Neurologic Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review

OBJECTIVE: To define the clinical characteristics, management, and outcome of neurological immune-related adverse events (n-irAEs) of immune checkpoint inhibitors (ICIs).METHODS: Systematic review of the literature following the PRISMA guidelines.RESULTS: A total of 694 articles were identified. Two hundred fifty-six articles, with 428 individual patients, met the inclusion criteria. Reports regarding neuromuscular disorders (319/428, 75%) were more frequent than those on central nervous system (CNS) disorders (109/428, 25%). The most common n-irAEs reports were: myositis (136/428, 32%), Guillain-Barre syndrome and other peripheral neuropathies (94/428, 22%), myasthenic syndromes (58/428, 14%), encephalitis (56/428, 13%), cranial neuropathies (31/428, 7%), meningitis (13/428, 3%), CNS demyelinating diseases (8/428, 2%), and myelitis (7/428, 2%). Other CNS disorders were detected in 25/428 (6%) patients. Compared to the whole sample, myasthenic syndromes were significantly more Ab-positive (33/56, 59%; p<0.001). Anti-PD-1/PD-L1 were more frequent in myasthenic syndromes (50/58, 86%; p=0.005) and less common in meningitis (2/13, 15%; p<0.001) and cranial neuropathies (13/31, 42%; p=0.005).Anti-CTLA-4 ICIs were more frequent in meningitis (8/13, 62%; p<0.001) and less common in encephalitis (2/56, 4%; p=0.009) and myositis (12/136, 9%; p=0.01). Combination of different ICIs was more frequent in cranial neuropathies (12/31, 39%; p=0.005). Melanoma was more frequent in patients with peripheral neuropathies (64/94, 68%; p=0.003) and less common in encephalitis (19/56, 34%; p=0.001). The highest mortality rate was reached in myasthenic syndromes (28%).CONCLUSION: Considering the increasing use of ICI therapy in the forthcoming future, this information can be valuable in assisting neurologists and oncologists in early n-irAEs diagnosis and treatment.