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High vigabatrin dosage is associated with lower risk of infantile spasms relapse among children with tuberous sclerosis complex.

ABSTRACT: 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.

SUBMITTER: Hussain SA

PROVIDER: S-EPMC6347124 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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High vigabatrin dosage is associated with lower risk of infantile spasms relapse among children with tuberous sclerosis complex.

Hussain Shaun A SA Schmid Ernst E Peters Jurriaan M JM Goyal Monisha M Bebin E Martina EM Northrup Hope H Sahin Mustafa M Krueger Darcy A DA Wu Joyce Y JY

Epilepsy research 20181002

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. Pa ...[more]

PMID: 30296632

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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.

Project description:ObjectiveEpileptic spasms (ES) are common in tuberous sclerosis complex (TSC). However, the underlying network alterations and relationship with epileptogenic tubers are poorly understood. We examined interictal functional connectivity (FC) using stereo-electroencephalography (SEEG) in patients with TSC to investigate the relationship between tubers, epileptogenicity, and ES.MethodsWe analyzed 18 patients with TSC who underwent SEEG (mean age = 11.5 years). The dominant tuber (DT) was defined as the most epileptogenic tuber using the epileptogenicity index. Epileptogenic zone (EZ) organization was quantitatively separated into focal (isolated DT) and complex (all other patterns). Using a 20-min interictal recording, FC was estimated with nonlinear regression, h2 . We calculated (1) intrazone FC within all sampled tubers and normal-appearing cortical zones, respectively; and (2) interzone FC involving connections between DT, other tubers, and normal cortex. The relationship between FC and (1) presence of ES as a current seizure type at the time of SEEG, (2) EZ organization, and (3) epileptogenicity was analyzed using a mixed generalized linear model. Spike rate and distance between zones were considered in the model as covariates.ResultsSix patients had ES as a current seizure type at time of SEEG. ES patients had a greater number of tubers with a fluid-attenuated inversion recovery hypointense center (p < .001), and none had TSC1 mutations. The presence of ES was independently associated with increased FC within both intrazone (p = .033) and interzone (p = .011) networks. Post hoc analyses identified that increased FC was associated with ES across tuber and nontuber networks. EZ organization and epileptogenicity biomarkers were not associated with FC.SignificanceIncreased cortical synchrony among both tuber and nontuber networks is characteristic of patients with ES and independent of both EZ organization and tuber epileptogenicity. This further supports the prospect of FC biomarkers aiding treatment paradigms in TSC.

Project description:IntroductionEven though adrenocorticotropic hormone (ACTH) demonstrated powerful efficacy in the initially successful treatment of infantile spasms (IS), nearly one-half of patients whose spasms were once suppressed experienced relapse. There is currently no validated method for the prediction of the risk of relapse. The Burden of Amplitudes and Epileptiform Discharges (BASED) score is an electroencephalogram (EEG) grading scale for children with infantile spasms. We sought to determine whether an association exists between the BASED score after ACTH treatment and relapse after initial response with ACTH.MethodsChildren with IS who achieved initial response after ACTH treatment were selected as the study subjects. Those who experienced relapse within 12 months after ACTH treatment were categorized as the relapse group, and those who did not were categorized as the non-relapse group. Their general clinical data and EEG data (using BASED scoring) after ACTH treatment were collected, and compared between groups. Cox proportional hazards models were fit to determine factors associated with relapse.ResultsA total of 64 children with IS were enrolled in the study, of which 37 (57.8%) experienced a relapse, and the median duration after ACTH treatment was 3 (1.5, 6) months. The BASED score was significantly higher in the relapse group than in the non-relapse group. Cox modeling demonstrated that BASED score was independently associated with relapse. The patients with a score greater than or equal to 3 showed a high rate (89.3%) of relapse. The relapse group had stronger, more stable EEG functional networks than the non-relapse group, and there were obvious correlations between BASED score and functional connectivity.ConclusionThis study suggests the BASED score after ACTH treatment has potential value as a predictor for relapse after initial response. Children with IS who have a BASED score greater than or equal to 3 after the initial response of ACTH carry a high risk of relapse within 1 year.

Dataset Information

High vigabatrin dosage is associated with lower risk of infantile spasms relapse among children with tuberous sclerosis complex.

Publications

High vigabatrin dosage is associated with lower risk of infantile spasms relapse among children with tuberous sclerosis complex.

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