FOOTNOTES:

[A] Reprinted from the "British Medical Journal" of March 15 & 22, 1879.

II.
AN INQUIRY
INTO THE
ACTION OF THE BROMIDES ON
EPILEPTIC ATTACKS.[B]

Bromide of potassium is generally recognised as the most effective anti-epileptic remedy we at present possess. There exists, however, great difference of opinion as to its method of administration and to the amount of benefit which we may expect from its use. Some physicians who employ the drug after one method come to totally different conclusions as to its efficacy from those who use another. Many believe the remedy to be only useful in certain forms of the disease, and to be very uncertain and imperfect in its action. Others, again, maintain that it is positively injurious to the general health of the patient. These and other unsettled points the following inquiry attempts to make clear.

Epilepsy, like all other chronic diseases, presents great difficulties in scientifically estimating the exact value of any particular remedy; and unless the investigation of the subject is approached with the strictest impartiality, and observations made with rigid accuracy, we are liable to fall into the most misleading fallacies. I believe that these are to be avoided, and facts arrived at, however laborious it may be to the experimenter and wearisome to the student, only by the careful observation and elaborate record of an extensive series of cases. If, in epilepsy, the disease, from its prolonged duration, its doubtful causation and pathology, its serious complications and the many other mysterious circumstances connected with it, offers almost unsurmountable difficulties to any definite and uniform method of treatment and the systematic estimation of the same, its symptoms furnish us with tolerably accurate data upon which to base our observations. The attacks, although only symptoms, may be practically considered as representing the disease, as in the large majority of cases, in proportion as these are frequent and severe, so much the more serious is the affection. The influence of the bromides on these paroxysms is taken in the following inquiry to represent the action of these drugs on the epileptic state.

Before proceeding to detail the facts arrived at, it is necessary briefly to state the method of procedure adopted in treatment. Each case in succession, and without selection, which was pronounced to be epilepsy (all doubtful cases being eliminated), was considered as a subject suitable for experiment. The general circumstances of the individual were studied; his diet, hygienic surroundings, habits, and so on, if faulty, were, when practicable, improved. The bromides were then ordered, and taken without intermission for periods which will subsequently be detailed. The minimum quantity for an adult, to begin with, was thirty grains three times a day, the first dose half an hour before rising in the morning, the second in the middle of the day on an empty stomach, and the third at bedtime. This was continued for a fortnight, and if with success, was persevered with, according to circumstances, for a period varying from two to six months. If, on the other hand, the attacks were not materially diminished in frequency, the dose was immediately increased by ten grains at a time till the paroxysms were arrested. In this way as much as from sixty to eighty grains have been administered three times daily, and, with one or two isolated exceptions to be afterwards pointed out, I have met with no case of epilepsy which altogether resisted the influence of these large doses; and, moreover, I have never seen any really serious symptoms of poisoning or injury to the general health ensue in consequence. Sometimes these quantities of the drugs have been taken for many months with advantage; but as a rule it is preferable, when possible, after a few weeks gradually to diminish the dose and endeavour to secure that amount which, while it does not injuriously affect the general condition of the patient, serves to keep the epileptic attacks in subjection. The form of prescription to begin with in an adult has been as follows:—

M. Ft. haust. ter die, sumendus.

According to the age of the patient so must the dose be regulated; at the same time, children bear the drug very well. The average quantity to begin with for a child of ten or twelve years has been twenty grains thrice daily.

In this manner I have personally treated about two hundred cases, and in all of these most careful records have been kept, not only of their past history, present condition, etc., but of their progress during observation. All these, however, are not available for the present inquiry. It is necessary in order to judge of the true effect of a drug in epilepsy that the patient should be under its influence continuously for a certain period of time. Now, a large number of patients, especially amongst the working classes, cannot or will not be induced to persevere in the prolonged treatment necessary in so chronic a disease. They either weary of the monotony of drinking physic, especially if, as is often the case, they are relieved for the time, or other circumstances prevent their carrying out the regimen to its full extent. The minimum time I have fixed as a test for judging the influence of the bromides on epileptic seizures is six months, and the maximum in my own experience extends to four years.[C] All other cases have been eliminated. I have arranged this experience in the form of tables for reference, in which will be seen at a glance—1st, the average number of attacks per month in each case prior to treatment; 2nd, the average number of attacks per month after treatment; and 3rd, in the event of these being fewer than one seizure per month, the total number during the last six months of treatment.

Table I.—Sixty Cases of Epilepsy, showing Results of Treatment by the Bromides during a Period of from 6 Months to 1 Year.

No. of Case.Average number attacks per month before treatment.Average number attacks per month after treatment.Number of attacks during six months of treatment.
190060
26005
360090
445012
53002
624090
718060
81505
91508
101507
111203
12120120
13903
14909
157020
16604
17606
186090
19307
20301
21302
223010
23168
24162
25124
261212
27123
28800
2982
3081
3181
3284
3381
3484
35600
3655
37500
3842
3941
4041
4141
4242
4343
4423
4522
4621
4721
4824
4921
5022
51100
5212
53100
5411
55100
56100
5711
5811
5911
601150

Table II.—Thirty-two Cases of Epilepsy, showing Results of Treatment by the Bromides during a period of from 1 to 2 Years.

No. of Case.Average number attacks per month before treatment.Average number attacks per month after treatment.Number of attacks during six months of treatment.
190060
2600120
330030
418060
51502
61501
7909
89015
9602
1064
11301
12304
13302
14303
15168
16123
17800
1883
1984
2081
21810
2261
2344
2444
2542
2621
2722
2822
29100
30100
3113
3213

Table III.—Seventeen Cases of Epilepsy, showing Results of Treatment by the Bromides during a Period of from Two to Three Years.

No. of Case.Average number attacks per month before treatment.Average number attacks per month after treatment.Number of attacks during six months of treatment.
160060
230015
3608
4304
5308
6302
7162
8128
982
1081
1183
1241
1341
1446
15100
16100
1713

Table IV.—Eight Cases of Epilepsy, showing the Results of Treatment by the Bromides during a period of from Three to Four Years.

No. of Case.Average number attacks per month before treatment.Average number attacks per month after treatment.Number of attacks during six months of treatment.
13003
2601
3604
4301
51610
6123
7800
8100

These four tables consist of all the characteristic cases of epilepsy which came under notice, without selection of any kind, all being included, no matter what their form or severity, their age, complication with organic disease, etc. In analyzing this miscellaneous series, the chief fact to be noticed, whether the period of treatment has been limited to six months or extended to four years, is the remarkable effect of treatment upon the number of the epileptic seizures. Of the total 117 cases, in 14, or about 12.1 per cent., the attacks were entirely arrested during the whole period of treatment. In 97, or about 83.3 per cent., the monthly number of seizures was diminished. In 3, or about 2.3 per cent., there was no change either for better or worse; and in 3, or about 2.3 per cent., the attacks were more frequent after treatment.

With regard to the fourteen cases which were free from attacks during treatment, it cannot, of course, be maintained that all of these were cured in the strict sense of the term. It is probable that if any of them discontinued the medicine the seizures would return. Still, the results are such as to encourage a hope that if the bromides are persevered with, and the attacks arrested for a sufficiently long period, a permanent result might be anticipated. Even should no such ultimate object be realized, it is obvious that an agent which can, during its administration, completely cut short the distressing epileptic paroxysms, without injuriously affecting the mental or bodily health, is of immense importance. Take, for example, cases 7 and 8 of Table IV., where, prior to treatment, in the one case eight fits a month, and in the other one, were completely arrested during a period of nearly four years. The experience of physicians agrees in considering that the danger of epilepsy, both to mind and body, is in great part directly proportionate to the severity of its symptoms. If these latter can be completely arrested, even should we be compelled to continue the treatment, if this is without injury to the patient, it is as close an approach to cure as we can ever expect to arrive at by therapeutic means. The permanent nature of the improvement, and the possibility of subsequent discontinuance of the bromides without return of the disease, is a question I shall not enter into, as my own personal experience is not yet sufficiently extended to be able to form a practical opinion. A satisfactory solution of this problem could only be made after a life-long private practice, or by the accumulated experience of many observers. With hospital patients such is almost impossible, as they are lost sight of, especially if they recover.

Of the total 117 cases which compose the tables, we find that in no less than 97 were the attacks beneficially influenced by the bromides. In the different cases this improvement varies in degree, but in most of them it is very considerable—for example, Nos. 2, 5, 8, 11, 20, in Table I; Nos. 5, 6, 11, 15, in Table II; Nos. 3, 4, 5, 6, in Table III; and all the cases in Table IV. In these and others the attacks, if not actually arrested, were so enormously curtailed, both in number and severity, in comparison to what existed before treatment, as to constitute a most important change in the condition of the patient. In those cases in which improvement was not so well marked, in many it was most decided, and in frequent instances caused life, which had become a burden to the patient and his friends, to be bearable.

Of the total number of cases, in 3 the administration of the bromides had no effect whatever in diminishing the attacks, and in 3 others the number of seizures was greater after treatment than before. Whether in these last this circumstance was the result of the drug, or due to some co-incident augmentation of the disease itself, I cannot decide, but am inclined to believe in the latter as the explanation.

After a consideration of these facts it is difficult to understand why most physicians look upon epilepsy as an opprobrium medicinæ, and of all diseases as one of the least amenable to treatment, and the despair of the therapeutist. For example, Nothnagel, one of the most recent and representative authorities on the subject, in speaking of the treatment of epilepsy, says, "Many remedies and methods of treatment have isolated successes to show, but nothing is to be depended on; nothing can, on a careful discrimination of cases, afford a sure prospect of recovery, or even improvement." Such a statement indicates either an imperfect method of treatment, or that in Germany epilepsy is more intractable than in this country, as a "careful discrimination" of the above cases affords a "sure prospect of improvement" and a reasonable one of recovery. That a critical spirit and healthy scepticism should exist regarding the vague and imperfect accounts of the efficacy of various drugs in disease is, I believe, necessary to arrive at the truth; at the same time, we must not refuse to credit evidence sufficiently based on observation and experiment. The above collection of cases are facts, carefully and laboriously recorded, and not originally intended for the purpose which they at present fulfil. Having been brought up in the belief that epilepsy was one of the most intractable of diseases, no one is more surprised than myself at the readiness with which it responds to treatment. So far, then, from this affection being the despair of the profession, I believe that of all chronic nervous diseases it is the one most amenable to treatment by drugs, resulting, if not in complete cure, in great amelioration of the symptoms which practically constitute the disease.

An important consideration next arises. Assuming that practically the treatment in all cases is alike, are there any special circumstances which explain why some patients should have no attacks while under the influence of the drugs, while others are only relieved; why some—though the number is very small—should receive no benefit, and others have a larger number of attacks after treatment? On a careful examination of all the clinical facts of each case, no explanation can be found, the same form of attack, the same complications and circumstances, occupying each group. For example, one of those who had no attacks during treatment was a woman who had been afflicted with epilepsy for eighteen years, of a severe form, with general convulsions, biting tongue, etc. Another was a very delicate, nervous woman, who suffered, in addition to the seizures, from pulmonary and laryngeal phthisis, who came of a family impregnated with epilepsy, and whose intellect was greatly impaired. By far the largest class are those benefited by treatment, and these comprehend every species of case, chronic and recent, complicated, inherited, in the old and young, and so on; yet the most careful analysis fails to discover why some should be more amenable to treatment than others, or give any indication which might be useful in prognosis. Neither does a study of the few cases which the bromides did not affect, or those which increased in severity under their influence, throw any light upon the subject, as some of these latter gave no indications beforehand of their unfortunate termination, and in none of them was there any serious complication or special departure from good mental or bodily health.

Another point must be noted, although there is no statistical method of demonstrating the fact, namely, that in those cases in which the attacks were not completely arrested, but only diminished in number, those seizures which remained were frequently greatly modified in character while the patient was under the influence of the bromides. These were less severe, and characterized by the patients as "slight," while formerly they were "strong." This by itself often proves of great service, as, instead of a severe convulsive fit, in which the patient severely injures himself, bites his tongue, etc., he has what he calls a "sensation," in other words, an abortive attack.

Having considered the general effects of the bromides on a series of unselected cases, we now proceed to investigate whether any particular form of the disease, or any special circumstances connected with the patient or his surroundings, have any influence in modifying the results of treatment. The following table shows epilepsy divided into its two chief forms, namely, E. Gravior and E. Mitior. By the former is understood the ordinary severe attack, with loss of consciousness and convulsions; the latter is the slighter and very temporary seizure, of loss of consciousness, but without convulsions.

Table V.—Showing Results of Treatment by the Bromides in—1. Epilepsia Gravior; and 2. Epilepsia Mitior.

No. of Case.Average number attacks per month before treatment.Average number attacks per month after treatment.Number of attacks during six months of treatment.
1. Epilepsia Gravior.
16005
245012
324990
418060
51203
6601
7606
8308
9304
103012
11231
12162
13124
14123
151210
16800
1784
1881
1984
2082
2161
2255
23500
2442
2541
2642
2721
2821
2921
3021
3122
3222
33100
34100
35100
36100
37100
38100
3911
4011
4111
4211
4312
4414
4512
4611
471150
2. Epilepsia Mitior.
190060
260060
33003
41501
51507
6120120
7909
8903
96015
106090
11132
12164
13168
1483
1583
1641
1746
1814

Of 47 cases of E. Major, we find that in 8 there were no attacks during the whole period of treatment, in 1 there was no improvement, in 1 the attacks were augmented after treatment, and in 37 there was marked and varying diminution of the seizures. Of 18 cases of E. Mitior there was no case where the attacks were wholly suspended, in 1 there was no improvement, in 2 the attacks were increased, and in 15 they were diminished in number by treatment. This is scarcely a fair comparison between the two forms, as the numbers are so unequal; but cases of uncomplicated E. Mitior are not common, being generally associated with the graver form, which combined cases are not inserted in this table. It is generally asserted in books that the non-convulsive form is much more intractable than the other, but the above table proves the contrary, as, for example, in Nos. 3, 4, 11, 12. It is true that the results do not appear so complete or striking in E. Mitior as in E. Gravior, but then it must be remembered that the number of cases is more limited, and the number of attacks originally much greater. In short, the table shows that if treatment does not completely avert the attacks of E. Mitior, it greatly diminishes their frequency.

TABLE VI.—Showing Effects of Treatment by the Bromides in Epilepsy. 1. Diurnal Form; 2. Nocturnal Form.

No. of Case.Average number attacks per month before treatment.Average number attacks per month after treatment.Number of attacks during six months of treatment.
1. Diurnal Form.
13003
2909
3606
4308
5241
6168
7124
883
984
1041
1121
12100
13100
14100
1511
2. Nocturnal Form.
1601
2164
382
421
542
61
71150

Another variety of epilepsy is that which is characterized by the time at which the attacks occur. In the large majority of cases these take place both while the patient is awake and when he is asleep. I have, unfortunately, no observations to offer as to the effects of treatment on the diurnal or nocturnal attacks in patients suffering from both. The preceding table shows the result of treatment in 15 cases in which the attacks occurred only while the patient was awake, and in 7 cases where they took place only while he was asleep.

Of 15 cases of the purely diurnal form, we find that in 3 there was a total cessation of attacks during treatment, and in all the others there was diminution in their number. Of the 7 nocturnal cases, in none were the seizures entirely arrested, in 1 the attacks increased in number after treatment, and the remainder were relieved to a greater or less extent. Here, again, our numbers are small, and therefore difficult to found any definite principle upon; still there is enough to show that, contrary to the opinion expressed by most authorities, the nocturnal form of epilepsy appears to be as amenable to relief as the diurnal variety.

The next point for consideration is the question whether the fact of the epilepsy being hereditary or not makes any difference in the results of treatment by the bromides. In the following table all the cases with a perfectly sound family history are placed in the first part, and the second includes those in which either epilepsy or insanity could be proved to exist in any near relation.

Thus in 39 cases with a perfectly sound family history, in 3 the attacks were totally arrested during treatment, in 2 there was no improvement, in 2 there was increase of seizures after treatment, and in the remainder there was diminution of the fits. In 18 cases, where at least one near relation suffered from either epilepsy or insanity, in 3 the attacks were arrested, in 1 they were increased, and in the remainder diminished. In short, from a review of the details of the table, it does not appear that the fact of the disease being inherited, or of its existing in other members of the family, makes any difference to the benefit we may expect to derive from treatment.

Table VII.—Showing Effects of Treatment by the Bromides in Epilepsy. 1. Non-Hereditary Cases, 2. Hereditary Cases.

No. of Case.Average number attacks per month before treatment.Average number attacks per month after treatment.Number of attacks during six months of treatment.
1. Non-Hereditary Cases.
16005
260060
345012
424090
53003
61507
71203
8120120
91501
107020
11606
126090
13601
143012
15903
16302
17164
18162
19800
2082
2183
2284
2361
24500
2555
2642
2741
2822
2921
3021
3122
32100
3312
3414
3511
3611
3711
3811
391150
2. Hereditary Cases.
190060
218060
3909
4241
5168
6124
7123
881
983
1084
1142
1246
1321
1421
15100
16100
17100
1841

The next table attempts to show whether or not the age of the patient when he came under observation has any effect in modifying the action of the bromides, or whether it assists us prognosing the probable result.

A survey of this table shows in general terms that the age of the patient is neither an assistance nor impediment to the successful action of the bromides in the treatment of epilepsy. Whatever the age may be, whether in a young child or in an old person, the average of beneficial effects appears to be the same. At first sight it would seem as if treatment would be more successful in the young; but it is not so, as the two cases in the table over fifty years of age received as much average benefit as any of the others.

Table VIII.—Showing Effects of Treatment by the Bromides in Epilepsy at Different Ages. 1. Under 15 Years; 2. Between 15 and 30 Years; 3. Between 30 and 50 Years; 4. Over 50 Years.

No. of Case.Average number attacks per month before treatment.Average number attacks per month after treatment.Number of attacks during six months of treatment.
1. Under 15 Years.
190060
26005
360060
445012
524090
618060
71507
8304
9800
1083
1146
1242
1321
141150
2. Between 15 and 30 Years.
13003
21507
31203
4120120
5903
6601
7606
86090
9164
10168
11162
12124
13814
1482
1584
167020
17500
1842
1941
2041
2122
2221
2321
2422
25100
26100
27100
2811
2912
3014
3111
3. Between 30 and 50 Years.
1302
23012
3123
481
583
655
722
8100
911
1011
4. Over 50 Years.
1308
2241

Does the fact of the disease being recent or chronic affect the prognosis of treatment? This will be seen by the following table, in which the length of time that the disease has existed is divided into four periods, namely—1, those cases in which the attacks first began less than a year before treatment was commenced; 2, those in which they had begun from one to five years before; 3, those in which they began from five to ten years before; and, 4, those in which the disease had existed for over ten years.

Table IX.—Showing Effects of Treatment by the Bromides in Epilepsy in Recent and Chronic Cases. 1. Under 1 Year; 2. From 1 to 5 Years; 3. From 5 to 10 Years; 4. Over 10 Years.

No. of Case.Average number attacks per month before treatment.Average number attacks per month after treatment.Number of attacks during six months of treatment.
1. Under 1 Year.
160060
2606
383
4500
542
642
721
821
922
2. From 1 to 5 Years.
16005
224090
318060
4903
5302
6308
73012
8168
9123
10800
111507
1282
1361
1441
1521
1622
17100
18100
1911
2011
211150
3. From 5 to 10 Years.
145012
23003
390060
4909
5601
6304
7162
884
983
1081
1141
1231
1311
1411
1512
4. Over 10 Years.
11501
21203
3120120
47020
56090
6164
7124
884
955
10100
11100
1214

In this table we observe very singular results in the treatment of this remarkable disease. In most ailments, the longer they have existed and the more chronic they are, the more difficult and imperfect is the prospect of recovery. This does not appear to hold good in the case of epilepsy. For when we analyze the above table we find that the results, on an average, are as satisfactory in those cases in which the disease has existed over ten years as in those which began less than one year before the patient came under observation. For example, we find in section 4 of Table IX. 12 cases in which epilepsy had existed for over ten years prior to treatment; of these, in 2 the attacks were completely arrested, in 1 there was no improvement, in 1 the attacks were increased, and in the remainder the seizures were as beneficially modified as in the other sections. Thus it would seem that we are not to be deterred from treating cases of epilepsy, however chronic they may be, as the results appear to be as good in modifying the attacks in old, as in recent cases.

Table X.—Showing Effects of Treatment by the Bromides in Epilepsy—1. In Healthy Persons; 2. In Diseased Persons.

No. of Case.Average number attacks per month before treatment.Average number attacks per month after treatment.Number of attacks during six months of treatment.
1. Healthy Persons.
190060
260060
31507
41501
51203
6909
77020
8601
9605
106090
11302
12308
133012
141600
15162
16164
17123
1882
19800
2083
2184
2284
2342
2441
2542
2621
2722
2821
2921
3022
3121
32100
3312
3411
35100
36100
3711
3811
3911
40114
411150
2. Diseased Persons.
145012
23003
324090
418060
5903
6606
7241
8124
983
1081
1161
1255
1341
1446
15100

Another important question arises: Does the general health of the patient in any way influence the effects of treatment? In the preceding table those cases are collected in section 1 whose general health was to all appearances robust and free from disease. In section 2. are those in which organic disease could be demonstrated, or in which the condition of the patient was evidently unfavourable.

Here, again, a consideration of the table demonstrates that the condition of the general health has no influence on the successful progress of treatment, as those cases under the head of diseased persons made apparently as satisfactory progress as those in a perfectly robust condition regarding their epileptic symptoms.

As a specimen, the following table shows the result in those cases complicated with a permanent lesion of a motor part of the brain, namely, hemiplegia, and of an intellectual portion, in the shape of idiocy:—

Table XI.—Showing effects of Treatment by the Bromides in Epilepsy complicated with—1. Hemiplegia; 2. Idiocy.

No. of Case.Average number attacks per month before treatment.Average number attacks per month after treatment.Number of attacks during six months of treatment.
1. Hemiplegia.
1450 12
2240 90
3 30 4
4 24 1
5 8 3
6 8 1
7 4 6
2. Idiocy.
1180 60
2120120
3 60 6
4 30 4
5 4 6

Here it may be observed that of 7 cases complicated with hemiplegia, in 1 the attacks were increased after treatment, but all the others were relieved in average proportion. Of the 5 cases in idiots, in 1 there was no improvement, in 1 the attacks were subsequently augmented, and in the others there was improvement. The numbers are far too limited to found any reliable dictum upon; at the same time, it must be admitted that while epilepsy complicated with these grave lesions is perfectly amenable to treatment, this table serves to show that the proportion of non-success is comparatively large.

It has been stated before that no attempt would be made in this paper to prove that epilepsy was curable by therapeutic means. Its aim has been to show the effects of the bromides on the attacks or symptoms of that disease. It is common to hear it remarked, as if this were of no importance, "You only arrest the fits, but you do not know, and cannot cure, the original lesion. You do not go to the fountain-head of the disease, but simply relieve its results." In reply, I would ask, Of what disease do we know the ultimate nature any better than that of epilepsy? and if we did, how would that assist us in treating it? What drug in our pharmacopœia cures any single disease, or do other than, by attacking and relieving symptoms, leave nature to remove the morbid lesion? Even quinine, to which therapeutists triumphantly point, only arrests certain paroxysms until time removes the poison from the blood, as it does in most malarious affections. So far from being a small matter, I believe there are few, if any, drugs at our disposal which can be demonstrated to have a more beneficial action in the treatment of disease than that of the bromides, in epilepsy. Besides, I decline to admit the statement that complete recovery does not follow their administration. Various authors have reported cases, and that these are rare is due to reasons stated before, and chiefly on account of the long period of treatment necessary to ensure success.

This inquiry may be summed up in the following general conclusions:—

  1. In 12.1 per cent. of epileptics the attacks were completely arrested during the whole period of treatment by the bromides.
  2. In 83.3 per cent. the attacks were greatly diminished both in number and severity.
  3. In 2.3 per cent. the treatment had no apparent effect.
  4. In 2.3 per cent. the number of attacks was augmented during the period of treatment.
  5. The form of the disease, whether it was inherited or not, whether complicated or not, recent or chronic, in the young or in the old, in healthy or diseased persons, appeared in no way to influence treatment, the success being nearly in the same ratio under all these conditions.