{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:07:59Z","timestamp":1791216479052,"version":"4.1.0"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2018,11,27]],"date-time":"2018-11-27T00:00:00Z","timestamp":1543276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) initiate antitumor immunity by blocking the action of immune inhibitor-signaled cytotoxic proteins, such as cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1, and programmed cell death ligand 1. However, in rare cases (\u223c1%\u201312% of patients), ICI treatment causes neurologic immune-related adverse events (irAEs). These include, but are not limited to, headache, encephalitis, neuropathies, myasthenia gravis, and myositis. The symptoms associated with irAEs can range from mild (grade 1\u20132) to severe (grade 3\u20134); however, they are often challenging to diagnose because they may present as generalized symptoms, such as fatigue and weakness, that can also be caused by the cancer itself. Here, we present an illustrative case of a 67-year-old woman who presented with signs of a neurologic irAE, including progressive dysphagia and weakness leading to falls, which started during treatment with pembrolizumab and worsened following initiation of ipilimumab. Following neurological and pathological evaluation, she was diagnosed with myositis. She was treated with steroids and improved rapidly. In this article, we review previous literature to provide guidance to frequently asked questions concerning the diagnosis and management of neurologic irAEs in patients with advanced cancer. With prompt and effective treatment, most patients will achieve a complete recovery.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Points<\/jats:title>\n                    <jats:p>Neurologic immune-related adverse events (irAEs) affect approximately 1% of patients treated with immune checkpoint inhibitor (ICI) monotherapy and 2%-3% treated with combination therapy. These irAEs can affect any portion of the nervous system, although peripheral nerve system manifestations are most common. Overlap syndromes with multiple neurologic irAEs or other affected organ systems frequently exist. Diagnosis of neurologic irAEs can be challenging. Routine testing may be unremarkable and symptoms frequently mimic those from cancer or side effects of other therapies. Optimal management is currently unknown. A systematic, highly coordinated, and multidisciplinary approach is critical. Outcomes from neurologic irAEs are typically favorable with the current practice of holding the ICI and starting corticosteroids. Some patients are even successfully retreated with an ICI. A subset of patients, however, have a fulminant and potentially fatal course. Improved risk assessments and targeted therapies are needed.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1634\/theoncologist.2018-0359","type":"journal-article","created":{"date-parts":[[2018,11,27]],"date-time":"2018-11-27T16:05:13Z","timestamp":1543334713000},"page":"435-443","source":"Crossref","is-referenced-by-count":130,"title":["Diagnosis and Management of Immune Checkpoint Inhibitor-Associated Neurologic Toxicity: Illustrative Case and Review of the Literature"],"prefix":"10.1093","volume":"24","author":[{"given":"Kerry L.","family":"Reynolds","sequence":"first","affiliation":[{"name":"Division of Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda C.","family":"Guidon","sequence":"additional","affiliation":[{"name":"Division of Neuromuscular Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,11,27]]},"reference":[{"issue":"suppl 15","key":"2021122506323530100_onco12746-bib-0001","doi-asserted-by":"crossref","first-page":"9005a","DOI":"10.1200\/jco.2015.33.15_suppl.9005","article-title":"Long-term efficacy of pembrolizumab (pembro; MK-3475) in a pooled analysis of 655 patients (pts) with advanced melanoma (MEL) enrolled in KEYNOTE-001","volume":"33","author":"Daud","year":"2015","journal-title":"J Clin Oncol"},{"key":"2021122506323530100_onco12746-bib-0002","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N Engl J Med"},{"key":"2021122506323530100_onco12746-bib-0003","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined nivolumab and ipilimumab or monotherapy in untreated melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N Engl J Med"},{"key":"2021122506323530100_onco12746-bib-0004","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1200\/JCO.2014.56.2736","article-title":"Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma","volume":"33","author":"Schadendorf","year":"2015","journal-title":"J Clin Oncol"},{"key":"2021122506323530100_onco12746-bib-0005","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1056\/NEJMoa1507643","article-title":"Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer","volume":"373","author":"Borghaei","year":"2015","journal-title":"N Engl J Med"},{"key":"2021122506323530100_onco12746-bib-0006","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1056\/NEJMoa1504627","article-title":"Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer","volume":"373","author":"Brahmer","year":"2015","journal-title":"N Engl J Med"},{"key":"2021122506323530100_onco12746-bib-0007","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1056\/NEJMoa1510665","article-title":"CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma","volume":"373","author":"Motzer","year":"2015","journal-title":"N Engl J Med"},{"key":"2021122506323530100_onco12746-bib-0008","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined nivolumab and ipilimumab or monotherapy in untreated melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N Engl J Med."},{"key":"2021122506323530100_onco12746-bib-0009","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1093\/annonc\/mdw558","article-title":"Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: A single centre experience and review of the literature","volume":"28","author":"Spain","year":"2017","journal-title":"Ann Oncol"},{"key":"2021122506323530100_onco12746-bib-0010","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1001\/jamaneurol.2017.1912","article-title":"Neurological complications associated with anti-programmed death 1 (PD-1) antibodies","volume":"74","author":"Kao","year":"2017","journal-title":"JAMA Neurol"},{"key":"2021122506323530100_onco12746-bib-0011","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.ejca.2016.02.024","article-title":"Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy","volume":"60","author":"Zimmer","year":"2016","journal-title":"Eur J Cancer"},{"key":"2021122506323530100_onco12746-bib-0012","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s40425-017-0300-z","article-title":"Managing toxicities associated with immune checkpoint inhibitors: Consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group","volume":"5","author":"Puzanov","year":"2017","journal-title":"J Immunother Cancer"},{"key":"2021122506323530100_onco12746-bib-0013","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejca.2016.12.001","article-title":"Neurological adverse events associated with immune checkpoint inhibitors: Review of the literature","volume":"73","author":"Cuzzubbo","year":"2017","journal-title":"Eur J Cancer"},{"key":"2021122506323530100_onco12746-bib-0014","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1212\/WNL.0000000000004359","article-title":"Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan","volume":"89","author":"Suzuki","year":"2017","journal-title":"Neurology"},{"key":"2021122506323530100_onco12746-bib-0015","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1634\/theoncologist.2018-0157","article-title":"Myocarditis associated with immune checkpoint inhibitors: An expert consensus on data gaps and a call to action","volume":"23","author":"Neilan","year":"2018","journal-title":"The Oncologist"},{"issue":"suppl 4","key":"2021122506323530100_onco12746-bib-0016","doi-asserted-by":"crossref","first-page":"iv119","DOI":"10.1093\/annonc\/mdx225","article-title":"ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"28","author":"Haanen","year":"2017","journal-title":"Ann Oncol"},{"key":"2021122506323530100_onco12746-bib-0017","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1200\/JCO.2017.77.6385","article-title":"Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline","volume":"36","author":"Brahmer","year":"2018","journal-title":"J Clin Oncol"},{"key":"2021122506323530100_onco12746-bib-0018","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1002\/art.38107","article-title":"Rituximab-induced T cell depletion in patients with rheumatoid arthritis: Association with clinical response","volume":"65","author":"M\u00e9let","year":"2013","journal-title":"Arthritis Rheum"},{"key":"2021122506323530100_onco12746-bib-0019","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/S0140-6736(03)15324-X","article-title":"Effect of methylprednisolone when added to standard treatment with intravenous immunoglobulin for Guillain-Barr\u00e9 syndrome: Randomised trial","volume":"363","author":"van Koningsveld","year":"2004","journal-title":"Lancet"},{"key":"2021122506323530100_onco12746-bib-0020","doi-asserted-by":"crossref","first-page":"3193","DOI":"10.1200\/JCO.2015.60.8448","article-title":"Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center","volume":"33","author":"Horvat","year":"2015","journal-title":"J Clin Oncol"},{"key":"2021122506323530100_onco12746-bib-0021","doi-asserted-by":"crossref","DOI":"10.1002\/cncr.31629","article-title":"High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma","author":"Faje","year":"2018","journal-title":"Cancer"},{"key":"2021122506323530100_onco12746-bib-0022","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1097\/WCO.0000000000000503","article-title":"Neurological toxicities associated with immune-checkpoint inhibitors","volume":"30","author":"Touat","year":"2017","journal-title":"Curr Opin Neurol"},{"key":"2021122506323530100_onco12746-bib-0023","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1200\/JCO.2015.66.1389","article-title":"Safety profile of nivolumab monotherapy: A pooled analysis of patients with advanced melanoma","volume":"35","author":"Weber","year":"2017","journal-title":"J Clin Oncol"},{"key":"2021122506323530100_onco12746-bib-0024","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ejca.2016.12.038","article-title":"Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity","volume":"75","author":"Gutzmer","year":"2017","journal-title":"Eur J Cancer"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1634\/theoncologist.2018-0359","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1634\/theoncologist.2018-0359","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/24\/4\/435\/41917212\/oncolo_24_4_435.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/24\/4\/435\/41917212\/oncolo_24_4_435.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,25]],"date-time":"2021-12-25T01:33:17Z","timestamp":1640395997000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/24\/4\/435\/6439110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,27]]},"references-count":24,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,11,27]]},"published-print":{"date-parts":[[2019,4,1]]}},"URL":"https:\/\/doi.org\/10.1634\/theoncologist.2018-0359","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,4,1]]},"published":{"date-parts":[[2018,11,27]]}}}