The expanding knowledge of epilepsy in leukodystrophies

INTRODUCTION: Leukodystrophies are hereditary disorders of the white matter of the central nervous system (CNS) and can be classified into five groups based on pathogenetic mechanisms and pathological changes. Epilepsy is defined as a neurological disorder marked by sudden recurrent episodes of sensory disturbance, loss of consciousness, or convulsions, associated with abnormal electrical activity in the brain. It is usually linked with disorders mainly involving gray matter. However, epilepsy might be one of the manifestations of leukodystrophies in children. The incidence of epilepsy among leukodystrophies and its clinical characteristics are unclear yet. This study aims to investigate epilepsy across leukodystrophies. METHODS: An electronic database search was conducted in PubMed for peer-reviewed studies that reported data for patients with leukodystrophies and epilepsy. Retrospective observational cohort studies, case reports and case series were included. Studies were firstly reviewed based on title and abstract and the studies that were (1) not written in English language, (2) involving animal models, (3) lacking abstracts, (4) presenting inconclusive diagnoses, or indicating comorbidities at the onset of epileptic seizures were excluded, as well as duplicates. The PRISMA guidelines for systematic reviews were followed. Data were analyzed for age at seizure onset, seizure type, treatment response, presence/absence of precipitating factors and status epilepticus. Treatment response was categorized as responder and refractory, with the former defined as seizure-free, >50% reduction of seizures, and improvement without specified details. RESULTS: A number of 6341 studies was totaled and a refined dataset of 202 records was retained for analysis, with a total of 328 patients reported. Most cases of leukodystrophy and epilepsy belonged to astrocytopathies (149/328) and myelin disorders of Zellweger spectrum (46/328). Conversely, in other myelinopathies epilepsy appeared less represented (83/328). The average age at seizure onset was lower in Zellweger spectrum disorders (0.06 y, range 0-10), followed closely by Astrocytopathies (1.33 y, range 0-38). GMFCS levels showed greater degree of neurological impairment at seizure onset in myelin disorders (6.7% Level I, 18.6% Level V, 70.54% Unknown), compared to astrocytopathies (14.8% Level I, 7.4% Level V, 74.5% Unknown). 63.5% of described patients were classified as treatment responders and 36.5% as refractory. A single type of seizure was mainly identified, with generalized motor seizures being the most common. While generalized tonic-clonic seizures appeared across all groups of leukodystrophies, focal seizures were more representative of astrocytopathies and myelin disorders, mainly among the Zellweger Spectrum. Status epilepticus and the presence of precipitating factors for seizures was more prevalent in astrocytopathies (14.8%, 27.5%). CONCLUSIONS: This review offers an in-depth analysis of the features of epilepsy in white matter disorders, contributing to a thorough understanding of the clinical spectrum of leukodystrophies.