Treatment of infantile spasms: An evidence-based approach

TREATMENTOF INFANTILESPASMS: AN EVIDENCE-BASEDAPPROACH

Mark Mackay, Shelly Weiss, and O. Carter Snead III Division of Neurology, ResearchProgram in Brain and Behavior The Hospital for Sick Children, Departmentof Pediatricsand Medicine (Neurology) The Bloorview Epilepsy ResearchProgram, Facultyof Medicine, Universityof Toronto Toronto, Ontario, Canada M5G 1X8

I. Introduction II. Methods III. Results A. Natural History of Infantile Spasms B. ACTH and Steroids C. ACTH and Steroids: Conclusions and Recommendations D. Vigabatrin E. Vigabatrin: Conclusions and Recommendations F. Other Drugs G. Newer Antiepileptic Drugs IV. Summary and Conclusions A. Recommendations for Future Clinical Trials Acknowledgment References

T h e object of this work was to subject established empirical medical treatm e n t regimens for infantile spasms to evidence-based m e d i c i n e analysis in o r d e r to d e t e r m i n e the current best practice for the t r e a t m e n t of infantile spasms in children. Clinical studies of infantile spasms r e p o r t e d d u r i n g the presteroid era were reviewed critically to define the natural history of the disorder. T r e a t m e n t trials of infantile spasms c o n d u c t e d since 1958 were rigorously assessed using MEDLINE and h a n d searches of the English language literature. Inclusion criteria were the d o c u m e n t e d prese n c e of infantile spasms and hypsarrhythmia. O u t c o m e measures i n c l u d e d c o m p l e t e cessation of spasms, resolution of hypsarrhythmia, relapse rate, d e v e l o p m e n t a l outcome, the presence or absence of epilepsy, a n d / o r an epileptiform e l e c t r o e n c e p h a l o g r a m . Evidence was defined as class I, II, or III, and practice p a r a m e t e r r e c o m m e n d a t i o n s were m a d e using the framework devised by the A m e r i c a n Academy of Neurology. Class I and III evidence support a standard of practice r e c o m m e n d a t i o n for the use of vigabatrin in the t r e a t m e n t o f infantile spasms in children with tuberous sclerosis. Class I and III evidence support a guidelines r e c o m m e n d a t i o n for the use of either A C T H or vigabatrin in infantile spasms in n o n t u b e r o u s sclerosis patients. T h e r e is no strong evidence that successful t r e a t m e n t of INTERNATIONAl. REVIEW OF NEUROBIOLOGY, VOL. 49

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Copyright 2002, Elsevier Science (USA). All rights reserved. 0074-7742/02 $35.00

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infantile spasms improves the long-term prognosis for cognitive outcome or decreases the incidence of later epilepsy. A practice option recommendation for the use of oral corticosteroids in the treatment of infantile spasms is supported by limited and inconclusive class I and III data. Based on the evidence, no recommendation can be made for the use of pyridoxine, benzodiazepines, or the newer antiepileptic drugs in the treatment of infantile spasms. ACTH and vigabatrin are the most effective agents in the treatment of infantile spasms, but concerns remain about the risk/benefit profiles of these drugs. © 2002, Elsevier Science (USA).

I. Introduction

Evidence-based medicine is not restricted to randomized controlled trials or meta-analyses, but rather refers to "the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patient" (Sackett et al., 1996). The lack of an evidence-based approach to infantile spasms is illustrated by the fact that a OVID MEDLINE search from 1975 until December 2000 resulted in 1385 articles, of which only 1 was an evidence based reviews (Hancock et al., 1999). An empirical approach to therapy may be defined as a strategy that is based on practical experience, but which is scientifically unproven. The first empirical treatment of infantile spasms was described by West (1841) and entailed the use of leeches, calomel purgatives, lancing of the gums, and opium, all to no effect. Modern day medical treatment of infantile spasms remains empirical because it is based on no theoretical u n d e r p i n n i n g of knowledge of the disease or of the mechanism of action of drugs t h o u g h t to be effective against spasms. Because of these gaps in our knowledge, it is possible to develop a rational approach to the treatment of infantile spasms only by the rigorous analysis of the empirical treatments that are in standard use for this disorder. However, this strategy is constrained by a n u m b e r of factors. First, there is a paucity of prospective studies and even fewer randomized or controlled treatment trials in this disorder. Second, the published outcome measures in treatment trials of infantile spasms are short term, vary from study to study, and are poorly described. Thus, the question whether successful treatment of the spasms leads to improvement of neurodevelopmental o u t c o m e and a decreased incidence of epilepsy remains unanswered. Nor do we know whether treatment-evoked cessation of spasms makes a difference in the developmental trajectory in symptomatic patients who have preexisting mental retardation, neurological deficits, and other seizure types. A n o t h e r problem with this approach is that most treatment

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trials of infantile spasms are plagued by small numbers of patients because of the rarity of the disorder. The incidence of infantile spasms is estimated between 0.25 to 0.60 per 1000 live births (Cowan et aL, 1991; Holmes et al., 1997; Riikonen, 1984) and a prevalence of 0.14-0.19 per 1000 live births (Cowan et al., 1989). A final limitation of the systematic analysis of treatment trials of infantile spasms is that the dosage regimens and treatment duration vary wildly from study to study, regardless of the drug used. This c o n u n d r u m is illustrated by the results of two large surveys that were p e r f o r m e d independently by the Child Neurology Society and the Japanese Society of Child Neurology in order to determine the drug of choice in the treatment of infantile spasms. In the first survey, which comprised mostly U.S. child neurologists, 88% of respondents used ACTH as the drug of first choice. The most frequently used regimen was a dosage of 40 IU per day for 1 - 2 months. The choice of drug was not influenced by whether the spasms was cryptogenic or symptomatic (Bobele et al., 1994). In the Japanese survey the drug of choice was pyridoxine, with synthetic ACTH being second- or third-line therapy. The Japanese neurologists used considerably lower doses of ACTH than their American counterparts (Watanabe, 1995).

II. Methods

In order to rigorously assess treatment outcomes in the literature, an understanding of the natural history of infantile spasms was d e e m e d necessary. Therefore, we examined the pre-ACTH literature on infantile spasms for natural history data. Following this analysis, an electronic OVID MEDLINE search was p e r f o r m e d on literature published from 1975 until December 2000 using the MeSH subject heading "Spasms, Infantile." All subheadings were included and 1385 abstracts were retrieved. All search titles and abstracts were analyzed for content, and English language articles on therapy and prognosis were selected, including both original and review articles. A hand search of listed references was also p e r f o r m e d where appropriate and wherever the article referenced appeared between 1958 and 1975. All articles were abstracted and data were recorded using a worksheet in order to assess the quality of the evidence (see later) based on study design and treatment effect ( w w w . m e d . u a l b e r t a / e b m / a r t h e r / h t m ) . All randomized open prospective studies, controlled and uncontrolled, were selected for analysis. In order to constitute class II evidence (see later) the prospective study had to be controlled with a well-defined and consistent treatment protocol. Selected retrospective case studies in which

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there was a clear documentation of methodology and results were also analyzed. Clearly stated diagnoses of infantile spasms and hypsarrhythmia, including modified hypsarrhythmia as defined by Hrachovy et al. (1984), were required for inclusion in the analysis. O t h e r details d o c u m e n t e d in the analysis of the literature included numbers of patients, age at onset of spasms, etiology, cointerventions, specific therapies, drug dosage, duration of therapy, and duration of follow-up. Infantile spasms were classified as either symptomatic or cryptogenic (Commission on Classification and Terminology of the International League against Epilepsy, 1989). Patients described as idiopathic, o f " d o u b t f u l " etiology, and those in whom spasms were attributed to immunization were included in the cryptogenic group for analysis. Outcome data in each paper analyzed were divided into short and long term. Short-term outcome measures had to be precisely defined in terms of complete cessation of spasms, resolution of hypsarrhythmia, and, where possible, normalization of electroencephalogram (EEG), reversal of developmental regression, and relapse rate. Long-term outcome measures were defined in terms of nonepileptiform EEG, absence of seizures, and normal development. We were unable to use stringent criteria for the analysis of developmental outcome data because the results of developmental assessments were, more often than not, based on clinical impression, developmental screening tools, and school placement rather than on standardized, age-appropriate pyschometric testing. Data were classified according to the levels of evidence described in the AAN Quality Standards Subcommittee practice guidelines (www.aan.com/public/practice_guidelines/definitn.htm): Class I: Evidence provided by one or more well designed randomized controlled clinical trials, including overviews or meta-analyses of such trials. Class II: Evidence provided by well-designed observational studies with c o n c u r r e n t controls, such as case control and cohort studies. Class III: Evidence provided by expert opinion, case series, case reports, and studies with historical controls. For each drug therapy assessed for infantile spasms, recommendations were rated as standard, guideline, or practice option based on the following criteria: Standard: A principle for patient m a n a g e m e n t that reflects a high degree of clinical certainty. Usually this requires class I evidence that directly addresses the clinical question or overwhelming class II evidence when circumstances preclude randomized clinical trials.

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Guideline: A r e c o m m e n d a t i o n for patient m a n a g e m e n t that reflects m o d e r a t e clinical certainty. Usually this requires class II evidence or a strong consensus of class III evidence. Practice option: A strategy for patient m a n a g e m e n t for which the clinical utility is uncertain. Evidence in support of a practice option is inconclusive or conflicting.

IIh Results

A.

NATURAL HISTORY OF INFANTILE SPASMS

T h e nature of the infantile spasms clinical trials and natural history literature poses a n u m b e r of challenges to analysis. Interpretation of natural history outcomes in infantile spasms that were stratified into cryptogenic and symptomatic patients proved difficult because of limited diagnostic testing in the 1950s and 1960s, particularly in regard to the relatively unsophisticated n e u r o i m a g i n g techniques used at that time. In addition, there were inconsistencies in the literature c o n c e r n i n g the use of the terms cryptogenic and symptomatic (Commission on Classification and Terminology of the International League against Epilepsy, 1989; H o l m e s et al., 1997; Dulac et al., 1994a,b). Also, inclusion criteria differed across studies, and assessment of cognitive o u t c o m e was based on qualitative assessments, including school placement, rather than on formal psychometric testing. With these caveats, however, it is instructive to examine o u t c o m e studies of children with infantile spasms in the presteroid era. Gibbs et al. (1954) r e p o r t e d long term follow up in 103 survivors over 5 years of age from an original cohort of 237 patients with infantile spasms. Detailed clinical a n d EEG data were available in 69 children (Holmes et al., 1997). This cohort can be considered untreated, as n o n e received steroids and all drugs used at that time are known to be ineffective against infantile spasms. At 5 years of age or older, 11% of the children still had infantile spasms, 45% had o t h e r seizure types, and 55% were seizure free. Hypsarrhythmia persisted in 31%, focal EEG abnormalities were n o t e d in 52%, and the EEG was normal in 17%. Only 13% of children over I year of age had n o r m a l intellectual development, but the m e t h o d of assessment was not stated and there was no stratification for cryptogenic and symptomatic groups. Mortality was 11% before age 2, but the cause of death was not given. T h e findings of Gibbs and colleagues are similar to reports f r o m o t h e r authors who have shown that infantile spasms are rare beyond age 5. Livingston et al. (1958) r e p o r t e d long t e r m follow-up in 457 children with

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" m i n o r m o t o r epilepsy" over the age of 3 from an original cohort of 698 infants. O f the children older than 3 years of age, 2.5% were of normal intelligence, but the m e t h o d of assessment was not stated. Forty-nine percent of those children over the age of 5 were seizure free with only 0.7% still having spasms. In a review of studies between 1953 and 1963, Jeavons and Bowers (1964) r e p o r t e d that the mortality of infantile spasms ranged f r o m 3 to 30% and that mental retardation was f o u n d in 7 5 - 9 6 % of cases. However, in most studies, formal psychometric testing was not p e r f o r m e d and the duration of follow-up was variable. T h e r e are also reports of early, spontaneous remission of infantile spasms (Bachman, 1981). Hrachovy etal. (1991) reported spontaneous remission in a retrospective review of a cohort of infantile spasms patients in 11% of 44 patients who had b e e n treated with metharbital or phenytoin, but not steroids, within 6 months of the onset of spasms and in 25% by 12 months of onset. However, it was not stated what p e r c e n t a g e of children in this g r o u p developed other seizure types. This is an i m p o r t a n t omission given the fact that approximately 20% of children with infantile spasms evolve into complex syndromes such as L e n n o x - G a s t a u t . T h e developmental o u t c o m e of the children in this g r o u p was poor, with only 9% being defined as normal. This o u t c o m e was not statistically significantly different when c o m p a r e d to a separate cohort treated with either low dose A C T H or prednisone (Glaze et al., 1988).

B. A C T H AND STEROIDS 1. Historical Perspective

A therapeutic effect of A C T H against seizures was first shown by Klein and Livingston (1950), who observed a beneficial effect of A C T H t r e a t m e n t in four of six children ranging in age f r o m 4.5 to 16 years who were suffering f r o m a variety of seizure types refractory to standard medical therapy. Sorel and Dusaucy-Bauloye (1958) first r e p o r t e d the use of A C T H in seven children with infantile spasms who had associated developmental regression at the onset of spasms. T r e a t m e n t resulted in a cessation of spasms in six children and an i m p r o v e m e n t in EEG and normalization of behavior in two children. This effect was confirmed the following year by others (Stamps et al., 1959; D u m e r m u t h , 1959). Since then there have b e e n a multitude of articles reporting usage of A C T H and corticosteroids in the treatment of infantile spasms. Most of these have b e e n retrospective reports with variable t r e a t m e n t regimens.

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2. Early Retrospective Studies and Reviews Jeavons and Bowers (1964) r e p o r t e d a retrospective review of 19 treatm e n t studies with steroids or A C T H conducted f r o m 1958 to 1964 that indicated that spasms stopped in 58% and EEG normalized in 54% of child r e n treated with A C T H or steroids. In the long term, EEG normalized in 20% and n o r m a l d e v e l o p m e n t was achieved in 1.8-25 % of children across studies, but the duration of follow up was not stated. T h e same authors (Jeavons and Bowers, 1964) also conducted a retrospective review of 112 children with infantile spasms, 66 of w h o m were treated with natural A C T H or steroids. O f those treated with steroids, 70% had cessation of spasms and 41% had normalization of EEG, but 54% had a relapse of spasms. Only 14% of children were cognitively normal and steroids a p p e a r e d to have no significant effect on the developmental outcome. T h e mortality rate was 13%, but the cause of death was not stated. In their classic review, Lacy and Penry (1976) r e p o r t e d a m a r k e d variability in dosage formulations of corticosteroids and A C T H used u p to that time. Also, those authors observed that the wide dosage range and variation in duration of therapy across studies m a d e data comparison difficult, if not impossible. They also f o u n d that inclusion criteria were not well defined and the study designs were p o o r t h r o u g h o u t the t r e a t m e n t studies reviewed. A m o n g the limited valid conclusions that Lacy and Penry were able to draw was that there was little valid evidence that either corticosteroid or A C T H treatment of infantile spasms had a beneficial effect on intellectual outcome.

3. Treatment Trials of Infantile Spasms with A CTH Fifteen studies were analyzed. Five were r a n d o m i z e d controlled studies providing class I evidence, three were prospective o p e n label trials with no controls providing class III evidence (Table I), and seven were retrospective case series, also providing class III evidence (Table II). N o n e of the r a n d o m i z e d controlled studies was placebo controlled a n d two were crossover studies using p r e d n i s o n e (Hrachovy et al., 1983) or vigabatrin (Vigevano et al., 1997). Children ranged in age f r o m 1 to 24 months and all trials used video EEG m o n i t o r i n g to d o c u m e n t a t r e a t m e n t response. Two studies used synthetic A C T H (Yanagaki et al., 1999; Vigevano et al., 1997). A C T H dosage in the r e m a i n d e r of the studies analyzed varied f r o m 0.2 I U / k g up to 150 I U / m 2 and duration of t r e a t m e n t at the highest dose ranged f r o m 7 to 40 days with total t r e a t m e n t time varying f r o m 3 to 12 weeks. All studies involved small n u m b e r s (5 to 50) of patients and n o n e were stratified at entry into cryptogenic and symptomatic groups.

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Forty-two to 87% of patients across studies had cessation of spasms. Time from initiation of treatment to cessation of spasms as stated in three studies was 8 - 1 2 days. In all studies except one (Baram et al., 1996), a greater percentage of cryptogenic patients responded to ACTH. Hrachovy et al. (1983) reported a response rate of 42% using low-dose and short duration ACTH therapy, whereas Baram et al. (1996) achieved a response rate of 87% using high-dose and longer duration ACTH therapy. Hrachovy et al. (1994) and Yanagaki et al. (1999) found no dose-related difference in the response rate of infantile spasms to ACTH therapy. T h e relapse rate in these studies ranged from 15 to 35%. T h e r e are three open label, prospective studies of ACTH treatment of infantile spasms; however, none of these treatment trials meet the requirements for class II levels of evidence due to a lack of controls (Snead et al., 1989; Lombroso, 1983; Hrachovy et al., 1980). T r e a t m e n t protocols were varied in one study for both dosage and duration during the treatment period (Lombroso, 1983). Therefore, the results of these studies constitute class III evidence. Hrachovy et al. (1980) reported that 100% of 5 children responded to low-dose ACTH, whereas Snead et al. (1989) reported a 93% response rate in 15 children treated with high-dose therapy. Relapse rates were 20 and 36%, respectively. Lombroso (1983) compared the efficacy of synthetic ACTH to oral corticosteroids and benzodiazepines. This study was stratified for symptomatic/cryptogenic etiology. In the 69 symptomatic patients treated with ACTH, 39% had cessation of spasms and EEG normalized in 32%. Analysis of comparative efficacy between ACTH and prednisone was not possible in the cryptogenic group because the short-term response to ACTH and to ACTH followed by prednisolone was combined into one treatment group. The majority of studies on the use of ACTH in infantile spasms are retrospective. Seven studies meeting selection criteria were analyzed (Table II) (Cossette et al., 1999; Sher et al., 1993; Fois et al., 1984; Snead et al., 1983; Lerman et al., 1982; Riikonen, 1982). Response rates for the cessation of spasms ranged from 42 to 100% and resolution of hypsarrhythmia from 23 to 97%, but the relapse rate ranged from 12 to 47%. In studies where outcome was stratified for etiology, 5 6 - 7 5 % of cryptogenic and 4 2 - 7 1 % of symptomatic patients had resolution of spasms when treated with ACTH. 4. Treatment Trials of Infantile Spasms with Oral Corticosteroids

A randomized controlled trial of hydrocortisone in a selected population of tuberous sclerosis patients (discussed later) was excluded from analysis because hypsarrhythmia was not required for inclusion (Chiron et al.,

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1997). An o p e n prospective study of prednisone in the treatment of infantile spasms was also excluded from analysis because of outcome measures that were poorly defined (Hrachovy et al., 1979). Five studies were analyzed: two randomized controlled studies providing class I evidence and two prospective open label trials with no controls plus one retrospective case series, both of which provided class III evidence (Table III). Both randomized controlled trials (Baram et al., 1996; Hrachovy et al., 1983) used 2 m g / k g of prednisone for 3 - 7 weeks and the response rate was 28-33%. In an open prospective study, Lombroso (1983) reported 39 symptomatic and 17 cryptogenic patients who were treated with prednisolone (2 m g / k g ) with cessation of spasms in 36 and 39%, respectively. The EEG normalized in 28% of symptomatic patients and 42% of cryptogenic patients. Snead et al. (1983) reported cessation of spasms and resolution of hypsarrhythmia in 59% of children treated with 3 m g / k g / d a y of prednisone. 5. Comparative Studies of the Treatment of Infantile Spasms with A CTH and Oral Corticosteroids: Short-Term Outcomes a. A C T H vs Prednisone. Two randomized controlled, one prospective o p e n label trials, and one retrospective case study comparing ACTH and prednisone described earlier were analyzed (Tables I-III). One randomized control trial showed no difference in efficacy between ACTH and prednisone (Hrachovy et al., 1983) and one (Baram et aL, 1996) demonstrated superior efficacy of high-dose ACTH therapy. In a retrospective case series, Snead et al. (1983) showed high-dose ACTH therapy to be superior to prednisone with cessation of spasms in 100% of patients treated with ACTH vs 59% resolution of spasms in the prednisone group. EEG was normalized in 97% of ACTH-treated patients vs 50% in the prednisone group. If all of the A C T H / p r e d n i s o n e data are combined, ACTH was effective in 39-100% of children with infantile spasms, whereas prednisone treatment was associated with cessation of spasms in 16-39%. 6. Comparative Studies of the Treatment of Infantile Spasms with A CTH and Oral Corticosteroids: Long-Term Outcomes A prospective, open-label, long-term follow-up study (Heiskala et al., 1996) was excluded from analysis because of poorly defined outcome measures. Eight studies that provided class III evidence were analyzed: n o n e were randomized or controlled; three were prospective open label, and five were retrospective case series. Glaze et al. (1988) reported longterm follow-up in 64 patients, 48 of whom had previously been entered in crossover treatment protocols. The other 16 children in this cohort were

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treated in a prospective open-label protocol of either A C T H or prednisone (Hrachovy et al., 1979,1980,1983). Low-dose A C T H (20 IU) and 2 m g / k g of prednisone were used across the studies, and o u t c o m e was stratified for t r e a t m e n t a n d etiology. T h e majority of children (88%) had symptomatic spasms. Mean duration of follow-up was 50 m o n t h s with a range of 9 m o n t h s to 10 years. T h e r e was a 5% mortality rate in symptomatic patients, but cause of death was not stated. Cryptogenic patients had a better o u t c o m e with 2 of 8 cryptogenic patients being cognitively normal c o m p a r e d with 3 of the 56 symptomatic patients (P < 0.05). Infantile spasms persisted in 42% of children, whereas 53% of patients developed o t h e r seizure types and 47% were seizure free. Stratification for t r e a t m e n t d e m o n s t r a t e d no significant difference in o u t c o m e for A C T H c o m p a r e d to prednisone. In the second prospective study, follow-up beyond 6 years was r e p o r t e d in 102 children f r o m an original cohort of 121 cryptogenic cases (Lombroso, 1983). Fifty p e r c e n t of ACTH-treated patients were developmentally normal; 62% were seizure free and 39% had a normal EEG. W h e n A C T H was c o m p a r e d to other therapies, such as oral steroids, benzodiazepines, or conventional anticonvulsants, there was a statistically significant difference in favor of A C T H for psychometric d e v e l o p m e n t and achieving a seizurefree state (P < 0.05). An improved n e u r o d e v e l o p m e n t a l o u t c o m e was also associated with early c o m m e n c e m e n t of therapy. In contradistinction, Glaze et al. (1988) f o u n d that a delay in initiation of t r e a t m e n t of the spasms had no influence on long-term cognitive o u t c o m e or on the d e v e l o p m e n t of epilepsy. In the third prospective study, Riikonen (1982) r e p o r t e d a series of 192 patients with infantile spasms followed for m o r e than 3 years; 162 of these children previously had b e e n treated with ACTH, but the specific treatm e n t used in the " n o n - A C T H " group was not defined. N o r m a l cognitive development, defined as an I Q > 85, was reported in 12 and 29% were seizure free with 18% achieving a normal EEG. Psychiatric disorders were noted in 27% of children. In the ACTH-treated group, a short t r e a t m e n t lag and a good response to A C T H were associated with a better long-term prognosis (P < 0.05). In addition, as reported by others, an "all-or-none" t r e a t m e n t response to A C T H was noted. W h e n o u t c o m e was assessed in relation to dosage, 6% of high-dose and 18% of low-dose groups had normal IQ. These findings persisted over time as indicated by follow-up data in the same cohort until death or until age 2 0 - 3 0 years (Riikonen, 1996). Two retrospective case series that address long-term prognosis in child r e n with infantile spasms involve large cohorts. Matsumoto et al. (1981) r e p o r t e d a greater than 6-year-follow-up in 200 patients with infantile spasms, 68% of w h o m were classified as cryptogenic. In the 162 survivors,

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A C T H had b e e n used to treat the spasms in 87.5% of patients. Forty-four p e r c e n t were seizure free, and " n o r m a l " mental d e v e l o p m e n t was n o t e d in 22% of children, but this o u t c o m e measure was based on school placement. In the cryptogenic ACTH-treated group, a short t r e a t m e n t lag was associated with a good cognitive o u t c o m e (P < 0.05). A relapse of spasms was associated with p o o r e r outcome. Overall the mortality rate was 19%, but cause of death was not stated. T h e other large retrospective series c o m p a r e d o u t c o m e in patients treated with A C T H or steroids to nonsteroid-treated patients (Jeavons et al., 1973). Long-term outcome was r e p o r t e d in 150 patients with infantile spasms, 105 of w h o m received either A C T H or steroids. In 117 survivors who were followed beyond age 5, only 16% overall and 37% of the cryptogenic g r o u p were n o r m a l in terms of their d e v e l o p m e n t as d e t e r m i n e d by school performance. Although the limitations of the o u t c o m e measures in this study constrain the conclusions that can be drawn, the authors believe that cognitive o u t c o m e in infantile spasms is i n d e p e n d e n t of treatment. T h e studies just described support the idea that a cryptogenic etiology of infantile spasms is associated with a better long-term outcome. O t h e r factors i n d e p e n d e n t of t r e a t m e n t r e p o r t e d to be associated with a good prognosis include normal d e v e l o p m e n t prior to onset of spasms, no neurological deficit, absence of other seizure types in association with spasms, and the absence of o t h e r EEG abnormalities (Glaze et al., 1988; Koo et al., 1993; Lombroso, 1983; Riikonen, 1982; Matsumoto et al., 1981; Jeavons etal., 1973). a. A C T H vs Nitrazepam. O n e study c o m p a r i n g A C T H to nitrazepam did not constitute class I evidence because the results were c o n f o u n d e d by cointervention with conventional anticonvulsants including valproate. T h e primary o u t c o m e measure in the nitrazepam study was defined as a 7 5 - 1 0 0 % reduction in spasms rather than complete cessation (Dreifuss et al., 1986). Therefore, no conclusions can be drawn f r o m this study. b. A C T H vs Vigabatrin.

These treatment trials are described later.

C. A C T H AND STEROIDS: CONCLUSIONS AND RECOMMENDATIONS Class I and class III evidence allow for r e c o m m e n d a t i o n s rated as guidelines for the short-term efficacy of A C T H in controlling infantile spasms and resolution of hypsarrhythmia. T i m e to response is within 2 weeks a n d an "all-or-none" response has b e e n r e p o r t e d in a n u m b e r of studies (Riikonen et al., 1989; Snead et al., 1989; Hrachovy et al., 1983).

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The optimum dosage and duration of therapy cannot be determined due to inconclusive evidence. T h e r e is no consensus of evidence that dosage determines response. Class I and class III evidence show only limited efficacy for the use of oral corticosteroids in infantile spasms and do not allow for strong recommendations regarding short-term efficacy for these drugs in the treatment of infantile spasms. Evidence indicates that the efficacy of ACTH in affecting the cessation of seizures and the normalization of the EEG in children with infantile spasms is superior to that of oral corticosteroids. T h e r e is reasonable class III data to suggest that an early initiation of treatment of infantile spasms may improve long-term outcome. However, there is inconclusive class III evidence that treatment of infantile spasms with either ACTH or corticosteroids improves the long-term prognosis for cognitive outcome or decreases the later incidence of epilepsy. Therefore, recommendations rated as a practice option can be made for the long-term efficacy of ACTH and corticosteroids.

D . VIGABATRIN

1. Vigabatrin in the Treatment of Infantile Spasms Nine studies were analyzed: one randomized controlled study providing class I evidence and eight prospective open label trials with no controls or retrospective case series, both providing class III evidence (Table 1V). T h e randomized controlled trial (Appleton et aL, 1999) showed that at the end of the double-blind phase, when compared with baseline patients treated with vigabatrin, 78% had a reduction in spasms compared with 26% in the group treated with placebo (P < 0.02). In the retrospective studies (Fejerman et al., 2000; Appleton et al., 1999; Granstrom et al., 1999; Koo, 1999; Siemes et al., 1998; Wohlrab et aL, 1998; Aicardi et al., 1996, Vles, 1993) the range of response was from 19 to 68% for children with symptomatic infantile spasms and from 50 to 100% for cryptogenic infantile spasms. The analysis of response for symptomatic infants excludes the evaluation of children with tuberous sclerosis alone, which is discussed in a separate section. In seven of eight studies, children with cryptogenic infantile spasms had a higher response rate to vigabatrin than those with symptomatic spasms. In the nine trials reviewed, vigabatrin dosages ranged from 30 to 200 m g / k g / d a y . In all studies, at least some of the children were on a dosage between 30 and 65 m g / k g / d a y . The numbers were not large e n o u g h to determine with statistical significance if the efficacy ofvigabatrin

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in infantile spasms was dose d e p e n d e n t ) . The time from initiation of therapy to cessation of spasms ranged from 4 to 15 days (Appleton et aL, 1999; Kwong, 1997; Aicardi et al., 1996; Fejerman et al., 2000; Koo, 1999; Wohlrab etal., 1998; Vies etal., 1993). Appleton etal. (1999) reported that those children who initially received placebo for 5 days before the crossover to vigabatrin had a similar outcome when compared to the children who received vigabatrin at the beginning of the spasms. T h e time to EEG response was 5 - 1 5 days and 53-100% of children had resolution of hypsarrhythmia (Appleton et al., 1999; Fejerman et al., 2000; Wohlrab et al., 1998; Koo, 1999; Vies et al., 1993). The relapse rate of infantile spasm after initial control ranged from 0 in one study with seven children with tuberous sclerosis to 33%; however, it is difficult to compare these data because the period of follow-up was widely variable, ranging from 0.5 to 78 months. When the relapse rate was analyzed separately for symptomatic vs cryptogenic spasms (Fejerman et al., 2000; Granstrom et al., 1999; Koo, 1999; Wohlrab et al., 1998), there was no consistent trend. The most significant side effect of vigabatrin is the development of concentric visual field defects, which has been reported in 4 0 - 5 0 % of adult patients on vigabatrin treatment (Lawden et aL, 1999; Wild et al., 1999; Daneshvar et al., 1999; Kalviainen et aL, 1999; Ruether et al., 1998; Eke et al., 1997; Miller et al., 1999). This side effect has also been shown in 6 of 12 children receiving vigabatrin who had visual field assessment. Visual field assessment could not be p e r f o r m e d in 141 additional children on vigabatrin because they were too young a n d / o r developmentally delayed (Wohlrab et al., 1999). Currently, the incidence of visual field deficits in infants u n d e r 1 year of age treated with vigabatrin is unknown. However, there is emerging evidence that abnormalities in the electroretinogram (ERG) may occur in children as a result ofvigabatrin therapy (Westall et al., 2001). 2. Vigabatrin in the Treatment of Infantile Spasms in Children with Tuberous Sclerosis

One study evaluating long-term mental and behavioral outcome of infantile epilepsy treated with vigabatrin in tuberous sclerosis patients was excluded from analysis because of a lack of information about dose, response, or relapse (Jambaque et al., 2000). A meta-analysis by Hancock et al. (1999) of the efficacy of vigabatrin for infantile spasms in children with tuberous sclerosis showed a response rate of 95% across eight studies; however, a critical appraisal of the literature was not done in this study. Anecdotal data were included as well as a large series of children up

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to 13 years of age with intractable spasms (Chiron et al., 1991). For the purposes of the current critical appraisal, only children with tuberous sclerosis and infantile spasms who were evaluated u n d e r 2 years of age have b e e n included (Wohlrab et al., 1998; Vigevano et al., 1997; Chiron et al., 1997; Aicardi et aL, 1996). Studies of vigabatrin as m o n o t h e r a p y as well as studies of infants treated with vigabatrin vs steroids were included in this analysis of tuberous sclerosis patients with infantile spasms. T h e response of infantile spasms to vigabatrin in infants with tuberous sclerosis was uniformly good with a high percentage of responders whose spasms remitted (Table V). Four studies showed cessation of spasms in 9 6 - 1 0 0 % of children treated with vigabatrin (Wohlrab et al., 1998, 1999; Chiron, 1997; Vigevano et al., 1997; Aicardi et al., 1996). O n e study of seven infants reported a 51% response rate (Fejerman et al., 2000). 3. Comparative Studies of the Treatment of Infantile Spasms with Vigabatrin vs Steroids O n e randomized controlled trial (Chiron et al., 1997) did not m e e t the criteria for analysis as set forth in the m e t h o d o l o g y section because only 9 of 22 children had hypsarrhythmia on the p r e t r e a t m e n t EEG. Two studies that c o m p a r e d vigabatrin to steroids in the treatment of infantile spasms were analyzed: a r a n d o m i z e d controlled trial providing class I evidence (Vigevano et al., 1997) and a retrospective case series providing class III evidence (Cossette et al., 1999). Although the vigabatrin doses were similar (100-150 m g / k g / d a y ) , the steroids used differed with either A C T H or hydrocortisone being used in varying doses. In the randomized controlled trial, the efficacy, defined as spasm free at 20 days, was better for A C T H (Vigevano et al., 1997). In the

TABLEV VIGABATRIN:SEPARATEANALYSISFORCHILDREN"WITH TUBEROUSSCLEROSIS(TS) + INFANTILESPASMS No.

Author, year Chiron, 1997 Fejerman, 2000 Wohlrab, 1998 Aicardi, 1996 Vigevano, 1997

Study design, evidence RCT, I POL,III RCS, III RCS, III RCS, III

responders/ total TS subjects(%) 11/11 (100%) 4/7 (57%) 3/3 (100%) 27/28 (96%) 3/3 (100%)

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retrospective study the drugs were of similar efficacy (Cossette et al., 1999), but the outcome measure was 12 months spasm free. In both studies the rate of EEG improvement was superior for ACTH as compared to vigabatrin, but the relapse rate was higher for ACTH-treated children.

E.

VIGABATRIN: CONCLUSIONS AND RECOMMENDATIONS

Class I and class III evidence support a standard of practice recommendation for the use of vigabatrin in the treatment of infantile spasms in children with tuberous sclerosis. Also, there is a strong consensus of class I and class III evidence that allows for guidelines recommendations for the use of vigabatrin in the treatment of infantile spasms in nontuberous sclerosis patients. Vigabatrin appears to be effective within 14 days of initiation of therapy. The safety of the drug remains uncertain because of concerns about retinal toxicity. The evidence is inconclusive as to which treatment is superior, vigabatrin or steroids. Therefore, only a practice option r e c o m m e n d a t i o n can be suggested for which of the two drugs to use in the treatment of nontuberous sclerosis patients.

F. OTHER DRUGS

1. Valproic Acid

Although valproate has been used in infantile spasms since the 1970s (Simon et al., 1975), there is little evidence to support its efficacy. One randomized, double-blind, placebo-controlled crossover trial of valproate in a highly selected group of 21 symptomatic infantile spasms patients was excluded from analysis because outcome was defined in terms of mean reduction in spasm frequency (Dyken et al., 1985). One prospective openlabel study was excluded because hypsarrhythmia was not required for inclusion (Bachman, 1982), and two studies of valproate were excluded from analysis because valproate was used in combination with other drugs (Ito et al., 1991; Schlumberger et al., 1994). T h r e e studies providing class III evidence were identified for analysis: two prospective uncontrolled open-label studies (Prats et al., 1991; Siemes et al., 1988) and one retrospective case series (Pavone et al., 1981). The prospective studies used high-dose (100-300 m g / k g / d a y ) valproate. Siemes et al. (1998) reported cessation of spasms in 73% of 22 patients and resolution of hypsarrhythmia in 91% of children at 6 months followup. The majority responded within 2 weeks, but 20% relapsed. Prats et al. (1991) reported resolution of hypsarrhythmia in 73% of patients with a

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19% relapse rate. At 2-year follow-up, 83% of cryptogenic and 33% of symptomatic patients were seizure free. Normal d e v e l o p m e n t was achieved in 83% of the cryptogenic group and in 7% of the symptomatic patients. T h r o m b o c y t o p e n i a occurred in a third of patients in each study requiring discontinuation of valproate in 4 patients. In a retrospective case series of 18 patients, Pavone et al. (1981) reported a complete cessation of spasms and normalization of the EEG in 22% of patients using valproate dosages of 2 0 - 3 0 m g / k g / d a y . T h e r e is limited class III evidence for efficacy for valproic acid in the treatment of infantile spasms. Therefore, a practice option r e c o m m e n d a t i o n can be m a d e for the use of this drug in the t r e a t m e n t of infantile spasms. 2. Benzodiazepines

Benzodiazepines that have b e e n used in infantile spasms include clonazepam, clobazam, diazepam, and nitrazepam (Volzke et al., 1967; Gibbs et al., 1965), but there are no studies that m e t the criteria for inclusion in this analysis. T h e only multicenter r a n d o m i z e d controlled t r e a t m e n t trial of nitrazepam vs A C T H in infantile spasms is limited by a lack of well-defined o u t c o m e measures. Response was defined as a 7 5 - 1 0 0 % reduction in seizure frequency (Dreifuss et aL, 1986). Nitrazepam was of similar efficacy to A C T H with 52 and 57%, respectively, responding. T h e nitrazepam-treated g r o u p experienced m o r e side effects but side effects were qualitatively m o r e severe in the ACTH-treated group. Because of limited inconclusive class III evidence and no long-term data, no recomm e n d a t i o n can be m a d e for the use of benzodiazepines in the t r e a t m e n t of infantile spasms. 3. Pyndoxine

Pyridoxine is the treatment of first choice for infantile spasms in J a p a n (Watanabe, 1995), but there are no prospective controlled trials of this drug. A study describing combination high-dose pyridoxine therapy with o t h e r agents (Ito et al., 1991) was excluded f r o m analysis. Two uncontrolled prospective open-label trials providing class III evidence were analyzed (Pietz et al., 1993; Ohtsuka et aL, 1987) (Table VI). T h e response rate ranged f r o m 13 to 29% in these two studies with the same percentage o f resolution of hypsarrhythmia. T h e r e is no evidence to suggest that the response rate of infantile spasms to pyridoxine therapy exceeds the spontaneous remission rate that would be predicted f r o m the natural history studies, and no r e c o m m e n d a t i o n can be m a d e for the use of pyridoxine in the t r e a t m e n t of infantile spasms.

TREATMENT OF INFANTILESPASMS: AN EVIDENCE-BASEDAPPROACH

G.

177

NEWER ANTIEPILEPTIC DRUGS

T o p i r a m a t e (Glauser et al., 1998), zonisamide (Suzuki et al., 1997; Yanai et al., 1999), felbamate (Hurst et al., 1995), lamotrigine (Veggiotti et al., 1994), tiagabine (Kugler et al., 1999), intravenous i m m u n o g l o b u l i n ( M G ) (van Engelen etal., 1994; E c h e n n e etal., 1991; Ariizumi etal., 1987), thyrotropin-releasing h o r m o n e (TRH) (Matsumoto et al., 1987), and the ketogenic diet (Livingston et al., 1958) all have b e e n advocated for the treatm e n t of infantile spasms. T h e r e are a few class III studies of these agents, either in uncontrolled small prospective open-label studies or retrospective case series (Table VI), but the evidence is insufficient. Therefore, no r e c o m m e n d a t i o n can be m a d e for the use of any of the newer antiepileptic drugs in the t r e a t m e n t of infantile spasms.

IV. Summary and Conclusions

Results of a critical a n d systematic review of the literature show clearly that class I and class III evidence support a standard of practice recomm e n d a t i o n for the use of vigabatrin in the treatment of infantile spasms in children with tuberous sclerosis. Limited class I and a consensus of class III evidence support a guidelines r e c o m m e n d a t i o n for the use of either A C T H or vigabatrin in infantile spasms in terms of cessation of spasms and resolution of hypsarrhythmia. T h e evidence does not support the superiority of one over the other. Further, there is no strong evidence that successful t r e a t m e n t of infantile spasms with either A C T H or vigabatrin improves the long-term prognosis for cognitive o u t c o m e or diminishes the incidence of epilepsy. A practice option r e c o m m e n d a t i o n for the use of oral corticosteroids in the t r e a t m e n t of infantile spasms is s u p p o r t e d by limited and inconclusive class I and III data. Based on the evidence, no r e c o m m e n d a t i o n can be m a d e for the use of pyridoxine, benzodiazepines, or the newer antiepileptic drugs in the t r e a t m e n t of infantile spasms. T h e validity of guidelines is d e t e r m i n e d by whether they can be applied to a particular population, whether they m e e t the needs of an individual practitioner, and whether the benefits exceed the risks and are worth the cost (Hayward et al., 1995). T h e r e is great geographical variability t h r o u g h o u t the world in the availability of agents such as natural or synthetic A C T H and, in the United States, vigabatrin. In addition, while A C T H and vigabatrin represent the most effective t r e a t m e n t modalities for infantile spasms, they also are associated with significant side effects. T h e potential of vigabatrin for retinal toxicity in children receiving the drug

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for infantile spasms is u n k n o w n and therefore cannot be factored into a risk-benefit equation.

A.

RECOMMENDATIONS FOR FUTURE CLINICAL

TRIALS

There is little disagreement about the desired goals of treatment in infantile spasms, namely seizure control and good cognitive outcome. However, as we have seen, there is little agreement on the means to the first end, and a major question whether the second can ever be achieved. Further prospective randomized studies (Commission on Antiepileptic Drugs of the International League against Epilepsy, 1994) are required, which should meet a n u m b e r of criteria in order to address these unresolved questions. Multicenter trials are essential in order to accrue e n o u g h patients to increase statistical power. Studies should be stratified at entry for etiology. Inclusion criteria should include infantile spasms and the presence of either classical or modified hypsarrhythmia. Infantile spasms and EEG should be characterized by video EEG monitoring. A standardized pretreatment developmental assessment is necessary to enable longitudinal evaluation of cognitive outcome. A standard dose and duration of treatment are essential to allow statistical comparison of short- and long-term outcomes across centers. Short-term measures should be precisely defined and should include complete cessation of spasms as well as a grading of the EEG response to include resolution of hypsarrhythmia, residual epileptiform activity, or complete normalization. Long-term measures should also be well defined and should include cognitive outcomes using standardized psychometric assessments. The long-term incidence of epilepsy should be documented. A multicenter infantile spasms treatment trial that meets a n u m b e r of these criteria is currently underway in the United Kingdom. The study is designed to compare the efficacy of vigabatrin to synthetic ACTH or prednisolone in the short term with assessment of developmental o u t c o m e at 1 2 - 2 4 months (Osborne et al., 1999).

Acknowledgment This studywas supported in part by the BloorviewChildren's Hospital Foundation.

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