Risk of Seizures and Epilepsy in the Leukodystrophies

Seizures and epilepsy in leukodystrophies are poorly understood. This multisite study aimed to capture the prevalence of seizures in a nationwide cohort of patients, identify factors associated with increased seizure and epilepsy risk, and quantify prevalence of refractory seizures.

Retrospective data was extracted from leukodystrophy clinics across eight pediatric health centers from January 1, 2013, to March 31, 2020. Patients 18 years old and younger and diagnosed with leukodystrophy, including those identified by newborn screening, were eligible. Epilepsy was defined as two or more unprovoked seizures. Clinical variables including patient age, diagnosis, imaging features (binary: normal vs abnormal), electroencephalogram (EEG) findings, the presence/absence, and diagnoses of seizures/epilepsy were obtained.

Data from 704 patients were analyzed. At least one seizure occurred in 29% of all patients. Epilepsy developed in 80% of patients with at least one seizure. EEG abnormalities were present in 84% of patients with seizures versus 54% without (P < 0.001). In a multivariate analysis of seizure risk, higher increased likelihoods were associated with every one-year increase in age (1.13 times higher; 95% confidence interval [CI]: [1.07, 1.19], P < 0.001), generalized epileptiform discharges (13.4 times higher; 95% CI: [2.22, 259], P = 0.019), focal and multifocal epileptiform discharges (3.56 times higher; 95% CI: [2.04, 6.36], P < 0.001), and focal slowing (3.57 times higher; 95% CI: [1.58, 8.58], P = 0.003). Diffuse slowing was not significantly associated with seizure in the multivariate analysis (odds ratio 1.45, 95% CI: [0.85, 2.45], P = 0.170). In a comparison of different pathological classifications, seizures, but not epilepsy, were more common in astrocytopathies compared to myelinopathies (seizures 41% vs 28%, P = 0.046; epilepsy 89% vs 79%, P = 0.376). Two or more antiseizure medications were required to control seizures in multiple leukodystrophies.

Age, focal slowing, and epileptiform discharges, but not generalized slowing or abnormal brain magnetic resonance imaging, were significant predictors for seizure in this population. Patients with generalized discharges have a higher risk of seizures compared to those with focal discharges. Seizure burden, age at first seizure, number of antiseizure medications needed, and presence of EEG abnormalities vary based on underlying leukodystrophy. Our findings suggest the need for targeted strategies for monitoring seizures and epilepsy in the leukodystrophies.