Combined Treatment of 'Vigabatrin and Corticoids' for Infantile Spasms: A Superiority Complex or Truly Superior to Corticoids Monotherapy?
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SUBMITTER: Gupta A
PROVIDER: S-EPMC5706355 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Infantile spasms (IS) have poor outcomes and limited treatment options, including vigabatrin, a ?-aminobutyric acid (GABA) aminotransferase inactivator. Vigabatrin has been associated with retinal toxicity. A high affinity vigabatrin analogue (CPP-115; Catalyst Pharmaceutical Partners, Inc., Coral Gables, FL, U.S.A.) has shown lower risk of retinal toxicity. Here, we test the efficacy of CPP-115 in reducing spasms and its tolerability in the multiple-hit rat model of IS, in which daily vigabatrin reduced spasms for only one day, but was not well tolerated.Male rats were treated with the protocol of the multiple-hit model of IS on postnatal day 3 (PN3). Using a randomized, blinded, vehicle-controlled, dose-response study design, CPP-115 (0.1, 1, or 5 mg/kg intraperitoneally [i.p.]) or vehicle was given daily (PN4-12) or as a single injection (PN7) after spasm onset. Intermittent video- or video-electroencephalography (EEG) monitoring was done. Secondary end points included the following: daily weights, survival, performance on open field activity, surface righting time, and negative geotaxis (PN3-20), horizontal bar (PN13-20), and Barnes maze (PN16-19). Statistics used a linear mixed model of raw or normalized log-transformed data, taking into account the repeated observations on each animal.The lower CPP-115 doses (0.1-1 mg/kg/day, PN4-12) reduced spasms between PN6 and 7 without increasing mortality. CPP-115 at 5 mg/kg/day (PN4-12) reduced spasms earlier (PN5), but was eventually lethal. A single CPP-115 injection (1 mg/kg, i.p.) decreased electroclinical spasms acutely but transiently. CPP-115 transiently improved the probability to >50% reduction of spasms, but did not accelerate spasm cessation. CPP-115 did not alter neurodevelopmental outcomes or visuospatial learning.We provide proof-of-concept evidence that CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of IS at considerably lower and better tolerated doses than vigabatrin did in our previous studies. Further optimization of the treatment protocol is needed. CPP-115 may be a promising new candidate treatment for IS with better tolerability than vigabatrin.
| S-EPMC4102583 | biostudies-literature
Project description:ObjectivesTo determine time to vigabatrin (VGB, Sabril; Lundbeck, Deerfield, IL) induced retinal damage in children with infantile spasms (IS) and to identify risk factors for VGB-induced retinal damage (VGB-RD).MethodsObservational cohort study including 146 participants (68 female, 81 male) with IS, an age-specific epilepsy syndrome of early infancy, treated with VGB. Participants ranged from 3 to 34.9 months of age (median 7.6 months). The median duration of VGB treatment was 16 months (range 4.6-78.5 months). Electroretinograms (ERGs) were performed according to the Standards of the International Society for Clinical Electrophysiology of Vision. Inclusion required baseline (pre-VGB or within 4 weeks of starting VGB treatment) and at least 2 follow-up ERGs. Significant reduction from baseline of the 30-Hz ERG flicker amplitude on 2 consecutive visits identified VGB-RD. Kaplan-Meier survival analyses depicted the effect of duration of VGB on VGB-RD.ResultsThese data represent the largest survival analysis of children treated with VGB who did not succumb to retinal toxicity during the study. Thirty of the 146 participants (21%) showed VGB-RD. The ERG amplitude reduced with duration of VGB treatment (p = 0.0004) with no recovery after VGB cessation. With 6 and 12 months of VGB treatment, 5.3% and 13.3%, respectively, developed VGB-RD. There was neither effect of age of initiation of VGB treatment nor sex of the child on survival statistics and no significant effect of cumulative dosage on the occurrence of VGB-RD.ConclusionsMinimizing VGB treatment to 6 months will reduce the prevalence of VGB-RD in patients with IS.
| S-EPMC4277676 | biostudies-literature
Project description:After initially successful treatment of infantile spasms, the long-term cumulative risk of relapse approaches 50%, and there is no established protocol to mitigate this risk. Although vigabatrin may be an effective means to prevent relapse, there is little guidance as to ideal duration and dosage. Using a cohort of children with infantile spasms and tuberous sclerosis complex (TSC), we evaluated the potential association of post-response VGB treatment and the rate of infantile spasms relapse. Patients with infantile spasms and clinical response to vigabatrin were identified among a multicenter prospective observational cohort of children with TSC. For each patient we recorded dates of infantile spasms onset, response to vigabatrin, relapse (if any), and quantified duration and dosage of vigabatrin after response. Time to relapse as a function of vigabatrin exposure was evaluated using survival analyses. We identified 50 children who responded to VGB. During a median follow-up of 16.6 months (IQR 10.3-22.9), 12 (24%) patients subsequently relapsed after a median of 7.8 months (IQR 3.1-9.6). Relapse occurred after VGB discontinuation in four patients, and during continued VGB treatment in the remaining eight cases. In survival analyses, risk of relapse was unaffected by the presence or absence of VGB treatment (HR 0.31, 95%CI 0.01-28.4, P = 0.61), but weighted-average dosage was associated with marked reduction in relapse risk: Each 50 mg/kg/d increment in dosage was associated with 61% reduction in risk (HR 0.39, 95%CI 0.17 - 0.90, P = 0.026). This study suggests that the risk of infantile spasms relapse in TSC may be reduced by high-dose vigabatrin treatment.
| S-EPMC6347124 | biostudies-literature
Project description:The treatment of infantile spasms is challenging, especially in the context of the following: (1) a severe phenotype with high morbidity and mortality; (2) the urgency of diagnosis and successful early response to therapy; and (3) the paucity of effective, safe, and well-tolerated therapies. Even after initially successful treatment, relapse risk is substantial and the most effective therapies pose considerable risk with long-term administration. In evaluating any treatment for infantile spasms, the key short-term outcome measure is freedom from both epileptic spasms and hypsarrhythmia. In contrast, the most important long-term outcomes are enduring seizure-freedom and measures of intellectual performance in later childhood and adulthood. First-line treatment options-namely hormonal therapy and vigabatrin-display moderate to high efficacy but also exhibit substantial side-effect burdens. Data on efficacy and safety of each class of therapy, as well as the combination of these therapies, are reviewed in detail. Specific hormonal therapies (adrenocorticotropic hormone and various corticosteroids) are contrasted. Those etiologies that prompt specific therapies are reviewed briefly, as are an array of second-line therapies supported by less-compelling data. The ketogenic diet is discussed in greater detail, with a focus on the limitations of numerous available studies that generally suggest that it is efficacious. Special discussion is allocated to cannabidiol-the investigational therapy that has received the most attention, and which is already in use in the form of various artisanal cannabis extracts. Finally, a treatment algorithm reflecting the concepts and controversies discussed in this review is presented.
| S-EPMC6293071 | biostudies-literature
Project description:Abnormal high frequency oscillations (HFOs) in EEG recordings are thought to be reflections of mechanisms responsible for focal seizure generation in the temporal lobe and neocortex. HFOs have also been recorded in patients and animal models of infantile spasms. If HFOs are important contributors to infantile spasms then anticonvulsant drugs that suppress these seizures should decrease the occurrence of HFOs. In experiments reported here, we used long-term video/EEG recordings with digital sampling rates capable of capturing HFOs. We tested the effectiveness of vigabatrin (VGB) in the TTX animal model of infantile spasms. VGB was found to be quite effective in suppressing spasms. In 3 of 5 animals, spasms ceased after a daily two week treatment. In the other 2 rats, spasm frequency dramatically decreased but gradually increased following treatment cessation. In all animals, hypsarrhythmia was abolished by the last treatment day. As VGB suppressed the frequency of spasms, there was a decrease in the intensity of the behavioral spasms and the duration of the ictal EEG event. Analysis showed that there was a burst of high frequency activity at ictal onset, followed by a later burst of HFOs. VGB was found to selectively suppress the late HFOs of ictal complexes. VGB also suppressed abnormal HFOs recorded during the interictal periods. Thus VGB was found to be effective in suppressing both the generation of spasms and hypsarrhythmia in the TTX model. Vigabatrin also appears to preferentially suppress the generation of abnormal HFOs, thus implicating neocortical HFOs in the infantile spasms disease state.
| S-EPMC4640943 | biostudies-literature
Project description:Infantile spasms (IS) is a developmental and epileptic encephalopathy with heterogeneous etiologies including many genetic causes. Genetic studies have identified pathogenic variants in over 30 genes as causes of IS. Many of these genetic causes are extremely rare, with only one reported incidence in an individual with IS. To better understand the genetic landscape of IS, we used targeted sequencing to screen 42 candidate IS genes and 53 established developmental and epileptic encephalopathy genes in 92 individual with IS. We identified a genetic diagnosis for 7.6% of our cohort, including pathogenic variants in KCNB1 (n?=?2), GNAO1 (n?=?1), STXBP1 (n?=?1), SLC35A2 (n?=?1), TBL1XR1 (n?=?1), and KIF1A (n?=?1). Our data emphasize the genetic heterogeneity of IS and will inform the diagnosis and management of individuals with this devastating disorder.
| S-EPMC6814289 | biostudies-literature
Project description:BackgroundEpileptic spasms are a devastating form of early infantile epileptic encephalopathy (EIEE) with various etiologies. Early diagnosis and a shorter lead time to treatment are crucial to stop the seizures and optimize the neurodevelopmental outcome. Genetic testing has become an integral part of epilepsy care that directly guides management and family planning and discovers new targeted treatments. Neuronal differentiation Factor 2 (NEUROD2) variants have recently been a cause of neurodevelopmental disorders (NDDs) and EIEEs with distinctive features. However, there is limited information about the clinical and electroencephalographic response of epileptic spasm treatment in NEUROD2-related NDD syndrome.Case presentationWe report a female patient of Southeast Asian ethnicity with global developmental delay and epileptic spasms commencing in the first few months of life. A novel de novo heterozygous pathogenic NEUROD2 variant, p. E130Q, was subsequently identified by whole-exome sequencing. Electroencephalogram before treatment showed multifocal independent spikes predominantly in both posterior head regions and demonstrated marked improvement following combined vigabatrin and high-dose prednisolone treatment. However, multiple courses of relapse occurred after weaning off the antiseizure medication.ConclusionsWe propose that epileptic spasms related to de novo NEUROD2 pathogenic variant respond well to combined vigabatrin and high-dose prednisolone therapy. These findings may imply the benefit of using combination therapy to treat epileptic spasms in NEUROD2-related NDD syndrome.
| S-EPMC9733267 | biostudies-literature
Project description:AimTo estimate the prevalence, and evaluate presentation, treatment response, treatment side effects, and long-term seizure outcomes in all known cases of children with Down syndrome and infantile spasms on the island of Ireland.MethodThis was a 10-year retrospective multicentre review of clinical records and investigations, focusing on treatment response, side effects, and long-term outcomes.ResultsThe prevalence of infantile spasms in Down syndrome was 3.0% during the study period. Fifty-four infants were identified with median age of spasm onset at 201 days (interquartile range [IQR] 156-242). Spasm cessation was achieved in 88% (n=46) at a median of 110 days (IQR 5-66). The most common first-line medications were prednisolone (n=20, 37%), vigabatrin (n=18, 33.3%), and sodium valproate (n=9, 16.7%). At follow-up (median age 23.7mo; IQR 13.4-40.6), 25% had ongoing seizures and 85% had developmental concerns. Treatment within 60 days did not correlate with spasm cessation. Seventeen children (31%) experienced medication side effects, with vigabatrin accounting for 52%.InterpretationPrednisolone is an effective and well-tolerated medication for treating infantile spasms in Down syndrome. Despite the high percentage of spasm cessation, developmental concerns and ongoing seizures were common.
| S-EPMC9303415 | biostudies-literature
Project description:Infantile spasms are a devastating epileptic encephalopathy characterized by early life spasms and later seizures. Clinical outcomes of infantile spasms are poor and therapeutic options are limited with significant adverse effects. Therefore, new strategies to treat infantile spasms are of the utmost importance. Animals models of infantile spasms are a critical component of developing new therapies. Here, we review current chronic animal models of infantile spasms and consider future advances that may help improve patient care, as well as our scientific understanding of this debilitating disease.
| S-EPMC5898247 | biostudies-literature
Project description:This study explores the etiology and lead time to treatment for infantile spasm (IS) patients and their effect on treatment responsiveness, in a limited resource setting. Patients with IS onset age ?12 months', seen over 3 years were recruited retrospectively. Clinical information, neuroimaging and genetic results retrieved. Patients categorized into three primary etiological groups: Structural (including Structural Genetic), Genetic, and Unknown. The effect of etiology and lead time from IS onset to initiating appropriate treatment on spasm resolution, evaluated. Total 113 patients were eligible. Mean IS onset age was 6.86(±4.25) months (M: F 3.3:1). Patients were grouped into: Structural 85, Genetic 11 and Unknown 17. Etiology was ascertained in 94/113 (83.1%) with neonatal hypoglycemic brain injury (NHBI) being the most common (40/113, 36%). A genetic etiology identified in 17 (including 6 Structural Genetic, of which five had Tuberous Sclerosis). Structural group was less likely to be treatment resistant (p = 0.013, OR 0.30 [0.12-0.76]). Median treatment lead time - 60 days. Longer lead time to treatment was significantly associated with resistant spasms (?2 for trend = 10.0, p = 0.0015). NHBI was the commonest underlying cause of IS. There was significant time lag to initiating appropriate treatment, affecting treatment responsiveness.
| S-EPMC7656466 | biostudies-literature