riiE NW PHYSIOLOGY IN SURGICAL AND GENERAL PRACTICE SHORT t-r*-T- r /' *^ |Gl^3A- Cohmtbia ^mbtt-^ttp S^partm^nt of fliustolnsg 2I^p Ji^ttttb .A . Digitized by the Internet Arciiive in 2010 witii funding from Columbia University Libraries http://www.archive.org/details/newphysiologyinsOOshor m^ Fiontispiece THE NEW PHYSIOLOGY IN SURGICAL AND GENERAL PRACTICE By a. RENDLE SHORT, M.D., B.S., B.Sc. (Lond.), F.R.C.S. CEng.), Examiner in Physiology Jor the F.R.C.S. ; late Hunterian Professor, Royal College of Surgeons ; Senior Assistant Surgeon, Bristol Royal Injirntarv ; Lecturer on Physiology, University of Bristol. Fourth Edition Revised and Enlarged NEW YORK WILLIAM WOOD AND COMPANY MDCCCCXX o^ "2- 0 - 3 ? V V First Edition, September, igil. Second Edition, Rez'ised, May, IQI2. Reprinted, December, iqj2. Third Edition, June, igi4. Reprinted, July, igib. Fourth Edition, March, IQ20. ^'OTE 0^ FRONTISPIECE. The picture, for which I am indebted to Miss D. PiHers and Mr. A. K. Maxwell, shows the condition in the patient referred to on page 115. The csecum has prolapsed through the wound in the abdominal wall, and is turned inside out to show the mucosa. Beneath the thin wall of the caecum, the colls of small intestine are seen bulging, in incessant peristalsis. The rough sketch at the top shows the position of the swelling on the abdominal wall. In the upper coloured picture the sphincter is quiescent, be- tween meals. Notice the contracted raised muscular ring. The lower picture shows the sphincter lying relaxed, and one of the intermittent gushes of fluid ileal contents pouring through, ten minutes after a meal. PREFACE TO FOURTH EDITION The last edition was published just before the war. Needless to say we have learned a great deal in the past live years. Research in pure physiology and its applications to the clinical sciences has fallen principally into the hands of the Americans, whilst the British investigators have devoted themselves especially to problems arising out of the material presented by the wounded in the war. The results of study, observation, and experiment along both these lines are here gathered together. Much of the book is new, but the objects and scope remain as in the preface to the original edition. To make way for additional material considerable sections have been deleted altogether. The chapters on food deficiency diseases, the blood and spleen, surgical shock, the spinal cord, and the functions of the cortex, have been re-written almost in their entirety. A new chapter on the heart has been contributed by my colleagues Dr. Carey Coombs and Dr. C. E. K. Herapath, to whom I am greatly indebted for this service. There are considerable additions to the chapter on digestion, and less important changes in nearly all the other parts of the book. Very little is left of the first edition, published in 1911. A. R. S. February, 1920. PREFACE TO FIRST EDITION These chapters are intended for the general practi- tioner, the consulting surgeon, and candidates for the higher examinations in physiology. There was a time when one man could be physio- logist and surgeon too, but the rapid march of progress in each field has left a great gap between the sciences, which is continually widening. The triumphs of the surgeon are unknown to the physio- logist, and the converse is equally true. Yet many of the discoveries of the past ten years which have so changed the face of physiology are fraught with vast possibilities for the clinician. This book is an attempt to sift out from the New Physiology that which is likely to be of value in the actual diagnosis and treatment of patients. It would be a small service to lay before the practical reader mere theories or guess-work. With but few exceptions, only the estabhshed and settled conclusions arrived at by many competent and independent workers have been introduced. Part of the chapter on cutaneous anaesthetics, and a few other researches and passing suggestions for which the author is personally responsible, must stand in a different category. viii PREFACE An effort has been made to explain matters so simply that they may be intelligible to those having the most elementary knowledge of physiology, and all technical terms have been avoided or defined. There are excellent manuals now published treating of the application of physiology to diseases which concern principally the consulting physician. This little book limits itself to surgical problems, and to the common every-day aspects of disease that confront us all, physicians, surgeons, and general practitioners ahke. I owe a debt of thanks to my chief. Professor A. F. Stanley Kent, for some valuable suggestions and criticisms. A. R. S. Bristol, September, 191 1. CONTENTS I. — Food Deficiency Diseases . . . i Carboh3^drate, protein, and fat deficiences — Neuritis — Growth — Scurvy — Rickets. II. — Researches on Blood- - i6 Recovery of blood after haemorrhage — Blood transfusion — The four blood groups — Fate of red blood-corpuscles — Functions of the spleen and liver — Coagulation of the blood — Purpura haemorrhagica — Haemophilia — Anaphylaxis — The therapeutics of calcium salts. III. — The Heart (by Dr. Carey F. Coombs and Dr. C. E. K. Herapath) - - - - 45 Development and structure of the heart — Modes of examination of the heart — Heart rhythm — Properties of cardiac muscle — The nervous system of the heart — Cardiac irregu- larities. IV. — Surgical Shock - - - - - 80 What is shock ? — The phenomena of shock — Experimental means of inducing shock-like conditions — Theories as to its nature — Pre- vention and treatment — Intravenous saline transfusion. V. — Recent Work on the Functions of the Stomach and Intestines - - . 107 Movements of the stomach — Movements of the intestine — Sensation in the alimentary canal — Variations in the hydrochloric acid of the stomach — The physiology of gastro- jejunostomy— Absorption in the colon. , X COXTENTS CHAPTER PAGE VI. — The Genital Glands - - - - I37 Functions of the ovary — Functions of the testis — Control of the genital glands by internal secretions — The secretion of milk — The ovum Chemical diagnosis of pregnancy. VII. — The Growth of Bone - - - 152 Recent change in our conception of the gro\vth of bone — Osteoblasts — Increase in the length of bone — Increase in the girth of bone — Func- tion of the periosteum — The regenerative powers of bone — Application of modern re- searches to surgical practice — Bone-grafting — Relation of the'ductless glands to the growth of bone. VIII. — The Thyroid and Parathyroid Glands - 166 Histon,' — Removal of the thyroid and para- thvroids-^Removal of the parathyroids alone — Removal of the thyroid alone — Thyroid feeding — Chemistn,' of thyroid colloid — Parenclwmatous goitre — Iodoform and thy- roidism— Action of iodides on gummata and atheroma — Exophthalmic goitre — Practical deductions. IX. — The Pituitary and Pineal Glands - 186 Structure of the Pituitary — The effects of removal in animals — Injection of extracts — Pituitary- feeding — Acromegaly and gigantism • — Frohli'ch's t^-pe — Functions of the pituitan.^ gland — Therap'eutic value of pituitary extract — The pineal gland. X. — Oxaluria - - - - - 198 XI. — Immediate and Remote Poisoning by Chloroform - - - - Sudden death under chloroform — The fatal adrenalin-chloroform combination — Delayed chloroform poisoning. 201 CONTENTS xi CHAPTER TAGE XII. — The Functions of the Spinal Cord and Peripheral Nerves - - - 208 The double motor path — The double sensory- path — The exact diagnosis of spinal cord in- juries— Lesions of the posterior nerve roots — Injuries and repair of peripheral nerves. XTII. — Localization of Function in the Brain - 237 Localization of sensation in the cerebral cortex ; vision, hearing, cutaneous and other forms of sensation — Functions of the frontal cortex — Apraxia — Aphasia — Misleading local- izing signs of intracranial tumour — Optic neuritis — The cerebellum — Tumours in the cerebello-pontine angle — The cerebrospinal fluid. XIV. — The Action of Cutaneous Anesthetics • 267 Drugs applied to the unbroken skin. Appendix - - - - - - 273 Absorption of nitrogen from amino-acids. The New Physiology in Snroical and General Practice, CHAPTER I. FOOD DEFICIENCY DISEASES. CARBOHYDRATE, PROTEIN, AND FAT DEFICIENCIES NEURITIS GROWTH — SCURVY RICKETS. THIS chapter is not a discourse on the phenomena of starvation. It rather aims at setting forth the consequences that may be expected when some one more or less essential ingredient of the food is omitted from the dietary. In the Report of a Committee of the Royal Society on the " Food Requirements of Man", issued in 1919, it is observed that as a general rule the brain worker requires from 2200 to 2600 calories as the energy value in heat units of his daily food, whereas the labourer needs 3300 ; but in the case of the brain worker the food will need to be lighter, more digestible, and to contain more protein, so that it will cost more in proportion. There is not much that is new to be related concerning the ill-effects of carbohydrate starvation. Except as a therapeutic measure, it seldom occurs. 1 2 FOOD DEFICIENCY DISEASES It leads to loss of flesh, as in the well-known systems of dieting for obesity, and to an increase in the formation of /3-oxybutyric and diacetic acids in the blood. Chittenden's work at Yale University showed that it is possible to maintain life, and apparently both mental and physical efficiency, on a diet containing less than half the amount of protein allowed in the standard dietaries. Hindhede, of Copenhagen, by supplying an ample total calorie value of food (4000 calories per day) , was able to maintain his laboratory attendant in health for 150 days on a diet of nothing but potatoes, margarine, and onions, containing only 4-425 grms. of nitrogen a day. It is very doubtful, however, whether the results would be satisfactory over a longer time. It has been demonstrated that the mental and physical efficiency of the various races of India, many of whom live very near the protein- starvation level, varies directly with the protein allowance in their dietary. The Royal Society Committee report that the diet of the average man should contain not less than 70 to 80 grms. of protein daily, and that some of it should be of animal origin. A colossal experiment in fat-starvation has been carried out on the population of Germany and the other Central European states. So far the informa- tion which has come through is too scanty to build much upon. We have heard of a high infantile mortality, of general loss of flesh, of bodily and mental torpor, of increased liability to tuberculosis, and so on. As might be expected, it is reported (by FOOD DEFICIENCY DISEASES 3 medical members of a commission of the Society of Friends) that rickets has become a widespread scourge amongst German infants. The only new fat-deficiency disease I have been able to get any account of is a chronic affection of the conjunctivae in infants (xerophthalmia) reported from Denmark and elsewhere. There seems to be a close relation between the assimilation of fat and the capacity for bodily work. " Where vigorous muscular exercise has to be undertaken, it is essential that the diet should contain not less than 25 per cent of its energy in the form of fat ". NEURITIS. For generations it has been a fundamental axiom of dietetics that a proper food allowance should contain proteins, carbohydrates, fats, salts, and water. Tables, such as Ranke's, have been drawn up and copied from book to book, setting forth the proper proportions of each to maintain health. During the past six or seven years, however, im- portant evidence has been adduced to show that these five proximate principles by themselves are inadequate, and that a mysterious something more is necessary. One of the first reforms leading up to the marvellous emancipation of modern Japan from her mediaevalism of half a century ago was concerned with a problem of this sort. The Japanese navy was reduced to complete ineptitude by the prevalence of beri-beri — a form of peripheral neuritis — amongst the crews, as many as a quarter of the men being afflicted. Baron 4 FOOD DEFICIENCY DISEASES Takaki, lately returned to his own country after a study of modern medicine, found that the dietary was very imperfect, and instituted an improved ration with complete success. Beri-beri was until recently a terrible scourge amongst the inhabitants of the Malay States ; was often seen in coolies at English seaports ; and has broken out in an asylum in Dublin. Improving the quantity of food in the prisons of the Straits Settlements failed to limit the disease. The outstanding feature of the incidence of beri- beri in the Straits was, that while the Tamils were exempt, the Chinese suffered severely. Rice is the main article of diet with both races, but with this difference, that whereas the Tamils store their rice and boil it in husk, the Chinese use husked white rice such as we are accustomed to in this country, though, of course, with us rice is a very much less important item in the daily dietary. The Chinese are extremely prone to beri-beri ; the Tamils very seldom suffer. This cannot be due to any racial peculiarity, because Tamils in prison and fed on husked rice are just as liable as the Chinese. The explanation originally given was that the bare rice grain had become contaminated in some way ; but recent experiments by Casimir Funk and others bring out another aspect of the case. It is possible in pigeons to produce a peripheral neuritis closely resembling beri-beri by feeding exclusively on polished rice, and when small quantities of husk are added the birds rapidly recover. The essential constituent of the husk which has this effect is only FOOD DEFICIENCY DISEASES 5 present in small quantity, but it can be isolated in crystalline form, and on analysis appears to belong to the pyrimidine group. It is not the coarse fibrous husk that contains so much of the anti- neuritic substance, but the thin film or ' silver skin ' just covering the grain, wherein also lies the embryo. Wheat embryo, wheat bran, yeast, and egg yolk also contain fair quantities of this element ; milk and meat only hold traces. From loo kilos of yeast 2*5 grms. of the crystals were obtained. There is clinical evidence in support of this experi- mental work. Research in the Philippines has shown that the infant of a mother fed on polished rice is Hkely to develop beri-beri, but that it is rapidly cured either by fresh cow's milk or by an extract of rice- husk. The substitution of parboiled for polished rice in a Siam prison has brought down the death- rate from 113 to nil. McCarrison shows that it is not only the nerves that are affected by a diet restricted to polished rice. The thymus, testes, ovaries, and spleen all atrophy, and in a less degree the pancreas, heart, liver, and kidney. The suprarenals, on the other hand, become hypertrophied, and there is usually oedema, which seems to run parallel to the degree of enlargement of the suprarenals. Doubtless this accounts for the ' wet ' form of beri-beri, and perhaps for ' war oedema ' amongst prisoners in Germany. GROWTH. The principle having been once established that a dietary to maintain health must contain, in addition 6 FOOD DEFICIENCY DISEASES to the five well-known elements — proteins, carbo- hydrates, fats, salts, and water — traces of other so- far unrecognized chemicals, a new field is opened for exploration, and several diseases come up for a similar explanation. The new chemical bodies which appear to be thus needful are called ' vitamines '. Hopkins has lately shown that something of the sort is necessary for ordinary growth. Young rats fed on purified protein, carbohydrate, fat, salts, and water, absolutely cease to grow, even if the quantity supplied is correct. If the experiment is prolonged, the animals die. If only a teaspoonful of milk is supplied daily, growth becomes normal. We now know that two vitamines are necessary for growth ; one of these is called fat-soluble A, and is contained dissolved in the fat of milk, and the other is water- soluble B, which appears to be identical with the antineuritic vit amine. Considerable research has been done lately on the fat-soluble A. It is shown by Halliburton and Drummond, using young rats, that none of the vegetable margarines which have come into such extensive use of late contain it. It is present in milk, butter, cream, animal fat, and the higher-priced (oleo-oil) beef-fat margarines. Lard contains little if any ; it has been spoiled in the process of preparation. The fat-soluble vitamine in mother's milk is derived in considerable part from cow's milk or cream she has taken as nourishment. These observations go to show the national impor- tance of providing milk and animal-derived fats both for young children and also for nursing mothers. FOOD DEFICIENCY DISEASES 7 Even sarcoma-cells require vitamines, and if they are withheld, Jensen's rat sarcoma only develops at a quarter its usual rate. At Romney there are two fields, apparently identical, but the animals pasturing in the one put on flesh, and in the other they become thin. SCURVY. It has been known for centuries that scurvy is a deficiency disease ; but exactly where the deficiency lies has always been uncertain. Nowadays it is very rare in adults in this country, though the writer has seen one case affecting a lonely man who was trying to live on his old-age pension. A few cases occurred in France during the war. I saw one quite severe example of the disease at a casualty clearing station. The man had been a long time in the trenches, and had had no fresh food. Much more commonly the disease is seen in young infants fed upon boiled, stale, or artificially-prepared milk. Some most interesting and important points have lately come to light with regard to scurvy. It should be remembered that the swollen gums, loose teeth, haemorrhages from the mucous membranes and beneath the skin and periosteum, and grave anaemia, are signs of an advanced degree of the food deficiency. There are less characteristic symptoms long before these develop — lassitude, inability to think or work, and general debility. When these signs appear in a body of men, undeclared scurvy should be thought of. It has been an article of faith for nearly a century 8 FOOD DEFICIENCY DISEASES that lime- or lemon-juice, and fresh vegetables, are the main preventives of scurvy, and yet there have been curious gaps in the evidence. Up to the beginning of the eighteenth century, both the British Navy and the mercantile service had suffered terribly from the disease, and many expeditions were ruined in consequence. In the days of Robinson Crusoe the antiscorbutic properties of lemons and fresh fruit and vegetables were known, but the supineness of the authorities was such that often no trouble was taken to provide sailors with them until about 1803, when the Navy began to get a regular supply of lemon-juice from Malta. It was often caUed ' lime- juice '. After about 1865 the juice of Montserrat limes came to be used instead, and this has been the main standby in the Army and Navy ever since. From 1803 onwards there has been very little scur\'y. The use of fruit- juices became compulsory in the merchant service after 1844, and was equally successful. Of course, shorter voyages and better food supplies generally have led to less and less need to place rehance on lime- or lemon-juice under ordinary circumstances. In several Arctic expedi- tions, such as Sir James Ross's in 1849, the lemon- juice supplied was thoroughly bad, and the company suffered severely from scurvy. Thus far the evidence is clear. There have been, however, several occasions when no fresh vegetables and no fruit-juice have been used for long periods, but fresh meat in large quantity has been eaten, and no scurvy has occurred. This was so with Nansen's expedition across Green- land, and with one of the subsidiary parties in FOOD DEFICIENCY DISEASES 9 Shackleton's expedition to the South Pole. The Hudson's Bay Company people Uve almost entirely on fresh meat and fish, and they never show signs of the disease. Yet fresh meat has failed to avert scurvy (as in the Kaffir campaign of 1846-7) when plenty of other food is taken at the same time. Evidently the amount of vitamine in fresh meat is low, and unless it is eaten in great quantity it proves inadequate. Also, the traditional Army stew probably destroys much of the vitamine by long cooking. During the war, doubts have grown up as to the preventive value of lime-juice. This has led Miss Alice Henderson Smith to bring to light many most interesting facts about the history of the disease in the records of Arctic and Antarctic exploration. There is a remarkable contrast between two expedi- tions, that of Sir Robert McClure in the Investigator in 1850, and that of the Alert and the Discovery in 1875. McClure went to seek for Sir John Franklin ; his ship was north of Alaska for twenty-seven months after leaving England before the first case of scurvy occurred, in spite of great hardships and many months on half rations. In the Alert and Discovery, north of Greenland, there was a severe outbreak of scurvy in eleven months, though on full rations. The Alert had sixty cases and three deaths out of a company of 122. The food supply of the Alert and of the Investigator was practically the same, except that on the latter lemon-juice was used, and on the Alert lime-juice. In each case the officers took great care to see that the juice was really drunk. 10 FOOD DEFICIENCY DISEASES Finally, an investigation has been made experi- mentally by Chick and Hume at the Lister Institute, which shows that lemon- juice has four times the antiscorbutic power of lime-juice. Oranges are as good as lemons, and the fruit is better than the bottled juice. The antiscorbutic power of fresh meat is low ; about four pounds a day is needed in man, whereas an ounce of lemon-juice will do. The most interesting discovery is that germinating peas and beans develop a high proportion of the vitamine. If they are soaked in water for twenty-four hours, then spread out to germinate for two days, and cooked not longer than an hour, they are powerfully antiscorbutic. V^^hat suffering it would have saved if this had been known before ! The Alert and Discovery brought back unused 6000 pounds of dried peas ! During the war there was a good deal of scurvy amongst Serbian soldiers in Macedonia, and Wiltshire was able to test the relative curative value of lemon- juice and of germinated beans by allotting a ward full of scorbutics to be treated by each method. In spite of the fact that the soldiers rather resented being fed upon * pig-food', its therapeutic virtues were, if anything, rather superior to those of the fruit-juice. Swedes, potatoes, and cabbage, unless cooked too long, all contain the antiscorbutic vitamine. Canned fruits and vegetables are almost useless. Beer had a great reputation in the old Navy ; native Kafhr beer certainly protects, but the ' high-dried kilned malt ' used by Sir John Franklin's expedition, and modern brewed beers, are of no value. FOOD DEFICIENCY DISEASES 11 Fresh milk contains the vitamine, but it is lost on boiling for more than five minutes. It disappears in stale or dried milk. Probably this vitamine may fail at the end of prolonged lactation, thus accounting for a few authentic cases of scurvy in breast-fed babies. In ordinary, sufferers from infantile scurvy have been fed on stale, artificial, sterilized foods. The disease is rapidly cured by giving fresh unboiled milk and fruit-juices. Infants reared on boiled milk ought to have a little orange- or grape-juice (though this is not quite as good) every few days. They like it. Also, the milk ought not to be boiled more than a minute. If no other source of vitamine is supplied, animals have to be given a great deal of milk to avert scurvy. The vitamines that prevent beri-beri and scurvy are both water-soluble, but they are not identical. The antineuritic body is not so readily destroyed by heat, and it keeps better. RICKETS. Rickets is probably another deficiency disease. The infants have usually been fed upon a diet con- taining too much starch and sugar, and too little fat and protein. The observations of Bland-Sutton at the London Zoo rather point to the deficiency of fat as being the more important. A lioness there was unable to suckle for long, and litter after litter of cubs had died of rickets. Investigation of the diet showed that they were fed upon London cab-horse, which naturally did not supply any fat, and their little teeth were not able to crush the bones and obtain the 12 FOOD DEFICIENCY DISEASES marrow. When they were given milk, cod-hver oil, and pounded bones they did excellently. It is well known, of course, that cod-liver oil, cream, and fresh milk are the best treatment for rickets. There is considerable difference of opinion at the moment whether rickets is due principally to deprivation of a fat-soluble vitamine, as the above observations and the researches of the Mellanbys would indicate, or to lack of fresh air and exercise, as is maintained by Noel Paton and other workers in the Glasgow school. At the Glasgow Zoo, cod-liver oil does not prevent rickets ; the only zoo free from it is said to be Hagenbeck's at Hamburg, where the animals are allowed great open spaces and natural conditions. Investigation of the home surroundings of children of the hospital class in Glasgow shows little differ- ence as to bottle-feeding and breast-feeding, or the amount of fat in the dietary, between the healthy and the rickety. If the rooms were small, crowded, high up, and ill-ventilated, and the children seldom taken out, the proportionate incidence of rickets was high. In the markedly rachitic children, 3*93 persons inhabited each room, and the cubic feet of air-space per person was 422 ; in the non-rachitic, there were 3 persons per room, and the air-space was 625 cubic feet. The homes of the rachitic were poorer and less well cared for. Of the rachitic, only 30 per cent were properly exercised ; of the healthy, 86 per cent. There is some animal evidence in the same direc- tion. Puppies kept in the laboratory are much more prone to rickets than those allowed to run wild FOOD DEFICIENCY DISEASES 13 in the country. The A-ray signs of rickets at the growing ends of a puppy's long bones are very well shown. In some cases the country puppies were given less fat than the laboratory ones. A particular instance is quoted of two identically fed puppies, one belonging to an active boy and the other to his invalid cousin ; the latter developed rickets, because it was more cooped up. The Mellanbys maintain the vitamine h}^othesis. E. Mellanby has used a much larger number of pups, over 200, and finds that a diet containing bread, meat, oatmeal, linseed oil, yeast, orange-juice, and an inadequate amount of milk causes rickets constantly in a few months. Giving more milk, or animal fats, prevents rickets. Fast-growing pups show symptoms more markedly than slow-growing. Calcium salts make no difference. Whether the vitamine is the same as that necessary for growth (fat-soluble A) is not certain. Mrs. Mellanby shows that on such a diet, adequate in all other respects, but lacking animal fats, the puppies' deciduous teeth are lost late, the permanent teeth erupt late and are badly placed, the enamel is defective, and the calcium content low. If plenty of milk or cod-liver oil is given, the teeth are normal. Mellanby replies to the Glasgow school, that the milk allowance for their dogs was always rather low, so that the difference between confinement and exercise might turn the scale when animals were already near the margin, by differences in appetite and assimilation. WTien pups have plenty of milk, confinement does not make them rickety. The 14 FOOD DEFICIENCY DISEASES amount of fat in the dietary of the Glasgow children was very near the minimum, and there was, as a matter of fact, less in the diet of the rachitic families ; also, if children eat a lot of bread the}^ tend to neglect the articles that contain the vitamine. There are other facts that tell in favour of the vitamine theory, though it must be allowed that Findlay and the other Glasgow workers have taught us a lesson as to the importance of fresh air and exercise in the prevention of rickets. In an American negro baby clinic, of thirty-two infants given 54 oz. of cod-liver oil in six months, only two were rachitic ; of sixteen given none, all but one became rickety. Experience surely teaches that milk, cream, and cod-liver oil are curative, but probably we have overdone the splinting for bow-legs and knock-knee ; it would be better to straighten the bones under an anaesthetic and get them running about in the open air as soon as possible. In Greenland, where the Eskimo children are cooped up all the winter in huts but get plenty of animal fat, rickets does not occur. In constructing a diet table for children it ought to be remembered that such a deficiency of vitamines as may produce scurvy, beri-beri, rickets, or stunted growth represents a gross deviation from the ideal, and that much chronic ill-health and liability to infection may result from less exaggerated deviations. FOOD DEFICIENCY DISEASES 15 REFERENCES.* Funk. — Brit. Med. Jour., 1913, i, 814; and articles in Journal of Physiol., 1911-13. Hopkins. — Proc. Royal Soc. Med. (Therapeutical Section), vol. vii, Nov., 1913, I ; Brit. Med. Jour., 1919, i, 507. Halliburton and Drummond. — Jour, of Physiol., 1917, li, 235- Alice Henderson Smith. — Jour. R.A.M.C., 1919, xxxii, 93, 188 ; Lancet, 1918, ii, 813, Wiltshire. — Lancet, 19 18, ii, 811. Findlay. — Glasgow Med. Jour., 1918, 268. Mellanby. — Lancet, 1919, i, 407. Chick and Hume. — Lancet, 1919, ii, 320. * References at the end of chapters are not meant to be exhaus- tive. Only a few accessible authorities are quoted, in some of which a fuller bibliography will be found. 16 CHAPTER II, RESEARCHES ON BLOOD. RECOVERY OF BLOOD AFTER HEMORRHAGE BLOOD TRANS- FUSION THE FOUR BLOOD GROUPS— FATE OF RED BLOOD-CORPUSCLES — FUNCTIONS OF THE SPLEEN AND LIVER— COAGULATION OF THE BLOOD PURPURA HEMOR- RHAGICA HEMOPHILIA ANAPHYLAXIS THE THERA- PEUTICS OF CALCIUM SALTS. THROUGHOUT the Great War haemorrhage has been a terrible bugbear. Not only did wounded men often lose a dangerous amount of blood before they could be collected from the forward areas and be brought to the nearest medical officer, but the surgeon's ancient enemy, secondary haemor- rhage, which in civil practice had almost ceased to interest us on account of its rarity, became a common and deadly foe once more. There is no doubt that the study of the blood and its problems had made greater advance in America than in the British Isles, and the valuable assistance of American medical officers, coming at a time when we were all thinking about such problems, has led to a better understanding of many important facts. We shall consider first the process of natural recovery from a big haemorrhage. It has long been known that within a few minutes the blood remain- ing in the vessels becomes diluted by taking up watery fluid from the tissues, and that the arteries RESEARCHES ON BLOOD 17 contract down on the reduced volume so as to maintain the blood-pressure and provide an efficient filling for the heart on the venous side. We now know that there is active spasm of the veins also, so much so that there may be serious difficulty in getting an intravenous infusion to flow. I have several times during a blood transfusion been compelled to use the internal saphenous vein at the groin on this account. There are several modem methods of estimating the total blood-volume. The best is by the use of an innocuous dye called ' vital red', introduced by Keith, Rowntree, and Geraghty. A sample of the patient's plasma (lo c.c.) is first obtained, citrated, and centrifugalized — or another person's plasma will do. Then a dose of the dye, well diluted, is given intravenously (3 mgrms. per kilo of body weight). Two samples of blood are then taken three and six minutes after from the two arm veins ; these are citrated and centrifugalized. The original plasma diluted with three parts of saline is then mixed with the dye solution to match the coloured plasma, withdrawn after injection, in a colorimeter. From this the plasma-volume in the body can be calculated. To obtain the whole-blood-volume, a haemocrit must be used. In normal persons the plasma-volume is one-twentieth the body weight, and the blood- volume is one-twelfth the body weight. This is a higher figure than that obtained by the older, less accurate, and more dangerous carbon- monoxide method, but it agrees well with the results got by another procedure — that is, by calculating 2 18 RESEARCHES ON BLOOD from the difference in the blood-count before and after transfusing with a known volume of gum- acacia solution. In obesity the plasma-volume is relatively low, and in chlorosis relatively high ; it is also high late in pregnancy. After a severe haemorrhage, the total blood-volume may fall to 60 per cent of the normal, and yet recovery may take place. Insisting on the patient taking large quantities of fluids by the mouth and per rectum greatly hastens the rate of recovery. In a few cases the capillary haemoglobin-count was higher than the venous (30 per cent and 26 per cent) ; as the patient improves, the difference passes off (Robertson and Bock). During the process of regeneration, the red marrow, which is normally confined to the flat bones, the bodies of the vertebrae, and the ends of the long bones, encroaches upon the yellow marrow in the shafts of the long bones to some extent. A few nucleated reds may turn up in the peripheral circulation. A much more constant sign of blood- regeneration is the appearance amongst the red corpuscles of reticulated cells, best seen after staining \\ith cresyl-blue, which may be used instead of Hayem's fluid for the blood-count. In normal blood these cells amount to i per cent ; during active blood-regeneration they may reach 20 per cent. Kerr, Hun\itz, and Wliipple have made a study of the restoration of the blood-serum proteins. If after a big bleeding the red corpuscles are centrifugaUzed RESEARCHES ON BLOOD 19 off, suspended in Locke's fluid, and returned to the circulation (in dogs), it takes some weeks to restore the protein to normal. If the animal is starved, recovery is retarded. If plenty of meat is given, however, the restoration will be speeded up, and a 50 per cent depletion may be recovered from in five to seven days. There is some evidence that the new protein is supplied by the liver. In a dog in which the liver has been partly cut out of the circulation by an Eck fistula, recovery of the serum protein after bleeding is slow and poor. In phosphorus poisoning, reduction of the liver protein and serum protein go together. BLOOD TRANSFUSION. It has passed into a hackneyed phrase to speak of ' infusing new blood ' into a committee or business undertaking ; but until the last two years of the war the procedure has been more metaphorical than literal in Great Britain. In America, blood trans- fusion has made immense strides. There is no doubt, now that so many medical officers have learned its value in France, that it will become a well-estabhshed method of treatment in this country. It is well known that animal's blood, or preserved serum, cannot be used, as violent toxic symptoms are produced if any considerable quantity is injected. The principal indication for blood transfusion is a severe haemorrhage of whatever origin. For this condition the benefit is very striking — much more lasting than that seen after a saline transfusion. 20 RESEARCHES ON BLOOD Traumatic shock apart from haemorrhage is also improved by injecting blood. For these purposes one needs large quantities ; about a pint is a usual dose. Blood transfusion is probably the best remedy we know for pernicious anaemia, but it is not a permanent cure. It appears to act not so much by directly increasing the volume and oxygen- carrying power of the blood, but by stimulating the red marrow to renewed activity, and so to bring on a remission. Yet another indication is continuing haemorrhage from haemophilia, as we shall see. For these two diseases, half a pint will be sufficient as a dose. Many different methods are in use for giving the blood. I have described these in some detail else- where. Direct arm-to-arm transfusion by connect- ing the donor's artery with the patient's vein is unsatisfactory in that one does not know how much blood passes ; it may be little or none. Some prefer to use unmodified blood kept from clotting by with- drawing from a vein into a paraffin-lined receptacle and injected as quickly as possible. Others prefer to use citrated blood, which is much easier to handle. I have given much larger doses of citrate intra- venously to wounded soldiers than we now consider necessary, and no harm resulted. Hedon finds that 4 grms. is safe for a dog. I have several times given 8 or 9 grms. to men. It is a curious point that the injection of citrate does not alter the coagulation time of the receiver's blood ; this has been verified by myself and others. It is also interesting that taking a pint of blood from a healthy RESEARCHES ON BLOOD 21 donor docs not produce any symptoms. In America there are professional donors who are wilhng to give blood once every three weeks or so. A very interesting research has been published by Abel that has borne good fruit during the war. He found in animals that a big haemorrhage can be replaced just as efficiently by the animal's red blood- corpuscles washed and suspended in Locke's fluid as by fresh whole blood. The plasma proteins do not seem to matter. Rous and Turner carried the matter further, and showed that red corpuscles kept in a citrate-dextrose solution may be preserved in an ice-chest for several wrecks, and will still func- tion if injected into an animal of the same species at the end of that time. If they are kept too long (three weeks in a rabbit, over four weeks in a man), they do no harm, but are rapidly removed, so that if the receiving animal is bled, and then transfused with the preserved corpuscles, the blood-counts show first the rapid fall due to the bleeding, then the rise to normal following transfusion, then in the course of a few days a rapid fall to the post- haemorrhage level. If the corpuscles have not been kept too long and are still functioning, this secondary fall does not occur. Captain O. H. Robertson was sent to the casualty clearing station where I was working just before the battle of Cambrai, to apply these results to man. Forty pints of blood (including a pint from a well- known surgeon) were taken and stored in ice, in a citrate-dextrose solution. It takes about a week for the corpuscles to settle ; the supernatant plasma 22 RESEARCHES ON BLOOD is then decanted off. The results were just as good as those obtained by using fresh blood. Needless to say it might be dangerous to inject plasma which had been kept any length of time. Miss Ashby has shown that after a blood trans- fusion the injected red corpuscles survive at least thirty days in man. This was determined by transfusing a patient belonging to Group II with Group IV cells, and then testing by agglutinins for the Group IV cells at various dates after- wards. Blood transfusion in man is not completely devoid of risks to the receiver. There is the possibility of conveying disease, such as syphilis, if the donor is not healthy. A rigor may follow, or vomiting, or a rise of temperature. If the transfusion is given too fast, the patient may complain of a feeling of disten- tion and bursting inside the chest. The most serious danger, however, arises from the use of an incompatible blood. If the donor and the patient do not belong to the same blood groups, there may be haemolysis of the injected corpuscles, resulting in vomiting, dyspnoea, an urticarial rash, a quick weak pulse, and perhaps con\ailsions or coma. These may come on during the transfusion, and may be followed by haemoglobinuria. In a few cases death has resulted. If the transfusion is stopped immediately, serious trouble may be averted. This brings up the importance of testing out the donor beforehand. If this precaution is not taken, alarming reactions may be expected in 5 to lo per cent of the cases. RESEARCHES ON BLOOD 23 THE FOUR BLOOD GROUPS. Strange to say, the bloods of different individuals, even of the same family, are not always compatible. Shortly after birth the blood takes up the characters of one of four groups, and these apparently persist throughout life unchanged. The blood of a person of a particular group may safely be given to another person of that group, but not necessarily to someone belonging to another group. The incompatibility lies in two directions : the one plasma will (i) haemo- lyze and (2) agglutinate the corpuscles of a patient of another group. It seems to be established that a blood which will haemolyze another will always agglutinate it ; this is convenient, because it is simpler to test out the agglutination reaction than the haemolysis. According to Moss, there are four classes of bloods, designated as Groups /, //, ///, and IV. The relative frequency of these groups, and their suit- ability as donors, are given in the following table : — Donor Percentage frequency. Suitable if patient belongs to Group I ., II ., Ill ,. IV 5 40 10 45 Group I ,. I. II „ I, III „ I, II, III, IV When the blood of a Group IV donor is given to a Group I, II, or /// patient, the plasma of the donor has a tendency to haemolyze and agglutinate the corpuscles of the patient ; but the plasma of the 24 RESEARCHES ON BLOOD patient does not so act on the corpuscles of the donor, and it is found in practice that what matters is the effect of the patient's plasma on the injected corpuscles, not the reverse. This is no doubt because the bulk of the patient's blood is so much greater than that of the transfused blood. The best method of determining the blood group of a donor is by the use of preserved stock sera belonging to Groups II and ///. To make the test, a glass slide is taken, and a large drop of the test serum placed one near each end. Then the donor's ear is pricked, and a small drop of blood taken with a match-stick and mixed with the Group II serum. Another drop is mixed by another match-stick with the Group III serum. The result may be as follows : — Blood Corpuscles agglutinated by Donor is Group II and Group III serum ,, III serum but not Group II serum ,, II serum but not Group III serum Neither serum Group I ,. II „ III ,. IV The agglutination is quite obvious to the naked eye in about five minutes. In choosing donors, we may use either 9ne belong- ing to the same group as the patient, or a Group IV donor. Groitp IV individuals are the universal providers. Thus, if a Group IV donor is available, it is not necessary to know what group the patient belongs to. On the other hand, if both patient and donor belong to Group II, the bloods will be compatible. RESEARCHES ON liLOOD 25 If one has not the two group sera in stock, it is necessary to test the patient's serum against the donor's corpuscles directly. Draw off a few c.c. of the patient's blood and allow it to clot in a tube. Obtain a large drop of quite clear serum, add a trace of citrate, and then mix in a small drop of the donor's blood. If agglutination occurs in five minutes, the donor is unsuitable ; if there is no agglutination, the donor's blood may be used for that patient. FATE OF RED BLOOD-CORPUSCLES. Some of the older text-books hazard a guess that red blood-corpuscles usually live about three weeks, but since even transfused corpuscles in man are surviving after a month it is probable that the ordinary life of a corpuscle is much longer. The normal fate of red cells in man, monkeys, and cats, according to Robertson and Rous, is to fragment in the blood-stream, and the fragments are swept up by the spleen. The poikilocytes and microcytes of grave anaemia do not appear to be preformed in the red marrow, and they are the result of breaking up of circulating red corpuscles. Often they show the reticulum which is characteristic of young cells. In the dog, rat, and guinea-pig, whole red cor- puscles are taken up by the spleen. FUNCTIONS OF THE SPLEEN AND LIVER IN RELATION TO THE BLOOD. It has been known for years that the spleen must have some relation to the formation or destruction of blood- corpuscles. The way in which it enlarges 26 RESEARCHES ON BLOOD in blood diseases such as leukaemia, pernicious anaemia, von Jaksch's anaemia, splenic anaemia, chronic malaria, and other tropical blood-parasite infections, is proof of this. Spleen pulp cells can be seen in the act of immolating damaged red corpuscles. But when we seek for further evidence, it becomes very dubious and uncertain, and a good many of the published observations are demonstrably incorrect. The whole subject has recently been re-investigated with care and restraint by Pearce and his fellow- workers, taking account both of experimental and clinical observations. Splenectomy in dogs gives rise to the following changes : — 1. A mild secondary anaemia of the usual type, reaching its maximum after a month, and recovering later. Why this occurs is unknown, except that injection of spleen- extract into a normal dog causes a brief rise of the red count by stimulating bone- marrow. This may furnish some experimental basis for spleen- extract therapy in anaemia. 2. A brief polymorphonuclear leucocytosis. Many other leucocvte variations have been described, but they are inconstant. 3. Increased resistance of the red corpuscles to haemolytic agents. We do not know why. 4. Reduced liability to jaundice and haemo- globinuria after the administration of haemolytic agents. This may be due to three factors. The animal being anaemic, the death-rate amongst the red cells is low, and the liver, the grave-digger in RESEARCHES ON BLOOD 27 ordinary when the spleen is gone, is not Hkely to be overworked even when the death-rate rises some- what. Again, the corpuscles are more resistant. And thirdly, as the spleen and splenic vein are gone, the liver receives less blood. The point is interesting, because we know that there are two varieties of splenomegaly associated with anaemia and jaundice. One variety is con- genital, the other is acquired. In each, splenectomy cures the anaemia and the jaundice. Probably the spleen contained a haemolytic toxin. In spite of older statements to the contrary, there is no constant difference in the cell-counts of the blood of the splenic artery and splenic vein, and no free haemoglobin in the vein. Nor does splenectomy in normal dogs cause metabolic changes. In man, splenectomy for a very large spleen reduces the excessive output of uric acid and urobilin. Diversion of the splenic vein into the inferior vena cava, to avoid the liver, has approximately the same effects in every way as splenectomy. In most cases after removing the spleen the yellow marrow in the shaft of the femur becomes red, signifjdng increased production. This takes about six months. The reason is unknown. The haemo- lymph glands contain an excess of endothelial cells, and if a haemolytic agent is given, these cells are abnormally full of red corpuscles in process of digestion. Probably this is compensatory. A new induced anaemia in a splenectomized animal is badly recovered from. Banti's disease is supposed to be a chronic inflam- 28 RESEARCHES ON BLOOD mation of the spleen with great enlargement (going on later to fibrosis) and excessive function, so that too many red corpuscles are destroyed. Splenec- tomy in the early stages cures the anaemia. Not much has been added to our knowledge of the blood-destroying functions of the liver. After Eck's fistula, the liver cells atrophy considerably, and bilirubin is considerably reduced in the bile, which suggests that the liver is normally active in blood destruction, and does not merely sweep up dead and degenerated red corpuscles. Splenectomy does not alter this effect (Wliipple and Hooper). COAGULATION OF THE BLOOD. We are still far from a clear conception of the exact pathology of haemophiHa, purpura, and the haemorrhagic tendency in jaundice, but it will be only by a sound understanding of the normal processes of coagulation of the blood that we shall be able to comprehend the abnormal. The phenomena of blood-clotting are beautifully designed to avoid two opposing evils : if no provision was made for fibrin formation, every injury would be fatal ; but on the other hand, if all the essentials for the process were already present in the plasma, the circulation would immediately be brought to a standstill by intravascular thrombosis. Therefore coagulation is made to be dependent on contact with damaged cells, either tissue-cells or leucocytes, and in particular with the nucleoprotein constituting their nuclei, while the intact lining endothelium of the blood-vessels has the power of preventing clotting. RESEARCHES ON BLOOD 29 We have all been told that a length of jugular vein containing blood may be tied at each end and hung up for a week, and no clotting occurs until damaged tissue-cells are added. Thus we find that the very incision or laceration which excites the haemorrhage provides also the wherewithal to stop it. The nucleoprotein furnished in this way by the tissues is called thromhokinase. Next, we know that calcium salts are needful for clotting, and if they are withdrawn by oxalates or citrates, no fibrin will be formed. An excess of calcium salts, however, delays clotting. Concerning thromhogen or prothrombin we cannot speak so confidently. It is intimately associated with, and hard to separate from, fibrinogen, but is probably derived eventually from the leucocytes and platelets. Hydrocele fluid, which does not contain any corpuscles, will not clot until blood or fibrin is added. The actual mother substance of the fibrin is of course the fibrinogen, a protein in the plasma. There is really a double reaction, thus : — (i) Prothrombin + Thrombokinase + Calcium salts ( = thrombogen) (from damaged (in plasma) (? from leucocytes) leucocytes or tissue-cells) I I ^1 I Thrombin ( = fibrin ferment) (ii) Thrombin + Fibrinogen (in plasma) i I Fibrin According to J. Mellanby, the name fibrin ferment 30 RESEARCHES ON BLOOD is a misnomer, as a particular weight of thrombin will liberate only a certain definite quantity of fibrin from fibrinogen, whereas a ferment knows no limits to its activities. We have yet one more provision to refer to. The cells lining the blood-vessels, and the leucocytes themselves, are not immortal. When they die, thrombokinase is shed out, and so thrombin would be formed and induce local clotting. This does actually occur in phlebitis and other forms of venous or arterial thrombosis. In the physiological state, however, the liver secretes into the blood an antithromhin sufficient in amount to deal with small formations of thrombin, but not sufficient to interfere with the natural process of arrest of haemorrhage. Recent research suggests that antithromhin is the product of interaction of two other substances, called heparin, which is derived from the liver, and proantithrombm. Both are said to be present in the blood. The heparin activates the proantithrombin when it is needed (Howell). Considerable variations take place in the readiness with which the blood coagulates, and it is often easier to understand why than how this is brought about. For instance, at the end of pregnancy clotting is rapid ; in the diseases mentioned above it is deficient or slow. After a haemorrhage, the fibrinoplastic (clot-forming) power rises quickly. Information may be obtained by means of the coagulimeier, a standard capillary tube into which the blood is sucked up so that the time which it takes sohdifj^ng may be measured. It requires some care in practice to avoid RESEARCHES ON BLOOD 31 variations in the calibre, variations in temperature, the inclusion of lymph or clots, etc. Associated with deficient coagulability there is often a tendency to effusions of plasma through the capillary walls on account of the low \dscosity of the blood. The symptoms of such a tendency to effusion are liabihty to chilblains, headaches, nettlerash or patchy oedema, and transient or functional albu- minuria. The conversion of fibrinogen into fibrin is only the first stage of a more prolonged process, just as the very similar conversion of caseinogen in milk into solid casein is only one step in the process of break- ing it do\\'n to simpler substances such as peptones and aminoacids. The fibrin is not a permanent body. Even in blood-clot kept at about 40° C. it undergoes partial resolution into simpler and soluble substances, under the influence of ferments already present in the clot, called fibrmolysins. It is probable that these, as well as leucocytes, play an important part in deter- mining the resolution of fibrin collections in the human body, such as may be found not only in bruises and thromboses but also in the lymph-clot which is the precursor of adhesions in the pleural and peritoneal cavities. It is well known that these adhesions may disappear spontaneously to a remark- able degree. Any value which thiosinamine and its derivative fibrolysin may have, given hypodermically to absorb young fibrous tissue, may possibly be due to the production of ferments such as these. 32 RESEARCHES ON BLOOD PURPURA HiEMORRHAGICA. English physiologists have expressed a good deal of doubt as to the very existence of platelets as preformed elements in the blood. It is said that the number to be found in a stained film depends upon the method of preparation, and that when blood stands and clots it deposits platelets in plenty. It is also said that they are never visible in the living circulation in the web of a frog's foot or in dog's omentum. American haematologists, on the other hand, seem to have no doubts as to their existence preformed in the living blood. Lee and Minot, whilst admitting that they do not occur except in mammals, say that platelets are visible in the circulating blood of the rabbit or guinea-pig. They are derived from the mega- karyocytes of the marrow. The number of platelets present runs parallel with the coagulability of the blood, and, in particular, blood-clot will not retract firmly so as to plug vessels unless platelets are present in normal numbers. Benzol reduces the platelet count, and may lead to a tendency to bleed. In purpura haemorrhagica, and the haemorrhagic type of some fevers, the platelets are few or absent in the blood. An observation that is interesting in itself, and also may throw light on the platelet problem, is published by Lee and Robertson, and also by Ledingham and Bedson. If the platelets are separated out from guinea-pig's blood by sedimenta- tion, and injected into some other species, such as the rabbit, an antibody is formed in the rabbit's RESEARCHES ON BLOOD 33 senim destructive to guinea-pig's platelets. If some of the serum thus obtained is injected into a guinea-pig, a condition closely resembling purpura ha^morrhagica is produced. There are bleedings from the nose, bowel, and other mucous membranes, and purple patches of hiemorrhage in the skin and conjunctiva\ The animal may die. Few or no platelets are to be found in its blood. It is not suggested, of course, that the disease in man is produced just in this way, but the experiment raises the probability that the underlying cause of purpura ha^morrhagica may be a toxin destroying the platelets, which as we have seen are markedly reduced. The blood in this disease may begin to clot in normal time, but the coagulum is soft and will not retract firmly. HiEMOPHILIA. Of all the many conditions in which the h^emor- rhagic diathesis is present, haemophilia is at once the most interesting, the best understood, and the most tragically dangerous. We will not stay to speak of the curious problems of its inheritance, nor of the well-known tendency to bruising, joint effusions, and bleeding after the most trivial injuries. One or two of its peculiarities, however, deserve a word of mention, as they may throw a light on the production of the haemorrhagic tendency. For instance, the locality and the nature of the injury have some significance. In a few cases, wounds below the neck may not bleed to excess, whereas abrasions of the most trifling description affecting the lips, cheeks. 34 RESEARCHES ON BLOOD or gums may baffle all attempts to stanch the flow. Again, needle pricks, if small, do not bleed, probably because the elastic skin seals the opening ; it is even safe to withdraw blood from a vein. Further, it is not true that the haemorrhage never stops. It may cease with or ^^^thout treatment, sometimes permanently, sometimes only to come on again later. If a subcutaneous haematoma develops, the wall is lined by well-formed clot, but the central portion contains blood which shows no tendency to coagu- lation in spite of the contact with clot. It is the capillaries, rather than the arteries, which continue to ooze. It will be a matter of opinion whether under the generic name of haemophilia we should include cases that arise every now and then, in either sex, of a congenital and persistent tendency to bruise and bleed from every slight abrasion, apart from any family history of a similar kind. There is no doubt that the symptoms and course of some of these cases are identical with ordinary haemophiHa,* and they are nearly as common. Bulloch states that the characteristic joint affections never occur except in the hereditary class. Up to a certain point modern observers are agreed as to the cause of haemophilia. Ever since Sir Almroth Wright, nearly twenty years ago, showed that the coagulation time in these patients is very greatly delayed, all students of the disease who have carefully fulfilled the proper conditions have been * See instances given by Squire, Brit. Med. Jour., 1910, i, p, 1168 ; and Osier, Lancet, 1910, i, p. 1226. RESEAIUJIKS ON BLOOD :i5 able to establish his discovery. Normal blood in a Wright's coagulimeter tube clots in 5 to 10 minutes ; hccmophilic blood may take anything from 15 to 90 minutes to solidify, although the eventual yield of fibrin is copious and firm. Addis has shown that the coagulation time is exactly related to the severity of the tendency to bleed, the mildest cases yielding the shortest times, and the severe cases the longest. It is true that a few who have used the blood shed out during an actual hremorrhage have found no delay in the coagulation time ; but apart from other fallacies, such as the danger of including fibrin ferment, the mere fact of the continued bleeding makes the blood clot more rapidly both in bleeders and in ordinary people, as Wright and Addis have shown. Another abnormality in the blood is a frequent deficiency in polymorphonuclear leucocytes. We may take it that the rival theory, that of the undue fragility of the vessel walls, is now definitely abandoned. Morawitz and Lossen have both shown that the oedema obtained by dry-cupping is no greater in haemophilics than it is in normal individuals. So far, then, there is substantial agreement. When w'e seek to go further, and to inquire just which we are to blame of the various elements that take part in regulating the coagulation of the blood, the problem becomes complicated. Theoretically, the delay might be due to : — (i) Deficient quantity or quality of the fibrinogen ; (2) Deficiency or excess of calcium salts ; (3) De- ficient quantity or quality of the thrombokinase ; 36 RESEARCHES ON BLOOD (4) Deficient quantity or quality of the prothrombin ; (5) Excess of antithrombin. In the examination of these factors we follow the researches of Addis. The main point to determine is whether the delay is in the first or the second of the two reactions involved, — that is, in the conversion of prothrombin into thrombin, or in the conversion of fibrinogen into fibrin. It proves that the former is at fault ; the latter is quite normal. Haemophihc fibrinogen is as readily clotted by normal or by hasmophilic thrombin as is normal fibrinogen, and normal fibrinogen is easily clotted by thrombin from a bleeder. But haemophilic blood must stand a long time before prothrombin is converted into thrombin. Taking up the points, then, in order : — 1. The defect is not in the fibrinogen, because it is readily clotted if isolated and treated with throm- bin. Moreover, when clot does at last form during a haemorrhage, it is as firm and abundant as in ordinary blood. 2. The defect is not in the calcium salts, because analysis shows no abnormality in quantity, and the addition of these salts to drawn haemophihc blood, though it may hasten the time of clotting, does not bring it to normal. 3. The defect is not in the thromhokinase. Here Sahli joins issue with Addis, because the addition of washed leucocytes to haemophihc blood rapidly causes it to clot. These may, however, bring in prothrombin as well as thromhokinase, and Addis shows that solutions of thromhokinase, derived by crushing up testis in saline, have far less effect on RESEARCHES ON BLOOD 87 haemophilic than on normal blood unless very concen- trated extracts are used. Again, there is just as much thrombokinase in the serum of a bleeder, squeezed out after coagulation, as in that of a normal person. 4. // is in the prothrombin that the defect lies. A very little normal plasma, or a few washed corpuscles from a normal person, restore the coagulation power forthwith. Addis believes that he has directly proved the point by the adoption of the following method for isolating the prothrombin, and at the same time he has established that in the haemorrhagic diathesis it is deficient not in quantity but only in character. He prepared a solution of fibrinogen from normal or hctmophilic plasma in the ordinary way by precipi- tating it b}^ passing a stream of carbon dioxide through plasma kept from clotting by citrate or oxalate. Fibrinogen so obtained, as Mellanby shows, always carries with it prothrombin, and in the presence of calcium salts and thrombokinase would liberate thrombin. Addis, however, added instead a trace of thrombin, which clotted the fibrinogen and left its prothrombin in solution. When a trace of prothrombin so obtained from a normal blood was added to hasmo- philic blood, this promptly coagulated. (The criticism would of course be that there was some unused thrombin present as well, too much having been added to the fibrinogen.) Thus, the exact pathology of hai'mophilia would be, in Addis's opinion, a congenital defect in the con- stitution of the prothrombin, whereby it yields thrombin much too slowly. Possibly the leucocytes are ultimately at fault. 38 RESEARCHES ON BLOOD The practical deduction we shall see later. 5. There is no excess of antithromhin in the plasma of the bleeder. If there were, the addition of a trace of normal blood would not cause haemophilic blood to clot as it does, because any thrombin in the former would be overpowered and destroyed b}' the anti- thromhin in the latter. To sum up, the secret of haemophilia Ues in a defective quahty of the prothrombin, such that it takes much longer than usual to develop into thrombin. No evidence is yet to hand to show whether the haemorrhagic tendencies in scurvy, purpura, pernicious anaemia, and occasionally in jaundice have the same explanation. It is important to bear in mind the fact that certain cases of jaundice may ooze to death by capillary haemorrhage after operation ; most of us can recollect instances of this calamity. It has been recommended to give drachm doses of calcium chloride for three days before the operation, but probably a more useful proceeding would be to take the coagulation time by means of a Wright's tube, and to refuse to operate on any cases showing serious delay. It will be gathered that unfortunately the under- lying causes of haemophilia do not lend themselves to direct remedy. We cannot, except by one drastic proceeding, influence the quality or quantity of the more complicated and specialized fibrinoplastic elements in the blood, and we can use only those means which in a general way are understood to increase the coagulability. RESEARCHES ON BLOOD 39 Sometimes the ordinary surgical means such as rest, pressure, plugging, or adrenalin may be success- ful. It is usually advised not to stitch wounds, for fear of bleeding from the punctures, but if these are made with a small, round-bodied needle, the elasticity of the skin will prevent oozing. Therefore, if tight stitching would obviously bring useful pressure to bear, it should be resorted to, but only in the skin, not in mucous membranes. It has been advised, and the advice is physio- logically sound, to apply normal human blood to the oozing point. Unhappily, even if a mass of clot is formed over the wound, it soon gets pushed away by the collection of unclotted blood beneath it. For the normal arrest of haemorrhage it is necessary either that clotting should take place inside the bleeding vessel or that it should fill the wound so tightly about this vessel as to present a complete block to the flow. It is often impossible to get the remedy near enough to the actual rent in the arter}^ or capillary to bring this about, and the shape of the wound may not lend itself to filling up tightly with firm clot. Nevertheless the method is simple and painless, and has some- times succeeded. Styptics such as ferric chloride, tannin, or alum may be applied to the wound, but they are painful and lead to much sloughing, so it is well first to give a brief trial to fresh normal blood apphed by wool pledgets, and to Wright's physiological styptic (thrombokinase), composed of one part of minced thymus in ten parts of normal saline. This produces a firm clot, but does not act as quickly as the escharotic styptics. 40 RESEARCHES ON BLOOD IntemaU}^ Wright gives calcium salts, preferabh'' the lactate, but admittedly this is a bow drawn at a venture, because the calcium is often absorbed very badly, and may already be at the optimum in the blood. The first difficulty may be obviated in some patients by using magnesium lactate or carbonate. The doses of any of these drugs should be 60 grains for adults, and 15 grains for children, at once, followed by lo-grain doses three times a da\^ for three days for adults, with a corresponding reduction for children. Calcium salts reverse their effect after three days. To the same authority we are indebted for the suggestion that we should administer carbon dioxide gas, either from a Kipp's apparatus containing marble and h3'drochloric acid, or from a cyHnder of the gas. Venous blood is much more coagulable than arterial. Dyspnoea should be avoided. Weil recommends the injection of horse-serum, conveniently obtained as diphtheria antitoxin. It probably increases the rate of blood-clotting, but apparently not until many hours have passed, and consequently it often fails in practice. There remains one last resort in the most desperate cases, and no patient should be allowed to die of hcemophilia without its being attempted. We have seen that there is only one way to restore prompt coagulability to haemophiHc blood, and that is to supply normal blood. Goodman has published a well- written, almost dramatic description of his treatment of a Jewish boy, aged two and a half, a well-known bleeder and RESEARCHES ON BLOOD 41 member of a bleeder family, who was moribund from haemorrhage from a cut mside the cheek, which had oozed incessantly for two days. Pressure, adrenalin, styptics, calcium salts, and horse-serum (antitoxin) had all been tried in vain, and finally the child lay motionless and pallid, scarcely breathing, with haemoglobin down to 12 per cent, and haemorrhage continuing. Goodman decided to inject normal human blood. A donor, not a relative, was tested by Wassermann's test for syphilis, and declared free. Under novocain anaesthesia his radial artery was connected by an Elsberg cannula with the child's femoral vein. There were some initial difficulties in getting a good flow, and hot cloths had to be applied ; finally the basihc vein was substituted for the femoral on account of differences in the level of these patients. Trans- fusion was continued for twenty-eight minutes. During this time colour gradually mounted up in the cheeks of the Httle sufferer, the breathing became audible once more, the almost watery blood acquired its normal hue, and the haemoglobin rose to 70 per cent. Most significant of all, the bleeding was completely and permanently arrested, and there was no haemorrhage from the incisions. ANAPHYLAXIS. It is well known that when certain proteins are injected into an animal's blood-stream, so far from antibodies being formed, there may be an increased sensitiveness developed, so that a second injection months or years afterwards may produce severe or 42 RESEARCHES ON BLOOD even fatal symptoms. A few cases are on record in which second injections of horse- serum containing diphtheria or other antitoxin have caused most alarming illness or death. Now that so many men who were wounded in the war and given a dose of antitetanic serum are about in the community, it is possible that there may be trouble one day when one of them is given diphtheria antitoxin or some other preparation of horse-serum protein. It is also well known that if the second dose is given \\ithin a week this sensitization (anaphylaxis) does not occur. The symptoms in severe cases are due to intense swelling of the mucosa of the bronchi, causing suffocation and conMilsions. In mild cases they resemble those of ordinary serum sickness — an urticarial or measly rash, joint pains, and the like. Evidence has accumulated that anaphylaxis may explain some other conditions besides serum poison- ing. It occasionally happens after tapping or operating on a hydatid cyst that there may be violent urticaria, or in a few cases fatal suffocative symptoms (intoxication hydatique). This is an anaphylactic phenomenon. Some cases of asthma and hay fever appear to be due to the inhalation of a foreign protein of animal or vegetable origin to which the patient is super- sensitive. Sometimes the foreign protein is con- veyed in the diet, and white of egg would seem to be the commonest offender. In yet other cases it is of bacterial origin. A careful history may help to detect the source of the trouble, and if the skin is RESEARCHES OX BLOOD 48 scratched and a solution of the suspected substance —grass pollen, egg-albumen, milk, or whatever it is— painted on the scariftcations, there will be swelling and redness. It may then be possible to avoid the article, or to obtain an acquired immunity by starting \nth exceedingly minute doses (say i mgrm. of egg- albumen) and increasing very cautiously. Intractable eczema in children may be caused in the same way. The testing out may need to be quite elaborate, using milk protein, fat and sugar separately, egg-albumen, and watery extracts of various food-stuffs filtered, precipitated with alcohol, washed, and appUed in powdered form. According to W^iite, in two-thirds of the cases a positive result was obtained to some food-stuff or other. THE THERAPEUTICS OF CALCIUM SALTS. So much interest has lately attached to this subject that brief mention only will be called for of the uses to which calcium salts have been put. It has long been recognized by physiologists that they are essential to the continued success of perfusion fluids, and now we know that they control the coagulation and viscosity of the blood, and probably the functions of the ovary and parathyroid glands also. Remarkable results have been obtained in many cases by giving calcium lactate in 15-gr. doses thrice a day, for three days only, in the following conditions : Transient or functional albuminuria. • Lymphatic ' headache frequently recurnng m anaemic young women. Some urticarial eruptions. 44 RESEARCHES ON BLOOD Chilblains. In this common complaint it may work like a charm. All varieties of tetany. The symptoms of the menopause are sometimes greatly relieved by calcium lactate. In all the above, however, there is one constantly recurring source of fallacy. The power to absorb calcium from the bowel varies much in different people, and some observers record negative results after giving the drug. Magnesium salts will some- times be more effectual if calcium fails to get into the blood. REFERENCES. Keith, Rowntree, and Geraghty. — Archiv. Int. Med., 1915, p. 547. Robertson and Bock. — Jour, of Exper. Med., 1919, Feb., PP- 139. 154- Kerr, Hurwitz, and Whipple. — Amer. Jour, of Phys., vol. xlvii, 191S, pp. 356, 370, 379. Rendle Short. — Med. Anmtal, 1919, p. 9. AsHBY. — Jour, of Exper. Med., 1919, March, p. 267. Robertson and Rous. — Jour, of Exper. Med., 191 7, xxv, pp. 651, 665. Pearce, Krumbhaar, Frazier. — The Spleen and Ancsmia, 1917. Whipple and Hooper. — Anier. Jour, of Phys., 191 7, xlii, P, 544- Ledingham and Bedson. — Lancet, 1915, i, p. 309. Lee and Robertson. — Jour. Med. Research, 1916, xxiii, p. 323- Lee and Minot. — Cleveland Med. Jour., xvi, 191 7, p. 65. Mellanby. — Jour, of Physiology, 1909, p. 28. Sir Almroth Wright. — Allbutt's System of Medicine, 1909, vol. V, p. 918. Addis. — Quart. Jour, of Medicine, 1910, Oct., p. 14 ; Brit. Med, Jour., 1910. ii, p. 1422. Goodman. — Annals of Sur^., 1910, Oct., p. 457. White. — Boston Med. and Surg. Jour., 191S, i, p. 5- 45 CHAPTER HI. THE HEART. By Carey F. Coombs, M.D., F.R.C.P. Lend., Assistant Physician^ Bristol General Hospital ; and C. E. K. IlERAPATH, M.C.. M.D., B.S., M.R.C.S., L.R.C.P., Medical Registrar, Bristol Royal Infirmary. DEVELOPMENT AND STRUCTURE OF THE HEART- — -MODES OF EXAMINATION OF THE HEART HEART RHYTHMS PROPERTIES OF CARDIAC MUSCLE — THE NERVOUS SYSTEM OF THE HEART CARDIAC IRREGULARITIES. A T the beginning of the third week of foetal life the heart consists of a straight muscular tube, demarcated into four parts : (i) The sinus venosus ; (2) The primitive auricle ; (3) The primitive ventricle ; (4) The bulbus cordis. The beat begins in the sinus venosus, and is carried on by a peristaltic wave through the various chambers ot the heart in the order given above. A little later the tube becomes bent upon itself, one bend occurring at the junction of auricle and ventricle ; the other involves the ventricular portion of the tube, which assumes a v form. As a result of these bends the auricle takes up a position dorsal to the ventricle ; the shorter curvature of the ventricular bend becomes absorbed, forming one chamber. At this time septa appear which divide the primitive auricle and ventricle into two, and the right and left auricles grow out from the dorsal portion of the primitive 46 THE HEART auricle, while the right and left ventricles grow out from the ventral and lateral portions of the primitive ventricle. The sinus venosus gradually comes to lie in the dorsal wall of the right part of the primitive auricle, and when the right auricle grows out it takes the sinus venosus with it, so that it comes to lie in the wall of the right auricle. The balbus cordis becomes incorporated chiefly in the left ventricle. The auricular canal, which is the connection between the primitive auricle and ventricle, becomes surrounded by an upgrowth of the base of the primitive ventricle, and very little of it remains in the adult heart ; but part is carried down in the inter auricular septum. The embryological heart muscle has the property of conducting the stimulus from the sinus venosus to the bulbus cordis, and a remnant of this muscular tube continues to act as the conducting path in the adult heart, so that to understand this it is necessary to trace this path as it appears in the adult heart. The sinus venosus has been seen to move across and to lie eventually in the wall of the right auricle, its structure lying chiefly between the superior and inferior venae cavae. From here the path runs down the auricular canal, of which the interauricular septum is the chief remains, though part is in- corporated in the wall of the right and left auricles. The ventricles are chiefly new structures, being formed as evaginations from the primitive ventricle, the remains of which are chiefly in the interven- tricular septum which grows from the apex upwards and takes most of the embryological ventricle with it. THE HEART 47 If we now examine the recent histolopjical work on the conduction path, we find that it agrees with what has been shown should be its path from the morphological aspect. The place of origin of the heart-beat has been proved to lie at a point in the sulcus terminale below the junction of the superior vena cava and the right auricular appendix, and a patch of specialized tissue is found in this position which is known as the sinu- auricular node. Another larger node of similar tissue is found in the posterior part of the interauricular septum below and to the right of the coronary sinus. From this a bundle of pale muscular fibres similar to Purkinje fibres passes forwards and downwards to the inter- ventricular septum, where it divides into right and left branches. Each of these passes down beneath the endocardium of the septum of its respec- tive ventricle, and divides into branches which are distributed to the papillary muscles and the mural muscles of the ventricles. Thus a complete path has been traced from the sinu-auricular node to the ventricles, except the part between the sinu-auricular node and the auriculoventricular node. The stimulus is supposed to cover this interval by passing through the auric alar muscle in all directions. But work on dogs by electrical methods suggests that the stimulus reaches the auriculoventricular node before the auricular muscle. Again, under certain conditions a reversed rhythm may take place, the sequence of beat being ventricle, auricle, and it has been 48 THE HEART shown that in this case the stimulus reaches the sinu-auricular node before the auricular muscle. These two data point to the existence of some direct path between sinu-auricular and auriculo- ventricular nodes which does not lie through the auricular muscle, but so far this path has not been certainty identified anatomically. In birds there is no auriculoventricular bundle and node such as has been described above, but the stimulus is conducted bj^ a muscular connection which lies in the posterior part of the auriculoven- tricular groove in the region of the left superior vena cava. A similar path has been described in this position in man, and also another lying in the right auricular wall almost on the extreme right lateral aspect of the heart slightly towards the posterior surface. So far as is known, these paths do not convey stimuli in man. MODES OF EXAMINATION OF THE HEART. ]\Iuch of the recent physiological work on the heart has been stimulated by clinicians who by means of special instruments, the polygraph and the electrocardiograph, have classified the irregulari- ties of the heart. The polygraph is an instrument bj' means of which simultaneous records of the venous and arterial pulses are obtained, with the addition of a time- marker, so that the actual time-intervals of the various events in the cardiac cycle may be worked out. The venous pulse is obtained from the jugular THE HEART Ay\ 49 bulb lying just above the clavicle, i to ij inches external to the sternoclavicular synchondrosis. The ri,XTIONS OF THE In infants, Willcox and R. Miller have stated that there are two t\-pe5 of dyspepsia causing pain, wasting, vomiting, and constipation. One is con- genital stenosis of the pylorus, in which the HCl is subnormal but the pepsin (which may be conveniently tested by the curdling effect on milk) is excessive, and mucin is also in excess. The other is ' acid dyspepsia ', in which the HCl is excessive and the ferments are subnormal. In this case peristaltic waves may be seen, but the pyloric tumour is not felt. The prognosis is very much better than in congenital stenosis, and operation is not needed as it so often is in the more serious condition. Enough has been said to show that hyperchlor- hydria and its advertisement, ' hunger-pain ', are more than an inconvenience to the patient ; they are in many cases the consequence and in other cases the precursor of serious organic mischief which may lead to dilated stomach, to chronic gastric ulcer — which in its turn is apt to become malignant — or to an abdominal catastrophe from perforation of the stomach or duodenum. When the hv'perchlorhydria is not associated with, or precedes, ulceration of the stomach or duodenum, the appendix or gall-bladder is probably at fault. The appendix, for instance, may show adhesions or stenosis. Sherren found the appendix normal in only 4 out of 65 cases of duodenal ulcer, and 5 out of 41 cases of gastric ulcer. Moynihan, Paterson, the Mayos, and others have shown that the majority of the gastric and duodenal ulcers met with on the operation table STOMACH AND INTESTINES 127 are associated with appendicitis. The sequence is, first appendicitis, then h3'perchlorhydria, and thirdly ulceration. Chronic dyspepsia is often the only complaint in persons who have no hyperchlorhydria, show no local symptoms of trouble in the appendix, but are cured by removal of that organ. The majority of patients diagnosed as gastric ulcer in the medical wards of a hospital, and recovering without operation, in all probabihty have no ulcer at all, but only reflex gastric symptoms following on gall-stones, movable kidney, or appendicitis. In 20 per cent of patients with symptoms of gastric ulcer operated on at the Bristol Royal Infirmary, no ulcer was found. Why disease of the appendix, or gall-bladder, should cause these symptoms it is difficult to decide. It can scarcely be due to toxic absorption, as the appendix may be quite fibrotic. Perhaps the simplest explana- tion is that the ileocaecal sphincter remains tightly closed and produces back-pressure. In other cases there may be irregular gastric peristalsis and hyper- chlorhydria as a nervous reflex. In chronic intes- tinal stasis the hydrochloric acid in the gastric juice is usually deficient. There may be all the symptoms of gastric ulcer, but the pain usually comes on soon after food, or persists all the time. Reflex closure of the pylorus and delayed or irregular emptying appears to be the cause of the symptoms in this type of case. This probably accounts for the dyspeptic pains endured by so many persons with chronic appendicitis whose gastric acidity is normal or subnormal. 128 FUNCTIONS OF THE The treatment of hyperchlorhydria is as follows. Medical means will often give a large measure of re- lief. Taking food, and especially a hard-boiled e§^, when the pain comes on, will generally abate the sym- ptoms. Alkalies are indicated, especially magnesia, which has two advantages : it does not dissolve and exert all its effect in a few minutes, and it does not give off carbon dioxide as the carbonates do. The bismuth lozenges of the B.P. are convenient to carry and very successful in stopping the dis- comfort. We will barely mention such useful measures as rest in bed, milk diet, and lavage. On theoretical grounds Pawlow recommends fats and oils to check the flow of the gastric juice. These measures are of course not applicable in the presence of an acute ulcer causing haemorrhage. If these means are not successful, it is very desirable to perform laparotomy and to explore the stomach, duodenum, appendix, kidney, and gall- bladder. If gastric or duodenal ulcer is present, gastrojejunostomy is of course indicated. If the ulcer is near the cardia, it is probably better to excise it. If no abnormality can be discovered in either stomach or duodenum without opening into them (which is seldom if ever called for), it may be that some adhesions or kinking of the appendix may be found, and removal of the organ will effect a cure in many of the cases, but not all. It is shown by Paterson, the Mayos, Sherren, and others that about 75 per cent of the many hundreds of cases of dyspepsia without ulceration treated by removal of the appendix are cured. Soltau Fenwick STOMACH AND INTESTINES 129 states that of 112 cases of hyperchlorhydria, in 34 the stomach and duodenum were normal ; in 22 of these the appendix was at fault, and in 12 gall-stones were present. In 9 cases appendix trouble compli- cated gastric or duodenal ulcer. In 66 patients an ulcer was present in the stomach or duodenum ; 4 of these were malignant. It is a remarkable fact that severe and repeated haemorrhage from the stomach may take place in the absence of any ulcer. Out of seven cases recently operated on for haematemesis at the Bristol Royal Infirmary, in only two was an ulcer found. A con- dition of universal weeping of blood, called ' gastro- staxis ', occurs in these cases, and with the gastroscope the mucous membrane may be seen to ooze blood wherever it is touched. THE PHYSIOLOGY OF GASTROJEJUNOSTOMY. What effect is produced upon the functions of the alimentary canal by the operation of gastrojejuno- stomy ? We have to ask : (i) Does the food pass through the new opening or by the pylorus ? (2) What is the effect upon the gastric juice ? and (3) What is the effect upon the absorption of proteins, fats, and carbohydrates ? Some light has been thrown upon the first of these questions by watching with the x rays the course taken by a meal containing bismuth oxide, and it would appear, as might have been expected, that both routes are followed, unless either the pylorus or the artificial opening is or becomes greatty nar- rowed. On this subject the writings of Cannon and Gra}' may be consulted. 9 130 FUNCTIONS OF THE The former used cats with a normal stomach on which the operation had been performed, and natur- ally the tendency was for the meal to take the pyloric route. Hartel* has made a study by this means of 22 patients operated on months or years before. About half of them, including those in which pyloric stenosis was found at the operation to be severe, emptied only by the new opening ; in the others the food took both directions. In one case it appeared to pass out only by the pylorus. The effect upon the gastric juice is nil if it has previously been normal ; if hyperchlorhydria was present, an efficient gastrojejunostomy appears invariably to restore the amount of acid to normal. Stenosis of the opening may be followed by a return to the greater acidity. If the HCl is absent, however, the operation will seldom, if ever, cause it to appear. That there cannot be any serious loss of power to digest and absorb foodstuffs is shown by the remark- able way in which the great majority of cases operated on become fat and flourishing after gastrojejunostomy for non-mahgnant affections, the improved condition being maintained for many years. There is at least one patient who at the age of seven was described by his father as strong and healthy, with good appe- tite and exceedingly good digestion, after a gastro- jejunostomy at the age of eight weeks for pyloric stenosis. Paterson has proved that the amount of fat and protein passed in the faeces without assimila- * Deut. Zeit. Chirurg., iqh. STOMACH AND INTESTINES 131 tion is very little greater than in the normal individual. In four cases it was only about 2 per cent above normal ; that is, the faeces contained about 9 to 9'5 per cent of protein nitrogen taken as food instead of the normal 77 per cent. Much less favourable results previously pubhshed by Joslin were due to the fact that he used cancerous cases on which to experiment. Paterson's results are confirmed by Cameron,* who finds that the only ill-effect is some slight diminution in the power of absorbing fat. ABSORPTION IN THE COLON. We may sum up the ordinary functions of the various parts of the bowel with regard to absorption thus : — Drugs, salts, and sugars are absorbed in the stomach. Proteins (as aminoacids) , carbohydrates (as sugar), and fats (as soap and glycerin) are absorbed in the small intestine. Water is absorbed in the large intestine. The practical physician or surgeon is concerned with the physiologist's answer to two questions. First, Is the colon a necessary organ, or may it be ehminated with safety ? Second, Can the large intestine absorb useful foodstuffs in case of need ? With regard to the first point, we are at once con- fronted with the fact that in some bats the colon is exceedingly short. Again, it is well known that patients with an artificial anus in the caecum are able * Brit. Med. Jour., 1908, i, p. 140. 132 FUXCTIOXS OF THE to keep up their nutrition. The same is true after the ileum has been cut across and turned into the sigmoid. Careful analyses made by Groves and Walker Hall under these conditions show that the normal amount of water can still be absorbed by the short piece of rectum and sigmoid traversed by the food ; the faeces are not too fluid. By comparing the amount of water in the intestinal contents at the ileocsecal valve and as passed naturally in man, they conclude that the colon absorbs about lo to 20 per cent of water from the faeces. Bacteria make up nearly half the weight of the faeces as passed normally. Treves, Lane, and others have excised almost the whole colon without the patient's nutrition suffering. We conclude then that the colon is not a necessary organ. If, however, a permanent artificial anus is made in the ileum more than 12 to 18 inci'ies away from the ileocaecal valve, absorption is inadequate, and the patient dies of starvation. Turning to the second question, it is scarcely necessary to call attention to its very great importance. If the colon cannot absorb a reasonable quantity of foodstuffs, the whole theory of feeding by nutrient enemata would coUapse. In the experiments described above, Groves and Walker Hall found that the absorption of nitrogen and fat by the colon was so small as to be neghgible. Laidlaw and Ryffel, analyzing the urine during rectal feeding, found that the nitrogen output corresponded pretty closely to the pubhshed figures for pro- fessional fasting men at the same date of starvation ; STOMACH AND INTESTINES 133 the enemata used were, however, not particularly suitable, consisting of the whites of nine eggs, six ounces of raw starch, and twenty-four ounces of peptonized milk. The albumin and starch were probably not touched. Langdon Brown found no difference in the urea of the urine, whether the patients were given peptonized milk or normal saUne. Careful analysis of the figures given by Boyd and Robertson, and also a number of observations made by the present writer, furnish convincing evidence that, as measured by the standard of the nitrogen output in the urine, the absorption of nitrogenous foodstuffs from the rectum is practically nil. Sharkey and others claim that a good deal of nitrogen can be absorbed by the rectum, basing their findings on the analysis of rectal washings ; but this method is open to criticism, as sometimes, in spite of washing out, the patient may pass an enormous putrid evacuation, showing that lavage was not effectual. Now this failure to absorb might be due to one of two causes. First, it may be that the large intestine has no power of absorbing nitrogenous foodstuffs in any form. Second, it may be that no erepsin is present in its secretion, so that there are no aminoacids formed from the peptone of the enema. The crucial experiment is. Can aminoacids be absorbed ? To determine this the writer, with Dr. Bywaters, has made by the Kjeldahl method daily analyses of nitrogen in the urine in patients to whom enemata were given, either of milk pancreatized for twenty- 134 FUNCTIONS OF THE four hours so as to convert most of the protein into aminoacids, or, in other cases, of synthetic amino- acids (Merck). Usually ordinary ward nutrients, peptonized for twenty minutes, were given for a few days first, and then the aminoacid preparations used instead. In each of five patients the nitrogen output in the urine was greatty increased by the use of aminoacids in the nutrients. Figures of two such cases are given in the Appendix. We conclude, therefore, that aminoacids can be absorbed, and that we may hope to give nourishment to patients by rectal injections of milk pancreatized for twenty-four hours, although ordinary peptonized milk is a failure. It is quite certain that dextrose can be absorbed from the rectum, because it wiU cure acidosis when given in this way, and also it will raise the respiratory quotient by increasing the amount of C0„ expired. Boyd and Robertson showed that practically no sugar can be recovered from the rectal washings of a patient given peptone and sugar enemata, although peptone is always returned. Lactose appears not to be absorbed ; it fails to control acidosis. It is very difficult to obtain evidence as to whether fats are absorbed. In a patient who had a fistula of the thoracic duct, only from 37 to 5*5 per cent of the fat given per rectum was recovered from the fistula. In another patient the thoracic duct was blocked and a l^miphatic vessel had ruptured into the urinary passages, so that most of the fat absorbed by the lacteals escaped into the urine, which became milky STOMACH AND INTESTINES 135 after a fatty meal (chyluria). There was no chyluria when all fats were stopped by mouth and nutrient enemata containing milk administered. It must not be supposed that rectal feeding supplies absolute rest to the stomach. It may be observed in patients with a gastrostomy wound that each nutrient enema excites a reflex flow of gastric juice. Those who believe in the possibility of feeding patients satisfactorily by nutrient enemata usually rely upon some incorrect pubUshed analyses by Ewald, an observation by Leube that a dog can be kept aUve for many months by injections of chopped meat and pancreas (this method causes toxic sym- ptoms in man), and the remarkable fact that the weight may be fairly well sustained at first. This happens even if nothing but water is given, and is due to the fact that the patients, usually sufferers from hcematemesis, are exsanguinated to start with and greedily absorb water. Patients have been kept alive on nutrients for several weeks, but it is well known that there are sometimes sudden and unaccountable deaths. It must not be forgotten that if water is suppHed Hfe will usually be prolonged for a month with no food at all, and in one instance a man was alive after sixty-four days of complete starvation. If water also is withheld, death takes place in about a week ; but a girl buried in an Italian earthquake lived eleven days without either food or drink. We conclude, therefore, that feeding with nutrients composed of peptonized milk is sheer starvation, 136 STOMACH AND INTESTINES but that better results may be obtained with enemata composed of dextrose and long-pancreatized milk. REFERENCES. FiSHBACK, etc. — Amer. Jour, of Physiol., 1919, xlix, p. 174. Whipple, etc. — Joiir. Exper. Med., 19 16, xxiii, p. 123. Dragstedt, etc. — Amer. Jour, of Physiol., xlvi, 1918, p. 366. DuNDON. — Ibid., 191 7. >^liv, p. 234. Carlson.— Z&ff^., xlv, p. Si. Hurst. — The Sensibility' of the Alimentary Canal. Oxford Med. Public, 191 1. SoLTAU Fenwick. — Proc. Royal Soc. Med., Surgical Section, 1910, p. 177. Paterson. — Ibid., p. 187. Walton. — Lancet, 190S, ii, pp. 17, 85 Groves. — Proc. Royal Soc. Med., vol. ii, 1909, part iii Surgical Section, p. 121. Langdon Brown. — Proc. Royal Soc. Aled., Therapeutic Section, 191 1, p. 63. Hurst. — Jour, of Physiol., 1913, vol. xlvii, pp. 54, 57 Sherren. — Brit. Jour, of Surg., 19 14. Jan., p. 390. Rendle Short and Bywaters. — Brit. Med. Jour., 1913. i> p. 1361. Carlson. — Amer. Jour, of Physiol., 1913, p. 8. i;:57 CHAPTER VI. THE GENITAL GLANDS. FUNCTIONS OF THE OVARY FUNCTIONS OF THE TESTIS CONTROL OF THE GENITAL GLANDS BY INTERNAL SECRETIONS THE SECRETION OF MILK THE OVUM — CHEMICAL DIAGNOSIS OF PREGNANCY. STUDENTS of physiology do not usually devote as much attention to the functions of the reproductive apparatus as the clinical importance of the subject demands, and writers of text-books have been in the habit of relegating it to a very brief chapter at the end of the book. FUNCTIONS OF THE OVARY. The functions of the ovary may be classed under three headings : the production of ova, the control of menstruation, and the internal secretion. The corpus luteum has other functions, to be considered separately. The ovary shows on microscopical examination ripe and unripe ova, the former enclosed in the Graafian folHcles, corpora lutea of varying age, and certain glandular interstitial cells which probably furnish the internal secretions, and are supposed to be the starting-point of multilocular cystic disease of the ovary. We shall consider menstruation first. Menstruation. — We shall not discuss the histology of this process, except to say that the mucous mem- 138 THE GENITAL GLANDS brane of the uterus becomes greatly thickened and engorged every month, and haemorrhages take place into it which carry away parts of the superficial layers. We are as far as ever from understanding the real value of its occurrence. According to Blair Bell, a large quantity of calcium salts accumulate in the blood, which menstruation removes, menstrual blood being very rich in calcium. There is no doubt that menstruation is determined by an internal secretion from the ovaries, and when these are both removed it almost invariably ceases. Marshall and Heape have shown that the process is by no means peculiar to the human subject. In a great variety of animals, such as deer, dogs, sheep, and monkeys, there is a regular cycle of changes leading up to the cestnim or rut, and after great overgrowth of the mucous membrane of the uterus there is a mucous and often bloodstained discharge, followed by a brief period of fertility. Ovulation. — The rupture of the Graafian follicle and shedding out of the ovum is called ovulation. It has been much debated whether the time of ovulation coincides with that of menstruation in the human subject. In the animals above described no doubt this is true, and in the human subject the age-hmits of fertihty and of menstruation are approximately the same. Nevertheless the relation- ship cannot be exact, because pregnancy has occurred before the first menstruation, and observa- tions on the ovaries during abdominal operations at various times in the menstrual cycle show that THE GENITAL GLANDS 139 although ovulation commonly takes place at about the same time as menstruation, this is by no means invariable. If it were so, the Jewish race would probably have become extinct, because, in obedience to the Levitical law, amongst strict Jews husband and wife hve apart during and for some days after menstruation. There is some evidence that in primitive man there was only one annual period of special fertihty. There is a Javan tribe amongst which all the births are said to take place in February. Many animals that in the wild state only go into oestrum once or twice a year become fertile all the time in captivity. After bilateral removal of the ovaries the patient is of course sterile and menstruation ceases, but in a few rare cases, apparently owing to abnormal outlying fragments of ovary remaining behind, pregnancy has occurred and menstruation continued. By some mysterious chemical attraction, the shed ovum finds its way into the Fallopian tube. If one tube is blocked, the other may receive the ovum, because cases are not very infrequent of a tubal pregnancy on one side with the corpus luteum in the opposite ovary. There appears to be in some famihes a hereditary tendency at each ovulation to rupture several Graafian foUicles and shed out more than one ovum at a time. A case was recently reported of a woman, age 35, who had two sets of quadruplets, three sets of triplets, and five sets of twins. Her mother had twenty-eight children, and her grandmother twenty- nine, including quadruplets and triplets. In another 140 THE GENITAL GLANDS case a woman had four twin pregnancies, her mother and aunt one each, and her grandmother two. Internal Secretions of the Ovary. — One internal secretion controls menstruation. Another, or the same, appears to act upon the vasomotor system ; when it is withdrawn by artificial removal of the ovaries or by the cessation of their function at the menopause, the patient often suffers from flushings, headaches, and other neuroses. Under these same circumstances the breasts, uterus, and vagina atrophy, and obesity may develop. The influence over breast tissue extends even to cancerous tumours growing in it ; double oophor- ectomy in a considerable number of cases of inoperable cancer has caused retrogression of the growth, and once or twice, apparently, a cure has resulted. On the other hand, pregnancy shortly after removal of cancerous breast usually leads to recurrence, and during pregnancy a cancer of the breast grows with frightful rapidity. We do not possess much information as to the consequences of removal of both ovaries in little girls. A statement appears in some books that the operation is performed in Persia, and that women of a masculine type result, but this is a traveller's tale. The symptoms of the artificial menopause following double oophorectomy may be much relieved by grafting a piece either of the patient's ovary, or less satisfactorily that from another person, into the abdominal wall. In some cases menstruation has remained unaffected, and when the graft has been THE GENITAL GLANDS 141 into the peritoneum, it is said that pregnancy has occurred.* The Corpus Luteum. — After ovulation has occurred, the Graafian follicle becomes converted into a gland containing a yellow fatty pigment, the corpus luteum. Ordinarily this is quite small ; if pregnancy follows it may reach a diameter of half to three-quarters of an inch. Apparently the internal secretion of this body determines the fixation of the ovum in the uterus, and perhaps also the subsequent overgrowth of that organ. If both ovaries are removed early in pregnancy, abortion always follows. In extra-uterine pregnancy the uterus enlarges although the foetus is not inside it. Removal of both ovaries in animals or in the human subject in the later months of pregnancy does not usually lead to abortion ; one patient went on to full term in spite of double oophorectomy as early as the sixth week. Whether the internal secretions of the ovary are due to the corpus luteum or to the interstitial glandular cells is quite uncertain. There is some evidence of other obscure internal secretory functions besides those mentioned. A rare disease called osteomalacia, characterized by softening and bend- ing due to decalcification of the bones, makes great progress during pregnancy, and in some cases at least is cured by a double oophorectomy. Ovarian feeding has been tried to reheve the symptoms of the natural or artificial menopause, but the results are dubious. It is always difficult to * See Archtv. gen. chirurg., 1911, p. 550. 142 THE GEXITAL GLANDS foretell when an internal secretion will be capable of absorption through the intestinal wall unchanged. Calcium salts have been used for the same troubles, and in some cases, at least, work remarkably well. FUNCTIONS OF THE TESTIS. The most obvious function of the testis, of course, is to produce spermatozoa, which it continues to do well on into old age. The testis, however, contains other secretory cells between the tubules, sometimes called the cells of Leydig, and to these is attributed the production of an internal secretion. It is not uncommon for one or both testes to fail to descend (cryptorchism), and in bilateral cases the individual is nearly always sterile, but the secondary sexual characters are usually preserved. On microscopical examination the tubules are Httle developed, but the interstitial cells of Leydig appear to be normal. It has been much debated whether the failure to descend is the cause or the consequence of the failure to develop, and on the answer to this question depends the surgical treatment ; if the first is true, it is highly desirable to find some operative procedure which will ensure the testis a permanent resting- place in the scrotum, but the evidence goes to show- that this does not lead to proper growth of the gland, so we must conclude that descent fails because it is not worth while for the gubernaculum to bring down a defective organ. When the testes on both sides are removed after puberty, the consequences are sterihty, atrophy of THE GENITAL GLANDS 14;} the prostate gland, and in a few cases in old men mental impairment. The secondary sexual characters are not lost, and it is very doubtful if the dotage which has sometimes followed is really due to loss of any internal secretion or nervous influence ; most probably it is merely the consequence of a mutilating operation preying on the mind of a broken-down indi\idual. In younger and healthier adults there is no mental change or loss of capacit}'. The atrophy of the prostate is not constant, but the effects of castration have been taken advantage of to reduce the size of a prostatic enlargement causing obstruction. Ligature or excision of the vas deferens blocks the way for the external secretion of the testis, and leads to atrophy of the tubules and consequent steriUty, but the internal secretion of the interstitial cells is not affected unless the main vessels of the cord are tied. In boys, the results of castration are more far- reaching, causing not only sterihty but also failure of the secondar}^ sexual characters (eunuchism). As is well known, the operation has been practised for centuries upon the attendants and guards of the harem at Oriental courts. The beard and moustache do not usually appear, the voice is childish, the body fat, and the mental attitude to the world modified, although there is no loss of business capacity. The prostate and vesiculae are atrophic, but there is not necessarily impotence. In cocks, testicular grafting partially obviated the effects of castration. Indeed, it is even recorded that in a hen, after removal of the ovaries, testicular grafting caused the bird to grow 144 THE GENITAL GLANDS a comb, wattles, and spurs, and start to crow, but this requires confirmation. Following upon Brown-Sequard's famous con- tention that feeding or injection of testicular extract had made him at 72 a young man again, attempts have been made, especially by vendors of expensive patent remedies, to convince the profession that the internal secretion of the testis can be taken as a rejuvenating drug, recalling the classical story of Medea's cauldron; but, as Biedl says, "exact and carefully controlled experiments with this substance have not been described ". Auto-suggestion probably accounts for much of the alleged benefit. CONTROL OF THE GENITAL GLANDS BY INTERNAL SECRETIONS. Not only are the genital glands themselves the source of internal secretions, but there is a good deal of accumulating though ill-assorted evidence to show that their own activity is dependent upon chemical messengers (hormones), reaching them by the blood-stream, derived from what we call the ductless glands. What is it that makes a man mascuHne and a woman feminine ? It used to be thought that the testis and the ovary were solely responsible. Now we know that masculinity and femininity may persist even after these glands are rem^oved. The mere fact of infertihty does not abolish sex, which is dependent upon the combined working of a num- ber of internal secretions. THE GENITAL GLANDS 145 The Ductless Glands before Puberty. — In young animals and in children the development of the ovary, testis, and other parts of the genital apparatus depends upon chemical stimuli received from the pituitary and thyroid glands. Experimental removal of these glands in young animals, or insufficiency diseases of either of them in man, may lead to sexual infantihsm. On the other hand, great enlargement, and therefore presumably hypersecretion, of the cortex of the suprarenal (hypernephroma) causes precocious sexual development of the male type. In boys this leads to overgrowth of the sexual organs, with early activity. In girls, there is enlargement of the clitoris, growth of hair on the face and pubes, and sometimes a male type of external genitals (pseudo-hermaphroditism), but there is not premature menstruation or fertility. Very few cases of overgrowth of the pineal gland are on record, but in some of these there has been sexual precocity in boys. Sexual precocity in girls is not uncommon ; it appears to be due to excessive ovarian secretion. In one case a girl seven years old showed precocious development and menstruation ; an ovarian swelhng was removed, and the signs of puberty subsided. It is found in gynaecological practice that thyroid and pituitary feeding may hasten puberty in cases where it is unduly delayed. After twenty, how- ever, a small uterus cannot be stimulated to grow. We have no sufficient evidence yet of the value or otherwise of feeding with the ductless glands in cases of cryptorchism with atrophic testes. 10 146 THE GENITAL GLANDS The Ductless Glands after Puberty, — Here again deficient internal secretion of the thyroid gland appears to be a cause of amenorrhoea, painful menstruation, and monthl}^ pain in the breasts, and Blair Bell states that thyroid feeding cures many such cases. It is of course well known that myx- oedema leads to amenorrhoea and sterility. In cases of pituitary disorder, also, amenorrhoea and sterility are the rule in women, and impotence in men. These are probably due to deficiency of the pituitary secretion, but this is not very clear. Not only do the secretions of the ductless glands influence the genital organs, but there is evidence of an effect in the reverse direction. During pregnane}' the thyroid gland usually enlarges a little ; in Italy this has been taken for years as a sign of conception. The pituitary gland also shows enlargement (Erdheim and Stumme). Berry points out that adenomatous goitre nearly always occurs in single or nulhparous women. It has already been stated that removal of the ovaries is a remedy for osteomalacia ; Bossi has recently advanced evidence that the same effect may be produced more conveniently by injections of adrenalin. THE SECRETION OF MILK. It is a very striking phenomenon that after twenty or thirty years of quiescence the mammary glands should suddenly spring into activity on the very day when the secretion is required. It cannot be due to nervous influences, because there is no nervous THE GENITAL GLANDS 147 mechanism controlling the flow of milk. For this reason pilocarpine does not increase and belladonna preparations do not check the secretion, in spite of their ancient reputation founded on analogy. It is true that when the child is put to one breast the other may pour out a little milk, but this is due to reflex contraction of the muscle about the ampullae of the ducts. The only drug which increases the flow of milk is pituitary extract, but here again the action is probably on the muscle, not on the gland cells. The physiological stimulus which starts the lactation is an internal secretion derived from the foetus. Injection of extracts of foetal animals into a non-pregnant female of the same species brings about hypertrophy and functional activity of the mammary glands (StarUng and Lane-Claypon) . The statement that this hormone is derived from the ovary can scarcely be true, because lactation is normal after double oophorectomy. It is not un- common for the rudimentary breasts, even of the foetus, to be stimulated to a few days' activity (' witch's milk '). One of a pair of conjoined Siamese twins was recently deUvered of a child, and both commenced lactating. Once started, the secretion of milk is kept up by suction. When this ceases, the glands return to the quiescent state. THE OVUM. The epithehal and other cells of the adult are not immortal, and require frequent renewal to repair 148 THE GENITAL GLANDS daily wear and tear. The cell-divisions bringing this about are initiated by the division of a body outside the nucleus, called the centrosome, which forms the achromatic spindle. A skein appears in the nucleus, which divides into V-shaped bodies called chromosomes, which in man are twenty-four in number. Each chromosome sphts into two, form- ing forty-eight ; of these, twenty-four pass to one daughter nucleus and twenty-four to the other. Finally, the cell protoplasm cleaves, and the nucleus returns to its resting condition. This process is called homotype (i.e. normal) mitosis. Before it meets a spermatozoon, the nucleus of the ovum divides twice, extruding the two polar bodies. At the second of these divisions,* half the chromosomes — that is, in man, twelve — are thrown out, and the centrosome with them. This is to prevent parthenogenesis — the development of an o\n.im into a foetus without a male element. In bees and wasps, where parthenogenesis occurs, tliis second or hcterotype mitosis does not take place. In the formation of the spermatozoon, also, a cell with twenty-four chromosomes divides into two spermatozoa with twelve each ; the head is the nucleus, the neck the centrosome, and the tail is the cell body. Thus the foetus starts Hfe with twenty- four chromosomes, twelve from each parent. In these, according to Weissmann, is bound up its heredity, including the impulse to assume the general shape of mankind, the \dscera with their proper • Some English text-books incorrectly say the first. THE GKNITAL GLANDS 149 anatomy and functions, and some resemblance to the facial appearance and even the tone of voice and character of the parents. How all this is crowded into such microscopical objects is the greatest marvel in biology. The spermatozoon probably brings in some chemical factor, at any rate in sea-urchins and starfish, because in these animals the purely female ovum can be induced to develop into a larva by con- centrated sea-water, tannin, or even violent shaking. Perhaps these animals arc not far removed from parthenogenesis, and the part played by the male in vertebrates is probably more important. Recently, however, it has been stated that stabbing an un- fertilized frog's ovum will make it develop as far as the tadpole stage, but no further. After fertihzation, the ovum starts to divide into two, four, eight, and so on. Much hght is thrown upon the process by the phenomenon of identical twins. Ordinary twins, due to the fertihzation of two ova by two spermatozoa, are no more alike than any other pair of brothers or sisters. Identical twins probably result from the accidental separation of the two cells produced from the first division of a fertiliz- ation ovum, and the children have an identical heredity. They are exactly alike in sex, appearance, and even in deformities such as hernia. This shows that the sex and general conformation of the child are probably fixed from the moment when a particular ovum and a particular spermatozoon meet. The causation of sex is still a puzzle. It has been suggested that the left ovary gives rise to ova that 150 THE GENITAL GLANDS will produce girls, and the right ovary generates boys, so that, as a critic remarked, it might be possible to prevent a national disappointment by removing a queen's left ovar^^ Differences in feeding a set of developing embr^-os are said to alter the proportion of males and females, but this is probably due to an excess in mortality of the one or the other. It is an ancient tradition that during a great war more boys than girls are bom because the m.others are physically superior to the male weaklings who have not gone to the front, but Europe's recent ordeal lends very little support to the theory. Bearing on the view that the offspring is likely to belong to the same sex as the feebler parent, it may be mentioned that statistics have been published sho\ving that when the man is older than the wife, male births are to female as 113 to 100 (the general average for all births is 106 boys to 100 girls) ; when the parents' ages are the same, there are 93-5 boys to 100 girls ; and when the woman is older, 88-2 boys to 100 girls. These figures are corroborated by some, but contra- dicted by others. It is said that when old men marry young wives (a May and December wedding) the children are usually boys. A German writer, drawing his observations from the relation between the time of a soldier's leave, the time in the cycle of the wife's menstrual periods when he was at home, and the sex of the next child, concluded that concep- tion just after menstruation leads to the birth of boys, and conception later to the birth of girls. None of these theories rests on any sufficient evidence. A more hopeful explanation may be based on the THE GENITAL GLANDS 151 fact that in some invertebrates there is an additional X chromosome in all the female ova, but only in half the male spermatozoa ; fertilization by a spermatozoon li'ith the x chromosome gives rise to females, and without it to males. If this is true, sex is pure chance, unless variations in the health of the father affect the proportion of the two types of spermatozoa. CHEMICAL DIAGNOSIS OF PREGNANCY. When an unusual protein passes repeatedly into the circulation, antibodies of a ferment nature are produced to destroy it. Some protein from the placenta passes into the maternal blood-stream during pregnancy. Abderhalden has based upon this a method of serum diagnosis. Fresh placenta is treated with the patient's serum, and if she is pregnant, peptones are formed by digestion. These can be dialysed off through an animal membrane, and tested for by the biuret reaction. Though requiring extreme care in the technique, the method appears to be sufficiently accurate and reUable to be of some clinical value. REFERENCES. Marshall. — The Physiology of Reproduction. BiEDL. — The Internal Secretory Organs, 19 13. Blair Bell. — Proc. Royal Soc. Metf. -(Obstetric Section), 1913. Dec, vol. vii, p, 47, 152 CHAPTER VII THE GROWTH OF BONE. RECENT CHANGE IN OUR CONCEPTION OF THE GROWTH OF BONE — OSTEOBLASTS— INCREASE IN THE LENGTH OF BONE— INCREASE IN THE GIRTH OF BONE — FUNCTION OF THE PERIOSTEUM THE REGENERATIVE POWERS OF BONE APPLICATION OF MODERN RESEARCHES TO SURGICAL PRACTICE — BONE-GRAFTING RELATION OF THE DUCTLESS GLANDS TO THE GROWTH OF BONE. TWO closely allied problems, how bones increase in length and girth in the child, and how regenera- tion of new bone takes place after loss or injury, are of great interest and practical importance in surgery. Every case of separation of an epiphysis by accident, and every operation on the growing end of a bone in children, involves a consideration of the first problem ; every case of fracture, necrosis, periostitis, or osteomyelitis depends for its proper understand- ing and rational treatment upon the second. A very important research has recently been pubUshed which necessitates a careful reconsideration of some of our conceptions of this subject. We may summarize the traditional teaching thus. Bone is laid down by certain cells called osteoblasts. In young animals, these are the direct descendants of cartilage cells. When the cartilage becomes vascular, the cells undergo proliferation for a time ; when they assume their individual maturity they THE GROWTH OF BONE 163 cease to divide, and lay down calcareous salts all around themselves just as a coral polyp does ; they are included in the midst of the bone thus formed as bone corpuscles. Increase in the le7tgth of the bone takes place by the new additions at each end, where the layer of cartilage between the shaft and the epiphysis is con- stantly being transformed into bone ; but inasmuch as its cells keep on dividing, the cartilage is not used up in the process until the age of eighteen to twenty- five is reached. It is usual for one epiphysis to unite later than the other, and in that case the increase of length is greater at this end than at the opposite, and the nutrient artery to the shaft will be directed away from the persistent epiphysis because the bone is, as it were, pushed down inside the periosteum. So far, the results of recent investigation entirely support and ampHfy the older opinion. A classical experiment of John Hunter's may be quoted. He inserted two leaden shot into the tibia of a young pig, exactly two inches apart. When the animal had grown up, he found that although the bone v/as of course much longer, the shot were still exactly two inches apart. Evidently, then, the increase of length must have been at the ends, not by interstitial increase of the shaft. More recently. Mace wen has removed almost the whole shaft of the right radius in a young dog by the subperiosteal method, leaving the two ends. After six weeks, there was strong and vigorous growth from each epiphysis, and, aided by a bending of the ulna, the two ends had come together, although no 154 THE GROWTH OF BONE periosteal growth of bone had taken place. One of the epiphyses was damaged ; from this end the new bony development was slenderer than from the un- injured end. In another experiment, two and a half inches of bone with its periosteum were removed from the radius of a young dog, and metal caps fitted over the sawn extremities of the shaft remaining in situ. Seven weeks later, the gap was found completely bridged by bone, and the two metal caps had come together. Owing to bending of the ulna, they did not absolutely meet, but passed one another laterally. In yet another case, the plate of cartilage between the shaft and epiphysis was removed from the radius of a young dog. The bone failed to grow at that end, and a lateral expansion of the epiphysis became attached to the ulna and stunted its growth also. This experiment is of course paralleled in man, when a separation of an epiphysis takes place, or when the growing end is removed in the excision of a joint. Increase in the girth of bone has been attributed to the periosteum. Between it and the bone, osteoblasts are to be found in young animals, and these lay down ring after ring of concentric lamellae. If the develop- ing animal is fed with pigment, such as madder, for a short period, there may be found months later a buried pigmented ring of bone which was laid down at that time. Another classical experiment we owe to Duhamel (1739), who buried a silver ring under the periosteum of a young animal, and found some time after that the ring had become covered by subsequent bone formation. THE GROWTH OF BONE 155 It was the natural corollary from this belief, that when bone has been destroyed by inflammation or removed by operation, we must look to the periosteum to regenerate new bone ; and as a matter of fact it is well known that if the periosteum is stripped up from the shaft by a purulent collection beneath it, it does in most cases lay down a sheath of bone outside the space in which the pus la}'. Again, after fractures we look to the periosteum to produce ensheathing callus to bind the broken ends together again. Some regenerating power, however, must be allowed to osteoblasts derived from the bone itself, to explain the formation of callus between the actual fractured ends and in the medullary cavity. Well entrenched as this view has been, it has recently been subjected to most damaging criticism by Sir WiUiam Macewen, who goes so far as to state that the function of the periosteum is not to produce bone but to limit the production of bone, and that osseous regeneration takes place from the osteoblasts of the bone itself, not from the periosteum. He supports his thesis by some most interesting experi- ments on animals, and observ^ations on man. It has always been admitted that some power of laying down bone must be allowed to osteoblasts quite apart from the epiphyseal cartilages or the periosteum, because of course it is their province to fill in the Haversian canals with concentric rings of new bone, and also to cement the ends of a fracture as intermediary and intramedullary callus. The hard- ness and density of bone rather blind our eyes to the fact that, like every other living tissue, the processes 156 THE GROWTH OF BONE of building up and breaking down, absorption and new formation, are continually going on in its cells and molecules. When it is irritated, as for instance when a pin is driven into compact bone, absorption takes place, and the pin may loosen in the course of a day or two ; when it is withdrawn, osteoblasts wander into the track and fill it with new bone. Even so soft an organ as the tongue helps to maintain the shape of the jaw, and after a successful operation for cancer the lower teeth come in time to slope towards the buccal cavity. The interstitial changes in bone are affected by various toxins and internal secretions : during rickets the osseous tissue is at first softened, and finally becomes more compact; the pituitary secretion causes it to undergo hypertrophy. So much is known and admitted. The evidence which enables ^lacewen to go further and to deny any share to the periosteum, as such, is as follows: — In a dog, a strip of periosteum a quarter of an inch broad and two inches long was peeled up from the radius, leaving the attachment to the epiphysis intact. It was buried between muscles. Eight weeks later, there was no trace of bone formation in the fibrous intermuscular band which represented the periosteum. On the other hand, there was a bony ridge outgrown from the area whence it had been stripped up. So far then from forming bone, the periosteum must have been pre- venting the outgrowth of bone. In other experiments, a strip of periosteum was excised and immediately implanted in the neck of the same animal around the jugular vein. Usually it TIIK GROWTH OP' BONE 157 was entirely absorbed ; once a tiny osseous nodule was found, derived probably from an attached chip of bone. Macewen points out the great practical importance of this in such an operation as sub- periosteal excision of the elbow. If care is not taken to inspect the periosteum, adherent bony flakes may be left which will grow, and lock the joint. If they are all removed, an excellent free joint results. This represents the experience of over two hundred cases. On the other hand, care must be taken not to encroach on the diaphysis of the humerus by removing too much, or it may sprout new bone. In other experiments, Macewen removed portions or the whole length of a bone subperiosteally. No regeneration took place to fill the gap, except in a few cases where the animal was young, and the grow- ing epiphyseal ends pushed the extremities together to diminish or obhterate the gap. No new periosteal bone was formed. He then repeated Duhamel's silver-ring observa- tion, and found that the bur\ang beneath new osseous tissue occurred just as well if the bone in that neigh- bourhood, or indeed in its whole length, was first deprived of periosteum. The new bone could be seen overflowing the ring from the edges. In this case it is perfectly evident that the osteoblasts providing for growth must have come from the shaft, not from the periosteum. A number of important observations are recorded demonstrating the regenerarive powers of bone itself, apart from periosteum, and more particularly m young animals. These may be briefly summarized. 158 THE GROWTH OF BONE Although grafts of periosteum into the neck will not grow osseous tissue, thin shavings of bone itself, similarly transplanted, will double in length and thickness in most cases. In a number of experiments, pieces of bone an inch or more in length, or even comprising the whole shaft of a long bone, were successfully transplanted from one dog to another. In a classical case, Macewen built up a new humerus for a lad who had lost the shaft by acute necrosis, and although the wedges of bone, derived from excisions for deformed legs, were not covered with periosteum, they grew and consolidated, and now, more than thirty years after, aided by the great growth of the upper epiphysis, which has contributed the bulk of the humerus, the arm is strong and useful. In other cases, fragments of bone have been replaced to fill gaps in the skull, with excellent results. Macewen has secured osseous growth by trans- plantation of bone chips into the omentum, and also, after burying glass tubes in the middle of a long bone, he has found the lumen of the tube invaded by osteoblasts, and osseous islands laid down. In one interesting case, a traumatic aneurysm formed from the brachial artery of a young patient in consequence of the penetration of the vessel by a spicule of the humerus, which was fractured. Osteoblasts washed out of the humerus were thus distributed throughout the clot hning the aneurysm, and it developed a regular bony wall. This would probably occur more frequently when the aorta erodes the vertebrae, but for the fact that in that case the patient's osteoblasts are usually senile. THE GROWTH OF BONE 169 In some experiments, after removing a length of the radius with its periosteum, the gap was filled with bone chips. Consolidation took place, but a large tumour-like mass of callus formed, infiltrating the surrounding muscles. The osteoblasts from each chip had wandered out and prohferated, and when they became mature had surrounded themselves with calcareous deposit, which bound together not only the detached fragments and the broken ends, but also the muscles and tendons in the neighbour- hood. The experimental and chnical work of Hey Groves on fractures strongly supports the view that callus is derived from bone and not from periosteum. The factors which induce bone-corpuscles to become active and prohferate are not perfectly understood. Macewen lays stress on rehef from pressure, and no doubt this has great importance. Dissemination of osteoblasts by increased vascularity of the part is another factor. The periosteum, v/hen intact, limits the osteoblasts to their own proper sphere, and prevents their encroaching on the muscles and fascial planes. According to some German and French observa- tions, blood-clot has an influence not only in pro- viding a suitable medium in which bone may be formed, but, further, in exerting a direct chemical stimulus upon the osteoblasts. We may now apply these researches to surgical practice, considering first the consequences and repair of fractures. In subperiosteal fractures, rapid and firm union takes place without any ensheathing 160 THE GROWTH OF BONE callus, and the bone feels quite normal after a few months. When the periosteum is extensively torn, osteoblasts wander out beyond its limits, and en- sheathing callus may be formed in quantity. Much will depend on the amount of movement to which the part is subjected. Vigorous movement, or, in those cases where the periosteum is stripped away, deep massage applied too early just over the site of the fracture, will disseminate the osteoblasts far and wide. Not only may the callus be excessive, and, perchance, lock the nearest joint, but muscles, nerves, or tendons may become ensheathed b}^ new bone, and their functions be impaired. Here belong those interesting and by no means infrequent cases in which, after a fracture, especially near the elbow-joint, an osseous mass develops in the muscles, as for instance in the brachialis anticus. This is called traumatic myositis ossificans. The mass can be moved apart from the bone, and casts a shadow with the x rays. What has happened is that massage or movements have scattered the osteoblasts far and wide, and they have, after a few weeks, performed their usual function, and regenerated bone in their new surroundings. It is significant that these cases have become common only since the modern treatment by massage and movements has been introduced, excellent as it is when suitably applied. If the periosteum had remained intact, this could never have occurred. The treatment, if such a lump forms, is not excision, which usually leads to recurrence, but strict limitation of movement by means of a splint. THE GROWTH OF BONE 161 The reason why so much more callus forms in animals than in man is because so much more movement of the broken ends takes place. In these circumstances there is often a stage in which cartilage is to be found in the callus, on its way to form bone. It is evident, therefore, that care should be exer- cised, after a fracture in which it is probable that the periosteum is torn, to avoid deep massage and move- ments close to the site of the fracture during the first fortnight, although they may well be applied to the neighbouring joints. When the fracture is very near a joint it is far better to trust to a single efficient movement once a week (to avoid adhesions) than to allow repeated small movements in the early stages. It is well known that exostoses or spurs of bone usually form in the attachment of muscles or tendons. The probable explanation is that by the continual drag and, it may be, sHght wTenches, some osteo- blasts are detached from the bone and invade the tendon. Universal myositis ossificans, such as occurs in a so-called 'brittle man', may be due to some such cause as this, or perhaps to embohsm of osteoblasts. The strongest evidence for the older \'iew, that bone is laid down by the periosteum, is provided by cases of acute periostitis, where pus forming inside the bone finds its way out between the shaft and the periosteum, so that the latter is extensively stripped up. In many cases, new bone begins to form under the detached periosteum, outside the pus, and the shaft usually necroses. Macewen explains this occurrence by declaring 11 162 THE GROWTH OF BONE that if the inflammatory mischief is not very acute, vasodilatation takes place within the bone, and the osteoblasts are carried out by the Haversian canals to the loose areolar space under the periosteum, to which fibrous membrane some of them adhere. When this is stripped up later, these osteoblasts lay down new bone, but those remaining on the shaft are deprived of their blood-supply and therefore die. If the inflammatory mischief in the centre of the bone is very acute, the whole shaft may die, especially if thrombosis occurs, and therefore no osteoblasts escape, so that no new bone at all can be laid down under the periosteum. This is by no means a rare occurrence. In local periostitis, again, which should rather be described as an osteitis, the bone-forming cells are brought by the blood-stream to the loose areolar tissue underneath the periosteum, and finding there a line of least resistance, are able to lay down young bone, and so produce a locahzed swelling, marked out in a skiagram by a faint line of shadow close to, and parallel with, the shaft. The truth of the matter probably is that the active osteoblasts beneath the periosteum in normal bone (the cambium layer) may adhere either to the surface of the bone, or to the under surface of the periosteum, under different circumstances ; in Macewen's experiments they adhered to the bone, and this is probably the rule. When there is inflammation, and the periosteum is stripped up by pus, many of them prefer to stick to the periosteum. During operations for the removal of bone, great THE GROWTH OF BONE 163 efforts are often made to preserve the periosteum, and sometimes, as for instance in excising the lower jaw, the membrane is preserved even at the risk of leaving septic material behind, in the vain hope that it will form new bone. The only possibility of its doing so is if osteoblasts have been driven out by inflammation and have become adherent to it. It is useless to expect healthy periosteum to regenerate bone, such as a piece of rib removed for empyema, though it may form a guide for the gap to be filled by growth from the epiphyseal end. Bone-grafting. — A great impetus has been given to the study of these problems by the numerous opportunities provided by war surgery for bone- grafting. Ununited fractures after wounds have been of common occurrence, and the surgeons have all been busy putting bone-grafts into the gaps. At the same time, the Albee operation of introducing a bone-graft from the tibia into a furrow in the split spinous processes of the vertebrae for Pott's disease has become popular. It must be granted that, whatever the technique, our experience has com- pletely established the fact that a transplant of living bone from the same patient (autogenous graft) will usually Uve and grow and unite firmly with the ends of the bone into which it has been introduced. There have been very many histological, skia- graphic, and other studies of the fate of the graft, and though controversy still rages between the two schools as to the part the periosteum plays in bone regeneration, one may begin to 164 THE GROWTH OF BONE see a wa}^ of reconciling the facts on the one side and the other. It is quite clear that young osteoblasts can reproduce bone, and that old ones, shut up as bone-corpuscles in lacunse, cannot. Also, we know that bone deprived of periosteum can survive and form a useful graft, uniting with the ends of the shaft into which it is ingrafted. Nevertheless its periosteum should always be preserved if possible, because the Httle vessels passing from the periosteum to bone are important for the nutrition of the bone, and the periosteum readily forms vascular connections with the surrounding tissues. Also, the most active young osteoblasts are found principally just beneath the periosteum, and on the surface of the bone-shaft. Other active osteoblasts hne the Haversian canals and the lacunae of cancellous bone, and are especially numerous in the endosteum, that is, the film of cells which lines the bony tube surrounding the marrow cavity. H a bone-graft is examined microscopically some months after the operation, the great bulk of it shows dead bone-corpuscles and some absorption going on, but beneath the periosteum and endosteum and around the lacunas there is li\ing, growing bone. The success of a bone-grafting depends also on some other factors. Asepsis is, of course, essential, and so is secure fixation and freedom from move- ment during the first couple of months or so. The permanence and strength of the graft, however, depend on the use that is made of it. Function- less bone, buried in a muscle for instance, tends to absorb ; useful bone, filling a gap in the j aw or THE GROWTH OF BONE 166 radius, becomes stronger as the part is used. Bone- grafts into the femur and humerus have not so far been successful. It is not yet decided whether rib-cartilage will survive well and function as a graft. I have used it for the lower jaw and also for closing skull gaps. It has two advantages, in that it is easy to work with and cut to shape, and that normally cartilage is accustomed to a scanty blood-supply. My cases did satisfactorily, but according to Leriche and PoUcarde the hyaline cartilage part of the graft is slowly absorbed. There is some relationship, not well understood, between the internal secretions of the ductless glands and the growth of bone. Over-secretion of the pituitary gland, as we shall see, results in overgrowth of the bones, and may lead to gigantism. On the other hand, inadequate thj^roid secretion will stunt the growth of the bones, as is seen in cretinism. Thyroid medication will occasionally lead to the consolidation of an ununited fracture, or, what comes to the same thing, the internal secretion of the thyroid gland may be increased by giving iodide of potassium. REFERENCES. Macewen. — The Growth of Bone, Glasgow, 191 1. Hey Groves, Joll, and Wheeler. — Articles ' Bone- grafts ', Med. Annual, 1919. 166 CHAPTER VIIl. THE THYROID AND PARATHYROID GLANDS. HISTORY REMOVAL OF THE THYROID AND PARATHYROIDS REMOVAL OF PARATHYROIDS ALONE REISIOVAL OF THYROID ALONE THYROID FEEDING — CHEMISTRY OF THYROID COLLOID — PARENCHYMATOUS GOITRE — IODO- FORM AND THYROIDISM ACTION OF IODIDES ON GUMMATA AND ATHEROMA EXOPHTHALMIC GOITRE PRACTICAL DEDUCTIONS. MUCH of the clinical and experimental work which has been done in connection with these glands can no longer be described as new, but it will be helpful to mention in passing some of the well-known results obtained by the first observers. HISTORY. As long ago as 1859, Scliiff described the fatal result which inevitably supervenes after removal of the thyroid gland in dogs, but it was not until ' cachexia strumipriva ', or operative myxoedema, was found to follow so man}^ of Kochers earh' operations for goitre on patients coming from the goitrous S\viss valleys, that this fact attracted much attention. The relation of the thyroid to myxoedema was then established by Gull and Ord. The highly successful treatment of myxoedema and cretinism by thyroid feeding was introduced by Murray, follow- ing on the observation by Schiff and subsequent THE THYROID GLAND 167 workers that transplantation of the gland beneath the skin of the thyroidectomized animal relieved the symptoms. REMOVAL OF THYROID AND PARATHYROIDS. We will consider first the consequences of removal of the thyroid gland in animals. The effect of total removal varies greatly with the species. Thus rodents are Httle if at aU affected, sheep and cattle more so; in man and monkeys the symptoms are marked, and in carnivores, especially foxes, a rapidly fatal result ensues. To some extent this striking diversity depends, as we shall see, on the Hability to simultaneous removal of the parathyroids; for a long time this was not recognized. Males are more severely affected than females, and castration is said to modify the symptoms. Thyroidectomized animals are very susceptible to cold, and keeping cats warm may save their Hves ; of course thyroid medication must be undertaken at the same time. It is weU known that human patients \vith myxoedema feel the cold very much. The symptoms in dogs and monkeys are vomiting, muscular prostration, emaciation, and often death. Of great importance is the frequent occurrence of tetany. The spasms are at first slight, affecting the jaw muscles, then they spread over the whole body and may be fatal. Tliis condition has several times foUowed a too extensive removal of the thyroid in man, and may also occur in myxoedema. Another symptom present frequently in monkeys is narrowing of the palpebral fissure, so-called enophthalmos ; we shall 168 THE THTROIL) AND see that administration of th^Toid extract may cause exophthalmos. True myxoedema is not often seen in the experimental animals. It has been induced in mild degree in monkeys by Horsley, Edmunds, and others, but not with any constancy, and in other animals it is not seen at all. It is not usually possible to save the Hves of dogs or monkeys whose thyroids have been removed, by feeding on sheep's th^^roid, although a good deal of reUef may be obtained for the symptoms in this way. Grafting a piece of the gland under the skin is successful for a while, but eventually it is absorbed. The effects of removal of, or insufficient secretion by, the thyroid gland in man are myxcedema, and occasionally tetany. In 408 cases in Kocher's cUnic at Beme complete extirpation of the thyroid was followed by myxoedema in 69 cases, and a similar operation in 78 cases in Billroth's clinic was followed by tetany in 13 cases, of which 6 proved fatal. Feeding with sheep's thyroid is wonderfully successful in myxoedema, but is not usually effectual in tetany. Partial removals of the thyroid in dogs produce symptoms of correspondingly lessened severity. Halstead found that in one case one-eighteenth of the gland sufficed to ward off symptoms of athyroidism, but the amount which could safely be left varied in different animals. One bitch which had lost two-thirds of her total thyroid became pregnant by a healthy male, and all her whelps had enormous goitres, a fact which has also been observed by Edmunds. PARATHYROID GLANDS 169 Histological examination of the portion remaining shows a sequence of changes remarkably like those occurring in exophthalmic goitre, namely, distention and irregular shape of the vesicles, with watery fluid instead of colloid, and columnar epithehum instead of cubical. REMOVAL OF PARATHYROIDS. The variation in the s^Tnptom-complex following on thyroidectomy, and the variability of response to thyroid feeding, both depend on any coincident injury to the parath\Toid glands. For many years these glands passed unrecognized, and most of the effects attributed above to removal of the thyroid are as a matter of fact due to loss of the parathyroids. These are two pairs of small glands, about one-third of an inch long and usually flattened in shape, l}dng behind the lateral lobes of the thyroid close to the trachea, not easUy distinguishable from the thyroid except by the microscope, when they are seen to consist of columns of polygonal cells with no regular arrangement into acini, and secreting no colloid. One pair was discovered by Sandstrom in 1880, and the functions were investigated by Gley in 1892 ; but the second pair was not recognized till Kohn's monograph appeared in 1895. A number of physiologists have since described the effects of removal (Vassali and Generali, Edmunds, Moussu). If all four parathyroids are taken away, the animal succumbs rapidly, with symptoms just such as have been described under the heading of thyroidectomy, tetany being a marked feature. The signs are the 170 THE THYROID AND same whether the thyroid gland is removed or left. Lea\ang one parathyroid is usually sufficient to prevent death, but tetany may still ensue. Swale Vincent does not believe in the relative importance of the parathyroid glands, but the evidence is so weighty and so well supported by many observers that it has to be accepted. Changes in the human parathyroids are said to be very frequent in cases of tetan}^ in children or pregnant women, and also in osteomalacia, in which the inorganic matter of bone is largely removed. There are facts in favour of the hypothesis that the tetany itself depends on some abnormality of the calcium metabolism of the body. The main function of the parathyroid glands is perhaps to control the calcium metabolism. Normally the amount of cal- cium in blood serum is about lo mgrms. in lOO c.c, but in spontaneously occurring tetany it sinks to about half that amount (Howland and Marriott). Calcium chloride administration raises the quantity nearly to normal, and rapidly cures the spasms, but it needs to be persisted with for many weeks. Noel Paton and fellow workers at Glasgow believe that the symptoms of tetany, whether arising clinically from malnutrition, chronic colitis, dilata- tion of the stomach, etc., or produced experimentally by excising the parathyroid glands in animals, are due to intoxication with a chemical substance called guanidine, which gives rise to identical symptoms (tendency to spasms, increase in muscular tone, rise in the non-urea-nitrogen output in the urine). They quote experiments, which, however, do not seem PARATHYROID GLANDS 171 quite conclusive, that go to show that guanidine is present in the blood in tetany. According to this view, the function of the parathyroid tissue is to control guanidine metabolism. It is not clear how the calcium theory and the guanidine theory fit in with one another. It would seem, then, that in man, myx oedema is due to loss of the internal secretion of the thyroid itself, but that tetany and fatal symptoms in both man and animals are due to loss of the parathyroids. The convulsions of tetany in dogs may be arrested by feeding on a watery extract of twelve to twenty horses' parathyroids (Moussu). REMOVAL OF THYROID ALONE. Removal of the th^Toid gland without the para- thyroids is usually not fatal ; myxoedema results in man ; occasionally, perhaps, in animals also, but more commonly only cachexia. In young animals, however, the results are much more distinctive, and von Eiselsberg and others have induced very con\'incing cretinism, with a remarkable stunting of grov/th, in lambs, goats, rabbits, and asses. It is interesting and important to notice that the animals so treated developed exceedingly marked atheroma of the aorta, of which von Eiselsberg gives good figures. THYROID FEEDING. We now turn to the effects of thyroid feeding in the normal man and animal. These are perfectly characteristic if large doses are given. The blood- pressure falls, the pulse becomes rapid (120-140 or 172 THE THYROID AND more), there may be fever, headache is usual, and there is great mental depression or excitement in many cases. Exophthalmos has been recorded several times after an overdose in man (Beclere, Notthaft), and monkeys (Edmunds). The metaboHc exchanges of the body are increased, consequently there are loss of weight and an increased output of urea, chlorides, and phosphates, and the gaseous exchanges in the lungs are above normal (Roos, Magnus Levy). It will be noticed that the parallel- ism with Graves' disease is very striking. CHEMISTRY OF THYROID COLLOID. Chemical investigation of the colloid has yielded some important results. There is a chemical sub- stance called iodothyrin, which has the characters of a globulin (Oswald) and contains a variable propor- tion of iodine. This element is usually abundant in the thyroid, but almost absent in the other tissues of the body. Its presence was first proved by Baumann, of Freiburg, in 1896, and has been abundantly confirmed since. The amount present Taries with the species and also with the individual ; in some cases it falls below the limits of chemical recognition. Herbivores possess it in abundance, most vegetables containing iodine. Orkney sheep, which feed largely on seaweed in the winter, have an extraordinary amount. In carnivores it is very scanty. In man it is nearly always present in recognizable quantities, except in young children. Wells finds that the amount varies with the locality, and in general is inversely in proportion to the local PARATHYROID GLANDS lia prevalence of goitre. In parenchymatous goitre the iodine content is too low ; in exophthalmic goitre it is too high. A principal function of the thyroid is to control the iodine metabolism of the body. It is a moot point whether iodothyrin is the active principle of the thyroid gland. The most recent researches suggest that it is not, and that the amount of iodine present on analysis may not be a rehable indication of the activity of a gland extract. On the other hand, Kendall has recently isolated from the colloid a crystalline indol deriva- tive, rich in iodine, to which he gives the formula of CnHjyO.jNI.5, and which is said to be effectual in curing myxoedema and cretinism. PARENCHYMATOUS GOITRE. Directing our attention now to enlargements of the thwoid gland, we rule out those that are merely due to tumour formation, such as adenoma or cystic disease, and confine ourselves to the parenchyma- tous goitres. It has long been known that there is some connection between drinking-waters and the incidence of goitre. The disease is extraordinarily prevalent in certain districts, and especially where the water-supply is derived from particular geological formations, such as the molasse in S\sitzerland and the carboniferous limestone in Derbyshire. In Khokand, Turkestan, a very large proportion of the whole population suffers, and Russian soldiers stationed there rapidly acquired the disease. The introduction of a new water-supply has several times induced an epidemic of goitre in a town, or, on the 174 THE THYROID AND other hand, reduced the number of cases in an endemic area. Thus at Rupperswyl, near Aarau, an endemic area in which 59 per cent of the children were goitrous, in 1884 the water-supply was changed for one from a non-goitrous district, and in ten years the percentage had fallen to eleven. There are on the Continent certain goitre wells called Kropfbrunnen, at which young men anxious to escape conscription drink. They have been known for centuries, and the water wall induce goitre in horses and dogs, as well as in man. Boiling the water destroys its remarkable effect on the thyroid gland. This has been taken to prove that some hving organism is the effective cause, but another theory is more probable, as we shall see later. During Captain Cook's vo3^age in 1772, it is related that the crew ran short of water, and had recourse to blocks of ice from the icebergs amongst which they were sailing, melting them, in iron pots. Quite a number of those who partook of this water developed a goitre, other members of the crew escaping. A large projecting sweUing of the thyroid is not uncommon in trout kept in certain tanks or streams. In the earher stages, parenchymatous goitre can usually be cured, either by feeding on thyroid extract or by means of potassium iodide. Marine* has pointed out that in America there was formerly a serious commercial loss in some districts from cretin lambs, and that sheep and dogs with goitre were numerous ; the substitution of an iodiferous salt * Johns Hopkins Hosp. Bull., 1907, xviii, p. 359. PARATHYROID GLANDS 175 for pure rock-salt has been completely successful in preventing all these manifestations. Chalmers Watson, and more recently Edmunds, have obtained goitre in fowls by a meat diet. The low iodine-content of the meat makes it necessary for the thyroid to enlarge, so as to take the greatest advantage of what iodine it can get. There is abundant evidence that iodides, and especially organic combinations of iodine such as iodoform, have great power in enhancing the activity of the th}TCtid gland. We have already seen that the gland normally secretes iodine into the blood-stream, combined with a globulin. Roos, and more recently Hunt and Seidel, have shown that the activity of the colloid varies directly with the amount of iodine contained in it, but this is not imiversally accepted. WTien iodides or iodoform are given by the mouth, they are taken up by the thyroid and secreted in the blood-stream in the form of iodo- thyrin, which may be the normal active principle of the gland. The amount of iodine in the gland in these circumstances rises considerably, as has been proved by Oswald in man, and by Hunt and Seidel in dogs. What, then, is the relation between iodine metabolism and goitre ? In the first place, we may conclude that the thjToid enlarges in goitre because it is necessary for it to do increased work. A certain quantity of iodothyrin is needful for the general well-being of the individual ; if the gland is scantily supplied with iodine, it must enlarge in order to take the fullest 176 THE THYROID AND possible advantage of all that may be brought to it by the blood-stream. In the same way a kidney hypertrophies when its fellow is degenerated, in order to obtain more urea for excretion ; and the red blood- corpuscles double in number when a man takes up his abode in the rarefied atmosphere of great alti- tudes, to make the best use of the diminished supply of oxygen. It has been shown by Oswald in a number of observations that in goitre the thyroid colloid is exceeding^ deficient in iodine, both in calves and man. Thus we get a clue to the successful treatment of the affection either by iodiferous compounds or by thyroid extract. It is weU known that either of these remedies will cure early cases of goitre, before the enlargement becomes chronic. The success of the iodiferous rock-salt on the American farms may be accounted for in the same way. An explanation is also offered of the fact, noticed previously, that the whelps of bitches from whom a good part of the thyroid has been removed are all goitrous, the plasma supphed to the foetal glands e\ddently containing a deficiency of iodine derived from the maternal thyroid. Of 2333 cases of con- genital goitre collected by Fabre and Thevenot,* the mother was almost invariably goitrous. The foetal thyroid enlarges in order to obtain as much iodine as it can. It was natural to suggest that the waters of the Kropfbrunnen were deficient in iodine, but this theory would overlook the fact that the bulk of our * Revue de Chirurgie, 190S, June 10. PARATHYROID GLANDS 177 iodine is derived from vegetables, not from drinking- water, and as a matter of fact these wells show no constant deficiency or excess of iodine. It is possible that they contain minute traces of some metal having a great affinity for iodine, and forming with it an insoluble compound. It is quite conceiv- able that boiling the water might precipitate such a metal. This, if taken into the body, would with- draw so much of the available iodine as inert metallic iodide, that the thyroid must enlarge to obtain the indispensable minimum. Major McCarrison, who has been observing endemic goitre amongst the Gilgit highlands in North India, has lately brought forward fresh arguments in favour of a bacteriological theory of its causation. He has induced a definite swelhng of the thyroid both in himself and in natives by drinking the muddy residue on the filter ; the filtered water, in a short experi- ment, did not give rise to goitre, nor did boiled water. No organism could be found in punctures of the gland. Goats given water to drink contaminated by the fasces of goitrous patients, in some cases, though not in others, developed a certain amount of swelling of the thyroid gland, and in man ten-grain doses of thymol, used as an intestinal antiseptic, reduced the size of a goitre in some patients. Hence, McCarrison beheves that the disease is due to an intestinal organism. According to Wilms, Bircher, and others,* the water of goitre wells retains the power of inducing * Bircher, Deut. vied. Wochensch., 1910, No. 37 ; Wilms, Deui. ined. Wochensch., igio, No. 13 ; Koile. Korrespond. j. schweiz. Aerzte, 1909, No. 17. 12 178 THE THYROID AND thyroid enlargement in rats after passing through a Berkefeld filter. It is true that a few tiny bacteria are filter-passers, but the immense majority are held back. It is easy to cause enlargement of the thyroid by various means ; Bircher shows that food con- taminated by the faeces of normal rats causes goitre in other rats. There are goitre wells in England. One is known to the writer near Berkeley, in Gloucestershire. Its water is used by only one or two families, but four cases of goitre have resulted. It is usually the growing children who suffer. IODOFORM AND THYROIDISM. The conclusions which modern phj-siology has reached with regard to the relation between iodine compounds and the thyroid gland lead us to some further important explanations of obscure problems. We are now able to understand the toxic effects of iodoform, and the beneficial action of iodides on arteriosclerosis, aneurysm, and gummata. Iodoform poisoning has become a well-recognized condition, and every text-book on pharmacology or toxicology gives a clear description of the chnical picture, which the writer has verified by consulting the reports on some lOO cases scattered through the literature, not including the very numerous records of dermatitis or erythema following its local use. A long list of well-described cases (not always very convincing) is given by Cutler.* * Boston Med. Soc. Journal, 1886, ii, pp. 73, loi, no. PARATHYROID GLANDS 179 There are four main varieties of iodoform poi- soning : — 1. Skin eruptions, such as dermatitis, erythema, and swelling. 2. Persistent subjective taste and smell of the drug long after its application has been discontinued. 3. Toxic amblyopia (5 cases), and optic atrophy (i case). 4. Acute thyroid symptoms, comprising rapid pulse, delirium, headache, vomiting, and a variable amount of fever. The most characteristic sequence is when the pulse is very rapid but the temperature normal. Of the above groups we are now concerned only with the last. It will be noticed that the clinical picture cor- responds exactly to that seen after administration of excessive doses of thyroid extract. Iodoform causes its toxic effects by stimulating the internal secretion of the thyroid gland, with the production of acute thyroid intoxication. I have described a case in which chronic thyroid intoxication, that is to say Graves' disease, clearly followed the application of iodoform to an absorbing surface. There was certain proof that too much iodoform was absorbed, because for weeks after the drug had been withdrawn the patient was haunted by its smell and taste. The tachycardia and wasting were first noticed a week or two after this symptom developed. The Graves' disease was still present in a mild form one year later, but eventually disappeared. Hunt and Seidel have shown that after dosing 180 THE THYROID AXD a dog with iodofonn, the iodine content and the acti\'ity of the th3Toid colloid are both increased greatly. The thyroid secretes into the blood, as iodothyrin, the iodine derived from the iodoform. \\Tien strychnine is excreted by the kidneys the excretion is merely discharged from the body, and therefore the drug can do no more harm. But the increased secretion of the thyroid is discharged not externally but into the blood, and may poison the patient. ACTION OF IODIDES ON GUMMATA AND ATHEROMA. A similar increase in the thyroid secretion may be obtained by giving iodides, but apparently the gland is not able to utilize these as readily as it does iodoform, for large doses do not so easily cause acute thyroid intoxication. Here we find the ex- planation, so long sought in vain, of the effect of iodides on gummata, arteriosclerosis, and aneurysm. The beneficial agent is really the increased internal secretion of the thyroid gland. Two important results of obser\"ation and experi- ment confirm this theory. In the first place, in cases of myxoedema, arterio- sclerosis is earh^ and intense. The same is true in animals after removal of the thyroid. \'on Eiselsberg gives a number of very convincing photographs of intense atheroma of the aorta in his cretin lambs in which the thyroid had been removed in early life. In the second place, thyroid extract has a wonderful power over young connective tissue, as is seen by the PARATHYROID GLANDS 181 way in which it absorbs the subcutaneous thickening of myxoedema and cretinism. It is not surprising, therefore, that it should be able to deal also with gummata and atheroma. By its absorptive effect on the atheroma, it may work some improvement in aneurysm. I have found th\Toid extract quite as effectual a? iodide of potassium in heahng tertiary syphilitic ulcers. EXOPHTHALMIC GOITRE. The arguments in favour of the hypersecretion theor\- of this disease appear to almost all observers to be of oven.vhelming strength. The th3Toid gland is enlarged, vascular, and soft in most cases ; occasionally it is normal in size. Microscopically, the acini are dilated and irregular, and the contents too water}'. These are just the changes seen in the actively secreting fragment left after a sub-total th}Toidectomy. The colloid contains too much iodoth\Tin as compared with the normal gland. The wasting, restlessness, and quick pulse may all be reproduced w*ith constancy in man or animals by thyroid feeding, and exophthalmos has also been obtained occasionally in both man and the monkey. The underhdng cause of the hypersecretion is still unknown. A few cases may be lighted up by fright or by iodoform poisoning. Emotional storms such as terror, anger, intense mental conflict, and the like, undoubtedly produce an increased outpouring into the blood both of ad- renalin and of the internal secretion of the thyroid 182 THE THYROID AND gland, and it has been suggested that some of the cases of nervous instabihty and rapid pulse with some dilatation of the heart occurring in soldiers after very anxious experiences, prolonged over weeks or months, may be due to hyperthyroidism (Johnson) . In a few cases a transient exophthalmos has been observed. PRACTICAL DEDUCTIONS. We may seek here to sununarize the conclusions, in so far as they are of importance to the cHnician, that the New Physiology has reached. We leam that parenchymatous goitre is a hypertrophy of the thyroid gland, designed to enable it to obtain sufficient iodine from the blood, this element being an essential constituent of its internal secretion. The deficiency in iodine is in some comphcated way connected \\^th the drinking-water. In the early stages, iodides, thjnroid feeding, or probably iodo- form will work improvement, and the water should be boiled, or the supply changed. Should operative measures be adopted, we leam that the whole gland must not be removed, or myxoedema may result, and that the four small parathyroids King behind it must also be respected, or the patient may develop tetan5^ In some cases the loss of the parathyroids on one side only has caused this unpleasant sequel. An attempt should therefore be made, in removing one lobe of the thjToid for goitre or adenomata, to leave these little glands intact and in situ, and to preserv^e their blood-supply. They will not be injured if the posterior part of the capsule of the thyroid is left. PARATHYROID GLANDS 188 If myxoedema or tetany do follow the operation, they may be remedied by thyroid and parath>Toid feeding respective!}'. There is some evidence that even the medical varieties of tetany are due to loss of the internal secretion of the parathyroids ; according to Kocher, this has been proved in the case of the tetany of pregnancy, and other obser\^ations have since been made in which the parathyroids were diseased when tetany was present. Parathyroid feeding should therefore be worth a trial in such cases also. Macallum* recommends the adminis- cration of calcium salts, or milk, which is rich in calcium salts. He has sho\\Ti experimentally, and Edmunds f has confirmed the statement, that these salts will cure tetany. Thyroid and parathyroid grafting have both been undertaken in man for cretinism and tetany respectively, with the idea of reheving the patient from the necessity of taking drusfs all his davs. In a few cases success has resulted, but unfortunately the graft becomes absorbed as a general rule, and soon ceases to function. In a case recently described by Brown, of Melbourne, parath\Toid feeding and calcium salts both failed to reheve tetany in a patient who had been treated by a too extensive thyroidectomy for Graves' disease. The in-grafting of parath>Toid tissue from dogs and monkeys gave pronounced relief for about twelve days, but she relapsed after each * Journal of Experimental Med., New York, 1909, vol. xi, p. 118. t Journal of Path, and Bad., 1910, p. 288. 184 THE THYROID AND operation. Human parathyroid was then grafted, and the cure seemed to be permanent. I have seen a case apparentl}^ cured by the grafting of human parathyroid. We see also that exophthalmic goitre is due to hypersecretion, as is proved by the artificial imita- tion of the disease by excessive thjToid feeding, by the excess of iodine present in the colloid in Graves' disease, and by the character of the histological changes. Thus we have reason to expect good from partial removal, which has been very successful in the hands of Kocher, the Mayos, and others. More than half the gland needs to be excised. It would be reasonable also to try the effect of iodine starva- tion, by eliminating vegetables and ordinary tap- water from the dietary, and substituting for the latter the water of a goitre well. It is well known that exophthalmic goitre and parenchymatous goitre show a sort of geographical antagonism, and the effect of the water in reducing the amount of iodine available for conversion into iodothyrin would be valuable. Further, we are helped to understand and to recognize cases of iodoform poisoning, and to learn caution in the use of this drug on absorbing surfaces. It is safer in children than in adults, possibly because the thyroid in children contains less iodine. It ought not to be used in patients who have ever shown a tendenc}^ to thyroidism, lest acute poisoning or an attack of Graves' disease be precipitated. Finally, we obtain a clue at last to the remarkable rARATHVROID GLANDS 185 action of iodides in arteriosclerosis and gummata, and it is reasonable to hope that organic compounds of iodine, which cause acute thyroidism more readily than the alkahne salts, may be yet more effectual in stimulating the activity of the thyroid gland. In fact, thyroid extract itself may prove to be the best remedy of all. REFERENCES. Richardson, — The Thyroid and Parathyroid Glands. Philadelpliia, 1905, Hunt and Seidel. — " Studies on Thyroid", Hygienic Labor- atory Bulletin of Public Health, Washington, igog. Rendle Short. — Bristol Med.-Chir. Jour., 1910, p. 122. McCarrison. — Lancet, 1913, i. Noel Paton. — Jour. Exper. Physiol., 1916, x, pp. 203, 382. Johnson.. — Brit. Med. Jour., 1919, i, p. 335. Rowland and Marriott. — Quart. Jour. Med., 19 18, p. 289 Kendall. — Jour. Amer. Med. Assoc, lx\'i, 1916, p. 811. 1S8 CHAPTER IX, THE PITUITARY AND PINEAL GLANDS- STRUCTURE Or THE PITUITARY — THE EFFECTS OF REMOVAL IN ANIMALS INJECTION OF EXTRACTS PITUITARY FEED- ING ACROMEGALY AND GIGANTISM FROHLICH'S TYPE FUNCTIONS OF THE PITUITARY GLAND THERAPEUTIC VALUE OF PITUITARY EXTRACT — THE PINEAL GLAND. THE pituitar}^ gland consists of three portions, the pars anterior, which is epitheUal in structure, the pars intermedia, also consisting of epithelium and varying much in different animals, and the pars nervosa, made up of neuroglia cells and fibres. The pars anterior is glandular, consisting of columns of epithelial cells which in young animals may line tubules ; later the lumen disappears. It shows three different types of cells, with eosinophile, basophile, or chromophobe protoplasm, whereof the last are ordinarily few and inconspicuous, and do not take the stains. There may also be masses of basophile colloid between the cells, especially near the pars intermedia. According to Blair Bell, the eosinophile cells are the normal active secretory- cells, the basophile form a storage secretion, the small chromophobes are exhausted cells, and the large chromophobes, which are abundant in preg- nancy and may take the eosin stain faintly, are only met with when there is an excessive demand for pituitany'' secretion. PITUITARY AND PINEAL GLANDS 187 The pars intermedia is poorly developed in man, extensive in the dog and cat. It consists of epithelial cells, faintly basophile, with a good deal of colloid, which may be eosinophile or basophile. There is often a cleft separating the pars anterior and the pars nervosa. The whole gland, and especi- ally the epithelial parts, is very vascular. In the cat the pars nervosa has a central cavity opening into the third ventricle. The pars anterior and pars intermedia are derived from a pit in the dorsal wall of the pharynx ; the pars nervosa is budded out from the brain, and the stalk persists. All the ductless glands are studied by four methods. We have to find the effects, firstly, of removal in animals ; and secondly, of the injection or ingestion of extracts. We have, thirdly, to make chemical analyses of the extracts, to isolate any active principle. Finally, a clinical study of symptoms in man associ- ated with any abnormalities of the gland may be expected to throw a light on the problem, and the effect of treating these conditions will also need to be known. These are here set forth in the rational, not in the historical, order. It may be said at once that the active principle or principles have not yet been isolated. THE EFFECTS OF REMOVAL OF THE PITUITARY GLAND IN ANIMALS. It is so difficult to remove the organ from its well- concealed nest that the earlier published results 188 THE PITUITARY AND inspired no confidence. It was said that the animals died, but the injury to vital structures was necessarily great, and it has been remarked that the result would probably have been equally fatal if the operator had removed the dorsum sellae instead of the gland ! But the careful and repeated observations of Paulesco on twenty-two animals, and of Gushing and his co-workers on about two hundred dogs, have completely established confidence in the state- ments now before us. It is proved that removal of the anterior lobe alone, in dogs, produces just as much effect as removal of the whole gland, but that a removal hmited to the posterior lobe causes no symptoms at all. The animal, after a total removal, shows no deviation from the normal for a period varving from thirty-six hours to two weeks after the operation. Then it becomes unsteady, there is arching of the back, low temperature, shivering, and death in unconsciousness. Achsner, Handelsmann and Horsley, Morawski and others, find that death is by no means inevitable after enucleation either of the anterior lobe or the whole gland, and if we could be sure that they had not left part of the organ behind, the positive evidence of survivals must outv/eigh statements to the contrary. The carefully described experiments of Blair Bell confirm Gushing' s observations that removal of the whole gland or pars anterior is fatal, and removal of the pars nervosa innocuous. Gushing has found it possible to effect partial removals of the gland. In young animals, the result PINEAL GLANDS 189 is that an ' infantile ' type is maintained, and the secondary sexual characters do not develop. In older animals, the genitals atrophy, and they get very fat. He gives ver\' convincing photographs showing that these changes are quite marked. Blair Bell found very Httle change except drowsiness and a variable degree of atrophy of the female genital organs after partial removals of the pars anterior, but in two cases he obtained adiposity and genital atrophy in marked degree by compression or separa- tion of the stalk. One of his specimens is in the Museum of the Royal College of Surgeons. Probably the effect is due to interference with the blood-supply of the whole gland. Another consequence is a remarkable influence upon the metaboUsm of sugar. It is well known that removal of the pancreas causes gh'cosuria. Partial removal of the pituitary, on the other hand, causes an increased power of warehousing sugar in the body. In man, if more than 150 grms. of glucose ^are taken at a dose, some \\ill overflow in the urine. If the action of the pituitary was subnormal, judging by the results of animal experiments and a few observations on man, even a larger dose than this would not cause glycosuria. Stimulation of the superior cervical s\'mpathetic ganghon causes glycosuria in the rabbit, cat, or dog. This occurs if all do\Mi-running nerves, such as the vagi, are blocked, but is abolished by previous removal of the posterior lobe of the pituitary. These experiments (Weed, Gushing, and Jacobson) support the view that the pars nervosa has an internal 190 THE PITUITARY AND secretion that turns glycogen into glucose, and that this internal secretion is controlled by the sympa- thetic nervous system. There is some obscure connection, not only between disease or removal of the pituitary and the genital glands, but also between the pituitary and the thyroid. Thyroidectomy leads to all the signs of excessive activity in the pituitary. INJECTION OF EXTRACTS OF PITUITARY GLAND. PITUITARY FEEDING. Injection of extracts of the anterior lobe causes no evident results. Injection of extracts of the posterior or nen,"ous lobe causes quite constantly a prolonged rise of blood-pressure. Not only the blood- vessels, but all varieties of unstriped muscle, are stimulated to contract. Peristaltic movements are set up in the bowel, and the bladder and uterus, whether pregnant or not, also contract. Prolonged pituitary feeding in animals leads to great emaciation. It was originally stated by Schafer that young rats showed an exaggeration of growth when fed with this gland, but repetition of the experiment by himself and others does not con- firm this. Pituitary extract also stimulates the flow of milk in animals, but it is not yet proven that it does so in the human subject. It appears probable that the effect is merely due to contraction of the unstriped muscle in the nipple ducts squeezing out secretion. Extract of the pars nervosa is also a powerful diuretic. PINEAL GLANDS 191 CLINICAL RESULTS OF LESIONS OF THE PITUITARY GLAND. It is well known that the somewhat rare diseases acromegaly and gigantism are general!}^ but not quite invariably associated with enlargement of the pituitary gland, which has usually been a simple overgrowth, although later adenoma or fibrosis may have developed. Whether acromegaly or gigantism will result appears to be principalh^ a question of the age at which symptoms commence. If they have their onset before gro^vth ceases, gigantism will result. The skulls of most of the classical cases of gigantism, including Patrick O'Byrne, Hunter's famous giant, and Patrick Cotter, the Bristol giant, have enormous sellae turcicae to accommodate the enlarged pituitary gland. It is probable that giants usually suffer from acromegal}^ as well. There are two authentic casts preserved in Bristol of Patrick Cotter's hand, one of which is much larger than the other ; indeed, it is colossal, measuring 12 inches from wrist to finger-tips, whereas the earlier cast measures onh' II inches. His shoes, which are also preserved, are 15 inches long. It is therefore clear that although he was 7 ft. 10 in. high, his hands and feet were large out of all proportion, and that the hand rapidly increased in size between the taking of the first and second casts. The lower jaw was enormous, and out of all relation to the rest of the skull.* Cushing gives some striking photographs of a living * E. Fawcett, Jour. Royal Anthropological Institute, 1909, vol- xxxix, p. 196. 192 THE PITUITARY AXD giant, S ft. 3 in. high, showing enormous hands and feet. Associated with the enlarged bones of the face, hands, and feet seen in acromegaly, there are in some cases other features ; these are glycosuria, amenor- rhoea, impotence, and, in the young, failure of the secondary sexual characters. The temperature is subnormal. This train of symptoms will recall the effects of total or partial removal of the gland in animals. Not only the bones, but also the \iscera, may be increased in size in acromegaly : the kidneys, liver, pancreas, and even the auriculo-ventricular bundle of the heart. Frohhch and others have shown that there is another group of cases, totally distinct from acro- megaly, but again associated with tumours of the pituitary gland. These are characterized by excessive fatness, by infantile stature and development, by a childish type of the genital organs, and by absence of the secondary sexual characters. It may be that we shall yet find abnormahties of the pituitary gland in other varieties of infantihsm or of adiposity. Most cases of pituitary tumour which have been diagnosed during hfe have given additional evidence of their presence by involving the optic chiasma and causing bhndness of the nasal half of each retina. The skiagram shows enlargement of the sella turcica. In many cases there are headache, vomiting, and other signs of intracranial pressure. We must now attempt to classify our information, and endeavour to com.e to some clear conception of PINEAL GLANDS 193 the functions of the pituitary gland, and the causa- tion of these various types of disease. A year or two ago it was the prevalent opinion that the anterior and posterior lobes must be con- sidered to be entirely unconnected glands, having a different development, histology, and function. The posterior lobe was connected with the production of an internal secretion, probably in the colloid fur- nished by the pars intermedia, which was poured into the ventricular system of the brain, and extracts of this lobe raised the blood-pressure. There is some evidence that in acromegaly the anterior lobe is specially at fault ; it may be disproportionately enlarged, and may show a superabundance of secre- tion granules. Now, however, there is a tendency to unify the functions of the hypophysis and to regard it as one gland, although the distribution of the colloid is unequal in the various parts. Whether the gland is necessary to Hfe is unsettled. The diseases fall into two groups : those in which the internal secretion is excessive (hyperpituitism), and those in which it is diminished or absent (hypo- pituitism). Hyperpituitism is characterized by signs of acrome- galy in adults, or gigantism if it begins before growth has ceased. The gland is usually enlarged, showing microscopically a simple overgrowth. There may be glycosuria. The cases run a chronic course for years unless symptoms of cerebral compression come on. Hypopituitism produces the FrohHch type, with 13 194 THE PITUITARY AND atrophy of the genitals, infantiUsm, and excessive fatness. There is often a drowsy mental state ; indeed, one is tempted to believe that that very accurate observer, Charles Dickens, must have had such a case in mind when he invented the immor- tal Fat Boy in Pickudck. All these symptoms can be mimicked by partial excisions of the pituitary gland in animals. Cushing's results as to which lobe is at fault are discordant. Probably, as Blair Bell suggests, it is the whole gland that is at fault. It is true that cases of acromegaly may eventually develop impotence, sterihty, and amenorrhoea ; this is explained as hypopituitism succeeding an excess. The same sequence is seen in diseases of the thyroid gland. A very valuable measure of the function of the pituitary gland may be obtained by observations on the power of warehousing sugar. If the internal secretion is deficient, huge quantities of glucose will not cause gtycosuria. This is the cause of the adipo- sity. Hypopituitism is usually due to maUgnant growths encroaching on the gland, and is frequently followed by death. We are now in possession of some indications for treatment. For acromegaly and gigantism little can be done. Pituitary feeding does more harm than good. If there are symptoms of cerebral compression or gradually increasing bUndness from involvement of the optic chiasma, an operation may be performed to relieve pressure and remove part of the gland. Scores of cases have now been treated in this way (Gushing reports 43 operated PINEAL GLANDS 195 on by himself), and the mortahty is not high. Several observers record a definite shrinkage of the bones afterwards. THE USES OF PITUITARY EXTRACT. Patients suffering from the Frohlich type may be treated by pituitary feeding, the whole gland of cattle being used. The dose is about 12 grains a day, but Gushing sometimes uses as much as 100 grains three times daily. This may be worked out by its influence on the sugar tolerance. Remarkable results have been obtained in a few cases. If mouth- feeding is not successful, a dose of whole-gland extract may be given hypodermically every twenty- four hours ; this has proved very effectual some- times. If there are signs of intracranial pressure a decompression operation is indicated. The hope that pituitary feeding would prove to be a remedy for increasing the stature of small children is not likely to be realized in \'iew of the fact that Schafer has failed to verify his earlier observations on young rats. Feeding with the whole gland is also advised for certain cases of amenorrhoea attributed to hypo- pituitism. Unfortunately it is apt to cause severe headache. On the other hand, there is said to be a t^-pe of headache which is due to disorders of the pituitary and is often cured by administering the whole gland. This headache is frontal, deep behind the eyes, gives rise to great prostration, and there may be vomiting. It is commoner in women than men, and may coincide with menstruation. The pain 196 THE PITUITARY AND lasts half an hour to two days. There may be a craving for sweets. There may be coarse hair with male distribution in the female (Pardee). Pituitary extract, containing the principle found in the posterior lobe which acts on unstriped muscle, is now an ordinary article of commerce for many therapeutic purposes. It is a favourite remedy for surgical and toxaemic shock, and many observers are con\'inced that it does good by raising the blood- pressure. For reasons discussed in the chapter on surgical shock, I am not sure that pituitary extract is really of any value in this condition. A very valuable effect is that it promotes peristalsis even when purgatives fail or are vomited, as in cases of intestinal paralysis after abdominal operations. A third indication is to increase labour pains ; some- times in cases of weak pains the child is expelled very rapidly after an injection. It must not be used in obstructed labour, or the uterus may rupture. It is also given — is invaluable according to some — in daily intramuscular doses for menorrhagia of puberty or the menopause. It is a powerful diuretic. As a galactagogue its success so far has been doubtful. Pituitan." extract must not be given frequently at short intervals, or its effect may be reversed. The dried extract of posterior lobe may be given orally in 5 -grain doses, combined with calcium lactate, for micnopausal flushings, and with great benefit {Blair BeU). The dose of the 20 per cent extract used for intramuscular injection is i to 2 c.c. for shock or intestinal paralysis, and 0*5 c.c. for uterine inertia. PINEAL GLANDS 197 THE PINEAL GLAND. It has been customary to look upon the pineal gland as a developmental relic. The functionless unpaired eye of Hatteria, which appears to have been present, possibly in functional form, in some fossil reptiles, is supposed to be the substance of which the pineal gland is the useless shadow. It would be trul}^ extraordinary if we had to believe that a super- fluous relic had been handed down from the beginning of the Triassic period, throughout the whole family of the Mammalia, and still persisted in man. Some evidence has lately come to light which would lead us to add the pineal to the list of glands with an internal secretion. It is true that excision, feeding, and injection of extracts throw no Ught on the problem ; but histology shows that it contains in children glandular cells, which more or less atrophy in adults. Tumour of the pineal gland, in about a dozen recorded cases, has been associated with a remarkable precocity, including increased stature, premature development of the genital organs, growth of hair, and, in a few instances, an extraordinary mental vigour. One boy, at the age of five, dis- coursed learnedly concerning the immortality of the soul ! REFERENCES. C'JSHiNG. — The Pituitary Gland and its Disorders, 191 1. BiEDL. — The Internal Secretory Organs, 1913. KiDD. — Med. Chron., 1912, vol. xxiv, p. 15^. Blair Bell. — The Pituitary, igig. Pardee. — Arch. Int. Med., 1919, xxiii, p. 174. 198 CHAPTER X, OXALURIA. IT has been found very difficult to obtain reliable estimates of oxalates in the urine. The method commonlj' employed, introduced by Dunlop, is open to serious objections from the chemical standpoint. Working \vith O. C. M. Davis, the writer has used a new and, theoretically, more reliable method, but it is not claimed that the results are more than approximate. There is still, therefore, some differ- ence of opinion as to the metabolism of the oxalates, but the following conclusions are becoming generally accepted. In ordinary circumstances, the whole of the oxalate in the urine is derived from articles of food. Milk, meat, and bread contain scarcely any oxalate ; most vegetables contain it, and rhubarb, strawberries, and sorrel contain a relatively large quantity. I have by taking much rhubarb induced an attack of oxaluria sufficiently marked to cause a good deal of smarting pain in the urethra from the sharpness of the oxalate crj^stals. On a milk diet, oxalates disappear from the urine. This may be demonstrated by adding methylated spirit and allowing to stand, when any oxalate present in solution is precipitated in characteristic octahedra. On a milk diet, no such crystals will be obtained. OXALURIA 199 None of the ordinary derangements of metabolism causes the appearance of oxalates in the urine if they are withheld from the food. Thus there is no oxaluria in fever, in leukaemia (illustrating the katabolism of nucleoproteins), or in diabetes. In a case of oxalic acid poisoning under my care, the excretion was enormous, and there was a heavy deposit of calcium oxalate crystals. It is not, however, correct to say that oxaluria never occurs on an oxalate-free diet, though such a condition is rare. As is well known, the usual products of bacterial fermentation of carbohydrates in the bowel are various gases (CH,, CO.J, lactic, acetic, and butyric acids, and alcohol. Miss Helen Baldwin has pointed out that in certain abnormal circumstances oxalic acid also may be formed in this way. Copious feeding on sugar will ruin a dog's digestion, and then oxalates may appear in the urine even on an oxalate-free diet. Occasionally she has met with such cases in man. I have not chanced to observ'e such a case personally, and believe that they are not common. Fermentation of carbohydrates in the stomach and intestines to an excessive degree is common enough, but it is only rarely that there is any formation of oxalates. I have never been able to obtain the crystals either from the gastric contents or from the urine of patients with obstruction of the pylorus and gastric dilatation, on an oxalate-free diet. When ammoniacal fermentation of urine takes place, as on standing, any oxalate crystals present are rapidly dissolved and disappear. 200 OXALURIA The oxalate calculus is by far the most important variety occurring in the kidney. B. Moore has shown that a pure uric acid stone is found only in the bladder, and that all renal calculi are composed for the most part of calcium oxalate. Tliis is fortunate for the x-Ta.y diagnosis of the condition, and as it is comparatively easy to control the oxalate excretion, it makes it possible for us to advise the patient how to avoid a relapse after operation. To draw the practical lessons from our study, it is evident that any patient suffering from oxaluria should abjure the use of green vegetables, and fruits should be taken sparingly. If he is obeying directions, a fresh specimen of his urine, mixed with an equal amount of spirit and allowed to stand, will deposit only a few small crystals of oxalate, and a specimen without the addition of spirit will show no crystals even on centrifugaUzing. Occasionally, however, one may find a case in which oxaluria persists even on a milk diet. We must then restrict the sugars and starches of the diet, and give remedies calculated to diminish fermentation in the stomach and intestines. If patients object to dietetic restrictions, potassium citrate will often reUeve, both by acting as a diuretic, and by making the urine alkaline, thus dissolving the crystals. REFERENCE. A. Rendle Short. — Von Noorden's Metabolism and Practical illedicine, vol. i, p. 148. 201 CHAPTER XI. IMMEDIATE AND REMOTE POISONING BY CHLOROFORM. SUDDEN DEATH UNDER CHLOROFORM THE FATAL ADRENALIN- CHLOROFORM COMBINATION DELAYED CHLOROFORM POISONING. ENTHUSIASTIC advocates of chloroform as the ideal anaesthetic (usually hailing from the north) used to say, " Chloroform kills your patient to-day, and ether kills him to-morrow". They referred of course to the pulmonary complications which used to follow the use of the latter drug in the days when it was given by a Clover's inhaler through- out the operation, instead of by the open method. We are now finding out that chloroform too may not claim its victims until to-morrow. Chloroform may cause a fataUty in three distinct ways : first, by sudden arrest of the heart ; secondly, by poisoning the heart and \'ital centres in the medulla of the brain ; and thirdly, by inducing acute fatty degeneration of the viscera, and acidosis. We shall here only consider the first and third. SUDDEN ARREST OF THE HEART. Some of the most tragic calamities of surgical practice are due to sudden death from chloroform, and few and happy are the surgeons who have never seen it. Here we must place those cases where the 202 IMMEDIATE AND REMOTE patient is far from under, perhaps struggling and shouting, and then without warning draws a few deep breaths and dies. Here also, those who seem to be under, but whose heart and respiration cease on being hfted into position for the surgeon. Here, again, those who have been given a mere whiff of the anaesthetic for a trifling operation, and whose hfe ebbs away at the bare touch of the knife. Until recently, it was supposed that these fatahties were due to sudden reflex stoppage of the heart by way of the vagus, and that view was given in the first and second editions of this book. Very im- portant research work by Goodman Levy appears to demonstrate that the chloroform acts directly on the ventricular muscle, and causes it to fibril- late, that is, to enter into flickering irregular contraction of individual fibres, instead of per- forming its proper rhythmical systoles. Working with cats, Levy was able repeatedly to observe fatal ventricular fibrillation, usually heralded by cardiac irregularity, and always when the chloro- form anaesthesia was fight, not deep. Stimulation of sensory nerves under a fight anaesthesia frequently caused death in this way ; in other cases, the animal recovered. The effect was just the same if both vagi were previously cut. Levy found great diffi- culty in discovering exactly by what means the sensory stimulus affected the heart. The connection is probably complex. If the chloroform is given in a perfectly continuous manner without intermissions, sudden death — in cats at any rate — can be avoided. Struggling, both in man and animals, is dangerous. POISONING BY CHLOROFORM 203 An apology must be made for saying again what we all know, yet never can know too well. It is courting disaster to hurr^' the patient under. We must feel the pulse all the time, as well as watch the pupil and the respirations. ' Whiffs ' are far more dangerous than proper anaesthesia. No lifting, or cutting, or painful pressure is permissible until the patient is properly under. There is no danger of an overdose during quiet breathing if the mask is kept half an inch away from the face. If Levy's results are to be accepted, the mask must not be entirely withdrawn if struggling occurs, but every effort made to keep the administration constant. W'hat is to be done if the calamity is not success- fully averted, and the heart and breathing cease ? The books advise a dozen expedients. A moment's consideration of physiological principles will lead us to put most of them aside. How can amyl nitrite, which is simply a vasodilator, possibly help a heart that is fibrillating ? Strychnine and brandy are perfectly futile. It is no use gi\'ing oxygen to a patient who is not breathing. ' Galvanization of the phrenics ' is equally likely to galvanize the vagus. There are just four measures which matter. The first is to have the head low, so as to keep the \dtal centres aUve. The second is, of course, artificial respiration, which fills the auricles with blood as well as the lungs with air, averts death from asphyxia, and so gives the heart time to recover if it can. The third is to stimulate the heart to contract again by manual compression, if possible through the diaphragm. The fourth is to administer as quickly 204 IMMEDIATE AND REMOTE as possible atropine, which must be injected right into the heart by a long hypodermic needle.* Its value in overcoming chloroform inhibition has been abundantly proved by Dixon and others in dogs, and though its use in such cases in man is but recent, successes are already recorded. That there have been failures is admitted, but there is good reason to hope for recovery with immediate injection into the heart .itself. The most dramatic recovery I ever witnessed, in a patient who seemed already dead and in whom all other means had failed, was brought about in this way. There is ground for hoping, also, that a preliminarv' injection of scopolamine, now becoming popular for employ- ment before the administration of a general anaes- thetic, may help to eliminate these terribly sad occurrences. Several patients apparently passed beyond the shadowy Rubicon which separates the living from the dead have been brought back to Hfe by rapidly opening the upper abdomen and rhythmically squeezing the heart against the chest wall through the diaphragm. THE FATAL ADRENALIN-CHLOROFORM COMBINATION. In Bristol, it has been well recognized for ten or twelve years that the combination of chloroform anaesthesia with injections of adrenalin, as for * Acropiae solutions are apt to grow a mould which is very poisonous. If such a growth is observed, the solution must not be used. POISONING BY CHLOROFORM 205 instance into the mucous membrane of the nose to- check haemorrhage in a nose operation, is a pecuharly deadly association of remedies. There have been several fatalities, and a number of narrow escapes. Levy has done most valuable service in working out the subject upon animals, and in demonstrating that adrenalin has a peculiar power in bringing on the ventricular fibrillation which is the particular danger of a light chloroform anaesthesia. A number of deaths have now been recorded from this cause in medical literature. The adrenalin-ether combina- tion appears to be safe. DELAYED CHLOROFORM POISONING. The third danger from chloroform anaesthesia is subtle and unexpected, and we do not know how to treat its symptoms. It is well known that the katabolism of fats ia the body may follow an abnormal sequence when the amount of glucose supphed to the tissues by the blood is deficient. In these circumstances,, /j-oxybutyric acid, diacetic (or aceto-acetic) acid, and acetone are produced, and the patient is poisoned by the acids, while the acetone imparts a sweet odour to the breath and urine. Starved patients- and diabetics are particularly liable to this condition of 'acidosis' or ' acetonaemia', as it is variously called. Fat children and sufferers from peritonitis are frequently the subjects of acidosis after opera- tions in which chloroform has been used, and there is greater danger if there has been a long interval between the last feed and the anaesthetic. A pro- 206 IMMEDIATE AND REMOTE longed administration is more dangerous than a brief one. The train of symptoms is referred to as delaj^ed chloroform poisoning. A hospital of 200 beds may perhaps furnish one or two such cases annually, if chloroform is used frequently as the anaesthetic of choice. The signs are incessant vomiting, drowsiness or unconsciousness, and a sweet acetone odour in the breath. Acetone and aceto-acetic acid are present in considerable amount in the urine. A trace may often be found after any anaesthetic. Death follows within a few days. At the post-mortem examination the liver, kidneys, and other organs show signs of acute fatty degeneration. Whether this is the cause or the consequence of the acidosis may be in doubt, but the vomiting and drowsiness are almost certainly due to the effect of the acid intoxication on the brain. Most surgeons who are aware of the condition can recall sad cases where an operation promised well, but this fatal comphcation stepped in and banished all hope of a favourable issue. Recently it has been found possible to imitate the condition in experimental animals. To draw the practical lesson, we can at present hope only to prevent, not to cure. Every patient to whom it may be necessary to administer chloroform should be guarded as far as possible against this comph- cation. The urine should be tested with ferric chloride. A prolonged starvation should be avoided. Glucose and alkalies have been advocated as remedies likely to prevent trouble, and the former appears to be the better. If possible, ether should be given POISONING BY CHLOROFORM 207 to patients who have been starved, to fat children, and especially to patients whose urine strikes a red colour with ferric chloride. Diabetics require special care. If prolonged v^omiting follows recovery from the anaesthetic, the poison should be diluted by a large injection of saline into the rectum, which often works wonders. If acetone can be smelt in the breath, glucose or alkalies, or both, should be intro- duced into the blood by transfusion, but success is not very probable, as these remedies cannot restore the fatty liver and other viscera to normal. Whether the acidosis is the cause of the vomiting, or whether the starvation consequent on the vomiting causes the acidosis, is not yet certain, but we may safely attribute the drowsiness to the acids in the blood, and they probably share in bringing about the fatal termination. REFERENCES. Goodman Levy. — Brit. Med. Joiir., 19 12, ii, p. 62 7. Goodman Levy. — Heart, 19 13, June, p. 319. 208 CHAPTER XI I. THE FUNCTIONS OF THE SPINAL CORD AND PERIPHERAL NERVES. THE DOUBLE MOTOR PATH THE DOUBLE SENSORY PATH THE EXACT DIAGNOSIS OF SPINAL CORD INJURIES LESIONS OF THE POSTERIOR NERVE ROOTS — INJURIES AND REPAIR OF PERIPHERAL NERVES. IN this chapter, as in so many others, we shall find that the injuries sustained by the wounded in the great war have shed a light on problems of function, though the investigations we have first to describe savour more of civilian than military practice. THE DOUBLE MOTOR PATH. We had become accustomed to think and speak of a single path for voluntary movements, consisting of an upper motor neurone, the pyramidal Betz cells of the precentral cortex and the pyramidal tract fibres, and a lower motor neurone, the anterior horn cells of the spinal cord (or motor nucleus in the brain stem) and the medullated fibres of the peripheral nerves. There is now to be considered a good deal of evidence that the motor path is doubled throughout. It has long been suspected that the pyramidal tracts could not be the only motor path. Babies can move their limbs before the pyramids myelinate. FUNCTIONS OF THE SPINAL CORD 209 After a hemiplegic stroke, certain stock movements such as standing and walking may persist, although the fibres of the pyramidal tracts may be almost entirely destroyed. In animals, as is well known, quite extensive lesions of these tracts or of the motor cortex do not produce lasting paralysis, even in the chimpanzee. Thromboses spoiling the arm centre, or the face centre, in man, give rise to paralysis, but there is often a remarkable degree of recovery of function later. In old hemiplegias, voluntary movement of the sound side may be accompanied by involuntary movements of the hemiplegic limbs. Similar movements may be obtained in the cat or chimpanzee by stimulating the red nucleus area. In the foetal cat the movements resemble those of walking (Graham Brown). The phenomena of spasticity point in the same direction. It is well knov/n that after a hemiplegic stroke due to a lesion in the internal capsule there is marked rigidity of the paralyzed side. Also in any animal a transection of the mesencephalon brings on a state of * decerebrate rigidity/ the limbs becoming as stiff as if frozen. A second transection below the fourth ventricle abolishes this rigidity ; a hemisection abolishes it on the side divided. Division of the posterior nerve roots of a limb sets that limb free from the rigidity. Evidently, there- fore, there is another innervation for the muscles besides that due to the pyramidal tract, and a re- flex arc responsible for producing the spasticity. The researches of Sherrington, Thiele, Weed, and Bergmark seem to indicate that the path for the 14 210 THE FUNCTIONS OF THE SPINAL reflex is as follows : posterior nerve root, tract of Gowers, cerebellum, superior cerebellar peduncle, red nucleus, rubrospinal tract. Section of any of these tracts will abolish decerebrate rigidity. Lesions of the inferior cerebellar peduncle do not influence the spasticity'. The pyramidal and frontopontic and temporo-occipito-pontic tracts inhibit muscular tone. A pure cortical lesion frequently causes a flaccid paralysis, whereas a lesion of the internal capsule gives rise to spasticity, because in the latter case all the inhibitory tracts are likely to be involved, whereas a pure lesion of the precentral cortex spares the corticopontic tracts. We find, then, two motor paths in the brain-stem and spinal cord : — • 1. The pyramidal tract, descending from the cerebral cortex, controlling finer and more skilled movements, inhibiting muscular tone. 2. The rubrospinal tract, descending from the red nucleus (probably influenced by the lenticular nucleus), controlhng stock elementary movements, and exaggerating muscular tone. Perhaps the various anterolateral descending tracts (vestibulo- spinal, tectospinal, and the like) share in the function. But it is not only in the central ner\^ous system that evidence has been found of a double motor path. Ramsay Hunt has some interesting observa- tions to bring forward pointing to a double path in the motor nerves. There are, for instance, end-plates in striped muscle of non-medullated as well as of medullated nerve-fibres (Boeke), and Ransom has CORD AND PERIPHERAL NERVES 211 shown by his silver-pyridine method that the peri- pheral nerves contain a lot of non-meduUated fibres. Striped muscle itself contains two elements ; each fibre consists of a great number of cross-banded sarcostyles packed in sarcoplasm, as though a bundle of cross-striped pencils were put into a cylinder-glass containing treacle. In muscles designed for rapid action the sarcostyles predominate ; in muscles where long, slow contraction is needed there is relatively more sarcoplasm. The sarcoplasm (corresponding to the treacle) is itself contractile. The suggestion is that there is an older, simpler mechanism, consisting of rubrospinal tract, fine and non-medullated nerve- fibres, Boeke's end-plates, and sarcoplasm ; and a newer mechanism capable of greater quickness and higher control — the pyramidal tract, coarse medul- lated nerve fibres, ordinary motor end-plates, and sarcostyles. In the intercostal nerves, fine fibres are in excess ; in the brachial plexus, coarse fibres. Some curious phenomena in the healing of nerve lend support to the hypothesis. Ramsay Hunt describes cases in which after suture there was a period during which muscular tone and associated movements had returned, but voluntary power had not yet been recovered ; indeed, in certain cases of musculospiral palsy it never did recover. The facial nerve shows this phenomenon best. There may be recovered tone, and even spasm, vnth restoration of such symmetrical movements as smiling, long before return of voluntary movement. The finer and non-medullated fibres have presumably regenerated before the coarser. 212 THE FUNCTIONS OF THE SPINAL THE DOUBLE SENSORY PATH. The researches of Head and his fellow-workers have shown that peripheral sensation may be grouped under three headings : — 1. Epicritic sense, including localization, light touch, and slighter variations of temperature. 2. Protopathic sense, a more elementary mechanism, preserved in the glans penis, and made evident after certain nerve-injuries, recognizing pain, and greater variations of temperature. 3. Deep sensibility, appreciating deep pressure. Probably there are three different nerve-fibre paths subserving these functions. In the spinal cord, however, a new grouping takes place ; heat, cold, and pain sense travel by one route, and stereognosis, tactile discrimination, and kinaesthetic sense (sense of weight, and sense of position) by another. An interesting investigation has just been pub- lished by Ransom throwing some light on the way in which this re-grouping occurs. The bulk of the fibres in a spinal posterior nerve-root are non- medullated, only shown by special stains ; they have the usual cell-station in the posterior root ganglion, and the axon shows the T-shaped bifurca- tion. The centripetal branch of these non-meduUated fibres enters the tract of Lissauer, and immediately plunges into the grey matter of the posterior horn. There are thus inner and outer divisions of the entering posterior nerve-roots ; the inner medullated fibres enter the columns of Burdach, and the outer non-medullated enter the gelatinous substance of CORD AND PERIPHERAL NERVES 213 Rolando, Section of the outer division abolishes the evidences of pain such as strugghng, the pressor vasomotor reflex, and quicker breathing, in the lightly anaesthetized animal, when the sensory nerves are stimulated. Section of the inner root has no such effect. It is suggested, therefore, that the outer non-medullated root is the path for pain and temperature sense, and that the inner medullated root is the path for muscular sense, stereognosis, and tactile sense. As already remarked, there is a double sensory path up the spinal cord. Leaving out of considera- tion those tracts (the dorsal and ventral cerebellar, etc.) which do not carry up messages to the centres for consciousness, and also leaving out of account the possibility that sensory impulses may be trans- mitted up the grey matter of the cord with its short endogenous connecting fibres, there remain two main ascending tracts. These are : — 1. The posterior columns of Gcll and Burdach, whose axons are derived from the entering posterior nerve-roots, which run uncrossed up to the gracile and cuneate nuclei ; and 2. The spinothalamic tracts, arising in the cells of the posterior horn, mostly of the opposite side, running up in the tract of Gowers, joining the mesial fillet in the brain-stem, and ending in the optic thalamus. The messages conveyed by the columns of Goll and Burdach are also carried on to the optic thalamus, by way of the mesial fillet. According to our present interpretation, which has 214 THE FUNCTIONS OF THE SPINAL to be based almost entirely on human evidence because animals cannot explain their feelings, pain and temperature sense are conveyed by the spino- thalamic tract, whereas muscular sense, joint sense, and tactile discrimination — by which we distinguish whether two compass points are double or single — ^pass up the posterior columns ; the sense (stereognosis) by which we recognize unseen objects by the feel — as on putting a hand into a pocket containing coins, keys, a penknife, paper, etc. — also travels by this route. Thus we find that whilst muscular sense, stereo- gnosis, and tactile discrimination pass up the cord uncrossed, heat, cold, and pain senses cross, and there is a cell-station in the grey matter. Pain crosses at once ; temperature and tactile sense usually about five segments above. Hence syringo- myelia and other lesions of the grey matter abolish temperature and pain sense. Sherrington has shown that the pain impulses are not totally crossed ; a few pass up on the same side. Tactile sense, apparently, can follow either of these two routes. The diseases which throw most light on these problems are tumours of the spinal cord, and syringomyelia. A tumour of the spinal cord : — 1. May affect the nerve-roots, in which case the symptoms may be confined to those roots. 2. May press on one side of the spinal cord. In this case there is usually pain radiating along the nerve-roots involved at the same time, which is important in the diagnosis. CORD AND PERIPHERAL NERVES 215 Let us take the case of a tumour in the left lower cervical area. This will involve : — (i). The emerging roots of the lower cervical nerves on the left side, causing pain, dulling of sensation, and flaccid paralysis with loss of reflexes, wasting, and reaction of degeneration, in the left arm. (ii). The pyramidal, ruhrospinal, and vestibulo- spinal tracts on the left side causing paralysis of the left le,(?. Inasmuch as the pyramidal tract is involved, muscular tone will be greatly increased. There will be, therefore, rigidity of the left leg and exaggerated reflexes. (iii). The cerebellar tracts and posterior columns of the left side, causing loss of muscle and joint sense, and loss of tactile discrimination and recognition of objects on the left side. Table to Illustrate the Effects of a Tumour OF THE Left Lower Cervical Region. Right Arm. Normal. Right Leg. Loss of sense of heat, cold, pain. Left Arm. Pain. Some anaesthesia. Flaccid paralysis, loss of reflexes, wasting. Left Leg. Loss of muscular sense, joint sense, tactile discri- mination and recognition of objects. Spastic paralysis ; exaggerated reflexes. (iv). The spinothalamic tract, by which heat, cold, and pain travel up from the right leg, will also be pressed upon. 216 THE FUNCTIONS OF THE SPINAL Tactile sense may not be lost in either leg, as a double path, the one crossed and the other uncrossed, is open to it. 3. It may arise in the central grey matter. In this case there will be loss of the heat, cold, and pain senses on both sides, but tactile and muscular sense will remain. There may be some spastic paralysis of both legs. In the early stages the diagnosis from syringomyelia may be only a matter of opinion. 4. In some cases it may produce bilateral spastic paralysis with involvement of the sphincter func- tions and with ansesthesia wdthout any dissociation phenomena. The diagnosis from transverse myehtis or vascular lesions is then ver^' difficult. Each of the thirty-one nerve roots issuing from the spinal cord has a definite distribution, which may be motor, sensory, and visceral, and these have now^ been ascertained with some accuracy by a com- bination of anatomical, physiological, and clinical methods. As given in the various text-books and monographs, the information is a good deal more than most of us can carry conveniently in our memories. It is hoped that the bare elements set down in the table may be found easier to remember, and adequate for most purposes. Xo two accounts agree exactly. The main points may be emphasized first. With regard to the sensory distribution, there is a good deal of overlap, especially in the hand, where the seventh cer\dcal supplies the radial half, the eighth cervical the inner half, and the first dorsal the one and a half fingers to which the ulnar nerve may be CORD AND PERIPHERAL NERVES 217 traced. The twelve dorsal nerves supply the chest and abdomen in bands like successive strips of plaster stretched round the body ; the nipple lies between the fourth and five dorsal, and the umbilicus between the ninth and tenth. If we place the open hand on the thigh just below and parallel to Poupart's ligament, we cover the first lumbar area ; the next handbrcadth below is the second lumbar, and the next, including the region of the patella, is the third himbar. The small sciatic nerve area corresponds to the second sacral, and the internal saphenous nerve area to the fourth lumbar segment. With regard to motor distribution, the fifth cervical supplies the deltoid + biceps -r- supinator longus group, as weU as the dorsal scapular muscles and rhomboids. In infantile palsy and other anterior horn or nerve- root affections, these muscles may be found paralyzed and atrophied in company. On the other hand, a fracture of the spine irritating this segment brings about a characteristic position of the arms | . The first dorsal gives off sympathetic branches dilating the pupil. The anatomy of the lumbosacral plexus makes it easy to remember that the quadriceps and adductors must be supplied from the lumbar ner\'es, whereas the hamstrings and crural muscles are innerv^ated from the sciatic roots. There is a general tendency for flexors to derive their nerve-supply from a level slightly below that for the extensors. It is easy to see why this should be the case if we glance at a quadruped, where the flexors are posterior to the extensors. 218 1^ O I— t H w H CO < H w ;^ o w CO t-H CO O W PQ < TH E FUNCTIONS OF THE SPINAL "w" ^ , , CO ^ 2 2 I1 3 0 < ft! U.2 1^ 5 ^ "Eh a, u u '? 13 -4-1 .2i 13 •♦J > C3 ^^ 6 'u 'C C rt S3 o5 c3 hi) u U* 0- a £ G s . , . , -^ ?^ 5j -M -M 05 CO 05 ■v4 H K C . g 0 c rt c5 1-1 v^ <5 o^ii 05 0 < • - C33 HH ^ •§-i 0 13 > T3 0 M-l *-^H ^ OJ '^ c 4:5 0 05 0 13 0 'H "5 l-c G G CO 0 P. Ph rc; 13 ^^' 0 0 ^ 0 ^ 3 0 ,G u 0 13 o5 oJ a 5 Jl t— 1 G 0} « - ^ 6 oj -a c 2 • • • in ex -J 05 O • - a. 2 "3 0 -t-i I • • 5 CO OJ w •s ^ 0 lg ^ % 6 ^ S3 ^ ox; 0 0 -M c3 0 0 w m 0 l-l t/^ 0 3 '0 CO g -d 13 8 0 0 0 0 0 -4-> +J -t-> J3 f3 -.J g£ o5 ^ ^ Q s E ffi t— ( Q 0 • • • • • • • Q u H-T > o t-H 1— 1 ^ CJ u > lo 0 d CJ ►-T I— t Q Q •—( > #, hH 1— < t— 1 •» '-H 1— 1 > > > > »— t CORD AND PERIPHERAL NERVES 219 |2 > ^ O ^ •r. ^ 3 If \-t — n5 > S-y fi u v-T ■M < a 4> 4) J2 !2 ji E rf 6 3 ■*■> u 'C o 3 -«-> ■-; i-i o 03 tfl 3 "^S t/3 '^ r^-^ Uh > C^rt ::h O -4-> O t^ o „QHf=^ aJ 2 3 O Ph Pu ■4-> C/J ''^ r- '2 G •d c o: Ph •< P4 1 c ctf O o rt -t-> ■J) o a o 13 o c "d O O o il fe U3 1 5 03 bc •2 o3 bo oj to r-* rt • • c •- 73 o o 6 C/5 Oh o . » '♦^ o . o rt CO u 9 c t-H to o o ■—1 o o o T3 b£i (O 66 O u IS ■4-> i o -t-J • en a a o -d CD s c 6 03 O P 3 ^« 2 -2 O 3 .9 "^ -d 03 C/3 p- o 'u 'd en o3 "o -t-> rt o 03 • -"o o o SH o CO to 3 o c« 3 C 03 G 0) d t— t < < I— ( § >J o Ph ' • • ■ • • • • • • c/j V. a S d Q d t-H ►-5 > o t— 1 1 > 1 > 1 X t— 1 t— t > en C/3 »— 1 > r-i 1— t 220 THE FU>XTIONS OF THE SPINAL Flaccid paralysis and anaesthesia of the lower limbs, with sphincter trouble, may be due to a tumour growing either in the cauda equina or in the conus medullaris of the cord itself. The diagnosis is often difficult, but tumours of the cauda are usually characterized by a slower course, asymmetry, very violent pain, and Lasagne's sign — pain on flexing the thigh and thus pulling on the nerve-roots. Operative interference gives better results in these cases than in those where the cord itself is affected. In a few cases recently recorded, where section of posterior nerve-roots had failed to relieve pain, a surgeon has divided the pain-path in the antero- lateral region of the cord. To give success, this should be done on both sides, although by far the greater number of pain-fibres are crossed. Sherrington worked out the path by dividing the mesencephalon in dogs, after which injury they still turn and try to bite and growl if a foot is hurt, although they cannot, of course, psychically feel it. If then the spinal cord is hemisected on the right side, painful stimuli applied to the right foot produce much livelier snapping and growling than the same on the left side. Souttar has recorded a case in which he divided the right anterolateral region of the cord in the upper dorsal region for unilateral left-sided gastric crises of tabes. The pain was completely abolished, but not the vomiting. No paralysis resulted. Pain sense in the left leg was abolished ; tactile, muscular, and joint sense remained. Strange to say, tempera- ture sense also remained unimpaired. Although CORD AND PERIPHERAL NERVES 221 pain sense crosses almost at the level at which it enters, and temperature sense several segments further up, one would have expected all the messages entering in the lumbospinal region to have got across before reaching the upper dorsal level. Great heat was interpreted as pain. THE EXACT DIAGNOSIS OF INJURIES OF THE SPINAL CORD. The following lesions of the cord may be responsible for symptoms of paralysis or anaesthesia after an injury to the back. 1. Simple concussion, the injuries being micro- scopical or functional only, and the paralysis transient. 2. Complete division of all the nervous elements. 3. Pressure on the cord, due to bone, callus, or a foreign body, not causing a total transection. 4. Haemorrhage into the spinal membranes. 5. Haemorrhage into the cord itself. 6. Later compHcations such as myelitis, traumatic neurasthenia, etc. This is not the place to consider all these in their surgical bearing. We want to look at them in relation to the physiology of the spinal cord. Both in man and in animals, particularly monkeys, a transverse injury to the cord leads to the pheno- menon known as spinal shock. All the reflex functions are severely depressed, and there is transient paralysis and anaesthesia. Sherrington has showTi in animals that a transection, e.g., in the upper dorsal region, causes spinal shock only distal to the lesion ; the cervical cord is normal. If after- 222 THE FUNCTIONS OF THE SPINAL recovery has occurred a second section is made in the mid-dorsal region, no spinal shock is produced. Evidently it was due to the withdrawal of impulses running downwards from the brain-stem, probably from the region of Deiters' nucleus, because tran- section of the upper pons or mesencephalon does not cause spinal shock. Considerable difficulty may be experienced for a day or two in deciding whether a patient is suffering from a complete division of the cord due to the nip at the moment of fracturing the spine, or whether the symptoms are due merely to concussion. In the latter case a few da^^s' rest will effect a cure. Sometimes one can get a hint earlier. If the distri- bution of the paralysis does not correspond to the distribution of the anaesthesia, and if the sym- ptoms are asymmetrical, it is probable that they are due partly at least to concussion. Spinal shock resulting from a complete transection in animals is very transient. In frogs it lasts a few minutes, in cats and dogs a day or less, in monkeys not much more. In a series of wounded men whose cords had been divided by gunshot injury, if the patient was carefully looked after, shock passed oft in one to three weeks. In such cases there are three stages distinguishable : — 1. Period of spinal shock, with absent reflexes and paralysis of the bladder. 2. Period of recovery ; reflexes returned, and bladder empties itself automatically when full. 3. Period of terminal failure, when the isolated segment of the spinal cord suffers, from toxic CORD AND PERIPHERAL NERVES 223 degeneration or myelitis, and reflexes again fail, with paralysis of bladder, great wasting of the legs and reaction of degeneration, and trophic changes. Sometimes the period of recovery is absent, especially if the patient becomes infected ; this used to be described as the normal in man when the cord is completely divided, but it is now abundantly proved that there may be well-marked recovery of reflexes and spasticity even with an absolute tran- section. It is frequently impossible from the symptoms and physical signs to decide whether the injur^^ to the cord is complete or incomplete. Of course, if any sensation persists, or any true voluntary control, some tracts must still be left. Even in the absence of any sensation or voluntary control in the parts below the injury, Riddoch has put us in possession of a sign that may sometimes be of value. It used to be taught that if the legs were rigid and showed reflexes, the transection was incomplete. This is not true. The spasms that may be reflexly elicited in a case of complete transection are, however, always flexor, never extensor. If extensor reflexes or movements of progression can be obtained, as by pricking the thighs or drawing the prepuce over the erect penis, the lesion of the cord is incomplete. The practical point of course is that with an incomplete injury it is well worth while to operate to remove pressure ; if the conducting elements are totally divided, operation is useless. The flexor spasms of the thighs elicited by stroking 224 THE FUNCTIONS OF THE SPINAL the inner side are often accompanied by reflex emptying of the bladder. This may aid in keeping the patient dry, by getting the urine evacuated regular!}' without needing a catheter. Marked wasting of the legs generally means a complete transection and a hopeless prognosis. Lesions of the cauda equina may wiseh' be explored, because suture of the roots or removal of pressure may lead to regeneration. Haemorrhage into the spinal membranes produces pain and spasm by involving the issuing nerve-roots. In addition, there will probably be some evidence of pressure on the cord, producing spastic paralysis and some anaesthesia below the lesion. Haemorrhage into the centre of the cord sometimes abolishes the pain and temperature senses while tactile sense escapes. There will probably be spastic paraplegia as well. It will not be necessary to refer here to the diagnosis of the later complications, such as myelitis and the various neuroses. Unfortunately the central nervous system is so highly specialized that it has lost the power of regeneration after injury, not only in man (unless we accept the evidence of the famous Stewart-Harte case I) but also in nearly all animals. The newt, it is true, can form a new cord if its tail is lopped off, but the newt has marvellous powers of regeneration, and can even grow a new lens if the front of its eye is removed ! Histological evidence of partial regenera- tion has been obtained in mammals by Marinesco and others, but not functional restoration. CORD AND PERIPHERAL NERVES 225 THE EFFECTS OF DIVISION OF THE POSTERIOR NERVE-ROOTS. The effects may be classified as follows : — 1. Anaesthesia of the spinal area of skin supplied. The distribution of these in the human subject has been worked out thoroughly, and the charts of Head, Sherrington, and others are well kno\NTi. Section of a single nerve-root scarcely ever causes any complete loss of sensation. 2. Ataxia of the corresponding limb, which may be severe. 3. Loss of tone, leading to marked fiaccidit}' of the corresponding limb. 4. A variable degree of functional paral^'sis. Owing to the loss of sensory impulses, the ataxia, and lack of tone, the patient, man or animal, prefers not to use the limb, although there is not a genuine paralysis. 5. Loss of reflexes. 6. Trophic lesions, such as ulcers, whitlows, etc. It has recently been shown by Eloesser that bone and joint diseases similar to the Charcot joints of locomotor ataxia can be produced in cats by dividing" all the posterior ner\-e-roots to a limb and then bruising or crushing the joints. Similar treatment of the joints on the side \\ith sensory nerves intact gave rise to no such changes. Extensive and grotesque departures from the normal were secured in some of the animals. 7. Usually not shock. This is rather surprising. I have taken the blood-pressure in two patients whilst four or five nerve-roots in the lumbar and 15 226 THE FUNCTIONS OF THE SPINAL sacral plexus were cut on each side, and there has been no sudden fall. There was a steady drop throughout the whole operation (under open ether anaesthesia) amounting to less than eight millimetres of mercury. 8. Certain degenerative changes. The posterior columns of the spinal cord show Wallerian degenera- tion running up to their termination in the gracile and cuneate nuclei of the medulla. As Warrington has pointed out, in animals the cells of the anterior horn on the same level as the severed roots show signs of chromatolysis, or dissipation of their Xissl granules. I have recently been able to demonstrate this in man. A patient who had been treated for gastric crises by resection of the posterior nerve- roots from the seventh to the tenth dorsal, died about two months afterwards. In the cervical region aU the nerve-cells were normal, but in the region of the divided roots more than half the anterior horn cells, and all the cells of Clark's column, showed marked chromatolysis. This is interesting in the light of the various affections of the motor functions just mentioned. The surgery of the posterior nerve-roots is yet in its infancy, but it promises to have a future. When it is resorted to earlier, it will most probably have a greater value. There are two main indications for dividing the posterior nerve-roots. The one is pain, and the other extreme rigidity in the course of spastic paraplegia of hemiplegia. The pain may be due to such a cause as the crises of locomotor ataxia, or the agonies CORD AND PERIPHERAL NERVES 227 of inoperable cancer. It is more successful for the latter than for the former. When many roots are cut for spasticity, it is necessary to leave one or two intact, or a very decided amount of ataxy may be induced. The relief of adductor or other spasm is often very marked, if it has not become permanent in con- sequence of fibrous shortening of the muscles and tendons. INJURIES AND REPAIR OF PERIPHERAL NERVE. The terrible frequency of nerve injuries in the war has given a fresh impetus to the study of these problems, and a number of valuable researches have been published on the histology of regeneration and on other points. One of our greatest difficulties has been to obtain reliable evidence, before operation, as to whether a nerve presenting all the signs and symptoms of complete division (paralysis, anaesthesia, and the like) was as a matter of fact cut across, or partly divided, or merely bruised or shocked. We found that a bullet passing near but not through a nerve frequently gave rise to a temporary paralysis of all its functions. If the electrical reactions remained normal (beyond the first ten days), a speedy recovery might be expected, but in very many cases there was reaction of degeneration just as in a case of anatomical severance, yet the functional nature of the injury would be proved by spontaneous cure in a few weeks' time. Electrical testing has its 228 THE FUNCTIONS OF THE SPINAL limitations. Occasionally normal muscle shows A.CC. greater than K.C.C. In practice therefore, in such doubtful cases, it became customary to wait about three months to give nature every chance. Another advantage of waiting was that it gave time for the wound to become sterile. Only too often we had to wait not months but years to secure asepsis, without which nerve suturing is foredoomed to failure. It is an interesting question just when this waiting rule ought to be applied to nerve injuries in civilian practice. Even after three months, natural recovery is not hopeless. A musculospiral case of mine, with complete electrical reactions of degeneration, got well quite suddenly after nine months without operation. In some of these patients there probably was an anatomical division, but the two ends of the nerve, being in apposition, united spontan- eously. A new test has been introduced by Tinel, called ' distal tingling on percussion', or D.T.P., intended to help clear up the diagnosis in these cases. If, shall we say, the ulnar nerve is divided in the middle of the upper arm, and, after several months, tapping the ulnar trunk behind the internal condyle at the elbow sends a tingling sensation down the arm to the little finger, it certainly suggests that new nerve fibres have grown down as far as the elbow. In practice, however, I have found the sign gravely misleading more than once. The tapping may be transmitted by pulling on the end of the nerve above the injury ; also, one has to be sure CORD AND PERIPHERAL NERVES 229 that the patient has not discovered that if he says he feels the tinghng he may be let off operation ! The only reliable test is to explore the nerve and stimulate the trunk with the faradic current above and below the lesion. If it conducts, it will recover ; if it does not, the scar should be excised and the two ends sutured. Pain and mottling of the skin are often more marked in cases of partial than complete division of a nerve. The old controversy as to the method of nerve- regeneration is now definitely settled in favour of the view that the new nerve-fibres formed after suture are budded out from the cut central end. It will be found that new medullated fibres are present only in the proximal part of the regenerating nerve at first, whereas at a later date they reach the peripher>\ Only a few millimetres may have regenerated in a month. It has recently been shown, by Perroncito, that the fine fibrils which constitute the axis cylinders of the central end commence to grow, curl, bud, and branch within a few hours of the injury, apparently ' feeling for ' the old track. Mott and HaUiburton have shown that if a nerve is cut and sutured, and time allowed for regeneration, after a second section at the same place the new medullated fibres peripheral to the injury all degener- ate. Had they been developed in situ by the activity of the sheath-cells, one would not expect degeneration after the second section, because they would not in that case have been cut off from their centre of origin. The deduction is that the new fibres were derived from the central end. 230 THE FUNCTIONS OF THE SPINAL Convincing proof has been advanced by embryo- logists that the nerves in the embryo are not formed in sitii, but are budded out from the nervous elements of the brain and spinal cord. By removing the medullary groove in frog embryos and planting it in lymph-clot, Ross Harrison has actually observed the developing nerve-cell grow out its axon at the rate of 20 fx in twenty-five minutes. The outgrowing axon is activety amoeboid. He was able also, by destrojdng the ventral part of the developing spinal cord, to obtain tadpoles in which the muscles had no motor nerves. If it is allowed that in the embryo the nerves grow out from the central nervous system, the theory of central regeneration is placed upon a strong basis. Two questions of great interest have recently received answers. First, Why does the medullary sheath of a nerve-fibre break up into fatty droplets when it is cut off from its trophic centre, that is from its cell of origin in the central nervous system ? Second, How does the budding axis cylinder of the central end of a divided nerve manage to find its way so accurately along the old path ? The questions are intimately related. Each fur- nishes the answer to the other. The medullary sheath breaks up that it may liberate the chemical substance which attracts the sprouting axis cylinder. The new fibre follows the old path, because of the chemical attraction along that path. Nature is full of analogies to this process of chemi- cal attraction. Chemical particles, though infinitely diluted with air or soil, attract the vulture to the corpse in the desert, or the bloodhound to the hunted CORD AND PERIPHERAL NERVES 231 i criminal. Smell is only a chemical analysis. Simi- larly, the leucocytes crowd out of the vessels to an inflamed area, in obedience to a law of chemical attraction. If two celloidin tubes are presented to the central end of a divided nerve, the one containing emulsion of liver, and the other emulsion of brain, all the sprouting fibres pass into the brain emulsion, none into the tube containing liver (Forssman). The disintegration of the nervous matter lays down a line of bait to entice the regenerating fibres along paths of usefulness. The phenomena of repair after suture next call for remark. It may be said at once that the sooner the operation is performed the better will be the results. If the muscles have ceased to contract to any form of electrical stimulus, operation is useless. It is very seldom that benefit will be obtained if two years have elapsed since the injury. Wlien secondary suture fails to give a good result, the fault lies not with the degenerated nerve-fibres so much as with the nerve- cells in the spinal cord. If asepsis is secured, accurate primary suture seldom if ever fails. Sherren, before the war, gave average time relations as follows : — 5-25 weeks : Commencing return of protopathic sense. 6-12 months : Complete return of protopathic sense. 12-18 months : Return of epicritic sense. 12-24 months : Motor recovery. 232 THE FUNCTIONS OF THE SPINAL Taking the ulnar nerve as an example, recovery may be hoped for in twelve months when it has been divided at the wrist, or in twenty-four months when the injury was at the elbow. These figures are rather on the slow side, judged by our experience during the war. According to Burrow and Carter the average for the ulnar nerve (327 cases) was nine months ; sensation was never perfectly restored. The musculospiral began to improve in seven to eight months ; complete recovery was seen about the fifteenth month. In cases of median nerve injury (242 cases) the forearm flexors were restored in eight months, and the intrinsic muscles of the hand in fourteen to twenty months. There is a good deal of variation, for some unknown reason, amongst the different nerves. The musculo- spiral recovers quickly and well after operation. The ulnar and sciatic, especially the internal popliteal, are relatively slower and less perfect. It is apparently an advantage in healing that a nerve should contain principally motor fibres and not motor and sensory mixed, because there is so much the better chance of the down-growing motor fibres finding their way to muscle and not to skin. In general, trophic and vasomotor recovery is the first to appear, then deep sensibility, then sensa- tions of roughness and pressure pain. Radiating and ill-localized sensations referred to wide areas come next, then these give place to sensibihty to light touch. By this time motor power is generally returning ; it may come quite rapidly within a few days, and usually before the electric responses have CORD AND PERIPHERAL NERVES 233 returned to normal. Stereognosis returns late if at all. Durin^^ recovery, a remarkable phenomenon has been described by Trotter, who had nerve sections performed upon himself. Any stimulus over the cutaneous area affected, gives rise to a decidedly painful sensation, referred usually to the most distant part of that area. Recovery after incomplete division of a nerve is more rapid, usually taking less than six months for sensory restoration ; it is perhaps a year before motor power is normal. Protopathic sense does not return before epicritic, as it does when the nerve is completely divided ; they are restored side by side at an equal rate. The last point we shall consider is how best to proceed when so much nerve has been lost that the ends cannot be got together. Many methods have been adopted, some of which are of little or no value and should be allowed to drop out of use. Amongst these may be mentioned the introduction of a bridge of silk or catgut, or of nerve derived from a cat, dog, or rabbit (which will undergo dissolution), and the device of splitting the nerve longitudinally and turn- ing down one-half across the gap. It is quite evident why these fail. The silk, catgut, and probably the animal's nerve, cannot provide the necessary chemical attraction for the down-growing nerve-fibres. The splitting ' en-Y ' does not lay down a continuous ' scent ' along the tract ; it is broken at the stem of the Y. Better results may be obtained by suturing into the interval a length of human nerve. This 234 THE FUNCTIONS OF THE SPINAL may be obtained from an amputated limb, but it is always possible to excise several inches of some unimportant nerve such as the internal cutaneous of the arm, and if this is too slender, two or more pieces may be used parallel to one another. The nerve can be located before the anaesthetic is given by testing with an electric current ; when the electrodes are applied over the nerve a tinghng or pain is felt throughout its distribution. It is con- sidered by some to be an advantage to protect the nerve junctions from invasion by fibrous tissue ; this may be done by enclosing them in a ring or tube of superficial vein. Probably Cargile membrane does more harm than good. There is yet another method, which is sometimes the only one available. Langley made some very interesting experiments on the effects of joining up the cut ends of different nerves, and found that their functions could be transposed. Thus he turned the cat's vagus into the cer\dcal sympathetic, and allowed regeneration to take place. The vagus is of course the ner\'e of swallowing, and therefore, whenever the cat lapped milk, all the effects of stimulation of the cervical sympathetic were seen on the side operated on — dilatation of the pupil, starting of the eye, sweating, retraction of the nictitating membrane, pallor of the ear, bristling of the hair, and quicken- ing of the heart-beat. Wlien, however, the (purely sensory) lingual nerve and the (purely motor) hypo- glossal were crossed in like manner there was no result. The method of nerve anastomosis was introduced CORD AND PERIPHERAL NERVES 235 into practical surgery by Ballance, who put part of the spinal accessory nerve into the peripheral end of the degenerated facial nerve to relieve intractable facial palsy. The result was excellent, but there was a tendency of course for the face and the trapezius to contract together, and smiling was accompanied by jerking of the shoulder. The hypoglossal is now utilized instead of the spinal accessory to avoid this. It was hoped that there was a wide field of usefulness before this device of nerve anastomosis, especially in infantile palsy. For instance, if the anterior tibial muscles and peronei alone were affected, the external popliteal might be divided and the peripheral end put into a notch in the internal popliteal. Unhappily, published results are very disappointing, at any rate in the case of infantile paralysis ; probably even the anterior horn cells supptying useful muscles have been somewhat damaged, and cannot take on more than ordinary work. Our war experience has shown us that direct end-to-end suture of nerves is much superior to either nerve grafting or nerve transplantation. Some surgeons consider that both these devices are useless. We still await adequate lists of published end-results to enable us to decide the question. I have followed through eight cases in which I bridged a gap by transplanting two or three plies of the internal cutaneous nerve. Two were successful (a musculo- spiral and an external popliteal) ; six probably or certainly failed. Nerve anastomosis suffers from the drawback that notching the sound trunk may 236 PERIPHERAL NERVES cause some paralysis of muscles that before the operation were intact ; it is said that if no more than one-third of a trunk is divided, no paralysis follows, but only a very \\dde experience of notching every nerve in the body and in every part of their courses could justify such a statement. Various de\dces of position may be made use of to get the two ends of a nerve together across the gap, such as acutely flexing the knee for the sciatic ; such a ner\^e as the ulnar may wdth great advantage be displaced from behind the condyle. These pro- cedures, whenever possible, are much to be preferred to nerve transplantation, and even more to nerve anastomosis. Some surgeons think it justifiable to resect the humerus and shorten it an inch, so as to get the ends of a nerve together. Sometimes, in the case of the musculospiral, a good result may be ob- tained by letting the nerve alone, and transplanting the tendons of the flexor carpi radialis, palmaris longus, and flexor carpi ulnaris into the extensors of the thumb and fingers. REFERENCES. Walshe. — Brain, 1919, xlii, p. i. Ramsay Hunt. — Brain, 1918, xli, p. 302. Ransom. — Amer. Jour, of Physiol., 1916, xl, p. 571. RiDDOCH. — Brain, 1918. FoRSTER. — Zeitschrift f. orthopdd. Chir., 190S, Bd. xxii, p. 203. Head and Thompson. — " The Grouping of Afterent Impulses in the Spinal Cord," Brain, 1906, p. 537. A. Rendle Short. — Proc. Royal Soc. Medicine, Surgical Section, July, 191 1. Sherrington. — Integrative Action of the Nervous Sysian. Eloesser. — Ann. Surg., 1917, p. 201. 237 CHAPTER XII I. LOCALIZATION OF FUNCTION IN THE BRAIN. LOCALIZATION OF SENSATION IN THE CEREBRAL CORTEX ; VISION, HEARING, CUTANEOUS AND OTHER FORMS OF SENSATION — FUNCTIONS OF THE FRONTAL CORTEX — APRAXIA — APHASIA MISLEADING LOCALIZING SIGNS OF INTRACRANIAL TUMOUR OPTIC NEURITIS — THE CERE- BELLUM— TUMOURS IN THE CEREBELLO-PONTINE ANGLE THE CEREBROSPINAL FLUID. THE large number of cases of localized injury to the brain occurring in the war have given a decided impetus to neurology. Painstaking investi- gations, of much larger groups of examples of a particular injury than civil practice could furnish, have been carried out by the most competent observers. Some of the results are given in this chapter. LOCALIZATION OF SENSATION IN THE CEREBRAL CORTEX. Vision. — It has long been known that visual sensations are received on the mesial surfaces of the occipital lobes, just above and below the calcarine fissure. Histologically, the area is mapped out by the white line of Gennari, which is a lamella of medullated fibres splitting the grey cortex, and by the occurrence in the pyramidal layers of certain 238 LOCALIZATION OP FUNCTION stellate cells. This area slightly encroaches on the convexity of the hemisphere at the occipital pole. This calcarine area is called the visttosensory cortex. For the interpretation of things seen we are dependent on the outer surface of the occipital cortex, the so-called visuopsychic area. It is well known that the right half of each retina (that is, the nasal half of the left retina and the temporal half of the right) is represented in the right visuosensory area. Gordon Holmes and Lister have shown that a lesion of the upper lip of the cal- carine fissure causes blindness of the upper half of each retina. This confirms previous work. There- fore a lesion of the left cortex above the calcarine fissure would render the upper left quadrant of each eye blind ; the patient would not be able to see his right foot when sitting in a chair and looking straight forwards. Further, they show that the macula, the point of most acute vision, with which we read, is represented in the little piece of visual cortex which overlaps the convexity of the hemisphere behind, and at the posterior end of the calcarine fissure. The representation is not bilateral, as used to be taught. If a bullet-track destroys the rest of the calcarine area but leaves the posterior poles intact, the patient's world looks as if seen through a telescope ; the periphery is cut off. Further, it is shown that each region of the visuo- sensory area corresponds to a region of the two retinae, which always work together. That is to say, if the right calcarine fissure be taken as repre- IN THE BRAIN 239 sented by the English Channel on the map, the North Sea standing for the occipital pole, then Dover and Calais correspond to the region for the macula ; Sussex and Hampshire, representing the sloping sides of the upper lip of the fissure, correspond to areas in each retina traversed by a line running from the macula horizontally to the right ; and going up the Thames Valley, which represents the upper limits of the visuosensory area, corresponds to areas in the retinae traversed by a line drawn vertically upwards from the macula — the higher on the cortex equals the higher on the retina, and the further forwards on the cortex equals the nearer the periphery of the retina. Lesions of lateral surfaces of both hemispheres, the visuopsychic cortex, involving the angular, supramarginal, post-parietal, and occipital regions, give rise to loss of perception of size, depth, and distance, inability to recognize the nature of objects, and impairment of convergence and accommodation. Hearing. — Although it is certain that monkeys which have suffered bilateral removal of the temporal cortex give every external e\adence that they can hear, it is very difficult to be equally certain that sounds are still appreciated in consciousness by them, and recognized for what they signify. It is no more evidence of conscious hearing that a monkey looks round when a bell sounds, than it is of conscious pain that a man with a fractured spine withdraws a foot pricked by a pin. It might be a reflex from a lower- level centre, such as the posterior corpus quadri- s^eminum. Recently the whole cerebral cortex has 240 LOCALIZATION OF FUNCTION been removed on both sides in monkeys (Macacus). One lived twenty-six days. They stiU responded to noises by movements of the body and ears. Stimulation of the temporal cortex in monkeys causes pricking up of the ears. At any rate, there is a fair amount of human evidence, both anatomical and clinical, to locate this function in the temporal convolutions and island of Reil, and none to locate it elsewhere. Fibres from the posterior corpus quadrigeminum, and some from the lateral fillet, which is well known to come from the cochlear nuclei, ma}^ be traced to this part of the cortex. Deafness and abnormal auditory sensations have been associated with disease of this region. Perhaps the most convincing observation on record was made by Harvey Gushing, who stimulated the exposed temporal cortex in a conscious man, and the patient said that he heard a buzzing noise. There are cases on record of complete bilateral destruction of the temporal cortex with persistence of the island of Reil, and normal hearing. This may indicate that the island is more important as an auditory centre than the temporal convolutions. Cutaneous and Other Forms of Sensation. — The great war has provided a wealth of clinical material for the study of those problems relating to the cerebral localization of the various forms of sensation derived from the limbs, which used to be so controversial. On this subject experiments on animals could give little or no information. Enormous lesions in monkeys were found to cause hemianaes- thesia, but smaller removals gave rise to little if IN THE BRAIN 241 any defect of sensation. Sherrington has recently removed parts of the postcentral cortex in a chim- panzee. The animal was not tame enough to allow detailed examination of its sensations afterwards, but there was no loss to the coarser methods of testing. Gushing excited the postcentral convolution in two conscious patients who had previously been trephined, by unipolar faradic stimulation. He found that the brain itself was devoid of any sort of feeling, but that sensations of stroking, tingling, or warmth were produced, referred to the hand of the opposite side. The sensation was quite well defined and localized ; one area corresponded to the index finger, and another to the back of the hand. When the electrode was applied in front of the fissure of Rolando instead of behind, the fingers or hand moved, but there was no sensation. An incision in the postcentral convolution was quite painless, and caused some numbness of all forms of sensation in the hand. Many years ago, before it was realized that the convolutions in front of and behind the fissure of Rolando differed in function. Ransom and also Laycock observed that a tingling sensation was elicited when they stimulated the exposed cortex in a conscious man, and apparently they both applied the electrodes in front of the fissure ; Gushing and others have failed to confirm this. Recently Sir Victor Horsley published an account of the only case in which he had removed a cortical centre (part of the hand area) without encroaching upon the 16 242 LOCALIZATION OF FUNCTION ascending parietal gyrus (for athetosis). Immedi- ately after the operation there was complete flaccid paralysis of the arm and some interference with sensation. The hand could detect cold but not warmth, stroking with a wool pencil was not felt on the ungual phalanges, there were inaccuracy of location of pain and touch and loss of the sense of position, and objects placed in the hand were not recognized by touch (astereognosis). A year later, movement was recovered, except for some spastic paralysis in the two ulnar fingers ; there were still astereognosis, inaccuracy of location, and slight dulling of sensation over the ulnar border of the hand. If the lesion had involved the postcentral cortex, the sensory disturbance, in his experience, would have been much more marked. The athetosis movements were cared. It is quite certain that lesions in man involving the ascending parietal (postcentral) convolution almost always cause some interference with sensa- tion, more so than defects of any other parts of the cortex would do. There is never complete anaesthesia, except just after an epileptic convulsion or injury, or in hysteria. Further, it is proved that the leg area is nearest the top, the arm area next, and that for the face lowest, corresponding to the distribution in the precentral (motor) convolution. Bergmark quotes thirty-three cases of lesions of the postcentral gyrus with sensory symptoms but no paralysis. Dr. Head has re-investigated the whole subject, using a large number of wounded officers and men as IN THE BRAIN 248 clinical material. The results are interesting and important. The more primitive sensations, those possessed by most vertebrates, such as tactile, heat, and cold, are appreciated by the optic thalamus, which represents the primitive sensory cortex. It is the optic thalamus, also, that gives emotional colour to the sensations — that regards some as pleasurable, and others as painful. Obviously pleasure and pain are very primitive sensations. The degree of pleasure excited by, shall we say, gentle stroking or a spray of warm water, and the degree of pain excited by a pinprick, are partially damped down by impulses derived from the cortex. Fibres from all parts of the cortex converge on the lateral nucleus of the thalamus, and tend to control and inhibit excessive pain or pleasure arising from impulses received from the spinal cord. When this lateral nucleus is damaged, and only the mesial part of the thalamus is left intact, pinpricks are much more painful, and stroking or warmth more pleasant, than on the normal side. Sometimes music produces a remarkable emotional effect in the affected limbs, especially if it is solemn and majestic. A complete destruction, say of the right optic thalamus, produces hemiansesthesia of the left side of the body, with blindness of the right half of each retina, sometimes athetosis, and a curious form of facial paralysis. When the pyramidal tract is injured, causing hemi- plegia, voluntary movements of the face are impaired but emotional movements persist — a smile or an involuntary frown are still symmetrical. When the thalamus is damaged, voluntary movements are 244 LOCALIZATION OF FUNCTION retained but the emotional movements are no longer symmetrical. The explanation is that the emotional movements are of primitive origin, and therefore controlled by the more primitive optic thalamus, not by the cortex. A lesion of the postcentral cortex, therefore, does not cause complete anaesthesia, or abolish any of the senses of heat, cold, touch, or pain, because these are apprehended by the thalamus. The function of the sensory cortex is not merely to receive sensory messages, but to interpret them. If I hold a glass of hot water in my hand, the thalamus tells me that it is touching my hand, that it is hot, that it is unpleasantly hot ; the middle part of the postcentral cortex, behind the motor area for the arm and hand, tells me that it is a smooth round glass, that it weighs so many ounces, and that it is of such and such a size. Lesions of the postcentral cortex in the arm area produce the follo^ving disabilities. Certain fingers are affected, others are normal. 1. Sensations are very irregular and easily fatigued. A light touch or other means of testing is appre- ciated better at one time than another. 2. Recognition of space is very defective. The patient cannot recognize how much his fingers have been moved by the physician, he locahzes badly, and two compass points are interpreted as one unless greatly spaced out on the skin tested. 3. He cannot judge weights, or compare shapes and sizes, or tell the difference between silk, velvet, cloth, and the ' like. When there is marked inter- IN THK BRAIN 245 ference with sensation from a postcentral injury, muscular tone is deficient in the corresponding part. We can go some way towards localization of these functions. A little loss of sensation may be pro- duced by a lesion of the precentral gyrus, much more by injury of the postcentral, and some if the parietal convolutions just behind, and the angular gyrus, are involved. These constitute the sensory area of the cortex. The little finger is represented nearer the leg area, the thumb nearer the face area. Lesions of the precentral cortex particularly affect spacial sense ; those of the postcentral gyrus have the greatest effect on judgements of weight and shape ; marked disturbance of tactile sense indicates a lesion farther back or in the angular gyrus, which may also interfere with temperature sense. It will be remembered that Sir Victor Horsley's case of excision of the motor area for the hand had difficulty in localizing. In reference to the views which have just been explained with regard to the emotional function of the optic thalamus, it is interesting to mention that Graham Brown has shown that stimulation of this nucleus in a chimpanzee gives rise to the movements which constitute laughter in apes. FUNCTIONS OF THE FRONTAL CORTEX. It is well known that the great motor centres are limited to the ascending frontal or precentral con- volution. This has been abundantly proved by many methods : by the study of paralysis following 246 LOCALIZATION OF FUNCTION localized lesions in man, or removals in man or apes ; by electrical stimulation in man and apes ; and histologically by the limitation to this region of the giant pyramidal or Betz cells, which are the only cells to undergo chromatolysis when the pyra- midal tracts are destroyed in the spinal cord. The whole field of the observations on great apes has recently been gone over again by Sherrington and Ley ton, using a truly generous amount of material — three gorillas, three orang-outans, and twenty-two chimpanzees. They give wonderful de- tailed diagrams of the exact spots that have to be stimulated to produce particular movements. They make a point that the cortex must not be allowed to cool, or the reactions no longer appear. After ablations of parts of the motor area, paralysis of course ensues, but there is a remarkable degree of recovery in a few days. It often becomes of great importance to the surgeon to know whether a tumour causing hemiplegia is accessible, either in the cortex or close beneath it, or inaccessible, in the internal capsule or isthmus. The principal evidences of the former are the occur- rence of monoplegias, the face, arm, or leg being affected alone without the others, whereas lesions of the internal capsule would paralyze all three ;* secondty, persistent aphasia may be present ; and thirdly, there may be recurring con\ailsions. The * In monkeys the fibres to the head, arm, and leg are grouped in bundles in the internal capsule, but apparently this is not the case in man, and consequently small lesions cause mild hemiplegia, not monoplegia. IN THE BRATX 247 degree of sensory impairment is not of much assist- ance, but the considerations just advanced may sometimes be helpful. There is a good deal of evidence that if the paralysis is of a flaccid type the lesion is most probably cortical, though the converse is not necessarily true. In man, a cortical lesion is often (not always) accom- panied by a flaccid paralysis with no Babinski sign and with normal or diminished reflexes (see cases quoted by Bergmark), but v/hen the optic thalamus and internal capsule are involved, there is always marked rigidity. This subject has been referred to in the preceding chapter. It is, however, true that irritation of the cortex, such as may be present just after a traumatic lesion, or during the growth of a tumour, may cause early contracture, so we should regard the presence of rigidity as an equivocal sign, but absence of rigidity as evidence of a cortical lesion. The frontal cortex lying in front of the motor region is described as a ' silent area ', and extensive tumours, degenerations, or injury may produce few or no symptoms. In a case under the writer's care, a wound one inch deep into the brain, from the vertex to the nose, caused by a chopper, made absolutely no difference to the woman's character, capacity, or intelligence, and indeed produced no symptoms at all beyond concussion, although she was under observation for many months. In the famous American crowbar case, where a large part of the frontal cortex on both sides was destroyed, there was 248 LOCALIZATION OF FUNCTION no paralysis, but on returning to work the man, previously a capable foreman, had become weak, vacillating, inattentive, and profane. There are quite commonly signs of mental dullness in patients with frontal lesions. In cats there are, after excisions of the frontal cortex, changes in the disposition, and recently acquired tricks may be lost. Stimulation of this region, in Sherrington and Ley ton's anthropoid apes, produced nothing but de\iations of the eyes and opening of the lids. Similar results were got by stimulating the occipital cortex. According to Sir Victor Horsley, abscesses of the brain invohdng the Rolandic area usually lead to a raised temperature on the opposite side of the body, whereas, if the location is in front of or behind this region, the temperature is subnormal. APRAXIA. More definite evidence, however, is now available. There are a number of carefuUy studied cases on record in which, with no actual paralysis, there has been a remarkable clumsiness in the performance of movements requiring any skiU, and in which the patient has been quite unable to make some movement voluntarily or in response to command, although he may unconsciously do that ver\^ thing under the influence of emotion or by accident. This condition is called apraxia. It is most convincing when it is unilateral. Thus, a musician may lose the power of pla3dng his instrument, or the clerk his power of writing. In Liepmann's classic case, one of the first IN THE BRAIN 249 to be described, there was apraxia of the right arm and leg. " Asked to put his right forefinger on his nose, he said, 'Yes', and with his stretched forefinger executed wide circHng movements in the air. He made the correct movement at once with his left hand. Asked to close his right hand into a fist, he performed various absurd movements of his arm and body, but attained the required goal at once with his left hand. When asked to give the examiner a certain object with his right hand, he frequently picked up the wrong thing, and, still holding it in his hand, used the left to take up the required object and present it to the physician". A patient of de Buck's, asked to hft her right arm, crossed it over her body, put it in her left axilla, and after making various other vigorous but futile efforts, said plain- tively, " Je comprends bien ce que vous voulez, mais je ne parviens pas a le faire " : this just expresses the condition. In some of the cases, there is imperfect recognition of objects or of their uses (agnosia), but these are compHcated and cannot be described here. It is an important fact that apraxia of the left arm is common in right hemiplegics, whereas apraxia of the right arm rarely occurs in left hemiplegics ; moreover, in the cases where there is apraxia of the left side with hemiplegia of the right, there is evidence that the lesion is cortical, not in the internal capsule. Thus Liepmann examined eighty-three hemiplegic patients, with these results : — Forty-two had left hemiplegia ; they could neariy all obey directions with the right arm. 250 LOCALIZATION OF FUNCTION Forty-one had right hemiplegia ; of these, 20 had apraxia of the left arm, and 14 in this group also had aphasia (therefore the lesion was cortical) ; 21 had no apraxia, and of these only 4 had aphasia (in most of the other 17 cases the lesion was probably in the internal capsule). Of course, as left-handed persons form one- twentieth of the community, it is possible to find a few cases of left hemiplegia with right apraxia. There is good ground, then, for believing that the centres which consciously initiate voluntary move- ments for both sides of the body are limited to the left cortex in right-handed people, and that the precentral convolutions are merely the departure platforms for messages from the brain to the cord. Instructions are sent to the right precentral convolu- tion by way of the corpus cailosum. It is still in doubt whether the above-mentioned initiating centre is in the left precentral gyrus, or whether it lies in front oj this, in the first and second frontal convolu- tions, as most neurologists maintain. It is quite certain that a lesion of the front part of the corpus cailosum is characterized by apraxia of the left arm ; this important discovery may well lead to successful surgical removal of tumours there situated. A lesion in the left frontal cortex may cause apraxia of both arms ; there will probably be right hemiplegia as well, which would mask the condition in the right arm. To sum up, a lesion is cortical if there are present : — I. A monoplegia. IN THE BRAIN 251 2. Hemiplegia with either (a) x\phasia which persists ; (b) Recurring convulsions ; (c) Flaccidity ; (d) Apraxia of the opposite side. Left-sided apraxia without hemiplegia indicates a lesion of the corpus callosum. APHASIA. The various types of aphasia have always presented problems of great complexity but of much interest. Recent studies of the subject have been very revolu- tionary' in their tendency. We used to learn that there were three main centres for the appreciation and utterance of language, namely : — 1. The motor centre, controlling utterance, in Broca's convolution (the third left frontal). 2. T^ie auditory word centre, appreciating spoken language, in the posterior part of the second left temporal convolution. This was also regarded as dominating and being necessary for the activity of the other two centres. 3. The visual word centre, appreciating written language, in the left angular gyrus, behind and above the auditory word centre. Recently, however, the searching analyses of Marie and his pupils have raised ver\' grave doubts about the first and third of the above, and many neuro- logists have agreed that Broca's convolution has no speech function at all ; very few now defend the existence of a separate \'isual word centre. Briefly, the contention of Marie and Moutier may be put thus. Between 1861 and 1906, there have been pubUshed 304 cases of aphasia with autopsy. 252 LOCALIZATION OF FUNCTION Of these 201 were useless and 103 were relevant. Useless Relevant Favourable to Broca's local- ization Unfavourable to Broca's localization 175 26 201 II 19 (Lesion too extensive ^ Badly described .... Cortical lesions with aphasia Subcortical lesions with aphasia Aphasia, but Broca's convolution normal 57 No aphasia, but Broca's convolu- tion destroyed (in two cases, bilateral destruction) - - 27 84 304 The majority even of the nineteen cases allowed by these writers they consider to be inconclusive for various reasons. Two cases of Burckhart's are of sufficient surgical interest to be worth quoting. In the first, he removed 5 grms. of grey matter from the foot of the first and second left temporal gyri, but no word-deafness resulted. Eight months later he resected the cap and foot of the left third frontal gjnnis (Broca's convolution), but no aphasia followed. In the second case he resected, in several operations, the left supramarginal, temporal, and third frontal gyri, but he failed to induce any speech defect. The patients were demented, with verbal delusions and logorrhoea. Sherrington and Leyton removed Broca's area in a particularly vociferous chimpanzee, but the operation did not quiet it at all. Marie maintains further that all patients with IX THK BRAIN 258 aphasia are mentally deficient ; thus, the cook can no longer compound an omelette, and the pianist can no longer play the piano. He locates all the speech functions diffusely in the left temporo- parietal region, maintaining that this is merely a region of intelUgence speciaUzed for language, and not a storehouse of sensory images ; a mild lesion destroys the function last acquired, viz., reading, and a severer lesion produces loss of voluntary speech and of recognition of spoken language as well. What Marie calls ' anarthria ' — a word previously used in another sense — meaning loss of the power to utter speech, although the individual can say the words over to himself, is due to a lesion in ' the quadrilateral ', bounded in front and behind by the anterior and posterior hmiting sulci of the island of Reil, internally by the wall of the lateral ventricle, and externally by the surface of the island of Reil. In most cases of so-called Broca's aphasia, both the temporal cortex and the ' quadrilateral ' are injured. Defenders of the classical view, Dejerine in par- ticular, have replied by advancing fresh cases with a lesion in Broca's gyrus ^^'ith aphasia resulting ; they contend that Marie's ' quadrilateral ' contains the projection fibres of the third frontal convolution, which in their view explains the anarthria ; and they maintain that most of the fifty-seven cases of aphasia in which Broca's convolution was intact were associated with much defect in understanding language spoken or written, and that the lesion was one of the dominant auditorv word centre in the 254 LOCALIZATION OF FUNCTION temporal lobe, without which Broca's convolution cannot work. If it were proved that in cases of apraxia, previously referred to, the lesion was in the first frontal con- volution for the legs, and in the second frontal for the arms, the location of speech just in front of the motor centres for the face and mouth would receive strong support by analogy, but all this is still very uncertain. To sum up, we may express current opinion by accepting the existence of a large diffuse centre in the left temporoparietal region in which recognition of spoken and written language and ' internal speech ' take place ; when it is seriously damaged these are all lost and the inteUigence is impaired. Whether there is a special departure platform in Broca's convolution for uttering speech is uncertain, but probably there is. Lesions of the projection fibres from the cortex (? of Broca's convolution) will cause ' anarthria ', that is, loss of external but not of internal speech. Practical deductions are, not to trust aphasia as conclusive locahzing evidence of a lesion in the left third frontal gyrus, but rather to look to the temporal region, especially if there is any defective apprecia- tion of what is said or written; patients with left temporosphenoidal abscess, for instance, are usually unable to name correctly objects shown them. More- over, we are encouraged to believe that there is no need to fear that small cortical injuries inflicted by the surgeon will cause aphasia ; subcortical injuries are much more Hkely to do so, by cutting off projection fibres. IX THE BRAIN 255 MISLEADING LOCALIZING SIGNS OF INTRA- CRANIAL TUMOUR. It is very disappointing when definite signs usually regarded as of importance in localization give colour to a diagnosis as to the position of a cerebral tumour, but on the operation table nothing is found in that region. It is more than disappointing, because un- successful attempts to find the tumour are more fatal than actual removals. Some study therefore of the physiolog}^ of the production of misleading signs mav be useful. The principal traps are furnished by the follo\\'ing : 1. Cr-\nial Nerve Palsies. — Paralysis of one or both sixth cranial ner\-es is quite common, and bv no means proves that the nerve itself or its nucleus is involved in the lesion. It has been accoimted for by stretching, due to a supposed backward displacement of the whole brain late in the development of a growth ; the abducent ner\-es run straight forwards and are slender, so the first sign of the displacement is a convergent squint. Other cranial nen*es, including the third, fifth, seventh, and eighth, are occasionally affected b\' dis- placements of the brain or by pressure. 2. Localized or General Convulsions. — Mis- takes are particularly apt to arise if the fit starts in some definite area, follows a slow and orderly march to other areas, and perhaps affects only one side, consciousness being lost late if at all {Jacksonian epilepsy). It must, however, be remembered that all this may occur \Wthout anv obvious cortical 256 LOCALIZATION OF FUNCTION lesion ; indeed, the commonest cause of a localized convulsion is ordinary idiopathic epilepsy. Again, localized or general convulsions may give a wrong impression when arising late in the course of an intracranial tumour or abscess, especially if it presses on the ventricular sj-stem of the brain and dams back the cerebrospinal fluid, causing hydro- cephalus. The accumulation of fluid in one or both lateral ventricles stretches the overlying cortex, and may give rise to fits, sometimes of a Jacksonian type. 3. Bilateral Spastic Paresis.- — In many cases a hint is given of the true nature of these seizures by the presence of a shght degree of bilateral spastic paresis, with clumsiness of movement, exaggerated reflexes, extensor plantar response, and a httle rigidity. Of course, if this should chance to be associated with paratysis of a cranial nerve, such as the sixth, the temptation to diagnose a lesion of the pons would be very great. Fortunately, this would not be of much surgical importance, as the pons is not an accessible structure. Pontine tumours are often unilateral, and optic neuritis is usually absent ; whereas in the class of cases we are now considering, optic neuritis is marked and old-standing, and there is a long history of headache, vomiting, or other signs, previous to the development of spasticity or cranial nerv^e palsy. In other cases, misleading locahzing signs may arise from patches of secondary thrombosis, spreading oedema, or meningitis ; but none of these is common. IN THE BRAIN 257 The suspicious feature about all the signs here mentioned is their late development. Localizing symptoms appearing when headache, vomiting, optic neuritis, or other evidences have been present for months or years are httle to be trusted. Early localizing signs, on the other hand, are trustworthy in the main. There is a condition called serous meningitis, specially affecting the cerebellar region, which may be most misleading. It is apt to get well in time. A few words may be said about the significance of ataxia. This is of course evidence of a lesion of the cerebellum, but it may be seen in other conditions also. Putting aside ataxia due to affections of the labyrinth, Friedreich's ataxia, and other general nervous diseases, it may also be caused by a tumour in the neighbourhood of the red nucleus in the isthmxus, or in the pons. OPTIC NEURITIS. It has long been in doubt why optic neuritis should develop in cases of cerebral tumour. It has been attributed to the effects of chronic meningitis, and to over-filling of the third ventricle, with consequent pressure on the underlying optic chiasma. It is now definitely estabhshed by the experiments of Gushing and Bordley, and confirmed by clinical experience, that it is a pressure effect. The growth of the neoplasm causes a great and continued rise of intracranial pressure ; this tends to dam back the lymph-flow returning in the sheath of the optic nerve. The usual consequence of lymphatic obstruc- 17 258 LOCALIZATION OF FUNCTION tion is produced, namely, cedematous swelling of the area drained. So the optic cup fills up, the disc is obscured by transudate, and the vessels are buried from view in the oedema fluid. x\ll this may be exactly reproduced by intracranial pressure in dogs, and when the pressure is removed, restitution to normal takes place. Several methods of raising the intracranial pressure were employed, the best results being obtained by the insertion of sponge-tent material inside the skull. SweUing and oedema of the disc, tortuosity of the veins, and over-distention of the lymph- sheath around the optic nerve were all marked. ReUef of the pressure rapidly cured them. .\lthough we use the conventional term ' neuritis \ the histological changes are not those of inflammation. For instance, there is no arterial hyperaemia, and the principal infiltration is ^rith cells of connective- tissue origin, not leucocytes. Further, it has been stated by many obser\''ers, and recently defended, \\ith all his great authority and experience, by Sir Victor Horsley, that the degree of the neuritis in the two eyes is a most reliable guide as to the side of the tumour. It is not so much the amount of swelling that is to be taken into account as the age and extent of the changes. These nearly always commence at the upper nasal quadrant of the disc. Thus, optic neuritis best marked in the right eye is of great value in pointing to a right-sided tumour. The further forward the tumcur, the more constant does this rule become. It is well known that even if a cerebral tumour IX THE BRAIN 259 cannot be localized, palliative trephining should be performed to relieve headache and save the sight. If this is undertaken early, the optic neuritis passes off. As the tentorium transmits pressure badly, the trephining should be in the temporal region for supratentorial tumours, and in the occipital region for cerebellar tumours. Another valuable observation which we owe to Gushing is that raised intracranial pressure, par- ticularly by cerebral tumour, induces a considerable limitation of the field of vision for blue ; indeed, there may be actual blue-blindness. THE CEREBELLU?A. We have been in urgent need of some improvement in our means of locaUzing tumours and abscesses in the cerebellum. During a period of ten years at the Bristol Royal Infirmar}^ there were eight cases of temporosphenoidal abscess, all of which were successfully diagnosed, and ten cases of cere- bellar abscess, of which only three were correctly located ; in three of these ten cases the cerebrum was explored in vain, and in two the lateral sinus was thought to be the cause of the s\TTiptoms. It remains to be seen how far the fresh light recently thro\sTi on the subject and herein set forth will help us to obtain materially better results. Sir Victor Horsley and R. H. Clarke have re\'ised our knowledge of the functions and relation- ships of the cerebellimi by an ingenious method. Reconstructions of a monkey's head have been made by cutting frozen sections and then piecing them 260 LOCALIZATION OF FUNCTION together again ; by this means it was possible to build a frame of metal to fit about the head of a living monkey, carrying an insulated needle which could be thrust through a small trephine hole into any desired portion of the cerebellum, its cortex, or its deep nuclei (roof nuclei), the exact position of the point of the needle having been determined by a study of the head reconstructed from the frozen sections. By this means various parts could be stimulated electrically without doing any but the slightest damage to the overlying structures ; more- over, by passing in a strong current and using a double needle shielded nearly to the points, small electrolytic lesions either of the cortex or of the roof nuclei could be made, and the resulting degenerations studied by suitable staining some weeks afterwards. The general result was to prove that the cortex cerebelli is a receiving platform, and that its axons merely pass to the roof nuclei, from which the efferent tracts start. Stimulation of the cerebellar cortex by ordinary currents produces no obvious response ; stimulation of the roof nuclei causes movements of the eyes and sometimes of the limbs. We see here the reason why laterally situated tumours or abscesses lie so quiet. The classic signs of a lesion of the cerebellum, determined both by physiologists and by clinicians, are the following : — (i) Ataxia ; (2) Atonia ; (3) Asthenia ; (4) Tremor : these all affect the same side as the lesion ; (5) Nystagmus ; (6) Vertigo. I. Ataxia. — This, one of the most constant signs. IN THE BRAIN 261 is easily detected if the patient is able to walk. When he is in bed, it may be brought out by making him try to pronate and supinate rapidly for a minute or two ; or to make and unmake a fist quickly, over and over again. This sign (adiadochokinesis) is the more convincing if it is unilateral. 2. Atonia is very variable ; the knee-jerks may be absent, normal, or excessive, and may change day by day. It depends on the degree of inter- ference with the reflex path for muscular tone, described in the previous chapter. 3. Asthenia may be evidenced by weakening of the grip, tendency to fall, or drooping of the head on the affected side. It is not very constant. 4. Tremor is only occasionally in evidence. 5. Nystagmus. — These curious jerkings of the eyes are of considerable importance in the diagnosis of cerebellar affections, because, although seen in such conditions as disseminated sclerosis, they are very unusual with locaUzed intracranial tumours. Un- fortunately they are not constantly present even when the lesion is in the cerebellum, and, on the other hand, are usually to be observed in patients with disease of the labyrinth (vestibule and semi- circular canals). Seeing that most cases of cerebellar abscess follow otitis media, it has been very difficult to be certain, in the past, whether any nystagmus in a patient with a suppurating ear was due to the labyrinth, or the cerebellum, or both. Barany, of Vienna, has shown that it is possible to induce nystagmus in a nonnal person by stimu- lating the labyrinth. This may be done either by 262 LOCALIZATION OF FUNCTION rotating the patient, or by allowing hot or cold (not tepid) water to trickle in as far as the membrana tympani. Hot water in the right ear causes a nystagmus in which the eyes slowly turn to the left and are corrected by rapid jerkings to the right ; with cold water the rapid jerkings would be to the left. If a patient with a suppurating ear has nystagmus, and it is desired to know whether this is due to affection of the labyrinth or of the cerebellum, hot or cold water should be injected to see if the nystagmus can be reversed in direction. If it can, the labyrinth cannot be at fault ; it must be the cerebellum. Again, a patient with severe vertigo following on otitis media may be suffering from lab3'rinthitis or from cerebellar abscess. If injection causes no nystagmus, the labyrinth is destroyed. The signs of a cerebellar lesion have recently been re-investigated by Gordon Holmes, using war material. His observations confirm the above de- scription in the main. He points out that if the patient is asked to push against resistance, and the resistance is suddenly removed, the cerebellar case will 'follow through', but a normal person almost immediately checks the movement of his arm. TUMOURS IN THE CEREBELLOPONTINE ANGLE. This is a very common location for cerebellar tumours, and a comparatively favourable one for surger}^ seeing that in many instances the growth IX THE BRAIN 268 is simple, and can be enucleated without recurrence. Unfortunately, the operative mortality has been very high, about 50 per cent. .Alien Starr finds in the literature sLxty-nine cases cured by removal. In many of these there was restoration to good, in some to perfect, health. Diagnosis, therefore, becomes peculiarly important. In addition to the signs mentioned above, certain nerve-root s3Tnptom5 may develop, and the pons may be pressed on. Mental trouble is quite unusual. We may classify the evidence as follows : — 1. General : headache, vomiting, optic neuritis, slow pulse, blue-blindness, perhaps convulsions. The headache is usually suboccipital, and there may be stiffness of the neck. 2. Cerebellar signs : staggering, vertigo, ataxia, weakness, tremor, and perhaps absent knee-jerk ; these may be unilateral, on the same side as the growth. Nystagmus. Cerebellar symptoms do not usually appear for about a year. 3. Neroe-root symptoms affecting the same side : pressure on the hfth, with corneal anaesthesia and loss of reflex, and weakness of jaw muscles ; pressure on the sixth, with internal strabismus ; pressure on the seventh, with facial weakness ; pressure on the eighth, with tinnitus, loss of perception for upper notes (tested by Galton's whistle), or absolute deaf- ness ; pressure on the ninth, tenth, and eleventh, with dysphagia, laryngeal palsy, cardiac attacks, etc. ; pressure on the twelfth, with deviation of the protruded tongue. Of these, the facial and auditory ner\'es are most often affected, there being 264 LOCALIZATION OF FUXCTIOX complete unilateral deafness in most of the cases. In cerebellar tumours these two nerves may be interfered with, but not to any considerable degree. It is a very important point that in the cases favourable for surgery the signs of involvement of the eighth nerve precede all the other symptoms. There is great lowering of irritability to Barany's tests, even if some hearing is presented. 4. Pressure on the pons, causing crossed hemiplegic weakness, ^vith exaggerated reflexes and extensor response. The cases maj' live for years, but there is a Uabihty to sudden death by crowding of the cere- bellum down through the foramen magnum. The symptoms may vary much from time to time, on account of circulatory changes. A serous meningitis of the same region sometimes occurs, and may mimic the symptoms only too accurately. Gushing has been able to reduce his operative mortahty to 20 per cent by better recognition of the early cases arising on the eighth nerve, and by his procedure of making a bilateral removal of the occipital bone. THE CEREBROSPINAL FLUID. This fluid is clear, watery, and of low specific gravity ; it contains almost no albumin, but some sugar. Until recently this reducing substance was thought to be a pyrocatechin body. It contains no cells in health, nor does it contain the antitoxins, opsonins, or alexins which are present in plasma. IN THE BRAIN 265 lymph, and most serous fluids. This explains the great liability to septic meningitis after injuries to or operations on the central nen'ous system. As urotropine is excreted into the cerebrospinal fluid when given by the mouth, it may usefully be admin- istered to prevent septic complications such as the above, or following on suppurative otitis media. Some success is claimed for this procedure. The fluid is secreted by the choroid plexus into the lateral and third ventricles ; it passes by the Sylvian aqueduct into the fourth ventricle, escapes by the foramina in the roof into the subarachnoid space, and is absorbed, partly by the aid of the Pacchionian bodies, into the superior longitudinal sinus and other veins. Hydrocephalus is produced by blocking of the foramina in the roof of the fourth ventricle. If an exit is provided, large quantities of cerebrospinal fluid may be lost daily. Lumbar puncture is a ver\' valuable aid to dia- gnosis in various forms of meningitis, parasj-phihtic affections, etc., and the fluid may be blood-stained after cerebral haemorrhage or inju^,^ It is also valuable in treatment as a means of reducing intra- spinal and intracranial pressure, particularly if the trouble hes below the tentorium. REFERENCES. Gushing and Bordley. — " Observations on Experimentally Induced Choked Disc ", Bulletin Johns Hopkins Hospital, 1909, XX, p. 95. HoRSLEY. — " Optic Neuritis ", British Medical Journal, 1910. i. p. 553. HoRSLEY AND Clarke. — " The Structure and Functions of the Cerebellum", Brain, 1908, xxxi, p. 45. 266 LOCALIZATION OP FUNCTION IN BRAIN Thiele. — " The Optic Thalamus and Deiters' Nucleus ", Jour, of Physiology, 1905, xxxii, p. 358. Allen Starr. — " Tumours of the Acoustic Nerve ", Amer. Journ. of Medical Sciences, 1910, cxxxix, p. 551. Bergmark. — " Cerebral Monoplegia ", Brain, 1909, xxxii, P- 342. Gushing. — " A Note on Faradic Stimulation of the Post- central Gyrus in Conscious Patients ", Brain, 1909, xxxii, p. 44. WiLSON.^ — " A Contribution to the Study of Apraxia " Brain, 1908, xxxi, p. 164. Collier. — " Recent Work on Aphasia ", Brain, 1908, xxxi, P- 523- Collier. — " The False Localizing Signs of Intracranial Tumour ", Brain, 1904, xxvii, p. 490. Head and G. Holmes. — " Researches as to Sensory Disturb- ances from Cerebral Lesions ", Lancet, 1912, i, pp. i, 79, 144- Head. — " Sensation and the Cerebral Cortex ", Brain, 1918, xh, p. 57. Holmes and Lister. — Brain, 1916, xl, p. 34, Holmes. — Brit. Jour. Ophthalmology, 191 8, July, 353 ; Sept., p. 449. Sherrington and Leyton. — Jour, of Experini. Physiol., 191 7. 267 CHAPTER XIV. THE ACTION OF CUTANEOUS ANESTHETICS. DRUGS APPLIED TO THE UNBROKEN SKIN. IT has been customary to relieve abdominal pain by the application of hot fomentations containing opium, to treat sprains and bruises with lead and opium, and to smear on glycerin of belladonna for the discomfort of white leg. Wliat dyspeptic old lady has not worn a belladonna plaster over her heart, and what practitioner has not prescribed a belladonna liniment for vague aches and pains ? The rationale of the treatment has been that bella- donna, opium, and menthol are alleged local anaesthetics, and it is further supposed that they are absorbed by the unbroken skin. The truth is that they are iwt local anaesthetics, and that they are scarcely if at all absorbed through the unbroken skin. Neither aconite, cocaine, carbolic acid, bella- donna, nor opium has any power to reheve pain when apphed to normal, healthy skin. It has been well said that " You have not proved a lie to be a he, until you have shown how it came to be believed". This is very true in science, and especially in medical science. The use of belladonna and opium to relieve local pain was an ob\dous 268 THE ACTION OF deduction from their great power, when given by the mouth, to relieve general pain by inducing sleep or allaying coUcky contractions. In the case of bella- donna and its alkaloid atropine, the fallacy was the more natural in that they have a genuine effect in paralyzing ner\-e-endings, but, unfortunately, it is only the efferent nerve-endings in glands and unstriped muscle that are paralyzed, not the sensory twigs in the skin. The fallacy has been maintained by the practice of combining these drugs with other and more potent treatment ; thus, belladonna is given with counter- irritants such as camphor or alcohol ; warmth may be appUed \\dth the opium ; friction helps the bella- donna liniment to keep its reputation, and even the support of the strapping, with counter-irritants in it, assists the patient to beheve in the value of a belladonna plaster. We may go one step further, and say that the application of opium and belladonna to mucous membranes is equally futile. There is no evidence that opium suppositories after the operation for piles, or laudanum dropped into aching ears, have any direct local effect. Of course, morphia may be absorbed from the suppository, but in that case it presents no advantage over a dose given by mouth or hypodermicalh', and is less certain in its action. To sum up, there is no drug in common use capable of acting as an anaesthetic on the unbroken skin, except ether and ethyl chloride, which freeze it, and the only drugs which relieve deep-seated pain when painted on or rubbed into the skin are the counter- irritants. CUTANEOUS ANESTHETICS 269 Full details of the experimental data for these conclusions, which are accepted by the leading pharmacologists, will be found elsewhere. Briefly, the methods adopted were as follows. Strong, even dangerously strong, solutions and ointments containing opium, atropine or belladonna, aconite, cocaine, carboUc acid, and menthol were rubbed into the skin of the finger, and on the tongue, and these were then examined to see if their sensi- bility was in any way altered. The methods of examining the skin of the finger were as follows. Each test was applied on more than one observer and after varying intervals of time. 1. The Intolerable Temperature Test. — For each observer there was a certain constant temperature which was just not intolerably hot when the finger was dipped into warm water for half a minute. This was determined before and after applying the drug under consideration. 2. The Faradic Pain Test. — The strength of current was determined, before and after the application of each drug, at which the damp finger first found electrical stimulation by means of electrodes led off from a faradic coil actually painful, the current used being small at first and gradually augmented. 3. Thermal Discrimination Test. — We found that we were able, by immersing the finger first in one beaker of warm water and then in another, to detect a difference in temperature of not less than one degree. This was tested before and after the apphcation of each drug. 4. General Testing by means of a pin point, the 270 THE ACTION OF sesthesiometer, a wool pencil, etc., was also used. In testing the sensibility of the tongue, we used the faradic pain test as described above ; we examined thermal discrimination by applying warm metal points at various temperatures ; we used the aesthesio- meter, and studied the effect of the drugs on taste. Judged by these standards, the various drugs fared as follows : — Opium. — -A 5 per cent solution of morphine tartrate in water had no effect on skin or tongue. Belladonna. — Very strong liniments had no aucES- thetic effect. Indeed, if they had, the drug could be used instead of cocaine for eye surgery. The only sign we could obtain was diminution of sweating over the skin area treated. There was no flushing or blanching of the skin or mucous membrane. Aconite. — Neither the B.P. liniment nor ointment had any effect on the skin. Solutions produced tinghng of the tongue, but we were not quite confident whether there was or was not a little reduction in sensibility. Cocaitie. — Strong ointments and alcohohc solutions had no effect on the unbroken skin. Of course, if the skin is damaged, the effect is marked. A lo per cent solution appHed to the tongue produced con- siderable reduction of sensibility, by all our tests. Menthol produces a curious stimulation of the nerve-endings which detect cold, as is weU known. A discussion of its other actions would lead us too far, but any anaesthetic effect is purely that of a counter-irritant. Carbolic Acid rather increases the sensitiveness of CUTANEOUS ANESTHETICS 271 the finger to painful stimuli. Its undoubted value in relieving toothache is due to its caustic action in destroying irritated nerve-endings. The numb feel- ing we get after prolonged soaking in i in 20 carbolic is due to the formation of a thin coating of killed epidermis over the hands. The fact that even cocaine, which is thoroughly proved to paralyze sensory nerves, fails to produce the slightest effect when a 10 per cent solution in alcohol, or a 10 per cent ointment made with lanolin, is rubbed into the skin, is strong evidence that little if any of these alkaloids reaches the nerve-endings at all. Atropine finds its way into the sweat ducts sufficiently to reduce but not to abolish sweating by its action on the sweat glands. It is true that cases of poisoning from the application of belladonna to the skin are recorded, but only where there were abrasions or sores present, or perhaps in young children whose skin is very delicate. It may be objected that there is sufficient clinical eWdence of benefit from these drugs to defy negative results by experimental methods, but any who claim this must not confuse the issue by combining the belladonna or opium with camphor, heat, rest, or strapping. Again, it may be suggested that atropine, at least, has some vasomotor effect, but we failed to observe any, and indeed we doubt if it ever reaches the blood-vessels when rubbed into the unbroken skin. It is a thankless task to pull down strongholds ot belief, but it is necessary, if only to direct more attention to the true means of giving relief to pain, including general drug treatment, rest, massage. 272 ACTION OF CUTANEOUS ANAESTHETICS counter-irritation, heat, and passive hyperaemia. Moreover, a recognition of the failure of drugs saves useless expense, and may banish from patients' houses some of the commonest of powerful poisons. Belladonna liniment, for instance, has been respon- sible for an immense number of alarms, illnesses, and even fatalities. REFERENCE. A. Rendle Short and Walter Salisbury, British Medical Journal, 1910, i, p. 560. 273 APPENDIX. ABSORPTION OF NITROGEN FROM AMINO-ACIDS. We have made several observations on patients ' fed ' with nutrients of milk digested with pancreatic extract for twenty-four hours in an incubator, so as to convert most of the protein into aminoacids. Such nutrients are not irritating. An example of such a case is the following (I am indebted to Mr. P. A. Opie and to Dr. Bywaters for some of the analyses). Case I. — A. H., age 25, female, suffering from vomit- ing and gastric pain, not relieved by a diet of peptonized milk, was put on nutrient enemata as follows : — March 28-29. — By mouth : water. By rectum : saline, 15 ounces three times a day. March 2g-April i. — By mouth : water. By rectum : 6 per cent glucose, I pint three times a day. April 1-4. — By mouth : water. By rectum : milk digested for twenty-four hoars, six ounces every four hours. April 4. — By mouth : peptonized milk. Urine in ounces Ammonia N per cent Daily output of N in urine in grams. March 28-29 29-30 29 22 3-2 8-03) 628 Av. 30-31 ,, 31-April I* April 1-2 „ 2-3 » 3-4 26 26 16 22 32 0-8 12-3 127 12-5 9-3 4-36 604 5-56 !t?)Av. ^■^ f770 9-53] ^ ^ •, 4-5 31 0-5 9-02 •Glu cose not wel 1 retained. 18 274 APPENDIX It will be observed that instead of showing the usual steady fall, the nitrogen output is increased during the three days of feeding on aminoacids. Case II. — This patient, a man, was fed as follows, the daily output of nitrogen in the urine being also shown : — By mouth 1 By -turn lYrJ" Ammonia N per cent Daily output of N in urine in grams April 26-27 Milk 1 Nil 1 21 1-4 I4'3 27-28 Water Saline 19 2-9 10-7 28-29 Milk pepto- \ nized 20 minutes ; \ .3V 6-hourly!) 3'5 9-6 29-30 30-May I May 1-2 >> ' Milk pepto- nized 24 hours, 3V i 6-hourly, with 3j of \^ glucose 20 16 ) Vio 4-8 2-9 2-9 6-8 7.9 7-2 2-3 »f >» 21 3.0 14-4 3-4 4-5 / Pept. milk 3V 2- i hourly ( iMilk . Nil 15 23 3'7 2-8 II-2 161 ) 5-6 -, 3 VI J 2- ( hourly [ 54 0-9 13-7 As the accompanying chart shows, the absorption and output of nitrogen are very considerably increased when the milk has been digested with pancreatic extract for twenty-four hours. The increased absorption, as usual, does not increase the output for about twenty-four hours. APPENDIX 275 a 17 < 15 gl4 z 13 o 10 a: H 9 ^ 8 O 7 t 5 §^ ^' =! 2 2 . DAY OF FAST. | 1 2 3 4 5 6 7 8 9 JO « f t 1 / \ V 1 \ / w 1 1 \ 1 \ 1 1 •^ 1 \ 1 r \ I / 1 \ \ , '%: ■^/ 1 \ / ^ s/ \ y U V ■ m, ''//M/.: ;^^^M^^WS^ m > Case II. Case I. Case I. Case II. v////y////\ Nutrients peptonized 20 minutes. ■■■I Nutrients peptonized Z4- hours- ^^^/A'j^ Mouth feeding. 276 INDEX PAGE ABDERHALDEX, serum dia- gnosis of pregnancy . . lol Abdominal injury and shock 82, 86 — operations, intestinal paraly- sis after, treatment . . 118 physostrgmine after .. 117 value of novocain . . 103 Abel, red corpuscles in Locke's fluid for transfusion . . 21 Abscess of brain 248, 254, 256, 259 Absorption in gastro-intestinal tract 131 Achromatic spindle . . . , 148 Achsner on pituitary gland . . 188 Acidosis or acetonaemia . . 205 — in shock . . . . . . 87 Aconite as local analgesic . . 270 Acromegaly . . . . 191, 193 — operation on pituitary gland for 194 — viscera in . . . . . . 192 Addis on haemophilia . . 36, 37 Adenoma of thyroid . . . . 146 Adiposity and pituitary gland 192, 193 Adrenalin dangerous in shock — in osteomalacia — and ventricular fibrillation. . Adrenalin-chloroform, fatal com- bination . . Adrenalin-ether combination , . Agnosia . . Albee, bone graft in Pott's disease Albtmiinuria Albuminuria, calcium therapy in Alcohol harniful ia shock Alimentary canal, sensation in Alkalosis in shock (Moore) Alum in haemophilia Amblyopia from iodoform Amenorrhoea — and pituitary lesions — • — ■ feeding . . — relation of thyroid gland 145, 146 Amino-acids in shock . . Ammonia-nitrogen in shock . . Amputation at hip- joint and shocK . . . . 8 Anaemia, pemiciotis, haemorrhage in . . — spleen-extract therapy in . . 100 146 205 204 205 249 163 31 43 100 121 .. 39 .. 179 .. 194 146, 192 145, 195 87 38 26 PAGE Anaesthesia in cortical brain lesions . . . . . . 242 — Crile's anoci-association method 102 — intraspinal, danger of . . 96 — spinal, bad in war . . . . 102 Anaesthetic, choice of . . . . 102 — nitrous-oxide-oxygen best to prevent shock . . . . 102 Anaesthetics . . . . . . 105 — cutaneous, no action on un- broken skin . . . . 267 Anal canal, sensation in . . 122 Anaphylaxis after operations on hydatid cysts . . . . 42 — risks of . . . . . . 41 — symptoms . . . . . . 42 Anarthria of Marie 253, 254 Aneurysm and iodides 178, 180 — traumatic, ossification in , . 158 Anoci-association anaesthesia . . 102 Anterior horn diseases . . . . 217 Antipepsin . . . . . . 125 Antiperistalsis, surgical import- ance . . . . . . 113 Antiscorbutics . . . . 8, 10 Antithrombin . . . . . . 30 — not in excess in haemophilia 38 Antitoxic serums, risk of ana- phylaxis . . . . . . 42 Antitoxins absent from cerebro- spinal fluid . . . . 264 Aorta, atheroma of, after thyroid- ectomy . . . . . . 171 Aphasia . . . . . . 250, 251 — former and recent views on 251 Appendicitis . . . . . . 119 — and chronic dyspepsia 127, 128 — ileal stasis . . . . . . 115 — relation to gastric and duo- denal ulcers . . . . 126 Apraxia . . . . . . . . 248 — corpus callosum and 250, 251 Arctic expeditions and scurvy 8, 9 Arms, attitude in fracture of cervical spine . . . . 217 Arteries and capillaries, calibre may vary independently 84 in histamine poisoning . . 91 — contracted in shock 83, 84 INDEX 277 PAGE Arteriosclerosis and iodides 178, 180, 185 — in myxcedcma .. ,. 180 Astereoijnosis . . . . . . 242 Asthenia in cerebellar lesions . . 261 Asthma caused by foreign pro- tein . . . . . . 42 Ataxia in brain localization 1'57, 261, 263 — cerebellar lesions . . 260, 263 — posterior ner\-e-root lesions 225 Atheroma in cretin lambs . . 180 Athetosis, operation for . . 242 — and the optic thalamus . . 243 Atonia in cerebellar lesions 261, 263 Atropine in chloroform poisoning 204 — solutions apt to grow a very poisonous mould . . 204 Attraction, chemical, in nature 230 Autolysis in shock . . . . 90 Axon, growth of in embryo . . 230 Bacteria, quantity in faeces . . 132 Baldwin, Miss H., formation of oxalates from carbo- hydrates 199 Ballance on nerve anastomosis 234 Banti's disease . . . . . . 27 Bdrdny on experimental nystag- mus . . . . . , 261 Baumann, iodine in thyroid .. 172 Bayliss's gum-saline solution .. 101 Beans, germinating, antiscor- butic vitamines in . . 10 Bederc on exophthalmos . . 172 Bedford on suprarenal theory of shock . . . . . . 92 Beef, time remaining in stomach 110 Beer and scurvy . . . . lo Bell, Blair, on pituitary gland 188, 189, 194 Belladonna as local analgesic . . 270 — and milk secretion . . . . 147 — poisoning from local applica- tions . . . . , . 271 — and sweat glands . . . . 271 Benzol, effect on blood . . . , 32 Bergmark on flaccid paralysis.. 247 — on lesions of postcentral gyrus 242 — on motor reflex arc . . . . 209 Beri-beri . . . . . . . , 3 — asylum . . . , . . 4 — and husked rice . . . . 4 — in Malay States , . . . 4 — ' wet ' form . . . . . , 5 Berkeley, Glos., goitre well at . . 178 Betz cells, Limitation to ascend- ing frontal convolution. . 246 Bircher on goitre in rats . . 178 PACK Bireher on goitre wells . . . . 177 Bladder in spinal cord injury . . 224 Bland-SuUon on rickets at the London Zoo . . . . 11 Blindness and pituitary tumour 192 Blood, calcium salts and 43, 170 — coagulation of . . . . 28 causes of delay . . . . 35 results of deficient . . 31 time, coagulimeter . . 30 effect of bleeding on 35 — corpuscles, function of liver and spleen in relation to 25 formation of microcytes and poilkiJocytes from . . 25 — in shock . . . . . . 87 — diseases and the spleen . . 26 — donor, restoration of blood- volume of . . . . 87 — effect of benzol on . . . . 32 — estimation of volume . . 17 — fat in (McKibben, Short) . . 93 — in liaemophilia . . . , 33 — platelets . . . . . . 32 — pressure and curare. . . , 96 dangerous fall with intra- spinal anaesthesia . . 96 and depressor fibres . . 62 high, pulsus alternans in 78 and pituitary extract . , 190 result of lowered . . 98 in shock . . . . 82, 86 — • in purpura haemorrhagica . . 32 — restoration after haemor- rhage . . . . 16, 87 — red-cell increase in high altitudes . . . . . . 176 — researches on . . . . 16 — scorching and shock after bums . . . . . . 82 — serum proteids, restoration of 18 — transfusion . . . . , . 19 animal's blood toxic to man .. .. .. 19 effect of citrated blood. . 20 fate of red corpuscles . . 25 four blood groups . . 23 for haemophilia . . 20, 41 for haemorrhage.. .. 19 incompatibility and , . 22 for pernicious anaemia . . 20 risks and dangers of . . 22 in shock . . 20, 102 contracted veins may cause diflficulty 17, 83 test for blood groups . . 24 by means of red corpuscles in Locke's fluid . . . . 21 — volume after severe haemor- rhage , 18 278 INDEX PAGE Biood volume, fall in shock-hsB- moixhage . . . . 86 as a guide to prognosis ia shock . . . . . . 86 in obesity . . . . 18 pregnancy . . • . 18 reduced in shock . . 85 vital-red estimation . . 86 Boeke on end-plates . . • . 210 Bone-grafting (see Bone Growth) Bone growth . . . . . . lo2 blood-clot and . . . . 152 callus and . . . . 155 in animals . . . . 161 excessive . . . . 160 cambium layer . . . . 161 chips in omentum . . 158 continual change . . 156 and ductless glands . . 165 effect of tongue on jaw. . 156 toxins and internal secretions. . . . 156 epiphyses . . . . 153 after excision of elbow . . 157 exostoses . . . . 161 ■ factors inducing bone- corpuscles to proliferate 159 from fragments . . . . 158 in girth . . . . . . 154 grafting . . . . . . 163 — — — factors concerned in 164 fate of grafts . . 164 relation of osteoblasts 164 periosteum to . . 164 of rib-cartilage . . 165 Haversian canals . . 155 Hey Groves on . . . . 159 Hunter's experiment . . 153 interstitial changes . . 156 in length . . . . . . 153 Macewen on . . . . 153 madder experiment . . 154 • massage after fracture causing . . . . 160 myositis ossificans and 160, 161 osteoblasts and . . . . 152 periostitis and . . . . 161 periosteum in relation to 153, 154, 155, 156 — — recent research on 152, 155 regeneration of bone . . 155 apart from periosteum 157 — — — from periosteum 161, 163 in subperiosteal fractures 159 surgical apphcation of, researches on . . . . 159 Bowel manipulation arrests peri- stalsis . . . . . . 117 Boyd and Robertson, on rectal feeding 133 PAGB Brain, abscess in Eolandic area 248 — American crowbar case . . 247 — calcarine area and vision . . 238 — concussion and shock . . 81 — function of optic thalamus 243 — internal capsule in man and monkeys . . . . 246 and rigidity . . . . 247 — localization . . . . . . 237 of aphasia . . . . 251 apraxia . . . . . . 248 ataxia . . . . . . 257 cerebellar lesions . . 259 ■ Holmes' test . . 262 cerebellopontine tumours 262 and convulsions . . . . 255 of cortical lesions 237-254 cranial nerve palsies 255, 263 early and late developed signs . . , . . . 257 frontal cortex . . . . 245 of function . . . . 237 Head's observations . . 242 of hearing . . . . 239 Horsley's apparatus . . 259 macula . . . . 238, 239 motor initiating centre . . 250 of pain and pleasure . . 243 in right-handed people.. 250 of sensation 237, 240, 245 sense of space . . . . 245 Sherrington and Leyton's recent work . . . . 246 ' silent area ' . . . . 247 of speech functions (Marie) 253 tumours . . 246, 259, 262 vision . . . . . . 237 — meningitis . . . . . • 256 — primitive sensory cortex of 243 — results of cortical lesion . . 210 internal capsule lesion.. 210 — sensory cortex .. .. 2-14 — and spinal shock . . . . 95 — tumour of 250, 255, 257, 259, 262, 264 and colour vision . . 269 Breasts, pain in, from deficient thyroid secretion — ovary, effects of ' Brittle man ' . . Brown, Graham, on laughter in apes on motor path . . — on tetany after thyroid- ectomy Brown-Scqnard and testicular extract . . . . BurckharVs cases of aphasia Burdach, columns of 146 140 161 245 209 183 144 .. 252 212, 213 INDEX 279 PAGE Burrow and'Cartcr''on recovery- tune of injured nerves . . 232 Cabbage as antiscorbutic . . 10 ' Cachexia strumipriva * . . KifJ Ctacoplioation .. .. .. 120 CsBCum, ell'wt of acids and alkalies on . . , . 116 Calcium in blood .. .. 170 — chloride before operations^in jaundice . . . . '. . 38 for tetany . . . . 170 — and magnesium salts, relative value of . . . . . . 44 — metabolism and tetany 170, 171 — no effect on rickets . . . . 13 — salts and blood coagulation 29 effect on ovary . . . . 43 parathyroids . . 43 in haemophilia . . . . 36 for htemophilic bleeding 40 and menstruation . . 138 and menopause . . . • 142 reverse action of . . 40 ■ therapeutics of . . . . 43 Calculus, oxalate . . . . 200 — uric acid . . . . . . 200 — urinary, and x rays . . . . 200 Callus formation . . 155, 159 in animals . . . . 161 Calories required in food . . 1 Camphor in shock . . . . 100 Cancer of breast, effect of ovary on 140 — section of posterior nerve- roots for pain of . . .. 227 Cannon, blood-count in shock. . 85 — and others, acidosis in shock 87 Capillaries in histamine poisoning 84 — in shock . . . . 84, 94 Carbohydrate starvation . . 1 Carbohydrates, fermentation of 199 — formation of oxalates from 199 — in stomach . . . . . . 109 Carbolic acid as local anaesthetic 270 Carbon dioxide and intestinal movements . . . . 112 for hnnmophilic bleeding 40 Cardia, ' nodal tissue ' sphincter of 114 Carlson on hunger sensation . . 122 — on pain in gastric and du- odenal ulcer . . . . 122 Case on ileocsecal valve incom- petence . . . . . . 117 Castration and thyroid depriva- tion 167 Cauda equina lesions, operation in 224 tumour, diagnosis of . . 220 Cell renewal . . . . . . 147 PAOB Cerebellar peduncle, inferior, function of . . . . 210 — tracts 215 Cerebellopontine tumours . . 262 Cerebellum, abscess of . . . . 259 Cerebrospinal fluid, absence of antitoxins, etc., from . . 264 composition of . . . . 264 and urotroi)ine . . . . 265 Cretinism, treatment of . . 173 Charcot joints, experimental . . 225 Chick and Hume, antiscorbutic value of lemon-juice and of lime-juice . . . . 10 Chilblains 31 — calcium salts in . . . . 44 Children, diet table for. . . . 14 — small, and pituitary gland. . 195 Chittenden on food required . . 2 Chloroform as anaesthetic . . 102 — poisoning . . . . . . 201 action on medulla . . 201 viscera and acidosis. . 201 adrenalin increases danger 204 atropine in . . . . 204 in cats 202 dangers leading to . . 202 delayed 205 — ■ and acidosis . . . . 205 pathology of . . 206 prevention . . . . 206 signs of . . . . 206 fibrillation of ventricle in 77, 202 heart massage in . . 204 — ■ — not due to vagus . . 202 — • — prevention by scopolamine 204 sudden arrest of heart . . 201 treatment . . . . 203 Cholera, hypertonic saline solu- tion for . . . . . . 103 Chromosome, additional, as a factor in the causation of sex . . . . . . 151 Chronic dyspiepsia and appendi- citis 127 Citrated blood, action of . . 20 Coagulation time in jaundice . . 38 Coagulimeter . . . . . . 30 Cocaine and the skin . . 267, 271 Cochlear nuclei . . . . . . 240 Cod-liver oil, effect on teeth . . 13 Coffee in shock . . . . . . 99 Cold in myxcedema . . . . 167 Colic, intestinal, cause of . . 118 Colitis and tetany . . . . 170 Colon, absorption in . . . . 131 — not necessary . . . . 132 Colour vision and intracranial tumour .. .. 259, 263 280 INDEX PAGE Constipation . . . . . . 118 Conus medullaris, tumour, dia- gnosis of . . . . . . 220 Corpus luteum, function of . . 141 Corpuscles, nucleated red . . 18 — red, fate of . . . . . . 25 Cotter, the Bristol giant . . 191 Cresyl-blue in blood examination 18 Cretinism and the thyroid gland 165 Crile method of anaesthesia . . 102 — on morphia in shock . . 99 — and Dolley on nerve cells in shock 88 Croton oil as purgative. . . . 118 Cryptorchism . . . . . , 142 — and ductless glands of . . 145 Cuneate nucleus .. .. 213 Curare and blood pressure . . 96 Cushing on blue-blindness . . 259 — on cerebellar tumour opera- tions 264 — on localization of hearing . . 240 — on pituitary gland . . 188, 194 — — operations . . . . 194 — on postcentral convolution 241 — and Bordley on optic neuritis 257 Cushing' s giant . . . . . . 191 Cutler on iodoform . . . , 178 PAGE 28 Dale on histamine and shock . , — and Laidlaw on histamine and and shock . . 91 Deafness De Buck, case of apraxia Deep sensibility . . Deiter's nucleus . . Bejerine on aphasia Dermatitis from iodoform Diabetic acidosis or acetonsemia Diabetics, general antethesia in Diarrhoea — lienteric Digitalis as a cause of sinus arrhythmia — and fibrillation — in shock Diphtheria antitoxin in haemo- philia D.T.P., or ' distal tingling on percussion ' Diuretic, pituitary extract as . . Lixon on atropine in chloroform poisoning Dog and sugar feeding . . Dropsy after saline transfusion Duhamel, experiment on bone growth . . . . 154, Dukes and Short, ammonia- nitrogen in shock Duodenojejunal flexure sphincter 84 , 94 240 249 212 222 253 178 205 206 111 113 64 74 101 40 196 204 199 104 157 114 ECK'S fistula Eczema, test for foreign protein as cause of Edmunds on exophthalmos — goitre in fowl — parathyroids — tetany Egg albumen, cause of asthma and hay fever . . — antineuritic substance, in . . — time remaining in stomach Eiselsherg, von, on atheroma in cretin lambs — on thyroidectomy in animals Elbow, excision of Electrocardiography Eloesser on trophic lesions Embolism of osteoblasts a possible cause of myositis ossificans Embryology of nerves . . Emotional movements and optic thalamus End-plates, medullated and non- meduUated Enemata, nutrient, chart of nitrogen output. . report of cases . . Enophthalmos as a consequence of thyroidectomy Epicritic sense . . Epilepsy, idiopathic, as a cause of localized convulsion . . — Jacksonian, and brain locali- zation Epiphyses, growth of . . Erepsin . . Erlanger and Gasser, blood-volume in pure shock . . gum and dextrose solution Ether as anaesthetic * Exam.-funk diarrhoea' Exopiithalmic goitre — • — cause pathology practical deductions treatment Exophthalmos in thyroid feeding 168, 172 Exostoses . . . . . . 161 Fabre and Thevenvt on congenital goitre . . . . . . 176 Facial paralysis and optic thala- mus 243 Faecies, bacteria in . . . . 132 Fallopian tube . . . . . . 139 Fat in blood 93 stomach . . . . 109 — effect on teeth . . . . 13 43 172 175 169 183 43 5 110 180 171 1 52 225 161 230 243 210 275 273 167 212 255 255 153 133 86 101 102 111 181 181 181 184 184 INDEX 281 PAGE 6 6 205 206 191 128 39 31 30 29 29 36 31 14: Fat-soluble A . . Fat-starvation . . Fatfs aiiimal-derived, importance of — katabolism of Fatty desreneration in delayed chloroform poisoning Fatccftt on Bristol eiant Fenwick on hyperchlorbydria Ferric chloride in hemophilic blee«iing . . Fibrin — ferment, a misnomer — table showing formation of Fibrinoeen — in haemophilia Fibrinolysins Foetus, internal secretion from, as cause of lactation Food, calories required in — deficiency diseases . . and vitamines signs of . . — fat required in — minimum nitrocreii required in — proteid require-! in . . — reqniremencs of man foreign protein as a cause of eczema test Forssman on nerve regeneration Fractores, disadvantage of mas- sage and movements after 160, 161 — regeneration after . . . . 155 — repair of . . . . . . 159 — ununited, thyroid feeding and potassium iodide for . . Froe, ovum development Frdhlich on pituitary and infantilism Frontopontic and temporopontic tracts and muscle tone . . Fruits and oxaluria Funk, Casimir, and beri-beri . . 3 — 1 — 43 43 231 165 149 192 210 200 4 Gall-bladder and gastric and duodenal ulcers . . 126 Gall-stone colic and arrest of peristalsis . . . , 117 Gas-gangrene and shock-like symptoms . . . . 90 ' Gas-pains * after abdominal operations . . . . 103 Gastralgia 122 Gastric crises, section of posterior nerve roots for . . 226 — and duodenal ulcer, causes of pain in . . . . . . 122 — ulcer 119 PAGE Gastric'nlcer, action of acid and alkalies . . . . . . 122 difficulty of diagnosis . . 127 excision of . . . , 128 and hydrochloric acid .. 121 hyperchlorbydria . . 125 Gastrojejunostomy . . . , 128 — cause of failure . . . . 125 — digestion after . . . . 130 — effect on hydrochloric acid. . 130 — physiology of . . . . 129 ' Gastrostaxis ' 129 Genital atrophy and hyi)o- pituitism — glands — glands, control by internal secretions GennarL white line of Geseli on fall of blood-pressure and blood-flow Gigantism — operation on pituitary for Gland, pineal overgrowth of — pituitary and pineal sterility and impotence associated with — suprarenal, enlargement — thyroid and amenorrhoea Glands, ductless, before and after puberty methods of study Glans penis, protopathic sense dey on parathyroids Glucose, deficient, effect of Glycosuria and pituitarr gland "189, 192, 193 — sympathetic system — vagi . . Goitre, exophthalmic (see Exoph- thalmic Goitre) (joitre (see also Thyroid) — on (Captain Cook's voyage . . — in carboniferous limestone district in Derbyshire — congenital — and drinking-water — in fowls on meat diet — iodine in relation to — parenchymatous — prevention bv iodiferous rock- salt '. . . , 174, 176 — reason of enlargement of thyroid .. .. .. 175 — theory of bacterial origin . . 177 — thymol in .. .. .. 177 — treatment .. .. .. 174 — wells .. 174, 176, 177, 178, 184 194 137 144 237 98 191, 193 194 197 145 145 186 146 145 145 146 145 187 212 169 205 189 189 174 173 176 173, 177 175 173, 175 173, 182 282 INDEX PAGE Goitre in whelps . . . . 168 GoU, columns of . . .. .. 213 Goodman, transfusion in haemo- philia . . . . . . 41 Gower's tract .. .. .. 213 Gracile nucleus .. .. .. 213 Groves, Hey. on bone growth . . 159 and Walker Hall, on colon 132 Growth in relation to vitamines 5 Griinbaum, oedema of lungs after saline transfusion . . 104 Guanidine intoxication and tetany . . . . . . 170 Gull and Ord on myxoedema . . 166 Gummata, iodides, and thyroid extract . . . . " 178, 180 Gum-saline solution in shock . . 101 HiEMATEMESiS uithout ulcer . . 128 Haemoglobin after haemorrhage 18 Haemolytic toxin in spleen . . 27 Haemophilia . . . . . . 33 — antithrombin not in excess in 38 — blood transfusion for . . 20 — calcium salts for . . . .36, 40 — carbon dioxide gas for . . 40 — causes of delay in coagulation 35 — deficiency of polymorplis in 35 — delay in thrombin formation 36 • — delayed coagulation time . . 34 — effect of locaUty and nature of injury . . — fibrinogen in. . — fragility of vessel wall in . . — horse-serum for — magnesium lactate for — non-hereditary cases — normal human blood for . . — prothrombin in . . 36, — relation of leucocytes to . . — researches of Addis 36, — reverse action of calcium salts — round-bodied needle in — Sahli on — spontaneous arrest of bleeding — styptics for . . — thrombokinase in . . — transfusion for — treatment of bleeding — — causes — Wright's physiological styptic for Haemorrhage, blood-pressure after — blood transfusion for — blood volume after severe . . — due to food deficiency — in haemophilia (see Haemo- philia) 36 35 40 40 34 39 37 37 37 40 39 36 34 39 36 41 39 38 39 17 19 18 40 PAGE Haemorrhage, jaundice and 28, 38 — nucleated red corpuscles in regeneration after . . 18 — in pernicious anaemia . . 38 — purpura . . . . . . 38 — recovery after . . . . 16 proteins after . . . . 18 — red marrow increased after 18 — restoration of blood-serum — proteins after . . . . 18 — reticulated cells in blood after 18 — in scurvy . . . . . . 38 — secondary, in war . . . . 16 — and shock . . . . . . 81 — spasm in veins after . . 17 Halliburton and Drummond, on fat-soluble A . . . . 6 Eandelsman on pituitary . . 188 Harrison, Ross, on growth of axon . . . . . . 230 Edrtel on gastrojejunostomy • . 130 Hatteria's functionless unpaired eye 197 Hay fever, foreign protein as a cause of . . . . . . 42 test for . . . . 43 Head on localization of sensation 242 — on peripheral sensation . • 212 — spinal areas . . . . . . 225 Headache . . . . . . 31 — ' lymphatic,' calcium salts for 43 — and pituitary gland . . 195 Hearing, cerebral localization . . 239 Heart, the 45 — abnormal ventricular complex 74 — afferent nen-es from . . 62 — arrhythmias of . . . . 63 prognosis in . . . . 78 — atrioventricular rhythm 52, 56, 57 — atropine and the . . . . 61, 68 — auricle and ventricle syn- chronous . . . . . . 52 — auricular fibrillation 52, 75, 79 flutter 79 — auriculo-ventricular bundle 47, 55 rate of conduction . . 58 node . . 47, 55, 71 — in birds, conduction path . . 48 — block 61, 64, 65, 67, 78 effect of atropine .. 68 — blood-vessels in shock . , 83 — complete irregularity of . . 52 — complexes from abnormal beats . . . . . . 54 — conduction path in man . . 47 — contractile power . . . . 61 — currents . . . . 52, 54 — depressor nerve fibres and blood pressure . . . . 62 — development and structure 45 INDEX 288 PAGE Heart, different actions of right and left vajn • • • • ^'^ — diaitalis as cause of fibrillation 47 — effect of movement and emotions on . . . . 03 riieumatism on . . 64, 76 — electrocardiotrrapby of . . 52 — extrasystoles of . . . . 69 — graphic methods, necessity 73 idioventricular riiythm 57, 01, 65, 66, 76 — irrepiilarities of . . . . 63 defect in conductivity . . 64 contractility . . . . 77 increased excitability . . 68 of nervous orii^in . . 63 — lesions of auriculoventricular node and bundle . . 68 — and medulla . . . . . . 60 — modes of examination . . 48 — miiscle, properties of . . 57 — nature of stimulus causing contraction . . . . 58 — nen'ous system of . . . . 60 — pace-makers of . . . . 57 — pain in . . . . . . 63 — paroxysmal tachycardia . . 74 — point of origin of heart beat 47 — polygraphic tracings . . 48 — premature beats . . 66, 69 pulsus altemans with 78 sisznificance . . . . 72 — pulsus altemans .. .. 77 — rate of beat, factors of . . 62 — refractory period . . . . 59 — retrograde beat in tachycardia 74 — reversed rhythm , . . . 47 — rhythms . . . . 56, 75 — sino-auricular node . . . . 47 — sinus arrhvthmia . . 63, 78 — stand-still" of .. 64, 67 — sympathetic fibres, action of 62 — tachycardia . . 62, 69, 73, 75 — tonicit.v of . . . . . . 59 — vagus nerve, action of . . 61 — ventricular fibrillation from adrenalin . . . . 205 in chloroform poisoning 77 Hemianaesthesia . . . . . . 243 Hemianopia . . . . 238, 243 Hemiplegia 209, 226, 243, 249 Heparin . . . . . . 30 Heredity 148 Hernia, stranqnlated, and arrest of peristalsis .. .. 117 Hindhede on food required . . 2 Histamine poisoning and shock 84, 91^ 94 Holmes, Gordon, on cerebellar lesions 262 PAGB Holmes, Oordon, and Lister on hemianopia . . . . 238 Hopkins on vitamines . . . . 6 'Hormonal' 120 Hormone, peristaltic . . . . 120 Honnones from ductless glands 144 Horse-serum for hajmophilic bleeding . . . . . . 40 Horsley on pituitary . . . • 188 — on removal of cortical centre 241 — and Clarke on the cerebellum 259 Hoicland and MarrioU on blood calcium in tetany . . 170 Hunt, Ramsay, on double motor path in nerves .. .. 210 on nerve suture . . . . 211 — and Seidel on activity of thyroid .. .. •• 1"5 on iodine in thyroid • . 175 on iodoform and thyroid 179 Hunter, experiment on bone growth . . . . . • 15S Hunter's giant . . . . . . 191 Hurst on ileocaecal sphincter . . 114 — on sensory functions of viscera 121 Huriritz on blood-serum proteids 18 Hydatid cysts, risk of anaphylaxis in operations on . . . . 42 Hydraemic plethora after saline transfusion . . . . 104 Hydrocephalus . . . . 256, 265 Hydrochloric acid in stomach, variations in .. .. 123 Hyperchlorhydria and gastric ulcer . . . . . . 125 — organic disease .. •• 126 — pyloric spasm . . • • 125 — relation to appendix and gall-bladder .. .,126 — treatment . . . . . . 128 Hypernephroma, effect of . . 145 Hyperpituitism, results of .. 193 — treatment . . . . • • 194 Hyperthyroidism in soldiers . . 182 Hypopituitism (Frohlich type), treatment . . . • 195 — results of 193 ILEAL kink 119 — stasis and gastric stasis . . 116 Ileocaecal sphincter, clinical observation of . . . . 115 function of . . . . 114 gastric symptoms .. 127 incompetence of . . 117 Heosigmoidostomy, ileal safety- valve operation . . 114, 120 — discomfort after .. -. 113 Ileum, artificial anus in, may be fatal 132 284 INDEX PAGE Impotence . . . . 146, 194 — and pituitary trland. . . . 192 Iodine and thyroid 174, 175, 178, 180, 182 Iodoform poisoning and tyhroid- ism .. .. .. 178 lodothyrin .. 172, 175, 181 Infantile palsy .. .. .. 217 Infantilism and pituitary gland 192, 193 Infants, two forms of dyspepsia in 126 Infections, acute, and shock . . Internal capsule, lesions of Intestinal colic, cause of — paralysis toxjemia in shock ■ treatment of . — shock — stasis, hypochlorhydria and Intestines, antiperistalsis in . . — mimicry of chronic stasis . . — constipation and — isolated loop causes fatal toxaemia . . — Jackson's pericolic membrane — Lane's chronic intestinal stasis in . . movements of — nervous mechanism of — and nervous reflexes — peristalsis of — toxins in stasis Intoxication hydatique 81 210 118 81 118, 196 11 127 112 119 118 120 119 119 111 111 119 111 120 42 JaCKSOK'S pericolic membrane 119 Javmdice, calcium chloride before operations in . . . . 38 — coagulation time in. . . . 38 — haemorrhage in . . . . 38 — risk of operations in . . 38 Jaw, shape of . . . . . . 1-56 Johnson on hyperthyroidism . . 182 Keith's ' vital red ' method of estimating blood volume 17 — on blood-volume in shock 86, 87 — on sphincters of gastro-iutes- tinal tube . . . . 114 KendaU, indol derivative from thyroid 173 Kerr on blood-serum proteids . . 18 Kidney hypertrophy, reason of 176 — movable, and gastric sym- ptoms . . . . . . 127 Kinsesthetic sense . . . . 212 Knee-jerks in shock . . . . 82 Kocher on parathyroids and tetany . . . . . . 183 Kohn on parathjToids . . . . 169 Kropfbrunnen or goitre wells 174, 176, 177 PAGB Labour pains, caution necessary in using pituitary extract for 196 Labyrinth and nystagmus . . 262 — vertigo 262 Lactation, foetal internal secre- tion and . . . . 147 — belladonna, pilocarpine and 147 — pituitary extract and 147, 190, 196 — recent increase of . . 146 — in Siamese twins . . . . 147 — 'witch's milk .. .. 147 Laidlaw and Ryffel, on rectal feeding . . . . . . 132 Lane's chronic intestinal stasis 119 Langley on nerve anastomoses. . 234 Lard, absence of fat-soluble A in 6 Lasesne's sign . . . . . . 220 Lassitude due to food deficiency 7 Lee and Minot on blood platelets 32 Left-handed persons, proportion of. in community . . 250 Lemon-juice and scurvy . . 8 Lenticular nucleus . . . . 210 Leriche and Policarde on cartilage grafts . . . . . . 165 Leucocytes and chemical attrac- tion 231 — in haemophilia . . 35, 37 Levy on adrenalin and the heart 205 — on chloroform poisoning . . 202 Liepman on apraxia . . 248, 249 Lime juice and scurvy . . . . 8 Lissauer"s tract . . . . . . 212 Liver and antithrombin forma- tion 30 — blood-destroying functions of 28 — not engorged in shock . . 84 — and restoration of blood pro- teins after haemorrhage. . 19 Lumbar piancture, aid in dia- gnosis . . . . . . 265 Lungs, (Oedema of, after saline transfusion . . . . 104 Macallum on tetany . . . . 183 McCarrison on endemic eroitre. . 177 — effect of rice on adrenals, testes, ovaries, and spleen 5 Macewen on bone growth 153, 155, 161 Magnesium lactate in haBmophilic bleeding . . . . . . 40 — salts more effectual than calcium . , . . . . 44 M'alnutrition and tetany . . 170 Margarine content of fat-soluble A 6 Marie on aphasia . . 251, 252 Marine on prevention of goitre in lambs and do^ . . 174 INDEX 285 PAG£ Harrow chances after splen- ectomy . . . . . . 27 Mtnhall and Heapt on menstrua- tion in animals . . . . 138 Iffeat, antineuritic substance in 5 — fresh, as antiscorbutic 8, 10 amount of vitamine in . . 9 Median nerve, recovery time after injury . . . . 232 Mecakaryocytes and platelets.. 32 Ueilanby on rickets .. 12, 13 Meninffitis . . . . 256, 257 — and cardiac arrtjythmia — lumbar puncture in . . — septic, atropine in . . Menopause, artificial, and ovarian feeding — and calcium salts . . 44, 142 Menstrual headache and pituitary extract Menstruation — painful — precocious Mental lethargy in bypopitui- tism . . Menthol as local analgesic Metabolism in shock. . Microcytes, source of . . Milk (see also Lactation) — antineuritic substance in . . — as an antiscorbutic . . — as a cause of asthma and hay fever. . — clotting in stomach, reason for — efifect on rickets teeth — fat-soluble A in — long pancreatized as nutrient enema — secretion of . . Mitosis Moore on alkalosis in shock Moratcski on pituitary . . Morphia in shock Moss on blood groups . , Motor path, the double . . MoU on nerve cells in shock . . MoU and Hailiburton on nerve regeneration Mould, poisonous, in atropine solutions Motissu on parathyroids Murray on thyroid feeding . . Muscle end-plates — heart and skeletal compared — refractory period — striped, structure and function 211 — submaiimal contractions . . 59 — tone 59, 210 63 265 265 141 — 195 137 146 145 194 27U 87 11 43 109 13 13 6 273 146 148 88 183 99 23 208 88 229 204 169 166 210 59 59 PAGE Muscle tone, loss of. in poet- central injury . . . . 245 in posterior nerve-root injury .. ..225 in shock . . 95, 96 and vestibular nerve nuclei .. .. 95, 98 — unstriped, and pituitary extract . . 190, 196 Musculospiral nerve injury, recovery time . . spontaneous recovery Music, effect of, in brain injury Myelitis, transverse Myositis o^ificans, traumatic, cause and treatment of . . universal, cause of Myxoedema . . . . 166, — arteriosclerosis — in monkeys . . — tetanv and — and thyroid grafting — treatment Nerve, anastomosis of . . — ceUs in shock . . 88 — diagnosis of injury to — effects of notching . . — injury, chemical attraction of new fibre in . . electrical tests of limited value . . end-to-end suture for . . Forssman's experiments incomplete section medullary degeneration — — operation for, by anasto- mosis . . — bridging Cargile membrane . . — — - — choice of devices for approxi- mating divided ends by grafting . . 233, — splitting — ■ tendon transplanting — transplantation 233, reaction of degeneration not always reliable . . prognosis — - — recovery time after 231, regeneration after repair of . . secondary suture, causes of failure — — spontaneous recovery from — — ■ time for operation 228, — — Tinel's test Trotter's phenomenon . . war experience of 232 228 243 216 160 161 171 180 168 167 183 173 235 , 93 227 235 230 227 235 231 233 230 234 233 234 233 236 235 233 236 235 227 332 232 229 227 231 227 231 228 233 235 286 INDEX PAGE Nerve roots, posterior, function of 209 section of . . 213, 225 structure of , . . . 212 surgery of . . . . 226 — supply of flexors and extensors 217 — peripheral, non-medullated fibres in . . . . . . 211 — sensory, overlapping of . . 216 — spinal, segmental distribution 216, 218 Nervous diseases and arrest of peristalsis . . . . 117 — instability in soldiers . . 182 — system, central, regeneration of 224 Neurasthenia, traumatic . . 221 Neuritis and beri-beri . . . . 3 Neuroses and arrest of peristalsis 117 Nitrogen absorption from amino- acids .. .. .. 273 — increased excretion after amino-acid feeding • . 274 — output after nutrient enemata 275 Notthajt on exophthalmos . . 172 Novocain for anoci-association anaesthesia . . . . 103 Nutrient enema, useful form of 134, 136 Nystagmus in cerebellar lesions 261, 263 — differential diagnosis of cause 262 Obesity, blood volume in . . 18 CEsophagus, temperature and tactile sense in . . . . 121 Oophorectomy, effects of . . 140 Operations, prevention of shock in 102 Opium, effect of, on skin . . 270 Optic atrophy from iodoform . . 179 — neuritis . . . . . . 257 — ■ thalamus, function of . . 243 Oranses as antiscorbutics . . 10 Osteoblasts .. 152, 154, 155 — embolism from . . . . 161 Osteomalacia and parathyroids 170 — treatment by adrenalin . . 146 — and ovary . . . . . . 141 Osicald on iodine in thyroid 175, 176 — on iodothyrin . . 172, 175 Ovary affected by polished rice diet . . . . . . 5 — effect of calcium salts on . . 43 — functions and structure . . 137 — graft of 140 — internal secretion of 138, 140, 141, 145 — internal secretion, effect of excessive . . . . 145 on mammary cancer 140 Ovary, internal secretion, on vascular system — and lactation — menstruation — before puberty — and osteomalacia Ovulation Ovum, development of. . — and heredity Oxalate calculi . . Oxalates, metabolism of — from carbohydrates.. — sources of Oxaluria . . — treatment of Oxygen famine in shock effect PAGB 140 147 137 145 141 138 147 148 200 198 199 198 198 200 98 Pacchionian bodies . . . . 265 Pain, localization of . . . . 243 — in nerve injury . . . . 229 — section of pain-fibres in cord for 220 posterior nerve-roots for 226 Paralysis, bilateral spastic . . 216 — of cranial nerves . . 255, 263 — flaccid 247 — functional, from division of posterior nerve-roots . . 225 — infantile, nerve anastomosis in 235 — spastic . . . • . . 256 Paraplegia, spastic, section of posterior nerve-roots for Parasyphilis of central nervous system Parathyroid glands effect of calcium salts on — removal of . and osteomalacia secretion of and tetany Pardee on pituitary Pastures, difference in . . Paton, Noel, on tetany . . Paulesco on pituitary . . Pearce on spleen and blood corpuscles Peas, germinating, antiscorbutic vitamines in Pelvirectal sphincter Periosteum (see also Bone Growth) — Macewen's views on role of — preservation in operations . . Peristalsis, arrest of, causes and treatment — pituitary extract . . 118, 196 Periostitis and formation of new bone . . . . . . 161 Pernicious anjemia, blood trans- fusion for . . . . 20 Perroncito on nerve regeneration 229 226 265 166 43 169, 183 ., 170 .. 183 170, 183 .. 196 7 .. 170 188 26 10 114 156 163 117 INDEX 287 PAGB Physostipmine in arrest of peristalsis . . . . 117 Piceons, neuritis in . . . . 4 Pike on spinal shock and blood- pressure . . . . . . 96 Pilocarpine and milk secretion 147 Pineal glands . . . . 145, 197 Pituitary extract for intestinal paralysis . . 100, 118, 196 for labour-pains, caution 196 and lactation 147, 190, 196 in shock . . . . . . 196 and unstriped muscle 190, 196 usage and dosage 190, 195, 196 — feeding causes emaciation . . 190 for delayed puberty . . 145 harmful in acromegaly.. 194 and headache . . . . 195 — gland and acromegaly 191, 193 and adiposity . . . . 192 anatomy of . . . . 186 and bone growth 156, 165 and blood-pressure . . 190 clinical results of lesions of 191 — — connection with thyroid 190 effects of removal of 145, 187, 192 functions of .. .. 193 gigantism 191, 193,19-4 in hyperpituitism and hypopituitism . . 193 and infantilism 189, 192, 193 and malignant growths 194 relation to sterility and impotence . . . . 146 and sugar metabolism 189, 192, 194 — tumour and blindness 192, 194 x-ray diagnosis of . . 192 Pleasure, localization of sensa- tion of 243 Poikilocytes, source of.. .. 25 Pollen a cause of asthma and hay fever . . . . 43 Potassium citrate and oxaluria 200 in shock . . . . . . 99 Potatoes as antiscorbutic . . 10 Pott's disease, Albee's bone- grafting for . . . . 163 Phloroglucin and vanillin test for HCl 123 Precocity, pineal tumour and.. 197 Pregnancy after bilateral ovari- otomy 139 — blood-volume in . , . . lb — chemical diagnosis , . . . 151 — and coagulation time of blood 30 Proantithrombin . . . . 30 Prostate, atrophy after castra- tion 143 PAGE Protein in diet . . . . . . 2 — foreign, cause of asthma and hay fever . . . . 42 — placental, serum diagnosis of pregnancy from . . 151 — in stomach . , . . . . 109 Prothrombin . . . . . . 29 — in haemophilia . . 36, 37 Protopathic sense .. .. 212 Puberty, delayed and pjecocious 145 Pugilist's ' knock-out blow ' on chin 98 Pulse tracings . . . . . . 48 Pupil, dilating fibres of . . 217 Purpura 28, 38 — hjemorrhagica . . . . 32 Pylorus, action of . . . . 108 — congenital stenosis of • . 126 — spasm of, and hvperchlor- hydria . . ' . . . . 125 — sphincter .. .. .. 114 Pyramidal tract . . . . 208 and muscle tone . . 210 Pyrosis . . . . . . . . 125 Ql1NrS"E-UREA-HYDR0CHT/0RroE for anoci-association ames- thesia 103 Ranke, diet tables . . . . 3 Ransom on sensory paths in cord 212 — and Laycock on sensation . . 241 Ranaom'.^ silver-pyridine method 210 Rectal feeding . . . . . . 132 Rectum, absorptive power of . . 132 Red marrow increased after haemorrhage . . . . 18 Red nucleus . . . . . . 210 Renal calculi mostly oxalate . . 200 Reticulated cells after haemorrhage 18 Retina, representation in cortex 238 Rhubarb and oxaluria . . . . 198 Rice and beri-beri . . . . 4 Rice-husk extract as antineuritic 5 Rickets 11 Ri'ldoch on injury of spinal cord 223 Right-handed people, brain localization . . • . 250 Rigidity 247 — decerebrate . . 95, 209, 210 Ringer's fluid . . . . . . 104 Roger on nerve-cell inhibition or fatigue in shock . . 93 Rogers, hypertonic saline solution in cholera . . . . 103 Romney, difference in pastures at 7 Roos on activity of thjrroid . . 175 — on thyroid feeding . . 172 Rous and Turner, on preserved red corpuscles . . . . 21 288 INDEX PAGE 36 99 103 169 PAGE Sahli on haemophilia . . Saline, rectal, in shock. . — solution in cholera (Rogers) Sandstrom on parathyroids Sarcoma cells, action of vita- mines on . . ScTiafer on pituitary gland . . Sciatic nerve, section of, effect on vessels Scopolamine in general anaesthesia 204 Scurvy . . . . . . • • 7 — haemorrhage in . . . . ^ 38 — infantile . . • . ", 11 Sea-urchins, ovum development in . . Sensation in alimentary canal. . — peripheral Sense, epicritic . . — muscle, joint, and tactUe, path of . . . . 214, 216 — pam . . . . • • -'-"» --■'■ and temperature, path of 214, 216 195 84 149 121 212 212 21: 212 212 42 149 145 132 — protopathic . . Sensibility, deep Sensory path, double Serum sickness . . Sex, causation of Sexual precosity Sharkei/ on rectal feeding Sfierreii on appendix in duodenal and gastric ulcers — on time relations in nerve injuries . . Sherrington on motor reflex arc — on pain impulses — on pain-path — on postcentral cortex — on spinal areas shock — on transection of cord — and Leyton on Broca's convolution recent brain localization on ' silent area ' Schi^ on thyroid Shock (see also under intra venous transfusion) — after abdominal injury 82, 86 — abdominal vessels not dilated 84 — acapnia theory of . . — acidosis in . . — adrenalin dangerous in — alcohol harmful in . . — alkaline and saline trans- fusions in — arteries contracted in — blood-count in 85, S — blood-pressure in — blood stagnation in 126 231 209 214 220 241 225 95 221 252 246 248 166 80 92 87 100 100 88 83 87, 94 94, 96 . 86 Shock, blood volume in . . — capillaries in — changes in cells of liver, adrenals, and brain (Crile) nerve cells — chemical poisoning (auto- lysis) theory of . . — (Mle's method of prevention — crush-products as a cause of — diagnosis of . . — experimental — heart and blood-vessels in — and histamine poisoning — ' intestinal ' , . — intravenous saline trans- fusion for — knee-jerks in — metabolLsm in — morfihia in . — phenomena of pituitary extract in 84 93 90 102 89 81 89 . 83 91, 94 . 117 . 103 . 82 . 87 99 . 82 100, 196 pre'^ention and treatment of 98 — prognosis from blood-volume and blood-pressure . . 86 saline per rectum in . . 106 — spinal . . . . 94, 221 — spasmodic contraction of superficial veins in . . 83 — strychnine useless, possibly dangerous, in . . . . 100 — theories of . . . . . . 91 — treatment, blood-transfusion 102 camphor . . . . . . 100 fluids 98 digitalin 100 gum and dextrose solution (Erlanger and Gasser) 101 gum-saline solution (Bay- liss) 101 potassium citrate . . 99 saline by rectum . . 99 transfusion . . . . 101 sleep 99 tea or coffee . . . . 99 warmth . . . . . • 99 Short, Rendle on absorption of aminoacids by rectum . . 133 — on absorption of nitrogen from amino-acids. 273 — on blood-count in shock . . 86 — on blood pressure . . . . 225 — on blood C0„ in shock , . 92 — on blood-volume in shock 85, 86 — on chronic thyroid intoxica- tion and iodoform ,. 179 — on nerve cells in shock . . 88 — on nerve injuries . . . . 235 — on oxaluria . . . . . • 198 — on rectal feeding . . . . 133 — on suprarenal theory of shock 92 INDEX 289 PAGE 181 97 Shctrt, Rendle, on svphilitic ulcers — tlieorj- of sliock — treatment of intestinal par- alysis — on wound of frontal lobe — and Salisbury on cutaneous ansEsthetics Sinus arrhythmia Sinu-auricuhir node Skin, unbroken, and local anses thetics Sleep in shock . . Smell a chemical aialysis Smith, Miff A. //., on value of lime-juice Sorrel and oxalates Souttar on gastric crises of tabes Space, recognition of . . Spasticity Spermatozoon, chemical action — division of . . Sphincters of pastro-intestinal tube (Keith) Spinal cord, complete transec tion, effects of . . Spinal cord, concussion of 81, 221, 222 degenerative changes after division of posterior nerve- roots . . functions of injuries, diagnosis of . operation for sensory paths tumours, effects of — shock Spinothalmic tracts Spleen affected by polished rice diet — and blood corpuscles diseases . . — haemolytic toxin in spleno- megaly Splenectomy in dogs, changes after — in man Splenic vein, diversion into in- ferior vena cava as sub- substitute for splenectomy Splenomegaly Squint, convergent, due to dis- placement of brain Starfish, development of ovum of Starling and Lane-Claypon on lactation . . Starr on tumours of cerebello- pontine angle Starvation, carbohydrate — fat — protein 118 247 267 63, 64 63 267 99 231 9 198 220 244 209 of 149 148 114 226 . . 208 . . 221 .. 223 212 '. '. 214 94, 221 . . 213 27 255 149 14? 263 1 2 2 92 64 125 126 170 121 126 109 109 108 128 PAGE Starvation, survival in . . 1 35 Sterility .. 142, 143, 146, 194 StereocmosLs 212, 213, 214, 233 Sleicart and Rogoff on suprarenal theory of shock . . Stokes-Adams syndrome Stomach, antipepsin in — congenital pyloric stenosis — dilatation and tetany — distention of — dyspepsia in infants — effect on, of tickling ribs — fast and slow types . . — form of, in life — hemorrhage without ulcer — and 'hunger-pain' 124, 126 — hunger sensation . . . . 122 — hyperchlorhydria . . 124, 125 and on^anic disease .. 126 treatment of . . . . 128 — and intestines, absence of temperature and tactile sense in . . functions of pain in . . the seven sphincters of — movements of delay in . . effect of character of food methods of observation of — peristalsis of . . recorded by balloon — post-mortem digestion of . . — reflex flow of gastric juice after nutrient enema . . — self-digestion of — self-regulating mechanism of acidity — stasis in . . 109, 116, 119 — symptoms associated with disease of appendix, gall- bladder, etc. — time of emptying and total acidity in relation to various foods — total acidity . . — variations in hydrochloric acid — r-ray examination of Strawberries and oxalates Strychnine in shock Styptics in haemophilic bleeding Sugar metabolism and pituitary gland Suprarenal gland, enlargement effect of polished rice diet Swedes as an antiscorbutic . . Sympathetic ganglion, superior cervicaC stimulation of, causes glycosuria 121 107 121 114 107 111 109 107 108 122 125 135 124 123 127 109 123 123 107 198 100 39 194 145 5 10 189 290 INDEX PAGE Syphilitic ulcers, thyroid feeding for 181 Syringomyelia .. .. 214, 216 Tabes, gastric crises, division of fibres in cord for . . 220 — ' posterior nerve-roots 226 Takaki on beri-beri . . . . 4 Tannin in haemophilic bleeding 39 Tea in shock . . . . • . 99 Teeth, effect of fat, milk, and cod-liver oil on . . 13 — loose, due to food deficiency 7 Temperature of body and pituitary gland . . . . 192 variation on two sides. . 248 Testicular extract . . . . 144 Testis affected by polished rice diet 5 — cells of Leydig . . . . 142 — crvptorchism . . . . 142 — effect of ligature of vas deferens . . . . • • 143 castration in men and boys 142 eunuchism — functions of . . — grafting in fowls — internal secretion . . — before puberty — and spennatozoa Tetany, calcium chloride treat- ment metabolism salts and 170, 182, 143 142 143 142 145 142 170 170, 171 44, 183 18; 170 170 170 170 183 cause of — and colitis — dilatation of stomach — a guanidine intoxication — and malnutrition . . — milk for — and parathyroids . . 170, 183 — in relation to thyroidectomy and myxcedema Thiele on motor reflex arc — on spinal shock Thiosinamine, action of.. Thrombin formation delayed in haemophilia 167 209 95 31 Thrombogen Thrombokinase . . — in haemophilia . . 3 Thrombosis Thymus affected by polished rice diet . . Thyroid colloid, chemistry of . . — feeding for delayed puberty in myxcedema and tetany in normal subjects for tertiary syphilitic ulcers . . 36 29 29 6, 39 28 172 171 145 168 171 181 PAGE Thyroid feeding for ununited fractures . . . . . . 165 — gland (see also Goitre) active principle of . . 173 and bone growth . . 165 in child 172 and cretinism . . . . 165 and drinking-water . . 182 effects of deficient secre- tion 146 effect of pregnancy on.. 146 and exophthalmic goitre 181 and iodoform poisoning 179 iodme and . . 180, 182 iodothyrin in . . . . 181 operations on . . . . 182 removal of . . . . 145 tumours . . . . . , 173 — and parathyroid glands . . 166 effects of removal . . 167 grafting . . . . 183 — swelling in trout . . . . 174 Thyroidectomy in animals . . 171 — atheroma after . . . . 180 — effect on pituitary gland . . 190 in dogs and monkeys 168 changes in remnant . . 169 — results of . . . . . . 171 Thyroidism and iodoform poisoning . . . . 178 Tinel's test 228 Topfer's test for hydrochloric acid .. .. ..123 Toxaemia, intestinal, from stasis 81, 120, 121 — intestinal paralysis in shock 81 Transfusion (see also Blood- transfusion) — Bayliss's gum-saline . . 101 — gum and dextrose solution 101 — intravenous saline . . 101, 103 Ringer's fluid . . 104 Transverse colic sphincter . . 114 Tremor m cerebellar lesions 261, 263 Trephinmg, palliative . . . . 259 Trophic lesions and posterior nerve-roots . . . . 225 Trotter on nerve section pheno- menon . . . . . . 233 Trout, thyroid swelling in 4, 17 Tumours of brain, diagnosis 255, 257, 262, 263 Turck on shock . . . . . . 87 Twins, hereditary tendency towards . . . . . . 139 — identical and ordinary . . 149 — Siamese, lactation in . . 147 Ulnar nerve, recovery time after injury . . . . 232 INDEX 291 Urine, ammoniacal fermentation and formation of oxalates Urotropino and cerebros])inal fluid Urticaria, deficient coagulability of blood . . — calcium salts in PACiK 199 265 31 43 234 143 169 10 Vagus nerve and glycosuria . . 189 and chloroform poisoning 202 — • — and partial heart-block G8 — and symjiathetic nerves, experimental anastomosis Yas deferens, result of ligature of Vassali and Generali, on para- thyroids . . Vegetables, canned, absence of antiscorbutic vitamine from Veins, spasm in, after hfemor- rhacre . . . . 17, 83 Venous puLse, record of . . 48 Ventricular fibrillation, in chloro- form poisoning . . . . 203 Vertigo in cerebellar lesions 262, 2G3 Vestibular nerve nuclei and muscle tone . . 95, 98 Vestibulospinal tract . . . . 210 Vi7icent, Swale, on parathyroids 170 Visceroptosis . . . . . . 119 Visuopsychic area . . 237, 239 Visuosensory cortex . . 237, 239 ' Vital red ' method for estima- tion of blood-volume 17, 86 Vitamines . . . . . . 6 — and beri-beri . . . . 5, 6 — in cabbage, swedes, potatoes 10 — in fresh meat . . . . 8, 9 — in germinating peas and beans 10 — in fruit juices .. .. 8-11 — in milk and fats . . 11-14 — and rickets . . . . . . 14 — and scurvy . . . . . . 8-1 1 PAQR War oedemn, cause of . . . . 5 Wasps, i):irtliogeiiesis in . . 148 Water, distilled, bacteria in . . 103 Walson, Cfialiners, on goitre in fowl 175 Weed on motor reflex arc . . 209 — dishing, \ and Jacobson, on pituitary and glycogen.. 189 Weight, power of judging, lost in post-central cortical lesions . . . . . . 244 Weil recommends horse-serum for haimophilic bleeding 40 Wei.isman on heredity . . . . 148 Wells on iodine in thyroid . . 172 Wiieat, antineuritic substance in 5 Whelps, goitre in . . . . 176 Whipple on blood-serum proteids 18 White on causes of eczema . . 43 Wilms on goitre wells . . . . 177 Wiltshire on lemon-juice and germinated beans . . 10 Windle, cases of pulsus altemans 78 ' Witch's milk ' 147 Word centres, auditory and visual . . . . . . 251 Wright on carbon dioxide for hajmophilic bleeding . . 40 — on hsemophilia . . . . 34 — • on physiological styptic . . 39 Xerophthalma from fat- starvation . . . . 3 X-ray evidence of course of food after gastrojejunostomy 129 — picture of movements of small and large intestine 115 of sella turcica in pituitary tumour . . . . . . 192 urinary calculi . . 200 YEAST, antineuritic substance 3449- 19 JOHN WRIGHT AND SONS LTD., PRINTERS, BRISTOI- ^v^^v