C.V262 W386p 1913

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THE PATHOGENESIS

OF SALVARSAN FATALITIES

WECHSELMANN MARTIN

THE

PATHOGENESIS

Lf

OF

SALVARSAN FATALITIES^

BY

SANITAJS-RAT DR. WILHELM WECHSELMANN

Directing Physician of the Dermatological Department, Rudolph Virchow Hospital in Berlin.

AUTHORIZED TRANSLATION

BY CLARENCE MARTIN, M. D.

First Lieut. M. R. C., U. S. Army; Late Clinical Assistant

St. Peter's Hospital for Stone and Other Urinary Diseases,

London; Member Association Military Surgeons,

Berlin Urological Society, etc.

ST. LOUIS, MO.

THE FLEMING-SMITH COMPANY

Medical Publishers

Saint Louis

U.S.A.

Translator's Note.

Just what role sal- varsan and its com- panion preparation, neosalvarsan, are to play in the future therapeutics of syphi- lis; whether they are to remain the principal form of treatment of this disease, and whether they possess sufficient spirillocidal power to warrant their unaided employment, are points that the clinical investigations of Professor Wilhelm Wechselmann alone will determine. His vast experience with salvarsan entitles his conclusions on any phase of salvarsan- therapy to the most respectful considera- tion, and his investiga- tions into the causes of salvarsan fatalities cannot but add in large measure in fixing sal- varsan's degree of

toxicity and the bodily factors involved in the fatal process. Whilst it is true that conclu- sions reached at the present time are sub- ject to revision, for, confessedly, the last word on salvarsan is far from having been written, yet it is safe to assume that much of our present-day knowledge of salvar- san-therapy is sound and worthy of reliance. The translator of this little book believes that all physicians interested in the treat- ment of syphilis by means of salvarsan and neosalvarsan will find much food for thought in these pages. He hopes, at least, that the reader will see the au- thor's purpose to teach greater caution in sal- varsan-th e rapy .

Clarence Martin, M. D.

St. Louis, Mo., U. S. A. June, 1913.

11

COPYRIGHT. 1913

BY THE FLEMING-SMITH COMPANY

ON THE PATHOGENESIS OF SALVARSAN FATALITIES

Of all the clouds which have encompassed salvarsan therapy there yet remains one to darken the horizon, but this is the blackest, viz. : the foudroyant fatalities in consequence of the intravenous injections of salvarsan. There cannot be the least doubt but that these cases are pure salvarsan fatalities, that is, the concerned patients would not have died at the time had it not been for the introduction of salvarsan into their veins.

One can estimate the collateral effects of salvarsan in two ways, just as one can those of any other sort of remedial agents. The one way is that the physician conscientiously reg- ister all of the untoward effects and after a time present the ascertained faults ; one is thereby, as a matter of course, convinced that these must become more widely extended from day to day, and that one, indifferent as to whether these unfortunate occurrences offer a common type or not, must reach the con- clusion that salvarsan is not free from marked dangers. Still wearier and more uncertain is the other way, that one, first of all, free from bias follow the genesis of the fatalities, prove whether or not the same really should be charged against the agent and also how they may be avoided. Only the second is the truly scientific way because it is free from prejudice. It becomes quite clear that this way has led to a knowledge of the causes and

SALVARSAN FATALITIES

to the control of the collateral effects which from the first presented themselves in the foreground. What Bessel said of inaccurate astronomical instruments, holds good here, viz. : when one has an exact knowledge of an error, then it is an error no longer.

Along these lines we must, therefore, pro- ceed to the investigation of the fatalities of salvarsan and their pathogenesis.

It is best that we base our conclusions not upon those cases of death which have oc- curred after subcutaneous or intramuscular injections of salvarsan in persons suffering from serious organic changes, but on the con- trary upon those which have occurred within a short time after injection — those dying in the acutest manner, as we might say — and in which no organic lesions were present. Such cases should be in the person of young, healthy patients, and there should be no error of tech- nique to influence results.

Millions of salvarsan injections have been given which have been without incident, there- fore, a purely toxicologic explanation of these fatalities is out of the question. Also, by reason of the foregoing one cannot draw a connection between the dose and evil ending. I have myself twenty-five times given in quick succession doses of 0.6 and 0.7 without un- toward collateral effects. Of neosalvarsan 1.5 has been administered at two-day inter- vals without harm. But on the other hand, is the single fatal ending occurring in my de- partment, which took place in the case of a young girl, who had received 0.1 and 0.2 of old salvarsan. The other fatalities also fol-

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SALVARSAN FATALITIES

lowed the usual doses. One might think that this bad luck resulted from a preparation which had undergone decomposition changes, but Ehrlich himself, more than once has sent me supplies of salvarsan made under the same circumstances as that which has caused death, and yet when used in my hands no evil re- sults followed. Still more clearly demonstra- ble of this fact is, that in our case a three gram tube had been made into solution, from which a series of patients received 0.5 and 0.6 without reaction, while the girl who died, and into whom was injected the identical solution, received but 0.2. Portner had a similar ex- perience, injecting four patients with a solu- tion made from the same tube and yet but one became ill and died. Querat injected eight patients from a common mixture, and again only one, the fourth injected, an apparently healthy young man, succumbed, death ensuing after a few hours. Thus it is sure that the drug in itself did not cause death; the deter- mining cause, therefore, for the deadly ac- tion must lie within the patient himself.

A hazily outlined hypothesis of a hypersen- sitiveness has been offered in the way of an explanation. Now this explanation would have value were we able to correctly estimate this hypersensitiveness in a clinical manner, for then before the injection of salvarsan we could preserve the patient from the unhappy termination. On the post-mortem table this hypersensitiveness has a worthless patholog- ical significance, and, therefore, according to its very nature — it could have only a relative clinical value — it must be held to be entirely

8ALVAR8AN FATALITIES

unacceptable. Then it must also be rememb- ered that the theory of hypersensitiveness be- comes still further weakened by the fact that in the majority of instances, the patients who succumbed to salvarsan did not die after the first injection, but, on the contrary, irregularly after subsequent ones, usually after the sec- ond. Also there could not be established the least connection between the hypersensitive- ness and the dose employed, in evidence of which may be introduced the case of Kliene- berger.* A pregnant waitress, 25 years of age, received on March 29th an intragluteal injection of 0.2; on April 3rd she was given 1.2 intravenously. Apart from an urticarial eruption radiating from the site of injection, and a temperature 38. (100.5 Fahr.), she bore this large dose well. On the 22nd of May she was given another injection of 0.6 where- upon the usual indications of salvarsan badly tolerated set in, and on May 25th death took place.

One is not justified in employing the theory of cumulative action; I have myself given 0.6 doses at two and three day intervals, ten or fifteen times, without any evil collateral ef- fect. These cases showed no cumulative ef- fects. On the other hand, in most instances, death has followed after a total dose of from 0.3 to 0.8.

This confusion is further added to by the pathological findings which reveal in a great number of cases a hemorrhagic encephalitis. For that reason one was disposed, in consider-

*Deutsche med. Wochensch., 1912, No. 36. — 10 —

SALVARSAN FATALITIES

ing the nervous manifestations produced by salvarsan, to locate the site of the hypersen- sitiveness in the central nervous system, and was prone to speak of congestion of the brain. Potzl and Schiiller who have observed the same brain congestion after the employment of mercury, give the following explanation: "The consequences of the early luetic infec- tion manifest themselves in a permanent change of balance between intracranial and extracranial circulation, as a result of which there may be an increased susceptibility of the brain to toxic influences. The brain then plays a more important role in the reaction to toxic influences of various sorts than under normal circumstances." The most that one can say about this explanation is that it is purely hypothetical. Were this hypothesis correct it would still be difficult to understand why, with the well known extraordinarily fre- quent participation of the brain and meninges in the syphilitic process, a hypersusceptibility to mercury is so rarely seen. That this super- sensitiveness to salvarsan is seen so dispro- portionately oftener indicates in itself that in- fluences other than brain syphilis enter into the question. Then add to this point that, in many salvarsan fatalities, the brain is found to be entirely free from luetic or other changes ; furthermore, no illuminating con- nection can be seen in the age of the infection, for the most casual inspection of statistical information shows that syphilitics in all stages of the disease have met with this sad fate. That the notion of a neurotoxic action is quite untenable is evident in the fact that even in

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8ALVARSAN FATALITIES

the presence of encephalitis hemorrhagica fol- lowing salvarsan, the brain substance does not seem to be affected (still further proven by Nissl's thorough examination of the cells) ; on the contrary, it is solely the blood vessels which are damaged. That these vessel lesions are caused by noxious influences of a general character is shown by demonstrable hyper- emia and hemorrhage in all of the inner or- gans.

Especially since I have myself experienced a fatality in consequence of the new therapy, I can look at the problem all the more sharp- ly; therefore in presenting my case I shall give every point in connection with it.

Marie St., born on November 21st, 1887, re- ceived in the hospital February 26th, 1912. The patient has always been well, knew nothing of her infection and has not been treated. Small papular, universal rash. Plaques on the tonsils. Wassermann + + + +. For two weeks has suf- fered with headache, sleeplessness, and tinnitus on the left side; according to the aural examina- tion the tympanic membranes of both sides are involved, but the findings do not reveal any lesion commensurate with the difficulty. Examination of the eyes reveals a nystagmus claimed to have existed for six years; a sister suffers from the same disorder. The retina is normal. Vision 5/5. Urine normal. Lumbar puncture on February 27th, marked by a forcible escape of fluid. Fluid spurts out in a stream. Cells ++, gold + + , Nonne — , Wassermann — . On March 1st, vomit- ing. From March 6th to March 18th patient was rubbed daily with 4 grams of ungt. hydr. On March 12th the patient received 0.1 salvarsan in an alkaline solution (0.9 per cent, salt solution). Borne without reaction; temperature 37.6 (99.7 Fahr.). March 13th temperature 38 (100.4 Fahr.). Thenceforth temperature normal. On March 18th,

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SALVARSAN FATALITIES

0.2 salvarsan with immediate rise of temperature to 40.3 (104.5 Fahr.); headache and vomiting; angina and swelling of the glands of the throat. Following the administration of 0.3 (5 grs.)' of pyramidon the temperature falls slowly; on the morning of the 20th temperature 36.4 (97.5 Fahr.). Six o'clock in the evening general convulsions suddenly appear with biting of the tongue. The pupils are widely dilated and do not react, coma, marked respiratory distress with deep contrac- tion of the jugular, no cyanosis, trismus and rigidity of the extremities. On March 21st, the advisability of trepanation considered, but as there are no evidences of brain pressure (pulse 120, soft), the idea is set aside and a venesection made, 200 c.c.' of blood being abstracted and then a saline infusion of 300 c.c. given. Patient is unconscious. No rigidity of the neck or of the limbs ; reflexes present; respiration free but groaning. Temperature in anus 40.7 (105.2 Fahr.). Corneal reflex weak, pupils just a bit dilated, right slightly more so than left, react promptly, motility cannot be tested, retina mildly hyperemic, veins some- what distended and very dark. Cyanosis of the retina but no hemorrhage, no circumscribed area, no iritis. Function of the bladder not observed. By means of a catheter a small quantity of urine has been evacuated; this contains much albumin, numerous granular casts and formed elements. Without any other changes death ensued at 5 o'clock in the afternoon. Spinal fluid abstracted shortly after death coagulated spontaneously like gelatine. Nonne + + + + , gold + + + (10-5000 white) cells + + +, lymphocytes: leucocytes 8:1, Wassermann 5 per cent. ++, 100 per cent.

AUTOPSY (Dr. Auffermann).

Brain. — No changes are to be recognized in the skull. The dura mater, especially in the hind segment, is firmly attached to the skull. Veins and sinuses distended with blood. The inner sur- face of the dura mater is covered with irregular arterial hemorrhages, arranged in stripes of a bright red color. The more delicate meninges to

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8 ALVARS AN FATALITIES

a site between the optic nerve and the olfactory tract in front of the chiasma, are transparent. The veins are markedly filled with blood. The brain substance is of a somewhat compact con- sistence; no gross changes are present. The ar- teries of the base are reddish blue and quite uni- formly thickened. At either side of the crus cerebri and somewhat over it the meninges are hemorrhagic.

Spinal Cord. — Everywhere the nerve tracts are freshly hemorrhagic; the hemorrhages extend to between the vertebrae. The blood vessels of the cord are distended. The coverings of the cord opposite the middle and upper dorsal vertebrae are somewhat congested. The substance of tne cord is rather firm; its appearance is nowhere out of the ordinary. The fluidity of the cerebrospinal fluid is not increased. On the posterior surface are rather firm adhesions between dura and pia mater.

Pharyngeal Organs. — These are somewhat uni- formly swollen. The palatine tonsils are larger than a bean.

Thorax. — Position of diaphragm, on the left fifth, on the right fourth rib.

Heart. — The pericardium shows nothing of in- terest. The heart is rather larger than the fist. The ventricles are contracted. The epicardium over the vessels thickened moderately. In the myocardial substance are to be seen golden and grayish brown stringy streaks, and very numer- ous striped, dark red foci of the diameter of 1 mm. but without a sharply defined border. Be- neath the endocardium of the left ventricle are confluent red specks. The valves are intact.

Lungs. — A few fibrous areas are seen in the covering of the right lung. The left pleura is normal. Both lungs are rather hemorrhagic and lymphedematous, besides they are studded with air-free foci of the size of a hazel nut. some of which are confluent. These foci, through their lighter color and more solid consistency, are quite distinct from the adjacent lung tissue.

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8ALVAR8AN FATALITIES

ABDOMINAL CAVITY.

Stomach. — Mucosa slightly swollen. There are extensive, light red hemorrhages in the folds of the upper curvature; these are made up of small, distinct foci.

Bowel. — On the valves of the large intestines appear irregularly distributed hemorrhages, dn connection with which, here and there, are ulcera- tions of the mucosa. The follicles are slightly swollen.

Spleen. — 14x91/ox4 cm. Consistence rather firm. No alteration in structural appearance. Follicle swollen moderately.

Liver. — Somewhat enlarged. Capsules thickened. Consistence soft. Structure indistinct.

Kidneys. — Enlarged. Capsule easily detachable; contains on the inner surface several hemorrhages of the size of a pin head. Surface of the kidney even. Cortex thickened, structural appearance not distinct. Color grayish red. The pyramids, which are also swollen in a marked manner, are filled in their lower third with yellowish white streaks.

Pancreas. — Firm, no change in structural ap- pearance.

Suprarenal Bodies. — Unchanged.

Pelvic Organs. — No change in rectum. Posteri- orly in Douglas's pouch numerous old adhesions. Uterus and ovaries in state of menstruation.

Dr. Bielschowsky's microscopical investiga- tion of the brain disclosed no noteworthy al- terations which the clinical picture could ex- plain. Sections from the cerebral cortex, the pons and the medulla were examined. In none were inflammatory changes found. Occasional pyramidal cells from the cerebral cortex pre- pared after Nissl's method, presented signs of a slight swelling with beginning chromatoly- sis. However, this finding is entirely without significance and could easily have had its ori- gin coincident with death. Probably a note-

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SALVARSAN FATALITIES

worthy point is the normal condition of the blood vessel walls. Hemorrhages are not pres- ent. Microscopical examination of the other organs by Prof. Pick discloses the following: Section from alcohol-hardened kidney, stained with hemalaun-eosin, shows : the epithelium of the tubuli contorti of the first order, is vari- ously swollen, cloudy with fine-grained strati- fications, with indistinct boundary toward the lumen. Still oftener in these cells the nuclei are missing (necrosis). In the lumen fine- grained coagulated contents. The epithelium of the tubuli contorti, second class, as well as that of the collecting tubules seems to be free from changes. No calcareous deposits in any form were to be found in the specimens examined. The stroma of the cortical layer between the injured tubuli uriniferi is some- what increased, slightly edematous, noticeably proliferated. Fresh small cell infiltration foci are lacking. In the glomeruli is apparently an increase of nuclear elements.

In general, therefore, a subacute parenchy- matous and interstitial nephritis.

Dr. Auffermann made a special examination of the kidneys, and concerning the microscop- ical stripes in the pyramids, established the following :

Microscopically, in a subdued light, the yellow stripes appear as dark, fairly homogenous casts which correspond to the site of the straight urin- iferous tubules. They do not dissolve with the addition of hydrochloric acid, nor is there genera- tion of gas. Fixation in formalin caused them to dissolve, but in denatured alcohol in great part they remain unchanged. Paraffine sections were treated with the usual nucleus and connective tis-

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SALVARSAN FATALITIES

sue stains. These showed severe damage to the epithelium as well as to the tubular systems, as the glomeruli and their capsules. Neither infil- tration nor interstitial or blood vessel change^ could be found. The nature of the yellow casts was as follows: They appeared entirely amorphous without any tendency toward crystalization, and did not stain with hematoxylin. With nitrate of silver they became of an intensely black color, and also occupied the site of the epithelia. The latter now became only partially recognizable. Notwithstanding the contradictory condition I would claim the casts to be of phosphatic nature. The circumstance that they did not appear to dissolve when treated with hydrochloric acid might be attributed to an error on my part in abbreviating the period of observation. Their solubility in formalin — formic acid — demonstrates this. According to the literature biliary pigment and uric acid are likewise excreted.

Examination of the liver and heart disclosed no special condition (Sections hardened in al- cohol, stained as usual).

The chemical examination (Prof. Loeb) shows in blood : Blood sugar 0.089 per cent., free nitrogen (Holweg) 0.0174 per cent, iron 0.210 per cent., total nitrogen 1.454 per cent, therefore marked increase.

Kidneys: Arsenic plainly demonstrable. Mercury very plainly demonstrable.

Brain: Arsenic plainly demonstrable. Only a slight trace of mercury.

Feces: Arsenic demonstrable in slight traces; no mercury.

The cerebrospinal fluid contains 0.05 per cent, arsenic.

The spontaneous gelatinous coagulation of the cerebrospinal fluid drawn off immediately after death, was most extraordinary. The

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SALVARSAN FATALITIES

significance of this condition is not yet suffi- ciently explained. In this connection it may be added that Mestrezat has made a study of this question. (Le liquide cephalorachidien, Paris, 1912, p. 425.)

Here I would remark that neither in arsenic poisoning nor in uremic coma is there any mention of this interesting condition. (In reference to this compare the Thesis by Petit, Meningite et reactions mcningces dans I'uremie, Paris, 1912, Declose.) The special, extraordinary terminal changes of the liquor, in part, must well have some connection there- with.

An entirely incorrect recital of a case was offered at the July meeting of the Dermato- logical Society, this being the history of a case which had been twice injected by Dr. Portner and which died in my department.

Portner gave me the following history :

"Franz Ro., 37 years old. At the beginning of April, 1912, infected with syphilis. Hard chancre. May 21st Wassermann was made by Dr. Meier. Positive. One injection of mercury. On May 24th given intravenous injection of 0.4 salvarsan. Am- bulatory patient. It is claimed that after the in- jection diarrhea set in, and after several days a feeling of faintness. Then came a return to nor- mal.

On June 13th another injection of 0.4 salvarsan (Dr. Weber). This was unattended by trouble. Patient was not taken into hospital. After injec- tion a very severe pain seized patient in wrist and ankle joints. The affected limbs could scarce- ly be moved. After a morphine injection (Dr. Steinitz) pain slightly moderated. Dr. Steinitz found patient in severe collapse, strongly acceler- ated, scarcely perceptible pulse. Ordered camphor. Fever present. Patient is an inveterate smoker.

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SALVARSAN FATALITIES

Large, corpulent man. Face flushed with fever. Expression of face indicative of suffering. On both thighs marked diffuse reddening of the skin. On the left thigh the redness at the knee' is in sharp contrast to the strikingly pale blue color of the lower leg. The toes of the left foot are cyanotic. The left hand also shows from the wrist downwards the same pale blue, lightly cyanotic coloring. Here as on the foot the blue color is most marked at the finger tips. Pulse is very much accelerated and scarcely perceptible. Temperature 38.8 (101.8 Fahr.). No appetite. Therapy: Coffee every two hours; hot hand baths; hot packs to the feet.

June 15th, 1912. Hand pale blue, but color, in general, not so pale as yesterday. But the pale blue color on the lower leg is still strongly marked. As before, the toes are still cyanotic. Pain in the left hand and in left wrist joint in the reclining posture is somewhat less. At an attempt to move the joint the patient cries out at once. Both thighs are brilliantly red.

Patient feels very weak. Occasionally tries to arise from bed hoping to find relief, but staggers and must again lie down. Pulse very small, scarcely perceptible, strongly accelerated. Tem- perature 39.5 (103.1 Fahr.). More frequent vomit- ing and difficulty of defecation. Upon taking nourishment (milk) vomiting sets in afresh. Highly smelling urine, light in color, turbid, trace of albumin.

N. B. — On June 13th, three other patients were injected with the same preparation, dose likewise 0.4. Well borne except in the case of a 19-year-old anemic girl, who vomited lightly two or three times."

I proposed to Dr. Portner that after the conclusion of my investigations we publish the case together, but he did not trouble him- helf to describe the case according to the in- formation he had, so the result was that he erred in needlessly burdening the literature

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8ALVARSAN FATALITIES

and further the discussion had to be conducted along false channels.

The report coincided in essentials with that which was published by Portner in the Der- matol. Zeitschr., Bd. XIX, No. 12. There Portner says that he made two further injections with the same solution which he employed in the case of the above mentioned patient, and that no untoward results occurred. Then, he adds thereto (1 .c. p. 1091) : "In the Virchow Hospital evidently a trepanation was undertaken in the case, well according with the proposal of Ehrlich that in cases of encephalitis after salvarsan, this operation be attempted."

The patient's history and our findings put the case in an entirely different light.

On admission into the hospital on June 15th, patient is somewhat stupified and has headache. Nine years ago underwent a course of mercurial inunctions with Dr. Schmilinski. A week after the first injection the patient felt bad. Vomiting and chills.

The upper half of the face and the forehead are covered with a relapsing erythema. Slight con- junctivitis. The left arm is lame, the left leg is paretic, but can be raised up. Urine dark brown; retention necessitates catheter; bowel movement black and paplike. Patient vomits black masses. Patellar reflex present. Right pulse soft, 120; left cannot be felt in the brachial.

Condition remains unchanged. Urine contains albumin and granular casts. Lumbar puncture on June 16th affords no relief. Nonne +, G +, C +, Wassermann 500 per cent — . Vomiting black masses. Patient is stupified, but no coma, no convulsions. With ascent of temperature to 38.4 (101.1 Fahr.), and increasing cardiac weak- ness, death came at 9 o'clock on the morning of June 17th.

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SALVARSAN FATALITIES

Arsenic in the urine and vomitus in abund- ance (Prof. Loeb).

Through questioning the patient's wife the his- tory of the case was completed as follows: In- fection nine years ago, after which one inunction course which was repeated a year later on ac- count of manifestations in the region of the neck.

Patient very intemperate, drinking daily 12 to 15, occasionally 40 glasses of beer and whiskey. Inveterate smoker. At the beginning of May he came under Dr. Portner's care by reason of small blisters appearing on the glans penis. After the first injection on May 24th, he became indisposed on May 30th. Chills on June 1st. Congestion of the eyes. In spite of his condition he went to the race course on June 2nd. On the same day a red eruption broke out on the legs, arms and trunk. Then followed dizziness and weakness. Immediately after the second injection on June 13th, the patient became very much distressed and vomited freely. He complained that the injec- tion had been very painful. On the same day an assistant who was called into the case confirmed the absence of pulsation in the left arm. Patient dragged himself about until 3 o'clock in the after- noon but gave up at four; the left hand and foot became ice cold and the site of agonizing pains. Dr. Steinitz had to give morphine, but notwith- standing this the pains continued to be extremely severe. Patient was very excited and wanted to kill himself.

Besides she reported what the patient had told her, that some years before he had been operated upon by Gen. Rat. Korte for epilepsy. The previous history so cheerfully put at my disposal, runs as follows:

During a brawl on the night of June 13th, 1904, he sustained a blow with a cane which injured the right side of the skull. The injury was dressed at a public dispensary. On June 18th convulsions for the first time seized the patient; during the course of the night and until noon of the next day

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SAL VAR8 AN FATALITIES

he had five seizures. Brought to the hospital by the ambulance at 5 o'clock on the afternoon of June 19th.

Immediately after admission a convulsion oc- curred which was closely observed by the medical man in charge. Patient draws left arm to the side with light convulsive movements, while at the same time, with the pupils dilated, the head is strongly drawn toward the left. Patient is un- conscious; general convulsions have set in. The mouth is widely opened, tongue remains behind '' the teeth. Lasts for a period of three-quarters of a minute. Following is a light comatose state.

The examination discloses two wounds in the region of the parietal bone, one of which runs in a straight line from front towards the back for an extent of 3 cm. In front of this is an irregular wound connected with two skin fissures which join one another. The length of the single wound is about 1% cm. Near the first described lacera- tion is a superficial cut 1% cm. long which the patient, upon the recovery of consciousness, says is an incision made by the attending physician. The wounds are matted with hair, and dressed with iodoform gauze. The borders of the wounds are slightly reddened. Abrasions of the front half of the head. Cleansed with alcohol and ether. Dressed with iodoform gauze.

Pulse, 72, respiration easy. The patient regains consciousness soon after the affair and gives a good account of the circumstances of injury.

During the night had three convulsive seizures of the character described above; similarly dur- ing the physician's morning rounds between 8 and 8:30. Patient received morphine 0.01 (1/6 gr.), following which improvement immediately takes place as on yesterday evening (June 19th).

A pronounced paralysis of the left facial nerve is present. The gross motor power of the left arm is plainly reduced. The tongue when ex- tended deviates slightly towards the left.

In the parietal region are three wounds. The one in front extends to the bone, but apparently the others do not. Employment of a crescent- shaped incis^oj^ with highest point of incision on

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SALVARSAN FATALITIES

line with parietal suture, base over the parietal bone; soft parts are elevated with profuse hemor- rhage. Corresponding with the anterior wound, close by the sagittal suture, is a defect in the bone, about the size of a 25 cent piece, with deeply de- pressed base and edges; between the splinters of bone are blood coagula filling up the site of the injury. Numerous hairs are in wound. Inoccula- tion shows staphylococcic infection.

Operation. — Circling the fracture, the edge of the bone is beveled with a chisel. Three large and numerous small deeply depressed fragments of the external table are removed. Adherent hair may also be seen on these pieces of bone. Moderate extravasation of blood between bone and dura. Removal of all splinters together with thorough cleansing of wound. Tamponed with iodoform gauze.

At seven o'clock on June 20th, an epileptiform attack, resembling the former one, except that head is turned toward the right.

Afternoon of June 21st: The patient feels bet- ter; the facial paralysis about gone; patient com- plains of burning in the operation wound.

Morning of June 22nd: Patient slept well; dressing, which yesterday had to be renewed, has not again become saturated; very slight paralysis of the facial; the left eye can be entirely closed; tongue still deviates a little towards the left.

A difference in the gross muscular power of the two arms is present in a minimum degree.

No lameness in legs; pain entirely gone.

Senses clear. Urine golden yellow, clear, con- tains no albumin.

On the 22nd of June, at midday, marked von- vulsize seizure.

On the 24th at 9:20 in the morning, convulsion affecting mainly the left side of the body.

June 25th, during the night at 12:15 and 12:20, further severe convulsive attacks.

Removal of the tampon, wound disinfected, re- dressed. Patient complains of anxious feeling and dizziness.

June 29th: No convulsive attack since removal of the tampon. Very slight paralysis of the left facialis.

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SALVARSAN FATALITIES

July 12th: Patient again twice had slight twitching of the left arm. Medication: Kal. brom. 1 gram (15 grs.) three times daily.

July 24th: The wound is almost closed; dress- ing of nitrate of silver salve. Patient feels quite well; no suspicion of any paroxysm; no dizziness; no convulsions. Under close examination twitch- ing in left leg. In the bone is a large defect, in which the pulsation of the brain may be clearly felt and seen.

According to information given by the wife, since the time above mentioned, the patient re- mained free from epileptic convulsions.

Post-mortem immediately after death (Geh. Rat. v. Hansemann) shows the following:

Anatomical Diagnosis. — Partial defect of calvar- ium. Yellow softening of brain. Pulmonary em- physema. Thrombosis of the left radial artery. Hepatitis, fatty infiltration. Parenchymatous ne- phritis. Subendocardial hemorrhage, also of the mucosa of the jejunum.

Trunk and Extremities. — Strongly built male body with well developed musculature and mod- erate deposit of fat Over the entire body, particu- larly left arm, bright red, irregularly outlined spots.

The radial artery in front of the styloid process of the radium for a distance of 4 cm., is entirely occluded by a firmly attached coagulum. The re- mainder of the radial artery and the brachial and axillary are free.

Thoracic Cavity. — Pericardium without change. Heart: large as the fist; musculature pale red; contracted. Valves and endocardium soft with a greenish yellow color. Ascending aorta shows slight fatty degeneration of the intima. Several hemorrhagic spots beneath the endocardium.

Left Lung: Agglutinated with easily soluble adhesions; everywhere filled with air; especially in marginal regions where it is inflated.

Right Lung: Same condition as left.

Larynx and pharynx without change.

— 24 —

8 AL VAR8 AN FATALITIES

Abdominal Cavity. — Peritoneum smooth and glistening.

Spleen: Slightly enlarged; surface smooth; color dark red; structure distinct.

Liver: Of natural size; capsule smooth; con- sistence normal; color bluish red with large yel- low areas.

Left Kidney: Of natural size; capsule detach- able; surface smooth; color grayish red; structure changed through tissue proliferation; cortex in- creased.

Right Kidney: Same condition as in left.

Suprarenal bodies, pancreas and stomach with- out change.

Bowel: In first part of the jejunum isolated mucous hemorrhages; color of the feces dark gray- ish blue.

Pelvic organs without change.

Head and Spinal Column: Brain remains in toto; in the right parietal bone, in the region of the parietal convulsion, is a defect the size of a dollar, the edges are smooth, and the whole is covered with dural tissue. Brain is adherent at this point and shows defect (the size of a chest- nut), has yellowish color. Over wound is a skin scar.

A microscopic examination carried out by myself reveals:

Kidneys: In the uriniferous tubules flat, granular masses (albumin), hyaline casts, vacuolar state of the epithelium of the tubuli contorti. Glomeruli rather richer in nuclei than normally, but without important changes.

Liver: Moderately rich in fat. Large drops of fat within the cells with well colored nuclei. No necrosis. Interstitial prolifera- tion such as seen in a drunkard's liver.

Spleen : Congested ; the inner lining of the artery of the duct here and there inlaid with

— 25 —

SALVARSAN FATALITIES

a somewhat homogenous substance (probably hyaline) ; beyond this no changes.

Bowel : Leucocyte infiltration in the super- ficial layer of the mucosa; no necrosis.

In the left radial artery fresh thrombosis (blood plates, leucocytes, erythrocytes, no or- ganization).

Dr. Bielschowsky found nothing in the brain indicating an acute inflammatory process. But there was found an old fibrous leptomeningitis which was most pronounced where the two hemispheres met. There were further chronic changes in the cells of the lamina pyramidalis and chronic fibrous tissue proliferation. In general, the picture was that of chronic al- coholism. As always, there were also present a few acutely changed cells, but these had no bearing on the diagnosis.

There cannot be the slightest doubt but that the heavy drinking and the former epilep- tic attacks should have been a sufficient notice of the possibility of chronic cerebral changes. A further cause for care should have been the drug exanthem following the first in- jection as well as the indisposition which lasted for days. That in all probability, the injection was made into the radial artery after recognition of the clinical picture and the con- dition of the artery, is, to say the least, not without significance.

The entire clinical picture and the patho- logical findings of our only case do not in- dicate arsenic poisoning. And furthermore, the majority of the other cases which have been carefully and thoroughly examined give only an irregular picture of the usual symp-

— 26 —

SALVARSAN FATALITIES

toms of arsenic poisoning. Most authors give special prominence to this in their discussions. For example Almkvist and Hedren say: "At autopsy there were no characteristic pathologic changes of acute arsenic poisoning, such as bowel paralysis, fatty degeneration of the kid- neys, the liver, the heart muscle and the in- tima of the blood vessels. Furthermore, there was no hemorrhage in the different organs such as occurs in acute arsenic poisoning, ex- cept in the brain. That this case cannot be considered as an ordinary poisoning by ar- senic as a result of the dose of salvarsan (0.6), is clear without question."

"Busse and Merian take the opposite view- point. Should, however, any doubt yet exist, it may be dissipated through study of the older and half-forgotten, yet helpful, litera- ture on the organic changes of arsenic pois- oning. From the description of isolated cases of poisoning as well as from experimental studies, one is led to conclude that in some in- stances arsenic, just as exactly as with the new preparations, has an individual, distinc- tive action, and that, at other times, it gives rise to the same changes which are observed in the modern treatment of syphilis. I shall pass over the quite extraordinary, varying action of arsenic on the different organs, such as the stomach, intestinal tract, liver, kidneys, etc., for I wish to refer here only to the sim- ilar, not to say identical, changes in the cen- tral nervous system produced by acute and chronic arsenic poisoning which may be ob- served, as in our case. The multiple hemor- rhages in the central nervous system, particu-

— 27 —

SALVARSAN FATALITIES

larly in the spinal cord, have been the object of various investigations (Popoff, Kreyssig, Wolkow, Silbermann, Heinz, et a/.) ; they were investigated jointly with the thrombotic obliteration of vessels, whose nature and man- ner of formation in arsenic poisoning was quite closely studied especially by Heinz, and explained by the appearance of thrombi (thrombi of blood corpuscles and mixed thrombi). "It must also be emphasized that in these cases of arsenic poisoning inflamma- tory infiltrations of the tissue occur, and, in- deed, not only following subcutaneous injec- tions but, on the contrary, also in cases where the poison reaches the tissues through oral administration."

"From this it appears that the unwelcome, severe and at times even fatal collateral ef- fects following the administration of salvarsan and neosalvarsan, are to be accepted as toxic actions of the introduced drug, and so it seems, principally of its arsenic constituent."

It is quite past understanding how the au- thors can find sufficient support in the cited literature to sustain their position that in ar- senic poisoning "similar, not to say identical, changes in the central nervous system may be observed, as in our case." Let one search the literature as he will, yet nothing can be found which could be offered as a parallel. In the Handbook of Experimental Pharmacology by Heinz nothing on the subject is to be found. In his Breslau Habilitation thesis (1891) he throws light on the occurrence of thrombi in the capillaries as well as larger vessels due to arsenic poisoning, this being based on

— 28 —

SALVARSAN FATALITIES

varied experimental work, but nowhere does he mention human pathology and certainly not hemorrhagic encephalitis. Silberrriann's investigation (Virchow's Archiv., 117, p. 304), so far as this point is concerned, contains just as little. Wolkow (Virchow's Archiv., 127, p. 477) concerns himself with an investigation into degenerative and progressive liver changes. Popoff (Virchow's Archiv., 113, p. 385) finally tries to prove in his dissertation that acute arsenic, lead and mercury poisoning can produce acute myelitis, a point that Kreyssig opposes. Popoff cites a fatal case of arsenic poisoning, but this died with gastro- intestinal symptoms and heart failure (cf. below) and without coma. Hemorrhages and plastic exudates were found in the spinal cord of this case. This is the only case in point which can be brought forward in substantia- tion of these claims, and even it offers an en- tirely different clinical picture from that of a salvarsan fatality.

In sharp contrast to this is to be mentioned that the acute arsenical poisoning described in the literature plays no role whatever as re- gards hemorrhagic encephalitis (vide litera- ture by M. B. Schmidt, Ziegler's contributions, VII supplement, Laignel Lwastine and Voisin, Archiv. de med. exp. et d'anat, path., 1907, No. 1 and Meyer Frankfurt, Zeitschnft fur Pathologie, No. 5, 1910). Furthermore, in Crete's valuable investigation, conducted under the guidance of Pick and Stadelmann, on the pathological anatomy of arsenical poison- ing (Berlin, 1912), the condition of the brain

— 29 —

SALVARSAX FATALITIES

is described in an entirely different manner; there is nothing on hemorrhagic encephalitis.

Now, there is an acute arsenical poisoning which corresponds to the picture of arsenical asphyxia. Concerning it, Grote says : "These cases which proceed to a promptly fatal ter- mination, this occurring even within ten hours can run their course quite entirely without any trouble referable to the intestinal canal. Finally the picture of narcosis predominates yet the convulsive forms are also observed. Taylor* reports a case of this character which terminated fatally within twenty minutes. This form is not so rare ; Harvey** was able to find it in 36 out of 697 cases.

Seidel in Maschka's Handbook of Medical Jurisprudence, No. II, p. 241, says concern- ing the cerebral form: "The picture of gas- troenteritis appears in the background with perhaps distress or occasional vomiting, but nothing else; these may be entirely lacking; in the foreground stands the extraordinary weakness with small pulse, cool skin, the oc- casional dizziness, pain and a feeling of numb- ness in the extremities preceding. The patient falls into a deep swoon, after recovery from which he is sleepless and finally becomes de- lirious. Thereafter follows a deep coma, now and then light convulsions and death comes in the midst of general paralysis with complete unconsciousness. The course is very rapid. Death may ensue as quickly as six or eight hours, and occurs at least in the course of the first day."

*Die Gifte, ubers. von Seydler, 1862. **Ind. Med. Gaz.. 1876.

— 30 —

SALVAR8AN FATALITIES

Heinz also says on this score (Handbook of Experimental Pathology and Pharmacol- ogy, Nos. 1, 2, p. 929) : "The acutest'form of arsenical poisoning, in which a large quan- tity of arsenic has been taken at one time, corresponds irregularly to the customary 'gastro-intestinal' form, showing, principally, evidences of impairment of the central ner- vous system and weakness of the heart — the paralytic form. The last form (especially rare in human beings) begins with an uneasy sensation and vomiting, yet these signs may be entirely lacking. The principal features are marked weakness, very weak pulse, and decline of temperature; the memory quickly wanes ; gradually come delirium, loss of con- sciousness and then coma until finally, with- out any special sign, death ends the scene. Death comes quickly; usually within a few hours, not often longer than ten."

That does not correspond to the picture of a salvarsan fatality. Especially in the cere- bral type of cases there is a latent period lasting for hours and even several days ; this does not correspond, as Fischer has emphasiz- ed, to the picture of an acute poisoning.

The question has occurred to me, whether the cerebral symptoms making up the clinical picture really constitute its central feature. In view of the fact that in all of these fatali- ties coma appears prominently in the fore- ground, I directed my efforts at an investiga- tion of the uremic phenomena. A prominent characteristic of uremia, as pointed out by v. Noorden* is its tendency to present strange

*Handbuch der Pathologic des Stoffwechsels, Bd. I, p. 1002. —31 —

8ALVAR8AN FATALITIES

and unexpected manifestations. As a matter of fact, Prof. Loeb found urea in the spinal fluid in the proportion of 0.5 gram to the litre, and marked increase of rest nitrogen in the blood. (0.0174 per cent., Holweg 0.21 per cent, iron, total nitrogen 1.454 per cent.)

If, after full consideration, we give this accumulation of nitrogenous products its most complete significance, we cannot, in view of Holweg's investigations,* consider it as ab- solutely indicative of uremia, but it is, how- ever, certainly an expression of kidney insuf- ficiency. This opinion conforms also to the quantitative investigations made by Mestre- zat,** who found in suspension of the renal function without uremia 0.25 to 1, in non- fatal uremia 0.98 to 2.55, in fatal uremia 3 to 6.34 grams of urea.

According to its urea-content our case be- longs to the first group.

Insufficiency of the kidney, therefore, and not hyper sensitiveness of the brain, is the point of the entire question of salvarsan fatalities.

It thus becomes evident, as a matter of fact, that in intravenous injections of salvarsan the overburdened organ is the kidney and not the brain.

The largest quantity of salvarsan disappears rather quickly from the blood, for injected salt solutions do not remain in the vessels.

*Ueber das Verhalten des Reststickstoffs des Blutes bei Nephritis und Uraemie. Archiv. f. klin. Med., 104 Bd., 3-4. Bei der Uraemie erreicht sie sehr hohe Grade nach Strauss (Reststickstoff in semen Beziehungen zur Uraemie). Ebenda, Bd. 106.

**Le liguide ccphalo-rachidienne, p. 592.

oo

— •)- —

SALVAR8AN FATALITIES

The blood is not subjected to elimination be- cause it contains no free water, on the. con- trary all water is associated as hydration- water with the colloid which is here present. Conversely, a salt solution disappears quickly from the circulatory system because it con- tains free water.* It has been shown by Say- nisch** that oftentimes in so short a space as an hour after the injection, arsenic could no longer be demonstrated in the blood, a point which control experiments have further con- firmed. Abelinf found the salvarsan reaction of the blood after one hour to be very weak ; after an hour and a half still less certain and after two hours and a quarter scarcely ap- preciable. Yet, as regards this point, it must be remembered that, as Prof. Loeb has shown me, there are marked individual variations.

After intravenous introduction, salvarsan, in largest measure, is eliminated through the kid- neys.

It is a well known fact that the kidneys al- ways tend to free themselves from foreign substances as quickly as possible, and possess much less tolerance to such than to the physi- ological urinary constituents. Also imme- diately, or at least in a few minutes after the injection, one may, by means of Abelin's test, demonstrate salvarsan in the urine, ff and, gen-

*Hoga and Martin H. Fischer. Theorie und Praxis der Transfusion in Ostwald, Kolloidal- chemische Beihefte, III, 10-11.

**Deutsche Med. Wochenschr., 1912, No. 44, p. 2070.

iMuenchner med. Wochenschr., 1912, No. 2, p. 81.

ttA&eHn. Abhandlungen uber Salvarsan, Bd. II, p. 61.

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SAL VAR8AN FATALITIES

erally speaking, its entire elimination is ac- complished in five or six hours. As a rule, the kidneys easily take care of this extra bur- den, and through careful examination albumin is rarely found. Schlasberg* who quite re- cently has thoroughly investigated these cir- cumstances mentions the same fact; he fre- quently found, however, occasional hyaline casts. We, too, have had urinary examina- tions made in 80 cases after intravenous in- jections but without being able to demonstrate hyaline casts. In isolated instances, however, we have discovered albumin ; Weiler reports the same condition. While it is a very rare occurrence, yet our work confirms Weiler's observations. Apparently, in these cases the question is, whether the affected patients did not have at a previous time a kidney lesion which progressed undiscovered until the in- jection and subsequent urinary examination. Now comes the question : How does an al- tered kidney, especially a luetic kidney, func- tion during the elimination of salvarsan ? We know that nephritis occurs during the pre- roseolous stage of syphilis but more especially during the secondary period. In general, the syphilitic kidney bears salvarsan well ; we even have reports of improvement and cure of syphilitic nephritis, and this, too, in instan- ces where mercury has failed. But this result is not without its exceptions. Thus Mariot** reports in a presentation on the action of ar-

*Gesammelte Abhandlungen tiber Salvarsan, Bd. II. p. 387.

**Les nephritis de syphilitiques et V Arsenoben- zol. Thtse. Lille. 1912.

— 34 —

SALVARSAN FATALITIES

senobenzol in regard to syphilitic nephritis, two cases that died in uremic states. •

As a rule, however, salvarsan is excellently borne in the presence of nephritis and only exceptionally are bad results registered. There- fore, there apparently is offered the contra- diction that plainly pathological kidneys stand the full burden of salvarsan without reaction, while on the other hand, seemingly normal kidneys are rendered insufficient. The judg- ment of such cases in no way depends upon the pathological state which is ascertained to be present; a nephritis may cause death with- out offering an anatomical picture even ap- proximately . in keeping with the severity of the clinical manifestations of the disease. Through the labors of Schlayer* it has been shown that the anatomical investigation of the organs does not always disclose as much dam- age of the renal arterial system as clinical find- ings would indiate is present. Notwithstand- ing the most careful studies of the glomeruli, particularly in acute nephritis, we have, in no sense, progressed so far as to be able to de- termine positively the state of their function from the anatomical picture presented in such cases. Schlayer and Heubner have shown that patients with a severe glomerulonephritis may offer only the most insignificant glomerular changes.

We encounter with extraordinary frequency in the literature on salvarsan fatalities, in- stances of death occurring with anuria or suddenly appearing albumin. In many cases

*ErgeT)nisse tier inneren Medizin, No. 2, p. 576. — 35 —

8ALVAR8AN FATALITIES

little or no attention whatever has been paid to the urinary function. By chance one may note that the patient has fallen into this condition, accidentally discovering that but a small quan- tity of urine is being eliminated.

Let me cite a few examples of this class:

Tucker's Case. (The Therapeutic Gazette, No. 9. 1911).

Patient well developed, muscular, 30 years old. Three weeks before chancre appeared on prepuce. Has always been healthy. Heredity without in- terest. The clinical examination disclosed nothing abnormal in heart or lungs. A trace of albumin, however, in urine. Skin pale, hot and damp. Ex- tirpation of right inguinal glands (adenitis) on April 29th. On May 5th, a maculo-papular erup- tion broke out on trunk and limbs. Patient com- plained of pains in joints. A few leucocytes in urine. Wassermann, + + +. At half past two in the afternoon of May 12th, patient received an injection of 0.6 of salvarsan. In one hour the injection was followed by nausea, chills, vomiting and diarrhea. Temperature rose to 39 (102.2 Fahr.), pulse 126. In the morning patient felt quite well, no more diarrhea but since the time of injection has not urinated. The bladder upon catheterization found to be empty. Forty-eight hours after the injection the condition of patient grew worse, the cord-like pulse slowed down and symptoms of dyspenea appeared. Death took place two and one half days after injection with pa- tient entirely conscious. No autopsy.

Luque Morata's case (Revista de Medicinia y Cinejica Practicas, Feb. 28. 1911).

Student 21 years old. Infected two years be- fore. Treated for one year with injections of grey oil. Mucus patches in mouth and pharynx. Pa- tient very emaciated, weight but 91 pounds. No albuminuria, heart and lungs without findings of interest. On January 31st, received injection of 0.4 of salvarsan in 200 c.c. 0.9 per cent physio- logical salt solution, alkaline. Three hours later

— 36 —

SALVARSAN FATALITIES

a feeling of distress, diarrhea, profuse perspira- tion. Soon vomiting of a green color, mixed with blood. Pale lips, dry tongue, pallid face, tempera- ture 36 (96.8 Fahr.), scarcely perceptible pulse. Complete anuria. With catheter no urine secured from bladder. Delirium, coma, death three days after injection. No autopsy.

Caussade and Regnard's case (Bull, de la Soc. m£d. des Hdpitaux, February 20th, 1911).

Patient 33 years old. Hard chancre. Later roseola and mucus patches. Mercury very badly borne for which reason patient was irregularly treated. Then considerable edema; albuminuria, 5 grams to the liter. As a result of milk diet declination of the edema; increase of albumin to 9 in 1,000. Patient very weak, emaciated, bed- ridden. Small urinary excretion — 450 or 500 grams a day. Notwithstanding mercurial injections, the oliguria continued. On January 6th, patient was given 0.3 of salvarsan intravenously. Well borne. However, the oliguria increased. On January 9th, the amount of urine excreted was but 50 grams; the percentage of albumin increased to 33 grms per liter. On the eighth day of anuria, patient died in a condition of cachexia but without pain.

Autopsy: Acute diffuse nephritis with granular epithelial and amyloid degeneration of the glom- eruli.

If the anuria passes, then recovery takes place, as illustrated by the following case.

George Livermore's case. Anuria after salvar- san (J. A. M. A., 1912, October 5th).

In May, 1911, a nineteen-year-old patient de- veloped a hard chancre, and a month or so later secondaries appeared. For six months he was treated with mercury, as a result of which all manifestations disappeared. The internal organs, especially the kidneys, sound. On July 2nd, the patient, who showed no signs of lues, was given an intravenous injection of 0.55 salvarsan. In one hour vomiting and diarrhea developed, and after a time anuria became evident. On the next day a small quantity of urine was drawn off. This urine contained much albumin. In a sLort time

— 37 —

SALVARSAN FATALITIES

bfi E

M

£

— 38 —

8ALVARSAN FATALITIES

the uremic symptoms moderated, after which full urinary excretion became established.

A similar case is also reported by Wolff and Mulzer.*

A seamstress, 27 years old, received on June 1st, 1912, 0.7 neosalvarsan intravenously, and 1.2 of the same on June 4th, all of which was borne without reaction. On June 8th, 1.4. On the following day temperature was normal, but patient suffered from severe vom- iting. This continued until the 15th. On June 13th complete anuria. Signs of interference with function of lower limbs. June 17th, se- vere cystitis, albumin, casts. June 19th, marked hemorrhagic nephritis ; anuria ; bed- ridden. July 2nd, anuria. Extremely small quantity of urine, free from blood. July 17th, condition the same, albumin and casts.

When we come to inquire why such a renal insufficiency should supervene, why an occa- sional patient of the thousands injected (I have given more than 25,000 injections), should suffer this fate, I am convinced, at least so far as my patient is concerned, that it is not to salvarsan but, on the contrary, to the combined treatment, mercury and sal- varsan, the disaster should be attributed. In my case mercurial treatment was carried on for two weeks under my supervision.

Physicians have argued with much warmth as to who was the first to have the idea of the combined treatment. Indeed, there is scarcely a syphilologist who has not made a

*Muenchner Med. Wochenschr., 1912, No. 31. — 39 —

8ALVARSAN FATALITIES

claim for priority in this matter. It cannot at all be questioned but that the combined treatment has certain advantages, and occa- sionally I have myself employed it, but looking at the matter with scientific eyes one cannot reach a definite conclusion as to the difference between the action of mercury and salvarsan, nor can one advance unassailable reasons for the use of mercury in one case and salvarsan in another, any more than he can say when the both should be employed. But still more regrettable is the fact that no one has yet answered the question: What harm can be produced through the use of this combination of two different substances?

It is quite inconceivable how we are going to determine the toxic or idiosyncratic action of salvarsan if we combine with it a drug such as quicksilver, which can cause, even in the smallest dosage and in the most mysterious fashion, varied and severe collateral effects and even, at times, a fatal termination. Just today, December 12th, 1912, I have received into my department a woman who from Oc- tober 5th on rubbed her husband five times with mercurial ointment, and who now suffers from a severe necrotic stomatitis, than which, notwithstanding my wide experience in this field, I have never seen a worse one.

Particularly so far as it relates to the kid- neys this observation is of the highest import- ance. It is now well known that mercury in a large percentage of cases causes an irrita- tion of the kidneys which becomes obvious

— 40 —

8ALVAR8A N FATALITIES

through albuminuria and cylindruria. Reiss* has lately pointed out the extraordinary fre- quency of this phenomenon. By reason of the disproportionate excretion of the mercury, this condition may reach at times, especially during the second week of the treatment, a very severe grade.

Salvarsan irritates the kidneys but little, es- pecially on account of the aromatic character of the arsenic combination. Atoxyl causes much more renal irritation ; arsacetin produced according to Spiethoff** a constant and often times a lasting irritation of the kidneys (al- bumin, hyaline and granular casts) a point other investigators of the drug (Neisser, Milian, Lambkin and Salmon) do not call at- tention to. Although of the two employed in the combined treatment, as far as the kidneys are concerned quicksilver is by far the most pernicious, yet, however, in view of all the circumstances salvarsan must not be held to be entirely innocuous.

If one would acquire an understanding of the circumstances operating in this matter, then one must quit thinking of the postmortem kidney which the pathological anatomist shows us to be more or less changed, but, on the contrary, one must make use of the living kid- ney functioning under physiological and patho- logical conditions. On this question the classic

*Beitrag zur Kenntnis der bei QuecTcsilberbe- Jiandlung vorkommenden Cvlindrurie. Archiv. f. Dermatol., Bd. Ill, 2 Heft.

**Compare Borcher's dissertation: Die toxischen NebenwirJcungen des Arsacetins mit besonderer Berucksichtigung der Nierenreizungen., Jena, 1910.

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SALVARSAN FATALITIES

experimental work of Schlayer* and his co- workers, on the toxic nephritides and the func- tion of diseased kidneys, casts a welcome beam of light. This work has established that there is a fundamental difference between the ac- tion of mercury and arsenic on the kidney; the two drugs act upon entirely different parts of the renal tissue. It has been proven with exactness that mercury belongs to that group of substances which produce a pronounced tubular nephritis ; of these chromium may be accepted as the type. Therefore, in the be- ginning there is a good secretion with com- pletely normal function of the vessels, not- withstanding free excretion of albumin and the presence of Targe numbers of casts with which the already extensive and fixed defects of the epithelia well coincide. After a rather lengthy existence of the nephritis there grad- ually comes a diminution in the capacity of the renal vessels to dilate and with it a decrease in diuresis. In sharp contrast to the above there is the other group of toxic nephritides, such as those produced by arsenic or cantha- rides ; these cause a vascular nephritis. In this group there occurs, even after minimum doses, a marked impairment of the renal ves- sels' power to dilate as well as to contract, with accompanying suppression. In these cases the clinical picture offers fewer charac- teristics than that of chromium and mercury poisoning; furthermore, the quantity of albu-

* Schlayer and Hedinger. Archiv. f. Tclln. Medi- zin., Bi. 90-91.

Schlayer and Takayasu, ebenda Bd. 98.

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8ALVA R8 AN FATALITIES

min as well as of casts is for a long time not so large. It is arsenic particularly which al- ways affects the capillaries, characterized, es- pecially after intravenous injection, in a short space of time by a severe impairment of the renal function even increasing in severity to the extreme of complete renal insufficiency. In connection with this clinical picture there is but a slight anatomical change.

Toward the better understanding of these fundamental facto'rs, let me quote several tests made by Schlayer and Hedinger during the course of their "Experimental studies on' toxic nephritis" (/. c.}. In these studies the renal volume was secured with an oncometer (Runne- Heidelberg), and the blood pressure in the carotid recorded with a special instru- ment. By means of an electric drop counter devised by Prof. Lowi of Vienna, the urinary excretion from both kidneys was accurately gauged. With normal animals the following results were gotten:

After the kidney volume had been deter- mined by means of an accurate level, an ap- preciable stimulation was employed, whereupon occurred a quickly transitory rise of blood pressure with a quick drop in kidney volume corresponding to the contraction of the splanchnic vessels. Then the kidney again quickly dilated with an approximate return to its original volume.

Then under an injection of adrenalin (1 drop of 1 per cent, solution in 0.5 c.c. 0.9 per cent, salt solution) the kidney volume showed a marked drop with enormous rise in blood pressure. After return to a normal height, 5

— 43 —

8ALVAR8AN FATALITIES

per cent, sodium chloride solution (5 c.c. to the kilogram) was injected. This caused di- latation of the renal blood vessels with strong pulsation, and also an immediate diuresis. After cessation of the dilatation and wane of the diuresis, caffeine (2 c.c. 5 per cent, solu- tion pro \]/2 kg.) was injected, whereupon occurred the same phenomena, viz., dilatation of the renal vessels and diuresis. Finally, fre- quent injections of phloridzin were given which in normal animals caused moderate diuresis with glycosuria but without increase in kid- ney volume.

The phenomena attending chromium pois- oning are shown by the following experiment and curve:

Rabbit No. 19, weight 1,500 grams, received 1 c.c. chrom. potassium (2.00 — 15.00) subcutaneously. No diarrhea. The animal is visibly sick. Bladder half full. Urine: enormous quantity of casts, es- pecially granular and epithelial, a few erythro- cytes; albumin about 6 per cent. (Esbach).

Upon appreciable stimulation fairly well marked contraction sets in; with adrenalin* somewhat less. With chloride of sodium minimum dilatation of the kidney but however, without diuresis, al- though the ureters, as shown by tests, are per- meable. With caffeine is noted a retarded and very slight dilatation with minimum secretion.

Pathological anatomy: Kidney large; medul- lary substance moderately hyperemic; cortex pale.

Microscopical: Almost complete necrosis of the

*During this contraction-reflex the secretion was incorrectly gauged. This was caused by the es- cape of the salt solution with which the bladder was filled, a consequence of contraction of the bladder and ureters due to the adrenalin. This occurred a number of times in the beginning of this work.

— 44 —

S ALVARS AN FATALITIES

entire cortex, only at occasional sites a few re- maining tubules, casts in lumen plentiful. Glom- eruli large, showing irregular swelling of the' cap- sule. Suggestion of albumin-ring in the fine net- work between capsule and glomeruli.

These phenomena are associated with sublimate poisoning:

Rabbit No. 11, weight 1,300 grams, received sub- cutaneously 21/£ c.c. of a 1 per cent, solution of sublimate 71 hours before. The animal is yet quite lively, has no diarrhea. The bladder is half full; the urine contains hyaline and granular casts and epithelium in plenty, but very few ery- throcytes. Albumen about 5 per cent.

Pathological anatomy: Kidney rather large, cortex pale.

Microscopical: Large quantity of casts in the tubules of the medulla, variously also in the cor- tex. Large quantity of a spotted, flaky disinte- grated substance (lime deposits) in the epithelium of the convoluted tubules; likewise in the ascend- ing loops; many of the tubules are entirely de- nuded of epithelium.

The glomeruli show a scarcity of nuclei, mod- erately congested, do not fill out the capsule en- tirely. Nowhere is there any exudate.

Finally, toward the end, with large doses and after three or four days' duration the following functional phenomena exhibited themselves :

Upon appreciable stimulation and adrenalin contraction of the kidney still occurred, upon which diuretics scarcely produced any im- pression. The diuresis itself is very slight. Neither diuresis nor glycosuria followed phloridzin. The bladder is still rather well distended. The urine contains many casts of all sorts, and epithelium. Erythrocytes not plentiful. Albumin in large amount.

The pathological findings in this stage reveal

— 45 —

SALVARSAN FATALITIES

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— 46 —

SALVARSAN FATALITIES

marked necrosis of the epithelium in the in- jured tubules and in the pyramids, particularly in the ascending limbs of the loops. In the glomeruli there are now no marked changes, only occasional epithelial swellings in the cap- sule, no definite exudates, none or only an oc- casional desquamation of the capsule epithe- lium.

This stage is illustrated by the following:

Rabbit No. 9, weight 1,550 grams, received 84 hours before 0.8 c.c. of a 1 per cent, solution of sublimate under the skin, then 60 and 36 hours before respectively, 1% c.c. of the same solution. The animal is somewhat weak. Has no diarrhea. The bladder is full. The urine contains large quantities of casts, principally granular, moderate- ly numerous epithelial cells and erythrocytes. Al- bumin 4 per cent.

Pathological anatomy: The kidney is very large, the cortex pale and shows fine radiating stripes.

Microscopical: Many casts in the excretory canals, also in the convoluted tubules of the laby- rinth and cortex. Occasional hemorrhages in the border regions. The injured uriniferous tubules and particularly the ascending loops exhibit very wide spread flaky necrosis (lime deposits), the still remaining epithelium shows mostly poor nuclear staining and cloudy protoplasm. Many tubules for long distances are denuded of epithelium. The glomeruli are hemorrhagic, rather poor in nuclei, entirely fill the capsules; only here and there can one find a suggestion of swelling of the capsule epithelium.

We see, therefore, that sublimate nephritis in its functional course offers exactly the same picture as chromium nephritis ; in the begin- ning there is good secretion with completely normal function of the vessels notwithstand- ing an abundant excretion of albumin and the

— 47 —

8ALVAR8 AN FATALITIES

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— 48 —

8ALVARSAN FATALITIES

presence of many casts with which the already extensive anatomical damage of the epithelium coincides.

Only after a lengthy existence of the ne- phritis and after high dosage of the causative agent, there occurs, with severe damage of the tubules, a gradual diminution of the renal vessels' capacity to dilate and a decline in diuresis, which both finally become entirely nil.

In all stages, however, the contractility of the renal vessels remains constant, except to- ward the end it is somewhat less than normal.

In regard to the functional phenomena it has been shown that the polyuria of the initial stage is not so marked in chromium poisoning as in poisoning by other drug, and further the sublimate nephritis distinguishes itself from chromium nephritis in two ways as far as the pathological anatomy is concerned : The one is the strikingly slight impairment of the glom- eruli as shown in the histological picture ; even with almost completely suspended capacity of the vessels to dilate, epithelial swelling of the capsule is found at only a few points. No- where is there exudate, etc. The second point of difference is to be found in the deposits of lime after large doses continued for some time.

We shall come back later to the first point. The second makes it clear that there must be a difference in the biochemical course between chromium and sublimate poisoning, but it shows, however, at the same time that not- withstanding this difference in the functional

— 49 —

SALVARSAN FATALITIES

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		— 50 —

SALVA RS AN FATALITIES

phenomena, the result to the organism, so far as investigated, can be entirely similar.*-

But entirely different are the conditions at- taching to cantharides, which point is illus- trated by the following :

Rabbit No. 7, weight 1,500 grams, four and one- half hours before the beginning of the experi- ment, received a subcutaneous injection of i/> c.c. of cantharidin, 1:100 or 0.005. Animal seems quite lively. The bladder contains bloody urine in small quantity. In the urine is an abundance of epithelial cells, large erythrocytes, rather plen- tiful epithelial casts, little albumin (about 1 per cent.) in filtered urine. Kidney pulsates fairly •well.

Rabbit No. 13, weight 1,400 grams, nine and one- half hours before beginning of experiment re- ceived a subcutaneous injection of % c.c. canthari- din, 1:100 or 0.005. The animal has diarrhea and appears weak. The bladder is nearly empty. In

•Observation. Our investigations show that the supposed capillary thrombosis held by Kaufmann, Silbermann and others to be the cause of the death of the epithelium, is not necessarily present in sublimate nephritis in rabbits or, at least, not to any great degree. We see, notwithstanding ex- tensive and severe lesions of the epithelium, a marked capacity of the renal vessels to dilate and contract as well as prompt reduction of kidney volume following the opening of a vein to produce death. It would be impossible for both to be present with any extensive capillary thrombosis. Even in the final stages the kidney still has good contractility, and its pulsation becomes stronger after the use of diuretics, so that also in this stage no marked capillary thrombosis can be present, as we would necessarily have to accept in explana- tion of the enormous destruction of the epithelium according to the explanation given by Kaufmann. Our results in this respect confirm the views pro- mulgated by Klemperer, that the condition is reached in some other manner.

— 51 —

SALVARSAN FATALITIES

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		— 52 —

8 ALVA RS AN FATALITIES

the urine are numerous swollen epithelial cells, few casts, many erythrocytes. Albumin not definite. Curve 4, figure III, illustrates the course.

Thus, the deleterious effect following can- tharidin is entirely different from that of chromium and sublimate. All experimental work shows with great clearness that can- tharidin has a totally different action on the kidneys from that produced by chromium.

After the shortest time, even after minimum doses, there occurred an enormous impair- ment of the dilatability as well as contractility of the renal vessels, with coincident failure of diuresis. At the same time the clinical in- vestigation showed much fewer phenomena than with chromium, likewise the quantity of casts as well as albumin was not near so great ; the striking feature was the abundance of ery- throcytes.

With longer protracted or severer poisonous influence a complete insufficiency of the renal vessels develops, the pulsation of the kidney and urinary excretion cease entirely, but the pathological examination does not disclose a condition that corresponds with the renal dis- turbance such as one may find in the less pronounced impairment of the urinary func- tion following chromium poisoning.

According to all observations in regard to cantharides nephritis, the clinical picture Is that of a marked, very rapidly setting in dis- ease of the renal vessels. If this assumption be correct, then it remains that a poison which spends its force mainly in the capillaries, will produce the same sort of an effect.

— 53 —

SALVAR8 A N FATALITIES

We found the same to hold good in regard to arsenic. Boehm* and Schmiedeberg** through their investigations have shown this characteristic, and recently it was demonstrat- ed through the efforts of Magnusf who pro- duced a marked edema through saline infusion following the injection of arsenic. He also holds the opinion that arsenic is to be looked upon as a typical capillary poison.

In our experimental work we subjected ani- mals to arsenic, and even employed arsenous acid in one per cent, solution intravenously as well as subcutaneously. In all, three demon- strations were made in this manner. Two of them, the one treated with an intravenous so- lution, the other with subcutaneous, are cited here.

Healthy rabbit of 1600 grams. No albumin in urine. Left kidney connected with oncometer.

Pathologico-anatomical findings. Kidney large, cortex rather markedly hyperemic.

Microscopical: Occasional hemorrhagic spots, especially in the border strata. But a few casts in the excretory canals. The epithelia of the tubuli contort! involved to a slight extent. No-' where damage to nuclei. Staining of nuclei good. No fusion of the protoplasm. The glomeruli are very much congested and fill their .capsules en- tirely. They contain nuclei in abundance. With most there is epithelial swelling of the capsule. With some desquamation (?). Nowhere exudate.

Rabbit, weighing 1550 grams, received a sub- cutaneous injection of 1% cc. of a 1% sol. arsen. acid, seven hours before beginning of experiment; four hours later another injection (1 cc.) of the

*Arch. f. exp. Pathol. u. Pharm. Bd. 2 and 16 **Schmiedeberg, Grundrisz der Pharmakol. 1 Aufl. p. 406. ff.

\. f. exp. Path. u. Pharm., Bd. 42, p. 267.

— 54 —

SALVARSAN FATALITIES

same. The bladder is empty. The animal has diarrhea and is somewhat weak.

Pathologico-anatomical findings: Kidney is large, the border regions markedly hyperemic.

Microscopical: Moderately abundant casts in excretory canals; likewise in the border regions; only moderately abundant hemorrhages. The epi- thelium of the tubuli contorti indicates rather ex- tensive cloudiness of the protoplasm, which in oc- casional tubules is coagulated in flakes. At the same time damage to the nuclei is not clearly es- tablished. The glomeruli are very much con- gested, and fill the capsules completely; rather rich in nuclear elements; occasional slight desquama- tion of the capsule, as a rule but moderate swell- ing, no exudate.

We find therefore, as was expected from the above mentioned observations, an entirely analogous behavior of the renal circulatory system with arsenic as with cantharidin. After a short period, especially with intravenous in- jection, serious impairment of the organ's power to dilate as well as to contract was noted, with complete cessation of diuresis.

Also in this experiment, there appears in its final stages a phenomenon of the renal blood supply similar to that attending the use of cantharidin. A secondary increase in vol- ume of the kidney following stimulation of the capacity of contraction. Likewise, as with cantharidin, the secretion of urine is relatively less ; there are rather more casts and a smaller amount of albumen with complete renal in- sufficiency. The pathological findings are even less than with cantharidin. It might well be that more marked phenomena, especially of the glomeruli, would appear with a longer duration of the nephritis; for us the essential

— 55 —

SALVARSAN FATALITIES

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— 56 —

SALVARSAN FATALITIES

feature was the determination of a less notice- ably marked anatomical change with well prov- en renal insufficiency.

A difference between arsenic and cantharidin is to be found in the blood pressure, which falls very much faster and deeper after the first than following the use of the latter agent.

In seeking a reason for this difference, we find it could be caused either through the ac- tive influence which, as is well known, arsenic exerts upon the vasomotor center, or through the wide extension of the damage inflicted upon the peripheral capillaries.

Perhaps one cannot entirely accept the prop- osition that salvarsan in the abstract has the same effect as arsenic upon the renal blood supply but it acts in the same sense as the demonstrated reduction of blood pressure (as shown in my patients by Professors Nikolai and Siesskind) proves, especially after intra- venous introduction. At times a slight impair- ment which has existed may become changed into a fatal danger, especially when the func- tion of the renal circulatory system has suffer- ed through the previous administration of an- other poison.

Practically all fatal cases of salvarsan therapy in the person of healthy, strong pa- tients, show the fatal combination of energetic mercurial treatment and the intravenous in- jection of salvarsan.

One might well complain that salvarsan fa- talities are not sufficiently explained by the above in view of the immense number of re- corded cases in which the combined treatment was employed without any evil feature. It

— 57 —

SALVARSAN FATALITIES

depends wholly upon what period of observa- tion an investigation of the burden thrown by salvarsan upon a kidney already damaged by mercury, is taken up. With moderately severe intoxication with sublimate, it is seen in ex- periments, that on the first day of the poison- ing, with increased intake of salt, polyuria oc- curs with somewhat augmented excretion of the saline, but that the same increase of intake on the second and following days is responded to by a marked incapacity to eliminate the saline. The excretion of iodide of potassium is also delayed. The excretion of milk sugar from the beginning and thenceforth proceeds well, so much so that from the second day the excretory curves of the saline and the sugar diverge widely. Only on the fourth day as the damage to the capillaries becomes marked does retardation of excretion of lactose set in. Therefore, the kidney can yet eliminate milk sugar when for a long period it has no longer responded to an increase of salt intake. In the case of renal congestion caused by arsenic, the animals, in most instances, die quickly in anuria. Where investigation was possible, re- tardation of lactose excretion manifested it- self. It is not fixed as to which type the sal- varsan excretion belongs ; however, it may by reason of damage done by mercury to the kid- neys, undergo, under all circumstances, a sub- stantial retardation. Concerning the above, one is at once clear, if he observes the circum- stances attending mercurial poisoning in cases which do not terminate fatally. Thus, for ex-

— 58 —

8ALVARSAN FATALITIES

ample, Pfeiffer* reports from the clinic of Quincke, a case of a young man who had taken a teaspoonful ( ?) of sublimate, but who at once drank lukewarm milk and vomited freely. This patient recovered. During his stay in the hospital polyuria took place on the first day, followed by suppression until the eighth day at which time polyuria again occurred. The circumstances are shown most clearly by the following record. (See Table VIII.)

Anuria is a conspicuous symptom of mer- curial poisoning. Only those cases in which it is overcome, end favorably. Thus Kolb** reports the case of a sister and brother who took bichloride with suicidal intent. The sister died with total suppression. The brother passed eight days with the excretion of but 31 c.c. of urine; this contained hyaline, granular and epithelial casts and white and red blood cells. There was an immense quantity of albumin for six days, after which the quan- tity diminished so that on the twelfth day but a slight trace was found with acetic acid-fer- rocyanide of potassium. At this period the excretion of urine ran up to 3,500 c.c., then dropped to 2,500-3,000 c.c. (sp. gr. ranging from 1,002 to 1,012) where it remained. Upon admission of the patients blood pressure was normal ; on the third day that of the sister 280, that of the brother 230. According to Geis- bockf the blood pressure at first rises and then sinks until the end comes; he recorded 125,

*Ueber akute Sublimat- und Oxalsdurevergift- ung. Archiv f. klin. Med. Nr. 90, S. 591.

**Muench. med. Wochenschrift. 1904, p. 582. iArchiv f. klin. Med. Vol. 83.

— 59 —

SALVA R8AN FATALITIES

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— 60 —

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8ALVAR8AN FATALITIES

110, 80, 70, 60. In such cases, as mentioned by Hohlweg,* notwithstanding that no evi- dence of uremic symptoms supervene, there is retention of nitrogenous products. He re- ports two cases of acute mercurial poisoning.

"Regarding the first patient (a female), who was received into the hospital 24 hours after taking four oxycyanate pastilles of one gram each, there was complete anuria from the be- ginning of the period of observation until seven days later when death took place. Not one drop of urine was secured through the ca- theter when introduced into the bladder. Mark- ed diarrhea with bloody passages occurred; edema was not a symptom. The blood pres- sure oscillated between 105 and 130 mm. Hg. The patient died without any uremic manifes- tations. Autopsy denied.

"The second patient (also a female) on December 15th, 1910, swallowed half of a sublimate pastille. Nothwithstanding the prompt attendance of a physician who em- ployed the stomach pump, washing out the stomach, there occurred on the following day intense abdominal pain and watery stools which, however, were not bloody. On Decem- ber 19th, the patient was sent to the hospital. Up to this time patient has not passed any urine. Upon admission into hospital patient was apathetic but not unconscious. During her second day in the hospital patient fre- quently vomited grayish green, vile smelling masses. On December 20th, blood pressure was 135 mm. Hg. On the same day by means of the catheter 4 c.c. of urine was removed ;

*l. c. p. 234.

— 61 —

SALVARSAN FATALITIES

this contained much albumin, many leucocytes, hyaline and granular casts. On December 21st 15 c.c. of urine secured. On the same day at 11 o'clock a. m. venesection was employed; 12 hours later death took place. No uremic symp- toms had set in. Autopsy disclosed eschars on tongue and mucous lining of cheeks, striped hemorrhages of the stomach and colon mu- cosa. There was about 200 c.c. of urine in the bladder. The kidneys showed extensive necrosis of the epithelium with proliferation of the uriniferous tubules (Geh. Rat. Bos- troem).

"In the first case venesection was performed 54 hours before death, in the second case 12 hours.

"The figures for the total rest-nitrogen were respectively 0.204 and 0.298; for the portion precipitated with tannin 0.000 and 0.015; for the portion not precipitated through tannin 0.033 and 0.045 ; for urea nitrogen 0.071 and 0.238."

This enormous retention of nitrogenous pro- ducts of the blood is the expression of the in- capacity of the kidneys to remove these pro- ducts from the organism. One can easily un- derstand that this insufficiency for foreign sub- stances, such as salvarsan, must be of a still higher grade and with marked oliguria can be fatal.

There may happen a vascular sensitiveness of the kidneys expressing itself in poly — and oliguria, but without albuminuria, in many pa- tients upon the administration of small doses of mercury. There is even a number of re- corded deaths from minimum doses of mer-

—62 —

8ALVARSAN FATALITIES

cury, for example, from a small quantity of gray ointment applied for the relief of pedicu- losis. Volk reports the death of a patient who only lay in the same room with other patients who wore small Welander sacks. It was a 21- year-old patient suffering from tuberculosis. In the room in question, which had an air ca- pacity of 750 cubic metres, there were 24 pa- tients of whom 5 or 6 wore the sacks, while with the others the application of mercury was not carried on in this room. In nine days there was swelling of the tongue which, not- withstanding the most careful attention, in- creased in severity. Although thereafter the patient was placed in a room practically free from mercurial influence, the condition pro- gressed to ulcerative stomatitis which contin- ued without stop until death came. Mercury was found in the urine and kidneys in abund- ance.* Hitherto, entirely too little consid- eration has been paid to the excretion of urine in persons manifesting a susceptibility to mer- cury. Thus, just lately I have observed a young man who exhibited indications of in- sufficiency of the pulmonary valves, this mani- festing itself in weakness of ventricular ac- tion, and a maximum blood pressure of 105 with a minimum of 80. On account of a re- curring angina he received on the 10th, 18th, 21st and 25th of September, 1912, salvarsan, 0.1 each time. As with each injection the tem- perature rose to 38 C. (100.5 Fahr.), with diarrhea and headache of a moderate degree, I refrained from further injections. On Oc-

*Dermat. ZeitscJirift, Bd. XV, 606. — 63 —

SALVARSAN FATALITIES

tober 14th, 15th and 16th, the patient was rub- bed with ungt. ciner., 4 grammes being used each time. On account of diarrhea and gen- eral discomfort this treatment was also in- terrupted. Loss of appetite continued. In the urine there was no albumin or sugar, nor were casts present ; the quantity of urine was 950 c.c. on October 19th, 950 on October 20th, 600 on October 21st, 600 on October 22nd, 400 on October 23rd, 400 on October 24th. In spite of the daily administration of 3 grams of diuretin the quantity of urine did not in- crease, but remained in small quantity. On the 24th of October it was 400, 500 on the 25th, 500 on the 26th, 400 on the 27th, 400 on the 28th, 400 on the 29th, 400 on the 30th, 400 on the 31st, 400 on November 1st, 600 on November 2nd, 600 on November 3rd, 600 on November 4th, 600 on November 5th, 600 on November 6th, 600 on November 7th. On November 5th, epithelial cells were found in sediment; no albumin or casts. In this man- ner the condition remained until December 7th.

Now, through the investigations of Schlayer and Takayasu, we know that vascular hyper- susceptibility in vascular nephritides, may re- main unchanged even after a year, as shown by the entirely unchanged character of the dis- turbed excretory conditions.

It is further known that the elimination of mercury does not take place uniformly, but on the contrary in an irregular manner. Cor- responding to the above are the toxic symp- toms of these hypersusceptible persons in re- missions and exacerbations (alternatives

— 64 —

8ALVAR8AN FATALITIES

d' ameliorations et de vechutes, Letulle). These may extend through many months, and indeed, years. Furthermore, after these" long periods, stomatitis, enteritis and particularly mercurial angina in the Plaut- Vincent form, with exanthemata may recur.

Quite characteristic is the following case which I observed some time ago. Pat. F., on account of syphilitic manifestations, was rub- bed January 17th, 18th, 19th and 20th, 1906, with unguentum ciner., 3 grams being employ- ed each time. Directly after the second rub- bing fever and universal reddening of the skin appeared. The treatment was suspended and with bathing and powder, the manifestations disappeared. Two weeks later without any further antisyphilitic treatment, there again ap- peared an extensive reddening of the skin, and with it angina and very high fever. The pro- cess impressed one as being scarlet fever. No albumin in the urine. After extensive des- quamation the patient was discharged cured on March 7th, 1906. From June 1st to June 27th, the patient was again under our care ex- hibiting the same serious clinical picture as before. Again there was no albumin. Four days after discharge again the same symptoms supervened, but the patient did not present himself at the hospital until July 2nd, 1906. Upon complete disappearance of the typical mercurial eruption, on account of a persisting papular eruption of the scrotum and a palmar psoriasis, an attempt was made to carefully ad- minister mercury ; on August 7th, at 1 1 :30, he received 0.015 hydrar. salicyl.

Immediately thereafter the patient was

— 65 —

SALVARSAN FATALITIES

seized with headache, chills, and rise in tem- perature; also, by 2 o'clock an intense exaiv- them covering the entire body was clearly vis- ible. No albumin or sugar in urine. After recovery, in order to accustom the patient to mercury, he was given a capsule of mergal (divided into two doses) on September 26th, 28th, 30th and 31st. A half hour after the administration of each dose there appeared headache, a sensation of heat, reddening and pruritus over the entire body.

On October 4th, 1906, he was again received by us, and showed, although he had not re- ceived any mercury, the same picture of der- matitis universalis and recurring papular erup- tion. He was treated with Zittmann's decoc- tion.

At this time there was a similar case in my department in which the disturbance of diure- sis often seen in these cases, became well es- tablished. Karl W., 23 years old, on account of syphilis, received from his physician six injections of salicylate of mercury. Follow- ing the fourth injection an eruption made its appearance, for the treatment of which the patient was received into the Virchow Hos- pital on December 21st. There was found a general dark reddening of the skin, desquama- tion of the skin in shreds ; after desquamation there was slight weeping of the desquamated areas. The urine contained albumin, epi- thelial cells, leucocytes and granular casts in moderate quantity. Finally toward the end of June the patient, after loss of hair and nails, was fairly well cured, although much reduced. On account of positive Wassermann and al-

— 66 —

SALVARSAN FATALITIES

terations in the spinal fluid (Nonne ++ Gold + + + Cells + + W. 500 per cent. 0) he re- ceived in July seven injections, one of 0.1, one of 0.3, five of 0.2, all of which he bore with- out trouble.

Without renewal of the mercurial treatment, he suddenly took sick on the night of Octo- ber 12th, showing the same picture of a gen- eral, slightly weeping mercurial dermatitis. The urine was at this time free from albumin and formed elements. However, upon admis- sion into the hospital the activity of the kid- neys was found markedly reduced, and later, coincidently with the drying of the skin and disappearance of the inflammation after des- quamation, suddenly developed into polyuria.

October 14- 15th, 260 c.c. sp. gr. 1032.

October 15-16th, 550 c.c. sp. gr. 1029.

October 16-17th, 740 c.c. sp. gr. 1021.

October 17- 18th, 2150 c.c sp. gr. 1010.

October 18- 19th, 2500 c.c. sp. gr. 1012.

In about this way the urinary secretion re- mained until November 5th, when the patient was completely restored. From November 6th on the urine was normal, and on November 7th, the patient was given y2 gram of iodide of potassium. It was normally eliminated; urine 1500-1700 c.c. with sp. gr. of 1012-1016. On November 13th, 0.1 and on November 16th, 0.4 of salvarsan given and borne without the slightest reaction.

Such exanthemata may take place under dif- ferent provocations, for example under the in- troduction of salvarsan in the presence of damaged kidneys. In this manner I under- stand the case of death reported by Brauer.

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8ALVAR8AN FATALITIES

In general, the course of this case did not re- semble the other fatal cases, but, on the con- trary, in a striking manner (nephritis with granular casts, bloody diarrhea, no convul- sions) the descriptions of those fatal cases fol- lowing the use of insoluble preparations of mercury.

S., 34 years old, gardener, well nourished, well muscled, internal organs without pathological changes, denied any former illness. The time of infection could not be determined. Chancre on the glans since January 14th, 1912. Condition on January 22nd, 1912: Lesion on glans, dis- seminated maculo-papular exanthem, papules on the margins of the tongue and upon the tonsils. Wassermann positive. Under the direction of his private physician had undergone twelve inunc- tions with ungt. cinereum of 4 grams each, the last of which was on February 2nd, 1912. From February 6th to February 23rd, patient received one calomel injection of 0.03, five calomel injec- tions of 0.05. On account of stomatitis treatment was interrupted. Urine free from albumin. On February 28th given one injection of salvarsan, 0.4. In the afternoon vomiting and diarrhea. March 6th, second injection of salvarsan 0.4 with diarrhea following in the afternoon. On the same day third injection of salvarsan given (0.4) with increase of diarrhea and vomiting. On March 7th diffuse, in places confluent, macular eruption of erythematous nature. Albumin present (marked opalescence), a few hyaline and granular casts. March 9th exanthem faded, but yet recognizable. Today fourth injection of salvarsan, 0.4 given. March 10th, exanthem has grown more marked reminding one of the Jarisch-Herxheimer reaction occurring in syphilitic exanthemata treated with sal- varsan. Albumin positive (marked opalescence). Few hyaline and granular casts. March 12th, exanthem extended. Efflorescences confluent, urticarial in character. Desquamation of the hands. March 16th, exanthem barely perceptible;

— 68 —

SALVARSAN FATALITIES

flaky desquamation of the body, that of the hands in larger pieces as in scarlet fever. Urinary con- dition as above. March 18th, eruption completely gone. Desquamation of the hands still going on. Wassermann negative. March 23rd, for two days a recent disseminated, and confluent urticarial, erythematous exanthem. Falling of the hair. Temperature 38.5 C. (101.4 P.). Bloody diarrhea, abdominal pains, urinary condition unchanged. March 25th the eruption has become universal. March 26th the dermatitis of the scrotum and anus is "weeping." Urine as above. Temperature 39.3 C. (102.7 F.). March 27th universal sero- fibrinous dermatitis, rhagades over joints. Con- tinuous fever. March 30th, rhagades on other sites. Desquamation of the skin over large part of the body, disclosing weeping surface beneath, especially on abdomen and back. Blisters on the mucosa of tongue. Diarrhea and marked prostra- tion. Temperature 38.7 C. (101.6 F.), pulse 120. On April 4th, with increasing somnolence and in- crease of temperature to 40 C. (104 F.), death took place. The skin of the entire body resembled a very severe burn of the second degree. Postmor- tem (pathological institute) : Extensive derma- titis, covering entire body. Severe parenchyma- tous nephritis. Slight degeneration of the heart muscle and liver. Small hemorrhages in the mu- cous membrane of the sigmoid and rectum. Hy- peremia of the lower lobes of the edema- tous lung. Enlargement of the spleen. Marked chronic meningitis. Very marked edema of the brain and moderate edema of the meninges. The bladder contains about 700 cc. of urine. Albumin positive (opalescence) ; occasional erythrocytes and leucocytes, granular and hyaline casts.

With its serofibrinous, general character, and merging borders, which give it a resemblance to scarlet fever, the exanthem is absolutely like a mercury-dermatitis. The salvarsan der- matoses are always lightly spotted or are uni- versal erythemata, which do not proceed to

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8ALVAR8AN FATALITIES

serous infiltration of the skin and to a char- acteristic desquamation. Furthermore, they do not have the long duration.

Just recently I saw an exanthem of similar character attributed to salvarsan. A young woman, on October 23rd, 1912, received at the hands of a dermatologist a salvarsan in- jection which was well borne. Following this, she was rubbed with six capsules of gray oint- ment. After this course an eruption of small water-filled blisters appeared. On December 4th, 1912, she came to my department with universal reddening of the skin and large- flaked desquamation, that from the feet and hands taking the form of a glove.

An examination of the desquamated epider- mis on December 8th, that is six weeks after the exhibition of the mercury, showed the same to have a rich mercury content, while arsenic was not present. The urine also con- tained mercury.

On the whole, one must wonder at the con- fusion of many physicians in regard to sal- varsan, for so many of them attribute to sal- varsan an effect which is clearly that of mer- cury. Thus the following item is to be found in the Presse Medicale, No. 100, December 4, 1912:

"Au non die M. Boulliard, M. Paul Guillon presente un malade atteint de syphilis en Aout dernier pui a suivi d'abord un traitement mer- curiel, puis un traitement par 1'arseno-benzol, quinze jours apres la troizieme injection d'arseno-benzol, la malade accusa une derma- tite exfoliante generalisee ainsi qu'une gen- givostomatitie ulcereuse aigue et persistante.

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SALVARSAN FATALITIES

Dans deux autres cas, 1'auteur a pu constater semblables lesions; il rapproche celle-ci des cas de gangrene de la bouche signales par M. Dritsky et recommande, dans le traitement par 1'arseno-benzol comme dans le traitement mer- curiel, de surveiller attentivement la bouche des malades."

These occurrences, according to the descrip- tion of the salvarsan reactions of Neisser and Hoffmann, are very much like the reactions of mercurial stomatitis.

Zimmermann who describes this salvarsan reaction on the teeth from the Herxheimer clinic, says :

"For a long time we have been able to ob- serve this salvarsan reaction on the teeth, and determined that it usually took place in pa- tients who had a more or less severe stomati- tis. It is a matter frequently concerning pros- titutes who have decayed teeth, and in whom, notwithstanding the most careful attention to the mouth, a severe stomatitis occurs even after small doses of mercury.

"The pain begins suddenly, often just after the patient has left the operating table. In some cases, in fact, it takes place before the injection is finished. The pain is partly local- ized in certain sites (it is immaterial whether especially marked stomatitic changes are pres- ent or not) and partly as a boring and draw- ing, like that of a burn. It may be seated at one angle of the jaw and then suddenly change to the other. In one or two hours the pain entirely ceases.

"We believe these phenomena may be traced, perhaps, to a sudden destruction of spiro-

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SALVARSAN FATALITIES

chaetes in the teeth and mouth and the libera- tion of toxins under the spirillocidal influence of the salvarsan. Since a stomatitis is highly favorable to the above process, we are able to understand why we never see the same sort of a reaction in cases of syphilis treated solely with salvarsan. We have never been able to establish a diminution of motility of spiro- chaetes from the teeth in the dark field, after an injection of salvarsan."

In my department where pure salvarsan therapy is employed such reaction never pre- sent themselves. Quite convincing that these stomatitides are of a mercurial nature is the circumstance that in my department, to which, at my request a dentist was appointed to take care of the mouth of patients undergoing mer- curial treatment, since the year 1910, that is, since the inauguration of my policy of em- ploying salvarsan alone, mouth disorders have been very infrequent and the dentist is the same as being without any duties.

These observations seem to indicate that following salvarsan injections reactions may take place in other parts of the body, especially in the renal arteries or other small vessels which have been damaged by mercury or where mercury still remains but is not securely an- chored in the tissues.

One must consider that, as the excellently conducted investigations of Moller and Blom- quist* show, the capacity of the kidney to eliminate mercury from the system is rather

*Dermatol. Zeitschr. Bd. XVII, H. II Veber die Quecksilberausscheidung durch die Nieren.

— 72 —

limited and marked individual deviations may be noted. According to the various investi- gations of Almkvist* mercury is retained in the renal cells and even in the epithelial cells of the collecting tubules, in which degeneration is brought about.

How such foci react to a blood current impregnated with salvarsan we do not know. Some accounts in the literature speak, with a certain plausibility, of an occasional explosive effect. I am inclined, in general, to explain the great difference in opinion of various au- thors in writing of the collateral effects of sal- varsan, as being based upon different modes of treatment, i. e., the pure use of salvarsan or the combined treatment.

Concerning this I cannot add anything of special import; the description of a so care- ful investigator as Gennerisch does not cor- respond in its various features with the pic- ture of the consequences of salvarsan injec- tions, as we usually see it.

But it is easy to understand that it is only in certain moments that the employment of salvarsan is dangerous, especially when through mercury a vascular oliguria is brought about and the eliminative function interfered with.

For example, my assistant. Dr. Pakuscher, in a case of moderate mercurial nephritis, was not able to demonstrate iodide of potash which had been given, in the urine until twelve days had elapsed.

Very recently a case of sublimate poisoning

*Dermatol. Zeitschr, Bd. XIX, H. II. — 73 —

8ALVARSAN FATALITIES

was subjected by Conzen to the newer methods of determining renal function. Concerning this Conzen wrote the following:

"The glomeruli are fully intact; the tubuli are the site of attack. The experimental investiga- tions of Schlayer prove functionally that there are isolated areas of tubular defects. Only with a quite severe damage is there a later impairment of the function of the glomeruli. Consequently this case is particularly well adapted to serve in measuring the value of the renal tests.

"CASE 12. — F. M., 31 years old, attempted suicide on January 7th, 1912, by drinking a glassful of water containing one gram of sublimate. Im- mediately red colored material was vomited; in the evening repeated attacks of dizziness, spots before the eyes, further wretching and vomiting of bloody masses. During the night and on the next day there was diarrhea. Received into hospital on January 8th. At this time strong flow of saliva, burning in mouth, difficulty in swallowing.

"On the evening of the 7th, after evacuation of a small quantity of urine from the bladder, com- plete suppression set in. Not until January 14th was any urine found in bladder and then but 50 cc. It was light in color, with one per cent, of albumin and containing an abundance of epi- thelial cells, some leucocytes and fragments of hyaline casts. On the 15th and 16th there were further diarrheal passages with the simultaneous discharge of an extremely small quantity of urine, so small in quantity as to prevent successful analysis. On the 17th about 250 cc. Albumin present showing a distinct cloudiness. Micro- scopical examination as on the 14th, except many granular casts.

"From January 18th until March 8th, and then from this date until April 1st, the renal powers were uninterruptedly under observation.

"The quantity of albumin still small, perceptible to slight clouding; the above named formed ele- ments gradually diminished. The blood pressure always remained at from 150 to 90 (the high

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SALVARSAX FATALITIES

blood pressure described as occurring on the first day of sublimate poisoning was not noted in this case). The condition of the heart and retina re- mained normal.

"From January 22nd on, the urinary secretion corresponded to the fluid intake; from February 1st to February 10th somewhat of a polyuria ex- isted, then normal diuresis. From the beginning the sp. gr. was 1007 to 1014. Just once it reached 1014. During a right-sided pneumonia, upper lobe, lasting from January 23rd to January 29th, and during a consequent miscarriage (in the fifth month), with a temperature which lasted until February 3rd, the sp. gr. never reached above 1010.

"The further discussion will concern itself chiefly with the period between January 18th and January 29th.

"With an average intake of 5 to 8 grams of salt, the elimination was 0.1 to 0.3 per cent, with an absolute quantity of 1.5 to 4.8 grams; it was thus too low. The addition of 10 grams of salt was not attempted, it not being thought wise. In view of the above, it seems undoubtedly that the case was that of tubular impairment. On January 23rd and 27th 0.5 of iodide of potassium was given. With the Sandow test I was unable to produce a measurably red coloring of the choloro- form. Severe damage of the tubuli therefore evi- dent. On January 25th 2 grams of lactose intra- venously. Only after 24 hours was elimination finished. At the time of injection the pneumonia had existed for two days, yet the urine did not contain more albumin than previously. Also the sediment was free from blood, there being only a few leucocytes, hyaline and granular casts and epithelial cells.

"Whether, therefore, a glomerular defect caused by the pulmonary infection was the reason for the delayed lactose elimination is somewhat doubtful, yet this should not be dismissed as being unworthy further consideration. That blockage of the tubules with detached epithelium paralyzed the filtration power of the otherwise normally func- tionating glomeruli, with interference with the elimination of the lactose, is, in view of the re-

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8ALVAR8 A N FATALITIES

storation of diuresis in a week's time, scarcely to be accepted.

"From February 2nd on, the absolute and per- centage quantities of salt elimination in compari- son with the intake reached a normal figure, so that only through the low and fixed sp. gr. did t,ne tubular hyposthenuria remain in evidence. An additional intake of 10 grams of salt which was given on February 8th was almost entirely retained. The elimination of about 3 grams took place not in an increase of concentration but, on the contrary, through a slight polyuria extending over several days. This polyuria had already been noticed in a slight degree since February 4th, which was the first day on which the patient was free from fever. Here would be the second point which might possibly indicate a slight functional damage of the glomeruli, a hypersusceptibility.

"February 9th 0.5 iodide of potassium. Elimina- tion in 53 hours, therefore occurring in the normal variation period. How this prompt iodide elimination, at a time of existing tubular concen- tration-defect, is to be explained, I am not able to say.

"February llth 2 grams of lactose. Elimination in 10 hours, therefore a retardation which, how- ever, did not correspond to a glomerular nephritis due to the pneumonia or miscarriage.

"February 14th, increase in water intake; eliminated in 24 hours.

"February 25th, 10 grams of salt added to usual salt intake. Eliminated in 48 hours and through increase in concentration.

"March 21st and 31st, again 10 grams of salt. Although not eliminated in entire quantity (5.5 and 7 grams) yet excretion secured through in- crease in concentration.

"March 19th, 0.5 iodide of potassium eliminated in 49 hours.

"March 23rd, 2 grams of lactose eliminated in 6 hours.

"March 25th, increase in water intake. Elimin- ated in 24 hours. A fixed and low sp. gr., but no polyuria. Trace of albumin in urine. Since March

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8ALVARSAN FATALITIES

7th no casts and leucocytes, only abundant epi- thelial cells.

"Regarding the reaction of the urine; • from January 18th to February 3rd that is, to the end of the fever, it was slightly acid, from then the acid values grew somewhat.

"With the salt addition on February 25th and on March 21st and 31st, an increase in albumin was noted each time, but without change in the diuresis or general condition of the patient.

"Since the elimination of albumin takes place through the glomeruli, then of course it is here we would look for disease when albumin is noted.

"In a case of poisoning with sublimate there is a pronounced and severe damage done to the tubuli (tubular hyposthenuria; iodide elimination rather markedly retarded) which is demonstrable only until about the middle of the 4th week after the ingestion of the poison. This shows itself in a reduction of concentration-power but not in re- tardation of iodide elimination; the functional im- pairment of the tubuli exists for several months, at least, after poisoning.

"A retardation of lactose elimination manifested itself as long as 11 weeks after the infliction of the damage done by the sublimate. At the beginning this was marked and associated with mild poly- uria. It was not shown that the pneumonia or miscarriage (as mentioned in the above case), could have given rise to the acute glomerular nephritis.

"Taken together with the excretion of albumin upon the increase of salt intake, the results of the functional tests indicate that in sublimate poison- ing in humans besides the anatomical damage done to the tubuli, a functional impairment of the glomeruli is also to be assumed."

To what extent only a temporary insuffi- ciency influences the accidents which are at- tributed to salvarsan may be seen in the fact that frequently the same accidents, that is to say the epileptiform attacks and even coma

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8ALVAR8AN FATALITIES

itself, may be overcome and then later salvar- san again administered without evil result. A case in point is that reported by Milian: A young officer received 0.6 of salvarsan, four days after which coma supervened and for a week amnesia existed. However, later the pa- tient tolerated injections of salvarsan, respec- tively, 0.2, 0.3 and 0.4 without reaction. Quite recently Bettmenn* has published a similar case. A 24-year-old carpenter received on May 29th and June 4th, each, a dose of 0.75 neosalvarsan. On June 7th, without warning the patient fell to the ground senseless. Pupils without reaction, vomiting, irregular pulse. The condition lasted for several hours; re- covery then followed. Albumin in urine. Pa- tient had been under mercury. On July 6th, 0.45 neosalvarsan was given without reaction.

A similar case occurred in the practice of Dreyfuss, which was reported by Ehrlich.**

To this category belong those cases which are cured after lumbar puncture. This meas- ure operates very frequently, as reported in gynecological publications, as a life-saving pro- cedure in eclampsia and uremia, that is clinic- ally similar conditions.!

Walter Freyff has also recently written from

*Muncher med. Wochen. 1912, No. 43. **Abhandlungen zur Salvarsantherapie, Bd. II, XXX S. 583.

"\KorrespondenzWatt f. Schweizer Aerzte, 1912, No. 17.

tt Compare Parades, due coma et de la ponction lombaire. These Montpellier, 1912. Further, in Gesammelte Abhandlungen zur Salvarsantherapie, Bd. II, S. 600, the cases of Meirowsky and Spiel- hoff.

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SALVARSAN FATALITIES

the Basle clinic concerning lumbar puncture in the presence of the cerebral type of ure- mia.

According to all experience up to the present time, one is warranted in accepting the con- clusion that a normal kidney is never func- tionally damaged by salvarsan, but that, on the contrary, disturbances of salvarsan elimin- ation take place only with already diseased kidneys.

It is also becoming clear why the acute and subacute inflammations of the kidney, for ex- ample those due to mercury, in general are more dangerous, even though the pathological changes are less, than the chronic nephritides. In these toxic renal inflammations the entire kidney is concerned, glomeruli and tubuli suf- fering a certain damage in common, whereas in the chronic nephritides the disease is focal or patchy alongside of completely functionat- ing areas, which even take on a compensatory activity.

One must remember that while such kid- neys may the first time successfully carry on salvarsan elimination, yet through the burden so extensive a functional impairment may be inflicted upon the vessels that with the sec- ond injection of salvarsan its elimination and also that of the urinary substances is seriously disturbed. Dreser injected animals with acid fuchsin following which the urine became red colored, while, at the same time, the renal cells remained uncolored. With the second injec- tion of this character the cells of the urinifer- ous tubules became colored. The cells be- come wearied and damaged. Likewise, as a

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SALVAR8AN FATALITIES

result of a temporary ligature of the renal ar- tery, renal cells retain the color. Heidenhain, Nussbaum and Graetzer have shown the same to hold good with indigo-sodium sulphate (Martin Fischer, Nephritis).

We have already pointed out that the clin- ical and pathological picture of salvarsan fa- talities does not agree with that of arsenical poisoning. Even less so does it resemble the picture of a fatal case of uremia; it is much more likely caused by salvarsan retained in the blood or in the tissues in consequence of the renal insufficiency. A clear conception of the process is given by the investigations of An- drews who showed at Ehrlich's institute that mice, to which salvarsan, arsenophenylglycin, sublimate, akridinsal and salicylarsenmethy- lester, are given and which are then injected with sulphorhodamin, a rose red coloring ma- terial, do not eliminate the coloring material in case the poison has caused renal insufficiency, and they die within 24 hours.

Several factors indicate that the exanthe- mata of salvarsan as well as those of mercury, play a part, in the presence of temporary ces- sation of the renal function, in the vicarious elimination of the remedial agent by means of the skin.

Following every injection of salvarsan the substance circulates in the blood, and the question arises, how is it that the usually inno- cent material may suddenly take on a poison- ous nature? Ostwald has compared salvarsan to a snapping dog carrying a muzzle. The question is, under what circumstances does salvarsan slip its muzzle? If we observe the

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SALVARSAN FATALITIES

type of innocuous arsenic combinations — Bun- sen's cacodyl — then we see that this, as point- ed out by Schulz, becomes poisonous so soon as the cacodyl combination remains for a long- er period than usual in the body. Miiller, Schoeller and Schrauth consider that the (chronic) poisonous action of the organic mercury products is the resultant of the quick- ness of elimination and the ease with which the complex preparations are broken up ; they understand thereby mercury's power to disas- sociate itself from its combination and to af- fect the body. Now we know that in the ma- jority of instances, salvarsan is quickly elim- inated from the organism, while arsenic re- mains somewhat longer in the body, especial- ly in the liver and the musculature. If a de- composable substance goes quickly through the body then it can easily be innocuous ; but on the other hand, let it go through slowly, then chemical changes consequent upon the longer duration of elimination become inevitable, and under certain circumstances the agent may be- come poisonous. Through Heffter's investi- gations of the retention of cacodylic acid in the organism, it is established that a number of animal organs (liver, stomach and bowel) contain substances which are endowed with an energetic power of reduction and are able to reduce cacodylic acid with the formation of cacodyloxid. It is therefore probable that sal- varsan with a long retention in the body also undergoes such reduction. In the case of the more easily decomposed neosalvarsan this probably occurs more often than with old sal- varsan.

— 81 —

In his memorable address on October 31st, 1909, before the German Chemical Society, Ehrlich offered information on the toxicity of products in the organism originating in the re- duction of arsanil.

It is a well known fact that in the compound Arsanil, the oxygen carrying complex of ar- senic attached to the benzene ring (or benzol ring) is pentavalent, hence Arsanil is to be considered as an aromatic acid of arsenic. Now it became necessary to convert this substance into the products obtained by reduction in which arsenic appears as a trivalent element (analogous to arsenous acid, As2 Os also called arsenic trioxide).

Following a new line of procedure Pro- fessor Bertheim and myself have succeeded in obtaining two distinct products according to the relative strengths of the various reducing agents employed, which correspond to those produced and ascribed by Michaelis to the graded stages of reduction of phenylarsenious acid, namely:

1. The monomolecular As O — product, white in color and soluble in acids and alkalis, the p-aminophenylarsenous oxid,

As=O

y

NH2

and

2. The product obtained by further reduc-

— 82 —

8ALVAR8 A N FATALITIES

tion, whereby through condensation of two molecules of the first described compound an entirely new compound of arsenic is produced, the yellow diaminoarsenobenzene, soluble only in acids;

As=As

NH2 NH2

The toxicological character of the sub- stances is radically changed through the above described process of reduction. It has been shown that the highest toxicity is always ob- tained in compounds in which the element ar- senic in union with oxygen occurs trivalent (As O — ). To become considered as import- ant is the relative nontoxic character of the arseno compounds of glycine.

Relative Toxicity of the products of reduction. (Lethal dose.)

	(Sod i u m salts of) Arsinacid.	As O— com- pounds.	Arseno com- pounds.
1. NH2 2. OH. 3. NH. CH2 .COOH.	1:200 1:75 1:20	1:15,000 1:13,000 1:1000	1:7000 1:1000 1:70

The above indicates the degree of dilution of which exactly 1 c.cm. is capable of killing a mouse weighing 20 grams.

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SALVARSAN FATALITIES

His Excellency Professor Ehrlich has kind- ly placed at my disposal his views relative to the theory as to the changes which may take place in the composition of salvarsan.

Through chemical influences three distinct compounds may be obtained from salvarsan, in which the substance occurs as an arseno- compound :

1st. Through further reduction a compound is formed which Ehrlich calls Phenylarsin, which is analogous to Arsin also called ar- senuretted hydrogen (As Hs)

As H2

NH2

OH

We have tested this compound known as Phenylarsin, the dose of which is 0.1, and have found the same more toxic but also more active than salvarsan. The formation of a compound as Phenylarsin in the animal body is practically an impossibility as the substance is only formed under the most powerful re- ducing influences.

2nd. On the other hand there is a possi- bility of the formation of a compound which Ehrlich calls "Arsenoxide," through the oxi- dation of salvarsan, which is a substance far more toxic in character than the previously described product, Phenylarsin. — 84 —

8ALVAR8AN FATALITIES

As O

NH2 /\

(Arsenoxide)

OH

:< 'Arsenoxide' is readily formed by expos- ing the alkaline solution to the air, and in my personal opinion this 'Arsenoxide' is the chief cause of the serious reactions so often com- plained of. In support of this statement I am relying upon the experiences which were ex- tensively described and related in the first ex- periments and observations with arsenophenyl- glycin disturbances occurred in the beginning; one case resulted fatally. The disagreeable manifestations were probably caused by my first method in preserving the arsenophenyl- glycin in which at least ten per cent, of cases of serious disturbances occurred in the beginning ; glycin in ordinary stoppered bottles instead of, as now, in vacuo"

"It is my belief," says Prof. Ehrlich, fur- ther, "that the interference with the renal function which you presume exists, is occa- sioned by the retention of salvarsan in the or- ganism or blood, which favors the formation of the more dangerous arsenoxide. At least it seems almost proven that certain easily oxy- dizable substances which under ordinary con- ditions do not color animals, cause a distinct bluish coloration of the body of animals which receive too large a dose of the substance which consequently causes an inhibition of proper

— 85 —

8ALVARS AN FATALITIES

elimination of the drug. There occurred then a biological oxydation, and this I prefer to ac- cept in explanation of the unhappy effects fol- lowing salvarsan."

3. "The Arsenoxide can be still further oxidized, to phenylarsin acid. I believe, how- ever, that this is but rarely the case; at any rate such an extensize oxydation cannot be drawn upon to furnish an explanation of death since the p-Oxymetamidophenylarsinacid is much less toxic than salvarsan and in the em- ployed dosage must be considered as without danger."

Salvarsan which has undergone decomposi- tion causes renal damage and anuria. Thus Eitner saw an anuria lasting two or three days in a patient in whose case the salvarsan pow- der, employed for injection, had been exposed for two weeks to the air. Malinowski saw an anuria lasting for ten days following an in- jection of salvarsan which had been exposed for five days to the air. Jakimoff demon- strated experimentally the -increased toxicity of oxydized salvarsan for the kidneys. Con- cerning this point we shall later by means of exact investigations secure an explanation of fatal poisoning. As the picture of this pois- oning does not correspond to the poisoning by arsenic, then it must be determined whether the groups which are related to arsenic do not cause the poisoning following decomposition. Sabbattini,* in this connection, has made many

*Physikalische Betrachtungen iiber toxiscJie Hg. Wirkungen. Biochem. Zeitschrift, 1908, 337, Festschrift fur Hamburger.

— 86 —

SALVARSAN FATALITIES

striking experiments relating to the complex mercury combinations and their division. .

As must always be emphasized, salvarsan fatalities do not resemble arsenical fatalities. But they do have a close resemblance to deaths caused by carbon monoxide. Here we find the same clinical picture, headache, convul- sions, vomiting, unconsciousness, coma, invol- untary passages of urine and feces, etc.*

The old investigations of Klebs** particularly show a close analogy ; from three cases com- ing to autopsy he pictured the last stage as presenting deep coma, marked dyspnea and cyanosis, which are so frequently mentioned in descriptions of salvarsan fatalities, added there to, in the first and third case, tetanic muscular rigidity and muscular twitchings with fully accelerated pulse. Especially strik- ing was the extraordinary abundance of blood in all regions. He particularly mentions the fine capillary congestion of the brain, especi- ally of the gray matter; and in the kidneys and liver an injection of so marked a charac- ter as to be comparable only to an artificial injection of the vessels. It is not encephalitis hemorrhagica but, on the contrary, the enor- mous distension of the vessels which is the constant finding in death from salvarsan.

The cyanosis and dyspnea in salvarsan fa- talities, which occurred in a particularly char- acteristic manner in the case of Busse and Merian and which were effectively combated with inhalations of oxygen, show plainly that

*Kunkel. Toxikologie, s. 336. **Wirkungen des Kohlenoxydes auf tierschen Organismus. Virchow's Arch. Bd. 32, s. 450.

— 87 —

SALVARSAN FATALITIES

one should not lose sight of the possibility of disturbance of respiratory innervation. One is also reminded somewhat of the "red as- phyxia" of Claude Bernard. Through this then also the cerebral irritation (convulsions, paralysis, coma) could easily be explained. It is generally known how violently the central nervous system reacts to interferences with its supply of oxygen. In carbon dioxide poisoning the most conspicuous findings are the capillary hemorrhages in the brain, and foci of softening. It must again be empha- sized that purpura of the brain and encephali- tis hemorrhagica are not characteristics of ar- senical poisoning. These do not depend upon capillary thrombi, as could occur in arsenic poisoning, but upon diapedesis through dam- aged blood vessels.* In conjunction with Dr. Pakuscher I have examined several cases of encephalitis hemorrhagica after salvarsan with the greatest exactness, reaching my former conclusion that this could depend upon emboli, yet at the same time I did not omit careful at- tention to the possibility of thrombi but with negative results.

An exception to this view occurs in the case of Marschalko and Veszprem.**

*Martin B. Schmidt (I. c.) cites a case: Jerome Schneider, 21 years of age, was treated for 11 days in the skin clinic at Heidelburg with chrysarobin and arsenic. Just as he was about to be dis- charged he was suddenly seized with headache and unconsciousness, dying in 36 hours. Autopsy: Ecchymoses in brain and endocardium. Hyper- emia of the kidneys and other abdominal organs. One could scarcely attribute this mysterious death to arsenic poisoning.

**Deutsche med. Wochen. 1912, 26.

— 88 —

SALVARSAN FATALITIES

A 38-year-old state's official received at the hands of his physician on November 10th, 1911, an intravenous injection of 0.53 salvar- san which was made up with distilled water that was not fresh. In two hours the patient became ill with vomiting, but this soon passed away. On the next morning there occurred chills, temperature of 40 C. (104 Fahr.), and vomiting; on the 14th unconsciousness, tem- perature 36.5 C. (97.7 Fahr.), epileptiform at- tack, etc. Death five days after injection.

Encephalitis hemorrhagica without purulent infiltration. The capillaries partly distended with uniform, hyaline thrombi, and also in some of the largest vessels pronounced thrombi of the vessel-walls were found.

Unfortunately the functional power of the kidneys and the condition of the chorioidal plexus was not observed. But it is fair to as- sume that damage occurred in the kidney through toxic action of the drug permitting an abnormal permeability of the capillary walls. (Magnus, Bildung der Lymph, in Op- penheimer, Biochemie, II, 2.)

But the resemblance extends still further, in that in carbonic acid gas poisoning and focal softening, these hemorrhages are most fre- quently to be found in the larger basal gang- lia especially in the lenticular nucleus, there- fore exactly as in salvarsan poisoning.

Polchen aptly explained this peculiarity of carbon dioxide poisoning. "The carbon diox- ide circulating in the blood impairs the nour- ishment of the vessels and thereupon follows necrobiosis." So we see fatty or hyaline (sal- varsan) changes of the same, but no thrombi.

— 89 —

SALVARSAN FATALITIES

"Especially the vessels of the regio innominata and of both the inner limbs of the lenticular nucleus become diseased, because these ves- sels at their origin are extraordinarily small, and very long, 5 to 5 cm. without anastomo- sis and without vasa vasorum, and thus solely dependent upon the blood circulating through their lumina for sustenance. The narrower the vessels become, the more deleterious, nat- urally, becomes the poisoned blood; thus we found the vessel walls close by to the broad trunk of the middle cerebral artery, still in- tact."*

It struck Klebs as strange that in carbon dioxide poisoning the trunks of the cerebral vessels are strikingly tortuous, especially the finer branches, and he gives a convincing de- scription of the microscopical appearance. He explains the lengthened and tortuous condition of the vessels through an atony of the vessels caused by the poison, in which, however, by reason of the strong systolic force of the heart, an abundance of blood is circulated. He ex- plains this phenomenon, 'especially as it oc- curs in the meningeal artery, thus : "While in elastic tissues, such as the lungs or spleen, an increase of arterial contents causes an increase in size of the entire organ without disloca- tion or change of position of the vessels, and in more solid tissues, renal for instance, on account of the intimate connection of vessel wall and parenchyma in general no dislocation of either part takes place, the wall of the men-

*Zur Aetiologie der Gehirnerweichungen nach Eohlendunstvergiftung. Virchow's Archiv, Bd. s. 26.

— 90 —

SAL VAR8 AN FATALITIES

ingeal artery with its adventitia lies as if in a canal, in the dura mater, the rigid wajls of which do not give before the impact of the pulsation."

In the future, therefore, in cases of salvar- san poisoning, one must direct his view more than formerly to the state of the blood current, especially as concerns its oxygen content; for salvarsan is an exceptionally potent reducing agent, as shown histologically by Tryb* through the delicate methods of Unna and Golodetz.

According to what has been said, in the future one will have to employ, when adminis- tering intravenous injections of salvarsan, the utmost care in estimating the renal function. Our observations relating to this matter with pure salvarsan therapy, show that in general in such cases diuresis is of a normal type; only now and then does it reach a stage of polyuria and but seldom does the quantity of urine sink to as low as 600-800 c.cm. In later cases we have frequently seen the injection of salvarsan responded to with headache, vomit- ing and exhaustion, and therefore we exercise the greatest care concerning the dosage and frequency of injection. With the combined treatment still greater care must be shown.

After the first injection of salvarsan, which for the purpose of testing the idiosyncrasy of the patient should not be in excess of 0.1 or 0.2, one must always pay strict attention to diuresis. In our department even a minimum reaction or slight increase in temperature oc-

*Monatshefte f. prakt. Dermat. Bd. 52, s. 406. — 91 —

8ALVAR8AN FATALITIES

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— 92 —

8ALVA R8 AN FATALITIES

curs with great rarity; even following the first injection such phenomena seldom occur. We carefully investigate every reaction, even the slightest, and extraordinarily frequently we find a dependence of the reaction upon im- pairment of renal function. As a paradigm let me cite the following case:

A 33-year-old woman, suffering with a luetic stricture of the rectum, who had been frequently treated with mercury, urine free from albumin, re- ceived 0.1 salvarsan on November 14th, 1912. Tem- perature at this time 37.6 C. (99.6 Fahr.). Novem- ber 15th 37.6 C. (99.6 Fahr.).

See chart III.*

We have observed the same in hypoplasia of the heart with oliguria.

It is also to be noted that long continuing infectious diseases, diphtheria and scarlet fever above all, can leave in their wake a vascular hyposthenuria.

Just recently we saw a young girl with oc- cult syphilis, who showed a positive Wasser- mann and who had never been treated, fol- lowing an injection of 0.1 salvarsan on Novem- ber 15th, develop a temperature of 39.6 C. (103.2 Fahr.). Then oliguria without albu- min occurred. On November 16th, amount of urine passed 700 c.cm., sp. gr. 1024; No- vember 17th, 200 c.cm. (!) sp. gr. 1028, No- vember 18th, 400 c.cm. sp. gr. 1030, Novem- ber 19th, 500 c.cm. sp. gr. 1030. Presumably

*Also the next injection of 0.1 of salvarsan was responded to with exactly the same; reaction. One can, very easily believe that such a patient, if re- ceiving two or three injections of 0.4-0.6 salvarsan might not eliminate tue drug.

— 93 —

8 A L V A R 8 A N FATALITIES

— 94 —

SALVARSAN FATALITIES

the cause for the drop in the functional curve was a diphtheritic attack suffered in 1911.

It is clear that the damage to renal vessels which produces polyuria is of a moderate grade, while that which is associated with oli- guria represents a severer grade. It is prob- able— further proof on this point must be worked out — that only with severe damage to the kidney is there sufficient interference with the elimination of salvarsan to produce a men- acing state. Practically speaking, then it is only oliguria which is to be considered in the question when confronted by a death after salvarsan. Whether the lighter grades of damage to the renal vessels, they can mani- fest themselves in an increase or even a (pseudo) normal quantity of urine, have a practical significance can only be determined by further observations. If no absolute stand- ard of the functional power of the renal vessels can be determined through observation of diuresis, then we must look to the pre- monitory symptoms which in such cases us- ually occur after the administration of salvar- san, these being coated tongue, prostration, vomiting, headache, a general discomfort due to disturbance of the renal function, and which point to the need for a more exact investigation of such symptoms according to the method of Schlayer and Takayasu, and then we must avoid further burdening the kidneys.

Generally speaking a determination of the quantity of urine and its specific gravity, se- cured over several days, suffices, and it is only seldom that one will be required to employ the more refined functional tests. It appears to

— 95 —

8 ALVARS AN FATALITIES

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8ALVARSAN FATALITIES

be of large importance not to reach conclusions based upon examinations made directly after injection but rather to postpone judgment until the second or third day, especially if there be a moderate temperature.

Chart V shows how a patient who had re- ceived five injections of salicylate of mercury, presenting a polyuria thereafter, had no change in urinary secretion following an injection of 0.1 salvarsan, but who after the second injec- tion of 0.4 salvarsan presented a polyuria of 3000 c.cm. The next day this dropped to a normal quantity, 1700 c.cm. The third injec- tion was responded to, not on the same day but on the following day, with a temperature of 39 C. (102.2 Fahr.) ; in contradistinction to this rise of temperature the urinary secre- tion was about normal, 1400 c.cm. The next day the temperature dropped to normal. How- ever, on the fourth day after the injection the blood contained, according to Prof. Loeb's es- timation, a strikingly large quantity of arsenic ; the exact quantitative amount was not ascer- tained.

Isolated cases of a similar character have been reported where death took place even with normal diuresis. The type is as follows. Case of Balzer and Candat.*

Male, 34 years of age, two chancres on chin. Calomel ointment 30 per cent. One week later mucous patches on right tonsil with abundant spirochaetes. No roseola. Urine normal. No- vember 24th 0.3 salvarsan intravenously. Four hours later chills, temperature 39.2 C. (102.6 Fahr.). December 1st urine free from albumin.

*Bulletin de la soci£t6 de dermat. 1912, No. 1. — 97 —

8ALVAR8AN FATALITIES

Salvarsan 0.3. Temperature 37.6 C. (99.7 Fahr.). December 2nd anorexia. December 3rd unrest, delirium, semi-consciousness, twitchings, rigidity. Reflexes retained. Unequally dilated pupils. Urine clear, in good quantity, without albumin or sugar. Coma. Cerebrospinal fluid showed high pressure and clear, few cells, marked quantity of albumin, positive Wassermann. December 4th cyanosis. December 5th some albumin in urine. Second lumbar puncture, abundant polynuclear cells. Epileptic attack. Death. No autopsy.

On the same day eight other patients were given the same dose in the same manner but without reaction. Therefore, it cannot be said that the preparation was in the least poisonous.

Arsenic in the spinal fluid. A noticeable quantity of arsenic in blood taken from a vein. This blood was drawn on December 4th. It is thus shown that in this instance there was a retention of arsenic. Since the elimination of fluids was normal but an abundance of arsenic could be demonstrated in the blood even after several days, there then could be present an interstitial nephritis, as a result of which the capacity for the elimination of fluids was not interfered with, while the power to eliminate substances circulating in the blood and the power of concentration were impaired. One must give heed to these circumstances in judg- ing the individual salvarsan fatalities, in which it may be alleged that only salvarsan was em- ployed. In all vascular nephritides following cessation of oliguria there comes a stage of polyuria in which lactose elimination is more or less interfered with ; often there will be al- most complete retention (Schlayer and Tak- ayasu, /. c., page 383). Neither an increased

— 98 —

SALVAR8AN FATALITIES

nor a normal urinary secretion permits a definite conclusion to be reached of an intact or specially good function of the kidneys. Gen- erally speaking, both represent a milder grade of damage to the renal vessels than the marked oliguria, yet either may exist in the presence of a high grade damage of the renal vessels (/. c. p. 389). This polyuria has for a cause a hypersensitiveness of the renal circulatory system in consequence of morbid irritations; these may be lasting or transitory. The same sort of condition can be caused by syphilis. Hirsch* directed attention to the frequency of contracted kidneys of an insidious character in syphilitics. Lohlein pointed out the possible connection of primary syphilitic disease of the blood vessels with this form. It is quite noteworthy that the cases of contracted kid- ney without arteriosclerosis collected by Roth** (under Jorl's guidance) mostly con- cerned young individuals.

Hirsch also emphasizes how in such cases which are unable by reason of renal insuffi- ciency to eliminate mercury, severe poisoning takes place. This also holds good with sal- varsan. In a case of Dr. Gey's (for this I am indebted to a private communication from his Excellency, Ehrlich, in which death took place two days after one injection, there was found a marked interstitial nephritis with extensive alterations in the glomeruli and fatty degener- ation of the uriniferous tubules together with beginning cirrhosis of the liver.

*VircJiow's ArcTiiv. Bd. 77. **Med. KliniTc, 1912, No. 23.

— 99 —

SALVAR8AN FATALITIES

In general, as shown by complications, al- terations in the internal organs referable to the abuse of alcohol, are strikingly frequently found at autopsy; particularly chronic lepto- meningitis is frequently found. In this con- nection the old French proverb, "La Syphilis et I'Alcool font mauvais manage," may per- tinently be quoted.

It is clear that insufficiency of the kidneys does not sufficiently explain all cases of sal- varsan fatalities. But for the most of these cases which are not to be included in this type, arsenic poisoning offers no explanation, on the contrary observation shows that here the vari- ous clinical pictures and death-causes are to be considered together. Almost always these patients are individuals with definite insuffi- ciency of various organs, demonstrable before injection of the agent and demanding great caution in every sort of surgical interference. Those cases in which our present methods of examination do not disclose the cause of death, are but rarely met with. That extra-renal con- ditions could influence a retardation of salvar- san elimination is evident. To be drawn into consideration are certain cardiac disorders.

Apparently salvarsan does not have a bad influence on the heart, in fact in heart dis- eases, especially in arteriosclerosis, it is us- ually well borne. As a rule it has a splendid effect on circulatory troubles due to syphilis. On the contrary, however, salvarsan is always a burden for an overworked, poorly balanced heart. This is demonstrated by the cases de- scribed by Martius* in which autopsy disclosed

*Abhandlungen uber Salvarsan. Bd. II. s. 473. — 100 —

SALVARSAN FATALITIES

valvular insufficiency, sclerosis of the coronary arteries and myocarditis. In this connection retarded elimination often plays a considerable part. Also hypoplasia of the heart or kid- neys may also cause the same. The same holds good in the employment of salvarsan in the presence of febrile disorders and at the conclusion of infectious diseases (influenza, diphtheria, scarlet fever) , in which, under cer- tain conditions, extensive functional disturb- ances, mayhap demonstrable only with the most exact methods, may be present.

Then the fever caused by contaminated water might also lead to the retention of sal- varsan ; the recent investigations of Schwenke- becher, v. Hosslin and others, show that in fever there is salt retention in the blood. It is to be mentioned, however, that patients who have been given intravenous injections of lac- tose and who had fever, 40 C. (104 Fahr.), and chills, normally excreted the sugar. Like- wise extra-renal circumstances have no essen- tial bearing on the elimination of iodide of potassium. While, therefore, foreign sub- stances are eliminated according to rather uni- form rules, the elimination of bodily sub- stances (water, Nad) is variable and influenc- ed by numerous conditions, both renal and ex- trarenal.

Generally speaking the diseased brain toler- ates salvarsan well. That in quite exceptional instances patients with extensive changes or with diseased foci in vital centers, do not tolerate the treatment, particularly when they receive rather large doses, is not difficult to understand ; it should be emphasized, however,

— 101 —

SALVARSAN FATALITIES

that oftentimes in such cases the injection is borne without reaction, and then frequently enough one experiences sudden deaths with mercury injections or even without any ther- apy whatsoever. Latent meningeal tubercu- losis appears to offer a certain danger as sev- eral fatal cases of Finger's show. It is our habit in tuberculosis with headache always to examine the spinal fluid before the employ- ment of salvarsan that it may be clearly de- termined whether it is lues or tuberculosis.

There yet remain to be considered occasional fatal cases due to acute yellow atrophy of the liver. Such cases are frequently observed in consequence of syphilis and the employment of mercury as treatment, so one cannot attribute them to the salvarsan, particularly since they as a rule occur at a considerable period after the injection; and the less so since just here the most surprising results of salvarsan (Umber*) have been described even after failure of the most active mercury prepara- tions (Duhot**). Therefore, it is to be con- sidered that acute yellow atrophy of the liver due to florid syphilis may associate itself with a severe epithelial necrosis of the kidney which is not recognized clinically, and offer- ing great difficulties in the way of elimination of every drug agent, as described by Janssen in his Dissertation (Berlin, January 14th, 1911). Therefore, the conclusion is that the condition which we have been in the habit of describing as acute yellow atrophy of the liver,

*Abhandlungen zur Salvarsantherapie, Bd. li, s. 365.

**Ebenda, s. 352.

— 102 —

8ALVAR8AN FATALITIES

is only the acute terminal process of a clinical- ly latent but clearly demonstrable, chronic condition.

In this connection the excellent, searching investigations of Severin and Heinrichsdorf* concerning these circumstances, are to be re- membered. One case especially of these au- thors, in which icterus followed immediately the third injection of salvarsan, can accord- ing to my opinion, best be explained on the as- sumption that the last injection of the hither- to well borne salvarsan, offered the broken link of a chain for the causative factor.

If one takes into consideration the pre- viously reported salvarsan fatalities, then may one entertain the hope that in the future sim- ilar cases can be avoided almost without ex- ception, and that but a few not sufficiently ex- plained, remain to be dealt with. Future in- vestigations will discover the genesis of these, and it must be endeavored to explain whether insufficiency of other organs plays a part in connection with these cases. One must now think especially of the choroidal plexus. Our case shows, as does that of Balzer, that with retention of salvarsan in the blood the choroid plexus may be so badly damaged that the pre- viously albumin-free liquor will contain an abundance of albumin, in fact, even to the point of spontaneous coagulation. With the normal choroid plexus, injections of salvarsan cause no increase in albumin.** As to this point it must be carefully determined if the

*Zeitschr. f. Tclin. Med., Bd. 76, s. 138. **Wechselmann: Die Wirkung des Salvarsans auf den Liquor cerebrospinalis. Berl. klin. Wochenschr., 1912.

— 103 —

SALVARSAN FATALITIES

plexus in the case of salvarsan fatalities under- goes pathological changes. We know that with tuberculosis the permeability of the same to certain substances is increased, and the same might occasionally hold good with syph- ilis.

Schmorl,* for instance, reported that a quantity of substances, which are dissolved in the blood, pass into the spinal fluid but not into the ventricular fluid, and conversely ; that in both of these fluids there may be differences in the content of biliary pigment, albumin, sugar and those substances which cause the Wassermann reaction. The normal inter- change of these substances could also be hin- dered if more or less severe changes are pres- ent in the plexus. In this case of Schmorl's there was a gummatous condition apparent in an anterior section of the corpus callosum. Syphilitic granulation tissue, taking the place of nervous tissue, had encroached upon the su- perior choroidal horns and in the tissue of the plexus there were extensive small-cell infiltra- tions ; the. epithelium, in great part, was miss- ing. The blood and ventricular fluid gave a positive Wassermann, the spinal fluid a nega- tive.

A recently published paper by Langbein and Oeller, a clinico-pathological contribution to the question of acute hemorrhagic encepha- litis (from the Leipziger Institute of von Strumpell and Marchand), seems to me to possess a distinct bearing on our question. A 35 year old woman, free from signs of lues

*Verhandlungen der pathologischen GesellscTiaft, 1910, B. 288.

— 104 —

SALVARSAN FATALITIES

and without demonstrable infection, died with clinical phenomena of hemorrhagic encephali- tis, which was" confirmed at autopsy. More- over, there were found primary and secondary inflammatory processes in the meninges of the base and convexity of the cerebrum. "In this case it seems justifiable to conclude that the other existing changes in veins and brain were consequent upon the inflammatory pro- cesses in the horns of the third ventricle and the choroid plexus of the lateral ventricle and of the third ventricle, but which, however, one had to designate as primary processes, as in other organs, and in the cranial cavity no in- flammatory focus could be found from which a metastatic involvement could have taken place. Always hereafter, with similar cases, it would be advisable to take into consideration the possibility of tuberculosis, and while the latter might be only in the initial stage, yet in a very short time it could lead to a tuber- culous meningitis with resulting thrombosis." After all this we are justified in saying that salvarsan per se employed in normal persons in the customary dosage is nontoxic. Any evil consequence observed is always due to some organic insufficiency, especially of the kidneys. For this insufficiency the responsible factors are frequently mercury, perhaps ex- ceptionally rare salvarsan, and also other weakening factors, such as the influence of syphilis on the blood vessels as well as other infections and intoxications. If the most effective results are to be secured from sal- varsan it is of the greatest importance to care-

— 105 —

8ALVAR8AN FATALITIES

fully heed the foregoing points during the drug's administration.

It is quite conceivable and, in fact, justifi- able, that some physicians, following the early experience with the other arsenic compounds, were distrustful of salvarsan from the very beginning, and friends of salvarsan, even though they had seen its elegant healing effect, feared that the not too well understood collat- eral effects might operate to deprive us of the advantage of this agent. But this stage is now passed. One should not forget that the same opposition arose against mercury at the time of its introduction as now against sal- varsan. Physicians have been too prone to minimize its good effects, and to place in the foreground the evil effects caused through improper employment. Let us now remember that from 1580 to 1655 every teacher at Heid- elberg had to take an oath that he would never use mercury! It is this divided condition of opinion among physicians which permits, even to the present, the quack to thrive so well! But the standpoint of those physicians who recognized the value of mercury even in early days and who through the greatest care, reduc- ed its evil effects to the lowest possible point, at last prevailed. Rightly, exclaims the great Botallius : "Quis criminabitur ignem, unde pro servorum negligentia basilica domini con- sumpta est!" The same holds good for sal- varsan. My entire experience with more than 25,000 injections forces me to the inevitable conclusion that salvarsan is much less toxic than mercury. My department in which sal- varsan is used almost exclusively has given

— 106 —

8ALVAR8AN FATALITIES

me much less care and trouble during the past three years than in the previous, period when mercury was employed ; it is certain that the undesirable effects of salvarsan with us have become much rarer and of less importance as we have better learned to master the technique of its use, and to employ a dosage adapted to the individual case. The clinician always has to deal with ununiform clinical material, and in that lies the main difficulty of properly em- ploying a remedial agent which has been ex- perimentally tested in a laboratory. The hope of a cure for infections binds the experimental worker and the clinician, but the material upon which they work is radically different; there the healthy animal with sound organs, here the patient exhibiting the most varied devia- tions from normal. Therefore, without the systematic, definitely planned aid of the clin- ician the introduction of a chemotherapeutic preparation is impossible.

In conclusion, I wish to present a list of salvarsan fatalities which have become known to me. Should I omit certain cases it is be- cause they possess no value for this table, as it is my purpose here to offer not a statistical presentation of cases, but rather to deal with their genesis. It is somewhat difficult to bring these observations from chaos to order, par- ticularly so since the greater number of these observations have been imperfectly described. These observations will serve for the establish- ment of certain principles which may be em- ployed in future anomalous cases of salvarsan therapy ; in this way it will be easier to find an explanation of the question involved. I am

— 107 —

8ALTAR8AN FATALITIES

taking into consideration only those cases of adults, for luetic infants die under such varied circumstances that one can scarcely pick out any special cause.

In the beginning, let it be emphasized that with subcutaneous and intramuscular injec- tions of salvarsan the cerebral type of fatal- ities has not been observed. In these methods of administration apparently there is never so severe a burden thrown on the kidney as tc occasion renal failure.

FATALITIES FOLLOWING SUBCUTANEOUS IN- JECTIONS.

Below are given the cases of death which have been reported as following the use of salvarsan subcutaneously. In all there are six. It will be seen that a direct connection between death and the use of salvarsan can hardly be established, as the patients concerned suf- fered from the severest involvements of vital organs, and salvarsan was employed as a last resort in a bare hope of saving the patient's life. Schiele's case (No. 3) which is given below, shows an intractable, malignant syphilis in the person of a young girl, who, after a temporary improvement, died two and a half months after the injection. One case reported by Marcus I am not considering at all, as the patient threw himself out of a window a month after the injection. Therefore, the sub- cutaneous method, as I have always main- tained, has not with certainty been the cause of a death. The cases show different types.

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1. Case of Ehlers and Jorgenson (Munch, med. Wochenschr, No. 42, 1911, p. 2183). A 40-year- old paralytic. .Infection eleven years previous. Since 1908 symptoms of paralysis. In June, 1910, apopletic attack. Since then decrease in bodily weight. On Aug. 25th, 1910, injection of 0.5 "606" subcutaneously. Thereafter gradually increasing indications of poisoning of the nervous system. Tremor, outbreaks of perspiration, etc. Rapid de- cline in strength. Five days after the injection death took place with symptoms of progressive paralysis of the heart.

Autopsy: Fatty degeneration of the heart, kid- neys and liver.

2. Case of Martius. (Munch med. Wochenschr. No. 20, 1911.) 56-year-old woman with cardiac at- tacks. Aortitis luetica, with insufficiency of the aortic valve, established clinically. A radiogram showed a diffused thickening of the aorta but no aneurism. In spite of inunctions the cardiac at- tacks increased, for which reason 0.5 gram of sal- varsan in neutral suspension was given sub- cutaneously. At first these attacks ceased, but two weeks later again began, and on the 17th day death took place in an anginal attack.

Autopsy: Hypertrophy of the left ventricle, aortic insufficiency, aortitis luetica, hydropericar- dium, hydrothorax, moderate interstitial nephritis.

3. Case of Schiele. (St. Petersburger med. Wochenschr., No. 33, 1911.) 29-year-old girl with congenital syphilis. In spite of every treatment the disease processes made progress. Poorly de- veloped, infantile appearance, completely deaf. Palace perforated. Both apices of lungs infiltrated, liver and spleen enlarged. Abdominal pain upon pressure, finally hallucinations, etc. A trepana- tion wound of the mastoid process suppurated for nine months. On Oct. 10th a subcutaneous injec- tion of salvarsan, 0.3 was given. Temporary im- provement. Death Dec. 26th.

4. Case of Schiele. (St. Petersburger med. Wochenschr. No. 33, 1911.) 28-year-old patient infected eight years before. Since then irregularly treated with mercury. Suffered from paralysis of

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the left side of the body, with disturbances of swallowing and speech. Injection of 0.4 salvar- san subcutaneously. Death in five days.

Autopsy: Large soft focus in cerebellum. Chronic leptomeningitis. Arteriosclerosis of the basal arteries.

5. Case of Spiethoff. (Munch med. Wochenschr., No. 4, 1911.) In a patient suffering from gastric crises of an indeterminate nature, there was found a well compensated, moderate aortic insufficiency. Wassermann positive. A careful x-ray examina- tion disclosed nothing, injection of 0.3 salvarsan subcutaneously. At first well borne. After a few days the heart became weaker and weaker, and on the llth day following injection, caused death.

Autopsy: Aortic insufficiency, aortitis luetica, myocardial degeneration, marked sclerosis of the coronary arteries.

6. Case of Hans Willige. (Muench. med. Wochenschr. No. 46, 1911, page 2403.) Patient 44 years old, infected with syphilis in 1892; be- came a diabetic ten years later. Since 1908 had disturbances of vision. Wassermann strongly posi- tive. Somewhat emaciated. Pupillary reaction sluggish. Vision, right, %; left, 1/10. Liver en- larged with nodular thickening. Urine, daily quantity 2 to 2y2 litres with 2.5 to 3.5 grams al- bumin. Patient shows a changeable disposition, now excitable now depressed. On Sept. 9th, 1910, injection of 0.35 gram of salvarsan given sub- cutaneously between the shoulder blades. The fol- lowing day patient could sleep, yet showed a deep, painful infiltration at the site of injection. The next day there came vomiting, abdominal pain, constant distress with marked thirst. At the same time an eruption appeared on the arms. On Sept. 12th condition the same. On the 13th coma, pulse 110, irregular. From the afternoon on patient's condition grew steadily worse. Death on the 15th.

Autopsy: Cerebral edema, myocardial degenera- tion, light parenchymatous inflammation of the in- testinal tract, the liver and the kidneys. Trace of arsenic in the urine and in the liver.

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DEATHS FOLLOWING INTRAMUSCULAR INJEC- TIONS.

Fifteen deaths have been reported follow- ing intramuscular injections. Besides these there are two other cases cited by Jadassohn, in which it could not be clearly determined whether the injection had been given intra- muscularly or subcutaneously. Also in these cases there could not be shown any connection between the salvarsan and death, that is, in the sense of a poisoning. In a few cases death follows a month or more later from septicemia or hemorrhage. Comparatively speaking em- boli often follow this method, in contradis- tinction to their non-occurrence in the sub- cutaneous method.

1. Case of Dr. A. in K. (Martius). (Muench. med. Wochenschr., No. 20, 1911.) Patient 47 years old, tabetic, suffering with aortitis and aneurism of the arch. Wassermann positive. Upon ex- pressed wish of patient 0.6 gram of salvarsan in- jected intragluteally. Following this with entire loss of appetite patient became weaker and weaker. Fifteen days after injection there appeared a pain- ful, hemorrhagic pemphigus. Death on the 21st day.

Autopsy: Hypertrophy and dilatation of the left ventricle, and moderate dilatation of the arch of the aorta. Atrophic liver showing fatty degenera- tion. Marked parenchymatous degeneration of the kidneys.

2. Case of Finger (Mucha). (Wiener klin. Wochenschr., No. 27, 1911, page 963, and No. 28, 1911, page 1012.) Child, seven years old, well de- veloped, with mucous patches on lips and papules on the genitals. Eyes normal. Chronic middle ear trouble (suppuration). Light bronchitis; no al- bumin. Jan. 17th intramuscular injection of 0.2 gram salvarsan. Following day, headache and

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Herxheimer reaction. Papules showing improve- ment; on following day cured. On Feb. 18th in- voluntary movements of the head and eyes. On Mar 18th, notwithstanding that the involuntary movements have ceased, patient is fully apathetic. Vomiting and headache.. Lumbar puncture shows high pressure, a clear liquid containing mono- and polynuclear leucocytes. The previously strongly positive Wassermann now became weakly positive. On March 26th, coma with purulent discharge from the ear, which makes one suspect an abscess of the brain. March 31st, trepanation was tried but without results. April 3rd, patient died.

Autopsy: Purulent leptomeningitis of the base. Increase of ventricular fluid. Tuberculosis, cal- culous nodules of the spleen.

3. Case of Herxheimer and Altmann. (Deutsche med. Wochenschr.. No. 10, 1911.) Male, 25 years old, with symptoms of a progressive paralysis. Several years ago apical tuberculosis. Intragluteal injection of 0.5 gram salvarsan in neutral solution Sept. 15th, 1910. On the 20th one can see a marked infiltration at the site of injection. Patient com- plains of sharp cough with slimy material from bronchi. Died suddenly on Oct. 5th of pulmonary embolism following a thrombus from the femoral vein, which was due to a streptococcus infection at the point of injection.

Autopsy: Old fibrous deposit in both apices, and encysted caseous foci. Peural adhesions.

4. Case 'of Hrdliczka. (Wiener Jclin. Wochen- schr., No. 21, 1911.) Officer, 33 years old, infected 1903. From then to 1908 well treated with mer- cury. Since 1909 increase of symptoms. Oct. 24th, 1910, intramuscular injection of 0.6 gram of sal- varsan in neutral suspension. At the time there was a periostitis of the tibia. With January came stomach disturbances, vomiting, attacks of dizzi- ness, and disturbances of vision. On February 6th, noticed weakness of memory. Wassermann nega- tive. Clinically there is nothing to be seen, neither of nervous nor organic ailments. February 28th came stiffness of jaws, facial paralysis, disturb- ances of speech, fever and unconsciousness. Pa- tient died March 8th.

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SAL VAR8 AN FATALITIES

5. Case of Jacquet. (Gazette des Hop., No. 120, 1911.) Patient 42 years old, alcoholic, with ulcer- ated syphilide the size of a dollar on thigh. For years patient has complained of vomiting and bowel disturbances, due presumably to dilatation of the stomach, t>ept. 17th intramuscular injec- tion of 0.5 gram salvarsan. Pronounced pain and moderate fever. The syphilide cleared up and healed over. On the seventh day following the injection patient vomited dark masses. The anemia and weakness increased. Death Sept. 29th.

Autopsy: Ulcus ventriculi with rough edges, pyloric stenosis, dilatation of the stomach.

6. Case of Lane. (Bri. Med. Jour., Sept. 23rd, 1911, page 673.) Patient 27 years old, infected six months previously. At the time of injection phagedenic ulcer on penis, ulcerations upon the inner side of the thigh and palate. Six calomel injections without any result. Sept. 24th intra- muscular injection of 0.5 gram salvarsan. Not- withstanding the injection the palate perforated; the completely necrotic jaw-bone had to be re- moved. Death occurred bee. 2nd from septicemia.

7. Case of Martius. (Muench. med. Wochen- schr., No. 20, 1911.) Patient with tabes. Clinical examination of the heart discloses an accentuated second aortic sound. Intramuscular injection of 0.6 gram salvarsan in 8 c.cm. olive oil. Well borne. Girdle pains disappeared. On the sixth day follow- ing injection death suddenly occurred.

Autopsy: Syphilitic aortitis. Moderate sclerosis of the aorta and ihe peripheral arteries. Moderate dilatation and hypertrophy of the left ventricle. Fresh foci of degeneration in the heart muscle, particularly in the left ventricle.

8. Case of Martius. (Muench. med. Wochen- schr., No. 20, 1911.) Paralytic, 47 years old, with lung tuberculosis. Intragluteal injection of 0.5 gram salvarsan in neutral suspension. Two weeks later death occurred from pulmonary emboli fol- lowing necrosis at site of injection.

Autopsy: Confirmation of clinical findings.

9. Case of Schiele. (St. Petersburger med. Wochenschr., No. 33, 1911.) Twelve year old scholar. Malignant syphilis. Great damage to

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bony parts of nasal passages; almost all of the soft palate is destroyed. The hard palate covered with deep ulcerations. Intramuscular injection of 0.3 gram salvarsan. Following injection patient is very restless. Temperature rises to between 38 and 40 C. (100.5 — 104). Ulcerations respond slowly. For this reason mercurial course is given. After six weeks an injection of 0.5 gram, salvarsan is given; necrosis at the site of the injection gives rise to a fatal hemorrhage.

10. Case of Spiethoff. (Muench. med. Wochen- schr., No. 4, 1911.) Female, 28 years of age, markedly cachetic, tertiary lues of the palate. Treated without results with atoxyl for three years. An intramuscular injection of 0.5 gram salvarsan given on the afternoon of June 20th. At ten o'clock in the evening no visible changes; slight pain at sight of injection required mor- phine. At five o'clock next morning the woman was found dead in bed.

Autopsy: Tertiary syphilis of the palate, cica- tricial stricture of the pharynx, gummatous scar in liver, hyperplasia of the heart and of the aorta. No trace of arsenical poisoning.

11. Case of Werther. (Muench. med. Wochen- schr., No. 10, 1911, page 505.) Sixty-year-old man, very anemic, suffering from cerebral syphilis and hemiplegia. Intramuscular injection of 0.5 gram, salvarsan. Death following day.

Autopsy: Large soft focus in brain. Endar- teritis of the cerebral arteries, syphilitic aortitis, myocardial degeneration.

12. Case of Westphal. (Berliner klin. Wochen- schr., No. 22, 1911, page 973.) Woman 33 years old, alleges no infection yet three miscarriages have occurred. (At an earlier period the hus- band had had a chancre.) Never treated for syphilis. Complained of lancinating pains, dizzy spells, difficulty of hearing, vomiting and double vision. Gradually locomotion became disturbed; after six months complete loss of locomotion. Then paralysis of arms. Clinical examination on June 22, 1911, discloses loss of pupillary and pa- tellar reflexes. July 14th received an intragluteal injection of 0.2 gram salvarsan in neutral sus-

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pension. At first well borne. Shortly afterwards complains of dyspnea, which in spite of artificial respiration quickly progresses to apnea. Death 36 hours later.

Autopsy: Syphilitic aortitis. -Degeneration of the posterior columns, and acute specific spinal meningitis.

13. Case of Willige. (Muench. med. Wochen- schr., No. 46, 1910, page 2403.) Following intra- muscular injection of 0.8 gram salvarsan appeared rather severe phenomena. At the site of injection there was visible a dark, hemorrhagic eruption, which quickly spread to the buttocks and thighs, and only cleared up after five days and then with scar formation. Wassermann became negative after four weeks. Appearance of an eruption re- sembling acne. At the site of injection one could note a painless infiltration. Death seven weeks after injection in consequence of a fresh paralytic attack.

14. Case of Jadassohn. (Deutsche med. Wochenschr., No. 51, 1910.) Forty-year-old patient in bad general condition. No history of syphilis. Aortic aneurism with much pain. Injection of 0.4 gram salvarsan. At first mild rise in tempera- ture, then drop to normal. On the ninth day after injection death took place.

Autopsy: Aortic aneurysm, spleen and kidney infarcts, pneumonia, left lower lobe.

15. Case of Jadassohn. (Deutsche med. Wochenschr., No. 51, 1910.) Forty-year-old pa- tient with severe cerebral syphilis, marked myo- carditis, weakness of heart. At request of the mother of patient, an injection of 0.1 of salvarsan was given notwithstanding that patient was al- ready in extremis. Death on following day.

DEATH AFTER INTRAVENOUS INJECTIONS.

And now will be reported these fatalities taking place after intravenous injections of salvarsan, which occurred shortly after the in- jection, and in which plain technical errors or

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organic changes might be held responsible for the death. It is evident that doses far in ex- cess of what the patient's condition warranted, were employed.

Generally speaking it is highly probable that fatalities which occur in a short time, even within a few hours, after the injection can take place as a result of unnoticed errors. Pointing to this is the circumstance that they are rarely reported, and practically never by physicians who have given many injections. To forget to render the salvarsan solution alkaline is especially dangerous if the solution is not very much diluted. Another dangerous factor is the non-detection of the so-called "anaphylactic" state, for the introduction of a large quantity of salvarsan, during such a state, could easily be the cause of death. It is noteworthy that these cases, once all too frequently reported, now, since the employ- ment of the intravenous method of adminis- tration, are but rarely recorded. Either these cases have been preventable cases or the fatalities have been due to lesions which were very severe within themselves.

1. Case of Paul Bar. (Bull, de I'Acad. de

No. 55, 1911.) Nineteen days after receiving an intravenous injection of 0.5 gram of salvarsan, dis- solved in 100 c.cm., a pregnant woman showed a marked albuminuria. Shortly thereafter an an- gina. The patient was delivered of a dead child. Died five days later of a double-sided pneumonia.

2. Case of Dind. An old man, addicted to tobacco and alcohol, in poorly nourished condition, circulatory disturbances, markedly tuberculous. Died three days after the injection with pulmonary symptoms and renal suppuration. (Dose and skill unknown.)

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3. Case of Dind. An old syphilitic. Reached hospital in coma and was given an injection of 0.1 gram salvarsan as a last resort. Died during afternoon.

Autopsy: Tuberculous meningitis, pulmonary tuoerculosis.

4. Case of De Favente. (Giorn. ital. delle mal. ven. e delle pelle, 1912.) Patient 31 years old; in- fected ten years before. Patient received three calomel injections. Wassermann still positive. Patient complained especially of severe headache at night. Intravenous injection of 0.48 gram sal- varsan. Two hours after injection unconscious, epileptic attack lasting an hour and a half, with conapse. Death ten hours after the injection.

Autopsy: Syphilitic basal meningitis, diffuse gummata of the liver, cerebral hemorrhage.

5. Case of Finger (Mucha). (Wiener klin. Wochenschr., Nos. 27-28, 1911.) Male, 33 years old, with secondary syphilis. (Iritis and neuritis optica.) Ears and internal organs healthy. Jan hrd, 0.4 gram salvarsan intravenously. Wasser- mann ++. On following day Herxheimer reac- tion. On the 14th gone. Wassermann +. Second injection of 0.4 gram well borne. Jan. 31st Was- sermann + + • March 9th recurrence with neuritis optica hemorrhagica. March 13th no particular nervous symptoms. On the following day patient complained of severe pain in the ears; headache, and indisposition. March 15th another intra- venous injection of 0.4 gram. The following day patient suffered from headache and vomiting, but on the 17th entirely well. March 18th patient had a double-sided paralysis of the lower extremities with a Babinski. March 23rd right-sided paralysis of the face. On the 25th left-sided hemiplegia. On the following day, clonic convulsions and fever. Marcn 28th, death.

Autopsy: Acute tuberculosis of base of brain, kidneys and intestines. Chronic tuberculosis of the bronchial and cervical glands.

6. Case of Finger (Mucha). (Wiener klin. Wochenschr., Nos. 27 and 28, 1911.) Woman, 22 years old, poorly developed. Infected ten weeks before. Has eruption on buttocks, neck and the

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extremities. Wassermann ++. No albumin. In- ternal organs sound. On March 29th given 0.4 gram "606," following which patient had headache and light fever. Notwithstanding headache which persisted patient received another injection of 0.4 gram on April llth. Wassermann +. The fol- lowing day patient complained of general indis- position, diarrhea and increased headache. Cn the 14th temperature 39 C. (102 Fahr.). A week later patient fell into a coma. Lumbar puncture, high pressure of fluid which contained many lym- phocytes, few polynuclear leucocytes and few bac- teria. Stiffness of neck together with eye and fas- cial paralysis. April 27th, death.

Autopsy: Acute miliary tuberculosis of the base of the brain and left lung. Caseated bronchial glands. Cerebral edema, parenchymatous degenera- tion of the heart, the liver and kidneys. Acute endometritis.

7. Case of Finger (Mucha). (Wiener klin. Wochenschr., Nos. 27 and 28, 1911.) Male, 33 years old, infected three months previously. At first treated with injections of mercury. Jan. 2, 1911, reseola on buttocks and the extremities. Wasser- mann + ++. Eyes, ears and internal organs sound. No albuminuria. Jan. 7th, intravenous injection of 0.4 gram salvarsan. Well borne. Temperature 39.2 C. (102 Fahr.). Jan. 2nd, second injection of 0.4 gram. Also well borne. Wasser- mann + ++. On Feb. 25th, patient presented himself with severe iridocyclitis of the right eye. Wassermann -f. On March 3rd, neuritis of the vestibular nerve. On March 7th, — 45 days after the injection — the urine still contained a trace of arsenic. On March 9th patient received third in- jection of 0.4 gram. Wassermann negative. Only headache. The vestibular neuritis showed improve- ment, yet the general condition of the patient steadily grew worse. Dizzy spells and headache until May 15th. On the night of this day an apoplectic attack with right-sided paralysis and bilateral neuritis optica. Lumbar puncture, no force, supplied about 25 c.cm. of a clear fluid which contained many mono- and polynuclear leucocytes,

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but no bacteria. Patient died on the same day in the evening, five weeks after last injection.

Autopsy: Fresh softening of the cerebral cor- tex. Leptomeningitis of the base- of the brain. Thrombosis of the vessels on the convexity. Men- inigitis and endarteritis luetica. Cicatrization of right lung with caseous foci in apices.

8. Case of Praenkel. (Muench. med. Wochen- schr., No. 34, 1910, page 1771.) Man, 25 years old, confused speech, deafness. Infected several years before. Aug. 5th, injection of 0.4 gram salvarsan intravenously in 115 c.cm. of water. Fifteen min- utes later symptoms of arsenical poisoning. Death in three hours.

Autopsy: Chronic leptomeningitis, heart weak- ness, hypoplasia of the kidneys, hyperemia of the liver, arsenic in large quantities in the spleen, lungs and liver.

9. Case of Hoffman. (Muencfi. med. Wochen- schr., No. 4, 1912.) Man, 42 years old, infected five and one-half years before, since then three courses of mercury and iodide of potassium. At this time patient suffered from loss of sensibility in left leg, loss of locomotion, and difficulty of urination. Urine free of morbid elements. Lumbar puncture shows a cloudy, bloody-tinged liquor, with considerable force. March 3rd, 1911, intra- venous injection of 0.6 gram salvarsan. After in- jection chills, vomiting, and rise of temperature to 39.7 C. (103.5 Fahr.). Next day left-sided fascial paralysis. The condition remained without note- worthy change until March 12th, when with slowly rising temperature and symptoms of increasing heart weakness death took place, nine days after the injection.

Autopsy: Sclerosis of the basilar artery. Brown atrophy of the heart and liver. Gumma of the spinal cord with degeneration of the posterior col- umns. Chronic luetic leptomeningitis.

10. Case of Klingmueller. (Muench. med. Wochenschr., No. 20, 1911.) Woman, 26 years old, in good health, complained of an occasional stick- ing pain in region of the heart. Careful clinical examination together with X-ray inspection dis- closed nothing. Patient knew nothing of luetic

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infection yet had two miscarriages. Wassermann + ++. Injection intravenously of 0.3 gram salvar- san. At first well borne. Despite physician's ad- vice, the woman worked in garden on the same day she received injection. She died three days later with evidences of increasing heart weakness. Autopsy: Embolus in pulmonary artery, luetic aortitis, myocardial degeneration.

11. Case of Kobler. (Gesellschaft fuer Innere Medizin und Kinderheilkunde in Wien, Nov. 3rd, 1910.) Death as a consequence of rupture of an aortic aneurysm not previously known.

12. Case of Dr. v. K. in S. (Martius). (Muench. med. Wochenschr., No. 20, 1911.) A case of aortitis syphilitica which died during the administration of salvarsan. Autopsy disclosed an extensive aortitis luetica, and a ruptured aneurysm or the thoracic aorta just above the diaphragm.

13. Case of Lane. (British Medical Journal, Sept. 23, 1911.) Male, 30 years of age, apparently in good health. Infected in 1909. At the time of examination without manifestations. Wassermann +. Treated with mercury. Since patient contem- plated marriage, he requested that an injection of salvarsan be given him. He received 0.6 gram intravenously. Immediately after the injection prostration, in the afternoon pain in breast, ayspnea and cyanosis. Pulse and temperature good. Through employment of stimulants patient re- stored. During night died suddenly.

14. Case from Mainz. (Ehrlich's Discussion of Salvarsan, 11 vol., page 576.) Strong man. In- fected in 1910. In Sept., 1910, received an intra- muscular injection of salvarsan. In August, 1912, on account of small papular syphilitic eruption patient received 0.5 gram salvarsan intravenously. In a snort time fever of 38.6 C. (101.5 Fahr.), vomiting, liquid stools; three hours and a half after the injection death occurred.

Autopsy: Nothing to account for the sudden death.

15. Case of Markus. (Muench. med. Wochen- schr., Jan. 10th, 1911.) Paralytic, infected 20 years before. Aug. 26, 1910, received intravenous injec- tion of 0.4 gram salvarsan. At first there was

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improvement, then new attacks and finally death by cerebral apoplexy two months after the injec- tion.

16. Case of Martius. (Muench. med. Wochen- schr., No. 20, 1911.) Male, 39 year's of age, with cerebral syphilis. Heart trouble since 1910. Clin- ically, an aortic insufficiency with compensation could be established. Intravenous injection of 0.5 gram salvarsan. Immediately thereafter indisposi- tion and vomiting. Death five hours later in coma.

Autopsy: Marked hypertrophy of both ventricles, high-grade aortic insufficiency, aortitis syphilitica, diffuse myocarditis. Degeneration and necrosis of urinary tubules of both kidneys.

17. Case of Milian. (Soc. med. des H6p. Meet- ing, Nov. 24, 1911.) Male, 60 years of age, obese, with unilateral paralysis and mitral insufficiency. Upon the express wish of the patient he was given an injection of 0.3 gram salvarsan. Thirty min- utes after injection patient fell into coma, with rise of temperature. Death 36 hours later.

Autopsy: Acute edema of the brain. Dilatation of both ventricles.

18. Case of Dr. B. in B. (Martius). (Muench. med. Wochenschr., No. 20, 1911.) Male, 35, strong, with pronounced paralysis. One-half hour after injection, while still in the physician's office, pa- tient suffered from a severe attack of heart failure. With caffeine and ether patient was restored. Four hours after the injection — in the meanwhile the patient had been carried to his hotel — death came with symptoms of increasing weakness of the heart muscle.

Autopsy: Hypertrophy of the heart, nephritis, cirrhosis of the liver, cerebral hemorrhage, arterio- sclerosis.

19. Case of Plehn. (Deutsche med. Wochenschr., No. 2, 1911.) Male, 49 years of age, afflicted with cerebro-spinal syphilis since July, 1910. Previous treatment given elsewhere. Oct. 1st, symptoms of a paralysis of the legs, bladder and bowels. Dis- turbances of speech and mentality. Cystitis, con- vulsions. In spite of cachexia, bed-sores, and weak

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pulse an injection of 0.5 gram salvarsan was given on Oct. 3rd. Death occurred next day.

Autopsy: Almost complete destruction of both kidneys by purulent processes.

20. Case of Ravauc. (Soc. de Dermatolog. et Syphil., June 1st, 1911.) Male, 45 years of age. At time of examination had cancer of tongue. Pre- sents picture of a very weak man. March 13th, 1911, patient received intravenous injection of 0.6 gram salvarsan. Well borne. On the 20th, a like dose. Fifteen days later patient died with symp- toms of progressive cachexia.

Autopsy: Extensive cancer of the tongue. Noth- ing to show arsenical poisoning.

21. Case of Schottmueller. (Muench. med. Wochenschr., No. 51, 1910.) Patient complained of severe painful tumor in the right upper ab- dominal quadrant. Upon exploratory laparotomy it was determined that the condition was due to syphilis of the liver. Wassermann +. Patient received 0.8 gram salvarsan in 100 c.cm. acid solu- tion intravenously. At first well borne. The next day, 18 hours following injection, the patient died suddenly with symptoms of dyspnea and pulmonary edema.

Autopsy: Gummata of the liver. Slight inter- stitial nephritis.

22. Case of Stern. This case reported by Stern to the Congress of German Physicians in Karlsruhe, bept, 1911, as following the use of a hyperalkaline solution of salvarsan.

23. Case of Treupel. (Deutsche med. Wochen- schr., No. 23, 1911.) Inveterate smoker, treated with mercury and iodide of potash without any results. Patient received two injections intra- venously of 0.4 gram each. Two days after the last injection patient manifested great cerebral ex- citement, dying shortly after.

Autopsy: Well advanced degeneration of the posterior columns. Diffuse hemorrhagic pachy- meningitis, with fresh hemorrhages and puncti- form hemorrhages in the medulla. Aortitis syph- ilitica.

24. Case of Voerner. (Monatshefte fuer prakt. Dermatolog., Bd. 53, No. 2, 1911.) Poorly nourished

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SALVARSAN FATALITIES

smoker. Infected twenty years before. Internal organs without demonstrable lesions. Following request of patient given intravenous injection of 0.6 gram salvarsan. After the injection patient suffered from chills, headache, and vomiting. The next week the patient was again sick with vomit- ing. In urine, one percent, of albumin. Six weeks later, after a temporary improvement, patient again in bad condition. Again prostrated, with diarrhea and complete apathy. Spleen and liver swollen. Death.

Autopsy: Tuberculous foci throughout periton- eum. Also in spleen, liver and bowels. Swollen tuberculous glands in mediastinum. Adhesions in both pleural cavities.

25. Case of Queyrat. (Bull, de la Soc. franc, de Dermatolog. et de Syphil., No. 1, 1912.) Male, 24 years of age, chancre for ten days. Oct. 21st, 0.6 gram of salvarsan injected intravenously. Urine free. Internal organs without abnormal findings. Injection caused no trouble. No headache. How- ever, one-half hour later patient suddenly seized with prostration. Unconscious and stertorous breathing. In spite of ether injections and artificial respiration patient died in five minutes.

Autopsy: In the right kidney, on the forward inner surface is a broad effusion of blood, of the size of a fifty-cent piece. The entire organ has sustained severe hemorrhages. Microscopically in the glomerulus, between the straight and convoluted tubules, are to be seen widely dilated vessels. The epithelium of the convoluted tubules is detached; the lumen of the tubules in places entirely ob- literated. The damage seems to be a diffuse, acute nephritis.

In the following cases, by reason of organs damaged by chronic alcoholism, syphilis or mercury, the system was unable to normally eliminate the administered salvarsan. The greater number of these cases were given the combined treatment. In Almkuist's case (No. 1) there was, indeed, an interval of four

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months between the last employment of mer- cury and the salvarsan injection, yet we know through Moeller's observations (*) that renal damage following the administration of mer- cury may be weeks in manifesting itself, yes, even months. A point to be observed is the frequency with which chronic leptomeningitis is to be seen in connection with other latent de- generations of an alcoholic nature.

1. Case of Almkuist. (Muench. med. Wochen- schr., No. 34, 1911.) Male, 32 years of age, infected in 1905. Treated during a period of three years with eight courses of mercury (inunctions) and six or eight injections of grey oil. Since 1908 increase of difficulties. March 29th, 1910, fresh recurrences. Until Oct. 3, 1910, treated with salicylate of mer- cury injection and grey oil injections. Since the Wassermann reaction was still positive, Feb. 16, 1911, received an injection of 0.6 gram of salvarsan. Severe vomiting during the night. On the 18th, patient complained of headache and light chills. Three days after injection vomiting started in anew. In the evening patient lay in his room in- different to surroundings. Face markedly cyanotic. Notwithstanding camphor injections patient re- mained unconscious, but, however, with slight im- provement. On the fourth day pulse became ir- regular. Albumin and hyaline casts in urine. Dif- ficult breathing. Stiffness and paralysis of the left arm. Coma. This state lasted for five days fol- lowing the injection, then came a profuse perspira- tory outbreak, loss of the corneal reflexes, tonic and clonic twitchings of the legs and arms, convulsions. Death on the sixth day.

Autopsy: Acute hemorrhagic encephalitis, chronic fibrous splenitis, chronic interstitial neph- ritis, swelling of the liver.

(*)On Mercurial Poisoning and Angina, par- ticularly Stomatitis Ulcero-gangrenosa, together with the indications for and dose of grey oil. Dermatol. Zeitschrift, xviii, Nos. 2 and 3.

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2. Case of Fischer. (Muench. med. Wochenschr., No. 34, 1911.) Male, 40 years of age, with be- ginning maculo-papular eruption. For several days patient complained of headache, weariness and fever. Intravenous, injection of 0.4 gram salvar- san; subsequent light vomiting and chills. On the following day there was a noticeable Herxheimer reaction, which, however, quickly disappeared. In conjunction with the above, patient given a course of 30 inunctions. Iodide of potassium not well borne. (*) Forty days after the first injection a second was given. Same dose. Again vomiting. On the morning of the third day following the in- jection, patient began suddenly to feel bad, became apathetic, refused to answer questions, soon out of his head. Then there followed a period of great excitement during which it was difficult to keep him in bed. Tonic convulsions and coma. The pulse became poor, temperature rose to 40 C. (104 Fahr.). On the fourth day after injection, death.

Autopsy: Parenchymatous degeneration of the liver and kidneys. Chronic leptomeningitis and acute encephalitis. Edema and swelling of the brain.

3. Case of Hammer. (Muench. med. Wochen- schr., No. 30, 1912.) Jan., 1911, patient showed a primary lesion on the prepuce. Wassermann + + + . For this reason patient received on Jan. 17th, 0.6 gram salvarsan intravenously. Temperature rose to 39 C. (102 Fahr.). June 20th, roseolar rash ap- peared. Another injection of 0.6 gram salvarsan. Temperature to 38.4 C. (101 Fahr.). Patient then took a course of inunctions. In Nov., 1911, on ac- count of an "eruption" patient took another course of 30 inunctions. In February, by reason of "hoarseness" took 12 more inunctions. March 23rd, 1912, papules on tonsils, leucoderma, laryngitis, papules on the iaryngeal borders. On the 25th, 0.6 gram salvarsan borne without reaction. Then 18

(*) Frequently here is to be observed an idio- syncrasy against iodide of potash, together with interference with its elimination. The patient re- acts with marked swelling of the lining membrane of the pharynx and larynx, which leads to difficulty of breathing.

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8ALVAR8 AN FATALITIES

inunctions. Then again 0.6 gram of salvarsan which at first was well borne, but -two days later peculiar sensations in the ears were noticed. Temperature 38.1 C. (100.5 Fahr.). In the even- ing marked twitching with outbreak of perspira- tion. The following night vomiting, sleeplessness, three pronounced epileptiform attacks. In urine, albumin, hyaline casts, epithelial cells and blood corpuscles. April 15th, death.

Autopsy: Chronic leptomeningitis. Punctiform hemorrhages in brain. Chronic endarteritis. Car- diac hyperplasia.

4. Case of Kannengiezer. (Muench. med. Wochenschr., No. 34, 1912.) Male, 29 years of age, infected in 1910. Treated with salicylate of mer- cury and one subcutaneous injection of salvarsan. April 6th, 1911, specific angina. Attacks of dizzi- ness, paralysis of the lower fascial branches, dif- ficulty of hearing. April 28th, intravenous injec- tion of 0.5 gram of salvarsan. Immediately fol- lowing a course of inunctions. May 10th, no phenomena except headache. May llth, another injection of 0.5 gram. Well borne, but on follow- ing day headache. No albumin in urine. On the third day following injection patient seized with convulsions, together with clonic and tonic con- vulsive movements. Bloody foam appeared on lips, then loss of consciousness. Shortly follow- ing the attack patient became very restless; only with difficulty could he be kept in bed. Con- stantly he attempted to put his hand to his head. Failed to respond to external irritations. Profuse outbreak of perspiration. Venesection failed to give any relief. Patient fell in coma. On the 4th day temperature 38.8 C. (101.8 Fahr.). Stiffness of neck and cramps in arms. Evening temperature 39.3 C. (102.7 Fahr.). Clonic-tonic movements. Death on the fifth day following injection. (*)

(*) It is noteworthy that on the day of the injection, the inunctions had to be stopped on account of a severe stomatitis which fs always ac- companied by an insufficiency of the renal func- tion, and therefore, is to be seen in uremia. The appearance of the tubular epithelium also points to damage by mercury.

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Autopsy: Chronic leptomeningitis. Punctiform hemorrhages in the brain. Double pneumonia. Brown atrophy and degeneration of the heart and kidneys. Granular condition of the tubular epithelium.

5. Resembling "the above is the case of Oltra- mare. (Ann. des mal. v6n., Vol. 6, page 881.) Generally speaking, the elimination of salvarsan may be interfered with by aortic stenosis. Male, 48 years of age, very corpulent, infected 15 years previously. Previously treated with injections of mercury. At the time without manifestations of syphilis. Heart and kidneys without change. Up- on the expressed wish of the patient, 0.6 gram sal- varsan was injected intravenously. Well borne. The following two days patient went about his duties. On the third day complained of light head- ache. On the fourth day he lay upon the floor like a dead man. On the fifth day in a state re- sembling coma, covered with perspiration, cyanotic face, slow pulse, accelerated breathing, always in a convulsive seizure. Temperature 40 C. (104 Fahr.). Death during the night.

Autopsy: Chronic leptomeningitis, stenosis of the ascending aorta, fatty degeneration of the heart, and chronic purulent bronchitis.

6. Case from Plojesti. (Ehrlich's Discussions on Salvarsan, vol. II, page 584.) Male, 35 years of ago, old syphilitic. One year previously an intra- venous injection of 0.6 gram salvarsan has been well borne. Heavy drinker. Even on the day be- fore the second injection indulged heavily in alcohol. Patient should have received 0.6 gram, but scarcely half the amount had been injected when he collapsed and died.

Autopsy: Pronounced heart, liver and renal changes of an alcoholic character.

7. Case of Dr. St. in D. (Ehrlich's Discussions on Salvarsan, Vol. II, page 587.) Male, aged 17, roseola and papules of the scrotum and tonsils. Treated with inunctions up to 4 grams each. On June 19th, received 0.3 gram salvarsan; fever and headache followed. July 3rd, 0.05 calomel in- jected. July 5th, sulphur bath. July 10th, 0.01 gram of calomel. July 14th, after the twenty-

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seventh inunction received the second injection of 0.3 gram salvarsan. Following this patient suffered vomiting, chills, headache. On the fol- lowing day also vomiting and headache. July 16th, status unchanged. At noon-time fainting spell. In the afternoon, stiffness of neck, noticeable trismus. Pulse 60. In the evening patient be- came confused. Died during the night.

Autopsy: Subpericardial hemorrhages. Hy- peremia of the brain and coverings. Beginning fatty degeneration of the heart muscle. Sclerosis of the aorta. Hydrocephalus internus.

8. Case of Tremtour. (Ibid.) Patient became infected Nov. 1st, 1911. Chancre appeared on shaft of penis on the 18th. One week later 0.6 gram salvarsan intravenously injected. Some vomiting, no fever. On the 26th, patient began a course of inunctions, 5.0 grams per diem. On Dec. 6th, mild gingivitis. Inunctions stopped. Dec. 8th, macular eruption on the buttocks. Dec. 9th, second intra- venous injection of salvarsan administered. No reaction. Three days later patient became com- pletely unconscious with tonic-clonic convulsions. Pulse regular. Stiffness of the neck. Picking at bed-clothes. Temperature 38 C. (100.5 Fahr.). Dec. 13th. Again loss of consciousness and clonic movements. Pronounced outbreak of perspiration. Picking at bed-clothes more marked. In the even- ing beginning edema of the lungs, cyanosis. On Dec. 14th, in the morning, death took place. Be- fore death pulse dropped to 32 per minute.

Diagnosis: Meningitis, inferior poliocephalitis.

9. Case of Portner. (See text.)

10. Case of Lesser. (Berliner klin. Wochen- schr., No. 13, 1912, page 593.) Male, 39 years old, infected fifteen years before. Present symptoms point to a beginning tabes dorsalis. On Nov. 10th, 1911, received 0.5 gram salvarsan intravenously. Following this injection, vomiting and fever. Nov. 16th, 0.6 gram salvarsan injected. Also after this injection, fever, vomiting and diarrhea. On Nov. 21st, that is, five days after the last injection, epileptiform attack, coma in which patient died.

Autopsy: Leptomeningitis.

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The following cases concern themselves with nephritis, in some instances of a toxic (mercurial) character, in others of a syphilitic nature. In some" instances nitrogenous reten- tion or uremic symptoms were noticed; in some anuria occurred (see cases cited in text) ; in others still the renal damage seemed to be of a mild character, or severe renal changes were found at autopsy, which were unsus- pected during life because the urine was not examined with care.

1. Case from Berlin. (Ehrlich's Discussions on Salvarsan, Vol. II, page 576.) Male, 26 years of age, infected in August. On Sept. 28th, a typical roseola appeared on breast and back. Hypodermic injections of salicylate of mercury (0.5 gram). Stopped on disappearance of lesions about Oct. 28th. Nov. 10th, appearance of new lesions. Al- bumin in urine, strikingly large spleen. The al- bumin pointed to the character of renal lesion. Adopting the opinion that the splenic enlargement was of a syphilitic character, 0.6 gram salvarsan was intravenously injected Nov. 25th. Vomiting after injection. On the evening of Dec. 6th — 11 days after the injection — complaints of headache. On the morning of the 7th, clonic convulsions with loss of consciousness. Deep unconsciousness, pro- nounced trismus. Temperature 39.5 C. (103 Fahr.). Death took place at noon.

Autopsy: Subacute parenchymatous nephritis. Acute encephalitis. Malignant granuloma of the lymph glands of the entire lower aorta and spleen.

2. Case of Caussade and Regnard. (Bull, de la Soc. med. des Hop. Session of Feb. 10th, 1911.) Male, 33 years of age, with nephritis and uremia. Emaciated and cachectic. Bedridden for three years. Despite various modes of treatment al- bumin remained at 9 grams pro litre; 5 grams nitrogenous retention in blood. Quantity of urine, 450 c.cm. per diem. One injection of 0.3 gram salvarsan had no influence on the course of the

1 on

i _ i1

SALTARS AN FATALITIES

disease. On the ninth day after injection the patient died of anuria.

Autopsy: Acute general, diffuse nephritis. Amyloid degeneration of the glomeruli.

3. Case of Ravaut and Bith. (Journal mcd. franc., No. 10, 1911.) Male, 40 years of age, in- fected in April, 1910. Two months later roseola and patches in mouth. In October papular erup- tion on buttocks and legs. At the same time mild albuminuria, which disappeared with milk diet. Soon, however, albumin newly makes its appear- ance, 15 to 18 grams per diem. General condition good. Passes between 2 and 2\'-> litres of urine daily. Notwithstanding energetic treatment with mercury, albuminuria remains unchanged. Jan. 5th, 1911, patient received 0.4 gram salvarsan which was well borne. It had no influence on quantity of urine or albumin. On the contrary, a slight edema of the ankles became noticeable. Jan. 9th, patient received 0.7 gram salvarsan in- tramuscularly. Immediately thereafter uremic de- lirium. The next day quantity of urine reduced to one litre which contained 5 grams NaCl and 8 grams nitrogen. Rapid increase of edema until it reached scrotum. Then followed headache, roar- ing noise in the ears, dyspnea, delirium, convul- sions, uremia and death on Jan. 28th, under al- most complete anuria.

4. Case of Wechselmann. (See text.)

5. Case of Gennerich. (Praxis der Salvarsan- behandlung, page 20, case 602.) Infected Jan., 1912. Chancre and secondaries disappear about the same time. From May 9th to June 7th, 1912, seven injections of calomel. After the fifth injec- tion a stomatitis occurred, by reason of which the injections were stopped from May 25th to June 6th. At the same time some albumin in urine. June 3rd, 0.5 gram salvarsan intravenously. June 5th, 0.9 gram neosalvarsan, and on June 7th, 1.08 neosalvarsan. Seven hours after the third injec- tion came fever, 38.5 C. (101.3 Fahr.), clearly a delayed reaction. Temperature normal next morn- ing, and general condition somewhat improved. At four o'clock in the afternoon convulsions and loss of consciousness. Venesection, salt infusion

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every three hours. Mental condition improved. On following morning repetition of the convulsions, cyanosis. Artificial breathing, etc. Death.

Autopsy: Pulmonary embolism. No essential changes in brain. High-grade parenchymatous de- generation of the renal epithelium in the con- voluted tubules with extensive, far progressed nu- clear necrosis. Gennerich classifies the case as one of toxic retention in consequence of renal insuf- ficiency.

6. Case of Lugue Morata. (Revista de Med. y Cirujica Practicas. Feb. 28th, 1911.) Male, 21 years of age, infected two years before. Treated one year with mercury. At the time of examina- tion patches in mouth and pharynx. Weight 43 kilograms. Internal organs without change. Urine normal. Jan. 31st, intravenous injection of 0.4 gram salvarsan. Three hours later vomiting, diarrhea, outbreak of perspiration. Pallid face. Dry mouth. Cyanotic lips. Pulse scarcely per- ceptible. Complete anuria. Catheter secures no urine from bladder. Delirium, coma, and on the third day following injection patient died.

7. Case of Busse-Merian. (Muench. med. Wochenschr., No. 43, 1112.) Woman. ) Condy- lomata and dirty ulcerations on the labia majora. As early as Oct., 1911, there was an ulcer on the genitals. Now followed a thirty-day course of in- unctions, five grams each. Urine normal. The ulcers were now healing slowly. After quitting hospital patient began to suffer from pain in throat. Gargles of no avail. Genital ulceration again making its appearance. Marked reddening of the palate, the uvula and back portion of the mouth. Urine clear and free from albumin. Sp. Gr. 1014. On Aug. 19th, intravenous injection of 0.6 gram neosalvarsan. Well borne. On Aug. 27th, another injection of 0.6 gram neosalvarsan. On the 29th, light tremor, increased patellar re- flex. On the 30th, tonic-clonic convulsive move- ments, loss of consciousness and cyanosis. On the 31st, coma and marked cyanosis. Died in the evening.

Autopsy: Extensive swelling of the epithelium of the convoluted tubules. The epithelium of the

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glomerular capsule is partially swollen, thickened and dequamating.

8. Case Levi. (Arch. d'Ophthalm., No. 1, 1911.) Weak male, inveterate smoker, with pyelonephritis. Intravenous injection of salvarsan. Death in three weeks. At autopsy nothing found to account for arsenical poisoning.

9. Case of Marcus. (Muench. med. Wochen- schr., No. 2, 1911.) Old, inveterate user of to- bacco, with chronic diarrhea, cystitis and pyelo- nephritis. Death in three weeks following the in- jection.

10. Case of Neuhaus. (Muench. med. Wochen- schr.. No. 18, 1911, page 955.) Poorly nourished, much reduced paralytic, with pyelonephritis; died of heart failure five days after an injection of 0.8 gram salvarsan.

11. Case Ravaut and Cain. (Journal med. franc.. No. 10, 1911.) Male, 32 years of age, with pronounced tabes, and paralysis of both motor oculi, infected ten years before. Patient, who is weak, was formerly an alcoholic. Albumin in urine. Heart and lungs without change. Mer- cury employed without results. Upon patient's particular wish he received 0.6 gram salvarsan on March 13th. Well borne. Slight improvement of the paralysis of the motor oculi. Seven days later received another injection of 0.6 gram sal- varsan. Four days later, the patient suddenly was seized with general convulsions; coma which lasted 13 hours. Death on the fifth day.

Autopsy: Acute edema and congestion of the lungs. Sclerotic gummatous changes in the liver, and marked changes in the liver cells. Sclerosis of the connective tissue and vessels of the kid- neys. Hemorrhagic foci in the suprarenals. Hy- peremia of the thyroid and pineal glands.

12. Case of Sciele. (St. Petersburger med. Wochenschr., No. 33, 1911.) Patient with severe pyelitis died shortly after injection of salvarsan.

13. Case of Schlasberg. (Dermatol. Zeitschrift., Oct., 1912. ) Male, 47 years of age, with tertiary syphilis, chronic nephritis and pulmonary tuber- culosis. In April, 1908, he was treated with seven injections of grey oil, each containing 0.1 gram

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of mercury. Albumin and casts in urine. Sept. 12th, 1911, received an injection of 0.4 gram sal- varsan intravenously. Following the injection pa- tient experienced prostration, headache, tempera- ture of 40 C. (104 Fahr.). Edema increasing daily. On the 20th day after injection the patient died.

Autopsy: Both kidneys enlarged. Chronic nephritis.

[This list contains twelve other cases but they are of similar character to those already given, and it is not thought necessary to publish them in this translation. — Translator.]

In the next four cases a combined treatment was employed. It is not clear just what de- ductions we are to draw from the deaths which took place after a second or later injection.

1. Case of Hallopeau. (Bull de I'Acad. Med., No. 61, 1911.) Male, 35 years of age, infected in 1902 with lues. First chancre, then roseola, mucous patches and now psoriasis palmaris and plantaris. Mercury and hektin without result. Injection of 0.3 gram salvarsan; five days later 0.4 gram. Soon after the second injection patient complained of dryness in the throat as well as an angina and congestion of the face. During the second night continued vomiting. On the third day patient suffered from oppression and had con- vulsions. Pulse good and regular, urine clear and abundant. The condition of the patient grow steadily worse. Several convulsive attacks, roll- ing of head and eyes, tonic and clonic twitching of the upper extremities. Temperature 40 C. (104 Fahr.). Death in deep coma.

2. Le Duigou. (Bull et M6m. de la Soc. Med. des Hop. Nov. 17th, 1911.) Male, 20 years of age, with secondary lues. Internal organs sound. Previously received 20 injections of hektargyr, also iodine pills. Manifestations again appeared four weeks after cessation of treatment. Patient then received three injections of 8 drops each of grey oil. Two weeks later injection of 0.4 gram

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salvarsan. After the injection mild fever and vomiting, after which condition was good. A week later the second injection of 0.4 gram sal- varsan. On the following two days patient com- plained of weariness and general feeling of dis- tress. At the same time, diarrhea and palid face. On tne third day following injection delirium and convulsiform attacks, vomiting of dark masses, and finally death occurred.

Autopsy: Pronounced congestion of all internal organs, especially the intestinal tract, the lungs, spleen and brain. In the brain in many places, punctiform hemorrhages.

3. Gase of Klieneberger. (Deutsche med. Wochenschr., No. 36, 1912, page 1691.) Wait- ress, 25 years of age. Six months pregnant. Maculo-papular eruption, large condylomata on vagina and anus. Wassermann positive. In- unction course, four grams daily; every seventh day an injection (0.1) of salicylate of mercury. On March 29th, 0.2 gram salvarsan intramus- cularly; on April 3rd, 1.2 grams intravenously. Rapidly disappearing urticaria followed injection. A stomatitis recurred during the mercurial course. May 22nd, 0. 6 gram salvarsan intravenously. On the following day moderate indifference to sur- roundings and apyrexia. May 24th, tonic-clonic movements. Unconsciousness. Treatment for ec- lampsia according Stroganoff. On the 25th, deep coma, sterterous breathing. Lumbar puncture gave a clear fluid with low pressure. Lymphocytes and albumin. Death at midnight.

Autopsy: Extensive fresh soft areas on both Sides in brain, also small hemorrhages in abund- ance. Hypostatic congestion in lungs just begin- ning.

4. Case of Dr. M. in C. (Ehrlich's Discussion of Salvarsan, Vol. II, page 588.) Male, 38 years of age, tertiary syphilis. Treated for a long period with mercury without results. Dec. 27th, 0.5 gram salvarsan intravenously. Eight days later 0.5 gram salvarsan again injected. Well borne. On the evening of the following day loss of conscious- ness. Lumbar puncture, salt infusion, camphor, etc. During the night epileptiform attacks, death.

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1. Cases in which mercury was not given at the same time with the salvarsan and in which the urine, remained free from albumin, and which, however, die after one or two in- jections of salvarsan, are but rarely encoun- tered. In the text of this work I have analyzed the case of Balzer-Condat. In Pinkus' case the status lymphaticus could be considered as underlying the failure of elimination. In Ravaut's case oliguria seems to have been ex- hibited. In F. Lesser's case, leptomeningitio (see above).

1. Case of Pinkus. (Dermatol. Zeitschrift, Aug., 1912.) Girl, 19 years of age, infected when 14. At that time had a course of inunctions. Re- peated in 1910. Nov. 29th, 1911, papules at vaginal entrance. Cervical gonorrhea. On the morning of Dec. 1st, she received 0.3 gram salvarsan intra- venously. Headache followed injection. On the 6th, received second injection of 0.5 gram. Vomit- ing followed this injection. On the 7th, complained of abdominal pains (diseased adnexa). No al- bumin. On the evening of the 8th, she was seized with an acute delirious attack, with shrieking and manifestations of fear. Staring eyes, pupils re- spond promptly. Unconscious. Pulse strong, rapid. On the 9th, deep coma, convulsions, stringy pulse, camphorated oil. Temperature 41.5 C. (106.7 Fahr.). Heart attack. Camphorated oil again. Temperature 42 C. (107.6 Fahr.). Cheyne-Stokes breathing. Death.

Autopsy: Hyperemia of lungs. Internal organs without change. Many punctiform hemorrhages in •me lenticular nucleus.

2. Case of Marschalks-Vesprzemy. Given in text.

The case of Spiethoff stands entirely by it- self. The urine showed a marked sugar con- tent in the presence of encephalitis hemorr- hagica. The renal condition was not given.

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Case of Spiethoff. (Muench. med. Wochenschr., No. 21, 1912.) Male, 19 years of age, in primary stage. Wassermann negative. On Oct. 3rd, 1911, patient received an intravenous injection of 0.5 gram salvarsan in a weakly acid solution. On Oct. 10th, another injection of 0.5 gram. Both in- jections well borne, aside from moderate fever. Oct. llth, patient felt well enough to leave the hospital. In the afternoon headache. On next day loss of consciousness, convulsions, poor pulse. In the evening patient returned to hospital. Tracheal breathing with the mouth open. Tem- perature 39.3 C. (102.7 Fahr.). Urine free from albumin, but Nylander strongly positive. Stiff- ness of neck, clonic movements. Foam appeared at lips. Lumbar puncture shows; pressure 180, no cellular increase, Nonne + + ++. One-half hour after entrance of patient into hospital death oc- curred.

Autopsy: Edema of the spinal cord, especially in upper part. Nothing else of a pathological nature to be found either macro- or microscopically.

3. Now comes cases dying of acute yellow atrophy of the liver, in which the dependence of death upon salvarsan is highly 3uspicious. (See text.)

1. Case of Hirsch. ^Muench. med. Wochenschr., No. 33, 1911.) Woman, 23 years of age, broad condylomata of the labia majora, erosions, within vagina, inguinal adenitis, leucoderma colli. Dec. 29th, injection of 0.3 gram salvarsan; well borne. Then six injections each of 0.1 salicylate of mer- cury, and on Feb. 3rd, 1912, patient was given an- other injection of the mercurial salicylate. After two months, April 19th, the patient suddenly be- came unconscious, rigid, widely open pupils, con- vulsiveform twitchings of the entire musculature, slow tense pulse, considerable icterus. Death on April 20th, in coma.

Case of Hoffman. (Muench. med. Wochenschr., No. 33, 1911.) Male, 15 years of age, with syphilitic iritis of the right eye. Wassermann and Stern

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8 ALVARS AN FATALITIES

positive. Therefore a course of inunctions. Dur- ing these inunctions there appeared an iritis of the left eye. No results from treatment with mer- cury; on the contrary, hot applications effected some good. On Feb. 21st, 1911, patient was given an injection of 0.3 gram salvarsan which was well borne. On Feb. 27th, given an intramuscular in- jection of 0.3 gram; also well borne. On April 8th, upon dismissal, a gastro-intestinal catarrh was discovered, on account of which patient was re- entered. April 13th, an icterus developed with fre- quent vomiting, prostration and headache. These phenomena increased daily. Pulse 55; loss of con- sciousness; death on June 5th.

Autopsy: Acute yellow atrophy of the liver with moderate ascites.

3. Case of Lane. (Bri. Med. Jour., Sept. 23rd, 1911.) Male, 29 years of age, malignant syphilis since 1909. Once during mercurial treatment did patient show improvement. Recurrences February, 1910 (ulcerations of both cheeks, lips and palate). February 22nd, received an injection of 0.5 sal- varsan; shortly thereafter vomiting and coma. Two days later a pronounced icterus appeared, the patient taking on a brownish black color from head to foot. March 1st, delirious; died the fol- lowing day.

4. Case of Rille. (Muench: med. Wochenschr., No. 11, 1911.) Male, 23 years of age, secondary and tertiary syphilis on account of which received on Sept. 7th, 0.7 gram salvarsan. In November icterus and severe hemorrhages from the nose took place. Nov. 5th, death occurred, just as pa- tient was about to be sent to hospital.

Autopsy: Acute cirrhosis, interstitial nephritis, fatty degeneration of the liver. Arsenic demon- strable in liver.

5. Case of Severin and Heinrischsdorff. (Zeit- schrift fuer klin. Med., Vol. 76, page 138.) Male, 30 years of age, acrobat. May, 1911, chancre, pig- mentation, adenitis, angina. Wassermann -K One injection of mercury in olive oil, 15% (0.05 gram mercury). June 10th, intravenous injection of 0.6 gram salvarsan. Chills, diarrhea and vomiting. On the 14th, another injection of salvarsan.

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Headache. August llth, 0.6 gram salvarsan. Wassermann +. In evening mild icterus; next morning entire body yellow. Headache, loss of appetite, vomiting. In the urine, hyaline, granular casts, epithelial cells, no leucin or tyrosin. Liver enlarged, sensitive to pressure. Death on Sept. 6th.

Autopsy: Arsenic in liver; less so in spleen. Chronic yellow atrophy of the liver. Hemorrhages in endo- and pericardium. Hemorrhages in both lower lobes. Hyperemia and edema in both under and right upper lobes. Hemorrhages in stomach and bowels. Pronounced icterus of the kidneys. Chronic enlargement of the spleen.

6. Case of Severin and Heinrichsdorff. (Ibid.'t Female, 29 years of age. Infected in 1909. Arsan, lod. June, 1910, 72 grams of mercurial ointment. In Sept., 1910, the same. On account of persist- ence of luetic manifestations patient received 0.35 gram salvarsan intravenously on Dec. 1st. Head- ache, diarrhea, disappearance of the manifesta- tions. Dec. 6th, 1910, 0.6 gram salvarsan and 1.5 indipin intramuscularly. Dec. 16th, 0.4 gram. Was- sermann negative. Jan. 21st, 0.6 gram salvarsan intravenously. Beginning March 13th, and until May 2nd, four injections of mercury. June, 1911, pregnant. Swelling of the limbs, coughing. In- strumental abortion produced Sept. 10th, 1911. Vomiting, diarrhea, bloody mucous discharges from bowels. Icterus. Sept. 21st, received in the hos- pital with a high-grade icterus, ascites, etc. Urine: Albumin, bilirubin, abundant deeply yellow hyaline and granular casts, epithelial cells, but no tyrosin or leucin. Death Sept. 28th. In the liver only slightest traces of arsenic could be demontrated.

4. We now come to salvarsan fatalities which by reason of inexact observation pos- sess no scientific worth. As a rule these pa- tients had organic lesions.

1. Case of Bloch. (Korrespondenzheit fuer Schweizer Aerzte, No. 3, 1911.) Patient with ad- vanced cirrhosis of the liver and severe circulatory

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disturbances, died shortly after an intramuscular injection of salvarsan in neutral suspension.

2. Case from -London. Male, 47 years old, in- veterate smoker, markedly cachetic. Intramus- cular injection of 0.5 gram salvarsan. Condition grew worse until death. Nothing of exactness de- termined.

3. Case of E. Frank. (Berliner klin. Wochen- schr., No. 31, 1911.) Male, infected fifteen years previously, suffered for two years from mental weakness. At times excited, at times depressed. Wassermann of blood and cerebro-spinal fluid positive. Oct. 15th, injection of 0.3 gram salvarsan. Memory for certain things rapidly improved. Ten days later another injection of 0.3 gram. Wasser- mann negative. Five weeks later patient died sud- denly in coma. Wassermann had again become positive.

Autopsy: Several indistinct lesions adjacent to the vessels of the cortex.

4. Case of Gaucher. (Mentioned by Lesser, Berliner Min. Wochenschr., No. 13, 1912, page 593.) Male, 48 years old, infected for fifteen years. Aug. 17th, 1911, received an intravenous injection of 0.6 gram salvarsan. On Aug. 21st, after preceding vomiting and prostration, occurrence of convul- sions and loss of consciousness. Coma. Death on the 22nd, five days after the injection.

Autopsy : Leptomeningitis.

5. Case of Gaucher. (Bull, de TAcad. m£d., Feb. 6, 1912.) Male, 24 years of age, treated with mercurial pills. Infected two years previously. Following professional advice patient received in Paris in a period of thirteen days, three injec- tions of salvarsan, each 0.3 gram. After each in- jection vomiting and fever. On the sixth day after the last injection became seized with convulsive attacks which followed severe headache. These re- peated themselves. Patient fell into coma and on the seventh day after the last injection, im- mediately after a transitory improvement, death occurred.

6. Case of Guilain and Ravant. (Bull, de la Soc. M6d. des Hdp., Nov. 4th, 1910.) Woman, 28 years of age, secondary syphilis and hemiplegia.

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Injection of 0.45 gram salvarsan without any re- sult. Death in seven days.

Autopsy: Small, soft foci in brain.

7. Case of Dr. H. in B. (Martius). (Muench. mcd. Wochenschr., No. 20, 1911.) Male, 41 years of age, infected 13 years before. Since April, 1910, pronounced paralysis. In obedience to the af- flicted man's wish, he was given an injection of salvarsan. Thereafter slight improvement. Oct. 19th, 1910, further complicated by a pneumonia. Death the next day in consequence of heart weak- ness.

Autopsy: Hypertrophy of the heart, croupous pneumonia (lower lobes).

8 to 10. Cases of Hamel. (Verein deutscher Naturforscher und Aerzte, Koenigsberg.

8. Aortitis syphilitica and aortic aneurysm. Death in three weeks.

9. Severe myelitis ascending. Death in six days.

10. Luetic meningitis. Death shortly after in- jection.

[Since it is not believed that the inclusion here of the remaining 27 cases of this group would serve any distinct purpose, they are omitted. — Translator.]

The following are cases of very severe in- fections or of serious chronic illnesses. It is not possible to charge salvarsan with being the cause of death in these instances.

1. Case of Dind. (Revue Med. de la Suisse K romande, No. 1, 1912.) Patient had large lympho- sarcoma. Death fifteen days after injection of 0.4 gram salvarsan with edema of the tongue and larnyx.

2. Case of Iverson. (Iverson, Discussion on Salvarsan, page 342.) Woman, alcoholic, hys- terical, suffering from recurring fever, treated fif- teen years previously with mercury. She received 0.3 gram salvarsan intramuscularly. Fourteen hours later the spirochetes which at first were found in the blood in abundance, had disappeared. On the fourth day the temperature, hitherto nor-

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mal, rose to 38 C. (100.4 Fahr.). .At the same time patient appeared to have a double-sided bron- cho-pneumonia. On the head there was a hemorr- hagic eruption which at first resembled that of scarlet fever. Later there appeared acute neph- ritis, edema of the upper part of the body, swell- ing of the liver and hemorrhages into the skin, which the reporter looked upon as a condition of idiosyncrasy.

Autopsy: Marked, well advanced general arterio- sclerosis, myocarditis, fatty liver, and other pro- nounced changes of the vital ograns.

3. Case of Leede. (Muench. med. Wochenschr., No. 22, 1911, page 1185.) Patient showed 40% hemoglobin, red blood corpuscles 1,400,000. Patient had worked up to within a short time of admission. He received an intragluteal injection of 0.4 gram salvarsan. Minimal rise of temperature. During the next two weeks became worse — hemoglobin it>%, red blood corpuscles 900,000. With this came dizziness, buzzing in ears, vomiting and rapid de- cline. Treated with iron-arsenical combinations and fresh air with result that in three months hemoglobin reached 80%. He was thereupon dis- missed. In four months recidives, hemoglobin 50%. At this juncture patient received 0.5 gram salvarsan. Thereafter followed striking declension with death in 20 days.

No autopsy.

4. Case of Moutot. (These de Chevalier-Seyvet, page 42, Lyons; 1911.) Woman with epithelioma of the tongue. Operated on Feb. 2nd, 1910. Re- currence. On Feb. llth, intravenous injection of 0.6 gram salvarsan in alkaline solution. The next day patient complained of dryness in throat. The 17th, hemorrhage and death.

5. 6. Cases seen by Schreyer in Tien Tsin, China. Suffering from tuberculosis, both quickly died following the injection. The reporter attri- buted death in a measure as due to the drug.

7. Case of von Tordey. (Dreyfus, page 11.) Female with severe, hopeless anemia and tumor of the spleen, received an injection of 0.3 gram subscapularly. After slight improvement patient

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became worse and died on the ninth day following injection. Patient was very cachetic. Autopsy: Splenomegaly.

8. Case of Treupel and Levi. (Muench. med. Wochenschr., No. 5, 1911.) Girl, 15 years of age, tumor of the brain and hydrocephalus internus. No symptoms of lues. Wassermann negative. In deference to the wishes of the parents and the physician in charge, she was given an intramus- cular injection of 0.5 gram. At first well borne. After three weeks died suddenly as a consequence of paralysis of respiration.

Autopsy: Glioma cerebelli; hydrocephalus in- ternus.

9. Case of Tscherne-Schwartz and Halpern. (Roussky Vratsch, Mar., 1912.) Death took place three hours after intravenous injection of 0.35 gram. Patient had typhoid fever. Death resulted from heart failure following transitory convul- sions.

10. Case of Tuchinsky. (Roussky Vratsch, March, 1911.) Death occurred six hours after an intravenous injection of 0.5 gram salvarsan in the case of a malarial patient. Death due to heart paralysis. At autopsy, acute nephritis.

From the literature of reported cases of deaths, one can see that such fatalities form a variegated group without showing a distinct type. In only the smallest number of these cases can death be attributed directly to salvar- san. The marked differences in the clinical pictures of fatal cases, among which encepha- litis hemorrhagica is a frequent type, show that salvarsan, insofar as the greater number of cases are concerned, is but an indeterminate factor and not a distinct cause of death. Thus no uniform explanation fitting all cases can be given. A glance at the reports of fatalities is sufficient to show how recklessly salvarsan

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was employed at first, and it is certain that many of the fatalities could have been avoided.

I am well aware of the fact that this presentation is not without defects, and that I had to use a wide variety of conclusions and deductions. But in view of the eminently practical lessons taught by the fatal cases, and in spite of obvious defects, I consider it my duty to offer these observations in order to impress upon those using salvarsan the need for greater precautions.

These precautions are :

1. The most exact technique.

2. A dose of the drug carefully adapted to the individual case.

3. Careful observation of the urinary se- cretion when employing salvarsan; resorting to the most exact chemical and microscopical examination of the urine. This holds good particularly when the combined treatment is employed.

4. The conjoint use of salvarsan with heavy mercurial treatment is dangerous! If one will use the combined treatment, then give mercury very carefully many days after the last salvarsan injection, but never reverse this rule !

5. Take into careful consideration every general reaction or rise of temperature, follow- ing the use of salvarsan, and make a full in- vestigation of the causes of such effect.

Only by close obedience to the above will it be possible to begin the more refined, scientific investigation of apparently so simple, but in reality highly complicated, an occurrence as a salvarsan fatality.

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1913 Wechselmann, Wilhelm

Pathogenesis of salvarsan fatalities

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