Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment yet are increasingly associated with neurological immune-related adverse events (n-irAEs), which can affect any part of the nervous system. Accurate diagnosis is often challenging due to overlapping features with classical paraneoplastic neurological syndromes (PNS) and autoimmune encephalitis (AE). They may also resemble other neurological conditions, including demyelinating diseases. In this review, we present four illustrative cases of post-ICI n-irAEs involving the central nervous system (CNS). Through these cases and accompanying commentaries providing a critical appraisal of the current literature, we highlight the diagnostic, therapeutic, and prognostic challenges associated with these presentations. We emphasize both the role and limitations of neuronal antibody testing. This review stresses the need for rigorous clinical phenotyping, comprehensive immunological screening, and multidisciplinary management to improve early recognition of these complex and often severe complications and guide future therapeutic strategies.
