Elsevier

The Lancet

Volume 364, Issue 9447, 13–19 November 2004, Pages 1773-1778
The Lancet

Articles
The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial

https://doi.org/10.1016/S0140-6736(04)17400-XGet rights and content

Summary

Background

Infantile spasms, which comprise a severe infantile seizure disorder, have a high morbidity and are difficult to treat. Hormonal treatments (adrenocorticotropic hormone and prednisolone) have been the main therapy for decades, although little evidence supports their use. Vigabatrin has been recorded to have a beneficial effect in this disorder. We aimed to compare the effects of vigabatrin with those of prednisolone and tetracosactide in the treatment of infantile spasms.

Methods

The United Kingdom Infantile Spasms Study assessed these treatments in a multicentre, randomised controlled trial in 150 hospitals in the UK. The primary outcome was cessation of spasms on days 13 and 14. Minimum doses were vigabatrin 100 mg/kg per day, oral prednisolone 40 mg per day, or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days. Analysis was by intention to treat.

Findings

Of 208 infants screened and assessed, 107 were randomly assigned to vigabatrin (n=52) or hormonal treatments (prednisolone n=30, tetracosactide n=25). None was lost to follow-up. Proportions with no spasms on days 13 and 14 were: 40 (73%) of 55 infants assigned hormonal treatments (prednisolone 21/30 [70%], tetracosactide 19/25 [76%]) and 28 (54%) of 52 infants assigned vigabatrin (difference 19%, 95% CI 1%–36%, p=0·043). Two infants allocated tetracosactide and one allocated vigabatrin received prednisolone. Adverse events were reported in 30 (55%) of 55 infants on hormonal treatments and 28 (54%) of 52 infants on vigabatrin. No deaths were recorded.

Interpretation

Cessation of spasms was more likely in infants given hormonal treatments than those given vigabatrin. Adverse events were common with both treatments.

Introduction

Infantile spasms, a rare form of epilepsy, presents in infants with ictal episodes consisting of spasms that usually occur in clusters. More than half of infants who develop infantile spasms have an underlying neurological disorder, such as: periventricular leucomalacia, hypoxic ischaemic encephalopathy, Down's syndrome, and tuberous sclerosis. About 10% of those with infantile spasms have tuberous sclerosis and roughly half of those with tuberous sclerosis develop infantile spasms. The chaotic and high-voltage interictal electroencephalogram (EEG) pattern is called hypsarrhythmia, but this term might not be used because the EEG can vary with the underlying cause of the spasms and can change as the disorder progresses. Onset of spasms is often associated with developmental arrest or regression. Many infants become severely disabled, physically and intellectually, and develop multiple types of seizure, even when no underlying cause is found. Infantile spasms are difficult to treat, because they do not respond to conventional antiepileptics. Since 1958, the usual interventions have been hormonal treatments, with either intramuscular adrenocorticotropic hormone or oral corticosteroids.1, 2 In the 1990s, vigabatrin, a γ-aminobutyric acid inhibitor, was introduced in Europe as an effective treatment for infantile spasms, especially in tuberous sclerosis.3 However, since 1997, visual-field defects have been identified in 30% of adults treated with vigabatrin and have also been reported in children.4, 5, 6, 7 Hormonal therapy can also have severe adverse effects, and so a comparison between these treatments was needed. We aimed to compare the relative effectiveness of hormonal treatments and vigabatrin by using a multicentre, randomised, parallel-group trial, the United Kingdom Infantile Spasms Study (UKISS), and report the outcome at 14 days.

Section snippets

Patients

UKISS was a pragmatic, randomised, parallel-group open trial, with follow-up at 14 days and then every 3 months until a final assessment at age 14 months. Local consultants enrolled infants from 150 hospitals in the UK with central allocation of randomised treatments from Bath. We saw little evidence8 and no consensus on whether to use tetracosactide or corticosteroids, or on their duration and dose. Most serious adverse events and deaths have occurred after long-term treatment. We opted for

Results

Of 208 infants assessed for eligibility, 107 (64 boys) were allocated a randomised treatment. Baseline characteristics, including underlying aetiology, were similar in all groups (table 1). 83 (78%) of 107 EEGs were reported as hypsarrhythmia, and the remainder (apart from three) recorded as almost hypsarrhythmia; we reviewed their reports and believed them to be compatible with infantile spasms.

52 infants were allocated vigabatrin, 25 tetracosactide, and 30 prednisolone (figure). One infant

Discussion

Hormonal treatments prevented significantly more infantile spasms over the 48 h comprising days 13 and 14 after randomisation than vigabatrin. Since resolution of hypsarrhythmia could only occur if the baseline EEG showed hypsarrhythmia, it was dependent on baseline characteristics. However, resolution of hypsarrhythmia occurred in significantly more infants allocated hormonal treatments than allocated vigabatrin. The response to treatment was not affected by underlying cause, but infants with

References (17)

  • L Sorel et al.

    A propos 21 cas d'hypsarythmia de Gibbs: son traitment spectaculaire par l'ACTH

    Acta Neurol Belg

    (1958)
  • NL Low

    Infantile spasms with mental retardation. II: treatment with cortisone and adrenocorticotropin

    Pediatrics

    (1958)
  • J Aicardi et al.

    Vigabatrin as initial therapy for infantile spasms: a European retrospective survey

    Epilepsia

    (1996)
  • JM Wild et al.

    Characteristics of a unique visual field defect attributed to vigabatrin

    Epilepsia

    (1999)
  • S Vanhatalo et al.

    Visual field constriction in children treated with vigabatrin

    Neurology

    (1999)
  • V Gross-Tsur et al.

    Visual impairment in children with epilepsy treated with vigabatrin

    Ann Neurol

    (2000)
  • P Iannetti et al.

    Visual field constriction in children with epilepsy on vigabatrin treatment

    Pediatrics

    (2000)
  • E Hancock et al.

    The treatment of infantile spasms (Cochrane Review)

    The Cochrane Library, Issue 2

    (2004)
There are more references available in the full text version of this article.

Cited by (0)

View full text