Vigabatrin Initiation Research Articles

Magnetic Resonance Imaging-Based Distribution and Reversibility of Lesions in Pediatric Vigabatrin-Related Brain Toxicity

BackgroundWe aimed to systematically characterize the magnetic resonance imaging (MRI) findings in vigabatrin-related neurotoxicity in children and determine the reversibility of lesions based on follow-up images. MethodsWe evaluated children with a history of refractory seizures who had a brain MRI while on vigabatrin therapy. We included available brain MRI studies before vigabatrin therapy initiation, during vigabatrin treatment, and after vigabatrin was discontinued. A pediatric neuroradiologist systematically assessed images on T2/fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging /apparent diffusion coefficient sequences to identify hyperintense lesions and/or restricted diffusion. The frequency of abnormal signal at each location was determined, as well as the reversibility of these after vigabatrin discontinuation. ResultsMRIs of 43 patients were reviewed: 13 before vigabatrin initiation, 18 during treatment, and 12 after vigabatrin discontinuation. In the MRIs acquired during vigabatrin treatment, most lesions on T2/FLAIR occurred in the globus pallidi, thalami, and midbrain. Correspondingly, the most common locations for restricted diffusion were the globus pallidi, thalami, and subthalamic nuclei. On MRI after vigabatrin discontinuation, complete resolution of lesions on T2/FLAIR in all patients was seen in the midbrain, dentate nuclei, subthalamic nuclei, and hypothalami. Complete resolution of restricted diffusion was observed in the globus pallidi, midbrain, dentate nuclei, hippocampi, anterior commissure, and hypothalami. ConclusionGlobus pallidi and thalami are the most commonly affected structures in vigabatrin-related toxicity, and most vigabatrin-related neuroimaging findings are reversible.

Early epileptiform EEG activity in infants with tuberous sclerosis complex predicts epilepsy and neurodevelopmental outcomes

To study the association between timing and characteristics of the first electroencephalography (EEG) with epileptiform discharges (ED-EEG) and epilepsy and neurodevelopment at 24months in infants with tuberous sclerosis complex (TSC). Patients enrolled in the prospective Epileptogenesis in a genetic model of epilepsy - Tuberous sclerosis complex (EPISTOP) trial, had serial EEG monitoring until the age of 24months. The timing and characteristics of the first ED-EEG were studied in relation to clinical outcome. Epilepsy-related outcomes were analyzed separately in a conventionally followed group (initiation of vigabatrin after seizure onset) and a preventive group (initiation of vigabatrin before seizures, but after appearance of interictal epileptiform discharges [IEDs]). Eighty-three infants with TSC were enrolled at a median age of 28days (interquartile range [IQR] 14-54). Seventy-nine of 83 patients (95%) developed epileptiform discharges at a median age of 77days (IQR 23-111). Patients with a pathogenic TSC2 variant were significantly younger (P-value .009) at first ED-EEG and more frequently had multifocal IED (P-value .042) than patients with a pathogenic TSC1 variant. A younger age at first ED-EEG was significantly associated with lower cognitive (P-value .010), language (P-value .001), and motor (P-value .013) developmental quotients at 24months. In the conventional group, 48 of 60 developed seizures. In this group, the presence of focal slowing on the first ED-EEG was predictive of earlier seizure onset (P-value .030). Earlier recording of epileptiform discharges (P-value .019), especially when multifocal (P-value .026) was associated with higher risk of drug-resistant epilepsy. In the preventive group, timing, distribution of IED, or focal slowing, was not associated with the epilepsy outcomes. However, when multifocal IEDs were present on the first ED-EEG, preventive treatment delayed the onset of seizures significantly (P-value <.001). Early EEG findings help to identify TSC infants at risk of severe epilepsy and neurodevelopmental delay and those who may benefit from preventive treatment with vigabatrin.

Effect of vigabatrin on seizure control and safety profile in different subgroups of children with epilepsy.

To evaluate the efficacy and safety of vigabatrin in pediatric epilepsy. We retrospectively reviewed patients with epilepsy treated with vigabatrin over a 2-year period at a pediatric tertiary center. We assessed the relationship between seizure frequency, etiology, vigabatrin dose, adverse events, medication discontinuation reasons, and electroencephalography (EEG) characteristics. One hundred three patients followed at Boston Children's Hospital were treated with vigabatrin and had complete medical records. Within the follow-up interval, 69 (67%) of 103 patients had discontinued vigabatrin therapy. Two patients (1.9%) died during therapy for unknown reasons. Median age at vigabatrin initiation was 8months (interquartile range [IQR] 5-15). Median starting dose was 48.1mg/kg per day (IQR 29.8-52.3) with a median target of 100mg/kg (IQR 81.9-107.9). Median treatment duration was 12.1months (n=89, IQR 5.0-22.9) overall, and 13.3months (IQR 5.2-23.2) for patients who discontinued vigabatrin. The most common reasons for discontinuation were controlled seizures in 31 (43.7%) of 71 and unsatisfactory therapeutic effect in 23 (32.4%) of 71. Median percent seizure reduction from baseline to first follow-up was 83.3% (IQR 27.4-99.8) and 96.7% (IQR 43.3-100) to last follow-up. Twenty-four (38.7%) of 62 patients with a follow-up posttreatment remained seizure-free. Four patients who had initially achieved seizure freedom relapsed. Patients with structural/metabolic etiology had greater median percent seizure reduction at first follow-up than patients with genetic etiology (98.7% vs. 61.4%, respectively, p=0.001). Hypsarrhythmia resolved after therapy in 18 of 20 (90%, 95% confidence interval [CI] 70-97) patients with pretreatment hypsarrhythmia, and 2 patients presented with hypsarrhythmia posttreatment. Risk of having hypsarrhythmia was reduced by 32% (95% CI 14.9-49.1) posttreatment. Vigabatrin is efficacious in all seizure types and resolved hypsarrhythmia in most patients. In this series with a median treatment duration of 12.1months, vigabatrin had a good safety profile with a low rate of discontinuation due to nonophthalmologic and ophthalmologic adverse effects.

Sabril® registry 5-year results: Characteristics of adult patients treated with vigabatrin.

Vigabatrin (Sabril®), approved in the US in 2009, is currently indicated as adjunctive therapy for refractory complex partial seizures (rCPS) in patients ≥ 10 years old who have responded inadequately to several alternative treatments and as monotherapy for infantile spasms (IS) in patients 1 month to 2 years of age. Because of reports of vision loss following vigabatrin exposure, FDA approval required a risk evaluation mitigation strategy (REMS) program. Vigabatrin is only available in the US through Support, Help, And Resources for Epilepsy (SHARE), which includes a mandated registry. This article describes 5 years of demographic and treatment exposure data from adult patients (≥ 17 years old) in the US treated with vigabatrin and monitored in the ongoing Sabril® registry. Registry participation is mandatory for all US Sabril® prescribers and patients. A benefit-risk assessment must be documented by the physician for a patient to progress to maintenance therapy, defined as 1 month of vigabatrin treatment for patients with IS and 3 months for patients with rCPS. Ophthalmologic assessments must be documented during and after completion of therapy. As of August 26, 2014, a total of 6823 patients were enrolled in the registry, of which 1200 were adults at enrollment. Of these patients, 1031 (86%) were naïve to vigabatrin. The majority of adult patients (n=783, 65%) had previously been prescribed ≥ 4 AEDs, and 719 (60%) were receiving ≥ 3 concomitant AEDs at vigabatrin initiation. Prescribers submitted an initial ophthalmological assessment form for 863 patients; an ophthalmologic exam was not completed for 300 (35%) patients and thus, were considered exempted from vision testing. Of these patients, 128 (43%) were exempted for neurologic disabilities. Clinicians discontinued treatment in 8 patients because of visual field deficits (VFD) (5 patients naïve to vigabatrin and 3 patients previously exposed). Based on Kaplan-Meier survival estimates, it is estimated that approximately 71%, 55%, and 40% of adult patients naïve to vigabatrin would remain in the registry at 3, 6, and 12 months, respectively. These demographic data suggest that a proportion of adult patients remain on vigabatrin long-term despite the risks of adverse events and significant underlying AED resistance and neurologic disease.

Phase IV Vision Study Evaluates Retinal Structure and Function in Adult Patients with Refractory Complex Partial Seizures Treated with Vigabatrin (P07.255)

Objective: To evaluate change in retina structure and function in vigabatrin-naive patients, we initiated a prospective, 1-year open-label trial in patients requiring vigabatrin treatment. Background An important safety issue for vigabatrin is risk of bilateral concentric constriction of visual fields. Design/Methods: ∼80 patients with rCPS for ≥1 year (with ≥2 seizures/month averaged over prior 3 months) will be enrolled at ∼25 US sites. Patients must have failed ≥3 prior therapies for lack of efficacy and must be receiving concomitant AEDs. Vigabatrin-naive patients ≥18 years of age will have visual static perimetry and optical coherence tomography (OCT) assessments at baseline, and 3, 6, 9, and 12 months following vigabatrin initiation. Key endpoints include change from reference value in field width (static perimetry), and change from reference value in retinal nerve fiber layer thickness (OCT and macular thickness OCT). After commencing vigabatrin, patients are assessed every 3 months through automated static perimetry (both standard 30-2 and horizontal meridian full field), OCT, and ancillary exploratory visual endpoints such as visual acuity, color vision, and visual fields by Tangent Corner Test. If deficits are discovered, investigators conduct benefit/risk assessments with patients. Results: By October 2011, 8 sites had been initiated. Screening was initiated for 8 patients. Five were screen failures, and three patients were enrolled. Of these three, two are ongoing study participants, and one was an early termination (seizures returned to baseline rate and patient was discontinued following benefit/risk assessment). One patient had abnormal baseline OCT results (before vigabatrin therapy), emphasizing that patients may have pre-existing afferent visual system conditions. Conclusions: This study is designed to provide a better definition of onset and progression of peripheral visual field defects, to assess the risk of developing vision loss during first year of exposure, and to evaluate OCT for monitoring retinal changes. Supported by: Lundbeck Inc. Disclosure: Dr. Sergott has received personal compensation for activities with Pfizer, Serono, Lundbeck, and Centocor as a speaker and consultant. Dr. Sergott has received personal compensation in an editorial capacity for Current Opinion in Neuro-Opthamology. Dr. Faught has received personal compensation for activities with Pfizer Inc, UCB Pharma, Ortho-McNeil Pharmaceutical, Inc., Valeant Pharmaceuticals, Ovation Pharmaceuticals, Inc., GlaxoSmithKline, Inc., Abbott Laboratories, Inc., and Novartis as a consultant or speaker. Dr. Faught has received research support from Eisai Inc., Marinus, Ortho-McNeil Pharmaceutical, Inc., and Schwarz Biosciences. Dr. Torri has received personal compensation for activities with Lundbeck Research USA as an employee. Dr. Wesche has received personal compensation for activities with Lundbeck Research USA, Inc as an employee.

Pathological Evidence of Vacuolar Myelinopathy in a Child Following Vigabatrin Administration

Vigabatrin, a gamma-aminobutyric acid (GABA) aminotransferase- inhibiting drug used for seizure control, has been associated with white matter vacuolation and intramyelinic edema in animal studies. Similar pathological lesions have never been described in the central nervous system of human participants treated with the drug. Described here is a child with quadriparetic cerebral palsy secondary to hypoxic-ischemic brain injury following premature birth, who received vigabatrin for the treatment of infantile spasms at 9 months of age. A severe deterioration of neurologic function immediately followed the initiation of vigabatrin, and the child died 3 weeks later. Neuropathological examination revealed white matter vacuolation and intramyelinic edema. This represents the first reported case of vigabatrin-induced intramyelinic edema in humans. It validates the concerns regarding vigabatrin safety in infants and individuals with preexisting abnormalities of myelin.

Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients

Vigabatrin (VGB) has demonstrated high efficacy in infantile spasms (IS) due to tuberous sclerosis. Our first objective was to evaluate the cognitive long term effect outcome of children whose refractory spasms definitely disappeared when VGB was given as an add on drug. Our second objective was to determine the response of generalized epilepsy (infantile spasms) compared to partial epilepsy on cognitive impairment. A non selected series of 13 children underwent psychometric and behavioural evaluation before VGB initiation at a mean of 3 years on VGB treatment. Eight of them could perform detailed neuropsychological tests at follow-up. Seven had infantile spasms (Group I), they all were spasm free before 2 years of age and five remained with rare partial seizures (mean age, 5.5 years). Six others had partial epilepsy without spasms (Group II) and five remained with rare seizures (mean age, 7.5 years). Patients of Group I experienced dramatic changes. Developmental quotient (DQ) significantly rose in six out of seven by ten to more than 45 points ( P=0.03) and autistic behaviour disappeared in five out of the six who presented with. The four tested children had normal verbal level after 5 years and could integrate at school but they remained with marked visuospatial disabilities. By contrast, patients of Group II remained with an unchanged DQ of about 60 so that both groups had similar DQ levels on follow-up. The cessation of spasms with VGB is therefore associated with significant improvement of cognition and behaviour in children with tuberous sclerosis. Controlling secondary generalization induced by infantile spasms seems to be a key factor for mental development.