Prospective preliminary analysis of the development of autism and epilepsy in children with infantile spasms. 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. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study. Sulthiame in the primary therapy of West syndrome: a randomized double-blind placebo-controlled add-on trial on baseline pyridoxine medication. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Vigabatrin for the treatment of infantile spasms: final report of a randomized trial. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study.
The objective of this study was to compare the efficacy of corticotropin (ACTH) versus vigabatrin in treating infantile spasms and to determine which medication has a more favorable long-term outcome in terms of cognitive function, evolution of epilepsy, and incidence of autism. Patients with infantile spasms were included in the study if they were 3 to 16 months old, had hypsarrhythmia, and had no previous treatment with vigabatrin or corticosteroids. Patient evaluation included electroencephalographic and psychometric measures before and after treatment. Patients were stratified based on etiology (idiopathic or symptomatic) and sex and then randomized between the ACTH and vigabatrin treatment groups. Each of the treatment groups received either ACTH or vigabatrin for 2 weeks. At the end of 2 weeks of treatment, patients were considered responders if spasms and hypsarrhythmia resolved. Nonresponders were crossed over and treated with the alternate drug. Nine patients were included in the study. Three patients received ACTH, one of whom was a responder. Six patients received vigabatrin, three of whom were responders. The five nonresponders received both therapies. All patients had some degree of developmental plateau or regression before the initiation of treatment. Four patients with idiopathic infantile spasms showed improved cognitive function following treatment. The remaining five patients remained significantly delayed. Five patients with symptomatic infantile spasms had epilepsy following treatment; three of them were in the autistic spectrum. The small number of infants in this pilot study is insufficient to determine which of the two drugs is more effective. However, the following trends were identified: vigabatrin may be more effective for patients with symptomatic infantile spasms; patients with idiopathic infantile spasms tend to have a better cognitive outcome; and patients with symptomatic infantile spasms tend to develop both epilepsy and autism. 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.
                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.
                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.
                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. Vigabatrin has been shown to be efficient in infants with infantile spasms and tuberous sclerosis, in open studies. In order to compare vigabatrin to oral steroids, a prospective randomized multicenter study was implemented using both drugs as monotherapy in newly diagnosed patients with infantile spasms and tuberous sclerosis. Eleven infants received vigabatrin (150 mg/kg per day) and 11 hydrocortisone (15 mg/kg per day) for 1 month. Spasm free patients continued vigabatrin or progressively stopped hydrocortisone in 1 month, non-responders were crossed to the other drug for a new 2 month-period. All vigabatrin patients (11/11) were spasm-free versus 5/11 hydrocortisone infants (P < 0.01). Seven patients were crossed to vigabatrin (six for inefficacy, one for adverse events) and became also totally controlled. Mean time to disappearance of infantile spasms was 3.5 days on vigabatrin versus 13 days on hydrocortisone (P < 0.01). Five patients exhibited side effects on vigabatrin but nine on hydrocortisone (P = 0.006). Vigabatrin should therefore be considered as the first choice treatment for infantile spasms due to tuberous sclerosis. Vigabatrin (VGB) has been shown to be an effective drug in the treatment of infantile spasms (West syndrome) in predominantly retrospective and open but also in prospective studies. This prospective, randomised, and placebo-controlled trial of VGB in infantile spasms was considered to be justified and feasible to confirm or refute these previous findings.
                Forty children with newly diagnosed infantile spasms received either VGB or placebo for 5 days in a double blind, placebo-controlled, parallel-group study, after which all the infants continuing in the study were treated openly with VGB for a minimum of 24 weeks.
                Compared with baseline, at the end of the double-blind phase, the patients treated with VGB had a 78% (95% confidence interval, 55-89%) reduction in spasms compared with 26% (-56-65%) in the group treated with placebo (p = 0.020). Seven VGB-treated patients and two placebo-treated patients were spasm free on the final day of the double-blind period (p = 0.063). At the end of the study, 15 children (38% of the original 40 patients or 42% of the 36 patients who entered the open phase) were spasm free with VGB monotherapy. No patient withdrew from the study because of an adverse event.
                This unique randomized, placebo-controlled study is the first to demonstrate the efficacy of a specific drug in the treatment of West syndrome and supports the results of previously published open and prospective trials. It further confirms that VGB could be considered as the drug of first choice in treating infantile spasms. To compare the efficacy of corticotropin (ACTH) (150 U/m2/day) and prednosone (2 mg/kg/day) given for 2 weeks, in suppressing clinical spasms and hypsarrhythmic electroencephalogram (EEG) in infantile spasms (IS). AACTH and prednisone are standard treatments for IS. ACTH at high doses causes severe dose- and duration-dependent side effects, but may be superior to prednisone, based on retrospective or uncontrolled studies. Blinded prospecive studies have shown equal efficacy of prednisone and low-dose ACTH, and low versus high-dose ACTH.
                A prospective, randomized, single-blinded study.
                Patient population consisted of consecutive infants fulfilling entry criteria, including the presence of clinical spasms, hypsarrhythmia (or variants) during a full sleep cycle video-EEG, and no prior steroid/ACTH treatment. Response required both cessation of spasms and elimination of hypsarrhythmia by the end of the 2-week treatment period, as determined by an investigator "blinded" to treatment. Treatment of responders was tapered off over 12 days; those failing one hormone were crossed-over to the other.
                OF 34 eligible infants, 29 were enrolled. Median age of patients was 6 months. Twenty-two infants were "symptomatic" with known or suspected cause, and seven were cryptogenic (two normal). Of 15 infants randomized to ACTH, 13 responded by EEG and clinical criteria (86.6%); Seizures stopped in an additional infant, but EEG remained hypsarrhythmic (considered a failure). Four of the 14 patients given prednisone responded (28.6%,, with complete clinical-EEG correlation), significantly less than with ACTH, (chi2 test).
                Using a prospective, randomized approach, a 2-week course of high-dose ACTH is superior to 2 weeks of prednsone for treatment of IS, as assessed by both clinical and EEG criteria. West syndrome (WS) is still one of the most difficult to treat epilepsies in infancy. Sulthiame (STM), which is commonly used in some countries in the treatment of benign focal epilepsies in childhood, has been suggested to be effective in WS too. This prospective, randomized placebo-controlled study was designed to prove or refute this hypothesis.
                Thirty-seven infants aged between 3.5 and 15 months with newly diagnosed WS received baseline therapy with pyridoxine (PDX). The children were randomized in a double-blind fashion to STM (n = 20) or placebo (n = 17), starting at day 4 at a moderate dose of 5 mg/kg body weight. Without complete cessation of infantile spasms (ISs) and resolution of hypsarrhythmia as the definition criteria of a response, the dose was doubled at day 7. The final examination was undertaken at the end of day 9.
                Based on the intention to treat, six (30%) of 20 patients responded to STM (p < 0.025), as did six (35%) of 17 infants fulfilling the study criteria (p < 0.01). Patients with tuberous sclerosis did not respond to STM (n = 3) No patient responded to placebo. One patient in the verum group was withdrawn because of reversible somnolence.
                As no child in the placebo group responded to the baseline PDX therapy, nor did any child in the STM group during the first 3 days of baseline therapy, PDX does not seem to be effective in WS. STM has a positive effect in the primary therapy of WS, comparable to that of vigabatrin. To study the effect of highdose prednisone on intracranial pressure (ICP), cranial computed tomographic (CT) findings, and clinical outcome in young children with moderate to severe tuberculous meningitis (TBM).
                Prospective, controlled, randomized study.
                Continuous lumbar, cerebrospinal fluid pressure monitoring and contrasted CT scanning were performed in 141 consecutive children with TBM at admission. All children were then randomly allocated to a nonsteroid group (71 children) or a steroid group (70 children) who received prednisone (first 16 children, 2 mg/kg per day; next 54 children, 4 mg/kg per day) for the first month of treatment. ICP monitoring and CT scanning were repeated regularly, and clinical outcome was assessed after 6 months of antituberculosis treatment.
                No statistically significant difference in ICP or the degree of hydrocephalus (as demonstrated by CT scan) was found between the steroid and nonsteroid groups after the first month of treatment. Basal ganglia infarcts developed in 16% of children in the steroid group and 24% in the nonsteroid group during the first month of treatment. Neither this incidence nor the eventual size of infarcts present at admission differed significantly between the two treatment groups. Single or multiple tuberculomas were seen on the first CT scans of 7 children (5%), whereas tuberculomas developed in 11 children (8%) at treatment. Both the response of the tuberculomas to treatment and the incidence of new tuberculomas were significantly improved by steroid therapy. Basal enhancement was also significantly less in the steroid group after 1 month of treatment. Steroids lowered mortality in stage III TBM significantly. Similarly, more surviving children in the steroid group had IQs of greater than 75 than did the those in the nonsteroid group. No significant difference was found in the incidence of motor deficit, blindness, or deafness.
                Corticosteroids significantly improved the survival rate and intellectual outcome of children with TBM. Enhanced resolution of the basal exudate and tuberculomas by steroids was shown by serial CT scanning. Corticosteroids did not affect ICP or the incidence of basal ganglia infarction significantly. A large randomized study was conducted in patients with newly diagnosed infantile spasms to compare 2 doses of vigabatrin in achieving spasm cessation. High (100-148 mg/kg/d) and low (18-36 mg/kg/d) oral doses of vigabatrin were evaluated in a randomized, single-blind study of 14 to 21 days with subsequent open-label treatment up to 3 years. Spasm cessation was defined as 7 consecutive days of spasm freedom beginning within the first 14 days, confirmed by video-electroencephalogram. A total of 221 subjects comprised the modified intent-to-treat cohort. More subjects in the high-dose group achieved spasm cessation compared with the low-dose vigabatrin group (15.9% [17/107] vs 7.0% [8/114]; P = .0375). During follow-up, 39 of 171 (23%) subjects relapsed; 28 of 39 (72%) regained spasm freedom. Adverse events were primarily mild to moderate in severity. Vigabatrin had a dose-dependent effect in spasm reduction. Spasm cessation occurred rapidly and was maintained in the majority of infants. To compare the efficacy and tolerability of vigabatrin (VGB) and adrenocorticotrophic hormone (ACTH) as first-line therapy in infantile spasms.
                Forty-two infants (22 males, 20 females) aged 2-9 months with newly diagnosed infantile spasms, were included in the trial. Patients were randomized to receive VGB 100-150 mg/kg/day or Depot ACTH 10 IU/day. The alternative drug was given if spasms were not controlled within 20 days or in cases of intolerance to initial therapy. Twenty-three patients (7 cryptogenic, 16 symptomatic) received VGB as first-line therapy; 19 patients (8 cryptogenic, 11 symptomatic) received ACTH as the first drug.
                Cessation of spasms was observed in 11 (48%) of the patients randomized to VGB and in 14 (74%) of those randomized to ACTH. Response to VGB was observed within 1-14 days, but two-thirds of patients (7/11) responded within 3 days. In the group treated with VGB, side effects such as drowsiness, hypotonia and irritability were observed in 13% of patients, compared with 37% in the group treated with ACTH. VGB was more effective than ACTH as treatment for cerebral malformations or tuberous sclerosis, whereas ACTH proved more effective in perinatal hypoxic/ischemic injury. The efficacy of the two drugs was similar in cryptogenic cases. Disappearance of interictal EEG abnormalities occurred sooner in patients randomized to ACTH than in those who received VGB as initial therapy. During the second phase, the alternative drug was given to the resistant patients. Spasms ceased in 2 of 5 patients treated with VGB and in 11 of 12 patients treated with ACTH. After 3 months, relapses of spasms were observed in 6 patients treated with ACTH and in 1 treated with VGB. VGB produced a therapeutic response in nearly half the patients receiving this drug.
                Our data lend further support to the view that VGB may be considered a first-choice drug in the treatment of IS.
To date, few well-designed RCTs have considered the treatment of infantile spasms, and the numbers of patients enrolled have been small. In the majority, methodology has been poor, hence it is not clear which treatment is optimal in the treatment of this epilepsy syndrome. Hormonal treatment resolves spasms in more infants than vigabatrin, but this may or may not translate into better long-term outcomes. If prednisolone or vigabatrin is used, high dosage is recommended. Vigabatrin may be the treatment of choice in tuberous sclerosis. Resolution of the EEG features may be important, but this has not been proven. Further research using large studies with robust methodology is required.