Epilepsy in childhood

EPILEPSY

IN CHILDHOOD

I I I . RESULTS WITH THE ]~ETOGENIC DIET

LAWSON

WILIZlNS, ~V~.D.

B A L T I M O R E ~ ~ViD.

H E results obtained in the t r e a t m e n t of epilepsy in childhood by ketogenie diet h a v e been r e p o r t e d b y P e t e r m a n , 1 Helmholz, 2 Talbot, "~ Eley, 4 P u l f o r d ~ and others and in adults by Barborka, 6 Doo]itt l e / B a s t i b l e , s and Notkin. 9 However, m a n y of these p a p e r s present only m e a g e r clinical descriptions of the cases t r e a t e d and fail to describe the response of the p a t i e n t to t r e a t m e n t . A l t h o u g h o v e r 400 children have come u n d e r o b s e r v a t i o n in the E p i l e p s y Clinic, either p o v e r t y or lack of inte]]igence or cooperation has p r e v e n t e d a s a t i s f a c t o r y trial of the ketogenie diet in all except a small n u m b e r of cases. The diet was a t t e m p t e d in f o r t y eases, ~ but six patients failed to cooperate sufficiently well to p e r m i t a n y judgm e n t of the results a n d h a v e been discarded f r o m the series. Two otticr patients who failed to respond to the diet h a v e been ruled out because t h e y h a d definite neurologic lesions. Two others were u n d e r observation f o r only a v e r y short period, and their status is not known. The r e m a i n i n g t h i r t y p a t i e n t s upon w h o m the p r e s e n t r e p o r t is based are those who h a v e been m a i n t a i n e d in ketosis for a sufficient length of time to w a r r a n t a j u d g m e n t of its effect on the course of the disease. In most instances the p a t i e n t s have cooperated excellently. A n y failure in cooperation has been given recognition in the discussion of the resnlts obtained. In general the usual ketogenic regime employed b y other w o r k e r s has been followed and a diet with F : C + P ratio of 4:1 has been given. In m a n y cases the diet was p r e c e d e d b y a s t a r v a t i o n period of three to seven days. Since e v e r y effort was being e x e r t e d to stop the pat i e n t s ' seizures, it was often f o u n d advisable to combine o t h e r therap e u t i c measures with the ketogenic diet. F r o m the scientific p o i n t of view this was u n f o r t u n a t e because in some instances it was impossible to determine w h e t h e r the i m p r o v e m e n t was due to the diet or to some other measure. H o w e v e r , it is true t h a t most of the p a t i e n t s h a d failed p r e v i o u s l y to r e s p o n d to sedatives and other measures of t r e a t m e n t . The restriction of fluid intake, the p r o d u c t i o n of acidosis b y m e a n s of a m m o n i u m chloride, the a d m i n i s t r a t i o n of low salt diets and of theobromine sodium salicylate h a v e all been tried in certain cases. Sedative

Tt h e

F r o m t h e H a r r i e t L a n e H o m e of t h e J o h n s H o p k i n s H o s p i t a l a n d t h e D e p a r t m e n t of P e d i a t r i c s of t h e J o h n s H o p k i n s U n i v e r s i t y School of lV~edicine. Aided b y the s u p p o r t of t h e - E p i l e p s y M e d i c a l R e s e a r c h F u n d a n d T h e J o h n H o w l a n d M e m o r i a l Fund. * T h e s e p a t i e n t s w e r e t r e a t e d u n d e r t h e s u p e r v i s i o n o f Dr. E d w a r d M. B r i d g e , Dr. L a s l o I~aJdi, o r t h e a u t h o r . In many instances detailed chemical and metabolic s t u d i e s w e r e m a d e b y Dr.: ]~ridgr 0I: Dr. K a j d i . 341

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drugs, such as p h e n o b a r b i t a l and bromides, have been added to the t r e a t m e n t of most patients not otherwise benefited. I t must be emphasized t h a t the patients r e p o r t e d as not benefited, or i m p r o v e d only t e m p o r a r i l y , f r e q u e n t l y have been t r e a t e d more intensively t h a n any others. I n some instances these children h a v e been b r o u g h t into the hospital r e p e a t e d l y for exhaustive studies; t h e y often have been given r e p e a t e d s t a r v a t i o n periods and e v e r y m e t h o d of t r e a t m e n t has been tried before t h e y were considered definitely unchanged. R E S U L T S OF TRF~kTME,NT W I T ~

K E T ' O G E N I C DIE,T

The results obtained b y the t r e a t m e n t w i t h the ketogenic diet are shown in Table I. TABLE

I

Complete freedom from attacks, now on normal diet 8 patieats Temporary freedom from attacks, relapse while on ketogenic diet 4 patients Possible temporary improvement 3 patients I% benefit 15 patients E a c h of these groups will be discussed in more detail in l a t e r sections. I t is of interest here to determine w h e t h e r the results were influenced b y the selection of a p a r t i c u l a r l y f a v o r a b l e g r o u p of patients, as we l~ have shown t h a t in a g r o u p of children t r e a t e d b y other means t h a n diet, the prognosis for remissions m a y v a r y according to the t y p e of epilepsy, the c h a r a c t e r of the attack, and the severity of the disease. TYPE

OF EPILF~PSY A N D S E V E R I T Y

OF

CASES TREATED

The 30 patients reported presented no evidence of organic cerebral lesions, either in their history, neurologie e x a m i n a t i o n or x - r a y of the s k u l l E n c e p h a l o g r a m s were not m a d e in m o s t ~nstances. All of these children except three h a d intelligence quotients above 80. These three had I. Q.% of 78, 78, and 76, respectively. Most of the patients were of r a t h e r high intelligence as shown in Table II. TABLE INTELLIGENCE QUOTIENT

100 or over 90-99 80-89 76-79

II

NUI~IBEI~ OF PATIENTS TR,EATED

6 14 7 3 30

FREE FROM ATTACKS

3 4 l 0 8

The g r o u p m a y therefore be c o m p a r e d with tlhe patients with I. Q.'s above 80 a n d without neurologie lesions, as r e p o r t e d in our previous papers. 1~ I t is possible t h a t the prognosis f o r remission is slightly b e t t e r in this group t h a n in t h a t in which a mental or neurologic defect occurs. The f r e q u e n c y of seizures in the p a t i e n t s t r e a t e d is shown in Table III.

WlLKINS :

TABLE FREQUENCY OF ATTACKS

343

EPILEPSY

llI

NUMBER OF PATIENTS TREATED

Daily to weekly W e e k l y to monthly Monthly to quarterly Remitting type

FREE FROM ATTACKS

26 1 1 2

6 0 1 1

3O

8

It is apparent from these figures that the children selected for treatment with the k e t o g e n i c diet in nearly all instances were subject to very frequent seizures. Six of the eight patients w h o became free from attacks had a severe f o r m of epilepsy. In one instance the attacks were infrequent and few, and in one instance the p a t i e n t had been subject to previous remissions. In a previous paper l~ dealing with children not treated by the ketogenic diet, it has been s h o w n that remissions are encountered much less f r e q u e n t l y in the severe forms of epilepsy than in the milder types. A m o n g patients h a v i n g attacks more f r e q u e n t l y than m o n t h l y , the incidence of remissions w a s 16 per cent as compared to 40 per cent w h e n the attacks occurred less frequently. R E L A T I O N OF R E S U L T

TO THE: C H A R A C T E I ~ O F A T T A C K

In Table I V we have recorded the result obtained in the various kinds of attacks treated. TABLE I V

TYPE

OF ATTACK

PERIOD ATTACKS OF STOPPED FREEDOM ENTIRELY THEN ! RELAPSE

Grand real Grand real with petit real or minor motor attacks Minor motor attacks Petit mal with occasional grand mal Only petit real Total

0 2

POSSIBLY TEMPORARY IMPROVEMENT 1 0

NO BENEFIT

TOTAL

3~

]l

4

t

1

0

4j

4

3

]5

FREE FROM ATTACKS

6 13 30

These groups are too small to be of statistical value. H o w e v e r , it is seen that a considerable proportion of the patients treated had attacks of the petit real type, w h i c h has been f o u n d to be less subject to remissions than other types. 1~ Of thirteen patients w h o s e attacks were p r e d o m i n a n t l y petit real, three became free from attacks. PATIENTS

PP~EE P R O M A T T A C K S

In Table V are s u m m a r i z e d the pertinent facts in regard to the patients w h o responded to ketogenic therapy. In order to give a clearer picture of the nature of the response, it is necessary to discuss these cases in more detail.

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CASE 1.--S. W., female, a private patient, aged thirteen years, at the begim[ing of treatment. A history of chewing Faint, and a sudden onset with a series of left-sided convulsions at the age of two years, and some disturbances in the gait and speech suggested that she may have had a lead eneephalopathy at that time. The convulsions continued, but at the age of nine years the character changed. From then on the attacks consisted of tonic convulsions with loss of consciousness but without localization. For eleven years she had been treated with phenobarbital, bromides~ and belladonna in various combinations without any effect. Menstruation, which had begun at eleven and one-half years, had caused no change in the disease. When she came under observation at thirteen years of age, the neurologie examination was negative, there was only slight mental retardation, and 5here were no evidences of lead poisoning. At this time she was having four or five seizures daily for a number of days followed by free intervals of not over three or four days. Treatment was begun • 1929, with a starvation period of two days followed by a ketogenic diet, beginning with a 2:1 ratio and increasing within a week to a ~:1 ratio. The patient had been receiving phenobarbital I gr. each night, and this was continued. Although the administration of the ketogenic diet caused an immediate diminution in the number of seizures, the attacks continued for four months, ceasing only after the dose of phenobarbital had been increased to 3 gr. daily. A f t e r freedom from attacks for four months, phenobarbital was withdrawn, and a f t e r a furthe~ period of six and one-hMf months, in January, 1930, a sudden shift from ~he 4:1 ketogenic diet to a dehydration regime with an otherwise unrestricted diet caused no relapse. A study of the fluid balance at the time of this transition indicated t h a t the ketogenie diet had already reduced the fluid stores of the body. A rigid restriction of fluid intake to 300 to 400 c.c. was maintained for two years (until January, 1932). There have been no attacks since August, 1929 (a period o f six and one-half years)~ although during the past year two or three episodes have occurred which were probably hysterical rather than epileptic. Her cooperation with treatment was excellent throughout. CASE 2.--N. L. (H.L.H. No. 59~06), male~ aged five one-half years at time of t r e a t m e n t . ' C I d i o p a t h i c " epilepsy. I. Q. was 110. Onset was at four years. Eleven generalized convulsions in the course of the first year. The convulsions then stopped spontaneously, and petit real seizures occurred instead, increasing in frequency up to 10 or 12 daily. A f t e r the petit mal attacks had continued for six months unaffected by 1.5 gr. of phenobarbital dMly, in March, 1929, the ketogenic diet was begin1 gradually without preliminary starvation. In the course of six weeks the ratio was increased from 1:1 to 4:1. The administration of 1.5 gr. of phenobarbital was continued. There was no improvement for two months. ~.s following several vomiting episodes which caused some dehydration, the attacks stopped entirely in 1VIay~ 1929. ]~etween June and October, 1929, the phenobarbital was gradually discontinued. A 3.5:1 diet was maintained until March, 1930, nine months after the attacks had stopped. T h e diet was then decreased by degrees to a 1:1 ratio in October~ 1930. This ratio was maintained until November, 1932. Since then the boy has taken an unrestricted diet. There have been no attacks since May~ 1929, a period of six and three-fourths years. Cooperation with treatment was excellent throughout. CAS~ 3.--T. S. (I-LL.H. No. 78510), male, aged nine and one-half years at time of treatment. ' ~Idiopathie ~' epilepsy. I. Q. was 97. The patient had a convulsion at four years and then no further seizures until he was seven and one-half years, in January, 1930. Petit real seizures then occurred, increasing up to ten daily. Between July, 1932~ and January, 1933~ phenobarbital and prominal and potassium borotartrate were tried without effect. I n February, 1933, following a starvation period of four days, a 4:1 ketogenic diet was begun. From then until September,

WILKINS

:

EPILEPSY

34~5

1933 (a period of seven months), only occasional attacks were noted at rare im tervals, and these were supposedly associated with breaks in the d i e t . . The 4:1 diet was maintained until October, 1934, a ~eriod of eighteen months. Then an attack of acute rheumatic fever caused the diet i:o be discontinued, lie has subsequently taken a normally bManced diet but has had some severe exacerbations of acute rheumatic fever with pericarditis and myocardial insufficiency. No attacks have occurred since September, 1933, a period of two and one-half years. The p a t i e n t ' s cooperation on the diet was fair although there were occasional breaks during the first year of treatment. CASE 4.--C. W. (li.L.tI. No. 85881), male; aged seven years at time of treatment.

"Idiopathic" epilepsy. I. Q. was 99. Onset was in September, 1933, at age of six and one-half years, with typical pe~it real attacks occurring three or four times a day. There were never any convulsions. Daily doses of 30 gr. of potassium bromide and 30 gr. of potassium borotartrate were begu~ in January, 1934, but in March, 1934, attacks became so numerous that the patient was in a constant daze. I n May, 1934, he was having two to seven attacks daily. Lumbar puncture and an air injection were 1)erformed May 9, 1934, and a tonsillectomy ~[ay ]7. I n June, 193~, after a starvation period of four days, a 4:1 ketogenic diet was begun. No drugs were given. No more attacks occurred. The 4:~ diet was maintained until March, 1935, and since then decreased to 3:1. In November, 1935, the diet was discontinued entirely. No attacks have occurred since the diet was first begun in June, 1934, a period of twenty-one months. ~towever, he has taken an unrestricted diet for only the past six months, a period too short to be sure that a relapse may not occur. ~ Cooperation was excellent throughout treatment, and ketosis was well maintained. OASE 5.--N. A., male, a private patient, aged seven and one-ha.If years at time of treatment. ~ I d i o p a t h i e " epilepsy with minor motor manifestations and also generalized convulsions. I. Q. was over 100. Ketogenic diet was begun in October, 1928, a f t e r the attacks ha6[ been occurring for only one month. No drugs were administered before treatment or during the first two years of diet. Attacks were as frequent as six a week. The diet was begun gradually, increasing by degrees to a 4:1 ratio. Definite improvement was not shown for four months. There was then marked improvement, although during the next eighteen months the patient continued to have one to three seizures monthly. These attacks were apparently associated with breaks in the diet. ~ September, 1930, the administration of :[ gr. of phenobarbital at bedtime was begun, and the attacks stopped entirely, in spite of the fact that at this time the patient began to break the diet more and more~ and ketosis was no longer well l~aintained. During the next six months the attempt to restrict him to a 3:1 dlet was unsuccessful. Finally dietary restriction was entirely discontinued in June, 1931. Phenobarbital was withdrawn in September~ 1931. The patient has had no attacks since September, 1930, a period of five and one-half years. The increasing failure in cooperation and the administration of a small dose of phenobarbital at the time the attacks ceased make it difficult to evaluate the effect of therapy. CASE 6.--C. W. (tI.L.li. No. 61086), ~ale, aged four years at time of treatment. P'ossibly slight mental 1.etardation. ~ I d l o p a t h i c " epilepsy with both convulsions and petit mal attacks. Onset was at the age of eighteen months. A t times the seizures were very infrequent, at other times there was status epilepticus. The seizures appeared to be influenced favorably by ehloretone, but not by phenobarbital. A f t e r a duration of two years, in Febrcary, 1929, the patient was put on a ketogenie diet without preliminary starvation. The f a t ratio was increased gradually to 4:1. CMoretone was also gNen. I n spite"of the fact that the diet was rigidly *Patient was still free from attacks in May, 1936.

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followed, the patient continued, until June, 1929, to have ene to ten convulsions daily and on some days hundreds of minor attacks. The attacks t h e n ceased a b r u p t l y without any change in the regime. There was no recurrence in spite of the fact t h a t a f t e r this period the boy began to break his diet constantly and h a d no dlaeetic acid in the urine. The mother a t t e m p t e d with doubtful success to restrict him to 4:1 diet until March, 1930. The f a t ratio was then decreased by degrees and in April, 1931, he resumed a normal diet. A n attempt was made to restrict his itui4s to 14 to 16 ounces dailyt but it is doubtful if there was close cooperation.' I-Ie continued to receive chloretone and bromides until June, "1931. Since t h e n he has had no treatment. He has now been free from attacks since June, 1929, a period of six and three-fourths years. The simultaneous administration of drugs and the failure to m a i n t a i n a rigid ketosis soon a f t e r the attacks ceased make the interpretation of the result difficult. CASE 7.--D. S. (H.L.H. No. 71343), female, aged eight and one-half years at time of treatment. ~ I d i o p a t h i e " epilepsy. Normal mentality. Onset was on Feb. 12, 1931. Generalized convulsions were repeated a n u m b e r of times each day, b u t there were sometimes free intervals of three or f o u r days. Phenobarbital seemed to lessen ~he severity, but not the frequency, of the attacks. A f t e r six weeks the child was given a preliminary starvation period of five days, and on April 1, 1931, she was restricted to a 4:1 ketogenie diet. I n addition to the diet, she was treated with potassium bromide. There was no definite effect on the course of the disease until the bromide was increased to 30 gr. daily i a A u g u s t , 1931. There were t h e n no attacks until September 4, and following this no more until M'arch 15, 1932. I t had been increasingly difficult to keep her on the diet, and the f a t ratio h a d been decreased to 2 : 8 : 1 in October. I n J a n u a r y , 1932, the bromide was reduced to 20 gr. daily. There was a mild convulsion March 15, 1932, and another Aug. 25, 1932. I n the fall of 1932 occasional petit real attacks were noted. I n November, 1932, the bromide was again increased to 30 gr. a day, and the administration of potassium b o r o t a r t r a t e 30 gr. daily was begun. The attacks stopped at t h a t time. A l~orderline ketogenie diet of 2.5:1 ratio was continued until May, 1932. The ratio was t h e n decreased to 1.5 :], and the diet was discontinued in September, ]933. Bromide and borotartrate were continued for some m o n t h s afterward. No attacks have occurred since November, 1932, a period of three and one-half years. The apparent relation of the bromide to the control of the attacks makes it difficult to evaluate the influence of the ketogenie diet. CASE 8 . - - P . M. (H.L.K. No. 65108), female, aged three years and ten months at time of treatment. I . Q . was 104. The child h a d only four series of generalized convulsions over a period of ten weeks on the following dates: Nov. 23, 1929, Dee. 3, ]929, Jan. 5, 1930, and Feb. 1, 1930. The first three were single generalized convulsions without apparent cause. On Feb. 1, J930~ she had severe ~ e r a m p s in the a b d o m e n , " vomited, seemed very jumpy, and occasionally twitched. She seemed sick all day. Throughout the night and the following day convulsions occurred at fouror five-hour intervMs. The patient seemed well for two days, but on F e b r u a r y 5 f r o m 5 to 7 A.~. she had almost continuous convulsions. On March 4 and March~5, 1930, the patient was given 3 ounces of 40 per cent cream a n d two ounces of orange juice three times daily, and on March 6 she was put on a diet of 3.5:1 ratio. Fairly good ketosis resulted. She was also given 1.5 gr. of phenobarbital daily. No more a t t a c k s occurred. I n A u g u s t , 1930, t h e f a t ratio was decreased to 3:1 and the phenobarbital to 0.75 gr. I n November, 1930, the phenobarbital was discontinued. Between J a n u a r y , 1931~ a n d November, 1932, the f a t ratio was g r a d u a l ly reduced, the diet being entirely discontinued in November, 1932. There have been no attacks since February, 1930, a period of six years. The fact t h a t this patient had h a d only four series of convulsions prior to t r e a t m e n t makes it difficult

WILKINS :

EPILEPSY

347

to e v a l u a t e the effect of t h e k e t o g e n i c diet. I t is not u n c o m m o n to e n c o u n t e r children who h a v e a f e w c o n v u l s i o n s w i t h o u t obvious cause, w hi c h c o n t i n u e over a period of some m o n t h s a n d t h e n cease s p o n t a n e o u s l y , never to recur. CO1Vs

The results in these eight eases have been v e r y s a t i s f a c t o r y (see Table V). F o u r p a t i e n t s h a v e been free f r o m a t t a c k s f o r o v e r six years, one f o r over five years, and one f o r three years, one f o r two and one-half years, and one f o r one and one-half years. All the patients h a v e been able to resume an u n r e s t r i c t e d diet w i t h o u t relapse. In all except Case 4 a sufficient period w i t h o u t restriction ( f r o m one and one-half to six y e a r s ) has elapsed now to j u s t i f y the belief t h a t f u r t h e r t r e a t m e n t is not necessary. In only Cases 4 a n d 8 did the a t t a c k s stop i m m e d i a t e l y a f t e r the diet was begun. I n the other six cases, i n t e r v a l s v a r y i n g f r o m three months to t w e n t y - t h r e e months elapsed before the seizures ceased entirely. The F : C + P ratio of 4:1 was m a i n t a i n e d for a period v a r y i n g f r o m one to two y e a r s in six cases, in one case f o r six months, and in one case for three months. In most instances the ketogenie ratio was decreased b y degrees so t h a t a total period of ten to t h i r t y - t w o months elapsed before an unrestricted diet was resumed. I n r e v i e w i n g these eight cases, it is difficult to d e t e r m i n e how much credit f o r the successful result should be a t t r i b u t e d to the ketogenic diet. Seven of the p a t i e n t s had severe f o r m s of epilepsy; the eighth patient, however, h a d h a d only a few episodes s c a t t e r e d over three months and a c c o r d i n g l y was of a type more prone to cease spontaneously. Before the k e t o g e n i c diet was begun, the disease had lasted for one m o n t h in one case, t h r e e months in one case, six to e i g h t months in two. cases, one to three y e a r s in four eases, and eleven y e a r s in one case. P r i o r to the d i e t a r y t r e a t m e n t , sedative d r u g s had been tried without s t r i k i n g effect in all except one instance (Case 5). Simultaneously w i t h the ketogenic diet, sedative d r u g s were a d m i n i s t e r e d in all b u t Cases 3 and 4. I n one case (Case 7) in which bromides were given, the f a v o r a b l e result seemed to be due m o r e p r o b a b l y to the bromide t h a n to the ketosis, as the a t t a c k s ceased only w h e n the dose of bromide was increased to 30 gr. and r e c u r r e d when it was l a t e r reduced to 20 gr. I n two other cases (Cases 1 and 5) the addition of p h e n o b a r b i t a l to the d i e t a r y t h e r a p y seemed closely associated with the cessation of attacks. The cooperation of the patients in a d h e r i n g to the diet and m a i n t a i n i n g a high degree of ketosis was p e r f e c t in only f o u r instances (Cases 1, 2, 4, and 8). I n the other f o u r instances, there were occasional b r e a k s in the diet, and at times the b r e a k s seemed t o be associated with a recurrence of the attacks, a l t h o u g h one could not always be certain of the association. In two cases (Cases

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WILKINS

9

EPILEPSY

349

5 and 6) the final cessation of attacks came at the very time w h e n the patients were becoming more and more lax in the maintenance of the regime. To summarize our impression in looking back over these clinical histories, the diet seems to have been closely associated with the favorable result in four patients with severe forms of epilepsy (Cases 1, 2, 3, and 4). Two of these four patients received sedatives and two no drugs. In two other patients (Cases 5 and 6) the results are confused by the increasing laxity in the diet at the time of improvement and also by the simultaneous use of drugs. In the seventh case the result could be attributed as readily to bromide as to the diet. The eighth patient had had only a few epileptic episodes over a three-month period and was of a type especially prone to spontaneous remissions. PATIENTS WI-tO IIAD TEMPORARY PERIOD O F FI~EEDO~s FOLLOWED BY ttELAPSE

Table u summarizes the important facts concerning the four patients who had fairly long remissions while receiving the ketogenic diet but afterward had relapses. Their histories are abstracted in detail below. CASE 9.--A. M. (H.L.H. 1~o. 75355), female~ aged twelve and one-half years at time of treatment. Idiopathic epilepsy. I. Q. was 100. P e t i t mal with three convulsions. Onset was in December, 1930, at the age of eleven years. Attacks increased iu frequency up to 2 to 5 daily. F r o m December, 1931, to June, 1932~ treatment with phenobarbitM, bromides, and potassium borotartrate caused no improvement. In June, 1932, after u preliminary starvation of four days, a 4:1 ketogeaia diet was begun. 17o drugs were adminietered. Petit real attacks stopped for two weeks~ then one generalized convulsion occurred. Following this occasional petit real attacl{s were observed until A u g u s t 1932. No attacks occurred from August, ]932~ until October, 1933, a period of fourteen months. The diet was then reduced to a 3 : ] ratio, and one or two petit real attacks beg~n to occur each month at about the time of the menstruM period. ]~etween October, 1933, and October, 1935, attacks continued but never became more frequent. I t was then decided to remove g~'adually the dietary restrictions. (According to the last report~ June~ ]936, the patient was receiving practically a normal diet, and no attacks had been observed for the preceding three months.) CASE 10.--M. P. (H.L.H. No. 64040), female, aged nine and one-half years at time of treatment. Idiopathic epilepsy. I. Q. was 100. P e t i t real attacks only. Onset was at eight years of age. Many attacks occurred every day. 'She had failed to respond to phenobarbital and bromides. A f t e r the illness lasted ten months, she was put on a 2:1 diet, increased to 4:1 at the end of three weeks. She received no drugs. The attacks gradually became less frequent and then ceased after three months. The child was then free from attacks for fifteen months. A f t e r the first six months of treatment~ the f a t ratio had been reduced gradually from 4:1 to 2:1. Although the patient had been very cooperative at first, at the end of this fifteen-month period she had begun to break the dict. The petit mul attacks now gradually returned. The child was pht back on a 4:1 diet, but good Cooperation could no longer be obtained~ and ketos~s was not constant. The ad-

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dition of phenobarbital and potassium borotartrate was ineffectual, and gradually the attacks returned to the same level of frequency as before treatment. Finally after thirty-two months the ketogenic diet w a s discontinued entirely. CASE ll.---L. D. (tt.L.tf. No. 60090), female, aged eight and one-half years at time of treatment. IdiopatMe epilepsy. I.'Q. was 78. Convulsions, minor motor attacks and petit real. Onset was a~ six years. ]Per the first fifteen months there were frequent convulsions, followed by a period of ten months of freedom While receiving phenobarbital. The child then began to have four to six minor attacks daily. These continued for five months and were not controlled by phenobarbital. After a preliminary fast of five days, the patient was restricted to 4:1 ketogenic diet. The attacks stopped the second day, and no more occurred during the next twelve months. No drugs were administered during this period. During tile first six months of freedom, the f a t ratio was 4"1 to 3"1; during the next six months it was reduced gradually to 2:1. Near the end of the twelve-month period the patient began breaking her diet. The attacks then began to recur, and some petit real attacks were occurring daily interspersed with occasional convulsions. The child continued a 2:1 diet for another six months but did not cooperate well and finally discontinued the diet. Subsequently phenobarbital, bromides, and borotartrate have had little effect. CASE 12.--S. ]3, female, a private patient, aged eight years at time of treatment. Idiopathic epilepsy. Slight mental retardation. Onset was at eight years with minor motor attacks occurring as often as thirty daily. Phenobarbital was of no apparent benefit. A f t e r two months drug therapy was discontinued and a ketogenic diet was begun and was increased gradually to 4:1 ratio. The attacks decreased markedly in number, averaging one each night, for the first six months of dietary therapy. During the next eight months, the child was still better, having only one to four attacks each month. She then returned to school and began to break her diet. The attacks increased in frequency up to five each night. The child was put in a nursing home under strict supervision for several months, but in spite of this she showed no improvement for nine months. Then, without apparent reason, the attacks ceased entirely for a period of nine months. The attacks then recurred, one to three each night~ and occasional attacks began to appear in the daytime. About this time the girl became more and more uncooperative, constantly stealing food and breaking her diet. Finally a f t e r a trial of forty months, the diet was discontinued and instead 0.75 gr. of phenobarbital was administered each night at bedtime. With the stopping of the ketogenic diet and the substitution of phenobarbital, the child again had a six-month period of freedom followed by another relapse. CO1VII~ENT

Four children treated by the ketogenic diet had periods of freedom from attacks lasting for nine months to fifteen months. Subsequently relapses occurred, and eventually the diet was discontinued. Drugs were not administered to any of these patients at the same time as the diet. In only one (Case 9) did the patient's cooperation in the diet remain perfect. In the other three (Cases ]0, 11, and 12) the relapse was associated with increasing laxity in the diet and failure in the maintenance of ketosis. In two (Cases 11 and 12) it is difficult to know whether the temporary remission was brought about by the diet because the attacks, either before or after ketogenie treatment, were very variable in frequency and at times there were periods of freedom from attacks.

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PATIENTS WHO SHOWED SO]YIE TEMPORARY IIV[PROVEMENT BUT DID NOT BECO~/IE FREE FI~01Vs ATTACKS

There were three instances (Table VII) in which the course of the disease seemed to be influenced favorably for a short period after the institution of the diet. These ,patients did not have remissions. Subsequently the disease became as severe as before treatment. CASE 13.--IQ tt. (It.L.H. No. 50597)~ female, aged thirteen and one-half Fears at time of treatment. Idiopathic epilepsy. I. Q. was 76. Petit real attacks and occasional convulsions. Onset was at seven years. Phenobarbita]~ bromides~ pyramidon, and fluid restriction had proved of no value. Salicy]ates and theobromine had caused some temporary improvement. At time of ketogenic treatment she was having twenty-five to fifty petit real attacks daily. The institution of the diet caused the petit real attacks to stop for three months~ although three convulsions occurred during" this interval. A f t e r this short period~ the disease became, i f anything, more severe than before treatment. Cooperation had been good. CASE 14.--E. 1%. (H.L.tL ~o. 5573~)j female~ aged eight and one-half years at time of treatment. Idiopathic epilepsy. Slight mental retardation. Minor motor attacks. Onset was at the age of five and one-half years. For the first fifteen months a f t e r the beginning of the diet~ the attacks were reduced from fifteen to twenty-five to one to three daily. At the end of this time~ without any apparent cause, the attacks returned to their former frequency and became more violent. Cooperation had been good throughout treatment. CASE 15.--1~. S. (H.L.H. No. 21918)~ male~ aged fifteen and one-half years at time of treatment. Idiopathic epilepsy. Slight mental retardation. Onset was at 6 years. Frequent and severe generalized convulsions with periods of status epilepticus. At time of treatment he was having llve or six severe attacks daffy and was dull and incapacitated most of the time. Phenobarbital and bromides had been ineffectual over a five-month period. There seemed to be gradual improvement with finally freedom from seizures for four weeks when he was treated with a 4.5:1 diet and 3 gr. of phenobarbital. A severe relapse into violent status epileptitus occurred at a time wheat the diet was being broken and phenobarbital decreased. Whether there would have been continued improvement with better cooperation cannot be determined. CASES SIIOWING NO EFFECTS FROM KETOGE,NIC DIET

The fifteen eases which showed no response to ketogenie therapy are summarized in Table VIII. Two of these patients (Cases 16 and 18) had seizures exclusively of the grand real type. Six (Cases 17, 19, 21, 26, 28, and 29) had seizures exhibiting minor motor manifestations, four (Cases 22, 23, 24, and 27) were subject only to typical petit real attacks without any motor manifestations, and three (Cases 20, 25, and 30) had predominantly petit real attacks with only occasional convulsions. These children were all over seven years of age, except one (Case 29). In six instances (Cases 19, 21, 22, 25, 26, and 27) the disease was of less than three years' duration at the time of treatment, and in four (Cases 21, 22, 25, and 26) of these cases less than eighteen months. The remaining eight children had been subject to seizures for five to thirteen years.

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In t h i r t e e n cases, the diet was preceded by a preliminary period of s t a r v a t i o n - - u s u a l l y lasting t h r e e to five days. It is of interest t h a t in seven of these thirteen cases the attacks stopped d u r i n g the starvation period only to r e t u r n within two to f o u r t e e n days after the diet was begun. In three instances starvation exerted no influence, and in the other three cases there was only slight improvement. There were two children (Cases 24 and 27) who eoulci n o t be maintained in ketosis by a ~ :1 diet, even though t h e y cooperated thoroughly. The t r e a t m e n t was carried out just as intensively in these cases as in the other groups which responded better. In all instances the diet was started in the hospital. M a n y of the children remained in the hospital for a n u m b e r of months. Their Cooperation was good both in the hospital and after r e t u r n i n g home. The diet was continued for three to sixteen months, in all except two instances. In combination with the ketogenic diet, various other types of t h e r a p y were tried in most instances. The psychologic side was not neglected and environmental adjustments were made. Phenobarbital, prominal, mebaral, and bromides were usecl in m a n y cases. The p r o d u c t i o n of anidosis b y means of NHdC1 was t r i e d in some instances. The reduction of body fluids b y means of periods of starvation, restriction of fluid intake, low salt diets, and the administration of theobromine sodium salieylate was used as adjuncts to ketosis in m a n y of the cases. A f t e r a careful review of these cases, we must admit t h a t none of these patients showed any benefit which could be a t t r i b u t e d to the ketogenic diet. DISGUSSIOI~7

Of t h i r t y patients treated, eight, or 26.6 per cent, have remained free from. attacks for long periods and have resumed an u n r e s t r i c t e d diet. F o u r patients h a d t e m p o r a r y remissions of considerable duration b u t relapsed to their previous condition. I n three other cases the disease was influenced f a v o r a b l y for a period but the attacks did not stop. I n the seven instances in which the attacks did not stop permanently, the continued maintenance of the diet was not considered w o r t h while. Fifteen patients (or 50 per cent) were not benefited. The group t h a t we have studied is too small to be of much value. It is true t h a t remissions have been encountered by the w r i t e r 1~ and by L e n n o x 12 and T u r n e r 11 in 19 to 24 per cent of epileptics who were either not t r e a t e d o r were t r e a t e d by methods other than the ketogenie diet. The incidence of remissions in our patients under ketogenic thera.py is not much b e t t e r t h a n this. On the whole, the t r e a t m e n t m a y be considered to have had some degree of success because almost all these patients had severe forms of epilepsy with n u m e r o u s and f r e q u e n t attacks and m a n y of them were suffering from the p e t i t real type. The expectancy of remission in these patients was considerably less t h a n the average.

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I n c o m p a r i n g the p a t i e n t s whose a t t a c k s have s t o p p e d w i t h those who were n o t benefited b y the ketogenic diet, it is seen thas seven of the eight p a t i e n t s of the f o r m e r group had been s u b j e c t to the disorder for less t h a n three years, w h e r e a s only six of the fifteen p a t i e n t s n o t benefited h a d h a d a t t a c k s for less t h a n three years. This m a y be of significance in the prognosis f o r success. A r e v i e w of the histories of the pas successfully treated, in an a t t e m p t to d e t e r m i n e w h e t h e r the k e t o g e n i e diet was directly responsible f o r the outcome, often leaves one in doubt. I u certain instances the diet a p p e a r s to h a v e i m m e d i a t e l y and definitely influenced the course of the disease a n d e v e n t u a l l y to have controlled the attacks. H o w it could h a v e p e r m a n e n t l y altered the neurophysio]ogic mechanism so t h a t a t t a c k s did n o t r e c u r a f t e r the diet was discontinued is a mystery. I n other cases the relationship of the d i e t a r y t h e r a p y to the f a v o r a b l e outcome is m o r e obscure, since in some of these the a t t a c k s s t o p p e d at the v e r y time t h a t the p a t i e n t was b r e a k i n g the diet and t h a t ketosis was p o o r l y maintained. The use of sedative d r u g s in addition to the diet has also obscured the i n t e r p r e t a t i o n . F i n a l l y the f a c t t h a t remissions, or even p e r m a n e n t cures, are sometimes encountered in patients w i t h even the most severe f o r m s of epilepsy, who are not r e c e i v i n g a n y t r e a t m e n t , m a k e s one hesitate to e v a l u a t e a n y t h e r a p e u t i c measures in a p a r t i c u l a r case. I n spite of our inability to evaluate scientifically the rgsults obtained with the ketogenic diet, we believe t h a t the f a v o r a b l e results sometimes encountered in cases of a t y p e most unresponsive to other therapeutic m e a s u r e s j u s t i f y its trial w h e n e v e r a t t a c k s r e m a i n Uncontrolled by sedatives. REFERENCES J. Peterman, M. G.: J. A. M. A. 84: 1979, 1925. Peterman, 51. G.: Internat. Clin. 2" 99~ 1935. 2. ]-Ielmholz~ H. F.: J. A. M. A. 88: 2028, 1927. I-Ielmholz~ H. F., and I~eith, IK. M.: J.A.M.A. 95: 707~ 1930. Helmholz, 21. F., and IKeith, II. M.: Proc. Staff Meet., 51ayo Clinl 7: 406, 1932. 3. Talbot, F.B.: Treatment of Epilepsy, New York~ 1930, The Macmillan Co., page 198. ~. Eley, i~. C. : J. PEDIA'I ~. 3; 359, 1933. 5. P'ulford, D. S.: Ann. Int. Med. 6" 795, 1932. 6. Barborka~ C. J.: '~gesults of Treatment by Ketogenie Diet in One Hundred Cases of Epilepsy in Adults, ~' Chapter X X I I of ~'Epilepsy and the Convulsive S t a t e , " Proc. Assoc. for Research in Nervous and Mental DiSease~ 7: 1931, Baltimore, ~u & ~Vilkins Co. 7. Doolittle, G. J.: Psychiat. Quart. 5 : 1 3 4 and 225, 2931. 8. ]~astible, C.: Irish J. Med. Sc. 6: 506, 1931. 9. l~!otkin, J.: Arch. l~eurol. & Psychiat. 31: 787, 1934. 10. Wilkins, L.: Epilepsy in Childhood. II. The Incidence of Remissions, J. PE])IA'r. 10: 329, 1937. 12. Turner, William Aldren: Epilepsy: A Study of the Idiopathic Disease~ London & New York, 1907, The Macmillan Company. 12. Lennox, W. G.: Epilepsy, Nelson's Loose-Leaf Medicine, Chapter XXXI, 1932.