Epilepsy and stroke: A mendelian Randomization study

Observational studies have established a relationship between stroke and epilepsy. While most studies have reported an increased risk of epilepsy following a stroke, fewer have concluded that a diagnosis of epilepsy increases the risk of future strokes. Precisely describing the causal relationship between epilepsy and stroke has clinical and public health implications.

We performed a two-sample Mendelian Randomization (MR) to analyze the relationship between epilepsy and stroke. We identified genetic instruments from the Stroke Multiancestry Genome-Wide Association Study [GCST005838 (67,162 cases and 454,450 controls)] and the International League Against Epilepsy Consortium on Complex Epilepsies [Generalized epilepsy: GCST007343 (n_case=3769, n_control=29677), Focal epilepsy: GCST007352 (n_case=9671, n_control=29677)]. We used a significance threshold of p-value <5 × 10^(-5) for genetic instrument identification. We included the following epilepsy phenotypes: generalized epilepsy (GE), focal epilepsy (FE), childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), generalized epilepsy with tonic-clonic seizures (GTCS), focal epilepsy with hippocampal sclerosis (focal HS), and focal lesion-negative epilepsy. Linkage disequilibrium (LD) reference panel of 1000 Genome Project pruning with Pearson correlation r² < 0.2 was applied to ensure that the analysis is restricted to independent variants. We used Steiger filtering for reverse causality and Z-scores for generalized epilepsy and focal epilepsy. We employed the following methods for causal effect estimation: inverse-variance weighted (IVW), MR-Egger, MR-RAPS, and MRPRESSO.

For the association between GE and stroke (GE> stroke), stroke and GE (stroke > GE), FE and stroke (FE>stroke), and stroke and FE (stroke>FE), the number of SNPs was respectively 253, 213, 187, and 210. GE was associated with an increased risk of stroke [IVW, 95 % confidence interval: 0.058 (0.028-0.088)], and stroke was also associated with an increased risk of GE [IVW: 0.059 (0.026-0.092)]. FE was associated with an increased risk of stroke [IVW: 0.066 (0.029-0.102)] and stroke was associated with an increased risk of FE [IVW: 0.037(0.005-0.068)]. The analysis by epilepsy subtypes revealed an increased risk only among patients with stroke and for the following epilepsy subtypes: JAE, CAE, Focal HS, and Focal lesion negative epilepsy.

Our findings support a bidirectional relationship between stroke and epilepsy. Studies on post-stroke epilepsy should account for this bidirectional relationship.