In this study, we used the two − sample MR framework by applying public data from different GWAS to decipher the causality between ischemic stroke and the risk of epilepsy. We provide genetic evidence that ischemic stroke leads to an elevated risk of developing epilepsy. In addition, no heterogeneity or horizontal pleiotropy was detected. Our findings suggest the need for timely intervention after ischemic stroke to prevent epilepsy.
At one time the relationship between stroke and epilepsy was thought to be bidirectional. One study showed that a quarter of all epilepsy patients over the age of 65 experience a stroke seizure[27]. A retrospective cohort study published in 2015 included a total of 21,035 epilepsy cases and 16,638 controls, and the results indicated that the incidence of stroke after seizures was 2.5 times higher in adults than in controls. After adjusting for comorbidities and other factors, the risk of stroke was as high as 60% in epilepsy cases compared to controls[28]. As a subtype of stroke, ischemic stroke is one of the leading causes of death and a major cause of disability worldwide. This study is the first to use Mendelian randomization to discuss the potential causal relationship between ischemic stroke and epilepsy.
The occurrence of epilepsy after ischemic stroke involves a variety of mechanisms, firstly, the ischemia and hypoxia caused by stroke leads to sodium pump failure, Na+ inward flow causes cell depolarization, when the depolarization reaches a certain level, calcium channels are activated and Ca2+ enters intracellularly in large quantities thus leading to abnormal neuronal discharge[29], meanwhile, neurotransmitter dysregulation is also an important cause of seizures, and studies have shown that with ischemia and hypoxia After glutamate and other excitatory neurotransmitters increase, which increases membrane excitability[30], and in addition, GABA inhibitory neurotransmitters undergo degeneration, weakening the inhibitory effect and lowering the membrane excitation threshold [30], which together cause abnormal neuronal firing leading to epilepsy. Stroke-induced disruption of the blood-brain barrier causes alterations in astrocyte gene expression, resulting in a decrease in the ability of astrocytes to take up K+. Elevated extracellular K+ concentrations can cause excessive neuronal firing, leading to seizures [31].
Several advantages exist in the present study. First, this study primarily used a large sample of genome-wide association studies (GWAS), which allows for a better overall analysis of stroke events. Second, in the experimental design of MR, because SNPs are randomly assigned, bias due to reverse causality or confounding factors is greatly reduced, which is not available in observational studies. Finally, we also performed several sensitivity analyses to test the consistency of the results and to correct for possible pleiotropy.
However, there are some limitations to this study. First, the epilepsy dataset provided by the ILAE used in this study had approximately 14% of non-European descent, Therefore, population stratification is likely to introduce biases here. Second, the results of the study were limited to Europeans and could not be generalized to other populations. Finally, because ischemic stroke and epilepsy are heterogeneous disorders with different genetic factors and may be differentially associated with each other, larger subgroup MR studies may be needed in the future to further explore causal relationships.