Dysautonomia associated with immune checkpoint inhibitors

Toshiki Tezuka, Shinichi Okuzumi, Chiho Nakashima, Toshihiro Ide, Shungo Imai, Satoru Mitsuboshi, Yuki Kuwahara, Tsubasa Takizawa, Morinobu Seki, Naoto Minematsu, Naoko Aragane, Jin Nakahara, Satoko Hori, Shunya Nakane, Shigeaki Suzuki

研究成果: Article査読


Objective: The purpose of this study is to report the clinical characteristics of dysautonomia associated with immune checkpoint inhibitors (ICIs). Methods: We reported two patients with autoimmune autonomic ganglionopathy (AAG) occurring as immune-related adverse events (irAEs). We also performed a review of previous case reports presenting dysautonomia during ICI therapy. Moreover, we conducted pharmacovigilance analyses using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to investigate dysautonomia associated with ICI. Results: Two patients in our care developed both AAG and autoimmune encephalitis following ICI therapy for lung cancers. We comprehensively reviewed 13 published cases (M:F = 11:2, mean onset age of 53 years) with ICI-associated dysautonomia including AAG (n = 3) and autonomic neuropathy (n = 10). Of these, ICI monotherapy was performed in seven and combination ICI use in six. In 6 of 13 patients, dysautonomia appeared within one month after the start of ICIs. Orthostatic hypotension was observed in 7 and urinary incontinence or retention in five. All patients except three showed gastrointestinal symptoms. Anti-ganglionic acetylcholine receptor antibodies were undetectable. All but two patients received immune-modulating therapy. Immuno-modulating therapy was effective in three patients with AAG and two patients with autonomic neuropathy, but ineffective in the others. Five patients died, of either the neurological irAE (n = 3) or cancer (n = 2). The pharmacovigilance analyses using FAERS showed that ipilimumab monotherapy and the combination of nivolumab and ipilimumab constituted significant risks for developing dysautonomia, consistent with the review of literature. Conclusion: ICIs can cause dysautonomia including AAG, and autonomic neuropathy is a neurological irAE.

ジャーナルJournal of Neurology
出版ステータスPublished - 2023 7月

ASJC Scopus subject areas

  • 神経学
  • 臨床神経学


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