Extra-Hepatic Manifestations of Hepatitis E Virus (HEV): A Narrative Review on Meningoencephalitis

Hepatitis E virus (HEV) infection, once regarded as a self-limiting hepatic disease confined to endemic regions, is now recognized as a systemic condition with a broad spectrum of extrahepatic manifestations. Among these, neurological complications—including peripheral neuropathies such as Guillain–Barré syndrome and neuralgic amyotrophy, and central nervous system involvement such as meningitis, encephalitis, and meningoencephalitis—are the most clinically relevant. Meningoencephalitis, though less common, is the most severe and underdiagnosed neurological expression of HEV infection. This narrative review examines current evidence on HEV-associated meningoencephalitis, covering epidemiology, pathogenesis, clinical features, and therapeutic strategies. Neurological disease is dominated by genotype 3 and frequently anicteric, with symptoms preceding or masking hepatic involvement. Pathogenesis is multifactorial, combining direct viral neurotropism—supported by HEV RNA detection in cerebrospinal fluid and replication in induced pluripotent stem cell (iPSC)-derived neurons and brain organoids—with immune-mediated mechanisms such as molecular mimicry and microglia-driven neuroinflammation. Diagnosis is often delayed by the absence of jaundice and low clinical suspicion, even though HEV remains an unrecognized cause in many unexplained encephalitis cases in high-income settings. Ribavirin remains the antiviral mainstay, but viral persistence within CNS sanctuary sites raises concerns about treatment adequacy and relapse; emerging antiviral and immunomodulatory strategies remain under investigation. HEV should be systematically considered in the diagnostic workup of unexplained neurological syndromes, regardless of overt hepatitis; heightened clinical awareness remains the most immediately actionable step toward reducing the burden of this still under-recognized condition.