Paraneoplastic Intracellular Neuropathies: A Narrative Review

Paraneoplastic neuropathies are rare, immune-mediated disorders caused by an antitumor immune response that cross-reacts with components of the peripheral nervous system, such as peripheral nerves and dorsal root ganglia. Unlike syndromes associated with antibodies targeting neuronal surface or extracellular antigens, in which auto-antibodies are considered directly pathogenic, neurological syndromes associated with intracellular onconeural antigens are predominantly mediated by cytotoxic T-cell responses. Accurate diagnosis of these syndromes relies on early identification of high-risk clinical phenotypes, combined with appropriate serum and cerebrospinal fluid antibody testing, neurophysiological investigations, imaging, and a comprehensive differential diagnostic work-up. Current treatment is primarily based on tumor control and immunomodulatory or immunosuppressive therapies. Nevertheless, no treatment has demonstrated consistent efficacy in neurological syndromes associated with intracellular onconeural antigens, particularly once irreversible neuronal damage has occurred. Emerging strategies, including chimeric antigen receptor T-cell therapies and agents targeting T-cell activation or co-stimulatory pathways, warrant further investigation. Close collaboration between neurologists and oncologists is therefore essential to improve early diagnosis, therapeutic management, functional outcomes, and prognosis.