Hepatitis E virus-associated neurological injury and neurotropic cellular mechanisms

Hepatitis E virus (HEV) is increasingly recognized as a cause of neurological disease beyond its hepatic manifestations. Neurological complications are the most frequently reported extrahepatic presentations and include both peripheral nervous system disorders, such as Guillain-Barré syndrome (GBS) and neuralgic amyotrophy (NA), and central nervous system (CNS) involvement, including encephalitis and myelitis, often in the absence of overt hepatitis. This review summarizes the clinical spectrum of HEV-associated neurological disease and integrates evidence from human studies and experimental models. Current evidence supports multifactorial pathogenesis, with direct viral neuroinvasion of the CNS and immune-mediated mechanisms predominating in peripheral neuropathies. Experimental in vivo and in vitro systems demonstrate that HEV can cross the blood-brain barrier (BBB) and replicate within neural tissues, providing biological plausibility for CNS involvement. By synthesizing clinical and experimental findings, this review highlights the dual pathogenic pathways underlying HEV-associated neurological injury and outlines key unresolved questions relevant to diagnosis, pathogenesis, and clinical management.