Dual checkpoint inhibitor induced autoimmune encephalitis

  • Natalie Elkayam Maimonides Medical Center
Keywords: Immunity, Encephalitis, Autoimmunity, PD-1 monoclonal antibody, CTLA-4 monoclonal antibody, Metastatic Cancer,


Immune checkpoint inhibitor therapy has become increasingly more used as a treatment modality for solid organ tumors. Nivolumab, anti-PD-1 and Ipilimumab, anti-CTLA-4 monoclonal antibodies are checkpoint inhibitors with well described immune related toxicities. Immune specific neurotoxicity is rare and not well elucidated in literature. We present a case of severe autoimmune encephalitis in a patient with metastatic renal cell carcinoma treated with both Nivolumab and Ipilimumab. A 53-year-old man with metastatic renal cell carcinoma presented due to visual and auditory hallucinations of sudden onset, confusion and weakness. Initial imaging and diagnostic workup did not demonstrate a clear source. However, a neurological etiology was suspected. It was concluded that the patient had autoimmune encephalitis induced by dual check point inhibitor therapy. This was further strengthened by his rapid response to systemic corticosteroid therapy. We present a summary of this case and its management and a review of literature on dual checkpoint inhibitor induced neurological adverse effects.

Author Biography

Natalie Elkayam, Maimonides Medical Center

Natalie Elkayam, M.D., Resident PGY-2

Department of Medicine

Maimonides Medical Center


Feng S, Coward J, McCaffrey E, Coucher J, Kalokerinos P, O’Byrne K. Pembrolizumab-Induced Encephalopathy: A Review of Neurological Toxicities with Immune Checkpoint Inhibitors. Journal of Thoracic Oncology 2017;12(11):1626-1635. doi: 10.1016/j.jtho.2017.08.007

Kao JC, Liao B, Markovic SN, Klein CJ, Naddaf E, Staff NP, Mauermann ML. Neurological Complications Associated With Anti–Programmed Death 1 (PD-1) Antibodies. JAMA Neurology 2017;74(10):1216. doi: 10.1001/jamaneurol.2017.1912

Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Hamid O. Pembrolizumab versus Ipilimumab in Advanced Melanoma. New England Journal of Medicine 2015;372(26):2521-2532. doi: 10.1056/nejmoa1503093

Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Gurney H. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2015;373(19):1803-1813. doi: 10.1056/nejmoa1510665

Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee J, Fong L, Quinn DI. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. New England Journal of Medicine 2017;376(11):1015-1026. doi: 10.1056/nejmoa1613683

Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, Arén FO. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer. New England Journal of Medicine 2015;373(2):123-135. doi: 10.1056/nejmoa1504627

Decatris MP, O'Byrne KJ. Immune checkpoint inhibitors as first-line and salvage therapy for advanced non-small-cell lung cancer. Future Oncology 2016;12(15):1805-1822. doi: 10.2217/fon-2016-0086

Bot I, Blank CU, Boogerd W, Brandsma D. Neurological immune-related adverse events of ipilimumab. Practical Neurology 2013;13(4):278-280. doi: 10.1136/practneurol-2012-000447

Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Chow LQ. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. The Lancet Oncology 2016;17(7):956-965. doi: 10.1016/s1470-2045(16)30066-3

Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro-Oncology 2014;16(4):589-593. doi: 10.1093/neuonc/nou001

Wilgenhof S, Neyns B. Anti-CTLA-4 antibody-induced Guillain-Barre syndrome in a melanoma patient. Annals of Oncology 2011;22(4):991-993. doi: 10.1093/annonc/mdr028

Salam S, Lavin T, Turan A. Limbic encephalitis following immunotherapy against metastatic malignant melanoma. BMJ Case Reports 2016:2016215012. doi: 10.1136/bcr-2016-215012

Posterior reversible limbic encephalopathy syndrome during ipilimumab therapy for malignant melanoma. Maur M, Tomasello C, Frassoldati A, Dieci MV, Barbieri E, Conte P. 2012, J Clin Oncol, Vol. 30, pp. 76-78.

Williams TJ, Benavides DR, Patrice K, Dalmau JO, de Ávila ALR, Le DT, Mowry EM. Association of Autoimmune Encephalitis With Combined Immune Checkpoint Inhibitor Treatment for Metastatic Cancer. JAMA Neurology 2016;73(8) doi: 10.1001/jamaneurol.2016.1399

Cuzzubbo S, Javeri F, Tissier M, Roumi A, Barlog C, Doridam J, Carpentier AF. Neurological adverse events associated with immune checkpoint inhibitors: Review of the literature. European Journal of Cancer 2017;73:1-8. doi: 10.1016/j.ejca.2016.12.001

Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, Samuels Y. Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nature Genetics 2011;43(5):442-446. doi: 10.1038/ng.810

Graus F, Saiz A, Dalmau J. Antibodies and neuronal autoimmune disorders of the CNS. Journal of Neurology 2010;257(4):509-517. doi: 10.1007/s00415-009-5431-9

Neurotoxicity from immune checkpoint inhibition in the treatment of melanoma: a single center experience and review of literature. Spain L, Walls G, Julve M, et al. 2016, Ann Oncol, Vol. 28, pp. 377-385.

Blackmon J, Viator T, Conry R. Central nervous system toxicities of anti-cancer immune checkpoint blockade. Journal of Neurology and Neuromedicine 2016;1(4):39-45. doi: 10.29245/2572.942x/2016/4.1040

Short Report