Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jul;270(7):3413-3423.
doi: 10.1007/s00415-023-11667-5. Epub 2023 Mar 20.

Dysautonomia associated with immune checkpoint inhibitors

Toshiki Tezuka  1 , Shinichi Okuzumi  2 , Chiho Nakashima  3 , Toshihiro Ide  4 , Shungo Imai  5 , Satoru Mitsuboshi  5   6 , Yuki Kuwahara  3 , Tsubasa Takizawa  1 , Morinobu Seki  1 , Naoto Minematsu  2 , Naoko Aragane  3 , Jin Nakahara  1 , Satoko Hori  5 , Shunya Nakane  7 , Shigeaki Suzuki  8
Affiliations
Review

Dysautonomia associated with immune checkpoint inhibitors

Toshiki Tezuka et al. J Neurol. 2023 Jul.

Abstract

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.

Keywords: Autoimmune autonomic ganglionopathy; Dysautonomia; Immune-related adverse events; Pharmacovigilance; Review of literature.

PubMed Disclaimer

References

    1. Das S, Johnson DB (2019) Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer 7(1):306 - PubMed - PMC - DOI
    1. Dubey D, David WS, Amato AA, Reynolds KL, Clement NF, Chute DF, Cohen JV, Lawrence DP, Mooradian MJ, Sullivan RJ et al (2019) Varied phenotypes and management of immune checkpoint inhibitor-associated neuropathies. Neurology 93(11):e1093–e1103 - PubMed - DOI
    1. Seki M, Kitano S, Suzuki S (2022) Neurological disorders associated with immune checkpoint inhibitors: an association with autoantibodies. Cancer Immunol Immunother 71(4):769–775 - PubMed - DOI
    1. Okada K, Seki M, Yaguchi H, Sakuta K, Mukai T, Yamada S, Oki K, Nakahara J, Suzuki S (2021) Polyradiculoneuropathy induced by immune checkpoint inhibitors: a case series and review of the literature. J Neurol 268(2):680–688 - PubMed - DOI
    1. Guidon AC, Burton LB, Chwalisz BK, Hillis J, Schaller TH, Amato AA, Betof Warner A, Brastianos PK, Cho TA, Clardy SL et al (2021) Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors. J Immunother Cancer 9(7):e002890 - PubMed - PMC - DOI

MeSH terms

LinkOut - more resources