S1PR modulators linked to seizure risk in MS trial meta-analysis

People with multiple sclerosis (MS) have a twofold higher risk of seizures compared with the general population, according to pooled data from clinical trials.

Among MS patients, treatment with sphingosine-1-phosphate receptor (S1PR) modulators, a class of MS disease-modifying therapies (DMTs) that includes the oral medications Gilenya (fingolimod), Mayzent (siponimod), Ponvory (ponesimod), and Zeposia (ozanimod), significantly increased the risk of seizures compared with other treatments.

“Epilepsy represents a significant comorbidity [co-existing condition] in the context of MS, warranting intensified efforts to uncover its underlying triggers and enhance strategies for both prevention and treatment,” the researchers wrote in “Incidence and determinants of seizures in multiple sclerosis: a meta-analysis of randomised clinical trials,” which was published in the Journal of Neurology, Neurosurgery & Psychiatry.

Although not a core symptom of MS, the reason for seizures’ association with the neurodegenerative disease isn’t known, but may be related to the presence of lesions and tissue loss in the brain, where seizures originate. Some evidence supports the idea that the risk of seizures is higher in MS patients with greater disease severity, and that epilepsy, a disease that features recurrent and unprovoked seizures, may be more prevalent in progressive forms of MS.

Most data on the topic comes from observational studies, which are poorly controlled and prone to bias, making it difficult to interpret and compare the findings, according to the researchers who conducted a meta-analysis of randomized and controlled Phase 3 clinical trials to identify the occurrence of new-onset seizures or epilepsy in MS patients. They included only large studies with at least 100 participants and a follow-up of at least six months. Studies where known seizure-causing medications were used were excluded.

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Studying rate of seizures in MS

The researchers retrieved 63 trials, from 1993 to 2022. Most were designed to evaluate the effects of an MS therapy relative to a placebo or comparator medication. Together, the trials involved 53,535 patients followed for a median of two years. Over that time, 120 patients had epileptic seizure events, which came to an incidence rate of 68 seizures per 100,000 patient-years, a measure that accounts for the number of patients and for how long they were followed.

By contrast, a meta-analysis of adults in the general population found the seizure incidence rate to be 34.6 per 100,000 patient-years, indicating MS patients are at about a 1.96-times elevated risk.

The researchers saw significantly higher rates of seizures in studies that enrolled people with progressive MS, a longer disease duration, higher disability levels, and more brain tissue loss, or atrophy. They emphasized that no causal relationship could be established to link MS and seizures.

“We cannot rule out a bidirectional relationship between disease burden and epilepsy, such that poor seizure control results in disability worsening and increased brain atrophy rate,” wrote the researchers, who noted that seizures in earlier years could have been underreported as a result of more rigorous reporting of side effects being adopted in clinical trials, which has seen rates of side effects increase over the time covered in this study.

An analysis of the DMTs used showed that nearly half of all observed seizures — 55 out of 120 — occurred in the eight trials that tested S1PR modulators, while the other half occurred in the remaining 55 trials. Across the eight trials, patients given an S1PR modulator were at a 2.45 times higher risk of seizures over those given a placebo or comparator treatment.

Preclinical research about the role of S1PR modulation and seizures hasn’t been consistent. Some studies suggest the molecules lead to pro-seizure nerve cell changes, but others have found them to be anti-epileptic.

“Mechanisms underlying such a higher incidence of seizures under treatment with S1PR modulators still need to be unraveled,” the researchers wrote.

Plus, since the medications were grouped together in the analysis, researchers can’t be sure all S1PR modulators apply, said John P. Ioannidis, MD, a professor at Stanford University in California, in an editorial commentary accompanying the research article. Ioannidis said another recent meta-analysis failed to find an association between DMTs and seizure risk with clinical trial data, but identified a possible association with Mayzent, Mavenclad (cladribine), and interferon-beta medications.

The varied findings likely relate to differences in the nature of the statistical analyses and the trials included, he said. Nevertheless, “the overall conclusion may not be as confusing as these two meta-analyses suggest,” Ioannidis wrote, noting that all medications identified might come with a seizure risk. “Small event numbers induce extra caution, but may still be used towards shared clinical decision-making,” he said.