Reprinted from the International Medical Magazine, March, 1892. THE TREATMENT OF EPILEPSY; WITH SPECIAL REFERENCE TO THE USE OF POTASSIUM BROMATE, MAGNESIUM BROMIDE, NITRO- GLYCERIN, ANTIFEBRIN, SULPHONAL, ETC. GUY HINSDALE, M.D., Assistant Physician to the Orthopaedic Hospital and Infirmary for Nervous Diseases, and to the Presbyterian Hospital; Fellow of the College of Physicians, Philadelphia. Ever since its introduction into the treatment of neuroses by Sir Charles Locock, in 1857, bromide of potassium has held a more and more prominent position as a therapeutic agent. Although the remedy is a valu- able one, there are frequently serious disadvantages attending its use in cases which require a long course of treatment. Fetor of breath and acne are common occurrences. The skin may even undergo severe ulceration,1 and its sensibility may be decidedly impaired. Impotence, aphonia, paraly- sis, hallucinations, loss of memory and of the senses, in short all the de- pressing features of bromism, have frequently convinced the patient that the remedy is worse than his disease. Bromides of ammonium, sodium, lithium, calcium, magnesium, gold, and nickel have been tried in the hope of finding some combination less liable to give rise to such unpleasant symptoms. Not only bromides of the metals but bromides of the organic bases have been used. No matter with what base bromine may be combined, it has a distinct and independent action, although it will not materially interfere with the action of the base. Dr. B. W. Richardson2 has used quinine bromide, morphine bromide, and strychnine bromide,-combinations which produced very interesting effects. The quinine bromide could be taken freely by those w'holly unable to take the alkaloid or its other salts ; combined with morphine bromide it favored the sedative action and obviated astringency; in the strychnine compound it was said to prolong or subdue the action of strychnine on the muscles. Besides bromides chemistry affords bromates; their composition is analogous to that of chlorates,-e.g., KBrO3, NaBrO3, etc. 1 S. Weir Mitchell, Transactions of the College of Physicians, 1870, p. 347. 2 The Practitioner, London, 1871, vol. vi. p. 337. 2 GUY HINSDALE, M.D., ON POTASSIUM BROMATE. Potassium bromate may be prepared by treating a strong solution of potassium hydrate with bromine until the brown color caused by the addi- tion of the latter is entirely discharged. The resulting mixture will consist of five molecules of bromide of potassium and one of bromate of potassium, -viz., 6KOH 3Br2 = 5KBr + KBrO3 + 3H2O. On evaporating the solution to dryness and treating repeatedly with alcohol, the bromide is dissolved, the bromate remaining insoluble. The salt forms in colorless anhydrous crystals; on slowly cooling it crys- tallizes in four-sided and six-sided plates or in cubes. It has a slightly-acrid taste, and is soluble in five parts of hot and in twelve parts of cold water. It is permanent in the air, but it is decomposed by strong acids and by heat in the presence of deoxidizing agents. There is nothing, however, to pre- vent its being mixed with sulphates of quinine and morphine, chloral hydrate or iodide of potassium. The bromate of potassium was prepared in the above manner, for Dr. Weir Mitchell, by Mr. Genois, and was used in the spring of 1881 in the Infirmary of Nervous Diseases and in Dr. Mitchell's private practice. I also made a personal trial of the substance. On one day I took twenty grains, on another day, forty grains in one dose. On other days doses of ten, twenty, and finally thirty grains were taken three times a day. The first dose of twenty grains caused a rise of the pulse in one hour from 70 to 90 and a subsequent fall in one hour to 68, but did not produce any feeling of weakness, sleepiness, or dis- comfort. The forty-grain dose lowered the frequency of the pulse from 78 to 60, and was followed in four and a half hours by loose watery dis- charges from the bowels and by drowsiness. The dose of ten grains taken three times in the day was followed by a fall of the pulse-rate from 78 to 58, the pulse continuing low until the next morning. Twenty grains three times in one day had the same effect, lowering the pulse to 54, with no weakness, sleepiness, or unusual manifestations. Thirty grains three times a day lowered the pulse-rate from 62 to 54 per minute, caused vomiting and purging, which continued freely and repeatedly through the night, with sleepiness and vomiting four times the next day. Not until the third day could the stomach retain food. The following notes are from the records of twelve cases of epilepsy in which bromate of potassium was ordered; four were in the private practice of Dr. Mitchell, and the remainder in his clinic at the Infirmary for Nervous Diseases. Case I.-Cora K., aged fourteen, an epileptic since the age of two and a half years. The first convulsion was accompanied by paralysis of the right side and followed by post-paralytic chorea. At her eighth year she had a set squint and choreal habits. These habits subsided towards the thirteenth year, when she had more control over herself. There were also delusions about seeing people, occasional diplopia, nausea, and confusion of ideas. Attacks occur about once a week, or THE TREATMENT OF EPILEPSY. 3 oftener, accompanied by loss of consciousness, numbness of the right side, nausea, but no twitching. Ordered potassium bromate, gr. v, with ginger, t. d. A few days later the dose was increased to gr. xv, which caused nausea. Reduced the dose to gr. x. At the end of two weeks she had had no attack. She was less irritable and was not sleepy. Increased to gr. xiiss. The last entry shows one attack during the month she was under observation. Case II.-Martha J., aged twenty-eight, a confirmed epileptic. The attacks had increased in frequency from one in a month to one daily. She had taken such large doses of bromide of potassium as temporarily to loose speech. Under bromide of lithium, gr. x t. d., with minute doses of chloral and morphine, two spells occurred in two weeks. For ten weeks the patient did very well under bromides given in doses of from twenty to forty grains and, later, ten grains t. d. April 9, 1881, bromate of potassium, gr. xii-xx t. d., ordered. Attacks occurred on the 11th, 20th, 26th, and 30th of April, and May 3, 5, and 28. No attacks then occurred for six weeks while taking the bromate. The patient's skin remained clear and free of any eruption. Once, however, the bowels became loose. She then took a mixture of potassium bromide (gr. xv) and bromate (gr. v) for several months. The attacks occurred in periods of from three days to three weeks. The disturbance of the stomach and bowels then demanded a change of treatment. Case III.-Annie A., aged thirteen, subject to general epileptic spasms aver- aging seven daily. They were brought on by the least excitement, and were prob- ably hysterical. Ordered potassium bromate, gr. v-x t. d. On the seventh day she had her first severe attack since taking the bromate. The drug made the patient quite sleepy and purged her freely, for which reason it was abandoned. Case IV.-D. L. D., aged eighteen months. In good health till the ninth month, when epileptic convulsions came on without known cause. She had from one to three and, later, ten seizures of petit mat in an hour. She was very consti- pated ; urinated irregularly ; had taken bromides freely. Ordered bromide of potas- sium, gr. ii, every two hours for two days; then bromide of potassium, gr. v, and bromide of ammonium, gr. ii., every two hours, and occasionally a dose every hour. Still no effect. Then bromide of potassium, gr. x, and bromide of ammonium, gr. v, every two hours, without effect. Then injections of five grains of chloral hydrate, with the same quantity of bromide of potassium administered by the mouth, with calomel purges and lactopeptine and phosphates, seemed to control the spasms. May 17, 1871, ordered potassium bromate gr. iiss every three hours. After four days' treatment she would have as many as ten or more spasms in an hour. Nausea coming on, the drug was discontinued. Case V.-George L. J., aged five, a weakly child, of bad family history. At the age of three he had his first convulsion. After three weeks spasms reappeared, numbering from six to as many as one hundred and fifty in a single day, during which he was rigid and unconscious. For two weeks he was free from attacks while taking potassium bromide, gr. iiss t. d. Then he was ordered to take potassium bromate in the same quantity. On the eighteenth day, having been free from spasms, he suddenly had thirty attacks in one day; in three days more, three attacks. He was then taking thirty grains daily ; this was reduced to ten grains, given in two doses. He vomited, but could eat again immediately afterwards. During the fol- lowing three weeks he had comparatively few attacks. Case VI.-George W. H., aged five. Epileptic seizures for one year past. Sudden losses of consciousness at first, lasting ten minutes; the patient falls, but is not convulsed. After taking from five to two and a half grains of potassium bromate, the drug was discontinued at the end of five days, on account of vomiting. Case VII.-W. J. 8., aged thirty-one. Epileptiform attacks for six years. Gr. v t. d. caused vomiting at first. Took the remedy for one month ; no attacks. Case VIII.-Lizzie V., aged fourteen. Epilepsy three years. Grand and petit 4 GUY HINSDALE, M.D., ON mal. Gr. v caused diarrhoea at first; it had to be suspended for one month. Some improvement. Case IX.-Rebecca H., aged twenty-one. Epilepsy twelve years, usually at intervals of about nine days. Bromate of potassium, gr. x t. d., with pulv. zingiber., gr. ii, pulv. rhei, gr. ii, and morphinse sulph., gr. four times daily, made the patient worse and produced nausea and vomiting. The other cases failed to report. In these twelve cases the result was satisfactory in one, doubtful in five and unsatisfactory in six. The drug evidently shares with the bromides the power of controlling epileptic seizures, but it is an irritant intestinal poison, lowering the pulse and depressing the heart to such a degree that in most instances it had to be abandoned. MAGNESIUM BROMIDE This substitute for the potassium and sodium salts was used at the in- firmary in Dr. Mitchell's clinic in 1883. Before using it on patients I tried it experimentally, as follows : Experiment I.-October 10, 1883, at 6.14 p.m., two and a half grains of mag- nesium bromide dissolved in twenty-five minims of distilled water were injected into the right breast-muscle of a grown pigeon. 6.16, vomiting kernels of corn; the bird has a forward-and-backward swaying motion of the body. 6.18, is stupefied; vomit- ing repeated. 6.21, walks about a little. 6.22, vomiting. 6.35, unsteady and quite drowsy. 7.30 and 10 p.m., quiet. The following morning it was bright and lively, and ate grain readily. Experiment II.-October 11, 1883, at 10.40 a.m., injected into the opposite breast of the same bird ten grains of magnesium bromide in thirty-five minims of water. The bird at once becomes stupid, but manages to stand. 10.42, prone; eyes closed. 10.45, breathing 32 per minute ; very drowsy. 10.53, dead. Experiment III.-October 13, 1883, 11.11 a.m., five grains of magnesium bro- mide dissolved in twenty-five minims of water were injected into a pigeon's breast. 11.16, crouched, with eyes closed; had a slight convulsive movement forward and backward. 11.21, another convulsive movement; the bird in attempting to rise falls over on its face; these movements are repeated. 11.50, bird in crouching posi- tion ; breathing quietly. 1.50 p.m., bird found dead, in crouching position. Similar experiments with potassium bromide were made for purposes of comparison. Experiment IV.-October 12, 1883, 9.50 a.m., two and a half grains of potas- sium bromide in twenty minims of water were injected into the breast-muscle of a pigeon. 9.54, bird apparently unaffected; walks about and picks up corn. 11.15, no apparent effect from the injection. October 13, apparently as well as ever. October 25, alive and well. October 29, dead. Experiment V.-October 11, 10.55 a.m., ten grains of potassium bromide were injected into the breast-muscle of a pigeon. Being placed on the floor, it makes no effort to rise. 11.01, stands up. 12 M., has continued standing; no disposition to walk about; seems dull, but shows much less effect than in the case of the pigeon receiving magnesium bromide in dose of two and a half grains. There is no vomit- ing. 1 p.m., condition the same; still standing. October 12, dead several hours. THE TREATMENT OF EPILEPSY. 5 A personal trial of a five-grain dose produced no nausea or vomiting. It seemed to have no effect on the pulse. The salt has a disagreeable taste ; it may be dissolved to the extent of eighty grains to the ounce of water. Magnesium bromide was prescribed at the infirmary for eleven cases of epilepsy as follows: W. W., aged four and a half, ten grains t. d.; did well for two months. Lizzie J., aged twenty-seven, twenty grains t. d.; temporary effect good. P. Bair, aged four and a half, from five to ten grains t. d.; no improvement. Mrs. S., aged thirty-three, from fifteen to sixty grains a day ; temporary improvement. Agnes McKall, aged four- teen, from ten to twenty grains t. d. for two years, with intervals; consider- able improvement, but not permanent. Esther F., aged fifteen, fifteen grains t. d. for one month; did well. ' Magnesium bromide was ordered for five other patients, but they failed to return. The remedy exerted an undoubted power in controlling the attacks, both as to frequency and severity; there was, however, apparently a greater liability to facial eruption than in the case of potassium or sodium bromide, and Fowler's solution of arsenic was usually given in addition. HYDROBROMIC ACID. This remedy was tried at the infirmary as early as 1884, and has been prescribed at various times since. The doses usually given were from one- half to one drachm of the dilute acid. As one fluidrachm of the dilute acid is reckoned equivalent to nine grains of bromide of potassium, the dose was never large. Hydrobromic acid has a very disagreeable, sour taste, and is best given well diluted in milk. In order to yield controlling effects it ought to be given probably in half-ounce doses, but this is rarely practicable.1 The effect of this remedy has been fairly successful. Apparently it is not liable to cause acne2 or muscular depression, and, in some cases, it is usefully added to lessened doses of alkaline bromides. Certainly, in some instances it does aid digestion, and, as Dr. Randolph proved by his experi- ments, has no tendency to impair that function. NITRO-GLYCERIN. The use of this remedy at the infirmary has not been sufficiently encouraging to insure its continuance. It was adopted in the service of Dr. William Osler in 1885-1886, in doses ranging from the one-hundredth to eight one-hundredths of a grain three times a day. Of nineteen cases under treatment for periods ranging from six weeks to six months, it was of temporary benefit to nine, evidenced by a reduction of the frequency of the attacks, whether petit mal or grand mal. In some cases, where the improvement was most striking at first, the attacks soon returned, and the remedy had to be abandoned.3 1 See British Medical Journal, 1885, ii. 587. 2 H. C. Wood. 3 Journal of Nervous and Mental Diseases, January, 1888, Report to Philadelphia Neurological Society. 6 GUY HINSDALE, M.D., ON NITRITE OF POTASSIUM. Nitrite of potassium was tried in 1880. Both Dr. Mitchell and the writer made trials first in our own persons, the writer taking in one day as much as thirty-five grains.1 In a few cases of epilepsy in which it was tried, there were encouraging results. A girl, aged nine, after taking from one-half grain to two grains t. d., was apparently cured until it was found that the attacks were due to lumbricoid worms. The remedy proved too depressing in doses of over four or five grains, producing marked cardiac irritability. As Dr. E. T. Reichert has shown, it is capable of producing paralysis of the nerve- centres as well as of the skeletal and unstriated muscles. These drugs are, in a word, difficult to handle in clinical practice, and I do not encourage their prolonged use. This remedy has been employed quite frequently at the infirmary. Better results were obtained in those lesser epilepsies, in which bromides failed, than in the greater epilepsies. The effect of this drug was fully observed in the case of a young man aged nineteen, a compositor by trade, who continued to use antifebrin for three years. Under the use of bromides his mental and bodily health became seriously impaired; in his fits he be- came maniacal, and he was so dangerous to those about him that he was compelled to abandon his vocation. Bromides made his condition worse. Antifebrin, on the other hand, kept his attacks down to such a number as to make life useful. He insisted that it did him no harm in doses of from ten to twenty grains thrice daily, and purchased the 'drug in half-pound packages. In the case of nine other patients, whose ages ranged from two to forty- two years, and in which antifebrin was used in doses of from one to twenty grains thrice daily, temporary improvement usually was noted, but in a few weeks it was necessary to return to bromides. ANTIFEBRIN. SULPHONAL. This remedy has been used as follows: Case I.-Mary F., aged twenty-two. Petit mal since ten years of age, occurring sometimes three or four times daily, but on application usually every three days. Sodium bromide was given without benefit for three months, from thirty to sixty grains daily. Biborate of sodium was used for two weeks, sixty grains daily, with- out benefit. Sulphonal five grains t. d., at first alone and then with sodium bromide fifteen grains t. d., controlled the attacks for a time, but they afterwards increased in frequency. Case II.-Fred. M., aged eleven. Epilepsy since one and a half years old, occurring, on application, once a week. Sulphonal, three to five grains t. d., was used for three months, with some relief. 1See American Journal of the Medical Sciences, July, 1880. THE TREATMENT OF EPILEPSY. 7 Case III.-Bella H., aged sixteen. Epilepsy since two and a half years of age. Attacks at irregular intervals,-from one to three months, or as frequently as twelve in one day; at time of application seven in one week. Sulphonal was used for ten months, three to six grains t. d. During the first three months from one to three attacks occurred wreekly. The sulphonal caused so much stupor that it was suspended in the fifth month, and the seizures returned to one weekly. During the last three months there has been great improvement. Under sulphonal the attacks have become fewer and of less severity. Intervals of three weeks occur without attacks. In this case bromides apparently had no effect. Case IV.-Florence M. First attack at the age of seven months, during den- tition. Has an aura; initial cry ; followed by movements of the upper extremities. Attacks from one to five weekly. Sulphonal was used for five months, four to six grains t. d., under which the attacks were reduced about one weekly. Case V.-Mary E., aged sixteen. Epilepsy since the age of ten. Four or five attacks daily. Sulphonal, five grains t. d., used for six months. Patient became very drowsy. The attacks were greatly reduced in number. Intervals of one or two weeks occurred, but the attacks returned on suspending the drug. The final result was not satisfactory. Case VI.-Mary M., aged eight. First attack at the age of nine months. Seven attacks daily on application. Sulphonal, four grains t. d., exercised no decided con- trol over the seizures after four weeks' trial. Attacks recurred as often as eight times a day. Antipyrin, five grains, and ammonium bromide, fifteen grains t. d., gave im- mediate, but temporary, relief. A large number of other cases were treated with sulphonal, but the results were more or less unsatisfactory. In many instances the patients failed to continue its use for a sufficient length of time. Dr. Dercum, at Dr. Mitchell's request, used this drug at the clinic of the University of Pennsylvania and elsewhere, confirming the conclusions reached by Dr. Mitchell and his clinical associates. He informs me that he believes it to be secondary in efficacy only to the bromides, and to answer admirably as a substitute when the latter have to be discontinued on account of bromism or other disagreeable complication. Three or four grains in the case of children, and six or eight grains thrice daily in adults, answer best. It frequently happens, however, that patients are made very sleepy by its use. Two doses daily may be given in such cases. Among other remedies which have been prescribed at the clinic are sodium biborate, lithium biborate, tincture of cannabis indica, tincture of digitalis, ammoniated copper, and antipyrin. None of these remedies have maintained themselves, although afforded a patient trial at the infirmary. The result has been that in epilepsy we have had to fall back upon the bromides of sodium, potassium, and lithium, and it is unlikely that any dependence will be placed on the thirteen drugs referred to. Sodium bromide is the remedy most frequently employed, and can be borne for long periods when arsenic is used occasionally to check cutaneous disturbances. The experience of Drs. Mitchell, Sinkler, Morris Lewis, Osler, and my own observations extending over the last ten years at the infirmary, at which over three hundred and fifty cases of epilepsy have been treated, show that we have no permanent satisfactory substitute for 8 THE TREATMENT OF EPILEPSY. sodium, potassium, and lithium bromide. These drugs have maintained their places in the order stated, and, as far as other remedies are concerned which are treated of in this report, it is probable that further trials will be futile. I have thus brought together into one report a summary of the efforts made by the staff of the infirmary during the last decade to render more efficient the treatment of epilepsy. By beginning in the physiological laboratory and following out the results there obtained by patient study in the clinical service of the hospital, the knowledge of the subject can be still further advanced. The profession will not give up the search for sub- stitutes for the alkaline bromides, notwithstanding the difficulties which attend such an investigation. The failure of a treatment and the great success of a treatment may alike serve to interrupt or put an end to the attendance of a patient; con- sequently, in the case of a chronic disease like epilepsy, the reports of hospital practice are too often of little value because the time element is insufficient. By the systematic method of recording cases of epilepsy adopted in the infirmary, and which may be illustrated on a subsequent occasion, it is possible to see at a glance any given feature of the disease or survey the whole number of attacks during an entire year of treatment. Dr. Weir Mitchell has expressed himself frequently in the clinic and has privately stated to me his own general conclusions as to the treatment of epilepsy, which I have the privilege of adding to this report. In the first place, great care is given to diet; meats usually are restricted. Occa- sional purges are employed and the condition of the skin is observed ; arsenic in small doses is used in conjunction with the bromides. In this way the latter may commonly be continued without mischief over long periods and in competent doses. In certain cases the bromides cause so much skin- trouble or mental disorder that it becomes desirable to lessen or stop their use for a time. Then sulphonal becomes valuable. Again, in the too fre- quent cases where the convulsive seizures are not controlled or do not exist, and we have to deal with only the lesser epilepsy in its many forms, anti- febrin will sometimes prove useful, and, when the patient becomes accustomed to it, may be employed for long periods, as some of the above cases show. Nothing but long and continuous use of new agents in epilepsy is of use as a test of value. The old experience still exists, to the effect that change of remedy, of place, of diet, etc., may for a time lessen the number of fits. It frequently happens that when epileptics are admitted to the hospital for medical or surgical treatment, it is found that the fits cease altogether for days or weeks, even when the bromides have been, for a pur- pose, abandoned. It is the experience of Drs. Mitchell, Sinkler, and Lewis, and of all connected with the infirmary, that there are rare epilepsies in which the bromides increase the number of fits, others in which they cause homicidal mania, and in these we have to fall back on other drugs and those general means which should in any case unfailingly accompany the use of bromides.