A Pilot Study of Topiramate in the Treatment of Infantile Spasms

zyxwvutsrqponmlkji zyxwvutsrqponm zyxwvutsrqpo zyxwvutsrqp Epilepsia, 39(12):132&1328, 1998 Lippincott Williams & Wilkins, Philadelphia 0 International League Against Epilepsy zyx A Pilot Study of Topiramate in the Treatment of Infantile Spasms Tracy A. Glauser, Peggy 0. Clark, and Richard Strawsburg Comprehensive Epilepsy Program, Children’s Hospital Medical Center, Cincinnati, Ohio, U.S.A. Summary: Purpose: West syndrome is a rare epileptic syn- drome associated with infantile spasms, a specific abnormal dose was reached, or the maximal dose of 24 mg/kg/day was zy zy achieved. Efficacy was primarily assessed by video EEG and electroencephalographic pattern (termed hypsarrhythmia). and secondarily by parental count of spasm frequency. mental retardation. Management of this disorder is difficult Results: Five (45%) subjects became spasm free during the because current treatment regimens, including many anticon- study, with absence of infantile spasms and hypsarrhythmia vulsants and hormones, are often ineffective. Topiramate (either classic or modified) proven by video EEG. Nine s u b (TPM) is a new antiepileptic drug that may be effective in jects, including the five spasm free, achieved a spasm reduction pediatric epilepsies. We conducted a pilot study to test the of 250%. Spasm frequency decreased from 25.6 f 19.3 to 6.9 effects of rapid TPM dosing in patients with refractory infantile r 5.9 spasmdday. Sixty-four percent of the subjects were able spasms. to achieve TPM monotherapy. Methods: Eleven children with refractory infantile spasms Conclusions: Results in this cohort of 1 1 patients with re- were given an initial dose of 25 mg TPM per day in addition to fractory disease show TPM to be a promising new agent for the their current therapy. Dosage was increased by 25 mg every treatment of infantile spasms. Key Words: Epilepsy-Infantile 2-3 days until spasms were controlled, the maximal tolerated spasms-Anticonvulsants-Children-Topiramate. West syndrome is a devastating pediatric epileptic dis- single- and multiple-drug therapies. Therefore, a signifi- order that consists of seizures called infantile spasms, an cant need exists for new agents that are safe and effective abnormal electroencephalographic (EEG) pattern termed in the control of infantile spasms. zyxwv hypsarrhythmia, and mental retardation or regression, Topiramate (TPM) is a potent new AED. Among its “although one element may be missing (l).” The sei- mechanisms of action are a state-dependent blockade of zures consist of brief, symmetric contractions of the sodium channels, potentiation of y-aminobutyric acid trunk, extremities, neck, or a combination of these. Clas- (GABA)-mediated neurotransmission, and antagonism sic or modified hypsarrhythmia is a poorly synchronized of glutamate (5). Topiramate has been used for adjunc- pattern that includes high-amplitude spikes and slow tive treatment of partial-onset seizures in adults (6), and waves (2,3). Infantile spasms are categorized into two a recent single-center study suggests that it may also be groups: symptomatic, in which a specific neurologic con- effective as monotherapy for adult epilepsy (7,8). A dition is thought to contribute to the development of the double-blind, placebo-controlled trial of adjunctive TPM spasms, and cryptogenic, in which no predisposing con- therapy in children with Lennox-Gastaut syndrome dem- dition can be identified (4). Patients with infantile onstrated a significant reduction in drop attacks (tonic/ spasms have poor long-term prognoses, often exhibit atonic seizures) and a significant improvement in seizure mental retardation, and frequently undergo subsequent severity, as evidenced by parental evaluation of the latter development of a condition called Lennox-Gastaut syn- (9). drome. Although current therapy for infantile spasms in- Because infantile spasms are often resistant to conven- cludes anticonvulsant agents (AEDs) and hormonal treat- tional therapy and are associated with a poor long-term ments, this condition often remains resistant to both outcome and because West syndrome can evolve into Lennox-Gastaut syndrome (in which TPM appears to be effective), we designed a pilot study to test the efficacy Accepted June 9, 1998. of TPM in children with refractory infantile spasms. Be- Address correspondence and reprint requests to Dr. T. A. Glauser at Division of Pediatric Neurology, Children’s Hospital Medical Center, cause of the severe nature of the disease, we sought to OSB-5, 3333 Bumet Avenue, Cincinnati, OH 45229-3039, U.S.A. control the symptoms as quickly as possible using a 1324  zy zyxwvutsr TOPIRAMATE IN INFANTILE SPASMS I325 rapid-dose TPM protocol. The results of this study sug- If it was determined that a titration-phase end point gest that TPM may be a safe and effective therapy for the had been reached, the subject entered a 1-week stabili- treatment of infantile spasms. zation phase during which that subject continued to re- ceive the dosage achieved at end point. After the end of METHODS the stabilization phase, the 24-h video EEG was re- peated. After the nature of the study had been fully explained, At the discretion of the investigator, subjects complet- subjects’ parents or guardians signed a Children’s Hos- ing the stabilization phase were enrolled in the extension pital Medical Center Institutional Review Board- phase, during which dose titrations continued toward the approved Informed Consent. To be eligible for consid- maximal TPM dose. Other AEDs could be added or de- eration, at least two courses of conventional therapy for leted during the extension phase. Telephone contact was infantile spasms had to have failed. The study included made in the week after each dosage increase. six male and five female subjects between 3 and 48 Evaluation of efficacy was primarily based on the months of age and weighing 2 7 kg. To qualify for the presence/absence of infantile spasms and hypsarrhyth- study, subjects were required to exhibit an average of one mia (classic or modified) during 24-h video EEG telem- spasm per day over a 2-week baseline period, and they etry. A secondary outcome variable was the change in could not be spasm free for 3 consecutive days. Patients parental count of seizure frequency. were eligible for the study if their baseline 24-h video EEGs had features consistent with infantile spasms (e.g., RESULTS electrodecremental electrographic seizures associated with a recognizable clinical infantile spasm). Eligible The clinical characteristics of the 11 subjects are sum- patients were judged to be refractory to other AEDs by marized in Table 1. The median age of onset of spasms the principal investigator. Exclusion criteria were (a) a was 3.6 months (range, 3-25 months). The median du- recent history or evidence of other medical disease; (b) ration of spasms before starting TPM was 13.4 months computed tomography (CT) or magnetic resonance im- (range, 4-39 months). Concomitant medications aver- aging (MRI) evidence of a progressive lesion; (c) use of aged 2.0 * 0.6 AEDs per patient (range, 1-3 AEDs) an investigational drug or an investigational device when TPM therapy was initiated. All patients were re- within the 30 days before the study; (d) use of felbamate sistant to previous treatments, an average of 4.5 -+ 1.3 (because of concern over the risk of aplastic anemia or AEDs per patient. Previous therapies included adreno- hepatotoxicity); or (e) a history of poor compliance with corticotropic hormone (ACTH) in doses ranging from 20 past AED therapy, as judged by the principal investiga- to 80 IU/day (n = 6), valproate (VPA; n = 11). la- tor. motrigine (LTG; n = 8), BDZs [diazepam (DZP), lor- The baseline phase of the study lasted G2 weeks, dur- azepam (LZP), chlorazepate (CLZ), clonazepam (CLZ); ing which time patient data were assembled and evalu- n = 81, PB (n = 7), carbamazepine (CBZ; n = 6), ated. By using the baseline 24-h EEG, the parents or phenytoin (PHT; n = 1), ethosuximide (ESM; n = l), guardians were educated about their children’s seizure and felbamate (FBM; n = 1). Vigabatrin (VGB) is not classifications and spasms and then asked to keep daily commercially available in the United States, and no pa- diaries of their occurrence. Each subject’s dose(s) of zyx zyxwvut background AEDs remained constant during the baseline TABLE l. Patient characteristics phase. zy On completion of the baseline phase, subjects entered the titration phase. Concomitant AEDs were tapered dur- ing the first week of titration, except in subjects taking benzodiazepines (BZDs) or phenobarbital (PB1; in these Sex Male Female Race 6 5 I zyxwv White patients, medications were tapered at the investigator’s African American 4 Age at onset of spasms [median, (range) in mo] 3.6 (3-25) discretion for S 3 weeks. Topiramate therapy was started Duration of spasms before study [median, (range) at 25 mg/day, and the dosage was raised by 25-mg in- in mo] 13.4 (4-39) zy crements every 2-3 days. If the dose was not tolerated, Age at study entry (mean f SD, in mo) 2 4 2 12 Weight at study entry (mean ? SD, in kg) 11.3f3.2 the rate of titration was reduced. Titration continued for Etiology (n) G4 weeks or until one of the following end points was Cryptogenic 2 reached: a maximal dose of 24 mg/kg/day was achieved, Symptomatic 9 Cytomegalovirus 2 a maximal tolerated dose was attained, or spasms were Tuberous sclerosis 1 absent for 7 days. Subjects were monitored by weekly Head trauma 1 zyx titration visits and were assessed either in person or by Lissencephaly 1 Unknown 4 phone every 2-3 days. Epilepsia, Val. 39, No. 12, 1998 1326 zyxwvutsr zyxwvu zyxwvuts T. A. GLAUSER ET AL. tient had been given that agent before entering the study. No patient was treated with oral steroids. TABLE 3. Reported adverse events during titration and stabilization uhases Overall five (45%) subjects became spasm free with- Adverse event No. out evidence of classic or modified hypsarrhythmia, as Imtability demonstrated by subsequent 24-h video EEG telemetry Sleep disturbance (Table 2). Two of the subjects, both with cryptogenic Constipation Lethargy spasms, became spasm free during the titration phase. Rapid breathing These remissions occurred on days 6 and 11, at TPM zyxwvut Unsteadiness doses ranging from 6.7 to 8.8 mgkglday. Three addi- tional subjects became spasm free on days 32,36, and 90 after their first TPM dose, at doses ranging from 19.2 to DISCUSSION 29.9 mgkglday. As of June 1, 1997, these patients had been spasm free for an average of 134 f 32 days (range, Although a wide variety of AEDs are used clinically 90-163 days) in long-term follow-up. There was a 69 f for infantile spasms, most are either ineffective or have zyxw zyxwvu 26% (range, 19-100%) decrease in the parental count of serious side effects (2). In this pilot study, we found that spasm frequency from the baseline to the stabilization treatment with rapid TPM dosing resulted in 45% of this phase. A 250% reduction in spasms was observed in refractory cohort becoming spasm free without classic or nine (82%) of the 11 subjects during stabilization. modified hypsarrhythmia (confirmed by video EEG), Six (55%) of the subjects had other types of seizures along with a significant reduction of the cohort's spasm before enrollment, including complex partial seizures (n frequency (230% in nine of 11 patients). In addition, a = 3), complex partial seizures with secondary general- majority of patients was able to progress to monotherapy ization (n = l), tonic-clonic seizures (n = l), and un- with TPM as the sole therapeutic agent. Topiramate was specified seizures (n = 1).There was a 63 f 35% (range, well tolerated and showed side effects consistent with 0-100%) decrease in parental count of ancillary seizure those previously reported in adult and pediatric trials frequency from baseline to stabilization, although the (6,10,11). The most significant adverse effect was imta- difference in mean seizure frequency did not attain sta- bility, resulting in a temporary dose reduction in three of tistical significance (Table 2). -A total of four patients the subjects. At no time during the study, however, did exhibited a 250% reduction in ancillary seizures during TPM have to be discontinued because of serious side stabilization. effects. The mean dose of TPM during stabilization was 15.0 For decades, hormonal therapy with ACTH has been ? 5.7 mgkglday (range, 8.3-23.7 mgkg/day). Seven considered by many to be the treatment of choice for (64%) of the 11 subjects were able to achieve TPM infantile spasms (12). Despite its efficacy, estimated'at monotherapy at the end of stabilization, and the number 50-67% (13), the use of ACTH is associated with serious and dosages of concomitant AEDs taken by the remain- side effects, including increased risk of infection, hyper- ing subjects were reduced. tension, hypertrophic cardiomyopathy, and electrolyte All patients reported at least one adverse effect during disturbances (2,14,15). In addition, ACTH must be ad- titration or stabilization or both (Table 3). The most com- ministered by intramuscular injection. mon side effect was irritability (n = 9). In three subjects, Standard AEDs, including PHT, CBZ, and PB, are irritability was significant enough to necessitate a tem- usually ineffective in reducing the frequency of infantile porary dose reduction. Other adverse effects included spasms (2). Benzodiazepines, although they show some sleep disturbance, constipation, lethargy, rapid breathing, efficacy for infantile spasms, are of limited value be- and unsteadiness. cause of the high degree of tolerance that develops (2). Valproic acid, a broad-spectrum AED, has demonstrated TABLE 2. Eficacy outcome variables some effectiveness. In one study, 73% of children treated with VPA were seizure free after 3 months. There was, Baseline Study period however, a high incidence of relapse and of serious side Primary (video-EEG confirmation) effects, including muscle hypotonia (all subjects) and Absence of infantile spasms zyxwvuts 0/11 5/11 (45%) Absence of classic or thrombocytopenic purpura (16). Irreversible hepatotox- icity is another potentially fatal side effect that has oc- zyxwvut modified hypsarrhythmia 0/11 5/11 (45%) Secondary (parental count) curred particularly in children younger than 2 years (17). Spasm frequency [&day c 25.6 c 19.3 6.0 f 5.9" SD (range)] (5.3-50) (0-20.6) The side effects associated with ACTH and the Jack of Ancillary seizure frequency * 6.9 9.9 3.0 5 5.1b efficacy of conventional AEDs have led to a search for [dday k SD (range)] (,0.3-26.4) (G13.4) new treatments for infantile spasms (3). Several new zyxwvutsrqponml a p < 0.003. AEDs have recently become available (although not in b p = 0.1. all countries), including LTG, FBM, VGB, and TPM. Epilepsia, Vol. 39, No. 12, 1998  zy zyxwvu TOPIRAMATE IN INFANTILE SPASMS I327 zyxwvuts Only limited data exist on the use of LTG and FBM in the treatment of infantile spasms. In two studies of LTG for the treatment of childhood epilepsies, responses (i.e., 250% reduction in spasms) were seen in nine of 30 subjects with infantile spasms in one study ( 18) and four of 13 in another (19). Three of four patients with infantile spasms responded to FBM (20). However, the recently reported increased pediatric risk of LTG for Stevens- Johnson syndrome (one in 50 to one in 100 risk) (21) and talung TPM were able to achieve monotherapy at the end of stabilization, and others were able to reduce concomi- tant AEDs. In our study, 45% of patients became spasm free, and 82% of the group experienced a 250% reduction in spasm frequency. Response to TPM was relatively rapid in the patients with cryptogenic infantile spasms and somewhat delayed (as late as 90 days into therapy) in the three symptomatic responders. The sample size is too the association of FBM with aplastic anemia will likely small to pursue subset analysis based on etiology. The limit their use in patients with infantile spasms (22). effectiveness of TPM was seen even as other AEDs were Vigabatrin appears to be effective in the management rapidly weaned. The results of this pilot study indicate zyxwvu of infantile spasms, particularly in patients with tuberous that TPM is a promising agent for the treatment of re- sclerosis (23,24). In an open-label, add-on trial of VGB fractory infantile spasms, and further investigations are in a similar population of children with refractory infan- warranted. tile spasms, 43% became spasm free (24). In our study, TPM had similar spasm-free efficacy results compared Acknowledgment: This study was funded by the R. W. with VGB in like refractory populations (45% TPM vs. Johnson Pharmaceutical Research Institute and was supported 43% VGB), but our study had a decidedly smaller in part by USPHS grant MOI RR 08084 from the General Clinical Research Centers Program, National Center for Re- sample size (1 1 compared with 68 for VGB). 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