Vigabatrin therapy for infantile spasms: review of major trials in Europe, Canada, and the United States; and recommendations for dosing


L. Carmant, Division of Neurology, Université de Montréal, CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Room 5421, Montreal, QC, Canada H3T 1C5


Carmant L. Vigabatrin therapy for infantile spasms: review of major trials in Europe, Canada, and the United States; and recommendations for dosing.
Acta Neurol Scand: 2011: 124 (Suppl. 192): 36–47.
© 2011 John Wiley & Sons A/S.

Infantile spasms (IS) are a unique and severe form of epilepsy associated with poor neurologic and developmental outcomes. The refractory spasms and abnormal electroencephalogram (EEG) patterns associated with the condition are believed to have a progressively detrimental impact. Therefore, rapid and complete control of spasms is the primary goal of treatment. Well-controlled clinical trials in Europe, Canada, and the United States have demonstrated that vigabatrin is efficacious and generally well-tolerated as monotherapy for IS. Several key studies, including pivotal trials that led to United States approval of vigabatrin in 2009, as well as comparative trials of vigabatrin and hormonal treatment, are the focus of this review. All studies assessed spasm cessation — usually as the primary endpoint — and adverse events. Vigabatrin dosages generally ranging from 100 to 150 mg/kg/day demonstrated efficacy to decrease or eradicate spasms and eliminate hypsarrhythmic EEG in patients with newly diagnosed IS. Several studies demonstrated long-term sustainability of spasm freedom with no negative impact on developmental outcomes. Vigabatrin was generally well-tolerated with few severe adverse events. Visual field defects cannot be adequately assessed in infants and young children, so this potential adverse effect was not evaluated in children with spasms. Notably, the time to response with vigabatrin was very rapid, generally occurring within 2 weeks of initial treatment. This allows for early treatment modification as needed. For infants who respond well to vigabatrin, treatment duration up to 6 months appears to be appropriate for realizing spasm freedom while limiting potential risks of adverse events and recurrences.


Infantile spasms (IS) are a unique and frequently severe type of epilepsy occurring in infants (1). IS is characterized by distinct seizures that include flexor, extensor, and mixed flexor-extensor spasms (2). Infants with IS display a specific electroencephalogram (EEG) pattern called hypsarrhythmia. IS is associated with poor long-term outcomes, including psychomotor delay (2), development of other seizure types, impaired cognitive and psychosocial functioning, and mortality in a small but significant number of patients (3).

The two primary categories of IS are symptomatic and cryptogenic. Symptomatic IS develops in conjunction with a history of pre-, peri-, or post-natal insult from damage or disease. In cases of symptomatic IS, there is an identifiable etiology. Conversely, cryptogenic IS arises without explanation in infants with normal development and has no definitive cause (4). Genetic conditions such as Down’s syndrome and tuberous sclerosis complex (TSC) are important causes of symptomatic IS (2). In addition, recent developments in genetic testing have revealed that mutations within the aristaless-related homeobox gene on chromosome Xp22.13 is associated with an X-linked IS syndrome (5). Likewise, X-linked IS can also be caused by mutations in the cyclin-dependent kinase-like 5 gene located on the Xp22.3 chromosome (6). Mutations in the lissencephaly-1 and the doublecortin genes also have been associated with IS (6). In a 2010 report from the International League Against Epilepsy (ILAE) (7), the genetic mutations associated with IS were described as having high clinical validity, indicating that genetic tests for these mutations can accurately predict risk for the disorder. Likewise, the ILAE stated that these mutations have very substantial clinical utility for establishing etiology, so further diagnostic tests can be avoided and genetic counseling can be considered (7). Another recent study provided evidence that genetic copy number variants in patients with IS may be related to abnormalities in ventral forebrain development and pathways of synaptic function (8).

Because continued spasms and abnormal EEG patterns associated with IS are believed to have a progressively detrimental impact on long-term development, rapid and complete control of spasms is the primary goal of treatment (9). Vigabatrin is a structural analog of γ-aminobutyric acid (GABA) that increases GABA concentrations in the brain by irreversibly inhibiting GABA-transaminase (10). Available outside the United States since 1989, vigabatrin was approved in the United States in 2009 as adjunctive therapy for adult patients with refractory complex partial seizures who have responded inadequately to several alternative treatments and as monotherapy for pediatric patients aged 1 month to 2 years with IS (11). Clinical experience with vigabatrin for refractory complex partial seizures is reviewed elsewhere in this supplement (12, 13).

Several open and retrospective studies provided early evidence that vigabatrin was efficacious for controlling IS (14–19). Randomized clinical trials in Europe, Canada, and the United States have further established the clinical efficacy of vigabatrin for IS (9, 20–26).

In clinical studies, vigabatrin was generally well-tolerated with an adverse event (AE) profile comparable with that of other antiepileptic drugs (AEDs) (27). Two potential vigabatrin-specific adverse effects, intramyelinic edema (IME) and peripheral visual field defects (pVFDs), are examined in detail in two separate articles in this supplement (28, 29).

A critical component of the treatment of IS is timing. Identifying IS early and finding an effective treatment is key to the long-term developmental outcomes of patients because continued seizures can have detrimental brain effects (2, 30). Refractory epilepsy, including IS, that begins before age 2 years has been shown to significantly increase the risk of mental retardation (31). On the other hand, determining an optimal duration of treatment is also very important to minimize potential adverse effects. Long-term exposure to vigabatrin increases the potential risk of developing a pVFD (27, 32). With steroids such as adrenocorticotropic hormone (ACTH), increased risks of long-term exposure may include infections secondary to immunosuppression, hypertension, Cushingoid features, and metabolic abnormalities associated with ACTH (33, 34). Therefore, it is important to find the safest and most-effective treatment and treatment duration and to adequately assess the benefit–risk ratio in infants with IS receiving vigabatrin (27). Dosing and duration of treatment will be highlighted throughout this article as the various vigabatrin trials are discussed.

This article reviews two pivotal clinical trials that led to the approval of vigabatrin for IS in the United States (9, 20) and five other randomized, prospective clinical studies conducted in Europe and Canada (21, 22, 24–26), providing a detailed examination of each. A summary of the study designs and key outcomes for the United States, European, and Canadian studies is provided in Table 1, and baseline characteristics for patients in each study are provided in Table 2. Outcomes for a key measure of effectiveness for IS, the percentage of patients with spasm cessation, are provided in Fig. 1.

Table 1.   Summary of clinical trials of vigabatrin for IS Thumbnail image of
Table 2.   Baseline patient characteristics
Baseline variableStudy
Appleton et al. (20) (N = 40)Elterman et al. (9) (N = 221)Chiron et al. (21) (N = 22)Vigevano and Cilio (22) (N = 42)Lux et al. (25) (N = 107)
  1. TBS, tuberous sclerosis; NA, not available; SD, standard deviation.

  2. Number of patients for each study represents the number for whom baseline data were collected at study entry. Lux et al. (24) and Darke et al. (26) were not included because baseline characteristics were reported in the study by Lux et al. (25).

  3. aMedian.

  4. bData on mean or median age, weight, race, duration of spasms before study entry, and specific etiology were not reported for some studies.

  5. cSome data were not available for patients who discontinued the studies; hence, in some instances, the sum of n-values may not equal N.

Age (months), mean (range or SD)0.5 (0.08–1.5)7.2 (±3.6)6.6 (4–9)5.5 (2–9)5 (4–7)a
Duration of spasms in weeks before entry, mean (range)6.5 (2–13)NAb3.5 (2–13)NAb (1–3)4 (0–4)
Male, n (%)19 (47.5)108 (48.9)10 (45)21 (50)64 (58)
Weight (kg), mean (SD)NAb8.0 (2.0)NAbNAbNAb
Race, n (%)
 WhiteNAb160 (72.4)NAbNAbNAb
 Black26 (11.8)
 Asian3 (1.4)
 Other32 (14.5)
Etiology, n (%)
 Symptomatic, other28 (70)126 (57.0)0 (0.0)27 (64)59 (56)c
 Cryptogenic12 (30)57 (25.8)0 (0.0)15 (36)46 (44)c
 Symptomatic, TBS0 (0.0)38 (17.2)22 (100)NAbNAb
Figure 1.

 Percentages of patients with spasm cessation in studies of vigabatrin for infantile spasms (IS). The percentages of patients who achieved spasm cessation with vigabatrin therapy are provided for each of the major studies of vigabatrin for IS (9, 20–22, 24–26). The denominators represent the numbers of patients who completed their respective studies and thus were included in efficacy analysis.

Pivotal US clinical trials of vigabatrin for IS

Two clinical trials form the basis for US Food and Drug Administration approval of vigabatrin for IS: a relatively small, short-term placebo-controlled study by Appleton et al. (20), and a larger, longer dosage-comparison trial by Elterman et al. (9).

A randomized, double-blind, placebo-controlled, parallel-group study with an open follow-up period: Appleton et al. (20)

This international, multicenter, randomized, placebo-controlled study evaluated vigabatrin in 40 infants who had been recently diagnosed with IS. Patients were observed during a 2- to 3-day baseline period and then randomized to vigabatrin or placebo for 5 days. Subsequently, all infants continuing in the study were treated with open-label vigabatrin for at least 24 weeks, with other AEDs allowed during this phase of the study. Although lengthy placebo-controlled trials in infants with IS would be considered unethical because of the potential brain damage caused by continued seizures, this very short trial was deemed justifiable and feasible to confirm previous reports from open-label, retrospective, or comparative studies that indicated that vigabatrin was an efficacious treatment for IS (14, 16, 21, 22). The earlier reports suggested that the response to vigabatrin was likely to be very rapid, with a large majority (82%) of infants who responded showing improvement within 5–7 days (16, 35). Therefore, the study by Appleton et al. (20) required only a 5-day, double-blind period. Investigators agreed that a maximum delay of 7–8 days, which would include both the baseline and double-blind period, would not affect either long-term spasm control or developmental outcome in infants receiving placebo.

Patients were previously untreated infants between the ages of 1 and 20 months who were recently diagnosed with IS and who had classic or modified hypsarrhythmia, as measured by EEG. Patients were excluded if they used any AED such as prednisolone, hydrocortisone, or ACTH within a 2-month period before entry. The starting dosage of vigabatrin was 50 mg/kg/day, which was maintained for 24 h. If spasms did not stop completely, the dosage was increased to 100 mg/kg/day for another 48 h. The dosage could be increased to a maximum of 150 mg/kg/day thereafter. Once a dosage was established for more than 48 h, it could not be altered during the double-blind period except for safety reasons.

The primary endpoint was the average percentage change in seizure frequency. Seizures were counted by nurses and parents. Another principal endpoint was the percentage of patients who were spasm-free at the end of the double-blind phase and at the end of the 24-week open-label phase. Repeated EEG recordings were conducted at both times. The infants’ development was assessed with the Denver test at baseline and after the 24-week open-label treatment period.

Forty infants from five European countries and Canada were enrolled, with 20 in each treatment group. Etiologies of IS were 30% cryptogenic and 70% symptomatic. No infant had tuberous sclerosis. Twenty-eight patients had classic hypsarrhythmia, and 12 had modified hypsarrhythmia. The mean dosage of vigabatrin at the end of the double-blind phase was 133 mg/kg/day (placebo, 148 mg/kg/day). The maximum dosage of 150 mg/kg/day was given to 11 of 20 patients in the vigabatrin group and to 19 of 20 patients in the placebo group. All 40 patients completed the double-blind phase, and 36 patients enrolled in the 24-week open-label phase, with 29 completing it. Of those who did not complete the open-label phase, five withdrew for lack of response to vigabatrin and two were lost to follow-up.

During the double-blind, placebo-controlled phase, seven (35.0%) vigabatrin-treated patients vs two (10.0%) placebo-treated patients achieved complete spasm-freedom (= 0.063). The percentage decrease in spasms was significantly greater for infants treated with vigabatrin compared with placebo (77.9% [95% confidence interval (CI): 55%, 89%] vs 25.9% [95% CI: −56%, 65%], = 0.02). At the end of the 24-week open-label treatment period, 15 of the original 40 patients (37.5%) were spasm-free. Of those 15 patients, 9 (60.0%) had become spasm-free within 12 days of the start of vigabatrin treatment.

Developmentally, infants appeared to have a favorable response when treatment resulted in cessation of spasms. At baseline, only three patients had normal Denver developmental test results, but by the end of the study, seven had normal results. All seven patients with normal developmental test results were spasm-free with vigabatrin monotherapy, whereas all patients who continued to have spasms had abnormal test results at the end of the study.

In the placebo-controlled phase, AEs occurred in 12 (60.0%) vigabatrin-treated patients and six (30.0%) placebo-treated patients (Table 3). The most common AE with vigabatrin treatment was drowsiness (n = 8). One patient had marked irritability. In the open-label phase of the study, 24 (66.7%) patients experienced one or more AEs. None of the events were clinically serious and no patient withdrew as a result of AEs. Overall, vigabatrin was generally well-tolerated. The study design did not include vision or MRI assessments.

Table 3.   Incidence of commonly reported AEs
AE, naStudy
Appleton et al. (20) (N = 40)Elterman et al. (9) (N = 222)Chiron et al. (21) (N = 22)bVigevano and Cilio (22) (N = 42)Lux et al. (25) (N = 107)
PBO (n = 20)VGB (n = 20)VGB (High + Low)HC (n = 12)VGB (n = 18)ACTH (n = 19)VGB (n = 23)HT (n = 55)VGB (n = 52)
  1. ACTH, adrenocorticotropic hormone; AE, adverse event; GI, gastrointestinal; HC, hydrocortisone; HT, hormonal treatments (combined); PBO, placebo; VGB, vigabatrin.

  2. Patients may have been counted twice if the same event was recorded during each therapy in a crossover study. AEs from follow-up studies to Lux et al. (24), Lux et al. (25), and Darke et al. (26) are not included; however, the types of AEs in follow-up studies were similar to types reported in randomization phase.

  3. aAEs reported for the randomized phase of the study only; open-label follow-up data not included. Some AEs were not reported for the studies; although the events may have occurred, they were not included among commonly reported events. Therefore, ‘–’ in this table means ‘not reported’.

  4. bSome data were not available for patients who discontinued the studies or because of crossover to another treatment group; hence, in some instances, the sum of n-values may not equal N.

Sleep disorder/neuropsychiatric103014
Decreased appetite7
Increased appetite71
Abdominal distension20
Cushing syndrome10
Patients with ≥1 AE61211095733028

The study by Appleton et al. was key in that it was the first double-blind, randomized, placebo-controlled trial of vigabatrin for IS, and it demonstrated the drug’s efficacy in this patient population. More patients treated with vigabatrin were spasm-free at the end of the double-blind period compared with placebo-treated patients. However, the difference was not statistically significant (= 0.063). The authors concluded that the short double-blind period and the absence of patients with IS with tuberous sclerosis, which is known to respond particularly well to vigabatrin, were the likely reasons for this occurrence. Another unique finding was that more originally placebo-treated patients (n = 11) than originally vigabatrin-treated patients (n = 4) were spasm-free at the end of the 24-week, open-label treatment with vigabatrin. This outcome suggests that a short delay in treatment (of up to 8 days) does not appear to negatively affect ultimate response to treatment. Response to vigabatrin was rapid, occurring within 12 days and confirming similar results of previous studies (16, 21, 22, 35).

A randomized, single-blind, dosage-comparison trial with open-label follow-up for up to 3 years: Elterman et al. (9)

This large randomized, single-blind study by Elterman et al. evaluated the effects of high- and low-dosage vigabatrin on spasm cessation in 221 patients with newly diagnosed IS. This dosage-comparison trial included an open-label follow-up phase of up to 3 years (9). Initially, infants with IS were randomly assigned to high (100–148 mg/kg/day) and low (18–36 mg/kg/day) dosages of vigabatrin for 14–21 days. Patients achieving spasm-freedom within the first 14 days remained on randomized therapy for an additional 7 days before entering the open-label phase. Patients not achieving spasm-freedom within the first 14 days entered the open-label phase after Day 14.

All patients had a diagnosis of IS of less than 3 months’ duration, were <2 years of age, weighed ≥3.5 kg, and could not have been treated previously with corticosteroids, ACTH, or valproic acid. Any investigational drugs other than vigabatrin — including ACTH, corticosteroids, valproic acid, and felbamate — were not allowed during the first 14 days. Stable dosages of AEDs used for other seizure types, such as phenobarbital and clonazepam, were permitted but dosage adjustments were not allowed during the first 21 days.

The primary outcome measure was spasm cessation, defined as 7 consecutive days of spasm-freedom beginning within the first 14 days. Spasm cessation was to be initially reported by caregivers and then confirmed by video-EEG within 3 days of the seventh day of the spasm-free period. As the study progressed, investigators realized that the 3-day video-EEG requirement was an extremely stringent condition that was difficult to meet logistically and had a negative impact on the primary efficacy end point. Therefore, alternate criteria were applied to make results more comparable to those of other IS trials (Fig. 2). The post-hoc primary criterion extended the time frame for video-EEG confirmation to 9 days, and the secondary criterion was defined as spasm-freedom based on caregiver assessment for 7 consecutive days at any time during the study with no relapse.

Figure 2.

 Vigabatrin effect on spasm cessation by different criteria for spasm cessation. The effect of high-dosage vigabatrin was consistently greater than low-dosage vigabatrin when different criteria for spasm cessation were applied. Primary criteria (which were determined by investigators to be overly stringent during course of the study) were defined as spasm-free by both caregiver assessment and video-EEG confirmation within 3 days of the seventh day of spasm freedom. Post-hoc criteria were defined as spasm-free by both caregiver assessment and video-EEG confirmation during a subsequent visit. Secondary criteria were defined as spasm-free for 7 consecutive days at any time during the study and remained spasm-free for the duration of the study period based on caregiver assessment. Elterman RD, Shields WD, Bittman RM, et al. J Child Neurol. Vol. 25, Issue 11, pp. 1340-1307, copyright © 2010 by SAGE Publications. Reprinted by Permission of SAGE Publications.

The modified intention-to-treat cohort of 221 patients was evaluated for vigabatrin efficacy. One additional patient, who had received an unknown dosage of study drug and was therefore excluded from efficacy evaluations, was included in the safety population. Two patients discontinued during the 21-day single-blind phase because of non-compliance and were evaluated as treatment failures. The majority of patients were not followed through the entire 3-year open-label period (183 of 221; 82.8%). Most patients left the study early for lack of efficacy (49 of 221; 22.2%), other reasons (36 of 221; 16.3%), or administrative reasons (35 of 221; 15.8%). Nineteen (8.6%) patients discontinued over the 3-year period because of serious or severe AEs.

The mean (SD) durations of vigabatrin exposure were 423.3 (317.2) days in the high-dosage group and 512.0 (372.1) days in the low-dosage group. Duration of exposure varied considerably between patients, with infants who responded to vigabatrin therapy but who had no other access to the medication staying in the study longer.

Based on the most stringent definition of spasm-freedom, 17 of 107 patients (15.9%) in the high-dosage group and 8 of 114 patients (7.0%) in the low-dosage group achieved spasm cessation (< 0.0375; Fig. 2). However, when spasm cessation was defined as video-EEG confirmation within 9 days of spasm cessation, the response rates were nearly double in each group: 30.8% in the high-dosage group vs 13.2% in the low-dosage group (< 0.0014). Applying the criterion of caregiver-reported spasm-freedom at any time during the study with no video-EEG requirement produced even greater rates of spasm cessation for both groups: 68.2% for the high-dosage group vs 51.8% for the low-dosage group (< 0.0126). Regardless of the definition of spasm cessation, significantly more patients receiving the greater dosage of vigabatrin achieved spasm cessation.

During follow-up, 39 of 171 patients (22.8%) relapsed, but 28 of the 39 (71.7%) achieved freedom from spasms again. Significantly more patients in the high-dosage group achieved spasm cessation within 1 week of treatment initiation compared with the low-dosage group (= 0.0016), with median times to spasm cessation being 6 and 13 weeks, respectively. Response to vigabatrin varied slightly by etiology of IS, although between-group differences were not statistically significant. Of patients with symptomatic IS due to tuberous sclerosis, 21.1% (8 of 38) achieved spasm-free status, whereas 7.9% (10 of 126) of patients with other symptomatic etiologies and 12.3% (7 of 57) of patients with cryptogenic etiologies achieved spasm-free status.

Over the course of the entire 3-year study, 115 of 222 patients (51.8%) experienced at least one AE, although only 13.8% of AEs were considered to be related to vigabatrin. The most common vigabatrin-related AEs occurring for at least 10% of patients were sedation (16.7%), somnolence (13.5%), and irritability (9.9%; Table 3). Like the study by Appleton et al. (20), this study design did not include the assessments of vision or imaging.

Based on these findings, Elterman et al. concluded that vigabatrin decreased IS in a dosage-dependent manner. Spasm cessation occurred quickly and was maintained in most infants who responded to vigabatrin. An interim analysis of the first 142 patients in this study was published in 2001 by Elterman et al. (23), and the results from the final analysis reported here are consistent with those from the earlier analysis, in which 36% (24 of 67) of patients in the high-dosage group achieved spasm cessation within 14 days of starting treatment compared with 11% (8 of 75) in the low-dosage group (< 0.001). IS of all etiologies improved with treatment, although a trend toward a greater response rate and shorter time to response was observed in infants with tuberous sclerosis compared with other etiologies. This is consistent with previous studies (4, 22). Vigabatrin was well-tolerated by the majority of patients, and AEs were generally mild to moderate.

Well-controlled European and Canadian trials of vigabatrin for IS

In addition to the major trials leading to the approval of vigabatrin for IS in the United States, several studies in other countries have supported its use in this indication. This section describes five randomized, prospective clinical studies of vigabatrin for IS conducted in Europe and Canada (21, 22, 24–26). Again, Tables 1 and 2 detail the study designs, key outcomes, and baseline patient characteristics of these studies. Fig. 1 shows the percentage of patients achieving spasm-freedom across studies.

Randomized, comparative trial of vigabatrin and hydrocortisone for IS arising from tuberous sclerosis: Chiron et al. (21)

This multicenter, open-label, prospective, randomized, response-mediated, crossover study was conducted to compare vigabatrin and hydrocortisone for symptomatic IS arising from tuberous sclerosis.

Infants with IS caused by tuberous sclerosis were randomized for 1 month to vigabatrin 150 mg/kg/day (n = 11) or hydrocortisone 15 mg/kg/day (n = 11). At the end of 1 month, infants who did not respond to the initial medication were crossed over to the other drug for a new 2-month study period. Patients who achieved spasm cessation continued to receive vigabatrin or were gradually tapered off hydrocortisone. The primary efficacy endpoint was complete cessation of spasms reported daily by parents and confirmed on EEG.

At the end of the initial 1-month period, all 11 vigabatrin-treated patients were spasm-free compared with 5 (45.5%) of 11 hydrocortisone-treated patients (< 0.01). The six infants who did not respond to hydrocortisone and one patient who had an AE with hydrocortisone were crossed over to vigabatrin and also became spasm-free in the second phase of the study. Spasms recurred in one patient treated with vigabatrin when the dosage was decreased to 75 mg/kg/day to improve tolerability. The patient regained freedom from spasm within 1 day when the dosage was partially increased to 100 mg/kg/day, which the infant tolerated. Response was more rapid with vigabatrin, with a mean time to response of 3.5 days compared with 13 days with hydrocortisone (< 0.01).

Hypsarrhythmia was present in nine patients at the beginning of the study (four randomized to vigabatrin and five randomized to hydrocortisone), all of which resolved by the end of the study. Similarly, epileptic spasms were recorded at the beginning of the study in 16 patients (seven randomized to vigabatrin and nine randomized to hydrocortisone), but none had subclinical recorded epileptic spasms after treatment, although one in each group had partial seizures.

Investigators observed no deterioration in psychomotor development, and some children had slight increases in their developmental quotients. Fourteen patients experienced AEs (five with vigabatrin treatment and nine with hydrocortisone treatment, = 0.006). Drowsiness and hyperexcitability were most common with vigabatrin (n = 3 for both), whereas hyperexcitability (n = 5), sleep disorders (n = 3), and change in weight (n = 3) were most common with hydrocortisone. Two severe AEs (hyperexcitability and axial hypertonia) were reported with vigabatrin, and three severe AEs (hyperexcitability, sleep disorder, and abdominal distension) were reported with hydrocortisone.

This study clearly indicated that vigabatrin was more efficacious and better tolerated than hydrocortisone for treatment of IS caused by tuberous sclerosis, with 100% response during this 1- to 3-month crossover trial. The very rapid time to response with vigabatrin suggests a substantial clinical advantage versus steroids, and it was noted that 2 months of exposure to vigabatrin was not detrimental to psychomotor status. Safety events were as anticipated and appeared to be dosage-dependent. Based on these results, the authors concluded that vigabatrin should be considered as the first-choice treatment for IS caused by tuberous sclerosis.

Prospective randomized trial comparing vigabatrin and ACTH for IS: Vigevano & Cilio (22)

Prior to the development of vigabatrin, hormonal treatment (most commonly ACTH) had been the clinical standard therapy for many years. This prospective, randomized trial compared efficacy and tolerability of vigabatrin and ACTH as first-line therapy for IS in 42 infants aged 2–9 months. Newly diagnosed patients received vigabatrin 100–150 mg/kg/day or depot ACTH 10 IU/day. Patients were switched to the alternate medication if spasms did not cease within 20 days or if the patient could not tolerate the current therapy. Vigabatrin was given as initial treatment to 23 patients, seven of whom had cryptogenic IS and 16 who had symptomatic IS. ACTH was first-line treatment for 19 patients (8 with cryptogenic IS and 11 with symptomatic IS). Baseline testing included ictal video-EEG and computed tomography scan or MRI.

In the first 20-day phase of this study, there was no statistically significant difference between treatment groups in spasm cessation (= 0.12). Spasms ceased in 11 (47.8%) vigabatrin-treated patients and in 14 (73.6%) ACTH-treated patients. Most patients (7 of 11) responded to vigabatrin within 3 days, and all vigabatrin responders reached spasm cessation within 14 days. Vigabatrin and ACTH were more efficacious in symptomatic cases of particular etiologies. Vigabatrin provided better efficacy for patients with cerebral malformations and tuberous sclerosis, whereas ACTH provided greater benefit for patients with perinatal hypoxic/ischemic injury. Efficacy was similar between treatments for cryptogenic IS.

Of patients who were switched to the alternate study drug in the second phase of study, spasm control was achieved in two of five vigabatrin-treated patients vs 11 of 12 ACTH-treated patients (40.0% vs 91.7%, = 0.052). Relapse occurred after 3 months for six patients treated with ACTH and one patient treated with vigabatrin. AEs occurred for 3 (13.0%) vigabatrin-treated patients and 7 (36.8%) ACTH-treated patients.

The success rate of 48% with vigabatrin was lesser than that of ACTH in this first-ever prospective trial comparing the two drugs. However, vigabatrin produced response in patients with both symptomatic and cryptogenic IS and was associated with fewer AEs and better maintenance of response compared with ACTH. Vigabatrin was more efficacious than ACTH for patients with cerebral malformations and tuberous sclerosis. Moreover, the response to vigabatrin was rapid, generally occurring within 3 days. The investigators concluded that vigabatrin may offer an effective first-line therapy with potentially better tolerability for some patients. Because of the rapid time to onset of response, an initial trial with vigabatrin could be conducted and if the patient did not respond quickly, he or she could be immediately switched to ACTH or another AED. In addition, investigators believed that vigabatrin could be valuable for patients who relapse after initial treatment with ACTH.

United Kingdom Infantile Spasm Study (UKISS) comparing vigabatrin with hormonal treatment in a multicenter, randomized controlled trial: Lux et al. (25)

Like the studies by Chiron et al. (21) and Vigevano and Cilio (22), UKISS compared vigabatrin with hormonal treatments for IS. However, UKISS elevated the comparison to a larger scale. Vigabatrin, prednisolone, and tetracosactide (a synthetic analog of ACTH) were compared in a multicenter, randomized controlled trial at 150 hospitals throughout the UK.

Patients received vigabatrin 100–150 mg/kg/day, oral prednisolone 40–60 mg/day, or intramuscular tetracosactide 0.5–0.75 mg (40–60 IU) on alternate days. For all drugs, the dosage was maximized within 1 week if spasms had not ceased. Patients included were aged 2–12 months, had a clinical diagnosis of IS and a baseline hypsarrhythmic EEG, and could not have had a diagnosis or high risk of tuberous sclerosis. Seizure diaries and follow-up EEGs were employed for outcome assessment. The primary outcome measure was cessation of spasms, defined as no reported spasms for at least 48 h on Days 13 and 14. Secondary outcomes were time to spasm cessation and EEG-confirmed resolution of hypsarrhythmia.

The study randomized 107 infants to treatment with vigabatrin (n = 52) or hormonal treatments (prednisolone, 30; tetracosactide, 25). Spasm cessation on Days 13 and 14 was achieved by 28 of 52 infants (53.8%) in the vigabatrin group vs 40 of 55 patients (72.7%) in the hormonal treatment group (prednisolone, 21 of 30 [70.0%]; tetracosactide, 19 of 25 [76.0%]; = 0.043). In addition, hypsarrhythmia resolved in significantly more infants randomized to hormonal treatments than to vigabatrin.

AEs were reported in slightly more than half of patients in both treatment groups (28 of 52 patients [53.8%] in the vigabatrin group and 30 of 55 patients [54.5%] in the hormonal treatment group). There were no deaths in the study.

Study results indicated that hormonal treatments were more likely than vigabatrin to provide seizure-freedom, and AEs were common with both therapies. Based on these findings, the investigators indicated a preference for hormonal treatment over vigabatrin. It should be noted, however, that infants with IS arising from tuberous sclerosis were excluded from this study. This may account, in part, for the lesser response to vigabatrin compared with hormone treatment. In other studies, patients with tuberous sclerosis responded well to treatment with vigabatrin (4, 9, 21, 22). Moreover, a follow-up study of long-term outcomes in this group of patients, which is discussed later, revealed more favorable outcomes associated with vigabatrin (24).

United Kingdom Infantile Spasm Study comparing vigabatrin with hormonal treatment on the developmental and epilepsy outcomes at age 14 months: Lux et al. (24)

Lux et al. conducted a follow-up evaluation of the infants enrolled in the original UKISS trial. The goal was to assess whether early control of spasms was associated with improved developmental and epilepsy outcomes at 12 to 14 months. Of the 107 infants in the original study, 101 reached follow-up assessments for clinical presence of spasms and developmental outcomes as measured by the Vineland Adaptive Behavior Scales (VABS). Five others died, and one withdrew from the study.

By 14 months, spasm-freedom was similar between treatment groups: 41 of 55 infants (74.5%) in the hormonal treatment group were spasm-free, as were 39 of 51 infants (76.5%) who had received vigabatrin (difference, 1.9%; 95% CI: −18.3%, 14.4%; = 0.82). Of the 55 infants initially randomized to hormonal treatment, 27 received vigabatrin after Day 14 (12 because of failure to achieve cessation of spasms, 14 because of relapse [defined as any spasm occurring after Day 14 in an infant who had cessation of spasms], and one for the treatment of focal seizures). Similarly, of the 52 infants initially randomized to vigabatrin, 22 received hormonal treatment after Day 14 (19 because of failure to achieve cessation of spasms and 3 because of relapse). Response rates for infants who did not respond to initial treatment and subsequently received the alternate treatment were 73.7% (14 of 19 infants) for the hormonal treatment group and 75.0% (9 of 12 infants) for the vigabatrin treatment group.

Developmental outcome measured by VABS at 14 months did not differ significantly between the treatment groups. The mean (SD) VABS score in the hormonal treatment group was 78.6 (16.8) compared with 77.5 (12.7) in the vigabatrin treatment group (difference, 1.0; 95% CI: 4.9, 7.0; = 0.73). For infants with no identified underlying etiology, the mean VABS score was greater for those given hormone treatment than for those given vigabatrin (88.2 [17.3] vs 78.9 [14.3]; difference, 9.3; 95% CI: 1.2, 17.3; = 0.025). However, as noted, there were no infants with IS arising from tuberous sclerosis enrolled in this study.

A similar number of infants were spasm-free at the final clinical assessment regardless of which treatment — hormone or vigabatrin — was received initially. In the majority of cases (slightly more than 75%), cessation of spasms was achieved. Importantly, there was also no detrimental impact on neurodevelopmental outcomes. The authors noted that when infants did not respond well to one treatment and were switched, resolution of spasms frequently occurred. Thus, initial treatment did not modify long-term spasm control. In contrast to a previous report that suggested that giving steroids to young infants adversely impacts later neurodevelopment (36), there was no evidence of this occurrence in this study. Subsequently, an even longer term follow-up of the UKISS patients was performed by Darke et al. and is summarized next.

Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for IS: Darke et al. (26)

This similar but longer term follow-up study by Darke et al. evaluated patients in the original UKISS at a mean age of 4 years. Evaluations were conducted by telephone with the VABS and an epilepsy questionnaire.

Of the 107 original infants, nine had died, and 77 were located and included in this follow-up study. Overall, epilepsy and development outcomes were similar between the two treatment groups at follow-up. With regard to seizures, only five infants from each original treatment group had any epilepsy at age 4 years. Median (quartile) VABS scores were similar between treatment groups: 60 (42, 97) for the 39 infants in the hormonal treatment group and 50 (36, 67) for the 38 infants in the vigabatrin group (Mann–Whitney U = 575; = 0.091; median difference: 8; 95% CI: −1, 19). Better developmental outcomes were observed for patients with IS of no identified etiology who had been given hormonal treatment, confirming a similar earlier finding from the 14-month follow-up study (24).

Summary of efficacy results in key vigabatrin studies in infants with IS

In the well-controlled, prospective randomized studies discussed in this review, vigabatrin produced spasm cessation in patients with newly diagnosed IS at dosages generally ranging from 100 to 150 mg/kg/day. Rates of spasm cessation ranged from 16% to 100%, but when outliers are excluded, complete spasm-freedom occurred in approximately 35–75% of cases. Response to vigabatrin was rapid, generally occurring within several days to 2 weeks. Vigabatrin demonstrated efficacy for IS of all etiologies but was particularly effective for IS caused by tuberous sclerosis (21).

All but one group of study investigators (the UKISS group [25]) preferred vigabatrin as first-line therapy for IS over other treatments (primarily hormonal therapies such as ACTH, hydrocortisone, and prednisolone) (9, 20–23). Despite the UKISS investigators’ preference for hormonal treatment, the long-term follow-up at 14 months and 4 years in the UKISS study indicated equivalent spasm-freedom and developmental outcomes with vigabatrin and hormone treatment, except for the subgroup with cryptogenic spasms (24, 26). However, baseline evaluations were not available for these children.

Summary of safety experience in key vigabatrin studies in infants with IS

Vigabatrin therapy for up to 6 months in patients with IS was generally well-tolerated. The most common AEs were sedation, somnolence, and irritation (Table 3) and AEs appeared to be dosage related and transient. There were no deaths attributable to vigabatrin in any of the studies reviewed, and the rate of severe AEs was low or non-existent. A more detailed overview of safety findings in studies of vigabatrin is presented in a separate review (28).

The risk of development of pVFDs with vigabatrin therapy is an important safety concern for both pediatric and adult patients (29), but evaluation of visual fields in infants and young children remains challenging (37). A recent study of children treated as infants with vigabatrin for IS found that one of the 16 school-aged children had a pVFD at long-term follow-up (38). The pVFD was considered to be mild, and the child had received vigabatrin for 19 months. This study suggested that the risk of developing a pVFD may be lesser in infants than what is reported with long-term use in adults, which is approximately one occurrence in every three cases. A more detailed overview of vision safety issues and visual field testing methods are provided in separate reviews (29, 37).


There is very good evidence from well-controlled studies that vigabatrin is efficacious for the treatment of IS. Most trials reviewed found vigabatrin to be at least as efficacious as hormonal treatment, with fewer relapses in at least one study (22). Current practice parameters from the American Academy of Neurology and the Child Neurology Society indicate that ACTH and vigabatrin are the only drugs with proven efficacy — demonstrated in a randomized clinical trial setting — to reduce or eradicate spasms and eliminate the associated hypsarrhythmic EEG (2, 39). Therefore, they are considered first-line treatments for IS.

Although vigabatrin is effective and well-tolerated, a safety concern associated with vigabatrin therapy for IS is the risk of vision loss. The risk of developing a pVFD may increase with longer exposure and greater cumulative dosage. For this reason, the duration of treatment becomes a critical question (2, 39). The limited data available to date suggest that if an infant is spasm-free for 6 months, vigabatrin treatment can be discontinued (2). Nonetheless, there is some concern about potential relapse and subsequent treatment resistance in infants with focal cortical dysplasia and tuberous sclerosis (31).

Studies of vigabatrin for IS indicate that the time to response with vigabatrin is quite short, <2 weeks in general and as short as 3–5 days in some cases. Therefore, current recommendations call for an evaluation of efficacy within 2 weeks of an initial trial or dosage escalation of vigabatrin (2). If the infant has not demonstrated clinical improvement at that time, vigabatrin should be discontinued and an alternate treatment for IS should be attempted. Treatment trials longer than 6 months are not likely to improve the infant’s clinical condition and may increase the risk of development of a pVFD.

Evidence also suggests that a delay in time to diagnosis and treatment is associated with less favorable outcomes for patients with IS. As such, it is important to identify and treat infants rapidly to avoid greater risk (2, 26, 30).

With adequate consideration of the benefits and risks associated with the treatment for IS with vigabatrin, this therapy is a valuable treatment option for many infants with this challenging, life-changing, and potentially life-threatening illness. To achieve the best possible outcomes, physicians should treat based on the needs of each child and the current best evidence in the medical literature about management of IS.

Conflicts of interest

Lionel Carmant has received consultancy fees from Lundbeck Inc., Eisai Canada, and UCB Canada.


Medical writing and editorial assistance were provided by Jennifer B. Koenig, MS, and Robin L. Stromberg, PhD, of Arbor Communications, Inc. (Ann Arbor, MI, USA) and Michael A. Nissen, ELS, of Lundbeck Inc. (Deerfield, IL, USA). This support was funded by Lundbeck.