Carpal Tunnel Syndrome and Immune Checkpoint Inhibitors: Review of French Pharmacovigilance Database and Literature

Aim/Objective: To characterize CTS in patients treated with ICIs. Methods: A search was conducted in the French Pharmacovigilance Database (FPD) and in PubMed with the following terms : "carpal tunnel syndrome", "nivolumab", "pembrolizumab", "cemiplimab", "dostarlimab", "atezolizumab", "avelumab", "durvalumab", "ipilimumab", "tremelimumab", "relatlimab" and "immune checkpoint inhibitors". Results: In the FPD, we found 7 cases of CTS with ICIs. All patients were women (median age: 66 years; range: 45-77). The ICIs were pembrolizumab (n = 4) and nivolumab (n = 3). The indication was melanoma in 6 cases. The median time to onset was 6 months (range 1-12). Carpal tunnel syndrome was bilateral in 5 cases. Surgery or systemic corticosteroid therapy were the corrective treatments in most patients. The outcome was favorable in 6 cases and unknown in one. In the literature, we found 6 publications describing 19 cases of CTS with ICIs, in 10 women and 9 men (median age: 74 years; range: 40-97). The ICIs were pembrolizumab (n = 9), nivolumab (n = 7), ipilimumab/nivolumab (n = 1), atezolizumab (n = 1) and avelumab (n = 1). The indication was melanoma in 11 cases. The median time to onset was 3 months (range 1-24). Carpal tunnel syndrome was bilateral in 17 patients (89,5%). Corrective treatment was mostly surgery and/or systemic corticosteroid therapy and/or corticosteroid infiltration. The outcome was favorable in 15 cases (79%). Conclusion: The significant relief and improvement of symptoms following treatment with steroids in some cases, along with the bilateral occurrence, strongly suggest that the symptoms are a result of a neurologic irAE rather than an independent coincidental event. The exact neurological irAE mechanism remains unclear, but hypotheses have been suggested (T cell dysregulation, inflammation of the vessels and perineural edema around the nerve). The association of CTS with ICIs is exceedingly rare. Given the prevalence of CTS in the general population and extension of indications of ICIs, development of carpal tunnel syndrome during treatment with ICIs is likely underrecognized and underreported.