ABSTRACT
Post-COVID cognitive deficits (often referred to as ‘brain fog’) are common and have large impacts on patients’ level of functioning. No specific intervention exists to mitigate this burden. This study tested the hypothesis, inspired by recent experimental research, that post-COVID cognitive deficits can be prevented by inhibiting receptor-interacting protein kinase (RIPK). Using electronic health record data, we compared the cognitive outcomes of propensity score-matched cohorts of patients with epilepsy taking phenytoin (a commonly used RIPK inhibitor) vs. valproate or levetiracetam at the time of COVID-19 diagnosis. Patients taking phenytoin at the time of COVID-19 were at a significantly lower risk of cognitive deficits in the six months after COVID-19 infection than a matched cohort of patients receiving levetiracetam (hazard ratio 0.78, 95% CI 0.63-0.97, p = 0.024) or valproate (hazard ratio 0.73, 95% CI 0.58-0.93, p = 0.011). In secondary analyses, results were robust when controlling for subtype of epilepsy, and showed specificity to cognitive deficits in that similar associations were not seen with other ‘long-COVID’ outcomes such as persistent breathlessness or pain. These findings provide pharmacoepidemiological support for the hypothesis that RIPK signaling is involved in post-COVID cognitive deficits. These results should prompt empirical investigations of RIPK inhibitors in the prevention of post-COVID cognitive deficits. Graphical Graphical