Seizure Risk in Patients With MS Nearly Double, Especially With S1PR Modulators

Compared with the general population, patients with multiple sclerosis (MS) face a nearly 2-fold higher risk for seizures, which is associated with disease burden and sphingosine-1-phosphate receptor (S1PR) modulators, according to study results published in the Journal of Neurology, Neurosurgery, and Psychiatry.

Researchers conducted a meta-analysis to determine the incidence of seizures in patients with MS participating in randomized clinical trials (RCTs), as well as to identify possible factors that contribute to the higher incidence of seizures in patients with MS. Phase 3 RCTs involving adults aged 19 and older, sample sizes of 100 and greater, and follow-up periods lasting 6 months and longer were selected for inclusion from 2 databases.

The outcome of interest was the number of seizures or epilepsy events. Pooled effect size on the incidence rate of seizure or epilepsy was calculated as the number of events per patient-years in the entire sample using a random-effect model. Patient-years were calculated as the sample size multiplied by the duration of the study in years. Univariable and multivariable meta-regression equations were fitted to assess which variables influenced pooled effect size. Inconsistency and between-study heterogeneity were expressed as I² and Cochran Q, respectively.

The researchers pooled data from a total of 60 articles comprising 63 RCTs that encompassed 53,535 patients and a median follow-up duration of 2 years, which corresponded to 100,469 patient-years.  

A total of 120 patients experienced epileptic seizure events, corresponding to a pooled incidence rate of 68.0 (95% CI, 49.1-86.9) per 100,000 patient-years. Compared with the general population, patients with MS experienced a 1.96-fold greater risk for incident seizures. The general population had an incidence rate of 34.6 (95% CI, 28.4-42.2) per 100,000 patient-years.

Of those who reported seizures, 47 (40.8%) patients experienced tonic-clonic seizures, 9 (7.5%) experienced focal seizures, and 5 (4.2%) experienced focal to bilateral tonic-clonic seizures. A total of 49 (40.8%) instances were generally categorized as “epilepsy” or “seizure.”

Higher incidence rates of seizures were linked to more progressive disease courses (k=63; β=0.020; P =.038), longer time since clinical onset (k=63; β=0.010; P =.046), greater levels of disability (k=63; β=0.031; P =.035), and lower normalized brain volume (k=25; β=-0.542; P =.008).

Of the total 120 seizure events, 55 occurred within RCTs involving S1PR modulators. There was an increased risk for incident seizures in patients allocated to S1PR modulators vs in those allocated to placebo or comparators, yielding an arcsine square root transformed risk difference of 0.031 (95% CI, 0.013-0.049), which corresponded to a back-transformed risk difference of 20.5 (95% CI, 1.7-39.3) events per 100,000 patient-years. The risk ratio for incident seizures was 2.45 (95% CI, 1.43-4.21; P =.008). Risk difference ranged from 14.7 to 27.8 per 100,000 patient-years and risk ratios ranged from 2.15 to 2.99.

Study limitations included the inability to rule out that patients with comorbid epilepsy were enrolled in RCTs, the potential under-reporting of adverse events (AEs) due to the inconsistencies in AE reporting across RCTs, and the unavailability of raw RCT datasets.

“Notably, among the various treatments evaluated in the analysed RCTs, S1PR modulators were linked to a more than twofold increased risk of seizures. Further investigations are imperative to unveil the underlying mechanisms behind this association,” the researchers concluded.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.