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 electroencephalography. Vitamin B6 therapy alone was continued in a single patient (8%) who remained seizurefree 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 initially 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, O k u n o T, Hattori H, Fujii T, M i k a w a H. Vitamin B6 and valproic acid in treatment o f infantile spasms. Pediatr N e u r o l 1991 ;7:91-6.
Introduction A C T H has been used as the drug o f c h o i c e for the treatment o f infantile spasms since Sorel and D u s a u c y B a u l o y e described its effectiveness in 1958 [ 1]; h o w e v e r , serious side effects s o m e t i m e s o c c u r during A C T H therapy [2]. R e c e n t studies h a v e demonstrated that A C T H induces apparent cerebral atrophy on c o m p u t e d t o m o g r a p h y (CT) [3-5]. In most patients the changes are reversible but in
From the *Department of Pediatrics; Shimane Medical University; Izumo, Japan; tDepartment of Pediatrics; Faculty of Medicine; Kyoto University; Kyoto, Japan.
s o m e patients subdural effusion occurs or r e c o v e r y from "cerebral atrophy" is delayed [4,5]. It is suspected that A C T H has an adverse effect on the d e v e l o p i n g brain. Therefore, a safer and more effective treatment is required. In the cerebrospinal fluid (CSF) of patients with infantile spasms, G A B A levels were l o w e r than in controls [6,7]. G A B A e r g i c neurotransmission m a y be impaired in infantile spasms and drugs that enhance brain G A B A e r g i c neuronal function m a y have s o m e effect on infantile spasms. Vitamin B6 is a c o e n z y m e o f glutamate decarboxylase [8] and m a y e n h a n c e 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 decreased b r e a k d o w n of G A B A [10,11]. In our study, we treated children with infantile spasms with high doses of vitamin 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 electroencephalograms (EEGs) of 19 patients revealed hypsarrhythmia or modified 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, chloride, calcium, phosphate, magnesium), blood pressure, amino acid analysis (serum and urine), chromosome analysis, EEG, cranial CT, and developmental testing. During hospitalization, routine laboratory examinations, 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
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./ Sex/Age at Onset (mos)
Seizure Frequency Per Day
Etiologic Factors
Electroencephaiography
Treatment During Admission (mg/kg)"
Plasma Level of VPA: Before: 2 hr* (~tg/ml)
I/M/IO
I-2/S
ACC, AS, and PDA
Hypsarrythmia
B, 311
2/F/5
3-5/S
Tuberous sclerosis
Hypsarrythmia
B+, 41) -~ B+~+ VPA 51)
40.2:69.8
No
3/F/12
5 15
Premature. blindness
Modified hypsarrythmia
B~+51) -> Be, + VPA 50
S().t): 96.2
No
4/M/10
2-4/S
Premature
ttypsarrythmia
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
Holoprosencephaly
Ilypsarrytllnlia
B+, 511 -~ B~, + VPA 51)
59.2: NP
No
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 hypsarrylhmia
B~+ 5(} + B+, + VPA 63 -~ ACTIt
50.7; 108.3
N~+
9/M/10
1-2/S
Congenital anomalies
Hypsarrythmia
B(, 51) ~ B~, + VPA 5(1 * ACTH
34.7; 65.(~
Nu
10/F/10
3-4/S
Porencephal~
Modified hypsarrythmia
BI, 40 ~ B~, + VPA 50 -~ ACTH
~ 1.9: NP
No
I I/M/6
7-8
Cryptogenic
Modified hypsarrythmia
B6 511 +÷ VPA 40
111).0:129.0
Nt~
12/F/2
5-6/S
Microcephaly, intracranial hemorrhage
Modified hypsarrythmia
B~, 50 ~ VPA 51) - + ACTH
NP
13/P/I
10-20/S
Aicardi syn.
ttypsarrythmia
B+, 50 ~ VPA 51) ~ ACTtf
NP
Yes
14/M/9
3-15
Cryplogemc
Hypsarrythmia
VPA 43
62.0:95.11
No
15/M/7
2 3
Cesarean section. eclampsia
Hypsarrythmia
VPA 50
75.5:911.11
No
16/F/14
5- I O/S
Unknown
Modified hypsan+ythmia
VPA 50 --÷ ACTH
41.0:92.0
17/F/10
5-6/S
Holoprosencephaly
Hypsarrythmia
B++311 + VPA 42 -~ VPA + CLZ O. 1
42.4:61.4
Nu
18/F/6
5-6/S
Premature. RDS
Hypsarrythmia
B6 411 + VPA 50
70.2:80.8
No
19/F/7
I-2/S
Tuberous sclerosis
Hypsarrythmia
B6 50 + VPA 32
NP
No
20/M/3
5-6
Premature
Multifocal spikes
B+, 20 + VPA 47 --> ACTH
N,,
NP: I00.0
* VPA concentrations before and 2 hours alter drug administration in the morning. .I Maintenance doses. Abbreviations: ACC = Agenesis of corpus callosum AS = Aortic stenosis B6 = Vitamin B(,
92
Seizures at I)ischarge
PEDIATRIC NEUROLOGY
CLZ = Clonazepam NP = Not performed PDA = Patent ductus arteriosus
Vol. 7 No. 2
RDS = Respiratory distress syndrome S = Series VPA = Valproic acid
No
Table 2.
Effects of treatment Seizure
EEG
Excellent or Good
Excellent or Good
Poor
Poor
Initial B6 only (N = 13)
3 (23%)
10 (77%) --
1 (8%)
12 (92%)-
Initial VPA only (N = 3)
2 (67%)
I (33%)
2 (67%)
I (33%)
Initial B6 + VPA (N = 4)
3 (75%)
1 (25%)
3 (75%)
1 (25%)-
Initial B6 --4 VPA (N = 3)
1 (33%)
2 (67%)
1 (33%)
2 (67%)
Initial B6 --) B6 + VPA (N = 9)
7 (78%)
2 (22%) -
7 (78%)
2 (22%)
Failures ~ ACTH (N =7)
6 (86%)
1 (22%)
6 (86%)
1 (14%)
.
Gab
* P < 0.05. ** P < 0.01, Fisher's exact probability test. Abbreviations: B6 = Vitamin B6 VPA = Valproic acid 15-20 mg/kg/day and increased 10 mg/kg every 3 days to a maintenance 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 discharges decreased by 50%; and poor, when seizure discharges decreased by less than 50%. When seizures did not disappear completely or seizure discharges on EEG were not reduced, another treatment was initiated. Finally, patients 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. Results
Effects of Vitamin B6, VPA, or Both. Thirteen patients were treated initially with only vitamin B6 (Patients 1-13; Table 1). An excellent effect on seizures was o b s e r v e d in 3 patients (23%) and a p o o r effect in 10 (77%; Table 2); h o w e v e r , an excellent E E G response was obtained in only Patient 1 (8%) and in the remaining 12 patients (92%) there was no i m p r o v e m e n t . In these 12 patients, VPA was substituted for or added to vitamin B6. VPA was the initial treatment in Patients 14-16. An e x c e l l e n t or g o o d effect on seizures was o b s e r v e d in 2 patients (67%) and a p o o r effect in 1 (33%). The effect on E E G s was the same. T h e r e w e r e no significant differences b e t w e e n initial vitamin B6 treatment and initial VPA treatm e n t (Fisher's exact probability test).
C o m b i n e d treatment with v i t a m i n B6 and V P A was g i v e n initially to Patients 17-20. A n excellent or g o o d effect on seizures was o b s e r v e d in 3 patients and a p o o r effect in 1 (25%). The effect on E E G s was the same. Initial vitamin B6 and V P A treatment was significantly m o r e effective on E E G s (P < 0.05; F i s h e r ' s exact probability test) than was initial vitamin B6 treatment alone, but their effect on seizures was not significantly different. VPA was substituted for vitamin B6 in Patients l 1-13 w h o did not respond well to vitamin B6 alone. In 1 patient (33%) there was an e x c e l l e n t effect on seizures and in 2 a p o o r effect (67%; Table 2). The effect on E E G s was the same. There w e r e no significant differences b e t w e e n the group treated initially with vitamin B6 and the group in which VPA was substituted for vitamin B6. VPA was added to vitamin B6 in Patients 2-10 who did not respond well to vitamin B6 alone. An e x c e l l e n t or g o o d effect on seizures was o b s e r v e d in 7 patients (78%), and a poor effect in 2 (22%; Table 2). The effect on E E G was the same. This treatment had a significantly greater effect on seizures (P < 0.05) and E E G s (P < 0.01 ) than did initial v i t a m i n B6 treatment alone (Fisher's exact probability test). There were no significant differences b e t w e e n the group in w h i c h VPA was substituted for vitamin B6 and the group in which VPA was added to vitamin B6. Effect of ACTH Therapy. Patients 12, 13, and 16, who did not respond well to VPA, and Patients 8-10 and 20, w h o did not respond well to the c o m b i n a t i o n o f vitamin B6 and VPA, w e r e treated with A C T H (Table 1). An excellent effect on seizures was o b s e r v e d in 6 (86%) and a p o o r effect in 1 (14%; Table 2). An e x c e l l e n t effect on E E G was o b s e r v e d in 5 patients (71%), a g o o d effect in 1 (14%), and a poor effect in 1 (14%). Patient 17 with holoprosenc e p h a l y , w h o did not r e s p o n d 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
Patient Number
Final Treatment During Admission
1
B~
2
B6 + VPA
3
Relapse of Seizure (seizurefree period)
Follow-up Period
Seizure
Follow-up Examination
(mos)
Type
EEG
AEI)
15
S/W
B~,
60
N
VPA, C B Z
B6 + VPA
59
N
V PA
4
B6 + VPA
50
N
VPA
5
B6 + VPA
6
+ ( 5 mos)
+ ( 3 mos)
30
IS
Poly S/W
VPA, CLZ, PHT
B0 + VPA
38
-
N
VPA
7
B0 + VPA
11
-
Hyps
VPA
8
ACTH
39
CPS
N
VPA, P H T
9
ACTH
28
-
N
B~, VPA
10
ACTH
6
TS
FS
Be,, VPA
11
VPA
N
VPA
12
ACTH
+ ( 1 mos)
-
S/W
V PA, C L Z
13
ACTH
No seizure-tree period
IS
Hyps
VPA. C L Z
14
VPA
N
VPA
15
VPA
+ (16 mos)
77
PSG
FS
VPA, PHT, CBZ
16
ACTH
+ ( 1 mos)
12
TS
Poly
VPA, C L Z
+ ( l 6 mos)
+ ( 3 mos)
18 12 7*
76
s/w 17
VPA + C L Z
14;"
FS
VPA, C L Z
18
B6 + VPA
33
FS
VPA
19
B6 + VPA
+ ( 5 mos)
38
AA, MS
S/W
VPA, C L Z , CBZ
20
ACTH
+ ( 1 mo)
9
IS
Poly spike
VPA, CLZ, PHT
* Died at 9 months of age. + Died at 26 months o f age.
Abbreviations: AA AED CBZ CLZ CPS
= = = = =
Atypical absence Antiepileptic drug Carbamazepine Clonazepam Complex partial seizure
FS Hyps IS MS N
= = = = =
Focal spikes Hypsarrhythmia Infantile spasms Myoclonic seizure No ,seizure discharge
vitamin B6 and VPA, did not receive ACTH therapy because of a high risk of infection; vitamin B6 was discontinued 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
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PEDIATRIC NEUROLOGY
Vol. 7 No. 2
PHT PSG S/W TS VPA
= = = = =
Phenytoin Partial seizures secondarily generalized Spike-and-wave complex Tonic seizure Valproic acid
in the morning ranged from 34.7-110 btg/ml and 60-
129 gg/ml, respectively (Table 1). Only 1 patient had increased SGOT and SGPT levels, 62 and 36 IU/dl, respectively. 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
observed, including moon face, obesity, irritability, sleep disturbance, electrolyte disturbance, hypertension, infection, 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 subsequent 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 patients (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 follow-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 disappear with ACTH therapy and one with holoprosencephaly (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 decarboxylase. 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 seizurefree at subsequent examination [ 15]. Blennow and Starck also reported 3 patients with infantile spasms whose seizures disappeared with megadoses of vitamin B6 (pyridoxine 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. Moreover, 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 significant in our study. High-dose VPA therapy sometimes causes thrombocytopenic 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 slightly 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 disease 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. References [1] Sorel L, Dusaucy-Bauloye A. A p r o p o s de 21 cas d'hypsarhythmia de Gibbs: Son traitment spectaculaire par I'ACTH. Acta Neurol Psychiatr Belg 1958;58:130-41. [2] Riikonen R, Donner M. ACTH therapy in infantile spasms: Side effects. Arch Dis Child 1980;55:664-72. [3] Deonna T, Voumard C. Reversible cerebral atrophy and corticotropin. Lancet 1979;2:207. [4] Ito M, Takao T, Okuno T, Mikawa H. Sequential CT studies of 24 children with infantile spasms on ACTH therapy. Dev Med Child Neurol 1983;25:475-80. [5] Okuno T, Ito M, Konishi Y, Yoshioka M, Nakano Y. Cerebral atrophy following ACTH therapy. J Comput Assist Tomogr 1980;4: 20-3.
Ito et al: Infantile Spasms
95
[6] ito M, Mikawa H, Taniguchi T. Cerebrospinal fluid GABA levels in children with infantile spasms. Neurology 1984;34:235-8. [7] L~scher W, Siemes H. Cerebrospinal f l u i d - Aminobutyric acid levels in children with different types of epilepsy: Effect of anticonvulsam treatment. Epilepsia 1985;26:314-9. [8] Chung S-H, Cox RA. Detemfination of pyridoxal phosphate levels in the brains of audiogenic and normal mice. Neurnchem Res 1983;8:1245-59. [9] L6scher W. Valproate induced changes in GABA metabolism at the subcellular level. Biochem Pharmacol 1981;30:1364-6. [10] Fowler LJ, Beckford J, John RA. An analysis of the kinetics of inhibition of rabbit brain gamma-aminobutyrate aminotransferase by sodium n-dipropyl acetate and some other simple carboxylic acids. Biochem Pharmacol 1975;24:1267-70. [!1] Harvey PKP, Bradford HF, Davison AN. The inhibitory effect of sodium n-dipropylacetate on the degradative enzymes of the GABA shunt. FEBS Lett 1975;52:251-4. [12] Gibbs FA, Gibbs EL. Epilepsy atlas of electroencephalography, vol 2. Cambridge: Addison Wesley, 1952:24-30. [13] Harachovy RA, Frost JD, Kellaway P. Hypsarrhythmia: Variation on the theme. Epilepsia 1984:25:317-25. [14] Stephens MC, Havlicek V, Dakshinamurti K. Pyridoxine deficiency and development of the central nervous system in the rat. J Neurochem 1971 : 18:2407-16. [15] Ohtsuka Y, Matsuda M, Kohno C, et al. Pyridoxal phosphate in the treatment of West syndrome. In: Akimoto H, Kazamatsuri H, Seino M, Ward A, eds. Advances in epileptology: Xllhh Epilepsy International Symposium. New York: Raven Press, 1982:311-3.
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[16] Blennow G, Starck L. High dose B6 treatment in infantile spasms. Neuropediatrics 1986; 17:7- I(1. [17] B a e h m a n DS. Use of valprnic acid in trealment of infantile spasms. Arch Neurol 1982;39:49-52. [18] Dyken PR, DuRant RH, Minden DB, King DW. Shnrl lenn effects of valproate on infantile spasms. Pediatr Neurol 1985:1:34-7. [19] Pavone L, lncnrpora G, Rosa ML, Vohi SL, Mollica F. Treatment of infantile spasms with sndium dipropylacctic acid. l)ev Med Child Neurol 1981:23:454-61. [20] Siemes H, Spohr L, Michael TH, Nau H. Therapy of infantile spasms with valproate: Results of a prospective study. Epilepsia 1988: 29:553-60. [21] Dreifuss FE, Santilli N, Langer DH, Sweeney KP, Molme KA. Menander KB. Valproic acid hepatic fatalities: A relmspective review. Neurology 1987;37:375-85. [22] ,leavons P, Bower B. Lnng-term prognnsis of 150 cases ol West syndrome. Epilepsia 1973:14:153-64. [23] Matsumoto A, Watanabe K, Negoro T, et al. Long-term prognosis after infantile spasms: A statistical study of prognostic factors in 2(X1 cases. Dev Med Child Neurol 1981;23:51-65. [24] Riikonen R. A long-term ['ollow-up study of 214 children with the syndrome nf infantile spasms. Neurnpediatrics 1982;13:14-23. [25] Snead OC lll, Benton JW, Myers GJ. ACTH and prednisonc in childhood seizure disorders. Neurology 1983:33:966-70.
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 electroencephalography. Vitamin B6 therapy alone was continued in a single patient (8%) who remained seizurefree 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 initially 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, O k u n o T, Hattori H, Fujii T, M i k a w a H. Vitamin B6 and valproic acid in treatment o f infantile spasms. Pediatr N e u r o l 1991 ;7:91-6.
Introduction A C T H has been used as the drug o f c h o i c e for the treatment o f infantile spasms since Sorel and D u s a u c y B a u l o y e described its effectiveness in 1958 [ 1]; h o w e v e r , serious side effects s o m e t i m e s o c c u r during A C T H therapy [2]. R e c e n t studies h a v e demonstrated that A C T H induces apparent cerebral atrophy on c o m p u t e d t o m o g r a p h y (CT) [3-5]. In most patients the changes are reversible but in
From the *Department of Pediatrics; Shimane Medical University; Izumo, Japan; tDepartment of Pediatrics; Faculty of Medicine; Kyoto University; Kyoto, Japan.
s o m e patients subdural effusion occurs or r e c o v e r y from "cerebral atrophy" is delayed [4,5]. It is suspected that A C T H has an adverse effect on the d e v e l o p i n g brain. Therefore, a safer and more effective treatment is required. In the cerebrospinal fluid (CSF) of patients with infantile spasms, G A B A levels were l o w e r than in controls [6,7]. G A B A e r g i c neurotransmission m a y be impaired in infantile spasms and drugs that enhance brain G A B A e r g i c neuronal function m a y have s o m e effect on infantile spasms. Vitamin B6 is a c o e n z y m e o f glutamate decarboxylase [8] and m a y e n h a n c e 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 decreased b r e a k d o w n of G A B A [10,11]. In our study, we treated children with infantile spasms with high doses of vitamin 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 electroencephalograms (EEGs) of 19 patients revealed hypsarrhythmia or modified 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, chloride, calcium, phosphate, magnesium), blood pressure, amino acid analysis (serum and urine), chromosome analysis, EEG, cranial CT, and developmental testing. During hospitalization, routine laboratory examinations, 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
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./ Sex/Age at Onset (mos)
Seizure Frequency Per Day
Etiologic Factors
Electroencephaiography
Treatment During Admission (mg/kg)"
Plasma Level of VPA: Before: 2 hr* (~tg/ml)
I/M/IO
I-2/S
ACC, AS, and PDA
Hypsarrythmia
B, 311
2/F/5
3-5/S
Tuberous sclerosis
Hypsarrythmia
B+, 41) -~ B+~+ VPA 51)
40.2:69.8
No
3/F/12
5 15
Premature. blindness
Modified hypsarrythmia
B~+51) -> Be, + VPA 50
S().t): 96.2
No
4/M/10
2-4/S
Premature
ttypsarrythmia
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
Holoprosencephaly
Ilypsarrytllnlia
B+, 511 -~ B~, + VPA 51)
59.2: NP
No
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 hypsarrylhmia
B~+ 5(} + B+, + VPA 63 -~ ACTIt
50.7; 108.3
N~+
9/M/10
1-2/S
Congenital anomalies
Hypsarrythmia
B(, 51) ~ B~, + VPA 5(1 * ACTH
34.7; 65.(~
Nu
10/F/10
3-4/S
Porencephal~
Modified hypsarrythmia
BI, 40 ~ B~, + VPA 50 -~ ACTH
~ 1.9: NP
No
I I/M/6
7-8
Cryptogenic
Modified hypsarrythmia
B6 511 +÷ VPA 40
111).0:129.0
Nt~
12/F/2
5-6/S
Microcephaly, intracranial hemorrhage
Modified hypsarrythmia
B~, 50 ~ VPA 51) - + ACTH
NP
13/P/I
10-20/S
Aicardi syn.
ttypsarrythmia
B+, 50 ~ VPA 51) ~ ACTtf
NP
Yes
14/M/9
3-15
Cryplogemc
Hypsarrythmia
VPA 43
62.0:95.11
No
15/M/7
2 3
Cesarean section. eclampsia
Hypsarrythmia
VPA 50
75.5:911.11
No
16/F/14
5- I O/S
Unknown
Modified hypsan+ythmia
VPA 50 --÷ ACTH
41.0:92.0
17/F/10
5-6/S
Holoprosencephaly
Hypsarrythmia
B++311 + VPA 42 -~ VPA + CLZ O. 1
42.4:61.4
Nu
18/F/6
5-6/S
Premature. RDS
Hypsarrythmia
B6 411 + VPA 50
70.2:80.8
No
19/F/7
I-2/S
Tuberous sclerosis
Hypsarrythmia
B6 50 + VPA 32
NP
No
20/M/3
5-6
Premature
Multifocal spikes
B+, 20 + VPA 47 --> ACTH
N,,
NP: I00.0
* VPA concentrations before and 2 hours alter drug administration in the morning. .I Maintenance doses. Abbreviations: ACC = Agenesis of corpus callosum AS = Aortic stenosis B6 = Vitamin B(,
92
Seizures at I)ischarge
PEDIATRIC NEUROLOGY
CLZ = Clonazepam NP = Not performed PDA = Patent ductus arteriosus
Vol. 7 No. 2
RDS = Respiratory distress syndrome S = Series VPA = Valproic acid
No
Table 2.
Effects of treatment Seizure
EEG
Excellent or Good
Excellent or Good
Poor
Poor
Initial B6 only (N = 13)
3 (23%)
10 (77%) --
1 (8%)
12 (92%)-
Initial VPA only (N = 3)
2 (67%)
I (33%)
2 (67%)
I (33%)
Initial B6 + VPA (N = 4)
3 (75%)
1 (25%)
3 (75%)
1 (25%)-
Initial B6 --4 VPA (N = 3)
1 (33%)
2 (67%)
1 (33%)
2 (67%)
Initial B6 --) B6 + VPA (N = 9)
7 (78%)
2 (22%) -
7 (78%)
2 (22%)
Failures ~ ACTH (N =7)
6 (86%)
1 (22%)
6 (86%)
1 (14%)
.
Gab
* P < 0.05. ** P < 0.01, Fisher's exact probability test. Abbreviations: B6 = Vitamin B6 VPA = Valproic acid 15-20 mg/kg/day and increased 10 mg/kg every 3 days to a maintenance 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 discharges decreased by 50%; and poor, when seizure discharges decreased by less than 50%. When seizures did not disappear completely or seizure discharges on EEG were not reduced, another treatment was initiated. Finally, patients 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. Results
Effects of Vitamin B6, VPA, or Both. Thirteen patients were treated initially with only vitamin B6 (Patients 1-13; Table 1). An excellent effect on seizures was o b s e r v e d in 3 patients (23%) and a p o o r effect in 10 (77%; Table 2); h o w e v e r , an excellent E E G response was obtained in only Patient 1 (8%) and in the remaining 12 patients (92%) there was no i m p r o v e m e n t . In these 12 patients, VPA was substituted for or added to vitamin B6. VPA was the initial treatment in Patients 14-16. An e x c e l l e n t or g o o d effect on seizures was o b s e r v e d in 2 patients (67%) and a p o o r effect in 1 (33%). The effect on E E G s was the same. T h e r e w e r e no significant differences b e t w e e n initial vitamin B6 treatment and initial VPA treatm e n t (Fisher's exact probability test).
C o m b i n e d treatment with v i t a m i n B6 and V P A was g i v e n initially to Patients 17-20. A n excellent or g o o d effect on seizures was o b s e r v e d in 3 patients and a p o o r effect in 1 (25%). The effect on E E G s was the same. Initial vitamin B6 and V P A treatment was significantly m o r e effective on E E G s (P < 0.05; F i s h e r ' s exact probability test) than was initial vitamin B6 treatment alone, but their effect on seizures was not significantly different. VPA was substituted for vitamin B6 in Patients l 1-13 w h o did not respond well to vitamin B6 alone. In 1 patient (33%) there was an e x c e l l e n t effect on seizures and in 2 a p o o r effect (67%; Table 2). The effect on E E G s was the same. There w e r e no significant differences b e t w e e n the group treated initially with vitamin B6 and the group in which VPA was substituted for vitamin B6. VPA was added to vitamin B6 in Patients 2-10 who did not respond well to vitamin B6 alone. An e x c e l l e n t or g o o d effect on seizures was o b s e r v e d in 7 patients (78%), and a poor effect in 2 (22%; Table 2). The effect on E E G was the same. This treatment had a significantly greater effect on seizures (P < 0.05) and E E G s (P < 0.01 ) than did initial v i t a m i n B6 treatment alone (Fisher's exact probability test). There were no significant differences b e t w e e n the group in w h i c h VPA was substituted for vitamin B6 and the group in which VPA was added to vitamin B6. Effect of ACTH Therapy. Patients 12, 13, and 16, who did not respond well to VPA, and Patients 8-10 and 20, w h o did not respond well to the c o m b i n a t i o n o f vitamin B6 and VPA, w e r e treated with A C T H (Table 1). An excellent effect on seizures was o b s e r v e d in 6 (86%) and a p o o r effect in 1 (14%; Table 2). An e x c e l l e n t effect on E E G was o b s e r v e d in 5 patients (71%), a g o o d effect in 1 (14%), and a poor effect in 1 (14%). Patient 17 with holoprosenc e p h a l y , w h o did not r e s p o n d 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
Patient Number
Final Treatment During Admission
1
B~
2
B6 + VPA
3
Relapse of Seizure (seizurefree period)
Follow-up Period
Seizure
Follow-up Examination
(mos)
Type
EEG
AEI)
15
S/W
B~,
60
N
VPA, C B Z
B6 + VPA
59
N
V PA
4
B6 + VPA
50
N
VPA
5
B6 + VPA
6
+ ( 5 mos)
+ ( 3 mos)
30
IS
Poly S/W
VPA, CLZ, PHT
B0 + VPA
38
-
N
VPA
7
B0 + VPA
11
-
Hyps
VPA
8
ACTH
39
CPS
N
VPA, P H T
9
ACTH
28
-
N
B~, VPA
10
ACTH
6
TS
FS
Be,, VPA
11
VPA
N
VPA
12
ACTH
+ ( 1 mos)
-
S/W
V PA, C L Z
13
ACTH
No seizure-tree period
IS
Hyps
VPA. C L Z
14
VPA
N
VPA
15
VPA
+ (16 mos)
77
PSG
FS
VPA, PHT, CBZ
16
ACTH
+ ( 1 mos)
12
TS
Poly
VPA, C L Z
+ ( l 6 mos)
+ ( 3 mos)
18 12 7*
76
s/w 17
VPA + C L Z
14;"
FS
VPA, C L Z
18
B6 + VPA
33
FS
VPA
19
B6 + VPA
+ ( 5 mos)
38
AA, MS
S/W
VPA, C L Z , CBZ
20
ACTH
+ ( 1 mo)
9
IS
Poly spike
VPA, CLZ, PHT
* Died at 9 months of age. + Died at 26 months o f age.
Abbreviations: AA AED CBZ CLZ CPS
= = = = =
Atypical absence Antiepileptic drug Carbamazepine Clonazepam Complex partial seizure
FS Hyps IS MS N
= = = = =
Focal spikes Hypsarrhythmia Infantile spasms Myoclonic seizure No ,seizure discharge
vitamin B6 and VPA, did not receive ACTH therapy because of a high risk of infection; vitamin B6 was discontinued 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
94
PEDIATRIC NEUROLOGY
Vol. 7 No. 2
PHT PSG S/W TS VPA
= = = = =
Phenytoin Partial seizures secondarily generalized Spike-and-wave complex Tonic seizure Valproic acid
in the morning ranged from 34.7-110 btg/ml and 60-
129 gg/ml, respectively (Table 1). Only 1 patient had increased SGOT and SGPT levels, 62 and 36 IU/dl, respectively. 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
observed, including moon face, obesity, irritability, sleep disturbance, electrolyte disturbance, hypertension, infection, 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 subsequent 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 patients (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 follow-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 disappear with ACTH therapy and one with holoprosencephaly (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 decarboxylase. 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 seizurefree at subsequent examination [ 15]. Blennow and Starck also reported 3 patients with infantile spasms whose seizures disappeared with megadoses of vitamin B6 (pyridoxine 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. Moreover, 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 significant in our study. High-dose VPA therapy sometimes causes thrombocytopenic 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 slightly 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 disease 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. References [1] Sorel L, Dusaucy-Bauloye A. A p r o p o s de 21 cas d'hypsarhythmia de Gibbs: Son traitment spectaculaire par I'ACTH. Acta Neurol Psychiatr Belg 1958;58:130-41. [2] Riikonen R, Donner M. ACTH therapy in infantile spasms: Side effects. Arch Dis Child 1980;55:664-72. [3] Deonna T, Voumard C. Reversible cerebral atrophy and corticotropin. Lancet 1979;2:207. [4] Ito M, Takao T, Okuno T, Mikawa H. Sequential CT studies of 24 children with infantile spasms on ACTH therapy. Dev Med Child Neurol 1983;25:475-80. [5] Okuno T, Ito M, Konishi Y, Yoshioka M, Nakano Y. Cerebral atrophy following ACTH therapy. J Comput Assist Tomogr 1980;4: 20-3.
Ito et al: Infantile Spasms
95
[6] ito M, Mikawa H, Taniguchi T. Cerebrospinal fluid GABA levels in children with infantile spasms. Neurology 1984;34:235-8. [7] L~scher W, Siemes H. Cerebrospinal f l u i d - Aminobutyric acid levels in children with different types of epilepsy: Effect of anticonvulsam treatment. Epilepsia 1985;26:314-9. [8] Chung S-H, Cox RA. Detemfination of pyridoxal phosphate levels in the brains of audiogenic and normal mice. Neurnchem Res 1983;8:1245-59. [9] L6scher W. Valproate induced changes in GABA metabolism at the subcellular level. Biochem Pharmacol 1981;30:1364-6. [10] Fowler LJ, Beckford J, John RA. An analysis of the kinetics of inhibition of rabbit brain gamma-aminobutyrate aminotransferase by sodium n-dipropyl acetate and some other simple carboxylic acids. Biochem Pharmacol 1975;24:1267-70. [!1] Harvey PKP, Bradford HF, Davison AN. The inhibitory effect of sodium n-dipropylacetate on the degradative enzymes of the GABA shunt. FEBS Lett 1975;52:251-4. [12] Gibbs FA, Gibbs EL. Epilepsy atlas of electroencephalography, vol 2. Cambridge: Addison Wesley, 1952:24-30. [13] Harachovy RA, Frost JD, Kellaway P. Hypsarrhythmia: Variation on the theme. Epilepsia 1984:25:317-25. [14] Stephens MC, Havlicek V, Dakshinamurti K. Pyridoxine deficiency and development of the central nervous system in the rat. J Neurochem 1971 : 18:2407-16. [15] Ohtsuka Y, Matsuda M, Kohno C, et al. Pyridoxal phosphate in the treatment of West syndrome. In: Akimoto H, Kazamatsuri H, Seino M, Ward A, eds. Advances in epileptology: Xllhh Epilepsy International Symposium. New York: Raven Press, 1982:311-3.
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[16] Blennow G, Starck L. High dose B6 treatment in infantile spasms. Neuropediatrics 1986; 17:7- I(1. [17] B a e h m a n DS. Use of valprnic acid in trealment of infantile spasms. Arch Neurol 1982;39:49-52. [18] Dyken PR, DuRant RH, Minden DB, King DW. Shnrl lenn effects of valproate on infantile spasms. Pediatr Neurol 1985:1:34-7. [19] Pavone L, lncnrpora G, Rosa ML, Vohi SL, Mollica F. Treatment of infantile spasms with sndium dipropylacctic acid. l)ev Med Child Neurol 1981:23:454-61. [20] Siemes H, Spohr L, Michael TH, Nau H. Therapy of infantile spasms with valproate: Results of a prospective study. Epilepsia 1988: 29:553-60. [21] Dreifuss FE, Santilli N, Langer DH, Sweeney KP, Molme KA. Menander KB. Valproic acid hepatic fatalities: A relmspective review. Neurology 1987;37:375-85. [22] ,leavons P, Bower B. Lnng-term prognnsis of 150 cases ol West syndrome. Epilepsia 1973:14:153-64. [23] Matsumoto A, Watanabe K, Negoro T, et al. Long-term prognosis after infantile spasms: A statistical study of prognostic factors in 2(X1 cases. Dev Med Child Neurol 1981;23:51-65. [24] Riikonen R. A long-term ['ollow-up study of 214 children with the syndrome nf infantile spasms. Neurnpediatrics 1982;13:14-23. [25] Snead OC lll, Benton JW, Myers GJ. ACTH and prednisonc in childhood seizure disorders. Neurology 1983:33:966-70.
