Neurological immune-related adverse events with checkpoint inhibitor therapy: challenges for the neurologist

Immune checkpoint inhibitors (ICI) have had a dramatic effect on cancer outcomes with their use increasing as indications expand. Despite impressive efficacy across a range of tumour types, their role in activating the immune system results in frequent immune-related adverse events (irAE). While gastrointestinal, endocrine, respiratory and cutaneous toxicities are common, neurological irAEs (N-irAEs) occur more rarely. N-irAEs have been well reported in the literature, can affect any part of the nervous system and are associated with significant morbidity and mortality. Treating oncologists have a high index of suspicion for irAEs and a low threshold for initiating treatment. The role of the neurologist is to consider the differential diagnosis, direct investigation according to the clinical syndrome and guide management, efficacy monitoring and rehabilitation. Once alternative aetiologies have been excluded, the ICI should be either paused or discontinued depending on clinical severity, and immunosuppressive treatment commenced. There is no high-level evidence for toxicity management in this emerging field, so there is much variation in clinical practice and the medical literature. While describing the range of neurological toxicities related to ICIs and current experience of management and outcome, this review focuses on the potential utility of predictive biomarkers, the risk of re-ignition of pre-existing neurological autoimmune disease and the question of rechallenge after a N-irAE. Given the paucity of data specifically relating to N-irAE, we also discuss cancer outcomes in the context of irAEs and associated immunosuppression and consider some outstanding questions pertinent to ICI-related neurotoxicity and potential future directions for research.