(Auto)immunity in focal epilepsy: mechanisms of (auto‑)immune-inflammatory epileptogenic neurodegeneration

Abstract

While the neuronal mechanisms of epileptic hyperexcitability (HE) have been studied in detail, recent findings suggest that extraneuronal, mainly immune-mediated inflammatory and vascular mechanisms play an important role in the development and progression of HE in epilepsy and the cognitive and behavioral comorbidities. Narrative review. As in autoimmune (limbic) encephalitis (ALE/AIE) or Rasmussen's encephalitis (RE), the primary adaptive and innate immune responses and associated changes in the blood-brain barrier (BBB) and neurovascular unit (NVU) can cause acute cortical hyperexcitability (HE) and the development of hippocampal sclerosis (HS) and other structural cortical lesions with chronic HE. Cortical HE, which is associated with malformation of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT), for example, can be accompanied by secondary adaptive and innate immune responses and alterations in the BBB and NVU, potentially modulating the ictogenicity and epileptogenicity. These associations illustrate the influence of adaptive and innate immune mechanisms and associated changes in the BBB and NVU on cortical excitability and vice versa, suggesting adynamic and complex interplay of these factors in the development and progression of epilepsy in general. The described concept of a neuro-immune-vascular interaction in focal epilepsy opens up new possibilities for the pathogenetic understanding and thus also for the selective therapeutic intervention.