{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T21:57:34Z","timestamp":1785275854417,"version":"3.55.0"},"reference-count":30,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,3,1]],"date-time":"2019-03-01T00:00:00Z","timestamp":1551398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The advent of immune checkpoint inhibitors gave rise to a new era in oncology and general medicine. The increasing use of programmed death-1 (PD-1) inhibitors in non-small cell lung cancer and in other malignancies means clinicians have to face up to new challenges in managing immune-related adverse events (irAEs), which often resemble autoimmune diseases. Neurological irAEs represent an emerging toxicity related to immunotherapy, and it is mandatory to know how to monitor, recognize, and manage them, since they can rapidly lead to patient death if untreated. Guidelines for the diagnosis and treatment of these irAEs have been recently published but sharing some of the most unusual clinical cases is crucial, in our opinion, to improve awareness and to optimize the approach for these patients. A literature review on the diagnosis and treatment of immune-related neurotoxicity\u2019s has been conducted starting from the report of four cases of neurological irAEs regarding cases of polyneuropathy, myasthenia gravis, Bell\u2019s palsy, and encephalopathy, all of which occurred in oncological patients receiving PD-1 inhibitors (pembrolizumab and nivolumab) for the treatment of non-oncogene addicted advanced non-small cell lung cancer. The exclusion of other differential diagnoses and the correlation between the suspension of immunotherapy and improvement of symptoms suggest that immunotherapy could be the cause of the neurological disorders reported.<\/jats:p>","DOI":"10.3390\/cancers11030296","type":"journal-article","created":{"date-parts":[[2019,3,4]],"date-time":"2019-03-04T05:22:26Z","timestamp":1551676946000},"page":"296","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["PD-1 Inhibitors-Related Neurological Toxicities in Patients with Non-Small-Cell Lung Cancer: A Literature Review"],"prefix":"10.3390","volume":"11","author":[{"given":"Aurora","family":"Mirabile","sequence":"first","affiliation":[{"name":"Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele, Via Olgettina 60, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Brioschi","sequence":"additional","affiliation":[{"name":"Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele, Via Olgettina 60, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Ducceschi","sequence":"additional","affiliation":[{"name":"Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele, Via Olgettina 60, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"Piva","sequence":"additional","affiliation":[{"name":"Department of Oncology, ASST Fatebenefratelli Sacco, 20121 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Lazzari","sequence":"additional","affiliation":[{"name":"Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele, Via Olgettina 60, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Bulotta","sequence":"additional","affiliation":[{"name":"Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele, Via Olgettina 60, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Grazia","family":"Vigan\u00f2","sequence":"additional","affiliation":[{"name":"Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele, Via Olgettina 60, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Petrella","sequence":"additional","affiliation":[{"name":"Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele, Via Olgettina 60, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Gianni","sequence":"additional","affiliation":[{"name":"Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele, Via Olgettina 60, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanesa","family":"Gregorc","sequence":"additional","affiliation":[{"name":"Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele, Via Olgettina 60, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E359","DOI":"10.1002\/ijc.29210","article-title":"Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012: Globocan 2012","volume":"136","author":"Ferlay","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Abdel-Wahab, N., Shah, M., and Suarez-Almazor, M.E. (2016). Adverse Events Associated with Immune Checkpoint Blockade in Patients with Cancer: A Systematic Review of Case Reports. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160221"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1016\/j.jtho.2017.08.007","article-title":"Pembrolizumab-Induced Encephalopathy: A Review of Neurological Toxicities with Immune Checkpoint Inhibitors","volume":"12","author":"Feng","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1001\/jamaneurol.2016.1399","article-title":"Association of Autoimmune Encephalitis with Combined Immune Checkpoint Inhibitor Treatment for Metastatic Cancer","volume":"73","author":"Williams","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.ejca.2017.05.041","article-title":"Myasthenia gravis: An emerging toxicity of immune checkpoint inhibitors","volume":"82","author":"Makarious","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_6","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":"ref_7","doi-asserted-by":"crossref","unstructured":"Salam, S., Lavin, T., and Turan, A. (2016). Limbic encephalitis following immunotherapy against metastatic malignant melanoma. BMJ Case Rep., bcr2016215012.","DOI":"10.1136\/bcr-2016-215012"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1158\/2326-6066.CIR-15-0186","article-title":"Eosinophilic Fasciitis and Acute Encephalopathy Toxicity from Pembrolizumab Treatment of a Patient with Metastatic Melanoma","volume":"4","author":"Khoja","year":"2016","journal-title":"Cancer Immunol. Res."},{"key":"ref_9","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":"ref_10","doi-asserted-by":"crossref","first-page":"701","DOI":"10.2217\/imt-2017-0043","article-title":"Myasthenia gravis induced by nivolumab in patients with non-small-cell lung cancer: A case report and literature review","volume":"9","author":"Hasegawa","year":"2017","journal-title":"Immunotherapy"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"39","DOI":"10.29245\/2572.942X\/2016\/4.1040","article-title":"Central nervous system toxicities of anti-cancer immune checkpoint blockade","volume":"1","author":"Blackmon","year":"2016","journal-title":"J. Neurol. Neuromed."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/mus.25163","article-title":"Myasthenia gravis induced by nivolumab therapy in a patient with non-small-cell lung cancer: Noteworthy Cases","volume":"54","author":"Polat","year":"2016","journal-title":"Muscle Nerve"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/mus.25212","article-title":"Benign form of myasthenia gravis after nivolumab treatment","volume":"54","author":"Sciacca","year":"2016","journal-title":"Muscle Nerve"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1002\/cncr.27969","article-title":"Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: Detailed safety analysis from a phase 3 trial in patients with advanced melanoma","volume":"119","author":"Weber","year":"2013","journal-title":"Cancer"},{"key":"ref_15","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":"ref_16","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":"ref_17","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1097\/WCO.0000000000000391","article-title":"Neurologic complications of immune checkpoint inhibitors","volume":"29","author":"Hottinger","year":"2016","journal-title":"Curr. Opin. Neurol."},{"key":"ref_18","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":"ref_19","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1750-1172-2-22","article-title":"Paraneoplastic neurological syndromes","volume":"2","author":"Honnorat","year":"2007","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1097\/CCO.0000000000000222","article-title":"Update on neurological paraneoplastic syndromes","volume":"27","author":"Rosenfeld","year":"2015","journal-title":"Curr. Opin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.5692\/clinicalneurol.52.1312","article-title":"New clinical entity of myasthenia gravis with autoimmune targets of heart and skeletal muscles","volume":"52","author":"Suzuki","year":"2012","journal-title":"Rinsho Shinkeigaku"},{"key":"ref_22","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":"ref_23","doi-asserted-by":"crossref","first-page":"94","DOI":"10.18773\/austprescr.2017.030","article-title":"Management of Bell\u2019s palsy","volume":"40","author":"Somasundara","year":"2017","journal-title":"Aust. Prescr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1177\/0194599815606701","article-title":"Bilateral Facial Palsy following Ipilimumab Infusion for Melanoma","volume":"153","author":"Altman","year":"2015","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1097\/CJI.0000000000000184","article-title":"Development of Bell\u2019s Palsy After Treatment With Ipilimumab and Nivolumab for Metastatic Melanoma: A Case Report","volume":"41","author":"Zecchini","year":"2018","journal-title":"J. Immunother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1080\/000164802760370736","article-title":"Bell\u2019s palsy: The spontaneous course of 2500 peripheral facial nerve palsies of different etiologies","volume":"549","author":"Peitersen","year":"2002","journal-title":"Acta Otolaryngol. Suppl."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1056\/NEJMoa072006","article-title":"Early treatment with prednisolone or acyclovir in Bell\u2019s palsy","volume":"357","author":"Sullivan","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gagyor, I., Madhok, V.B., Daly, F., Pitkethly, M., Comerford, N., and Sullivan, F. (2015). Antiviral treatment for Bell\u2019s palsy (idiopathic facial paralysis). Cochrane Database Syst. Rev, CD001869.","DOI":"10.1002\/14651858.CD001869.pub6"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/S0140-6736(14)60958-2","article-title":"Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial","volume":"384","author":"Robert","year":"2014","journal-title":"Lancet"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Spain, L., Walls, G., Julve, M., O\u2019Meara, K., Schmid, T., Kalaitzaki, E., Turajlic, S., Gore, M., Rees, J., and Larkin, J. (2016). Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: A single centre experience and review of the literature. Ann. Oncol., mdw558.","DOI":"10.1093\/annonc\/mdw558"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/3\/296\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:35:43Z","timestamp":1760186143000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/3\/296"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,1]]},"references-count":30,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["cancers11030296"],"URL":"https:\/\/doi.org\/10.3390\/cancers11030296","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,1]]}}}