Vitamin B6 and Valproic Acid in Treatment of Infantile Spasms

Masatoshi Ito, MD*, Takehiko Okuno, MDt, Haruo Hattori, MDt, Tatsuya Fujii, MDt, and Haruki Mikawa, MDt

Twenty patients with infantile spasms were treated with high doses of vitamin B6, valproic acid, or both. Three of 13 patients (23%) treated initially with high doses of vitamin B6 demonstrated a definite reduction in seizures; 2 patients had no improvement on electro- encephalography. Vitamin B6 therapy alone was con- tinued in a single patient (8%) who remained seizure- free during the 15-month follow-up period. Initial treatment with vitamin B6 and valproic acid improved the electroencephalogram significantly more (P < 0.05) than initial vitamin B6 treatment alone. The group which had valproic acid added to vitamin B6 therapy had significantly fewer seizures (P < 0.05) and better electroencephalograms (P < 0.01) than did the group treated initially with vitamin B6 alone. There were no significant differences among the group treated initial- ly with vitamin B6, the group treated initially with valproic acid, and the group in which valproic acid was substituted for vitamin B6. ACTH was more effective in abolishing seizures than was valproic acid or vitamin B6 and valproic acid. ACTH had an excellent effect on seizures in 86% of patients who did not respond well to vitamin B6, valproic acid, or both; however, many of these patients had later recurrence of infantile spasms. The combination of vitamin B6 and valproic acid is effective and safe in the treatment of infantile spasms.

Ito M, Okuno T, Hattori H, Fujii T, M i k a w a H. Vi tamin

B6 and valproic acid in t reatment o f infanti le spasms.

Pediatr Neuro l 1991 ;7:91-6.

Introduction

A C T H has been used as the drug of choice for the

t reatment o f infanti le spasms since Sorel and Dusaucy-

Bauloye descr ibed its e f fec t iveness in 1958 [ 1 ]; however ,

serious side effects somet imes occur during A C T H therapy

[2]. Recen t studies have demonst ra ted that A C T H induces

apparent cerebral atrophy on computed tomography (CT)

[3-5]. In most patients the changes are reversible but in

some patients subdural effusion occurs or recovery f rom

"cerebral a t rophy" is de layed [4,5]. It is suspected that

A C T H has an adverse effect on the deve lop ing brain.

Therefore , a safer and more effect ive t reatment is required.

In the cerebrospinal f luid (CSF) of patients with infantile

spasms, G A B A levels were lower than in controls [6,7].

G A B A e r g i c neurotransmiss ion may be impaired in infan-

tile spasms and drugs that enhance brain G A B A e r g i c neu-

ronal funct ion may have some effect on infantile spasms.

Vitamin B6 is a coenzyme of glutamate decarboxylase [8]

and may enhance G A B A e r g i c neuronal function. Valproic

acid (VPA) increases the brain G A B A content through

increased synthesis of G A B A from glutamate [9] or de-

creased breakdown of G A B A [10,11]. In our study, we

treated children with infanti le spasms with high doses of

v i tamin B6, VPA, or both.

Methods

The patients included 20 children with infantile spasms (9 males, 11 females) admitted to our hospital between 1982 and 1988 for control of seizures. The clinical profiles are listed in Table 1. The onset of spasms occurred at 1-14 months of age (mean: 7.2 months). The patients had more than 2 seizures per day with or without series formation. The etiologic factors were various; the presumed causes included prenatal in 10, perinatal in 5, unknown in 3 (patients with developmental delay before onset and no significant history), and idiopathic in 2 (normal development before onset and no significant history). The electroen- cephalograms (EEGs) of 19 patients revealed hypsarrhythmia or modi- fied hypsarrhythmia, as defined by the criteria of Gibbs and Gibbs [12] and Harachovy et al. [13], respectively. One patient had multifocal spikes without hypsarrhythmia.

Examinations before the initiation of treatment included general physical and neurologic examinations, complete blood count, platelet count, urinalysis, blood chemistries (i.e., SGOT, SGPT, LDH, alkaline phosphatase, total protein, albumin, total bilirubin, total cholesterol, uric acid, BUN, creatinine, glucose, serum sodium, potassium, chlor- ide, calcium, phosphate, magnesium), blood pressure, amino acid anal- ysis (serum and urine), chromosome analysis, EEG, cranial CT, and developmental testing. During hospitalization, routine laboratory exam- inations, plasma concentration of antiepileptic drugs, and EEG were performed weekly. The frequency and characteristics of the seizures were described by the parents.

Vitamin B6 (pyridoxine chloride) therapy was initiated at 10-20 mg/kg/day and increased 10 mg/kg every 2-3 days. The maintenance dose was 20-50 mg/kg/day. VPA was administered initially in a dose of

From the *Department of Pediatrics; Shimane Medical University; Izumo, Japan; tDepartment of Pediatrics; Faculty of Medicine; Kyoto University; Kyoto, Japan.

Communications should be addressed to: Dr. Ito; Department of Pediatrics; Shimane Medical University; 89-1 Yenya-cho; Izumo, Shimane 693, Japan. Received July 20, 1990; accepted October 22, 1990.

Ito et al: Infantile Spasms 91

Table 1. Clinical data of patients

Patient No./ Seizure Plasma Level Sex/Age at Frequency Etiologic Electroen- Treatment During of VPA: Before: Seizures at

Onset (mos) Per Day Factors cephaiography Admission (mg/kg)" 2 hr* (~tg/ml) I)ischarge

I/M/IO I-2/S ACC, AS, Hypsarrythmia B, 311 N,, and PDA

2/F/5 3-5/S Tuberous Hypsarrythmia B+, 41) -~ B+~ + VPA 51) 40.2:69.8 No sclerosis

3/F/12 5 15 Premature. Modified hyp- B~+ 51) -> Be, + VPA 50 S().t): 96.2 No blindness sarrythmia

4/M/10 2-4/S Premature t typsarrythmia B(~ 20 ~ Be, + VPA 311 40.5:65.8 No

5/M/5 I-2/S Down syn. Hypsarrythmia B+, 50 ~ B(, + VPA 31) 50+0:60.0 No

6/t:/7 5-6 Holoprosen- Ilypsarrytllnlia B+, 511 -~ B~, + VPA 51) 59.2: NP No cephaly

7/F/6 2-5 Unknown Hypsarrythmia B+, 40 -+ B~, a- VPA 50 73. l: 90.2 No

8/M/4 2-3/S Unknown Modified hyp- B~+ 5(} + B+, + VPA 63 50.7; 108.3 N~+ sarrylhmia -~ ACTIt

9/M/10 1-2/S Congenital Hypsarrythmia B(, 51) ~ B~, + VPA 5(1 34.7; 65.(~ Nu anomalies * ACTH

10/F/10 3-4/S Porencephal~ Modified hyp- BI, 40 ~ B~, + VPA 50

sarrythmia -~ ACTH

I I/M/6 7-8 Cryptogenic Modified hyp- B6 511 +÷ VPA 40 sarrythmia

~ 1.9: NP No

111).0:129.0 Nt~

12/F/2 5-6/S Microcephaly, Modified hyp- B~, 50 ~ VPA 51) - + NP intracranial sarrythmia ACTH hemorrhage

13/P/I 10-20/S Aicardi syn. t typsarrythmia B+, 50 ~ VPA 51) ~ NP

ACTtf Yes

14/M/9 3-15 Cryplogemc Hypsarrythmia VPA 43 62.0:95.11 No

15/M/7 2 3 Cesarean Hypsarrythmia VPA 50 75.5:911.11 No section. eclampsia

16/F/14 5- I O/S Unknown Modified hyp- VPA 50 --÷ ACTH 41.0 :92.0 san+ythmia

17/F/10 5-6/S Holoprosen- Hypsarrythmia B++ 311 + VPA 42 42.4:61.4 Nu cephaly -~ VPA + CLZ O. 1

18/F/6 5-6/S Premature. Hypsarrythmia B6 411 + VPA 50 70.2:80.8 No RDS

19/F/7 I-2/S Tuberous Hypsarrythmia B6 50 + VPA 32 NP No sclerosis

20/M/3 5-6 Premature Multifocal B+, 20 + VPA 47 --> NP: I00.0 No spikes ACTH

* VPA concentrations before and 2 hours alter drug administration in the morning. .I Maintenance doses.

Abbreviations: ACC = Agenesis of corpus callosum CLZ = Clonazepam RDS = Respiratory distress syndrome AS = Aortic stenosis NP = Not performed S = Series B6 = Vitamin B(, PDA = Patent ductus arteriosus VPA = Valproic acid

92 PEDIATRIC NEUROLOGY Vol. 7 No. 2

Table 2. Effects of treatment

Seizure Excellent or Good Poor

EEG Excellent or Good Poor

Initial B6 only 3 (23%) 10 (77%) -- (N = 13)

Initial VPA only 2 (67%) I (33%) (N = 3)

Initial B6 + VPA 3 (75%) 1 (25%) (N = 4)

Initial B6 --4 VPA 1 (33%) 2 (67%) (N = 3)

Initial B6 --) B6 + VPA 7 (78%) 2 (22%) - (N = 9)

Failures ~ ACTH 6 (86%) 1 (22%) (N =7)

* P < 0.05. ** P < 0.01, Fisher's exact probability test.

1 (8%) 12 (92%)-

2 (67%) I (33%)

. 3 (75%) 1 (25%)-

1 (33%) 2 (67%)

7 (78%) 2 (22%)

6 (86%) 1 (14%)

G a b

Abbreviations: B6 = Vitamin B6 VPA = Valproic acid

15-20 mg/kg/day and increased 10 mg/kg every 3 days to a main- tenance dose of 30-63 mg/kg/day. Both drugs were given 3 times daily in equally divided portions. The patients were not randomly assigned to either treatment.

The initial seizure control was evaluated as follows: excellent, when there was total cessation of seizures; good, when seizure frequency was decreased by 50%; and poor, when seizure frequency was decreased by less than 50%.

The effect on EEG recordings was evaluated as follows: excellent, when seizure discharges almost disappeared; good, when seizure dis- charges decreased by 50%; and poor, when seizure discharges de- creased by less than 50%.

When seizures did not disappear completely or seizure discharges on EEG were not reduced, another treatment was initiated. Finally, pa- tients whose seizures did not disappear with vitamin B6, VPA, or both were treated with ACTH (0.01-0.02 mg/kg) in daily injections for 2 weeks, once every other day for 2 weeks, and then twice weekly for a total of 30 injections. ACTH was decreased gradually and stopped when seizures disappeared and EEG readings improved.

After discharge, the patients were followed monthly in the outpatient clinic for a period ranging from 6 months to 6 years, 5 months.

R e s u l t s

Effects of Vitamin B6, VPA, or Both. Thir teen patients

were treated initially with only v i tamin B6 (Patients 1-13;

Table 1). An excel lent ef fec t on seizures was observed in

3 patients (23%) and a poor effect in 10 (77%; Table 2);

however , an excel lent E E G response was obtained in only

Patient 1 (8%) and in the remaining 12 patients (92%)

there was no improvement . In these 12 patients, VPA was

substituted for or added to v i tamin B6.

VPA was the initial t reatment in Patients 14-16. An

excel len t or good effect on seizures was observed in 2

patients (67%) and a poor effect in 1 (33%). The effect on

E E G s was the same. There were no signif icant differences

be tween initial v i tamin B6 t reatment and initial VPA treat- ment (Fisher ' s exact probabil i ty test).

C o m b i n e d t rea tment with v i t amin B6 and VPA was

g iven initially to Patients 17-20. An excel lent or good

effect on seizures was observed in 3 patients and a poor

effect in 1 (25%). The effect on EEGs was the same. Initial

v i tamin B6 and VPA treatment was s ignif icant ly more

effect ive on E E G s (P < 0.05; F isher ' s exact probabil i ty

test) than was initial v i tamin B6 treatment alone, but their

effect on seizures was not s ignif icantly different.

VPA was substituted for v i tamin B6 in Patients l 1-13

who did not respond wel l to v i tamin B6 alone. In 1 patient

(33%) there was an excel len t effect on seizures and in 2 a

poor effect (67%; Table 2). The effect on E E G s was the

same. There were no signif icant differences be tween the

group treated initially with vi tamin B6 and the group in

which VPA was substituted for v i tamin B6.

VPA was added to vi tamin B6 in Patients 2-10 who did

not respond well to v i tamin B6 alone. An excel len t or good

effect on seizures was observed in 7 patients (78%), and a

poor effect in 2 (22%; Table 2). The effect on E E G was

the same. This t reatment had a s ignif icantly greater effect

on seizures (P < 0.05) and E E G s (P < 0.01 ) than did initial

v i t amin B6 t reatment a lone (Fisher ' s exact probabil i ty

test). There were no signif icant differences be tween the

group in which VPA was substituted for v i tamin B6 and

the group in which VPA was added to vi tamin B6.

Effect of ACTH Therapy. Patients 12, 13, and 16, who

did not respond wel l to VPA, and Patients 8-10 and 20,

who did not respond well to the combina t ion o f v i tamin

B6 and VPA, were treated with A C T H (Table 1). An ex-

cel lent effect on seizures was observed in 6 (86%) and a

poor effect in 1 (14%; Table 2). An excel len t effect on E E G

was observed in 5 patients (71%), a good effect in 1 (14%),

and a poor effect in 1 (14%). Patient 17 with holoprosen-

cephaly , w h o did not respond to the c o m b i n a t i o n o f

Ito et al: Infantile Spasms 93

Table 3. Long-term effects

Final Treatment

Patient During Number Admission

1 B~

2 B6 + VPA

3 B6 + VPA

4 B6 + VPA

5 B6 + VPA

6 B0 + VPA

7 B0 + VPA

8 A C T H

9 A C T H

10 A C T H

11 VPA

12 A C T H

13 A C T H

14 VPA

15 VPA

16 A C T H

17 VPA + CLZ

18 B6 + VPA

19 B6 + VPA

Relapse of Seizure (seizure-

free period)

+ ( 5 mos)

+ ( 3 mos)

+ ( l 6 mos)

+ ( 3 mos)

+ ( 1 mos)

No seizure-tree period

+ (16 mos)

+ ( 1 mos)

+ ( 5 mos)

Follow-up Follow-up Examination Period Seizure (mos) Type E E G AEI)

15 S/W B~,

60 N VPA, CBZ

59 N V PA

50 N VPA

30 IS Poly VPA, CLZ,

S/W PHT

38 - N VPA

11 - Hyps VPA

39 CPS N VPA, PHT

28 - N B~, VPA

6 TS FS Be,, VPA

18 N VPA

12 - S/W V PA, CLZ

7* IS Hyps VPA. CLZ

76

77

20 A C T H + ( 1 mo) 9

* Died at 9 months of age. + Died at 26 months o f age.

12

14;"

33

38

Abbreviations: A A = Atypical absence FS = Focal spikes AED = Antiepileptic drug Hyps = Hypsar rhy thmia C B Z = Carbamazepine IS = Infantile spasms C L Z = Clonazepam MS = Myoclonic seizure CPS = Complex partial seizure N = No ,seizure discharge

PSG

TS

AA, MS

IS

N VPA

FS VPA, PHT,

CBZ

Poly VPA, C L Z s/w

FS VPA, C L Z

FS VPA

S/W VPA, CLZ, CBZ

VPA, CLZ, PHT

Poly spike

PHT = Phenytoin

PSG = Partial seizures secondari ly general ized S/W = Spike-and-wave complex TS = Tonic seizure VPA = Valproic acid

vitamin B6 and VPA, did not receive ACTH therapy be- cause of a high risk of infection; vitamin B6 was discon- tinued and clonazepam was added to VPA and seizures disappeared (Table 1).

Plasma Level of VPA and Side Effects. The plasma levels of VPA before and 2 hours after administration

in the morning ranged from 34.7-110 btg/ml and 60- 129 gg/ml, respectively (Table 1). Only 1 patient had in- creased SGOT and SGPT levels, 62 and 36 IU/dl, respec- tively. No other side effects were observed in patients treated with vitamin B6, VPA, or both; however, in the ACTH-treated group slight to moderate side effects were

94 PEDIATRIC N E U R O L O G Y Vol. 7 No. 2

observed, including moon face, obesity, irritability, sleep disturbance, electrolyte disturbance, hypertension, infec- tion, and transient "cerebral atrophy" on CT.

Subsequent Examinations. Patient 1, whose seizures and EEG results both demonstrated excellent responses to vitamin B6, had no relapses and was seizure-free at sub- sequent examination 15 months after the cessation of seizures (Table 3).

Of the 3 patients (Patients 11,14,15) whose seizures were finally controlled by VPA only, 1 (34%) had a relapse after a seizure-free period of 16 months. The other 2 pa- tients (66%) were seizure-free at subsequent examination, 1 at 18 months, the other at 76 months follow-up period.

Of the 8 patients (Patients 2-7,18,19) whose seizures finally disappeared with a combination of vitamin B6 and VPA, 3 (38%) had relapses (after 5, 3, and 5 months of seizure-free period). The other 5 patients (62%) had been seizure-free when re-examined (at 11-59 months of fol- low-up period).

Five of 6 patients (Patients 8-10,12,16,20; 83%) whose seizures were controlled by ACTH therapy, had relapses 1-16 months after treatment, and only 1 patient (17%) remained seizure free (28 months of follow-up period).

Two patients died during the follow-up period. One with Aicardi syndrome (Patient 13) whose seizures did not dis- appear with ACTH therapy and one with holoprosen- cephaly (Patient 17) whose seizures disappeared with VPA and clonazepam therapy. Both patients died of pulmonary infection.

Discussion

Vitamin B6 is a coenzyme of glutamic acid decarboxy- lase. Vitamin B6 deficiency produces seizures possibly due to a decrease of brain GABA [14]. Vitamin B6-dependent and -responsive seizures have been proposed. Ohtsuka et al. treated 118 infantile spasm patients with 30-400 mg pyridoxal phosphate per day, 15 (12.7%) of them became seizure-free initially, and 12 (10.2%) remained seizure- free at subsequent examination [ 15]. Blennow and Starck also reported 3 patients with infantile spasms whose sei- zures disappeared with megadoses of vitamin B6 (pyridox- ine chloride) [ 16].

In our study, 3 of 13 patients (23%) responded to high doses of vitamin B6 initially; however, 2 demonstrated no EEG improvement. In 1 patient (8%), vitamin B6 therapy was successfully continued and no seizures were recorded at subsequent examination. Therefore, even though very few patients with infantile spasms respond to it, high doses of vitamin B6 should be given a trial.

VPA may also enhance GABAergic neurotransmission [ 10,11]. In 40-66% of children with infantile spasms VPA treatment provided excellent or good control [17-19]. Recently, Siemes et al. reported that 16 of 22 children (77%) were seizure-free after 6 months of therapy with high doses of VPA [20]. In our study, 2 of 3 children (67%) with initial VPA monotherapy had an excellent or good

response. Three of 4 children (75%) initially treated with the combination of vitamin B6 and VPA demonstrated an excellent or good response. The group treated initially with vitamin B6 and VPA had significantly better EEGs than did the group treated initially with vitamin B6 alone. More- over, the group in which VPA was added to vitamin B6 had significantly fewer seizures and better EEGs than did the group treated initially with vitamin B6. There were no significant differences among the group treated initially with vitamin B6, the group treated initially with VPA, and the group in which VPA was substituted for vitamin B6. Therefore, the combination of vitamin B6 and VPA may be more effective than VPA monotherapy in controlling infantile spasms; however, it was not statistically signifi- cant in our study.

High-dose VPA therapy sometimes causes thrombo- cytopenic purpura [20] or fatal hepatotoxicity [21 ]. In our study, plasma levels of VPA administered in maintenance doses were in the effective range and side effects were rare. In only 1 patient SGOT and SGPT levels were slight- ly elevated.

ACTH was more effective in abolishing seizures than VPA or the combination of vitamin B6 and VPA. It had an excellent effect on seizures in 86% of patients who did not respond well to VPA or the combination of vitamin B6 and VPA; however, 83% of patients who responded well to ACTH had relapses. The relapse rate after ACTH therapy has been reported to be 47-64% in some studies [22-25]. The relapse rate in our study was higher, perhaps because we gave ACTH to patients with relatively intractable dis- ease who did not respond to VPA or a combination of vitamin B6 and VPA. The patients treated with VPA or a combination of vitamin B6 and VPA had a lower relapse rate than did those treated with ACTH in the other studies, perhaps because this group included patients with less intractable disease. Side effects were more common with ACTH therapy than with VPA or vitamin B6 and VPA therapy.

A combination of vitamin B6 and VPA is an effective and safe therapy for infantile spasms and may merit a trial before ACTH; however, because this study included patients with various etiologies, it is necessary to study larger series with the same etiology, especially cryptogenic patients.

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96 PEDIATRIC NEUROLOGY Vol. 7 No. 2