kyrle, Verhandl. d. phys. u. morph. Gesellsch. Wien., 5, 4, 1909.

Kolisko, Uber plb'tzlichen Tod aus natiirlichen Ursachen. Handb. d. arztlichen Sach-
verstandigentatigkeit, 2, 1906.

Kundrat, H., Uber Vegetationsstorungen. Wien. klin. Wchenschr., 1893, Xr. 28.

Miinzer, Zur Lehre von den vaskularen Hypotonien. Wien. klin. Wchenschr., 1910.
Xr. 38.

v. Neusser, Ausgewahlte Kapitel der klinischen Symptomatologie und Diagnostik.
Braumiiller, 1911, 4. Heft.

Paltauf, A., tlber die Beziehung des Thymus zum plotzlichen Tod. Wien. klin. Wchen-
schr., 1889, Xr. 46 and 1890, Xr. 9.

v. Sury, t)ber die fraglichen Beziehungen der sog. Mors thymica zu den plotzlichen
Todesfallen usw. Vrtljahrsschr. f. gerichtl. Med. 36, 3. T., 36, 88, 1906.

Wiesel, see chapter on suprarenals.

Wiesner, Verhandlungen d. morph. u. physiol. Gesellsch. Wien., 4 Mai, 1909.

636

CHAPTER X

SEXUAL GLANDS

Achard and Demanche, Un cas d'atrophie testiculaire. Soc. h6p. med. de Paris, 21 Dec.,

1906.

Adler, L., Versuche mit Mamminum Poehl. Miinchen. med. Wchenschr., 1912, 13.
Alterthum, Die Folgezustande Kastration und die sekundaren Geschlechtscharaktere.

Beitr. z. Geburtsh. u. Gynaek., 1899.

Ancel and Bouiri, Sur les cell, interstitielles du testicule des mammiferes et leur significa-
tion. Rev. biol. Nancy, 10 Nov., 1903. Compt. rend. soc. biol., 1903, 1397,

ibidem, 1683.

Apert, E., Obesite, etat eunucho'ide., etc. Bull. soc. pediat., Paris, 3, 108, 1901.
Babonneix and Paisseau, see chapter on hypophysis.
Becker, Uber das Knochensystem eines Kastraten. Arch. f. Anat. u. Physiol. Anat.

Abt., 1899.
Belfield, A case of retrograde puberty impotence and diabetes insipidus relieved by

suprarenal cortex. J. Am. M. Ass., 55, 215, July 10, 1910.
Bellinzona and Tritondani, Ref. Jahresb. Ophthalmol., 1904, 406.
Bernhardt, Demonstration in der Berl. Gesellsch. f. Psych. Sitz. v. n, Marz, 1901. Arch.

f. Psychiat., 36, 914.

Bertelli, Falta, and Schweeger, Uber Chemotaxis. Ztschr. f. klin. Med., 71.
Biedl, Innere Sekretion. Ueban and Schwarzenberg, 1910.
Biedl and Konigstein, Untersuchungen liber das Brustdrusenhormon in der Graviditat.

Ztschr. f. exp. Path., 8, 358, 1910.
Bihler, Uber das Verhalten des Blutdruckes bei Chlorotischen. Arch. f. klin. Med., 52,

281, 1894.

Birch-Hirschfeld, Kongr. f. innere Med., 1892, 28.
Blumenthal, Ergebnis der Blutuntersuchung in der Geburtschilfe und Gynakologie.

Beitr. z. Geburtsh. u. Gynaek., II, 3, 414, 1907.
Bondi, S., Osteomalacie mit Struma und latenter Tetanic. Sitzungsbr. d. Gesellsch.

f., innere. Med. in Wien., 1908, und Osteomalacie beim Manne, ibid., 1910.
Bossi, Die Nebennieren und die Osteomalacie, Arch. f. Gynsek., 83, 505; Nebennieren

und Osteomalacie. Zentralbl. f. Gynak., 907, Nr. 3 u. 6.
Breuer, R., and v. Seiller, R., Uber den Einfluss der Kastration auf den Blutbefund

weiblicher Tiere. Arch. f. exper. Path. u. Pharmakol., 50, 1003.
Breus and Kolisko, Die pathologischen Beckenformen. Wien., 1900.
Bro-wn-Sequard, Expose des effets produits chez l'homme par les injections sous-cutanees.

Paris, Massoh, 1890. Arch, de physiol. norm., 1889, 1890, 1891.
Bucura, Uber die Bedeutung der Eierstocke. Volkmann's Vortr. Neue Folge 513/514.
Bunge, Lehrbuch d. physiol. u. pathol. Chemie., Leipzig, 1889, 85.
Byrom Bramwell, Chlorosis in a male. Clinical study, April 5, 1907.
Capellani, Ann. di ostetr. et Ginecol. 2, Nr. 8.
Charcot, Semaine med., Mars, 1891.
Charrin, Cited by v. Noorden and v. Jagic.
Chatin, Du chloro-brightisme. Paris, 1894. Bailliere et fils.

Chrobak, Uber Einverleibung von Eierstockgeweben. Centralbl. f. Gynak., 20, 1896.

637

638 LITERATURE

Claude and Goiigcrot, Insuffisance pluriglandulaire endocrinienne. J. Physiol. et path.

gen., 1908, 469 et 505.
Coffin and Lereboullet, Atrophie testiculaire consecutive a une orchite surlienne. Gaz.

hebd. de med., 1877.
Comte, Contribution a 1'etude de 1'hypophyse humaine, etc. These de Lausanne, 1898.

Beitr. z. path. Anat. u. Physiol., 23, 1898.
Cordier and Francillon, Un cas d'infantilisme de type reversif avec syndromes pluriglandu-

laires, Lyon med., i Janv., 1911.
Cordier and Rebatlu, L'infantilisme regressif ou tardif n-. iconogr. de la. Salpetriere, 1911,

405-
Cramer, Ovarium und Osteomalacie. Munchen. med. Wochenschr., 1909, 758 und Zur

Physiologic der Milchsekretion, ibidem, 1521.

Cristofoletti, Zur Pathogenese der Osteomalazie. Gynak. Rundschau, 5, 1911.
Dalche, Dystrophie orchidienne. Bull, et mem. med. hop. de Par., 7 Juin, 1901, 23 Mai,

1902.

Davis, cited by Schlichter. Wien. klin. Wchenschr., 1889, 979.
Delbet, cited by Halban.

Doderlein, Uber Rontgentherapie. Munchen. med. Wochenschr., 17, 929, 1911.
Dubnikojf, Klinische Untersuchung iiber Eisenwirkung und larvierte Chlorose. Disserta-
tion, Bern, 1908.
Duckworth, W. L. H., Notes on the anatomy of an eunuchoid man, etc. J. Anat. and

Physiol., Vol. 41, Oct. 1906, p. 30-34.
Dupre, These de Paris, 1904/05.

Duval, R., De la secretion de la mammaire nonpuerperale. These de Paris, 1881.
Englander, B., Adrenalin bei Knochenerweichung. Centralbl. f. Gynak., 1909, Nr. 13.
Eppinger, Sella turcica bei Hypoplasie der Genitalien. Ges. f. inn. Med. Wien. Sitz.,

27 Jan., 1910.
Erdheim, Uber Epithelkorperchenbefunde bei Osteomalazie. Stizungsb. d. k. Akad. d.

Wissensch. Wien., 116, 311. 1907, Abt., 3.
Erdheim and Stumme, Schwangerschaftsveranderung der Hypophyse. Munchen. med.

Wchenschr., 1908, 1202 u. Beitr. z. path. Anat. Physiol., 46, 1909.
Etienne, Jeandelize and Richon, Malformations organiques multiples chez un castrat

naturel. Compt. rend. soc. de. biol., 62, 1907.
Folk and Hesky, Uber Ammoniak-Amminosauren- und Peptidstickstoff im Harn Gravider.

Ztschr. f. klin. Med., 71, 261, 1910.
Falta, W., Spateunuchoidismus, etc. Berl. klin. Wchenschr., No. 30 u. 31, 1912 und Die

Krankheiten der Driisen mit innerer Sekretion. Mohr-Staehelihsches Handb. d.

inneren Med., IV., 191.
Falta and Freund, Uber die Behandlung innerer Krankheiten mit Radiumemanation.

Munchen. med. Wchenschr., 1912, Nr. 14.
Fehling, Verhandl. d. deutsch. Gesellsch. f. Gynak. Halle, 1888. Freiburg, 1889, internet

Kongr., 1890.

—Die Form des Beckens beim Fotus und Neugeborenen. Arch. f. Gynaek., 10.
—Uber Wesen und Behandlung der Osteomalazie. Arch. f. Gynaek., 28, 1890 u. 29, 1891.
Ferrari, Sulla clorosi masc. della puberta. Giorn. intern, di sc. med., 1908, 263.
Fichera, Sur Phypertrophie de la glande pituitaire consecutive a la castration. Arch.

ital. de Biol., 43, 405, 1905.
Foa, C., Su fattori che determinano la funzione della ghiandola mammaria. Arch, di

Fisiol., 5, 1909.

Foges, Zur Hodentransplantation bei Hahnen. Centralbl. f. Physiol., 1898.
Formanolli, Sur la chlorose masc. Gazz. med. ital., Torino, 1905.
Frankel, Berl. klin. Wchenschr., Nr. 2, 1911.

SEXUAL GLANDS 639

Freund, H., Die Bezieh'ung der weiblichen Geschlechtsorgane, etc. Ergebn. d. Path.

Lubarsch-Ostertag, 3, 1896.
Gall, cited by Mobius. .
Gaillard, citation in Cordier et Rebattu.
Gallavardin and Rebattu, Lyon. med., 30 Janv., 1910.

Candy, Soc. med. d. hop. de Par., 7, Dec., 1906, 1226, 17. Mai, 1907, et Juin, 1911.
Gauthier, Ein Fall von Milchsekretion aus den Brusten an Stelle der Menstruation bei

einem jungen Madchen. Reference in Centralbl. f. Gynak., 1904, 127.
Geinitz, citation in Kussmaul.

Giudiceandrea, Traitement de la chlorose, etc. Semaine med., 1901, Nr. 3.
Giudiceandrea, Archangdi, and Bastianelli, liber die Veranderungen der Schilddriisen bei

Chlorosis. Reference in Folia haematol., 2, 581.
Glavecke, Korperliche und geistige Veranderungen im weiblichen Korper nach kiinstlichem

Verlust der Ovarien und des Uterus. Arch. f. Gynaek., 35.
Glynn, see suprarenals.

Godard, Egypte et Palestine. Paris, 1867. Citation in Pelikan.
Goodman, The cyclical theory of menstruation. Am. J. Obst., 9, 1878.
Gougerot, Brisseaud, and Gy, Insuffisance endocrinienne thyroi'do-testiculaire. Revue

neurol. 2, 1908. N. iconogr. de la Saltpetriere, 24, 449, 1911.
Grawitz, Klinische Pathologie des Blutes. IV. AufL, 1911, Verl. Thieme, Leipzig.
Griffith, The condition of testes and prostate gland in eunuchoid persons. J. Anat., 28,

1894.
Grigoriu, M. Christea, Beitrag zur Milchsekretion. Gynaek. Rudschau., 4. Jahrg., Nr. 20,

740.

Groag, P., Untersuchungen iiber Chlorose. Miinchen med. Wchenschr., 1910, Nr. 30.
Guggenheimer , Uber Eunuchoide, etc. Deutsches, Arch. f. klin. Med., 107, 518, 1912.
Guiyesse, see suprarenals.
Haberer, v., and Stoerk, see suprarenals.

Halban, J., Die Entstehung der Geschlechtscharaktere. Arch. f. Gynaek, 70, 205, 1903.
— Uber den Einfluss des Oyariums auf die Entwicklung des Genitales. Monatschr.

f. Geburtsh. u. Gynaek., 12, 1900, 498.

— Protokoll d. Gesellsch. d. Aerzte. Wien. klin. Wchenschr., 21, 1910.
— Die innere Sekretion von Ovarium und Plazenta und ihre Bedeutung fur die Funktion

der Milchdriise. Arch. f. Gynaek., 75, 1905.

— Zur Lehre von der Menstruation, etc. Centralbl. f. Gynak., 35, 46, 1911.
Holler, A. v., Elementa physiologica, 8, 116, 1766.
Halliday, Crom, Ueber einen Fall von Uberpflanzung des Ovariums mit nachfolgender

Schwangerschaft und Geburt eines lebenden Kindes. Frage: Wer ist die Mutter?

Edinburgh obstetr. soc., 1905/06. (Ref. Centralbl. f. Gynak., 1906.)
Hammond, Am. J. Neurol. and Psychiat., 1882.
Hanau, Uber Knochenveranderungen in der Schwangerschaft. Fortschr. d. Med., 7,

1892.
Handmann, Schilddriisenveranderungen und Hamoglobingehalt des Blutes bei Chlorose.

Miinchen. med. Wchenschr., 1911, Nr. 22.
Hastings, Gilford, see pluriglandular disease.

Hayem, A propos du traitement de la chlorose. Semaine med., 1895, 179.
— De la mort subite au cours de la chlorose. Semaine med., 1896, 116.
Hegar, Die Kastration der Frauen. Volkmann's Samml., Nr. 136-138, 1878. Der

Geschlechtstrieb, Stuttgart, 1894.
— Zur abnormen Behaarung. Beitr. zu Geburtsh. u. Gynaek., 4, 1901.

640 LITERATURE

— Korrelation der Keimdriisen und Geschlechtsbestimmung. Ibidem 7, 201, 1903.

Hcidcnhain. Hermann's Handb. d. Physiol., 5, 1883.

Heyn, Pseudohermaphroditismus masculinis completus. Ztschr. f. Geburtsh. u. Gynaek.,

65, 642, 1910.
Hildcbrandt, Zur Lehre von der Milchbildung. Beitr. z. chem. Phys. u. Path., 5, 463,

1904.

Howitz, citation in Pick.
Hudovernig, Un cas de Gigantisme precoce, Etude comp'lementaire, 1906. N. icong. de la

Salpetriere, 3, 1903.
Hudovernig and Popovicz, Gigantisme precoce abec developpement precoce des organes

genitaux. N. iconog. de la Salpetriere, 3, 1903.

Huntind, Pseudochlorose der Sauglinge. Allg. Wien. med. Ztg., 1908, 408 u. 418. Trans-
lated fromLe monde med., 1908, Nr. 25.
Immermann, Krankheiten des Blutes. v. Ziemssen's Handb. d. spez. Path. u. Therap.,

13, Abt., II, 275-349, 1879.
Jacobi, M., The question of rest for women during menstruation. The Boylsten Prize

Essay of Harvard Univ. for 1876, London, 1897.
Jacobs, Eierstocktherapie. Policlinique, 1896.
Jentzer und Beuttner, Experimentelle Untersuchungen zur Frage der Kastrationsatrophie.

Ztschr. f. Geburtsh. u. Gynaek., 42, 1900.
Jose/son and Lundquist, Abnormes Langenwachstum, etc. Deutsche Ztschr. f . Nervenh.,

39, 1910.
Kehrer, F. A., tJber gewisse synchrone Nervenerscheniungen und zyklische Vorgange in

den Genitalien und anderen Organen. Beitr. z. Geburtsh. u. Gynaek. 4, 228, 1901.
Kisch, tiber Feminismus mannlicher lipomatoser Individuen. Wien. med. Wchenschr.,

1905, 366.

Klein, Ein Fall von Pubertas praecox. Deutsche med. Wchenschr., 1899, 47.
Kleinhans and Schenk, Experimentelles zur Frage nach der Funktion des Corpus luteum.

Ztschr. f. Geburtsh. u. Gynaek., 66, 283.

Krauer, Die Ovarientransplantation. Arch. f. Gynaek., 60, 322, 1900.
Koppen, citation in Recklinghausen.
Kolisko, citation in Tandler and Grosz.

Kon, Jutaka, Hypophysenstudien. Beitr. z. path. Anat. u. Physiol., 44, 1908.
Kottmann, Ueber innere Sekretion und Autolyse mit spezieller Beriicksichtigung der

Eiweiss-Autolyse und klinische Fragen tiber Basedow, Myxodem, Chlorose, etc.

Cor.-Bl. d. schweiz. Aerzte, 1910, Nr. 34.
Krajft-Ebing, Psychosis menstrualis. Enke, Stuttgart, 1902.
Kussmau1, tiber geschlechtliche Frtihreife. Wtirzb. med. Ztschr., 3, 1862.
Laache, Die Anamie. Chris'tiania, 1883, 785.
Landau, M., Zur Behandlung der Beschwerden der naturlichen und anticipierten Klimax

mit Eierstocksubstanz. Berl. klin. Wochenschr., 1896, 557.
— citation in Pick.

Larrey, Mem. de chir. mil. et camp., 2, 1812.
Launois and Moulon, Les cellules cyanophiles de 1'hypophyse chez la femme encente.

Compt. rend. soc. de. biol. Paris, 1903, 448.
Launois and Roy, Des relations qui existent entre 1'etat des glades genitales males et le

developpement du squelette. Arch. gen. de med., 1903, 186.
Latzko, Gesellsch. d. Aerzte Wien. Ref. Wien. klin. Wchenschr., 1893, Nr. 17.
— Wein. klin. Wchenschr., 1894, Nr. 28 u. 29, 1907, Nr. 8.
Leersum, van, Uber die Ausscheidung von Aminosauren wahrend der Schwangerschaft

und nach der Entbindung. Biochem. Ztschr., n, 121, 1908.

SEXUAL GLANDS 641

Lemos Magelhaes, Infantilisme et degener. psych. N. iconogr. de la Salpgtriere, 19, 50,

1906.
Leopold and Mironow, Beitrag zur Lehre von der Menstruation und Ovulation. Arch. f.

Gynaek., 45, 506, 1894.
Lohlein, Erfahrungen uber den Wert der Kastration bei Osteomalazie. Ztschr. f. Geburtsh.

u. Gynaek., 29, 1894.
Lowy and Richter, Zur Frage nach dem Einfluss der Kastration auf den Stoffwechsel.

Centralbl. f. Physiol., 1902.
Lordet, Allongement des membres inf. chez un eunuque. Arch, d'anthrop. crim. Lyon.,

Par., 1896. Soc. de med. de Lyon., 16 Mars, 1896, in Lyon med.
Liithje, Uber Kastration und ihre Folgen. Arch. f. exper. Path. u. Pharmak., 48, 184,

1902.
Mainzer, Die doppelseitige Ovariotomie bei Schwangeren. Munchen. med. Wchenschr.,

1895, 1117.
Mandl and Burger, Die biologische Bedeutung der Eierstocke nach Entfernung der Gebar-

mutter. Leipzig u. Wien, 1907.

Marie, A., Eunuchisme et erotisme. N. iconogr. de la Saltpetriere, 19, 472, 1906.
Martin, Gaz. hebd., 1877.
Matthes, Uber die Einwirkung des Oophorins auf den Stoffwechsel. Monatschr. f.

Geburtsh. u. Gynaek., 1903.
Meige, Henry, L'infantilisme, le feminisme et les hermaphrodites antiques. Antropologie,

1895- . '

Merletti and Angeli, Die Nebennierentherapie der puerperalen Osteomalazie. Klin.-

therap., Wchenschr., 1907, Nr. 42.

Mobius, cited by Bab. Volkmann's Samml. klin. Vortr. N. F., Nr. 538.
— Ueber die Wirkungen der Kastration. Halle, 1906.
Monari, La clorosi. Modena, 1900.

Morawitz, Untersuchungen uber Chlorose. Munchen med. Wchenschr., 1910, Nr. 27.
Miiller, Fr. v., 24. Kongr. f. innere Med., 1906. Discussion.
Naegeli, Blutrankheiten und Blutdiagnostik. Leipzig, 1908, 230-251.
Neu, Med. Klin., 1910, Nr. 46, 1813 u. Munchen. med. Wchenschr., 1910, Nr. 48, 2533.
Neubauer and Novak, Zur Frage der Adrenalinamie und des Blutzuckers in der Schwanger-

schaft. Deutsche med. Wchenschr., 49, 1911.
Neugebauer, Hermaphroditismus beim Menschen. Leipzig, 1908.
Neumann and Herrmann, Biologische Studien uber die weibliche Keimdruse. Wien.

klin. Wchenschr., 1911, Nr. 12.
Neumann and Vass, Uber den Einfluss der Ovariumpraparate auf den Stoffwechsel.

Monatschr. f. Geburtsh. u. Gynaek., 15.
Neurath, Vorzeitige Geschlechtsentwicklung (Menstruatio praecox). Wien. med.

Wchenschr., 1909.
—Die vorzeitige Geschlechtsentwicklung. Ergebn. d. inneren Med. u. Kinderheilk., 4,

1909.

—Uber Fettkinder, etc. Wien. klin. Wchenschr., 1911, Nr. 2.
Neusser, v., Klinisch-hamatologische Mitteilungen. Wien. klin. Wchenschr., 1892, Nr.

3 u. 4.

— Zur Diagnose des Status thymico-lymphaticus. Wein, 1911.
Noorden, v., Die Fettsucht. Holder, Wien u. Leipzig, 1910.
Noorden, v., and v. Jagic, Die Bleichsucht. Holder, Wien u. Leipzig, 1912.
Novak, Die Bedeutung des weiblichen Genitales fur den Gesamtorganismus, etc. Xoth-

nagel. Suppl.-Bd., 1912.
41

642 LITERATURE

Novak and Jeiter, Beitrag zur Kenntnis der puerperalen Bradykardie. Monatschr. {.

Geburts. u. Gynaek., 1910.
Oerum, Quantitative Blutuntersuchungen. Deutsches Arch. f. klin. Med., 92, 356,

1908.
Ott, Gesetz der Periodizitat physiologischer Funktionen im weiblichen Organismus

Centralbl. f. Gynak., 1890, Beil. S., 31.

Otten, M., Zur Klinik der Chlorose. Jahrb. d. Ham. Staatskrankenanst., 10, 1905.
Pdl, IJber das Vorkommen mydriatisch wirkender Substanzen im Harne. Deutsche med.

Wchenschr., 1907, 1735.

Pankow, Die Ursachen der Uterusblutungen. Miinchen. med. Wchenschr., 52, 1909.
Parhon and Mihailesco, Sur un cas d'infantilisme dysth. et dysorch. J. de Xeurol., 14,

210, 1908.
Pelikan, Gerichtlich-medizinische Untersuchungen iiber das Skopzentum in Russland.

Translated by Ivanico, Giessen, 1876.
Pellizzi, G. B., La sindrome epifisaria " macrogenitosomia precoce," Riv., ital. di neuro-

pat. [etc.], 3, 1910.

Peritz, Uber Eunuchoide. Neurol. Centralbl., 1910, 1286.
Pfister, Die Wirkung der Kastration. Arch. f. Gynaek., 56, 583, 1898.
Pfliiger, E., Uber die Bedeutung und Ursache der Menstruation. Untersuchungen aus

dem physiol, Lab., Bonn., 1865.

Pick, Uber Neubildungen am Genitale bie Zwittern. Arch. f. Gynaek., 76, 191, 1905.
Pirsche, De Tinflueace de la castration sur le developpement du squelette, Paris, 1902.
Pittard, La castration chez 1'homme. Compt. rend. Acad. d. sc., 1903.
Plesch, Hamodynamische Studien. Berlin, Hirschwald, 1909.
Ploss, see Neurath.
Pommer, G., Untersuchungen iiber Osteomalazie und Rachitis, etc. F. C. W. Vogel,

Leipzig, 1885.
Forges and Novak, Uber die Ursache der Azetonurie bie Schwangeren. Berl. klin.

Wchenschr., 1911, Nr. 39.
Pregl, Zwei weitere ergographische Versuche iiber die Wirkung orchitischen Extraktes.

Arch. f. d. ges. Physiol. de med., 62, 1896.
Rabuteau, De Finfluence de la menstruation sur la nutrition. Gaz. hebd., 1870. Jahresb.

ii. d. Fortschr. d. Theirchemie, i, 291, 1871.
Ravano, Uber die Frage nach der Tatigkeit des Eierstocks in der Schwangerschaft.

Arch. f. Gynaek., 83, 587, 1907.
Rebaudi, Atti soc. ital. d'obstetr. e gin., 15. Cited by Holfbauer, Arch. f. Gynaek., 93,

4°5-

Recklinghausen, v., Untersuchungen iiber Rachitis und Osteomalazie, Jena, 1910.
Recklinghausen, v., Festschrift f. Virchow, 1891.
Regis, cited by Novak.
Reinl, Die Wellenbewegung der Lebensprozesse des Weibes. Volkmann's Samml., 1900,

243-
— Untersuchungen iiber den Hamoglobingehalt des Blutes in den letzten Monaten der

Graviditat. Beitr. z. Geburtsh. u. Gynak., Stutrg., Stuttgart.
Reuss, v., Sehnervenleiden infolge von Graviditat. Wien. klin. Wchenschr., 1908, Nr. 31,

1116.

Redlich, Ein Fall von Gigantismus inf. Wien. klin. Rundschau, 1896.
Reinhardt, Adrenalin und Osteomalazie. Centralbl. f. Gynak., 1907, Nr. 52.
Rethers, Th., Beitrage zur Pathologic der Chlorose. Dissertation, Berlin, 1891, 8.
Ribbert, Uber Veranderungen transplantierten Gewebes Arch. f. Entwickelngsmechn. d

Organ, 6, 131, 1897.

SEXUAL GLANDS 643

—Uber Transplantation von Ovarien, Hoden und Mamma, 7, ibidem, 1898.

Riedel, Menstruatio praecox und Ovarialsarkom. Wien. klin. Wochenschr., 1904, 942.

Rieder, cited by v. Noorden und v. Jagic.

Reidinger, J., Uber Folgen des Verlustes beider Hoden am Ende der Wachstumsperiode.

Ztschr. f. orthop. Chir., 25.

Rieger, C., Die Kastration. Gust. Fischer, Jena, 1900.
Rist, and Guillemont, De 1'oligosideremie des jeunes enfants et de ses rapports avec la

chlorose des jeunes filles. Semaine med., 1906, 547.
Roberts, citation in Bischo/, Beweis der von der Begattung unabhangigen periodischen

Reifung und Loslosung der Eier, etc. Giessen, 1844, 40.
— Cited by Mobius.
Romberg, Bemerkungen iiber Chlorose und ihre Behandlung. Berl. klin. Wchenschr.,

1897, Nr. 25.

Sacchi, E., Di un case di gigantismo infantile, etc. Riv. sper. di freniat., 21, 1895.
Sainton, Paul, Un cas d'eunuchoidisme familial. N. iconog. de la. SalpStriere 15, 1902.
Sainton and Dupre, Les characteres cliniques de 1'insuffisance testiculaire. These de

Paris, 1904/05.
Salen, E., Ein Fall von Hermaphroditismus verus unilateralis. Verhandl. d. deutsch.

path. Gesellsch., 1899, 241.

Salomon and Saxl, Beitrage zur Karzinomforschung, 1910, Heft 2.
Scanzoni, Schmidt's Jahrb., 39, 1853.

Schauta, Die Pygopagenschwestern Blazek. Gynaek. Rundschau, 1910, 437.
Schmidt, B., Referat iiber Rachitis und Osteomalazie. Verhandl. d. deutsch. path.

Gesellsch., 1909, 15-17, April.

Seiler, F., Uber larvierte Chlorose. Cor.-Bl. f. Schweiz. Aerzte, 1909, Nr. 17.
Seitz, Die Follikelatresie wahrend der Schwangerschaft, insbesondere die Hypertrophie
und Hyperplasie der Theca-interna-Zellen und ihre Beziehung zur Corpusluteum-
bildung. Arch. f. Gynaek., 77, 203, 1905.
Sellheim, Kastration und Knochenwachstum. Beitr. z. Geburtsh. u. Gynak., Leip., 2,

1899.
— Kastration und sekundare 'Geschlechtscharaktere. Beitr. z. Geburtsh. u. Gynak.,

Leip., 5, 409, 1901.
Siegert, Die Atiologie der Rachitis auf Grund neuerer Untersuchungen. Munchen. med.

Wchenschr., 1905, 622.

Simon, Hermaphroditismus verus. Arch. f. path. Anat. [etc.], Berl., 172, 1903.
Simonds, Uber die Einwirkung von Rontgenstrahlen auf die Hoden. Fortschr. a. d.

Geb. d. Rontgenstrahlalen, 14, 1909/10.

Slocum, citation in Halban. Wien. klin. Wchenschr., 1906, Nr. i.
Smith, A discussion on the blood in disease. Tr. Path. Soc., London, 2, 311, 1900.
Starling and Lane Claypon, Hormon der Brustdrxise. Proc. Roy. Soc. London, 77, 1005.
— Citation in Bayliss und Starling, Ergebn. d. Physiol., 5, 664, 1906.
Steinach, Willkiirliche Umwandlung von Saugetiermannchen in Tiere mit ausgepragtem
weiblichem Geschlechtscharakter und weiblicher Psyche, etc. Arch. f. d. ges.
Physiol., 144, 71, 1912.
— Geschlechtstrieb und echt sekundare Geschlechtsmerkmale als Folge der innersekre-

torischen Funktion der Keimdrusen, etc. Centralbl. f. Physiol., 24, 551, 1910.
Stieda, A ., Uber einen im jugendlichen Alter Kastrierten. Deutsche med. Wchenschr.,

1908, Nr. 18.
Stacker, citation in Floss.

Stoeltzner, W., Schwere Sauglingsanamie durch primaren Eisenmangel. Med. Klin.,

1909, Nr. 26.

644 LITERATURE

Stone. R., Extraordinary precocity, etc. Am. J. of Med., 24, 561, 1852.

Strada. Patologica, I, 17, 1909.

Swinarski-Pfanncnsticl. citation in Pick.

Tandler, J., Untersuchungen an Skopzen. Wien. klin. Wchenschr., 1908, 277.

— Uber den Einfluss der innersekretorischen Anteile der Geschlechtsdrtisen auf die

aussere Erscheinung des Menschen. Wien. klin. Wchenschr., 1910, 459.
Tandler and Grosz, Einfluss der Kastration auf den Organismus. Wien. klin. Wchenschr.,

1907, 1596.
— Beschreibung eines Eunuchen-Skeletts. Arch. f. Entwcklngsmechn. d. Organ., 27,

1909.

— Die Skopzen. Ibidem, 30, 1910.
— Die Eunuchoide. Ibidem, 29, 1910.
Thibierge and Gastinel, Un cas de gigantisme infant. N. iconog. de la Salpetriere, 22, 442,

1909.

Trousseau, Med. Klinik, Hotel de Dieu. Wiirzburg, 3, 405, 1868.
Uhlhojj!, Ein Beitrag zu den Sehstorungen bei Zwergwuchs und Riesenwuchs resp. Akro-

megalie. Berl. klin. Wchenschr., 1897.

Variot, Observations sur un cryptorchide. Gaz. med. de Par., 1892, 76.
Variot and Besanqon, P., Independance de la spermatogene et de la secretion testiculaire.

Bull. Soc. anthrop., 1892.
Villemin, Sur le role du corps jaune ovarien chez la femme et la lapine. Compt. rend.

Soc. de biol., 64, 363, 1908.

— Sur les rapports du corps jaune avec la menstruation chez le rut. Ibidem, 444.
Virchow, Ueber Chlorose and die damit zusammenhangenden Anomalien im Gefass-

apparat. Berlin, 1872.

Walcher, Verhandl. deutsch. Naturforscher u. Aerzte. Stuttgart, 1906.
Wallart, J., Untersuchungen liber die interstitielle EierstockdrUse beim Menschen.

Arch. f. Gynaek, 81, 271.

— Uber das Verhalten der interstitiellen Eierstockdruse bei Osteomalazie. Ztschr. f.

Geburth. u. Gynaek., 61, 851.
Weber, M., Uber einen Fall von Hermaphroditismus bei Fringilla coelebs. Zool. Anz.,

13, 508, 1890.
Wetzler, citation in Ploss. Das Weib in der Natur- und Volkerkunde. v. Bartels Arch.,

i, 1899, VI. Auflage.
Widal and Lutier, Atrophie congenitale complete des testicules. Absence d'infantilisme

et de feminisme. Bull, et men. Soc. med. d. hop. de Par., Mars, 1912.
Woljf, Br., Zur Kenntnis der Entwicklungsanomalien bei Infantilismus und bei vorzeitiger

Geschlechtsreife. Arch. f. Gynaek., 94.
Zander, Zur Lehre von der Atiologie, Pathogenic und Therapie der Chlorose. Arch. f.

path. Anat. [etc.], Berl., 84, 177.
Zangemeister, Die Beschaffenheit des Blutes in der Schwangerschaft und der Geburt.

Ztschr. f. Geburts. u. Gynaek., 49, 92.
Ziehen, Demonstration in der Gesellsch. der Charite-Arzte Berlin. Berl. klin. Wchenschr.,

1906, 1905.
Zoth, Zwei ergographische Versuchsreihen Uber die Wirkung orchitischen Extraktes.

Arch. f. d. ges. Physiol., 62, 1896.

— Neue Versuche (Hantelversuche) Uber die Wirkung orchitischen Extrakts. Ibidem,

69, 1898.

Zuntz, L., Weitere Untersuchungen Uber den Einfluss der Ovarien auf den respiratorischen
Stoffwechsel. Arch. f. Gynaek., 96, 188, 1912.

CHAPTER XI

PLURIGLANDULAR DISEASES

A pert, see suprarenals.

Biedl, Innere Sekretion. Urban u. Schwarzenberg, Wien u. Berlin, 1910.

Bellinger, Uber Zwerg- und Riesenwuchs. Samml. gemeinn. wiss. Vortr. Virchow u.

v. Holzendorf, Nr. 455, Berlin, 1895.

Brissaud and Meige, Journal de med. et chir. prat., 25 Janv., 1895.
Buday and Janscd, Ein Fall von pathologischem Riesenwuchs. Deutsches. Arch. f.

klin. Med., 60.

Claude, Acromegalie sans Gigantisme. Encephale, 1907, 295.
Claude and Gougerot, Sur 1'nsufisance simultanee de plusieurs glandes a secretion interne

(Insuffisance pluriglandulaire). Compt. rend. soc. de biol., 63, 785, 1907.
Claude and Gougerol, Les syndromes d'insuffisance pluriglandulaire, leur place en noso-

graphie. Rev. de med., 10 Nov. et Nov., 1908, 861, 950.
Cordier and Rebattu, Infantilisme regressif ou tardif. N. iconog. de la Salpetriere, 24, 405,

1911.
Gushing, The pituitary body and its disorders. J. B. Lippincott Co., Philadelphia and

London.

Djemil Pascha, Un cas de myxoedeme operatoire, etc. Arch, internal, de chir., 1903, 81.
Folk, Fr., Gesellsch. f. inn. Med. u. Kinderh., i Juni, 1911. Wien. med. Wchenschr.,

1911, 1819.
Falta, W., Spateunuchoidismus und multiple Blutdriisensklerose. Berl. klin. Wchenschr.,

Nr. 30 u.-3i, 1912;
Fischer, B., see hypophysis:
Candy, M., Myxoedeme acquis de 1'adulte avec regression sexuelle, etc. Soc. med. d.

hop. de Par., 7 Dec., 1906, 19, 1226.

— Infantilisme tardif de 1'adulte. Bull. et. mem. Soc. med. d. hop. de Par., Juin, 1911,

387 et Bull, med., Juin, 1911.

Gougerod and Gy, Insuffisance pluriglandulaire interne thyreotesticule surrenale. N.
iconog. de la Salpetriere, 24, 449, 1911.

— Insuffisance endocrinienne thyreoido-testicul. Rev. neurol., 2, 1354, 1908.
Gouilloud, Soc. med. de Lyon, 14, May, 1900, in Lyon med.

Griinfeld, Sitzungsb. Deutsche med. Wchenschr., 5, 45, 1901.

Hastings, Gilford, The disorders of postnatal growth and development. London, Adlard

and Son, 1911.

- See also Med. Chir. Tr. 80, 1897 and Practitioner 73, 188, 1904.
Huchard and Launois, Gigantisme acromeg., etc. Bull, et mem. Soc. med. d. h6p. de Par.,

Dec., 1903.

Hutchinson, Jonathan, cited by Gilford Hastings.
Hutchinson, Woods, Acromegaly and gigantism. N. York M. J., July 21, 1900 and

Am. J. M. Sc., 1895, 190.

Josserand, A propos de 1'infantilisme reversif. Lyon med., 8 Janv., 1911.
Longer, C. v. Wachstum des menschlichen Skelettes in bezug auf. den Riesen. Denkschr.

d. kais. Akad. d. Wissenschr. Wien. Math-naturw. Kl., 31, i, 91, 1872.
Larrey, Memoires de Chirurgie militaire et campagnes, 2, 62, 1912.

645

646 LITERATURE

Lamwis and Roy, Des relations, qui existent entre Petat des glands genitales et le develop-

pement devie du squelette. Compt. rend. Soc. de Biol., 10 Janv., 1903, 22 et N.

iconog. de la Salpetriere., 1902.
— Etude biologique sur les geants, Paris, 1904.
Levi, E., and Frachini, Contribution a la connaissance du Gigantisme, etc. N. iconog. de

la Salpetriere, 22, 449, 1909.

Lorand, Das Altern. Werner Klinkhardt, Leipzig, 1910.
Manasse, Sitzungsber. Berl. klin. Wchenschr., 1890, Nr. 18, 411.
Marie, P., see Launois et Roy.

Massalongo, Sull'acromeglia. Riforma med., 1892, 74.
Meige, H., Sur le Gigantisme. Arch. gen. de Med. Oct., 1902, 410.
Noorden, v., tJber Chlorose. Med. Klin., 1910, Nr. i.
Poncet and Leriche, Tuberculose inflammatoire des glandes vasculaires sanguines. Bull.

Acad. de med., 27 Juin, 1911.

Ponfick, Myxodem und Hypophyse. Ztschr. f. klin. Med., 38, i, 1899.
Ransom, cited by Gilford Hastings.
Rumpel, Fall von myxodemartiger Erkrankung bei Hodenatrophie. Neurol. Centralbl.,

15, 428, 1896.
Sainton and Rathery, Myxoedeme et tumeur de 1'hypophyse. Contribution a 1'etude des

insuffisances pluriglandulaires. Bull, et mem. Soc. d. hop. de. Par., 8 Mai, 1908,

647.

Sternberg, Beitrage zur Kenntnis der Akromegalie. Ztschr. f. klin. Med., 27, 1895.
Thompson, Atrophy of the parathyreoi'd glands and other glands, structures in primary

infantile atrophy. Am. J. M. Sc., Oct., 1907, 562.
Variot and Pironneau, 'Nanisme avec Dystrophie osseuse et cutanee speciales; soupcon

d'agenesie des capsules surrenales. Bull. Soc. de pediat. de Par., Juin, 1910, 307

et la clinique infantile, 8, 705, 1910.
Wiedenmann, Uber partiellen Riesenwuchs. Beitr. z. klin. Chir., 8, 625, 1892.

CHAPTER XII

VEGETATIVE DISTURBANCES, ETC.

Agosiini, Infantilismo distrofico et infantilismo mixoedematoso, etc. Riv. de patol.

nerv., 1902.
Anton, Vier Vortrage xiber Entwicklungsstorung beim Kind. Berlin, 1908 und Reiner

Psychoinfantilismus. Forens. Psychiatric, 1910, 2.
A pert and Rouillard, Juvenilisme pur. Origine dysthroi'den de 1'infantilisme et de

juvenilisme. Bull, et mem. Soc. med. d. hop. de Par., 28, 84.
Aschner, B., tlber einen Fall von hypoplastischem Zwergwuchs mit Graviditat, etc.,

Monatschr. f. Geburtsh. u. Gynaek., 32, 644, 1910.
A unet-Br6ton, cited by di Gasper o.
Baillarger, cited by di Gaspero.
Bartel, see suprarenals.

Bauer, Infantilisme et chetivisme. Presse med., 4 Dec., 1909.
Bertoletti, M., Contribution a 1'etude du Gigant. acrom. inf. N. iconog. de la Salpetriere,

1910, i.
Bourneville, Idiotic und Infantilismus. Kongr.-Ber. Briissel. Ref. Monatschr. f.

Kinderh., 1903, 326.
Bourneville and Bord. Cas d'iodiotie mongolienne. Rev. d'hyg. et de med. inf., 5, 221,

1906.

Bramwell, Case of infantilism. Clinical study, Edinburgh, 1903, 157.
Breus and Kolisko, Die pathologischen Beckenformen I. Leipzig und Wien, Deuticke.
Brissaud, Lecons sur les malad. nerv. (Hop. St. Antoine) Paris, 1899 und De 1'infantilisme

myx. N. iconog. de la Salpetriere, 1897 und De 1'infantilisme vrai. Ibidem, 1907.
Cestan, A propos d'un cas d'achoridroplasie. N. iconog. de la Salpetriere., 14, 277, 1901.
Comby, Le mongolisme. Arch, de med. des enf., 1903, 1906 u. 1907. Bull, et mem.

Soc. d. hop. de Par., 1905 u. 1906.
Dancel, cited by di Gaspero.

Decroly, Policlinique Bruxelles. 1902, Nr. 2, 1906, Nr. 15.
Diederle, tlber endemischen Kretinismus und dessen Zusammenhang mit anderen

Entwickelungsstorungen. Jahrb. f. Kinderh., 1906, 465, 576.
Dolega, Ein Fall von Kretinismus beruhend auf einer primaren Hemmung des Knochen-

wachstums. Beitr. z. path. Anat. u. Physol., 9, 488.
Dufour, Achondroplasie partielle, forme atypique. N. iconog. de la salpetiere, 19, 133,

1908.
Dupre and P. Pagniez, Infantilisme degen. (type Lorain) complique de dysthyreoidie

puberale (type Brissaud). N. iconog. de la Salpetriere, 15, 124, 1902.
Eichholtz, Achondroplasia. Brit. M. J., i, 1229, 1910.
Euziere and Delmas, A propos d'une nouvelle observation d'achondrodysplasie. N.

iconog. de la Salpetriere, 1911, 380.
Ferranini, Uber den von der Schilddriise unabhangigen Infantilismus. Arch. f. Psychiat.,

38, 1904.
Franchini, G., et Zanasi, M., L'achondroplasie est-elle hereditaire, etc. N. iconog. de la

Salpe'triere, 23, 245, 1910.

Gaspero, di, Der psychische Infantilismus. Arch. f. Psychiat., 43, 28, 1907.

647

648 LITERATURE

Gilbert and Ratltery, Nanisme mitral. Presse med.,' 37, 38, 1900.

CiliissHcr. Protokoll der k. k. Gesellsch. d. Aerzte in Wien. Wien. klin. Wchenschr.,

1909, Nr. 10.

Gulcckc. Zwergwuchs infolge pramaturer Synostose. Arch. f. klin. Chir., 83, 1907.

Hagenbach, see chapter on hypophysis.

Hanscmann, v., Echte Nanosomie, etc. Berl. klin. Wchenschr., 1902, Nr. 52.

Hcgar. Munch, med. Wchenschr., 1905, Nr. n. Entwickelungsstorungen. Deutsche

med. Wchenschr., 1910, Nr. 40.
Hertoghe, De I'hypothyreeiidie benigne chronique ou myxoedeme fruste. N. iconog. de la

Saltpetriere, Juli/Aug., 1899.

His, W., Zur Kasuistik des Kretinismus. Arch. f. path. Anat. [etc.], Berl., 22, 104, 1861.
Hitschmann. Augenuntersuchungen bei Kretinismus und Zwergwuchs, etc. Wien.

klin. Wchenschr., 27, 1898.
Holdmoser, Uber einen Fall von Zwergwuchs, verbunden mit angeborener Enge der Aorta.

Wien. klin. Wchenschr., 15, 408, 1899.

Joachimsthal, Uber den Zwergwuchs, etc. Deutsche med. Wchenschr., 1899, Nr. 17.
Jojfroy, Paralysie generate juvenile, etc. Encephale, 1908, 7, i.
Kassowitz, Infantiles Myxodem, Mongolismus und Mikromelie. Wien. med. Wchenschr.,

1902, Nr. 22 u. Forts.
Katolicky, Protokoll der Gesellsch. d. Aerzte in Wien. Wien. klin. Wchenschr., 1909,

Nr. 10.

Kaufmann, E., Untersuchungen liber die sogennante fotale Rachitis. Berlin, 1892.
Krauss, Inaug.-Diss. Frieburg, 187-5.
Kundrat, see status lymphaticus.
Lampe, Inaug.-Diss. Marburg, 1895.

Langdon-Down, Clin. lect. A report of the London Hosp., 3, 1866.
Lange, Beitr. zur pathologischen Anatomic des Mongolismus. Monatschr. f. Kinderh.,

1906, 233.
Langenbach, Ein Fall von Chondrodystrophia foetalis mit Asymmetric des Schadels.

Arch. f. path. Anat. [etc.], Berl., 189, 1907.
Langer, Ztschr. d. Gesellsch. d. Arzte in. Wien., 17, 1861.
Launois, Essai biologique sur les nains. Le Bull, med., 1909, 957.
Lauze, De 1'achondroplasie specialement etudiee au point de vue mentale. These de

Paris, 1910, 335.
Lereboullet, Sur un cas de cirrhose biliaire anicterique. Bull. soc. de ped. de Paris, 3,

89, 1901.

— Les cirrhoses biliaires. These de Paris, 1902, 76.

Levi, Ett, Contribut. a la connaissance de la microsomie, etc. N. iconog. de la Salpetriere,

1910, 522.

— Encore sur la question des infantilismes. N. iconog. de la Salpetriere, 1910, 20.
Lorain, Lettre preface a la these de Faneau de la Cour, 1871.

Marie, Pierre, L'achondroplasie dans 1'adolescence et 1'age adulte. Presse med., 14

Juill, 1909.
Meige, Remarques complementaries sur les nains dans 1'art. N. iconog. de la Salpetriere,

1896 u. 1901, 371.

— L'infantilisme. Gaz. d. hop., 22, 207, 1902.

Meige, and Allard, Deux infantiles, Infantile myx. et infant, de Lorain. N. iconog. Sal-
petriere, 2, 1898.

Moro, Fotale Chondrodystrophie u. Thyreodysplasie. Jahrb. d. Kinderh., 66, 1807.
Miiller, H., Wiarzb. med. Ztschr., i, 1860.

VEGETATIVE DISTURBANCES, ETC. 649

Neumann, H., Uber den mongoloiden Typus der Idiotic. Berl. klin. Wchenschr., 1899,

210.
Neurath, Mongolismus mit myxodemahnlichen Symptomen. Wien. med. Wchenschr.,

1907, 1132.

Paltauf, A., Uber den Zwergwuchs. Wien, 1891, Holder.
Pende, Begriff und Pathogenese des Infantilismus. Deutsches Arch. f. klin. Med., 105,

179, 1910.

Peretz, Der Infantilismus. Ergebn. d. inn Med. u. Kinderh., 7, 405, 1911.
Poncet and Leriche, Nains d'aujourdhui et nains d'autrefois. Ann. de med. et chir. inf.,

1903, Nr. 21.
Porak, De 1'achondroplasie. Cermont, 1890. N. Arch, d'obst. et de gynec., 1890, 19.

L'obst., 1905, 249.
Ranke, H. and Voit, Uber den amerikanischen Zwerg Frank Flynn, genannt, General

Mite, etc. Arch. f. Anthrop., 16, 1886.
Rentoul, Pancreat. infantilisme. Brit. M. J., n, 1694, 1904.
Richon and Jeandelize, Sur 1'origine testiculaire possible de certains cas d'infantilisme.

Province med., 23 Juin, 1906.
Saiton, Les nains. Tribune med., 8 Mars, 1909.
Sanctis, Sante de, Gli infantilismi. Annali di nevrolog., 26, 1908 and Riv. sper. di freniat.,

3> 1905-

Schaafhausen,~Ber. der niederrhein. Gesellsch. f. Naturh., Bonn., 25, 1898.
Schauta, Die Beckenanomalien. Mailer's Handb. d. Geburtsh., 1888, 308.
Scholz, W., Kretinismus und Mongolismus. Ergebn. d. inn. Med. u. Kinderh., 3, 505,

1909.

Schuller, Uber Infantilismus. Wien. med. Wchenschr., 1907, Nr. 13.
Shuttelworth, Mentally deficient children. London, H. K. Lewis, 1909, III. Edition.
Siegert, F., Der Monogolismus. Ergebn. d. innere. Med. u. Kinderh., 6, 565, 1910.
— Der chondrodystrophische Zwergwuchs. Ergebn. d. innere Med. u. Kinderh., 8, 64,

1912.

Sommering, cited by Kaufmann.

Sumita, Jahrb. f. Nervenh., 73,' 1911. Deutsche Ztschr. f. Chir., 107, 1911.
Tandler, J., Uber Infantilismus. Wien. med. Presse, 1907, Nr. 15.
Tarujfi, cited by Levi.

Vogt, Uber den mongoloiden Typus der Idiotic. Neurol. Centralbl., 1906, 476.
Weil, Albert, Une famille d'achondroplasiques. Bull et mem. Soc. radiol. med. de Par.,

4, 134, 1912.
Woljff, see eunuchoidism.
Ziehen, Ideenassoziationen des Kindes. Samml. aus Abhandl. a. d. Gebiet. d. Pada-

gogik. Psych, u. Physiol., i, Heft 6.

CHAPTER XIII
PANCREAS

A belmann, Uber die Ausnutzung der Nahrungsstoffe nach Pankreasexstirpation. Inaug-

Diss. Dorpat, 1890.
Albu, Beitrag zur Diagnostik der inneren und chirurgischen Pankreaserkrankungen.

Samml. zwangl. Abhandl., 3, i, 1911.
Allard, Die Acidose beim Pankreasdiabetes. Arch. f. exper. Path. u. Pharmakol., 59,

388, 1908.

Aschner, see chapter on hypophysis.
Asher, Das Krankheitsbild des traumatischen Diabetes vorwiegend vom forensischen

Standpunkte. Vrtljschr. f. gerichtl. Med., 8, 219, 1894.

Balser, Fettnekrose der Bauchspeicheldriise. Arch. f. path. Anat. [etc.], Berl., 40.
Bence, J., Untersuchungen in einem Fall von Pankreatitis und Hepatitis interstitialis,

etc. Wien. klin, Wchenschr., 1907, Nr. 24.
Benedict, Fr. G. and E. M. P. Joslin, Metabolism in Diabetes mellitus. Publ. Nr. 136.

Carnegie Institution of Washington, 1910.
Bernard, Claude, Vorlesungen iiber Diabetes, 1878.
Bernstein and Falta, Uber die Einwirkung von Adrenalin, Pituitrinum infundibulare

und Pituitrinum glandulare auf den respiratorischen Stoffwechsel, 29. Kongr. f.

innere Med., 1912, 536.

Biedl, A., Innere Sekretion. Urban und Schwarzenberg, 1910.
Biedl, A., and Th. Offer, Uber Beziehungen der Duktuslymphe zum Zuckerhaushalt,

etc. Wien. klin. Wchenschr., 1907, 1530.
Du Bois, Eugene F., and Borden S. Veeder, The total energy requirement in diabetes

mellitus. Arch. Int. Med., 5, 37 Jan., 1910.
Bor chard, Uber das Auftreten und die Ursache von Glykosurie, Albuminurie und Cyl-

indrurie nach schweren Schadelverletzungen. Monatschr. f. Unfallheilk., Dec.,

1902; Wien. med. Bl., 1903, 23.

Bouchardat, Monographic sur le diabete. Paris, 1875.
Burckhardt, Uber die Leistungen verlagerter Pankreasstiicke fur die Ausnutzung der

Nahrung im Darm. Arch. f. exper. Path. u. Pharmakol., 58, 251, 1908.
Cantani, Diabetes mellitus. Translated by S. Hahn, Berlin, 1880.
Cdtola, Un glioma dei plessi corroidei de IV ventricolo. Reference in Centralbl. f.

Neurol., 1902, 364.
Cecil, Russel L., A study of the pathological anatomy of the pancreas, etc. Proc. N.

York Path. Soc., Dec., 1908 and Jan., 1909.
Chauveau and Kaufmann, La pancreas et le centre nerveux. Compt. rend. Acad. de sc.

1893, 463; Pathogenic du diabete. Ibid., 1893, 226.
Chrelitzer, Festschrift. Beitr. z. Dermat. u. Syph., 1900.
Deucher, Stoffwechseluntersuchungen bei Verschluss des Ductus thoracicus. Cor.-Bl. f.

Schweiz. Aerzte, 28, 327.
Diamare, V., Zur vergleichenden Physiologic des Pankreas and iiber die physiologische

Bedeutung der Langerhansschen Inseln im Pankreas. 3. Mitteilung. Centralbl.

f. Physiol., 1905, Nr. 19 und 1908, Nr. 21.
Dieckhojf, Chr., Beitrage zur pathologischen Anatomic des Pankreas, etc., Inaug.-Diss.,

Rostock, 1894.

650

PANCREAS 651

Drummond, David, Clin. et path, illustrations of cerebral lesions. Reference in Neurol.

Centralbl., 1877, 83. •
Dub, Ein Beitrag zur Lehre vom Diabetes mellitus. Prag Vrtljschr. f. prakt. Heilk., 20,

i, 1863.

Dutrait, Diabetes; Apoplexie am Boden des 4 Ventrikels. J. d. Bruxelles, 61, 422.
v. Ebner, V., Kollikers Handb. d. Gewebelehre, 6 Aufl., 3, Leipzig, 1899.
Ebslein, Traumatische Neurose und Diabetes. Arch. f. klin. Med., 54, 1895.
Ehrmann, R., Uber schweren Diabetes infolge syphilitischer Infektion. Deutsche med.

Wchenschr., 1908, Nr. 30.
Emden and Laites, Uber die Acetessigsaurebildung in der Leber des diabetischen Hundes.

Beitr. z. chem. Phys. u. Path., n, 327.
Eppinger and Falta, see Falta, Therapie des Diabetes mellitus. Ergebn. d. inn. Med.

u. Kinderh., 2, 1908.
Eppinger, Falta, and Rudinger, Uber die Wechselwirkung der Driisen mit innerer Se-

kretion. Ztschr. f. klin. Med., 66 u. 67, i. u. 2. Mitteil.
Falta, W., Uber die Gesetze der Zuckerausscheidung beim Diabetes mellitus. 10.

Mitteil., Ztschr. f. klin. Med., 61, 63, 65 u. 66. Die Therapie des Diabetes

mellitus. Ergebn. d. inn. Med. u. Kinderh., 2.
— Uber die Bedeutung der Blutdriisen in der Pathogenese des Diabetes mellitus. Prag.

med. Wchenschr., 35, 1910.
Falta, in collaboration with Benedict and Joslin, Untersuchungen mit dem Respirations-

kalorimeter iiber den Energieumsatz beim Diabetes mellitus. 26. Kongr. f . innere.

Med., 498, 1909.
Falta and Fleming, Uber die Wirkung des Adrenalins und Pituitrins auf den iiberle-

benden Kaninchenuterus, etc. Miinchen. med. Wchenschr., 1911, Nr. 50.
Falta, Grote, and Staehelin, Versuche iiber Stoffwechsel und Energieverbrauch pan-

kreasloser Hunde. Beitr. z. chem. Phys. u. Path., 10, 1907.
Falta, Newburgk, and Nobel, Uber die Wechselwirkung der Driisen mit innerer Sekretion.

Uberfunktion und {Constitution. Ztschr. f. klin. Med., 72.
Falta and Priestly, Beitrag zu Regulation von Blutdruck und Kohlehydratstoffwechsel

durch das chromaffine System. Berl. klin. Wchenschr., 1911, Nr. 47.
Fleckseder, Rr, Uber die Rolle des Pankreas bei der Resorption der Nahrungsstoffe aus

dem Darm. Arch. f. exper. Path. u. Pharmakol., 59, 1908.
Flint, J. M., Das Bindegewebe der Speicheldriisen und des Pankreas, etc. Arch. f.

Anat. u. Physiol., Anat. Abt., 1903, 61.

Frerichs, Uber den Diabetes. Berlin, Aug., 1884. Hirschwald.
Forschbach, Parabiose und Pankreasdiabetes. Deutsch. med. Wochenschr., 1908, i; Zur

Pathogenese des Pankreasdiabetes. Arch. f. exper. Path. u. Pharmakol., 60, 1909.
v. Filrth and Schwarz, Uber die Hemmung der Adrenalinglykosurie durch Pankreas-

praparate. Biochem. Ztschr., 31, 113, 1911.
Gigon, Uber Gesetze der Zuckerausscheidung beim Diabetes mellitus. 3. Mitteil.

Ztschr. f. klin. Med., 65, 313; 1908.
Gley, E., Sur le diabete alimentaire chez les animaux prives du pancreas. Compt. rend.

soc. de biol., 1891, 752.

Gulecke, N., Uber die experimentelle Pankreasnekrose, etc. Arch. f. klin. Chir., 85.
Guttmann, Beitrage zur Histologie des Pankreas. Arch. f. path. Anat. [etc.], Berl., 177,

Spplbd., 1904, 128; Beitrage zur Pathologic des Pankreas bei Diabetes mellitus.

Areh. f. path. Anat. [etc.], Berl., 172, 493, 1903.
Haedke, Metatraumatische alimentare Glykosurie. Deutsch. med. Wchenschr., 1900,

501.

652 LITERATURE

v. Halasz, Uber Veranderungen des Pankreas bei Zuckerkranken unter Beriicksichtigung

Atiologischer Momente und des klinischen Yerlaufs. Wien. klin. Wchenschr.,

1909, Nr. 43.
Hammond cited by Migazzini Pathologic und Symptomatologie der Kleinhirner-

krankungen. Ergebn. d. Neurol., i, 1912.
Hansemann, Uber die Struktur, das Wesen der Gefassinseln. Verhandl. d. path.

Gesellsch., 1901, 187.
H6don, E., Greffe sous-cutanee du pancreas. Arch, de physiol. norm, et path., 1892,

617.
Heiberg, K. A., Studien iiber die pathologisch-anatomische Grundlage des Diabetes

mellitus. Arch. f. path. Anat. [etc.], Berl., 204, 175, 1911. Uber Diabetes bei

Kindern. Arch. f. Kinderh., 56, 1911.
Hemptenmacher, Uber einen Fall von Diabetes mellitus syphiliticus. Mitt. a. d. Hamb.,

Staatskrankenanst., 1901, 616.
Herxheimer, Pankreas und Diabetes mellitus. Deutsche med. Wchenschr., 1906, 829.

Zur Frage liber das Verhalten der Langerhansschen Inseln bei Diabetes mellitus.

Festschr. f. Orth, Berlin, 1903. Uber Pankreaszirrhose. Arch. f. path. Anat.

[etc.], Berl., 183, 228, 1906.
Hess, Experimented Beitrage zur Anatomic und Pathologic des Pankreas. Med.-naturw.

Arch., i, 1907.

Higgins and Ogden, Monatschr. f. Unfallheik, 3, Nr. i.
Hirschfeld, Uber infektiose Entstehung der chronischen Pankreatitis und des Diabetes.

Berl. klin. Wchenschr., 1908, Nr. n.
— Weitere Beitrage zur Atiologie^des Diabetes mellitus. Berl. klin. Wchenschr., 1912,

198.

Hofmeister, F., Nothnagelvorlesung. Wien., Dec., 1912.
Honiger, Uber die ephemare traumatische Glykosurie bei Neugeborenen. Deutsche

med. Wchenschr., 1911, 500.

Kahn, %. H., Zuckerstich und Nebennieren. Arch. f. d. ges. Physiol., 140, 209, 1911.
Kdmnitz, Uber einen Fall von Kopfverletzung mit darauffolgendem Diabetes. Arch.

d. Heilk., 1873, 447.
-v. Karakaschejf, K. J., Uber das Verhalten der Langerhansschen Inseln bei Diabetes

mellitus. Deutsches Arch. f. klin. Med., 82, 1904; 87, 1906.
Katz and Winkler, Experimentelle Studien iiber Fettgewebsnekrose des Pankreas.

Arch. f. Vedauungskr., 4, 289, 1898.

Kausch, Trauma und Diabetes. Ztschr. f. klin. Med., Festbd. f. Naunyn, 1904.
Keuthe, W., Ein Fall von Pankreasatrophie. Berl. klin. Wchenschr., 1909, 47.
Knouthon and Starling, Uber den Zuckerverbrauch im normalen und im diabetischen

Herzen. Centralbl. f. Physiol., 26, Nr. 4, 169, 1912. — See also On the nature

of pancreatic diabetes. Preliminary communication, Lancet, Sept. 21, 1912, 812.
Korte, Chirurgie des Pankreas. Handb. d. prakt. Chir., 3. Aufl., 1907.
Kilhne and Lea, Uber die Absonderung des Pankreas. Untersuchungen a. d. physiol.

Institut Heidelberg, 2, Heft 4, 1882.
Kyrle, Uber die Degenerationsvorgange im tierischen Pankreas. Arch. f. mikr. Anat.

u. Entwcklugsgesch., 72, 141, 1908.
Laguesse, G., Sur la formation des ilots de Langerhans du pancreas. Compt. rend.

soc. de Biol., 44, 1893 u. 65, 1908; J. de 1'ariat. et physiol. [etc.], 30, 31, 32, 95,

96, 1894.
Lanceraux, Notes et reflexions a propos de 2 cas du Diabete sucre avec alterations du

pancreas. Bull. Acad. de med.: 3. Serie, 7, 12-15, 1877.
— Nouveaux faits de Diabete sucre avec alterations du pancreas. Ibidem, 1888.

PANCREAS

653

Langerhans, P., Beitrage zur mikroskopischen Anatomic der Bauchspeicheldriise. Inaug.-

Diss., Berlin, 1869.
Lazarus, Beitrage zur Pathologic und Therapie der Pankreaserkrankungen. Ztschrift.

f. klin. Med., 51 u. 52, 1904.
Leimdorfer, A., tjber den respiratorischen Stoffwechsel des'Diabetikers bei verschiedener

Kostform. Biochem. Ztschr., 40, 326, 1912.
Lemcke, Ein Fall von sehr -defer Erniedrigung der Korpertemperatur nach primarer

Hamorrhagie in der Medulla oblongata, etc. Deutsches Arch, f . klin. Med., 34, 84.
Lemoine and Launois, Lesions du pancreas dans le diabete. Arch, de med. exper. et

d'anat. path., 3, 1891.

Lemonier, Diabete syphilitique. Ann. de dermat. et de Syph., 9, 398, 1888.
Leo, tjber den respiratorischen Stoffwechsel bei Diabetes mellitus. Ztschr. f. klin.

Med., 19, Suppl.-Bd., 101, 1891.
Lepine, R., Die Beziehungen des Diabetes zu Pankreaserkrankungen. Wien. med.

Presse, 1892, 108.

— Le diabete sucre. Paris, 1909, Felix Algan.
Leudet, Moniteur de science, 1860.

Levene, T. A., and G. Meyer, On the combined action of muscle plasma and pancreas

extract, etc. J. of biol. chem., 9, 97, 1911.

Liefmann and Stern, Uber Glykamie und Glykosurie. Biochem. Ztschr., 1906, 299.
Levieralo, Uber die Schwankungen der vom Diabetiker ausgeschiedene Kohlensaure bei

wechselnder Diat und medikamentoser Behandlung. Arch. f. exper. Path. u.

Pharmakol, 15, 161, 1889.
Loeb, Uber Glykosurie und Albuminurie nach Gehirnapoplexien. Deutsche med. Ztg.,

1899, 1057.
Lombroso, U., Kann das nicht in den Darm sezernierende Pankreas auf die Nahrstoffe

einwirken? Arch. f. Path. u. Pharmakol, 60, 99, 1908.

— Die Gewebselemente, welche die innere Funktion des Pankreas besorgen. Lubarsch-

Ostertag, Ergebn. d. Path., 9, 1909.
Lombroso and Sacerdotte, Sqlle modificazioni istologiche del pancreas dei Conigli dopo la

ligatura del dutto del Wirsung. Rend. R. Acad. di Lincei., Roma, 1908.
Lowi, 0., Eine neue Funktion des Pankreas und ihre Beziehung zum Diabetes mellitus.

Arch. f. exper. Path. u. Pharmakol, 50, 1908.
Lusk, The influence of cold and mechanical exercise on the sugar excretion in phloridzin

glykosuria. Am. J. Physiol., June, 1908.
- Science, N. S., 33, Nr. 846, 433, 1911.
Lulhje, H., 1st die Zerstorung des Zuckers nach Pankreasexstirpation vollstandig aufge-

hoben? Mvinchen med. Wchenschr., 1903, 1537.
Mac Callum, Hypertrophy of islands of Langerhans in diabetes mellitus. Am. J. M. Sc.,

1907, 432.
Magnus-Levy, Der Einfluss von Krankheiten auf den Energiehaushalt im Ruhezustand.

Ztschr. f. klin. Med., 60, 1906.

— Respirationsversuche an diabetischen Menschen. Ztschr. f. klin. Med., 56, 1905-
Manchot, Uber die Beziehungen der Glykosurie und des Diabetes mellitus zur Syphilis.

Monatsh. f. prakt. Derm., 27, 221, 295, 1898.
Mayo Robson, Die Beziehungen der Anatomic zu den Krankheiten des Pankreas. Bed.

klin. Wchenschr., Nr. 4 u. 7, 1908.
Mering and Minkowski, Diabetes nach Pankreasexstirpation. Arch. f. exper. Path. u.

Pharmakol., 26, 371, 1889.
Michael, Zur Atiologie des Diabetes mellitus. Arch. f. klin. Mod.. 44, 1889.

654 LITERATURE

i, Untersuchungen iiber den Diabetes mellitus nach Exstirpation des Pankreas.

Leipzig, 1893.

Minnich, Fall von Pankreaskolik. Berl. klin. Wchenschr., 1894, Nr. 6.
Mironescu, t)ber die Entwicklung der Langerhansschen Inseln bei Embryonen. Arch.

f. Anat. u. Entwicklurigsgesch, 76, 1910/11.
Mohr, L., Ztschr. f. exper. Path. u. Therap., 4, 910, 1908.
v. Miiller, Fr. Untersuchungen iiber Ikterus. Ztschr. f. klin. Med., 12.
Naunyn, B., Der Diabetes mellitus. Wien., 1906, A. Holder.
Nehring and Schmoll, Uber den Einfluss der Kohlehydrate auf den Gaswechsel des

Diabetikers. Ztschr. f. klin. Med., 31, 59, 1897.
Neubauer, E., Uber die Wirkung antiglykosurischer Mittel und iiber Leberglykosurie.

Biochem. Ztschr., 43, 335, 1912.
Nevrat-Perrotton, These de Paris, 1859.
Nishi, Uber den Mechanismus der Blutzuckerregulation. Arch. f. exper. Path. u.

Pharmakol, 61, 186, 1909.
v. Noorden, Die Zuckerkrankheit. V. Aufl., 1910. VI. Aufl., 1912. Berlin, Hirschwald.

— New aspects of diabetes. New York, 1912, Treat & Co.

— Uber Diabetestherapie. Med. Klin. 1909, Nr. 35.

— Uber Theorie und Therapie des Diabetes mellitus. Ibidem, 1911, Nr. i.

— Uber neurogenen Diabetes. Ibidem, 1912, Nr. i.

O'Connor, Uber Adrenalinbestimmung im Blute. Munchen rned. Wchenschr., 1911,

1439-
Opie, On the histology of the islands of Langerhans of the pancreas. Johns Hopkins

Hosp. Bull., 206, 1900.
Opie, G. L., Pathology changes affecting the islands of Langerhans of the pancreas. J.

Exper. M., 5, 397, u. 527, 1900/01.
Van Ordt, Beitrage zur Symptomatologie der Geschwiilste des Mittelhirns und der

Briickenhaube. Deutsche Zeitschr. f. Nervenh., 18, 126, 1900.
Oser, Erkrankungen des Pankreas. NothnageVs Handb., 1898.
Pearce, Am. J. Anat., 2, 1903.
Pettenkofer and Voit, Uber den Stoffwechsel bei Zuckerharnruhr. Ztschr. f. Biol., 3,

380, 1867.
Pfliiger, Das Glykogen und siene Beziehungen zur Zuckerkrankheit. II. Aufl. Bonn,

1905.

Plagge, Traumatischer Diabetes. Arch. f. path. Anat. [etc.], Berl., 13, 93.
Porges and Salomon, Uber den respiratorischen Quotienten pankreas-diabetischre Hunde

nach Ausschaltung der Abdominalorgane. Biochem. Ztschr., 27, 143, 1910.
Reimer, Lehrb. f. Kihderh., 10, 306, 1876.
Reinhold, Beitrag zur Kenntnis der Lage des vasomotorischen Zentrums in der Medulla

oblongata des Menschen. Deutsche Ztschr. f. Nervenh., 10, 67, 1896.
Renaut, Sur les organs lymphoglandularies et le pancreas des vertebre. Compt. rend.

Acad. de. sc. Par., 89, 247, 1879.
Rennie, Quart. J. of. Micr. Sc., 48, 1904.
Robin et Binet, Les echanges resplratoires dans le diabete glycosurique. Arch, gen.,

9, 283, 1898.

Rosenberger, Fr., Die Ursachen der Glykosurie. Munchen, 1911.
Rumpf, Untersuchungen iiber den Diabetes mellitus. Ztschr. f. klin Med., 45, 1902.
Saltykow, Uber Pankreasdiabetes. Cor.-Bl. f. schweiz. Aerzte, 18, 625, 1909.
Sandmeyer, Uber die Folgen der partiellen Pankreasexstirpation beim Hunde. Ztschr. f.

Biol., 31.

PANCREAS 655

Sauerbeck, Langerhanssche Inseln und Pankreasdiabetes. Arch. d. allg. Path. u. Anat.,

1902, 538.
— Die Langerhansschen Inseln im normalen und im kranken Pankreas des Menschen.

Arch. f. path. Anat. [etc.], Berl., 177, Spplbd. 1904.
Scheuplein, C., Verletzung der Wirbelsaule, Diabetes mellitus acutus, vollstandige

Heilung. Arch. f. klin. Chir., 29, 365, 1883.
Schlesinger, Die Erkrankuiig des Pankreas bei hereditarer Lues. Arch. f. Path. Anat.

[etc.], Berl., 154, 1898.
Schmidt, M. B., Uber die Beziehungen der Langerhansschen Inseln zum Diabetes mellitus.

Miinchen med. Wochenschr., 52, 1902.
Schulze, W., Die Bedeutung der Langerhansschen Inseln im Pankreas. Arch. f. mikr.

Anat., 56, 491, 1900.
Schivenkendick, Ein Fall von traumatischem Diabetes mellitus. Allg. med. Centr.-

Ztg., 76, i, 1907.
Seegen, Diabetes mellitus, 1893.
v. Seo, Ueber den Einfluss der Muskelarbeit auf die Zuckerausscheidung beim pankreas-

diabetischen Hund. Arch. f. exper. Path. u. Pharmakol., 59, 341, 1908.
Sinn, Der Einfluss experimenteller Pankreasgangunterbindung auf die Nahrungsresorp-

tion. Inaug.-Diss., Marburg, 1907.
Ssobolew, Zur normalen und pathologischen Morphologic der inneren Sekretion der

Bauchspeicheldriise. Arch. f. path. Anat. [etc.], Berl., 168, 91, 1902.

— Uber die Struma der Langerhansschen Inselnder Bauchspeicheldriise. Arch. f. path.

Anat. [etc.], Berl., 177, Supplbd., 123, 1904.

— Beitrage zur Pankreaspathologie. Beitr. z. path. Anat. u. Physiol., 47, 1910.
Strauss, H., Alimentare spontane und diabetische Glykosurien. Ztschr. f. klin. Med., 39.

— Glykosurie und Geisteskrankheiten. Ibidem, 39.

— Neurogene und thyreogene Glykosurie. Deutsche med. Wchenschr., 19, 19 u. 20,

1897-
Stiive, Arbeiten aus .dem stadtischen Krankenhaus. Frankfurt a. M. 44 (Festschr).,

1896.

Swale Vincent and Thompson; Int. Montaschr. f. Anat. u. Physiol., 24, 1908.
Thiroloix, Diabete pancreatique. Bull. Soc. anat. de Par., 62, 1891, et Gaz. d. H6p Par.,

1894.
Tiberti, N., Intorno all modo di comportarsi dell' isola del Langerhans, etc. Arch. ital. de

biol., 51, 1908; Arch, de Fisiol., 5, 1908; Sperimentale 62, 1908.
Tscheboksarojf, Sur les nerfs secreteurs des surrenales. Russki Wratsch, 8, 873, 27 Juin,

1909. Ref. J. de physiol. et path, gen., u, 962.
Tuckett, J. L., On the production of glykosuria in relation to the activity of the pancreas.

J. Physiol., 41, 1910.
Visentini, A., Uber das Verhalten des Pankreas nach Unterbindung und Durchschneidung

seiner Ausfiihrrungsgange. Arch. f. Anat. u. Physiol., Physiol. Abt., Supplbd.,

1908.

Voit, C., Physiologic des Stoffwechsels. 1881, 228.

Voit, Fr., Uber den Stoffwechsel bei Diabetes mellitus. Ztschr. f. Biol., 1892, 141.
Watermann and Smit, Nebenniere und Sympathikus. Arch. f. d. ges. Physiol., 124, 198,

1908.
Weichselbaum, A., Uber Veranderungen des Pankreas bei Diabetes mellitus. Sitzungsb.

d. k. Akad. d. Wissensch. Math.-naturw. Cl. Wien. Abt., 3, 119, 1910.
- Uber veranderungen des Pankreas bei Diabetes mellitus. Wien. klin. Wchenschrift,

1911, Nr. 5.

656 LITERATURE

Weichselbaum and Kyrle, Uber das Verhalten der Langerhansschen Inseln des mensch-

lichen Pankreas. Arch. f. mik. Anat., 74, 1909.
Weichselbaum and Stangl. Zur Kenntnis der feineren Yeranderungen des Pankreas

bei Diabetes mellitus. Wien. klin. Wchenschr., 1901, 968.

— Weitere histologische Untersuchungen, etc. Ibidem, 1902, 969.
Weintraub, Die Heilkunde. 1898.

— Untersuchungen iiber den Stoffwechsel bei Diabetes mellitus und zur diatetischen Ther-

apie der Krankheit. Bibliotheka medica, Abt. D., i, Heft, 1893.
De Younghe, Tumor der Medulla oblongata; Diabetes mellitus. Arch. f. Psychiat., 13,

658, 1882.
Zulzer, Untersuchungen uber den experimentellen Diabetes. 24. Kongr. f. innere. Med.,

1907.
Zulzer, G. G., Dohrn and Mayer, A., Neuere Untersuchungen iiber den experimentellen

Diabetes. Deutsche med. Wchenschr., 1908, 1380.
Zuntz and Mayer, Sur les effets de la ligature des canaux pancrgatiques chez les chiens.

Bull. Soc. roy. d med. pub. de. Belg. Brux., 19, 409, 1905.

CHAPTER XIV
[OBESITY

Ballet, G., L'adipose douloureuse (maladie de Dercum). Presse med., I, 285, 1903.

v. Bergmann, Der Stoff- und Energieumsatz beim infantilen Myxodem und bei Adiposis

universalis. Ztschr. f. exper. Path. u. Therap., 5, 640, 1909.
Bochroch, A case of adiposis dolorosa. Am. J. M. Sc., 124, 569, 1902.
Burr, C. W., and Riesman, David, Report of a case of tumor of the hypophysis without

acromegaly. J. Nerv. and Ment. Dis., 26, 20.

Cheinisse, L'identite de la lipomatose symmetrique douloureus avec la maladie de Der-
cum. Semaine med., 23, 221, 1903.
Cegard and Roussy, Deux cas d'adipose douloureus suite d'ovariotomie. Presse med.,

n, 740, 1903.

Debove, Lipomatose douloureuse. Gaz. d. Hop., Nr. no, 1069, 27 Sept., 1904.
Dercum, A subcutaneous connective-tissue dystrophy of the arms and back, etc. Univ.

M. Mag., Dec., 1888, and Three cases of a hitherto unclassified affection, etc.

Am. J. M. Sc., 114, 5.21, 1892.
Dercum and McCarthy, Autopsy in a case of adiposis dolorosa. Am. J. M. Sc., 124, 994,

1902.

Ewald, Organtherapeutisches. Therapie der Gegenwart, 1899.
Fulconis, Maladie de Dercum et lipomatose douloureuse symmetrique. These de Lyon,

1904.
Guillain and Alquier, Etude anatomique et pathologique d'un cas de maladie de Dercum.

Arch, de med. exper. et d'anat. path., 18, 680, 1906.
Haskovec, Lud., Adipose douloureuse ou maladie de Dercum. Rev. neurol., Nr. 23, 15

Dec., 1906.
Hertoghe, Hypothyreoidie benigne chronique. N. inconogr. de la Salpetriere, 1899,

Nr. 4.
Jaquet and Sevenson, Zur Kenntnis des Stoffwechsels fettsiichtiger Individuen. Ztschr. f.

klin Med., 41, 375, 1900.
Koettnitz, Uber symmetrisches Auftreten von Lipomen. Deutsche Ztschr. f. Chir., 38,

75, 1893.
Launois and Bensaude,-De 1'adenolipomatose symmetrique a predominance cerv. N.

inconogr. de la Salpetriere, 13, 41, 184, 243, 1900.
Loning and Fuss, Schilddriisenveranderungen bei Adiposis dolorosa. Kongr. f. innere.

Med., 1906, 222.
Lorand, Uber die Entstehung der Fettsucht, mit Riicksicht auf Veranderungen gewisser

Blutgefassdriisen. Med. klin., 1905, 387.

Lyon, J. P., Adiposis and lipomatosis considered in reference to their constitutional rela-
tions and symptomatology. Arch. Int. Med., 6, 28, 1910.
Magnus-Levy, Untersuchungen zur Schilddrusenfrage. Ztschr. f. klin. Med., 33, 1897;

ibid., 60, 177, 1906.

Miguel, De la valeur nosologique de la maladie de Dercum. These de Paris, 1004.
v. Noorden, Die Fettsucht. Nothnagels Path. u. Therap. i. Aufl., 1900 und 2. Aufl., 1910.

Wien und Leipzig, Holder.
- Pathologic des Stoffwechsels, 1893, 448.
42 657

658 LITERATURE

v. Noorden, t'ber verschiedene Formen der Fettsucht. Med. Klin., Nr. i.

— Uber Fettsucht. Med. Klin., Nr. i.

— Uber Fettsucht. Intern, med. Kongr., Budapest, 1909.

Reach, Stoffwechselversuch an einem fettleibigen Knaben. Festschr. f. Salkowski.,

1904, 319, Berlin.

Pic and Gardere, Un cas d'atrophie generalisee de la face. Lyon med., 2, 61, 1909.
Price, G. E., Adiposis dolorosa. Am. J. M. Sc., 137, 705, 1909.
Raymond and Claude, see chapter on epiphysis.
Rubner, M., Beitrag zur Ernahrung im Knabenalter mit besonderer Beriicksichtigung der

Fettsucht, Berlin, 1902.
Salomon, H., t)ber Drustkuren, besonders bei der Fettleibigkeit. V. Noorden's Samml,

med. Abhandl. Berlin, 1905, Heft 6.

Schwenckenbecker, Uber die Adiposis dolorosa. Arch. f. klin. Med., 1904, 324.
— Uber die Ausscheidung des Wassers durch die Haut. Deutsches. Arch. f. klin. Med., 79,

29, 1904.
Simons, A ., Eine seltene Trophoneurose "Lipodystrophia progressiva." Ztschr. f. Neurol.

u. Psychiat., 5, 1911.
Staehelin, R., Der respiratorische Stoffwechsel eines Fettsuchtigen im nuchternen Zustand

und nach Nahrungsaufnahme. Ztschr. f. klin. Med., 65, 425, 1908.
Strubing, Uber "Adiposis dolorosa" (Dercum) und das "oedeme blanc and bleu." (Char-
cot). Arch.'f. Dermat. u. Syph., 59, 171, 1902.
Thiele, O., und 0. Nehring, Untersuchungen des respiratorischen Gaswechsels unter dem

Einfluss von Thyreoideapraparaten, etc. Ztschr. f. klin. Med., 30, 41, 1896.
Thimm, Adiposis dolorosa und schmerzende Lipome. Monatschr. f. prakt. Dermat., 36,

282, 1903.
Umber, tJber einen Fall von Neurolipomatosis dolorosa. Hamburger arztl. Verein, 9.

Febr., 1909.

Vitaut, Maladie de Dercum (Adiposis dolorosa). These de Lyon, 1901.
Weiss, A., Adiposis dolorosa. Sammelref. Zntralbl. f. Grenzgeb. d. Med. u. Chir.

7, Nr. i, 1904.
White, A case of adiposis dolorosa. Brit. M. J., II, 1533, 1899.

INDEX

Abderhalden reaction, 50, 145, 439, 463
Abscesses in the floor of the ventricle, 554
Absorptive disturbances in Basedow's dis-
ease, 68, 70

after extirpation of the pancreas, 510
"Abwehr" theories, 50
Achondroplasia, see chondrodystrophy
Acromegaly, 235

action of adrenalin in, 265

blood picture, 260

definition, 235

diabetes in 263, 276

differential diagnosis, 280

ductless glandular system, 259

early acromegaly, 277

eye changes in, 266

genitalia in, 248

genital disturbances in, 248

and gigantism, 454

hairiness in, 243

heart, vascular system, 259

hypophysial enlargement, symptoms in,
265 '

hypophysis, 267

mental disturbances in, 265'

metabolism, 261

muscles in, 236

myxedema and, 259

nerves and nervous system, 263, 266

occurrence, 235

osseous system, 236, 265

operation in, 281

pancreas, 260

pathogenesis, 269

pathological anatomy, 267

pilocarpine injection, 264

polyuria in, 263, 275

and pregnancy, 250

skin in, 241

status lymphaticus, 260

suprarenals, 259

symptomatology, 236

teeth in, 237

thyroid gland in, 253

thymus gland, 260

treatment, 281

vascular system, 259

Acromegaliform syndrome, 276
Actinomycosis of the thyroid gland, 117
Addison's disease, 336

adynamia in, 336

blood picture in, 337

course of, 338

definition, 336

differential diagnosis of, 347

gastrointestinal disturbances in, 337

hyperplasia of the thymus in, 338

metabolism of, 337

occurrence of, 337

pathological anatomy of, 340

pathogenesis of, 346

pigmentations in, 337, 346

prognosis of, 348

status lymphaticus in, 337

suprarenal implantation in, 348

symptomatology, 337

thrombosis of the suprarenals, 348

treatment of, 348
Adenocarcinoma of the hypophysis, 267

of the thyroid gland, 54
Adenomata of the hypophysis, 267, 312

of the suprarenals, 356

of the thyroid gland, 54
Adiposis tuberosa simplex, 587
Adiposity, see obesity.
Adipositas dolorosa, 575

differential diagnosis, 587

forms, 582

mental symptoms, 583

and myxedema, 586

pathogenesis, 584

pathological anatomy, 583

symptomatology, 581

treatment, 587
Adrenalin, arteriosclerosis through injection

of, 355
biological methods for demonstration of,

355
chemical methods for demonstration of,

343
contents of the suprarenal in hyper-

tonia, 354
in diabetes, 540
diuresis in diabetes, 540

659

66o

INDEX

Adrenalin, general action. 25, 27
glycosuria after castration, 367
in diabetes, 540

after extirpation of the pancreas, 506
in myxedema, 108
in osteomalacia, 435
in pregnancy, 377
in the premenstrual period, 375
intoxication in tumors of the supra-

renals, 377

relation to iron-free pigment, 346
therapy in Addison's disease, 348
in Basedow's disease, 149
in esophageal carcinoma, 350
in gastric ulcer, 349
in gynecology, 379

Adrenalinemia in Basedow's disease, 71
Adynamia in Addison's disease, 338
Aged, ductless glands, system in, 49, 109
Allen's treatment of diabetes, 569
Agenitalism, 391
Alcoholism in infantilism, 474

differential diagnosis from Basedow's

disease, 98
Amino-acid elimination in gigantism, 462

in tetany, 194
Ammonia elimination in endemic cretinism,

162

in gigantism, 462
in pregnancy, 377
in tetany, 194

Anencephaly, suprarenal aplasia in, 350
Angina, Basedow's after, 93
myxedema after, 118
thyroiditis after, 56
Anoci-association, 50
Antithyroidin in Basedow's disease, 102
Aparathyrosis, 177
Apinealism, 331, 332
Apituitarism, 14; see also hypophysial

dystrophy.

Aplasia of the sexual glands, 385
Apoplexia cerebri in diabetes, 553
Arsenic in thyroidin treatment, 142
Arteriosclerosis, in myxedema, 109
premature in diabetes, 544
in suprarenal hyperplasia, 355
in tumors of the sympathetic, 355
Articular rheumatism, myxedema after, 118

thyroiditis after, 56
Asthenia, Stiller's, 46
Asthma thymicum, 10
Atheromatosis, see arteriosclerosis.
Athyroidism, 14, 103
Atropine in Basedow's disease, 81
general actions, 25

Autonomous nervous system, 25
Autolysis, 71

Balancement in pancreatic tissue, 503
Basedow's disease, 57

blood picture, 70, 147

cardiac vascular system in, 58

in chlorosis, 429

complications, 89

contrasted with myxedema, 86

course of, 97

in diabetes, 565

diabetes in, 79

in diagnosis, 98

diarrheas in, 68

definition, 57

dysfunction in, 85, 145

emaciation in, 75

etiology, 93

eye-symptoms, 61

fat stools in, 68, 70

formes frustes, 94, 96, 97

forms of, 91

gastrointestinal tract, 67

genitalia, 83

glycosuria in, 79

heat, regulation in, 81

heart and vascular system in, 58

iodine contents of the thyroid gland, 91

mental symptoms in, 66

metabolism in, 75

muscles in, 66

and myxedema, 89

nervous system in, 65

osseous system in, 83

pathogenesis of, 84

pathology, 148

pigmentation in, 82

prognosis, 98

psyche and psychoses, 66

relations with epilepsy, 147

respiratory organs in, 64

scleroderma and, 83

skin, 82

sympathicotonic, 95

symptomatology, 58

tachycardia in, 60

temperature in, 82

thymus glands in, 152, 175, 229, 230

after thyroiditis, 56

treatment, 98, 148

tremor in, 66

vagotonic, 95
Basedowoid, 95

Bladder disturbances in hypophysial dys-
trophy, 294

INDEX

66l

Bladder disturbances in tetany, 192
Blood coagulability after -castration, 397
distribution after injection of adrenalin,

343
Blood picture in acromegaly, 260

in Addison's disease, 337

after injections of adrenalin, 343

in Basedow's disease, 70, 172

after castration, 431

in chlorosis, 429

in diabetes, 542

in endemic cretinism and goiter, 147,
165, 172

in hypophysial dystrophy, 298

in infantilism, 472

in multiple ductless glandular sclero-
sis, 446

in myxedema, 108, 112

in osteomalacia, 437

in the premenstrual period, 375

in sporadic cretinism, 134

in status lymphaticus, 365

in tetany, 185

in thymus gland hyperplasia, 227

after extirpation of the thymus gland,

224
-pressure, after injection of adrenalin,

344

in Addison's disease, 336
in Basedow's disease, 60
in chlorosis, 428
in hyperplasia of -the chromaffin tissue,

353

in multiple ductless glandular sclero-
sis, 446

in the permenstrual period, 375
after use of pituitrinum glandulare,

273
of pituitrinum infundibulare,

271
regulation of, by the ductless glands,

27

in status lymphaticus, 366
after sugar puncture, 516
after thyroid feeding, 60

in diabetes, 542

sugar after adrenalin injection, 343
after cervical cord transection, 32
in diabetes mellitus, 527
in hypertonia, 355

after injections of pituitrinum glandu-
lare, 274

of pituitrinum infundibulare, 272
after pancreas extirpation, 504, 514

in birds, 512
in phosphorus posioning, 350

Blood sugar after peroral administration of

adrenalin, 348
regulation of, through the chromaffin

tissue, 346

after suprarenal extirpation, 342
in tetany, 221

Brain tumors and diabetes, 555
Bryson's symptom in Basedow's disease, 65

Cachexia thyreopriva, 104

Calcium metabolism in endemic cretinism,

163

after castration, 396
in neurasthenia, 38
in osteomalacia, 436
in tabes, 38
in tetany, 195
therapy in Basedow's disease, 102

in tetany, 210
Caloric production in diabetes, 537

see metabolism.
Calzine in Basedow's disease, 102

in tetany, 219

Carbohydrate metabolism, 16
in Basedow's disease, 78
in brain diseases, 38
in chlorosis, 429
chromaffin tissue and, 355
in diabetes mellitus, 527
after extirpation of the pancreas, 503
after injection of pituitrin, 272, 274
after ligation of the pancreatic duct, 506,

5ii

in myxedema, 113

regulation through the ductless glands,
1 6, 565, 566

in tetany, 193
Carcinoma of the epiphysis, 330

of the hypophysis, 262

of the pancreas, 524, 525

of the suprarenal cortex, 356

of the thyroid gland, 54

of the thymus gland, 228
Carpopedal spasm, 181
Castration, blood picture, 397

loss of pigment, 393, 396

oophorin action, 397

in osteomalacia, 435

respiratory metabolism, 396

see also eunuchs.

Cataract formation in tetany, 197
Catatonia, metabolism, 37
Chemotactic actions of the hormones, 27, 28,

34
Chlorosis, 42

cardiovascular symptoms, 428

662

INDEX

Chlorosis and eunuchoidism, 428

generative glands in, 4X1

genitalia in, 430

infantile, 428

pathogenesis, 431

symptomatology, 428

tardive, 428
Chlorotoid, 428

Cholelithiasis and pancreatitis, 520
Cholin. general action, 25

in the suprarenal cortex, 3, 345

systeme cholingene, 345
Choked disc in acromegaly, 267

in epiphysial tumors, 330

in tetany, 183
Chondrodystrophy, 484

definition, 485

differential diagnosis, 493

etiology, 493

familial occurrence, 491

forms, 489

occurrence, 491 '

partial, 487

symptomatology, 485

unilateral, 488

Chondroma of the hypophysis, 312
Chromaffin tissue in chlorosis, 433

in diabetes mellitus, 566

in Grawitz tumors, 357

in hypertonia, 353

in osteomalacia, 437

in phosphorus poisoning, 350

physiology of, 342

in status lymphaticus, 366

in sugar puncture, 316, 317

in tetany, 200

in thymus-gland hyperplasia, 227

tumors of, 352

Chvostek's symptom in diabetes mellitus,
179

in tetany, 178

in the tuberculous, 179
Cirrhose bronze"e, 10
Cirrhosis, see sclerosis.

of the liver in infantilism, 474
Climacteric, 384
Conarium, see epiphysis.
Colloid in the hypophysis, 116

in the thyroid gland, 55, 156
Conjunctivitis in endemic cretinism, 159

in tetany, 184

Constitution and ductless glands, 12, 46-49
Correlation, see reciprocal action.
Corpus luteum, 377

Creatinin elimination in Basedow's disease,
81

Creatinin elimination, in endemic cretinism,

162

in tetany, 194
Creatorrhea, in diseases of the pancreas,

523

Cretinic degeneration, geographical distri-
bution of, 155
Cretinism, endemic, 154

blood picture, 165

brain, 160

dentition, 165

differential diagnosis, 171

epiphysial junctures, 164

etiology, 171

genitalia, 163

growth disturbances, 164

habitus, 158

hearing disturbances, 161

hypophysis, 163

intellectual disturbances, 162

metabolism, 162

mutism in, 161

nervous systems, 1 60, 162

parathyroid glands, 166

pathogenesis,. 169

pathological anatomy, 160

respiratory metabolism in, 162

skeleton, 164

skin, 158

speech development, 162

symptomatology, 158

teeth in, 165

thyroid gland, 165

treatment, 166
marine, 170
sporadic, 120

blood picture, 134

definition, 120

dentition, 133

differential diagnosis, 138

enlargement of the liver, 133

epiphysial junctures, 131

etiology, 138

genitalia, 133

growth disturbances, 130

hearing disturbances, 136

hypophysis, 136

hypothermia, 136

metabolism, 135

nervous system, 136

pathology, 121, 122

respiratory metabolism, 135

symptomatology, 123

thymus gland, 136

treatment, 138

umbilical hernia, 133

INDEX

663

Crile, see kinetic theory and anoci-associa-

tion.
Cryptorchidism, 371

in partial gigantism, 463
Cyst goiters, 156
Cysts of the epiphysis, 330

of the hypophysis, 268, 312

of the pancreas, 518

of the suprarenal cortex, 357
Cysticerci of the floor of the ventricle, 554

Definition of ductless glandular secretion, 4

of internal secretion, 4
Degeneratio genito-sclerodermica, 450
Dentition in endemic cretinism, 165

in myxedema, 105

in premature development, 426

in sporadic cretinism, 133

in tetany, 197
Dercum's disease, see also adiposis dolorosa,

575
question of pluriglandular disturbance,

43
Dermatographism in diabetes mellitus, 542

in tetany, 183

Detoxication theory of Basedow's disease, 84
Diabetes insipidus, idiopathic in brain dis-
eases, 294

in diseases of the hypophysis, 321, 322
mellitus, 499

in acromegaly, 263
adrenalin 'diuresis, 541

glycosuria, 540

production, 355
after adrenalin injection, 517
adrenalinogenic, 562
alimentary factor, 527, 528, 562
in Basedow's disease, 79
blood picture, 542
blood pressure increase through thy-

roidin in, 542
in brain tumors, 555
carbohydrate metabolism, 527
in cerebral hemorrhage, 553

lues, 560

tumors, 555
clinical aspect of, 518
complications of, 544
decipiens, 541
dermatographism, 542
diet in, 567, 569
differential diagnosis, 566
in diseases of the hypophysis, 565
diuresis, 541
in eunuchoidism, 409
experimental nervous, 515

Diabetes mellitus, after extirpation of the

pancreas, 503, 514
from fat, 529
genuine, 526
granular atrophy of the pancreas in,

546

after head injury, 556
hypeitonic, 29, 38, 543, 569
hydropic insular degeneration, 549
insular theory, 547
ketonuria, 530
in myxedema, 115

nervous factor of the glycosuria, 529
obstipation in, 541
pancreas hormone, 507
parathyroids and extirpation of the

pancreas, 506

pathological anatomy of, 546
after pituitrinum glandulare injec-
tion, 517

premature arteriosclerosis, 544
protein metabolism, 529
question of disturbance of glycogene-
sis, of the disturbance of sugar com-
bustion, and of sugar production,
5U
of the formation of sugar from

protein, 528

quotient D: N, 513, 530
respiratory metabolism, 531
salt metabolism, 530
Sandmeyer's, 504
Allen's treatment of, 569
theory, 549, 561
thyrogenic, 565
after trauma, 556
treatment, 567, 569
vegetative nervous system, 540
water economy, 530
Diaphragm spasm in tetany, 181
Diarrheas in Basedow's disease, 67
Diathesis, 47

exudative, 367
hypertonic, 355
spasmophilic, 213
Diet in diabetes mellitus, 567, 569
Diphtheria, adrenalin treatment of, 349
suprarenals in, 341
toxin suprarenals in injection of, 341
Diplopia in tetany, 181
Dissociation of the hormone actions, 1 1
Diuresis in diabetes, 541

in hypophysial tumors, 294
Ductless glands in adipositas dolorosa, 585,

586, 588
autonomy, 33

664

INDEX

Ductless glands, degeneration in gigantism,

462

grouping of, 22
in hypergenitalism, 425
hypoplasia of, 449
influence of, on hairiness, 391

on the sexual characters, 390
in pregnancy, 378
in progeria, 452, 453
regulation of the metabolism, 16

sugar metabolism, 565
glandular diseases, etiology andpatho-

genesis, 35

sclerosis, multiple, 441
blood picture, 446
case histories, 442
definition, 442
differential diagnosis, 453
etiology, 448

late eunuchoidism in, 446
secondary, 4^52
symptomatology, 445
treatment, 453
Ductus thyreoglossus, 53
Dwarfism, in cretinism, 130, 164

hypophysial, 301 ,:

hypoplastic, 474, 477
Paltauf's type, 481
primordial, 480
rachitic, 484

in suprarenal tuberculosis, 351
true, 480
Dysfunction, 10-13

in Basedow's disease, 85
in marine cretinism, 171
Dysthyrosis, 85
Dystrophia adiposo-genitalis, 282

eunuchoid, see eunuchs and eunuchoid-
ism, and late eunuchoidism in gigan-
tism in epiphysial tumors, 330
Dystrophy, hypophysial, 282
in acromegaly, 278
adrenalin action, 293
bladder disturbances, 293
blood picture, 298
definition, 283
differential diagnosis, 324
genitalia, 289
growth disturbances, 301
heat regulation, 297
infantilism, 302, 477
metabolism, 290
obesity in, 283
pathological anatomy, 311
pilocarpine action, 293
polyuria, 294

Dystrophy, psyche, 311
skeleton, 306
symptomatology, 283
thermoreaction, 298
tumor symptoms in, 311
vegetative nervous system, 293

Early acromegaly, 277
Eclampsia, 205, 207
Edema in Basedow's disease, 82
Edeme neuropathique Mathieu, 585

segmentaire Debove, 585
Eleodona moschata, 203
Electrical hyperexcitability in tetany, 177,

i?8

Embryology of the ductless glandular sys-
tem, 20

Enamel, defects of the enamel in tetany, 197
Encephalomalacia in diabetes, 553
Endothelioma of the dura mater, 325

of the suprarenal cortex, 356
Eosinophiles in acromegaly, 260

after injection of adrenalin, 343

in cretinism, 165

in ductless glandular sclerosis, 446

in osteomalacia, 437

postpartum, 383

in status lymphaticus, 365
Epilepsy in Basedow's disease, 145

in ductless glandular sclerosis, 449

in tetany, 182, 217, 218
Epiphysial junctures in Basedow's disease, 38

in chlorosis, 430

in chondrodystrophy, 486

in cretinism, 131, 164

in dwarfism, 480, 482, 483

in early acromegaly, 278

in eunuchoidism, 407

in eunuchs, 393

in hypophysial dystrophy, 310

in late eunuchoidism, 419

in progeria, 452

in rachitis, 484

in sporadic cretinism, 131
Epithelial bodies, see parathyroids.
Erb's symptom in tetany, 177
Ergotin poisoning, 209, 21 1
Eunuchoidism, 397

in acromegaly, 438

blood findings, 410

case reports, 377

definition, 397

differential diagnosis, 411

from hypophysial dystrophy, 411
from infantilism, 411

genitalia, 408

INDEX

665

Eunuchoidism, hair in, 408.

metabolism, 409

obesity, 407

pathogenesis, 410

prognosis, 412

skeleton, 405

suprarenal hypoplasia, in, 351

symptomatology, 405

treatment, 412
Eunuchs, 391

occurrence, 391

skeleton in, 393

skin in, 393

symptomatology, 391
Exophthalmus in acromegaly, 255, 311

in Basedow's, 62

Fat stools in Basedow's, 70

in pancreatic diseases, 522, 523
Ferment production in Basedow's, 68
Fetalism, 479

Fibrillary contractions, see muscles.
Fibroma of the hypophysis, 312
Freundian hypothesis, 50, 53, 145
Function, pharmaceutical testing of, 25
Fundamental exchange, 18; see respiratory
metabolism.

Galactogenous substances in the hypophysis,

272

Galactorrhea in aoromegaly, 248
Galactosuria in visceral neuroses, 38
Gartner's duct, 370

Gas metabolism, see respiratory metabolism.
Gastric tetany, 214

treatment of, 220
Gastrointestinal disturbances in Addison's

disease, 336

in Basedow's disease, 67
in chlorosis, 428

Gelatinous struma of the thyroid gland, 55
Generative apparatus, 374
Genitalia in acromegaly, 248

in Basedow's disease, 83

in chlorosis, 430

in chondrodystrophy, 490

in endemic cretinism, 163

in eunuchoids, 408

in extirpation of the hypophysis, 315,
3i6, 317

in gigantism, 456, 459

in hypophysial dystrophy, 289

in infantilism, 472

in late castrates, 394, 395

in late eunuchoidism, 418

in marine cretinism, 170

Genitalia in Mongolism, 496

in myxedema, 115

in sexual glandular tumors, 425, 426

in sporadic cretinism, 133

in suprarenal tumors, 359

in thymus tumors, 228

under thyroidin treatment, 412, 422

in tumors of the epiphysis, 331
Genu valgum in eunuchoidism, 407
Gigantism, 454

and acromegaly, 248, 280, 454

in chlorosis, 430

hypophysis in, 461

late eunuchoidism in, 459

partial, 463

pathology, 460

transient, in suprarenal cortical tumors,
362

types, 459
Glioma of the epiphysis, 330

of the suprarenals, 352

of the floor of the ventricle, 555
Glycogen, loss after suprarenal extirpation,

342

mobilization through adrenalin, 343

Glycosuria in acromegaly, 264
through adrenalin, 343
after castration, 397
in cerebral hemorrhage, 553

syphilis, 560

tumors, 555
in chlorosis, 429
in diabetes mellitus (laws), 527
in eunuchoidism, 409
in extirpation of the hypophysis, 315
after head injury, 556
in hypophysial dystrophy, 291
after injection of pituitrinum glandulare,

275
of pituitrinum infundibulare, 273

in myxedema, 115

nervous, 529

in pain, 559

in sugar puncture, 344

after trauma, 556
Goiter, 155

blood picture, 172

heart, 156

differential diagnosis from Basedow's
disease, 98

iodine treatment, 156

noxus, 155

in tetany, 211

Goiter, exophthalmic; see Basedow's disease.
GoDorrheal orchitis in late eunuchoidism,
461

666

INDEX

Grafe's symptom in Basedow's, 63
Granular atrophy of the pancreas, 546
Grawitz tumors, 356
Growth, regulation of, on the part of the

ductless glandular system, 1 1
disturbance, u

in cretins, 130, 164

in epiphysial tumors, 330

in eunuchs and eunuchoids, 393,

407
after extirpation of the thymus gland,

225

in hypophysial dystrophy, 301
in idiots (Mongolian), 496
influencing of, through thyroidin, 143,

167

in late eunuchoidism, 419
in suprarenal diseases, 351, 358
in tetany, 199

see also osseous system and epiphysial
junctures.

Hair growth, see hairiness.
Hairiness in acromegaly, 243

in epiphysial tumors, 330

in eunuchoids, 408

in eunuchs, 393

in hypergenitalism, 425

in infantilism, 473

in late eunuchoidism, 419

in pregnancy, 378

in suprarenal tumors, 361
Hearing disturbances in myxedema, 104

in sporadic cretinism, 136

thyroidin treatment in, 142
Heart disturbances in chlorosis, 428

in tetany, 183, 184

see also vascular system.
Heat regulation, 19, 20

especially through the chromaffin
tissue, 343

in Basedow's disease, 81

in brain diseases, 38

through the ductless glands, 19

in hypophysial dystrophy, 297

in myxedema, 115

in neuroses, 38

in the premenstrual period, 375

in tetany, 192
Hematopoietic apparatus, 33-35

see also blood picture.
Hemichromatopsia, bitemporal, 328
Hemochromatosis, 449
Hemorrhages, in the parathyroids, 207, 208,

213
Hemosiderosis, 10

Hermaphroditism, 386, 438

Historical development of ductless.glandular

diseases, 1-6

Hoffman's symptom in tetany, 178
Hormones, 5

Hydrocephalus in aplasia of the suprarenal
medulla, 340

in endemic cretinism, 160

in hypophysial dystrophy, 315
Hydrochloric acid treatment in Addison's

disease, 349

Hydrotherapy in Basedow's, 102
Hyperacidity in Basedow's, 67

in chlorosis, 428

in tetany, 188
Hypergenitalism, 424

in tumors of the epiphysis, 330

in suprarenal tumors, 358
Hyperglobulia through injection of adrenalin,
i 08, 343

in tetany, 185
Hyperglycemia, 504

in injection of adrenalin, 343

see also blood-sugar.
Hypernephroma, 357

in Addison's disease, 340
Hyperparathyroidesia, 221
Hyperpinealism, 132, 332
Hyperpituitarism, 14; see also acromegaly

and early acromegaly.
Hyperthermia after injection of adrenalin,

343

in Basedow's disease, 81

in brain diseases and neuroses, 38

in tetany, 192
Hyperthymization, 226
Hyperthyroidism, see Basedow's disease.
Hypertonia, see blood-pressure.
Hypertrichosis, 390

in suprarenal tumors, 359, 363
Hypertrophy, vicarious, of suprarenals, 341
Hypoparathyrosis, 177
Hypophysis, 231

anatomy, 231

in adiposis dolorosa, 583

and diabetes insipidus, 294, 296

in ductless glandular sclerosis, 447

in endemic cretinism, 164

in gigantism, 454, 459, 462

effect on growth, 15

in hypophysial dystrophy (see dys-
trophy), 311

in marine cretinism, 171

in myxedema, 116

in obesity, 574

pathological anatomy, 267

INDEX

667

Hypophysis, physiology, and pathology, 2,
270

in pregnancy, 379

relation to the thyroid gland, 323

respiratory metabolism after extirpation
of, 290

in sporadic cretinism, 122, 136

tablets, treatment with, 326
Hypopinealism, 332

Hypopituitarism; see dystrophy, hypophysial.
Hypoplasia of the parathyroid, 213
Hypothermia in brain diseases, 38

in hypophysial dystrophy, 297

in myxedema, 115

in sporadic cretinism, 136
Hypothyroidism, 14, 104; see myxedema

and sporadic cretinism.
Hypothyrosis, 85
Hysteria, 37, 50

differential diagnosis from tetany, 217

Idiots, 121

Imidoazolylethylamin, 2.11
Implantation of the thyroid gland, 139
Indicanuria in cerebral diseases, 38
Infantilism, 45, 465

blood picture in, 472

classification, 473

definition, 468

differential diagnosis, 475
from eunuchoidism, 476

etiology, 474

forms, 473

genitalia in, 472

in osteomalacia, 437

pancreaticus, 478

pathogenesis, 479

prognosis, 479

symptomatology, 472

transitional forms, 477

treatment, 479

Influenza, thyroiditis after, 56
Insuffisance pluriglandulare, 441
Insular apparatus of the pancreas, 502
Interstitial glands, 330

see also sexual glands.
Intestinal colics in Addison's disease, 336

disturbances, see gastrointestinal dis-
turbances.

Intoxication theory, 12
Iodine Basedow's disease, 92

in the pathology of the thyroid gland, 91

treatment in goiter, 156
lodism, 92
lodothyrin, 140
Iron therapy in chlorosis, 435

Juvenilism, 479

Kalzine in Basedow's disease, 102

in tetany, 219
Ketonuria in diabetes, 530

after extirpation of the pancreas, 505

in pregnancy, 378
Kinetic theory, 50

Lachrymation in tetany, 184

Langerhans's islands in diabetes mellitus,

546

Laryngospasm in tetany, 181
Larynx in acromegaly, 237

and eunuchoids, 407

in eunuchs, 393
Late castrates, 394

eunuchoidism, 413

Lead poisoning, differential diagnosis from
Basedow's disease, 98

in tetany patients, 209
Leucorrhea, cyclical, 377
Levulose in diabetes, mellitus, 528
Levulosuria in the vasomotor neuroses, 38
Lipodystrophia progressiva, 584
Lipoidemia in pregnancy, 377
Lipomatoses, 585, 587
Lowi's reaction, 8, 29, 30, 506

in diabetes, 543
Lymphatism, 365

in ductless glandular diseases, 366

in sporadic cretinism, 135
Lues, see syphilis.
Luetin tablets, 423

Malaria, thyroiditis after, 56
Malformations of the sexual glands, 385
Magnesium sulphate treatment of tetany,

222

Mammary glands in hypergenitalism, 426

in pregnancy, 381
Melancholia, 37

in Basedow's, 66

in myxedema, no
Melanoma of the suprarenals, 356
Menstruation, relation to ovulation, 376

precocious, 426
Metabolism, in acromegaly, 261

Addison's disease, 337

in adipositas dolorosa, 583

after adrenalin injection, 343

in Basedow's disease, 75

after castration, 396

in chlorosis, 429, 430

in cretinism, 162

in diabetes mellitus, 527

668

INDEX

Metabolism after extirpation of the hy-
pophysis, 316

gigantism in hypophysial dystrophy, 290
in infantilism, 473
in myxedema, 112
in pregnancy, 373

regulation through the ductless glandu-
lar system, 16-20

see also carbohydrate metabolism, pro-
tein metabolism, salt metabolism,
respiratory metabolism, and purin
metabolism.

under treatment with thyroidin, 140
Methyl cyanide, 84
Mikulicz's syndrome, 43
Mobius's symptom in Basedow's, 63
Molimina menstrualia, 373
Mongolism, 494

Mononucleosis, see blood picture.
Mors thymica, 226, 230
Mucin in the tissues in myxedema, 105
Muller's duct, 370

Multiple ductless glandular sclerosis, see
ductless glandular sclerosis multiple.
Muscular atrophy, progressive, 471
system in acromegaly, 241
in eunuchoids, 408
in eunuchs, 393

mechanical hyperexcitability, I, 180
in tetany, 180, 184
Musset's sign, 59
Mutism, 161
Myasthenia, 41

and tetany, 221

Myoma uteri, relation to goiter, 156
Myoneural junction, 344
Myotonia, 41

in tetany, 180, 182, 184, 218
Myxinfantilism, see infantile myxedema and

sporadic cretinism.
Myxedema, 104

in acromegaly, 241

in Basedow's disease, 89

blood picture, 108, 112, 147, 148

cardiovascular system in, 106-108

contrasted with Basedow's disease, 87

course, 117

definition, 104

and diabetes, 115

differential diagnosis, n 8

ductless glandular sclerosis, 446

etiology, 117

formes frustes, 119

genitalia, 115

glycosuria in, 114, 115

Myxedema, hair in, 105

hearing disturbances, 104

heat regulation, 115

hypophysis, 116

in hypophysial dystrophy, 284

in infantilism, 476

mental symptoms in no

metabolism, 112

metabolism under thyroid treatment,

H3

incomplete forms, hypothyroidism, 119
in Mongolism, 497

nervous system, 106, 108, 109, no', 111
occurrence, 104
osseous system, 1 1 1
psyche, no
in scleroderma, 118
skin, 104, 109, in
symptomatology, 104
after thyroiditis, 118
vascular system, 106, 108

Nanisme type senile, 405

Narcosis death in thymus hyperplasia, 226

Nervous diseases and ductless glandular

system, 37

system, somatic and vegetative in Ad-
dison's disease, 336

in acromegaly, 263, 266

in adrenalin injection, 343, 344

in Basedow's disease, 65

in the climacteric, 384

in cretinism, 136, 160, 161

in diabetes, 540

in eunuchoidism, 410

hypophysial dystrophy, 293

in infantilism, 473

in myxedema, 106, 108, 109, no, in

in neurofibromatosis, 353

in osteomalacia, 438

after extirpation of the parathyroids

201, 204

after extirpation of the pancreas, 506

in rachitis, 484

relations to the ductless glandular

system, 23, 37
sexual glands, 384
after sugar puncture, 516
in tetany, 177, 184
after extirpation of the thymus gland,

224-226

Neurofibroma, 353
Neuroses, 37, 50
Nicotine, 25

in infantilism, 474

INDEX

669

Nicotinism, differential diagnosis from Base-
dow's disease, 98

Oats treatment in diabetes, 567, 569
Obesity, in Addison's disease, 337

in Basedow's disease, 75

in epiphysial tumors, 331

in eunuchs, 393

forms (exgenous, endogenous), 570

in hypophysial tumors, 283, 317, 574

in hydrocephalus, 283

in late castratus, 419

in late eunuchoids, 414, 419

pancreatogenic, 572

respiratory metabolism, 570

in suprarenal cortical tumors, 359

thyrogenic, 573
Oophorin tablets, 423

metabolism on the use of, 396
Operation in Basedow's, 99, 150, 151
Opotherapie associe"e, 43, 44, 453
Orchitis, gonorrheal, 416

after mumps, 416

syphilitic, 416
Osseous system in acromegaly, 236, 265

in Basedow's disease, 83

in chondrodystrophy, 486

in cretinism, 130, 164

in eunuchoids, 405

in eunuchs, 392

in idiots, 172

in myxedema, 1 1 1

in tetany, 196, 199

see also epiphysial junctures.
Osteitis, Paget's, 281
Osteoarthropathie hypertrophiante, 281
Osteomalacia, 439

in tetany, 199

treatment, 327

Osteophyte formation in pregnancy, 379
Osteoporosis congenita, 493
Ovaraden, 423
Ovarian tablets, 423
Ovaries, see sexual glands.
Ovarin, 423
Ovulation, 376

Oxyproteinic acid elimination in pregnancy,
378

Pancreas, absorption disturbances, 508, 511
in acromegaly, 260, 276
anatomy, 501
colics, 521
embryology, 501
extirpation, 503

Pancreas, hormone of Zulzer, 508

lithiasis, 521

ligation of excretory duct of, 509

pathological anatomy, 518

physiology, 504, 508

rdle of, in fattening, 573

sclerosis, 521
Pancreatitis, 518
Paraganglia, 335, 353
Paragangliomata, 353
Paralysis agitans, 41, 221, 463
Paralysis, progressive, 38, 42
Parathyroids, anatomy, 174

in adipositas dolorosa, 555

detoxication theory, 202

in endemic cretinism, 166

embryology, 175

function, 201

importance for life, 201

nervous system, 203

in osteomalacia, 437

in pregnancy, 381

in thyroaplasia, 122

see also tetany.
Parathyroanititoxin, 219
Parathyroid tablets, 210
Pedatrophy, 450
Pellagra in infantilism, 474

pigmentation in, 348
Pentosuria in neurosis, 38
Peptid nitrogen elimination in pregnancy,
378

in tetany, 194

Peremeschko's medullary layer, 233
Placenta, internal secretion of, 382
Plasma contents of the blood regulation

through the chromaffin tissue, 27
Pharmacological tests of function, 25, 52
Physostigmine, 25
Pigmentation in Addison's disease, 337, 346

in animals deprived of suprarenals, 347

in Basedow's disease, 82, 347

in chlorosis, 429

in cirrhosis bronze"e, 347

in ductless glandular sclerosis, 446

in Grawitz tumors, 357

in leucemia of the suprarenals, 348

in myxedema, 348

in osteomalacia, 437

in pellagra, 348

in pregnancy, 378

in suprarenal cortical tumors, 357

in tetany, 196

in the tuberculous, 347
Pigment, loss of, after castration, 396

670

INDEX

Pilocarpine, action in acromegaly, 264
in cretinism, 133
general action, 25
in hypophysial dystrophy, 293
in myxedema, no
in tetany, 184
Pineal gland, see epiphysis.
Pituitary gland; see hypophysis.
Pituitrinum glandulare, 28, 273, 327

in osteomalacia, 436
therapeutic use, 327

thermoreaction, 298
infundibulare, 28, 271, 272, 327
in acromegaly, 264
in osteomalacia, 436
in sexual glandular insufficiency, 422
therapeutic use, 326
Pluriglandular diseases, 42, 449
Polyuria in bitemporal hemianopsia, 294
in cerebral syphilis, 294
in diabetes, 571

in ductless glandular sclerosis, 447
after extirpation of the pancreas, 505
in hypophysial dystrophy, 294
in tumors of the epiphysis, 331
Postbranchial bodies, 53, 122 <

Pregnancy, 377
cells, 136, 379
hypertrophy of the suprarenal cortex,

363, 378

hypophysis in, 379

reaction, 383

parathyroids in, 381

placenta, 382

tetany, in, 214

thyroid gland, 381
Premature development, 14

in tumors of the epiphysis, 331
Progeria, 450
Prostate, 370

in eunuchoidism, 408

in eunuchs, 392

in late eunuchoidism, 418

in new-born boys, 383
Protein metabolism, 16

in Basedow's disease, 77

in catatonia, 37

in diabetes, 529

in myxedema, 112

in extirpation of the pancreas, 37

in psychoses, 37

in tetany, 194

Protrusio bulbi in Basedow's, 61
Psammoma of the epiphysis, 330
Pseudochlorosis, 430
Pseudoodeme catatonique Dide, 585

Pseudohermaphroditismus, 386, 387

in tumors of the suprarenals, 360
Psyche in Basedow's, 66

in chondrodystrophy, 493

in eunuchoidism, 410

in tumors of the epiphysis, 331

in hypophysial dystrophy, 311

in infantilism, 473

influence of the sexual glands, 384

in myxedema, no

in sexual glandular tumors, 425
Psychoses, ductless glands in, 38

in Basedow's, 66

in hypophysial dystrophy, 311

in myxedema, no
Purin metabolism, 17

in acromegaly, 263

in brain diseases, 38

in eunuchoidism, 409

in hypophysial dystrophy, 291

regulation through the ductless glands,

17

Pylorospasm in tetany, 189

Quinine in Basedow's disease, 81

in thyroiditis, 56
Quotient (D : N) in diabetes mellitis, 537

after extirpation of the pancreas, 506

respiratory, see respiratory quotient.

Rachitis, 484

tetany in, 212
Radium treatment in eunuchoidism, 413

in hypergenitalism, 427
Rathke's cysts, 242
Raynaud's disease, 38

Reciprocal action of the ductless glands, 6-10
Reichmann's disease in tetany, 179, 220
Respiration calorimeter, 531
Respiratory metabolism, 17

in acromegaly, 261

after adrenalin injection, 343

in Basedow's, 78

in cretinism, 135

in eunuchoidism, 409

after extirpation of the pancreas, 505

in obesity, 570, 571

after pituitrin injection, 273

regulation by ductless glands, 17

in tetany, 194

organs in Basedow's disease, 64
quotient after adrenalin injection, 343

in Basedow's, 76

in diabetes, 531

after exclusion of the subdiaphrag-
matic circulation, 514

INDEX

67I

Respiratory quotient after extirpation of
the pancreas, 505

after injection of pituitrin, 273
Retinitis in acromegaly, 266

in tetany, 286
Rodagen, 102
Rontgen, examination, etc.,- see X-ray.

Salt metabolism in acromegaly, 262

after extirpation of the pancreas, 505
Sarcoma of the epiphysis, 330
of the hypophysis, 312
of the sexual glands, 426
of the suprarenal cortex, 376
of the thymus gland, 228
of the thyroid gland, 54
Schlesinger's symptom, 180
Scleroderma, ductless glands in, 39
in Addison's disease, 348
with myxedema, 118
pigmentations, 348
thyroidin treatment, 144
Sclerose tubereuse du cerveau, 356
Sclerosis, multiple, 41
of the pancreas, 521
of the parathyroids, 207
premature, of the cerebral arteries in

tetany, 216

of the thyroid gland, 56
Sella turcica in acromegaly, 221
after- castration, 393
in eunuchoids, 407
in eunuchs, 393
in hypophysial dystrophy, 3 1 1
in myxedema, 116
in sporadic cretinism, 136
in thyroidless animals, 116
Senilism, 48

Sensorium in tetany, 183
Sertoli's cells, 370
Sexual characters in chlorosis, 431
in eunuchs, 13, 392
in premature development, 425
relation to the sexual glands, 388
in suprarenal cortical tumors, 358
glands, 369
see also interstitial glands, genitals,

generative apparatus,
in Addison's disease, 337
in adipositas dolorosa, 584
anatomy, 370
aplasia, 385
in chlorosis, 430
in chondrodystrophy, 490
in climacteric, 384
in diabetes, 544

Sexual characters in ductless glandular

sclerosis, 446
in eunuchoids, 13, 408
in gigantism, 459
in hermaphroditism, 384
in infantilism, 472
in late castrates, 395
malformations, 385
in Mongolism, 496
in myxedema, 1 1 5
in obesity, 574
in osteomalacia, 437
physiology, 371, 374
in pregnancy, 378
pseudohermaphroditism, 387
sarcoma of, 427

transplantation of, 371, 388, 423
X-ray irradiation of, 371, 427
glandular insufficiency, treatment of, 422
Skeleton, see osseous system.
Sodium phosphate in Basedow's disease, 102
Speech development in cretinism, 162
Spermin, Poehl, 385, 422
Squamous-celled epithelial carcinoma of the

hypophysis, 321
Status lymphaticus, 34, 365
in acromegaly, 259
in Addison's disease, 337
in Basedow's, 75
hypoplasticus, 367
in thymus hyperplasia, 226
Steatoma of the hypophysis, 312
Stomach tetany, 214

treatment of, 220
Strabismus in tetany, 181
Struma, see goiter.

hyperplastica parenchymatosa teleangi-

ectodes, 58

of the hypophysis, 269, 312
Sugar puncture, 515

in animals without suprarenals, 344

without thyroids, 576
Suppuration of the suprarenals, 340
Suprarenal cortex, in acromegaly, 260
in Addison's disease, 361
aplasia, 350

in ductless glandular sclerosis, 447
in gigantism, 462
hyperplasia, 351
hypoplasia, 351
in nanisme type senile, 351
physiology, 345
in pregnancy, 379
in the premenstrual period, 375
in pseudohermaphroditism, 360
scleroses, 351

672

INDEX

Suprarenal cortex, tumors of, 356
hairiness in, 390

veins, thrombosis of, 340
Suprarenals, 334

in acromegaly, 260

anatomy, 334

aplasia, 340

blood picture, 337

blood sugar, 337

conditions of hyperfunction, 352

detoxication theory, 345

embryology, 334

in hemicephaly, 340

hyperplasia in atheromatosis, 355

in hypertonia, 354

implantation of, 349

importance for life, 342

in infections, 341

leucemia, 348 •

loss of glycogen after extirpation, 349

in multiple ductless glandular sclerosis,

447

pathological anatomy, 340
physiology, 342

in progeria, 452

in sugar puncture, 516

tumors of cortex and medulla, 363

see also chromaffin tissue.
Sympatheticus in Addison's disease, 371

see nervous system.

tumors of, 352
Sympathicotony, 31

in Basedow's disease, 95
Syphilis of the brain and diabetes, 560

in ductless glandular sclerosis, 448

in infantilism, 474

of the pancreas, 520

of the suprarenal glands, 340

of the thyroid gland, 55
Syringomyelia, differential diagnosis from
acromegaly, 281

Tabes, 38

Tachycardia in Basedow's, 58

Teeth in acromegaly, 236

in myxedema, 105

see also dentition.
Teratomata of the epiphysis, 330

of the hypophysis, 312
Testicular extract, 422
Tetanoid, 207
Tetany, 177

action of adrenalin, 183

in adipositas dolorosa, 588

bladder symptoms, 192

blood picture, 185

Tetany, calcium metabolism, 195

cardiovascular apparatus, 184, 185

cataract, 197

child tetany, 212

choked disc in, 183

conjunctivitis in, 198

definition, 177

dentition, 197

differential diagnosis, 216

in ductless glandular sclerosis, 499

eclampsia, 182

enamel, defects of, 197

epilepsy, 182

etiology, 208, 210, 211

forms, 207

formes frustes, 216

in gastrointestinal diseases, 214

gastrointestinal disturbances, 188

growth disturbances in, 199

hair in, 196

heat regulation, 192

idiopathic, 210

in infectious diseases and intoxications,
209

lachrymation, 184

magnesium sulphate treatment of, 222

maternity tetany, 213

mental symptoms, 183

metabolism, 193

myotony, 183

nervous system, 177

neuroretinitis, 183

occupation tetany, 210

osteomalacia, 199

parathyroprivic, 207

pathogenesis, 200

pathological anatomy, 212

pigmentations, 196

pilocarpine action, 183

prognosis, 218

pylorospasm, 190

sensorium, 182

skin, 196

spasm in, 180

symptomatology, 177

thermoreaction, 193

thyroid gland in, 200

in thyroid glandular diseases, 209

treatment of, 218, 222

trophic disturbances, 196

vascular system, 185

Tetanus, differential diagnosis from. tetany,
216

aponicus, 181
Thermoreaction, 298
Thorium treatment, 427

INDEX

Thymus gland, 223

in acromegaly, 260

anatomy, 223

aplasia, 225

asthma thymicum, 228

blood picture, 227

clinical aspect of, 225

in cretinism, 136

diseases of, 223

in eunuchoidism, 410

experimental physiology, 224

mors thymica, 227

status lymphaticus, 228

tumors, 228
hyperplasia, 226

in acromegaly, 260

in Addison's disease, 337

in Basedow's, 73, 90, 152

treatment in Basedow's, 102
Thyraden, 140
Thyreoidinum siccatum, 140
Thyroaplasia, see also cretinism, sporadic.
Thyroid elixir, 141

gland in acromegaly, 265

in adipositas dolorosa, 584

adrenalin action after extirpation,

343

anatomy, 53

in Basedow's, 58

in chlorosis, 430

in chondrodystrophy, 493

in ductless glandular sclerosis, 447

embryology of, 53 '

effect on growth, 15 '

in eunuchoidism, 408

and hypophysis, 323

inflammation, 56

iodine contents, 91

metabolism, 76

in obesity, 573

after pancreas extirpation, 506

in the premenstrual period, 375

in pregnancy, 381

in tetany, 202

tumors, 54

Thyroidip action on nervous system, 28
treatment in adipositas dolorosa, 587

in athyrosis, 139, 140

in cretinism, 143

combination with arsenic, 142

in eunuchoidism, 413

in hypophysial dystrophy, 326

in sexual glandular insufficiency, 422

in thyrogenic obesity, 573
Thyroidism, 85

Thyroiditis, 55, 114
Thyroprivic equivalents, 119
Tongue goiter, 117, 122
Trauma in diabetes, 556

in late eunuchoidism, 414
Tremor in Basedow's, 66
Trophedema, 585
Trophoneurosis, 43, 45
Trousseau's symptom, 179
Tryptophan as mother-substance of pigmen-
tations in Addison's disease, 283
Typhus abdominalis, infantilism after,

474

late eunuchoidism after, 418

thyroiditis after, 56
Tubercles in floor of ventricles, 534
Tuberculin injection in tetany, 182
Tuberculosis in Addison's disease, 336

of the body of the sphenoid bone, 325

in ductless glandular sclerosis, 448

the hypophysis, 312

infantilism, 474

of the parathyroids, 209

of the suprarenals, 340

of the thyroid gland, 56

Umbilical hernia in cretinism, 133

Vagal neurosis, 38
Vagotony, 31

in Basedow's disease, 95

in status lymphaticus, 367

in thymus hyperplasia, 227
Variola, thyroiditis after, 56
Vascular system in acromegaly, 259

in Basedow's disease, 58

in infantilism, 473

in myxedema, 106
Vegetative disturbances, 464

nervous system, 25

see also nervous system.
Voice in acromegaly, 237

in eunuchoids, 407

in late eunuchoidism, 420

Water economy, 20, 38

in chlorosis, 430

in diabetes mellitus, 530
Wave movement in women, 374

Xanthalasma, 40

Xanthin bases, elimination in endemic cre-
tinism, 162

X-ray examination in acromegaly, 237
in hypophysial dystrophy, 311

674 INDEX

X-ray examination, see also epiphysial June- X-ray treatment in acromegaly, 282
tures, and osseous system, and growth in Basedow's disease, 101, 150

disturbances. in chlorosis, 434

irradiation of the sexual glands, 371, in dysmenorrhea, 434

427 in hypergenitalism, 427

CD

CO

E

H

Q>
A
i-H

•H

co

0)
CO

c8
<D

CO

a

o

UNIVERSITY OF TORONTO
LIBRARY

Do not
re move

the card
from this
Pocket.

Acme Library Card Pocket

Under Fat. " Ref. Index Kile."

Made by LIBRARY BUREAU