Human Cytomegalovirus Associated Neuropathies: A Comprehensive Review From Pathophysiology to Clinical and Therapeutic Considerations

Human cytomegalovirus (HCMV) is a neurotropic, double-stranded DNA virus from the Herpesviridae family. It has a large genome, infects the majority of populations, and typically causes asymptomatic infections in healthy individuals. After the initial infection with established lifelong latency, HCMV can reactivate and cause disorders including neuropathies. Besides the infections typically in immunocompromised patients, HCMV may also trigger autoimmunity leading to tissue injury and associated pathologies. HCMV-associated neuropathies are a pathogenically heterogeneous group of peripheral nervous system (PNS) disorders that include direct HCMV infection of the nerve(s), as well as non-infectious associated neuropathies such as axonal or degenerative, vasculitic/ischemic or necrotizing, inflammatory demyelinating, and immune-mediated forms. Congenital HCMV-associated neuropathies primarily involve the cochlear/auditory and optic nerves with somewhat distinct pathogenic mechanisms compared with their postnatal counterparts, largely due to the immaturity of the fetal immune system. This article reviews the pathophysiology of PNS involvement in HCMV infection, followed by congenital HCMV-associated neuropathies with a case demonstration, and various postnatal HCMV-associated neuropathies, including a detailed review of HCMV-associated optic neuropathies, from pathogenic mechanisms to clinical and therapeutic implications. As the PNS has a few immune protective mechanisms against pathogens, direct HCMV infection of nerves is rare and occurs only in immunocompromised patients; most HCMV-associated neuropathies are secondary with multiple pathogenic mechanisms including varying degrees of autoimmunity. While the clinical manifestations of HCMV-associated neuropathies are variable, their treatment is typically empirical and case-based, focusing on antiviral therapy often combined with immunomodulatory approaches. Prompt and appropriate management can improve outcomes of HCMV-associated neuropathies.