Is There a Relationship Between Multiple Sclerosis and Epilepsy? If So What Does It Tell Us About Epileptogenesis?

Commentary

Epilepsy in Multiple Sclerosis: A Nationwide Population-Based Register Study.

Burman J, Zelano J. 2017;89:2462–2468. doi: 10.1212/WNL.0000000000004740.

OBJECTIVE: To determine the cumulative incidence of epilepsy in a population-based cohort of patients with multiple sclerosis (MS) and to investigate the association between epilepsy and clinical features of MS. METHODS: All available patients in the Swedish MS register (n = 514,545) and 3 age- and sex-matched controls per patient randomly selected from the population register (n = 543,635) were included. Data on clinical features of MS were retrieved from the Swedish MS register, and data on epilepsy and death were retrieved from comprehensive patient registers. RESULTS: The cumulative incidence of epilepsy was 3.5% (95% confidence interval [CI] 3.17– 3.76) in patients with MS and 1.4% (95% CI 1.30–1.52) in controls (risk ratio 2.5, 95% CI 2.19–2.76). In a Cox proportional model, MS increased the risk of epilepsy (hazard ratio 3.2, 95%CI 2.64–3.94). Patients with relapsing-remitting MS had a cumulative incidence of epilepsy of 2.2% (95% CI 1.88–2.50), whereas patients with progressive disease had a cumulative incidence of 5.5% (95% CI 4.89–6.09). The cumulative incidence rose continuously with increasing disease duration to 5.9% (95% CI 4.90–7.20) in patients with disease duration ≥34 years. Patients with an Expanded Disability Status Scale (EDSS) score ≥7 had a cumulative incidence of epilepsy of 5.3% (95% CI 3.95–7.00). Disease duration and EDSS score were associated with epilepsy after multiple logistic regression (odds ratio [OR] 1.03, 95% CI 1.01–1.04 per year, p = 5 0.001; and OR 1.2, 95% CI 1.09–1.26 per EDSS step, p < 0.0001). CONCLUSIONS: Epilepsy is more common among patients with MS than in the general population, and a diagnosis of MS increases the risk of epilepsy. Our data suggest a direct link between severity of MS and epilepsy.

It has long been recognized that persons with multiple sclerosis (MS) are at increased risk for developing seizures. The relationship between MS subtype, severity of MS, and impact of MS treatments on development of seizures. however, is not well understood. Anecdotally, it appears that persons with advanced MS are more likely to present with seizures, but some studies do report seizures occurring at time of MS diagnosis (1). Clarification of risk of seizures and epilepsy in this population not only increases our understanding of a significant comorbidity of MS but also provides epilepsy specialists with an opportunity to consider why persons with MS may be at increased risk for having seizures and the implications of epileptogenesis as it relates to MS.

Multiple studies have reported incidence and prevalence of epilepsy among persons with MS. A systematic review (2) evaluating seizure disorders in persons with MS found that among population-based studies the incidence of seizure disorders (18 studies) was 2.28% (95% CI: 1.11–3.44) and the prevalence (24 studies) to be 3.09% (95% CI: 2.01–4.16); both are higher than reported in the general population (3). Heterogeneity among these studies was substantial. Diagnosis of epilepsy was not always systematic. For example, some studies relied on self-report to establish diagnosis. The authors conclude that what was needed was a well-designed population-based study reporting age- and sex-specific estimates of incidence and prevalence and that findings should be standardized to a common population. Retrospective analysis (4) of Swedish MS cases compared with controls at time of cohort entry from a population register provides this much needed data. The Swedish MS register collects data prospectively recorded by treating physicians on clinical characteristics of MS and has an estimated coverage of 82%. In this analysis, for each individual present in the Swedish MS register three age- and sex-matched controls were randomly created from the comprehensive national patient register. Reporting to the comprehensive register is mandatory for all Swedish caregivers. Epilepsy, seizure, and status epilepticus were defined using codes from the International Classification of Diseases 9th and 10th editions. Cumulative incidence was referred to as the proportion of patients with a diagnosis ever, and estimation of prevalence was determined using the definition of Hauser et al., that is, patients admitted or seen with an epilepsy diagnosis within the 5 years before a specified date (5). In this population, epilepsy was more common among patients with MS compared with age- and sex-matched controls. The cumulative incidence was 3.5% (95% CI: 3.17–3.76) in patients with MS and 1.4% (95% CI: 1.30–1.52) in controls with a risk ratio of 2.5 (95% CI: 2.19–2.76). Similarly, the risk of patients having a single seizure (relative risk 2.5 [95% CI: 2.20–2.82]) and status epilepticus (relative risk 7.2 [95% CI: 4.72–11.1]) were significantly higher among patients with MS.

Are there factors related to MS that puts one at increased risk for seizures and epilepsy? Although it has been speculated that disease severity may increase the risk, an association between disease severity and seizure risk has never been shown. A systematic review and meta-analysis (1) found that patients with MS who had seizures were more likely to have a younger age of onset than those without seizures, and there was a trend demonstrating higher disability scores among those with seizures compared with those without. In addition, cortico-juxacortical lesions were more frequently observed in patients with epilepsy. Although these findings are provocative and suggest risk factors associated with increased seizure risk among patients with MS, the studies included in the review and meta-analysis are variable and often suboptimal with small sample sizes. In the Swedish nationwide population-based study, Burman and Zelano hypothesized that increasing disease duration, disability, and progressive disease suggest an increased epilepsy risk in patients with MS. The Swedish MS register is based on voluntary submission of data from neurologists and includes detailed data, which allowed the authors to test their hypothesis. It is important to recognize that the register may not capture patients with very advanced disease, such as those living in nursing homes. Therefore, if an association between disease severity and epilepsy risk is found, the actual risk may be underestimated. The analysis supported the investigators' hypothesis. The cumulative incidence rose continuously with increasing disease duration to 5.9% (95% CI: 4.90–7.20) in patients with disease duration ≥34 years. In addition, patients with an Expanded Disability Status Scale (EDSS) score ≥7 had a cumulative incidence epilepsy of 5.3% (95% CI: 3.95–7.00). The investigators also analyzed the effect of MS subtype and found that progressive disease had a cumulative incidence of 5.5% (95% CI: 4.89–6.09), whereas patients with relapsing remitting MS had a cumulative incidence of 2.2% (95% CI: 1.88–2.50). Given that this potential relationship has been referred to in multiple papers, it is remarkable that this study is the first to clearly show an association between MS severity and epilepsy, which highlights the importance of inclusive well-designed population-based studies.

The finding of an association between MS disease severity and seizures facilitates speculation as to why persons with MS develop seizures. Traditionally, MS is considered a white matter disease. In persons with secondary progressive MS, gray matter lesions are seen more frequently and are related to increasing disability (6). The gray matter involvement is presumably the reason for increased incidence of epilepsy. The finding of similar cumulative incidence of epilepsy between controls and patients with relapsing remitting MS who had no disability further supports this mechanism. This is, however, likely too simplistic an explanation. Even though the cumulative incidence of epilepsy is higher among persons with EDSS ≥7, it is less than 10%. Factors in addition to gray matter involvement are likely mediating seizure risk. Inflammation is being increasingly recognized as important in the pathophysiology of human epilepsy (7). Perhaps brain inflammation associated with MS plays a role in epileptogenesis. Increasingly, patients with MS receive disease-modifying treatment and those with severe exacerbations are more likely to receive corticosteroids. It is interesting to speculate that these disease-modifying therapies not only affect MS disease progression but also influence whether seizures and epilepsy occur.

Determining whether a person with a chronic neurologic disorder such as MS is at increased risk for developing seizures and epilepsy is important, as epilepsy is a significant comorbidity that adds to the disability of MS secondary to the seizures themselves and antiseizure medications used to prevent seizures. The retrospective Swedish population-based register study clarifies that epilepsy is more common among persons with MS than among the general population, and persons with more severe MS, including those with increased duration, increased disability, and progressive as opposed to relapsing remitting disease are at even greater risk. Understanding why these patients are at increased risk provides some insight into epileptogenesis mediated by a combination of gray matter involvement and inflammation and is likely influenced by disease-modifying therapies.