Therapeutic efficacy of ACTH in symptomatic infantile spasms with hypsarrhythmia

The records of twenty-six infants with both symptomatic infantile spasms and classic hypsarrhythmia were reviewed to determine the efficacy of various ACTH dosages and time of initiation of therapy. Mean age of infantile spasm onset was 6.4 months. Most patients (13) had sustained perinatal hypoxic-ischemic insults. Seventeen patients (65%) had complete cessation of spasms. Between these responders and the 9 nonresponders there was no difference in duration of spasms prior to treatment (2.6 and 2.0 months) or mean ACTH dose (87.4 and 84.5 U/m², respectively). Infants treated with high-dose ACTH (> 100 U/m²) did not have an improved response rate. The most favorable outcomes were associated with spasm onset at > 8 months of age (all of whom were responders, regardless of dose) or when treatment was started within 1 month of onset of infantile spasms with > 80 U/m² ACTH (88% responders). Infants treated more than 2 months after onset often did not respond (57%) regardless of dose. Nonresponders with spasm onset at < 4 months of age had the worst prognoses; all had poorly controlled seizures and regressed developmentally. Although all infants in the study were neurologically abnormal, development either improved or did not deteriorate in most responder infants following spasm resolution and one-half remained seizure free. Nonresponder infants continued to have infantile spasms or other seizure types. These data suggest that ACTH is valuable in the treatment of significantly impaired infants with symptomatic infantile spasms, but the most important determinants of outcome may be age of onset and rapidity of treatment rather than dosage.     

ACTH Therapy for Infantile Spasms: A Combination Therapy with High-Dose Pyridoxal Phosphate and Low-Dose ACTH

Summary: Combination therapy consisting of high-dose pyridoxal phosphate (40–50 m/kg/day) and low-dose synthetic ACTH (0.01 mg/kg/day) was prescribed in 28 children with infantile spasms. Monotherapy with pyridoxal phosphate provided excellent seizure control in 3 of the 28 (11%) patients. ACTH was subsequently added to the regimen of the remaining 25 patients. As of 1 month after discontinuing the ACTH treatment, 21 of the 25 (84%) patients had experienced no seizures. The mean interval until seizure control was achieved was 4.1 days after the start of treatment with ACTH. The 21 patients have been monitored for a mean of 34.9 months (range 2–81 months); 6 patients (29%) have had recurrences of infantile spasms, and 10 (48%) have experienced normal development. Fourteen of the 28 patients (50%) have had transient increases in liver enzymes, but none of the patients developed more serious side effects.     

Prospective preliminary analysis of the development of autism and epilepsy in children with infantile spasms

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.     

Medical treatment of patients with infantile spasms

Infantile spasms are the main feature in West syndrome, an age-related epilepsy syndrome that affects 1 in every 2,000-4,000 infants. The authors provide a comprehensive review of the literature about infantile spasms and their therapy. In the United States, the drug of choice for infantile spasms, at least the cryptogenic cases, has been adrenocorticotropic hormone (ACTH). It is generally considered to be more effective than corticosteroids. Adrenocorticotropic hormone appears to alter long-term prognosis of cryptogenic infantile spasms, and helps in some cases of symptomatic infantile spasm. Vigabatrin has been considered the drug of choice for infantile spasms secondary to tuberous sclerosis, and possibly, according to many neurologists, for all cases of infantile spasm. Recent concerns regarding retinopathy associated with vigabatrin therapy are, however, limiting the use of this drug. Valproic acid benefits 40%-70% of patients who failed a trial of ACTH. Nitrazepam is as effective as ACTH in acutely controlling infantile spasms; however, its long-term effects on prognosis have not been studied. Pyridoxine, lamotrigine, topiramate, zonisamide, ketogenic diet, immunoglobulin therapy, felbamate, and thyrotropin-releasing hormone have all been used for the treatment of infantile spasms, but are usually reserved for cases refractory to vigabatrin and/or ACTH.     

Seizure outcome in infantile spasms--a retrospective study

Purpose: Prior to the United Kingdom Infantile Spasms Study (UKISS), our practice was to initiate vigabatrin for infantile spasms. However, since then we tend to use steroids as first‐line agent for infantile spasms. Herein we compare seizure‐free outcomes in children with infantile spasms on steroid therapy or vigabatrin therapy. Methods: This was a retrospective case study over 8 years of children with infantile spasms who were treated at our center. A positive response to therapy was defined as a two‐week spasm‐free interval. Key Findings: Of the 98 children presenting to us, 75 were included for this study. The ratio of cryptogenic to symptomatic spasms was 24:51. The response rate for steroid therapy was 61.1% and 42.5% for vigabatrin. Cessation of spasms was achieved faster in the group receiving steroids. Both groups had similar relapse rates. Steroids had significantly better response in the cryptogenic group, whereas in the symptomatic group both the medications were equally effective. Cryptogenic spasms have a better neurodevelopmental outcome. Early introduction of therapy for spasms did not predict a good neurodevelopmental outcome. Seventy‐eight percent of children with spasms had seizures of other types at 12 months follow‐up. Significance: At our center, steroids are now the preferred choice for initial therapy of infantile spasms. This is likely to have been a beneficial change, particularly for children with cryptogenic spasms. Spasms in 25% of the patients tend to be refractory, and the majority of patients from the cohort continue to have epilepsy with motor and cognitive disabilities.     

Prognostic factors of infantile spasms from the etiological viewpoint

We investigated the prognostic factors for mental and physical development and seizure control by dividing the subjects into various etiologic groups in 200 patients with infantile spasms, all of whom (except 48 who died) were aged six years or older. The results were as follows: 1) Intermediate (4-12 mos) onset was found to be a favorable prognostic factor for seizure control in cryptogenic cases, although there was no relation between the age of onset and prognosis in other etiologic groups. 2) There was a significant correlation between the treatment lag and long-term prognosis for mental and physical development only in cryptogenic cases. A short treatment lag (0-2 mos) was associated with a good prognosis. All cryptogenic patients who had no relapse after ACTH therapy developed normally, although in symptomatic cases, there was no correlation between the relapse and the outcome.     

Treatment of infantile spasms by pediatric neurologists in Japan

Objective

To clarify changes in clinical practice for infantile spasms, including West syndrome, in Japan over the past two decades.

Outcomes among patients with infantile spasms treated with hormonal therapy and adjuvant topiramate versus hormonal therapy alone

Aims: Hormonal therapy is the first‐line treatment for infantile spasms and is sometimes used in combination with topiramate for better seizure control and potentially improved developmental outcomes. Methods: Retrospective review of pediatric patients with infantile spasms, with data compiled on patient sex, age at onset, etiology, electroencephalographic and imaging findings, topiramate use, spasm resolution (at one, six, and 12 months), and developmental outcome (at 12 months). Results: Of 105 patients screened, 55 (28 female) met inclusion criteria (28 [51%] had spasms with known etiology and 27 [49%] had spasms with unknown etiology). Forty‐six patients were followed for 12 months or longer to determine seizure outcome; a 12‐month developmental assessment was documented for 49 patients. Thirty‐seven patients (67%) received combination therapy; 18 (33%) received hormonal therapy alone. Resolution of spasms was comparable among treatment groups, with no difference relative to spasm etiology (p>0.18 for all). No difference was found in developmental outcomes with and without adjunct topiramate (p=0.38). Conclusions: Combination therapy was the most common treatment at our institution. However, combination therapy was not found to be beneficial for the treatment of spasms or developmental outcomes when compared to hormonal therapy alone.     

A retrospective study on aetiology based outcome of infantile spasms

PurposeThe goal of this retrospective study is to review the causes of infantile spasms and to correlate aetiology with outcome.MethodsAll children diagnosed with infantile spasms between 1990 and 2003 at our institution were included. Charts were reviewed for the presence or absence of a defined aetiology/association, response to treatment, long-term epileptic and cognitive outcome.Results80 out of 95 children are included in this review. 50 children (63%) had symptomatic spasms with disorders of cortical development being the most frequent cause followed by neonatal injury and tuberous sclerosis. Symptomatic children with developmental brain lesions responded at a rate of 54% to vigabatrin versus 62% for ACTH/prednisone, while other symptomatic aetiologies 83% responded to vigabatrin versus 63% for ACTH/prednisone. Cryptogenic spasms responded at a similar rate to both drugs. Other than children with cryptogenic spasms, very few went on to develop normally. Our results are however biased by on average more than 30 days of delay to diagnosis. None of our children developed Lennox-Gastaut syndrome but a number developed severe epilepsy with multifocal spikes.DiscussionThe aetiology and prognosis of infantile spasms is evolving. To improve outcome, we need to reduce the delay to diagnosis and develop prospective double-blind randomized clinical trials looking at not only the epileptic outcome but also cognitive outcome of these children.     

Vigabatrin Versus ACTH as First-Line Treatment for Infantile Spasms: A Randomized, Prospective Study

Summary: Purpose: To compare the efficacy and tolerability of vigabatrin (VGB) and adrenocorticotrophic hormone (ACTH) as first-line therapy in infantile spasms. Methods: 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. Results: 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. Conclusions: Our data lend further support to the view that VGB may be considered a first-choice drug in the treatment of IS.     

A pulse rapamycin therapy for infantile spasms and associated cognitive decline

Infantile spasms are seizures manifesting within a spectrum of epileptic encephalopathies of infancy that often lead to cognitive impairment. Their current therapies, including adrenocorticotropic hormone (ACTH), high dose steroids, or vigabatrin, are not always effective and may be associated with serious side effects. Overactivation of the TORC1 complex of the mTOR pathway is implicated in the pathogenesis of certain genetic and acquired disorders that are linked with infantile spasms, like tuberous sclerosis. Here, we tested the therapeutic potential of rapamycin, a TORC1 inhibitor, as a potential treatment for infantile spasms in the multiple-hit rat model of ACTH-refractory symptomatic infantile spasms, which is not linked to tuberous sclerosis. Rapamycin or vehicle was given after spasms appeared. Their effects on spasms, other seizures, performance in Barnes maze, and expression of the phosphorylated S6 ribosomal protein (pS6: a TORC1 target) in the cortex, using immunofluorescence, were compared. Rapamycin suppressed spasms dose-dependently and improved visuospatial learning, although it did not reduce the frequency of other emerging seizures. High-dose pulse rapamycin effected acute and sustained suppression of spasms and improved cognitive outcome, without significant side effects. Therapeutically effective rapamycin doses normalized the pS6 expression, which was increased in perilesional cortical regions of pups with spasms. These findings support that pathological overactivation of TORC1 may be implicated in the pathogenesis of infantile spasms, including those that are not linked to tuberous sclerosis. Furthermore, a high-dose, pulse rapamycin treatment is a promising, well tolerated and disease-modifying new therapy for infantile spasms, including those refractory to ACTH.     

Treatment of infantile spasms with high-dose ACTH: efficacy and plasma levels of ACTH and cortisol

Fifteen children with infantile spasms and a hypsarrhythmic EEG defined by EEG-videotelemetry monitoring received a regimen of high-dose (150 IU/m2/d) ACTH for their seizures. We carried out an endocrinologic evaluation before and after initiation of the ACTH and conducted a time course study of plasma ACTH and cortisol levels after ACTH dosing. Spasms were controlled and the EEG normalized in 14 of the 15 children. Prior to starting ACTH therapy all the patients had normal prolactin, insulin, cortisol, and ACTH levels in plasma and normal thyroid function. Although the pattern of rise of ACTH levels in plasma after ACTH dosing was similar in all the children, there was great individual variation in the absolute concentrations. However, both the pattern of rise and absolute level of cortisol in plasma after ACTH was highly predictable in all patients. Plasma cortisol rose rapidly within 1 hour of ACTH administration and continued a slower rise for 12 to 24 hours after the ACTH dose. High-dose ACTH therapy seems quite effective in infantile spasms, perhaps because of a sustained high level of plasma cortisol. This sustained plateau of cortisol may be more effective in controlling infantile spasms than the pulse effect expected with oral steroids or lower doses of ACTH.     

Treatment of Infantile Spasms with High-Dosage Vitamin B6

Summary: High-dose vitamin B₆ (pyridoxine-HCl, 300 mg/kg/day orally) was introduced as the initial treatment of recently manifested infantile spasms in 17 children (13 symptomatic cases with identified brain lesion and 4 cryptogenic cases). 5 of 17 children (2 cryptogenic, 2 with severe pre/perinatal brain damage and one with Sturge-Weber syndrome) were classified as responders to high-dose vitamin B₆. In all 5 cases the response to vitamin B₆occurred within the first 2 weeks of treatment and within 4 weeks all patients were free of seizures. Two patients' developed other seizures (partial seizures, etiologically unclear blinking attacks), but no relapse of infantile spasms was observed among the five responders to vitamin B₆. No serious adverse reactions were noted. Side effects were mainly gastrointestinal symptoms, which were reversible after reduction of the dosage. Considering the life-threatening side effects of treatment with ACTH/corticosteroids or valproate, a controlled clinical trial with high-dose vitamin B₆ would appear justified to either prove or disprove efficacy.     

Vigabatrin in the treatment of infantile spasms

Infantile spasms (IS) have been conventionally treated with adrenocorticotropic hormone (ACTH), which is often associated with significant side effects. This study assessed the efficacy of vigabatrin (VGB) as an alternative in the treatment of IS and compared the efficacy of VGB in symptomatic vs cryptogenic patients. The study retrospectively reviewed 25 infants with IS (19 symptomatic, six cryptogenic) who were treated with VGB. Of the symptomatic group, 13 (68.4%) of 19 had clinical improvement, and 15 (78.9%) had electroencephalographic improvement. Three (50%) of six in the cryptogenic group had clinical improvement, and two (33%) had electroencephalographic improvement. Overall, three patients demonstrated clinical spasm control but electroencephalographic deterioration or persistence of hypsarrhythmia coupled with further cognitive decline. Four of the six partial clinical responders had deterioration of spasms with additional VGB dosage increases. VGB is comparable with ACTH in effectiveness for treatment of symptomatic IS. Higher doses of VGB may sometimes cause deterioration rather than further improvement, and therefore an optimum dosage of VGB needs to be titrated for every patient. Persistent electroencephalographic abnormalities and even electroencephalographic deterioration despite clinical control have been observed with VGB treatment; electroencephalographic monitoring during VGB treatment is recommended.     

Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms

Two-year postsurgical developmental outcomes were assessed in 24 children with infantile spasms who underwent resective surgery. The mean age of onset of infantile spasms was 12.0 weeks and the mean age at surgery was 20.8 months. Developmental outcomes were assessed using the Vineland Adaptive Behavior Scales (VABS). There was a significant increase in developmental level at 2 years postsurgery compared with presurgical levels. At 2 years postsurgery only one of the children in this series was severely retarded. The developmental outcomes of patients in the series were better than those in prior studies of symptomatic patients receiving medical treatment for infantile spasms. It is surprising that the children in the UCLA series frequently had developmental outcomes equal to and sometimes superior to other groups of children with infantile spasms, since all the UCLA patients were symptomatic, had neurologic deficits and had failed to respond to adrenocorticotropic hormone (ACTH) and antiepileptic drugs. The 2-year postsurgery developmental outcomes were best for the children who received surgery, when they were relatively young and who had the highest level of developmental attainments presurgically.     

Treatment of Infantile Spasms: Results of a Population-Based Study with Vigabatrin as the First Drug for Spasms

PURPOSE: The efficacy of a protocol consisting of vigabatrin (VGB) as the first and adrenocorticotropic hormone (ACTH) or valproate (VPA) as the second drug was studied in the treatment of newly diagnosed infantile spasms (IS) during 1994 to 1997 in a population-based design. METHODS: Only total disappearance of the spasms with a minimal duration of 1 month was accepted as a response. The treatment response was confirmed by video-EEG study. All infants were studied by magnetic resonance imaging (MRI) or computed tomography (CT) for etiology. RESULTS: Altogether 42 infants, 10 with cryptogenic and 32 with symptomatic etiology, were treated. Eleven (26%) responded to VGB, five (50%) with cryptogenic, and six (19%) with symptomatic etiology; 91% of infants responded to a dose of 50-100 mg/kg/day, and 82% of them within 1 week. ACTH was offered in combination with VGB to 22 and VPA to four infants for whom VGB failed. Eleven responded to ACTH and one to VPA. In total, 26 (62%) infants responded to the treatment protocol; all (100%) with cryptogenic etiology and 16 (50%) with symptomatic etiology. ACTH treatment was associated with more severe side effects than VGB or VPA. Only one infant relapsed after a spasm-free period with VGB of >4 months, but none after ACTH was combined with VGB. CONCLUSIONS: We suggest VGB as a first drug to all infants with IS. After a treatment trial of 10-14 days with increasing dose from 50 to 150 mg/kg, ACTH should be considered.     

Treatment of infantile spasms

Although the syndrome of infantile spasms has been known for 150 years and its treatment described since 1958, controversy still surrounds the appropriate therapy for this devastating disorder. The rationale, dosage, and side effects of ACTH treatment of infantile spasms is described. The recommended treatment regimen is placed in the context of the literature on the therapy of spasms and its relation to outcome.     

West syndrome: individualized ACTH therapy

Individualized ACTH treatment of the West syndrome (WS) was assessed in a prospective multicenter study, in which each patient's dosage was increased stepwise according to response. Our series included six patients with cryptogenic and 24 with symptomatic infantile spasms. During the treatment period the total ACTH dose ranged from 58 to 373 IU / kg. In the cryptogenic group one patient responded to pre-ACTH pyridoxine and four to the lowest dosage of ACTH (3 IU / kg daily) with cessation of spasms and good outcome; one patient needed the highest dosage (12 IU / kg daily) for cessation of seizures and became developmentally retarded. In the symptomatic group, 21 of the 24 patients needed 6–12 IU / kg daily; 12 became seizure-free or having infrequent non-IS fits. Complications such as arterial hypertension, cerebral ventricle dilatation, cardiac hypertrophy, and prolonged adrenocortical hyporesponsiveness were related to the dose. The individualization provides all the benefits of ACTH treatment with minimal side effects and cost.     

Prenatal stress promotes development of spasms in infant rats

We have developed a new model of cryptogenic infantile spasms with prenatal betamethasone brain priming to increase susceptibility to development-specific spasms triggered by N-methyl-d-aspartate (NMDA). A recent clinical study linked severe prenatal stress to increased risk for development of infantile spasms. Here, we determined whether prenatal restraint stress (2 × 45 min) in rats on gestational day 15 would increase susceptibility to develop spasms on postnatal day 15. Prenatal stress significantly accelerated onset and increased number of NMDA-triggered spasms compared to handled controls. A single adrenocorticotropic hormone (ACTH or corticotropin) dose delivered acutely had no effects, whereas long-term (3 day) ACTH pretreatment significantly increased latency to onset and decreased number of spasms (an effect similar to that in the human condition). Our data support the notion that extra care should be provided during pregnancy to minimize stress.     

Facilitation of Infantile Spasms by Partial Seizures

Summary: We report 16 patients with infantile spasms in whom onset of the clusters of spasms appeared to be triggered by close temporal association with partial seizures. Common features included the presence of focal cerebral lesions in 12 infants (3 were classifiable as cryptogenic); all had partial seizures with EEG localization, clusters of bilateral spasms always preceded by partial seizures, and response to adrenocorticotropic hormone (ACTH) and traditional antiepileptic drugs (AEDs) generally was poor. Three had complete agenesis of the corpus callosum, which argues against interhemispheric callosal spread of focal discharges resulting in the generalized spasms. Surgical cortical resections were performed in 6 of the infants, with good outcomes. This group of patients supports a model in which the spasms, although probably generated at a subcortical level, are facilitated or possibly induced by focal discharges from cortical pathology.