Stuart W Edwards

The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial

BACKGROUND Infantile spasms is a severe infantile seizure disorder that is difficult to treat and has a high morbidity. Absence of spasms on days 13 and 14 after randomisation is more common in infants allocated hormone treatments than in those allocated vigabatrin. We sought to assess whether early control of spasms is associated with improved developmental or epilepsy outcomes. METHODS Infants enrolled in the United Kingdom Infantile Spasms Study (UKISS) were randomly assigned hormone treatment (n=55) or vigabatrin (n=52) and were followed up until clinical assessment at 12-14 months of age. We assessed neurodevelopment with the Vineland adaptive behaviour scales (VABS) at 14 months of age on an intention to treat basis. FINDINGS Of 107 infants enrolled, five died and 101 survivors reached both follow-up assessments. Absence of spasms at final clinical assessment (hormone 41/55 [75%] vs vigabatrin 39/51 [76%]) was similar in each treatment group (difference 1.9%, 95% CI -18.3% to 14.4%; chi(2)=0.05; p=0.82). Mean VABS score did not differ significantly (hormone 78.6 [SD 16.8] vs vigabatrin 77.5 [SD 12.7]; difference 1.0, 95% CI -4.9 to 7.0; t(99)=0.35, p=0.73). In infants with no identified underlying aetiology, the mean VABS score was higher in those allocated hormone treatment than in those allocated vigabatrin (88.2 [17.3] vs 78.9 [14.3]; difference 9.3, 95% CI 1.2 to 17.3; t(95)=2.28, p=0.025). INTERPRETATION Hormone treatment controls spasms better than does vigabatrin initially, but not at 12-14 months of age. Better initial control of spasms by hormone treatment in those with no identified underlying aetiology may lead to improved developmental outcome.

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

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.

The underlying etiology of infantile spasms (West syndrome): Information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification

Purpose:  To examine the underlying etiology of infantile spasms from the United Kingdom Infantile Spasms Study (UKISS), using the pediatric adaptation of ICD 10.

The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: Evidence from the United Kingdom Infantile Spasms Study

Purpose:  Infantile spasms is a severe infantile seizure disorder. Several factors affect developmental outcome, especially the underlying etiology of the spasms. Treatment also affects outcome. Both age at onset of spasms and lead time to treatment (the time from onset of spasms to start of treatment) may be important. We investigated these factors.

Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre randomised trial

Background Infantile spasms is the name given to a difficult to treat, severe infantile epilepsy with high morbidity. The United Kingdom Infantile Spasms Study (UKISS) showed that absence of spasms on days 13 and 14 after randomisation was more common in infants allocated hormonal treatments than vigabatrin. At 12–14 months, those with no identified aetiology allocated hormonal treatment had better development. However, epilepsy outcome was not affected by treatment allocated. It is not known if the difference in development persists as the infants grow. Methods Infants in UKISS were followed up blind to treatment allocation by telephone at a mean age of 4 years using the Vineland Adaptive Behaviour Scales (VABS) and an epilepsy questionnaire. Findings 9 of 107 enrolled infants had died. 77 were traced and consented to take part. The median (quartile) VABS scores were 60 (42, 97) for the 39 allocated hormonal treatment and 50 (36, 67) for the 38 allocated vigabatrin (Mann–Whitney U=575; p=0.091; median difference (95% CI): 8 (−1 to 19)). For those with no identified aetiology, VABS scores were 96 (52, 102) for the 21 allocated hormonal treatment and 63 (37, 92) for the 16 allocated vigabatrin (U=98.5; p=0.033; median difference (95% CI): 14 (1 to 42)).The proportions in each treatment group with epilepsy were similar. Interpretation For all 77 infants, development and epilepsy outcomes were not significantly different between the two treatment groups. The better development seen at 14 months in those with no identified aetiology allocated hormonal treatment was seen again at 4 years in this study.

Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial

BACKGROUND Infantile spasms constitutes a severe infantile epilepsy syndrome that is difficult to treat and has a high morbidity. Hormonal therapies or vigabatrin are the most commonly used treatments. We aimed to assess whether combining the treatments would be more effective than hormonal therapy alone. METHODS In this multicentre, open-label randomised trial, 102 hospitals (Australia [three], Germany [11], New Zealand [two], Switzerland [three], and the UK [83]) enrolled infants who had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) EEG no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing electro-clinical outcome were masked to treatment allocation. Minimum doses were prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without vigabatrin 100 mg/kg per day. The primary outcome was cessation of spasms, which was defined as no witnessed spasms on and between day 14 and day 42 from trial entry, as recorded by parents and carers in a seizure diary. Analysis was by intention to treat. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 54363174, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2006-000788-27. FINDINGS Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (186) or hormonal therapy alone (191). All 377 infants were assessed for the primary outcome. Between days 14 and 42 inclusive no spasms were witnessed in 133 (72%) of 186 patients on hormonal therapy with vigabatrin compared with 108 (57%) of 191 patients on hormonal therapy alone (difference 15·0%, 95% CI 5·1-24·9, p=0·002). Serious adverse reactions necessitating hospitalisation occurred in 33 infants (16 on hormonal therapy alone and 17 on hormonal therapy with vigabatrin). The most common serious adverse reaction was infection occurring in five infants on hormonal therapy alone and four on hormonal therapy with vigabatrin. There were no deaths attributable to treatment. INTERPRETATION Hormonal therapy with vigabatrin is significantly more effective at stopping infantile spasms than hormonal therapy alone. The 4 week period of spasm cessation required to achieve a primary clinical response to treatment suggests that the effect seen might be sustained, but this needs to be confirmed at the 18 month follow-up. FUNDING The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, the BRONNER-BENDUNG Stifung/Gernsbach, and University Childrens Hospital Zurich.

An investigation into the relationship between vigabatrin, movement disorders, and brain magnetic resonance imaging abnormalities in children with infantile spasms

We aimed to investigate the relationship between movement disorders, changes on brain magnetic resonance imaging (MRI), and vigabatrin therapy in children with infantile spasms.

OP51 – 3033: Prednisolone or tetracosactide depot for infantile spasms – A meta-analysis from UKISS and ICISS

Objective To examine the relative efficacy of prednisolone and tetracosactide depot in the treatment of infantile spasms using data from trials where treatment had been randomly allocated. Prednisone trials (against ACTH) were not included since prednisone is an inactive compound that infants poorly convert to the active compound, Prednisolone. Methods A meta-analysis of results from both UKISS and ICISS clinical trials. Both trials compared hormonal treatment alone (either Prednisolone or Tetracosactide Depot) to another treatment regime but had randomly allocated the hormonal treatment in all (UKISS) or some (ICISS) infants. Both trials used the same dosages: Prednisolone 10 mg qds increasing to 20 mg tds after 7 days if spasms continued or Tetracosactide depot 0.5 mg on alternate days increasing to 0.75 mg after 7 days if spasms continued. Cessation of spasms was defined as in UKISS: no visible spasms on Days 13 and 14. This outcome was also available for infants in ICISS where a more stringent definition was used. Results 124 infants (53 in UKISS and 71 in ICISS) were randomly allocated either Prednisolone (64) or Tetracosactide depot (60). Results for all infants are available. Cessation of spasms was achieved in 43 (67%) of those allocated Prednisolone and in 45 (75%) of those allocated Tetracosactide depot. There is no significant difference between these outcomes (Treatment difference 7.8%, 95% CI: –8.7% to +24.3%; Chi-square 0.92 and p=0.34). Conclusion When these two treatments are used as initial single treatments and where cessation of spasms is the outcome measure, there is no evidence that one treatment is better than the other.