BaisJUn644 12 December 1970 Thromboembolic Occlusions and Streptokinase-Amery et al. MEDICAL JOURNAL

non-fatal bleeding was reported in 4-1 %.The higher complication rate in our study could be due to

other criteria for evaluating the complication rate, tocomplications related at least partly to the frequent use ofarteriography, to the bad general condition of most of ourpatients on admission, or to the use of a rather high initialdose of streptokinase.

Since the introduction of Fogarty's catheter (Fogarty et al.,1963) the possibilities of vascular surgery have been extended,and this method represents an important alternative for thetreatment of patients having the condition under study. Anattempt has therefore been made to review published workwith the purpose of comparing streptokinase treatment, mod-ern medical therapy, and vascular surgery in patients withrecent thromboembolic occlusions of the limb arteries(Amery, 1969).

Streptokinase was kindly supplied by Kabi AB, Stockholm.

REFERENCESAmery, A. (1969). Activation of the Human Plasma Fibrinolytic System

by Streptokinase, Thesis, Acco-Louvain, Belgium.Amery, A., Maes, H., Vermylen, J., and Verstraete, M. (1963). Thromnbosis

et Diathesis Haemorrhagica, 9, 175.Amery, A., Roeber, G., Vermeulen, H. J., and Verstraete, M. (1969).

Acta Medica Scandinavica, Suppl. No. 505.Cotton, L. T., Flute, P. T., and Tsapogas, M. J. C. (1962). Lancet, 2, 1081.Fletcher, A. P., Alkjaersig, N., and Sherry, S. (1959). journal of Clinical

Investigation, 38, 1096.

Fogarty, T. J., Cranley, J. J., Krause, R. J., Strasser, E. S., and Hafner,C. D. (1963). Surgery, Gynecology and Obstetrics, 116, 241.

Gross, R., Hartd, W., Kloss, G., and Rahn, B. (1960). Deutsche medizinischeWochenschrift, 85, 2129.

Haan, D., and Tilsner, U. (1965). Munchener nzedizinische Wochenschrift,107, 638.

Hess, H. (1967). Arterielle Embolien und Thrombosen. Stuttgart, Schattauer.Hiemeyer, V., Rasche, H., and Diehl, K. (1969). Klinische Wochenschrift,

47, 371.Kahn, P., Stacher, A., and Deutsch, E. (1961). Wiener klinische Wochen-

schrift, 73, 677.McNicol, G. P., Reid, W., Bain, W. H., and Douglas, A. S. (1963). British

MedicalJournal, 1, 1508.Marchal, G., et al. (1964). Archives des Maladies du Coeur et des Vaisseaux,

57, 753.Nilsson, I. M., and Olow, B. (1962). Acta Chirurgica Scandinavica, 123, 247.Poliwoda, H., Alexander, K., Buhl, V., Holstein, D., and Wagner, H. H.

(1969). New England journal of Medicine, 280, 689.Remy, D., and Gebauer, D. (1966) Medizinische Klinik, 61, 220.Salmon, J., Lambert, P. H., and Delvigne, J. (1963). Acta Cardiologica,

18, 254.Schmutzler, R. (1963). Helvetica Medica Acta, 30, 608.Schmutzler, R. (1968). Angiologica, 5, 119.Schoop, W., Martin, M., and Zeitler, E. (1968). Deutsche inedizinische

Wochenschrift, 93, 2321.Verstraete, M., Amery, A., and Vermylen, J. (1963). British MedicalJournal,

1, 1499.Verstraete, M., Vermylen, J., Amery, A., and Vermylen, C. (1966). British

MedicalJournal, 1, 454.Verstraete, M., Vermylen, J., De Vreker, R., Amery, A., and Vermylen, C.

(1964). Scandinavican journal of Clinical and Laboratory Investigation,16, Suppl. No. 78, p. 15.

Winckelmann, G., Hiemeyer, V., Weissleder, H., and Schoop, W. (1963).Deutsche medizinische Wochenschrift, 88, 2331.

Folic Acid in Folate-deficient Patients with EpilepsyRICHARD H. E. GRANT,* M.B.. B.S., D.C.H.; OLGA P. R. STORES,t M.B., CH.B.

British Medical journal, 1970, 4, 644-648

Summary: A double-blind trial using folic acid 15 mg.daily and identical placebo was carried out in 51 epi-

leptic patients having a serum folate level below 3.6 ng./ml. Treatment was for a minimum of six months and in41 patients was for more than one year. There were nosignificant changes in the frequency of seizures, behaviour,and personality, or in a number of cognitive functions.

Introduction

Treatment with certain anticonvulsant drugs, especiallyphenytoin, produces folate deficiency in a high proportion ofpatients, estimates varying from about 30 to 80%,/ (Klipstein,1964; Reynolds et al., 1966a, 1966b). Megaloblastic anaemia isthe most obvious manifestation of this deficiency but it israre, though a megaloblastic bone marrow may be found innearly 40%S of treated epileptic patients (Reynolds et al.,1966b) and macrocytosis in the peripheral blood in between11 and 53%0,x, (Reynolds, 1968). Phenytoin inhibits folateabsorption from folate polyglutamates, a major component offood folate, and possibly folate deficiency is at least partlydue to inhibition of intestinal absorption of folates in the diet(Hoffbrand and Necheles, 1968; Rosenberg et al., 1968).The clinical consequences of drug-induced folate deficiency

have been described by Reynolds (1968, 1970). These includeapathy and retardation, loss of concentration and self-con-fidence, schizophrenic-like psychoses, dementia, and possiblycerebellar or spinal cord damage. If the folate deficiency iscorrected by treatment with folic acid the mental state mayimprove, -but at the -same time the frequency or severity of

*Director, David Lewis Colony, Alderley Edge, Cheshire.t Registrar, David Lewis Colony, Alderley Edge, Cheshire.

fits has been reported to increase in a significant proportionof patients. Reynolds (1967) studied 26 chronic epilepticpatients with folic acid deficiency. Folic acid improved themental state, but the frequency or severity of fits wasincreased, necessitating cessation of treatment in ninepatients. Other reports include the case of a man of 43 withmegaloblastic anaemia due to phenobarbitone in whomadministration of folic aicd rapidly precipitated status epilep-ticus on two occasions (Chanarin et al., 1960) and a casereported by Wells (1968) in which the patient died in uncon-trolled status epilepticus. Dennis and Taylor (1969) describedtheir experience with 5-mg. tablets of folic acid in childrenwith epilepsy as "alarming" but gave no clinical details.Lanzkowsky et al. (1969) studied an 18-year-old girl with anisolated defect of folic acid absorption associated with mentalretardation and cerebral calcification who developed epilepsy.They reported that fits decreased in frequency during folatedepletion and increased on folic acid administration, but thedegree of change was not stated.Our clinical impression and that of our colleague, Dr. Neil

Gordon (1968), was that folic acid had little observable effecton either the incidence of seizures or behavioural aspects. Thisimpression was gained both from patients and from childrenattending the outpatient department. It was therefore decidedto carry out a controlled clinical trial to assess a number ofvalues in our patients.

Methods

Preliminary screening of serum folic acid levels in in-patients was carried out, and 51 patients whose serum folatelevel was less than 3.6 ng./ml. were selected for study, thislevel being the lower limit for the laboratory concerned. Of

on 24 March 2020 by guest. P

rotected by copyright.http://w

ww

.bmj.com

/B

r Med J: first published as 10.1136/bm

j.4.5736.644 on 12 Decem

ber 1970. Dow

nloaded from

12 December 1970 Folic Acid in Epilepsy-Grant and Stores

these 26 were men and 25 women, ranging in age from

65 (mean 33.4) years. The patients were allocated at

to treatment with folic acid 5 mg. three times a day

identical placebo tablet 5 mg. three times a day;

domization took into account the frequency of seizuresthat

their distribution was about equal in the two groups,

the type of epilepsy. Treatment was double-blind to

cerned within the trial. All the patients were observed

weeks before treatment and for at least 26 weeks after

ing treatment. In 41 of the patients the period of observation

was over one year. Anticonvulsant therapy remained

throughout the trial unless a change was essential on clinical

grounds. Patients with serum phenytoin levels in excess

pg. /ml. were either excluded from the trial or stabilized

beforehand (Stensrud and Palmer, 1964).

Observations were made on the following criteria:

(1) Seizures.-These were recorded in the following categories:

A, grand mal with definite tonic/clonic convulsions; B,

grand mal in which the tonic or clonic phase may be

C, petit mal; D, akinetic ("drop") attacks; E, focal attacks,

motor or sensory; F, psychomotor attacks; and G,

not conveniently falling into any of the categories A-F

are described individually. This classification is

patients at the colony and daily records are maintained

All staff have been instructed in the classification. The

ficulty has been found in classifying psychomotor attacks,

type F inevitably contains a rather heterogeneous

seizures. Nevertheless, we believe this classification

relatively comprehensive list of seizures with reasonable

for staff, most of whom are not trained nurses.

(2) Cognitive Functions and Memory Tests.-The following

tests were done on each patient before and after

ment: (1) Wechsler adult intelligence scale (W.A.I.S.)

standard progressive matrices: the test was carried

dard way, but in addition to the total score a record

score attained 15 minutes after starting the test;

effective in-

increasing speed of thought and

score at 15 minutes might increase after treatment

score might not. (3) Sorting random letters:

presented with a series of 156 randomized

rows of 26 and instructed to cross out all the "I"s;

test was timed with a stop-watch and three trials

with a separate randomization; the mean

recorded; this test was used as an indication of

and action. (4) Rey-Davis peg board test (Williams,

Delayed recall of pictures (Williams, 1968).

the subject is asked to count aloud from one

he can: the 'core is the number reached in Eeconds,stop-watch.

(3) Personality and Behaviour.-(1) Eysenck-Withers

inventory: though normally the subject inventory

himself, because many of our patients have

we asked the appropriate questions and marked

selves. (2) Behaviour rating scale (Pritchard,

the considerable difficulty in standardizing

behaviour, but felt it was desirable to use

be used by nursing staff. Though Pritchard

measuring changes in behaviour in children,

the target symptoms were important in

those which might be expected to improve

ment. The scale was modified slightly, the

omitted. Nine bipolar items were used, the with

extremes of -3 and + 3. Each of the

scored by the senior nursing staff on

patient lived and to whom he was best

made before treatment and monthly throughout

Results

Details of the 51 patients are given in Table

serum folate 1*4 ng./ml.) received folic

placebo tablets (mean serum folate 1.11 ng./ml.). Of the

patients in the folic acid-treated group, electroencephalograms

showed that 12 had centrencephalic epilepsy,2 non-specific changes, and the remaining

recent E.E.G.s. In the placebo-treated group,

cephalic and 7 focal epilepsy, 3 non-specific changes,

had not had recent E.E.G.s.Three patients were withdrawn from the trial. One (Case 3),

a 45-year-old woman receiving folic acid, was withdrawn

because she was transferred to other accommodation. Another

(Case 16), a 19-year-old man, went home for a four-week

summer holiday, during which time he had frequent attacks,

probably akinetic (type D). His mother stopped the acid

tablets. No change in anticonvulsant treatment was made.

his return to the colony the attacks immediately subsided

the previous frequency. On further questioning it appeared

that he often had more frequent attacks at home, possibly

related to complete lack of occupation, but it was decided

to begin folic acid again. The third withdrawal (Case 32)

a 16-year-old youth taking placebo tablets who discharged

himself against advice before completion of the trial.

ttacks.-The actual number of attacks recorded in

weeks before and after treatment in each patient are

in Table I. None of the patients had focal (type E) attacks,

and it was impractical to analyse the petit mal (type C)

attacks numerically. No patient was observed to

clinically significant increase in the frequency of petit

attacks. Table II gives the number of patients showing

incrcase/decrease/no change in the frequency of grand mal

(A), modified grand mal (B), akinetic (D), and psychomotor

(F) attacks, and also for all grandmal attacks (A + B)

ing the first 26 weeks of treatment, the actual figures being

represented graphically in Figs. 1 and 2. In the folic-acid-

treated group 10 patients showed an increase, 11 a decrease,

to 124/47100

-0

u

a

u

.-

C)

0

-bu

a

4-n

0

-0

(2pc

75.

50-

25-

.

0

(points)

25 50 75

Grand mal attacks after folic acid

100 125

FIG. I.-Incidence of grand mal attacks before

26 weeks' treatment with folic acid.

100.

75

5

Ca

E

25

(3

.0

178/145,Jo

0

0

5b255 0

I

mal attacks after placebo

75 lis

FIG. 2.-Incidence of grand mal attacks before and

26 weeks' treatment with placebo.

BRITISHMEDICAL JOURNAL 645

I

on 24 March 2020 by guest. P

rotected by copyright.http://w

ww

.bmj.com

/B

r Med J: first published as 10.1136/bm

j.4.5736.644 on 12 Decem

ber 1970. Dow

nloaded from

646 12 December 1970 Folic Acid in Epilepsy-Grant and Stores

TABLE I.-Details of Patients with Seizure Frequency Before and After Treatment

A = Grand mal. B = Partial grand mal. D = Akinetic. F = Psychomotor.

and 2 no change in frequency of major fits. In the placebogroup the corresponding figures were 5, 16, and 4. Thedifference is not statistically significant at 5%. The results forthe period 27-52 weeks' treatment compared with the controlperiod in the 41 patients who have been observed for over

one year are also given in Table II. The mean changes ingrand mal attacks are shown in Table III, together with thedifferences in these means and the value for Student's t test.There is no significant difference between folic-acid-treatedand placebo-treated groups.

Cognitive Functions.-The mean changes in all cognitivefunctions are shown in Table III. There were no statisticallysignificant differences in these values. In the random letterstest the placebo-treated group showed a mean reduction of4.28 seconds in the time taken to cross out the letters, and in

the folic-acid-treated group there was a mean increase of 3.05seconds. This difference approaches but does not reach statis-tical significance (t=1-96, O-1>P>0-05). Though we did notexpect any major changes in "general intelligence," we feltthat some of the timed items of the W.A.I.S. and the imme-diate recall test (digit span) might show an improvement.Comparison of the number of patients showing improvementor deterioration in these items is shown in Table IV, togetherwith the difference in the mean changes, the latter being veryclose to zero. None of these changes is significant.

Personality and Behaviour.-The mean changes in the threescales of the Eysenck-Withers personality inventory areshown in Table III. Patients treated with folic acid showed a

mean increase of 1.32 on the neuroticism scale, whereas theplacebo-treated patients decreased by a mean of 1.24. This

BynlMa;DICAL JOURNAL

on 24 March 2020 by guest. P

rotected by copyright.http://w

ww

.bmj.com

/B

r Med J: first published as 10.1136/bm

j.4.5736.644 on 12 Decem

ber 1970. Dow

nloaded from

12 December 1970 Folic Acid in Epilepsy-Grant and Stores

TABLE II.-Number of Patients Showing Increase/Decrease/No Change in Fit Frequency after 26 Weeks' Treatment andfor 27-52 Weeks' Treatmentfor Major Seizures

Folic Acid Placebo

All GrandMal All GrandMalType of Attack ! (A+B) (A+B)

A RB D F A B D F

0-26 27-52 0-26 27-52Weeks Weeks Weeks Weeki

Increasei 11 o10 2 4 10 10 4 8 7 6 5 8Decrease .. 9 7 4 5 11 10 15 8 3 9 16 8No change ... 3 6 17 14 2 0 6 9 15 10 4 5

TABLE III.-Mean Changes of All Values

Mean change on:Folic acid .. .. -2-65S.E. .. .. 4-26Placebo .. .. -2-92S.E .. .. 2-48

Difference in mean change:F.A.-P. 0 27

.. .. .. 0-05Significance .. N.S.

Grand Mal Attacks

0eeks 1 t27-520-26s Weeks

Wes(41 Patients)

3.755-46

-7-05-31

3-250 43N.S.

I W.A.I.S.

V. P.

IQ IQ

1-960-640-440-78

1-521-5N.S.

1-091-612-080-78

-0-99-0-55N.S.

Raven's Matrices

F.S. Full OS

.0SMQm'uteIQ Score Score

1HH

1-641-070-920-76

0-720-54N.S.

-0-091-270-240-90

-0-33-0-21N.S.

2-321-051-180-92

1-140-72N.S.

305 2-323-09 0-73

-4-28 4-042-12 1-15

7-33 -1-721-96 -1-26

011>P>0 05|I N.S.

-0-640-54

-1-000-48

0-360-50N.S.

J0-951-930-042-71

I099-0-30N.S.

Eysenck-WithersPersonality Inventory

N E L

1-320-55

-1-240-73

i2-562-8

P<0 05

-0-270-720-520-94

-0-79-0-67N.S.

0-640-420-760-44

-0-12-0-20N.S.

S.E. = Standard error of mean change.N.S. = Not significant.

V.IQ=Verbal I.Q.P.IQ= Performance I.Q.F.S.IQ= Full scale I.Q.

N = Score on neuroticism scale.E Score on extraversion scale.L Lie scale.

TABLE V.-Number of Patients Showing ImprovementlDeterioration/NoChange in the 9 Items of the Behaviour Rating Scale at the End of 26 Weeks'

Treatment

ImprovedItem

F.A.

1. Speech2. Motor activity . ..3. Relationship to environment4. Mood lability .

5. Predominant mood .6. Social relationship to patients7. Social relationship to staff8. Aggression.9. Anger

49

7177

669

11

Total .. .. 60

P.

675

12563810

62

NoDeteriorated

IF.A.40

2464463

33

P. F.A.

3 151 14

1 203 124 104 131 134 83 9

24 114

TABLE IV.-Number of Patients Showing Improvement/Detcrioration/NoChange in Timed Items and Immediate Recall in the W.A.I.S.

Digit span .Digit Symbol ..Block Design -.

Picture arrangementObiect assembly.

Improved

F.A. P.

1085814

118

111012

IDeterioratedF.A. P.

6 59 78 6 L

NoChange

F.A.

7

61083

P.

99896

F.A. = Folic-acid-treated patients. P. = Placebo-treated patients.

difference is significant (t=2.8, P<0.05). The changes in theextraversion and lie scales are not significant. The evaluationof changes in the behaviour rating scale presented some dif-ficulty as only one control observation was available for eachpatient. This was compared with the observation made at theend of 26 weeks after starting the treatment. The number ofpatients showing an improvement/deterioration/no change ineach of the nine items rated is shown in Table V. There areno significant differences in these changes.

Discussion

The primary object of the present investigation was tofollow up a clinical impression that the administration of folic

acid to folate-deficient epileptic patients made no significantdifference to the frequency of seizures in the majority.Reynolds (1967), in an uncontrolled study, reported results in26 chronic epileptic patients. Five were living sheltered livesand 21 were in normal occupations. Folic acid was givenorally 5 mg. three times a day for from one to three years. In13 (50%) of these patients the frequency and/or severity ofseizures was increased, necessitating cessation of treatment innine. In six of these nine it was after five months' treatment(range 10 days to 22 months). In one patient status epilep-ticus was precipitated after 10 months. In only one patientwas there an improvement in the frequency of seizures, theremaining 12 patients showing no change. In addition tothese changes in seizure frequency, 22 patients showed a defi-nite improvement in mental state (11 of them "very notable")in the form of increased personal drive and initiative, speedof cerebration in thought, speech, and action, alertness, self-confidence, and sociability. Most showed improvement withinthree months of starting treatment.In our folic acid-treated patients, 10 out of 23 (43.5%)

showed an increase in frequency of grand mal attacks duringthe first 26 weeks of treatment, but 11 (47.8 %) showed a

decrease. Two patients (8-7%) showed no change. Thoughthe number showing an increase in fits was less in theplacebo-treated group (5/25), the difference is not statisticallysignificant, and when the degree of change is taken intoaccount the differences between the folic acid and placebogroups are even smaller (t=0-05, P>1.0). Reynolds (1967,1968) pointed out that in six of his nine patients in whomfolic acid had to be stopped this action was taken five monthsor more after starting treatment. It might therefore be saidthat our period of treatment was too short, but in the 41patients whom we have now observed for at least one yearthere is still no difference in the fit frequency in the two

groups. The general tendency throughout the trial was for fitfrequency to decrease, especially during the period 27-52weeks after starting treatment, the mean change in grand malattacks in the folic acid group being -3-75 and in the placebogroup -7-0. We did not consider it necessary to alteranticonvulsant treatment in any of the patients.

Since our trial began Ralston et al. (1970) reported a dou-

BamSeMEDICAL JOURNAL 647

I.

_

1 -- 1-

I-

-LI

on 24 March 2020 by guest. P

rotected by copyright.http://w

ww

.bmj.com

/B

r Med J: first published as 10.1136/bm

j.4.5736.644 on 12 Decem

ber 1970. Dow

nloaded from

648 12 December 1970 Folic Acid in Epilepsy-Grant and Stores MDBICALJORNALble-blind trial in 27 patients with epilepsy whose serum folatelevels were below 3 ng./ml. The duration of the trial wasonly three months, and is thus not really comparable toReynolds's original study; nevertheless, no significant changesin fit frequency were seen.There was, as expected, no change in the "general" level of

intelligence. Neither was there any effect on the timed itemsof the Wechsler adult intelligence scale or the 15-minutescore on Raven's standard progressive matrices, most of thechanges being close to zero. This contrasts with the findingsof Reynolds (1967, 1968) that 22 out of 26 patients showedimprovement in "drive," speed of thought and action, alert-ness, and concentration. In the random letters test, in whichspeed of thought and action was important, the placebo-treated group were on average faster than the folic-acid-treated group, though the difference is not quite significant.We can find no evidence that folic acid has altered the

behaviour or personality of our patients as a group, andthough there is a difference (P<0.05) in the mean changes anthe neuroticism scale of the Eysenck-Withers personality in-ventory it is the placebo group which improved slightly. Wecan suggest no reason for this difference. None of thepatients in either group complained of the gastrointestinaland sleep disturbances, malaise, vivid dreaming, and excitabil-ity reported by Hunter et al. (1970) in the 14 normal volun-teers given folic acid 15 mg. daily. Most patients showed nochange in the behaviour rating scale; changes which occurredwere equally distributed between the two groups (Table V).There was a tendency for the ratings for aggression (item 8)and anger (item 9) to show a higher proportion of improve-ments at the end of 26 weeks' treatment, but there was nodifference between the two groups.We originally intended to include the patients' subjective

assessment of their progress, but this was abandoned. Almostwithout exception patients in both groups claimed "consider-able" improvement in their general condition and mostclaimed a reduction in fit frequency despite documentedevidence to the contrary. Two patients, however, wereparticularly insistent that they had derived great benefit.

Case 7.-A 21-year-old woman had had centrencephalic epilepsysince the age of 8 and was taking folic acid tablets. During thecontrol period she had 39 grand mal, 3 modified grand mal, and140 akinetic attacks. During the first 26 weeks on folic acid theseizures were reduced to two modified grand mal and 58 akineticattacks. There was a further reduction to 37 akinetic attacks dur-ing the period 27-52 weeks, but she was observed to have 52psychomotor attacks; she had had these before entering the trial.Anticonvulsant treatment was not altered. There was no signifi-cant change in full scale I.Q. (83, 88) nor in the subtest scores,but there was a significant increase from 18 to 31 in the 15-minute score on Raven's matrices, the total score being unaffected(28, 32). The patient insisted that she was "able to think muchmore quickly, do things quicker; I feel more lively and with it."The only other value to change significantly was an increase

in the neuroticism score on the Eysenck-Withers personalityinventory from 9 to 19.

Case 30.-A 26-year-old woman had had epilepsy due to arather indefinite right temporal focus since the age of 3. She wason placebo and showed a reduction of grand mal attacks from 64to 13 and psychomotor attacks from 42 to 3 during the first 26weeks. There were no significant changes in any of the othervalues, but she insisted that she was greatly improved, usingalmost identical phrases as Case 7.

Results confirm our impression that the administration offolic acid has little or no effect on fit frequency, speed ofthought and action, personality, or behaviour, except perhapsin isolated cases. Though changes occurred they did so inboth directions and to an equal extent in both groups. Thisis in line with our experience generally that epilepsy is a con-dition profoundly affected by psychological factors. Theseconclusions can, of course, be applied only to our population-that is, people whose epilepsy, and related problems, are ofsufficient severity to require admission to an institution-butwe must emphasize that less than half (47%) of the patientsin the trial were regarded as permanent residents. Twenty-four per cent. were patients all likely to return to the commu-nity after 18 months' treatment, the remainder requiringsomewhat longer.

We thank our nursing staff, who co-operated with all the neces-sary record-keeping; our secretaries, Mrs. Valerie Bradley andMrs. Betty Davey, who showed great patience; and Mr. ColinClark, of I.C.I. Pharmaceuticals Division, for statistical advice. Dr.G. Stores and Mrs. Shelagh Whittaker gave invaluable help andadvice on psychological tests. Dr. C. A. K. Bird kindly carried outall biochemical and haematological investigations. Dr. AlanGalbraith, of Geigy Pharmaceuticals Ltd., kindly supplied thefolic acid and placebo tablets.The work was supported by a grant from the British Epilepsy

Association.

REFERENCESChanarin, I., Laidlaw, J., Loughridge, L. W., and Mollin, D. L. (1960).

British Medical Journal, 1, 1099.Dennis, J., and Taylor, D. C. (1969). British Medical Journal, 4, 807.Gordon, N. (1968). Developmental Medicine and Child Neurology, 10, 497.Hoffbrand, A. V., and Necheles, T. F. (1968). Lancet, 2, 528.Hunter, R., Barnes, J., Oakeley, H. F., and Matthews, D. M. (1970). Lancet,

1, 61.Klipstein, F. A. (1964). Blood, 23, 68.Lanzkowsky, P., Erlandson, M. E., and Bezan, A. I. (1969). Blood, 34, 452.Pritchard, M. (1963). British Journal of Psychiatry, 109, 572.Ralston, A. J., Snaith, R. P., and Hinley, J. B. (1970). Lancet, 1, 867.Reynolds, E. H. (1967). Lancet, 1, 1086.Reynolds, E. H. (1968). Brain, 91, 197.Reynolds, E. H. (1970). In Modern Trends in Neurology, ed. D. Williams,

Vol. 5, p. 271. London, Butterworths.Reynolds, E. H., Chanarin, I., Milner, G., and Matthews, D. M. (1966a).

Epilepsia, 7, 261.Reynolds, E. H., Milner, G., Matthews, D. M., and Chanarin, I. (1966b).

Quarterly Journal of Medicine, 35, 521.Rosenberg, I. H., Godwin, H. A., Streiff, R. R., and Castle, W. B. (1968).

Lancet, 2, 530.Stensrud, P. A., and Palmer, H. (1964). Epilepsia, 5, 364.Wells, D. G. (1968). Lancet, 1, 146.Williams, M. (1968). BritishJournal of Social and Clinical Psychology, 7, 19.

on 24 March 2020 by guest. P

rotected by copyright.http://w

ww

.bmj.com

/B

r Med J: first published as 10.1136/bm

j.4.5736.644 on 12 Decem

ber 1970. Dow

nloaded from