Chronic Idiopathic Axonal Polyneuropathy: Current Evidence and Future Directions

Chronic idiopathic axonal polyneuropathy (CIAP) is one of the most common diagnostic categories encountered in patients with chronic polyneuropathy, yet it remains insufficiently defined and incompletely understood. CIAP has been regarded as a slowly progressive, length-dependent, predominantly sensory or sensorimotor axonal polyneuropathy affecting middle-aged and older adults after exclusion of recognized acquired and hereditary causes. Increasing evidence suggests that CIAP is unlikely to represent a single disease entity. Instead, it may constitute a heterogeneous clinical phenotype arising from the convergence of several biological pathways on distal axonal degeneration. We summarize current knowledge regarding the definition, epidemiology, clinical presentation, diagnostic approach, pathophysiological hypotheses, and treatment of CIAP. Particular attention is given to metabolic and vascular risk factors, endoneurial microvascular alterations, neurotoxic 1-deoxysphingolipids, inflammatory and immune-mediated mechanisms, oxidative stress, genetic susceptibility, and age-related axonal vulnerability. We also discuss how deeper phenotyping and genetic testing may reclassify a subset of patients initially labeled as having CIAP. No disease-modifying therapy has been established for CIAP. Management focuses on symptomatic treatment and rehabilitation; whether risk-factor modification alters the disease course remains unproven. Future studies should aim to harmonize diagnostic criteria, improve biomarker-based phenotyping, and identify mechanism-defined subgroups that may become accessible to targeted therapeutic strategies.