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Original article

Vol. 150 No. 4748 (2020)

Immune checkpoint inhibitor therapy-associated encephalitis: a case series and review of the literature

Cite this as:
Swiss Med Wkly. 2020;150:w20377



Immune checkpoint inhibitors (ICIs) can cause a wide spectrum of immune-related adverse events, including encephalitis. To date, no prospective randomised controlled trials examining the patient characteristics, treatment and outcomes of ICI-associated encephalitis have been published. Therefore, we aimed to review case reports and to provide recommendations for the management of ICI-associated encephalitis.


A literature search using Google Scholar and PubMed was performed in December 2019. Published case reports and case series of ICI-associated encephalitis were reviewed, and a case series from the Limmattal Hospital in Schlieren, Switzerland was added. The results are presented as numbers and medians (ranges).


Five different ICIs caused encephalitis in the 47 patients included in this case series. Nivolumab was the most frequently involved drug (27/47, 57%). The median time between treatment and onset of symptoms was 65 (4–630) days. Patients presented with rapidly evolving confusion, reduced level of consciousness, headache, seizures and focal neurological deficits. A total of 19 out of the 44 (43%) magnetic resonance imaging (MRI) scans performed revealed findings suggestive of encephalitis. No specific electroencephalogram (EEG) pattern consistent with encephalitis was found, but epileptiform discharges were detected in 7/20 (35%) of all tested patients. Typical findings of cerebrospinal fluid (CSF) analysis were pleocytosis, elevated protein levels and normal glucose concentrations. Forty-four out of 47 (94%) patients received corticosteroids. Intravenous immunoglobulins (IVIG), rituximab and plasma exchange therapy were less frequently prescribed. Nine out of 47 (19%) patients died during the index hospitalisation.


Encephalitis should be suspected in patients treated with ICIs who present with rapidly evolving confusion. Blood tests, CSF analysis, cerebral MRI and an EEG should be performed. Therapy with intravenous corticosteroids is recommended. Steroid unresponsiveness is rare and should lead to a review of the diagnosis. Alternative treatment options are IVIG, plasma exchange therapy and rituximab.


  1. Brown MP, Hissaria P, Hsieh AH, Kneebone C, Vallat W. Autoimmune limbic encephalitis with anti-contactin-associated protein-like 2 antibody secondary to pembrolizumab therapy. J Neuroimmunol. 2017;305:16–8. doi:.
  2. Cuzzubbo S, Javeri F, Tissier M, Roumi A, Barlog C, Doridam J, et al. Neurological adverse events associated with immune checkpoint inhibitors: Review of the literature. Eur J Cancer. 2017;73:1–8. doi:.
  3. Astaras C, de Micheli R, Moura B, Hundsberger T, Hottinger AF. Neurological adverse events associated with immune checkpoint inhibitors: diagnosis and management. Curr Neurol Neurosci Rep. 2018;18(1):3. doi:.
  4. Larkin J, Chmielowski B, Lao CD, Hodi FS, Sharfman W, Weber J, et al. Neurologic serious adverse events associated with nivolumab plus ipilimumab or nivolumab alone in advanced melanoma, including a case series of encephalitis. Oncologist. 2017;22(6):709–18. doi:.
  5. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al.; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078–92. doi:.
  6. Schneider S, Potthast S, Komminoth P, Schwegler G, Böhm S. PD-1 checkpoint inhibitor associated autoimmune encephalitis. Case Rep Oncol. 2017;10(2):473–8. doi:.
  7. Bossart S, Thurneysen S, Rushing E, Frontzek K, Leske H, Mihic-Probst D, et al. Case report: encephalitis, with brainstem involvement, following checkpoint inhibitor therapy in metastatic melanoma. Oncologist. 2017;22(6):749–53. doi:.
  8. Shah S, Dunn-Pirio A, Luedke M, Morgenlander J, Skeen M, Eckstein C. Nivolumab-induced autoimmune encephalitis in two patients with lung adenocarcinoma. Case Rep Neurol Med. 2018;2018:2548528. doi:.
  9. Williams TJ, Benavides DR, Patrice K-A, Dalmau JO, de Ávila ALR, Le DT, et al. Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer. JAMA Neurol. 2016;73(8):928–33. doi:.
  10. Niki M, Nakaya A, Kurata T, Nakahama K, Yoshioka H, Kaneda T, et al. Pembrolizumab-induced autoimmune encephalitis in a patient with advanced non-small cell lung cancer: A case report. Mol Clin Oncol. 2019;10(2):267–9.
  11. Cook C, McKown AC, Brummel NE. A Rare Case Of Pembrolizumab-Associated Autoimmune Limbic Encephalitis Following Treatment Of Malignant Melanoma. A58 Critical Care Case Reports: Neuro-Critical Care: American Thoracic Society; 2017. p. A2005-A.
  12. Kim A, Keam B, Cheun H, Lee S-T, Gook HS, Han M-K. Immune-Checkpoint-Inhibitor-Induced Severe Autoimmune Encephalitis Treated by Steroid and Intravenous Immunoglobulin. J Clin Neurol. 2019;15(2):259–61. doi:.
  13. Mandel JJ, Olar A, Aldape KD, Tremont-Lukats IW. Lambrolizumab induced central nervous system (CNS) toxicity. J Neurol Sci. 2014;344(1-2):229–31. doi:.
  14. Laserna A, Tummala S, Patel N, El Hamouda DEM, Gutiérrez C. Atezolizumab-related encephalitis in the intensive care unit: Case report and review of the literature. SAGE Open Med Case Rep. 2018;6:X18792422. doi:.
  15. Levine JJ, Somer RA, Hosoya H, Squillante C. Atezolizumab-induced encephalitis in metastatic bladder cancer: a case report and review of the literature. Clin Genitourin Cancer. 2017;15(5):e847–9. doi:.
  16. Arakawa M, Yamazaki M, Toda Y, Saito R, Ozawa A, Kosaihira S, et al. Atezolizumab-induced encephalitis in metastatic lung cancer: a case report and literature review. eNeurologicalSci. 2019;14:49–50. doi:.
  17. Salam S, Lavin T, Turan A. Limbic encephalitis following immunotherapy against metastatic malignant melanoma. BMJ Case Rep. 2016;2016:bcr2016215012. doi:.
  18. Ito M, Fujiwara S, Fujimoto D, Mori R, Yoshimura H, Hata A, et al. Rituximab for nivolumab plus ipilimumab-induced encephalitis in a small-cell lung cancer patient. Ann Oncol. 2017;28(9):2318–9. doi:.
  19. Conry RM, Sullivan JC, Nabors LB, 3rd. Ipilimumab-induced encephalopathy with a reversible splenial lesion. Cancer Immunol Res. 2015;3(6):598–601. doi:.
  20. Burke M, Hardesty M, Downs W. A case of severe encephalitis while on PD-1 immunotherapy for recurrent clear cell ovarian cancer. Gynecol Oncol Rep. 2018;24:51–3. doi:.
  21. Boyd K, Kalladka D, Overell J, Waterston A. Ipilimumab induced encephalitis: a case report. Immunome Res. 2015;11(2):1.
  22. Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One. 2013;8(1):e53745. doi:.
  23. Cao Y, Nylander A, Ramanan S, Goods BA, Ponath G, Zabad R, et al. CNS demyelination and enhanced myelin-reactive responses after ipilimumab treatment. Neurology. 2016;86(16):1553–6. doi:.
  24. Khoja L, Maurice C, Chappell M, MacMillan L, Al-Habeeb AS, Al-Faraidy N, et al. Eosinophilic fasciitis and acute encephalopathy toxicity from pembrolizumab treatment of a patient with metastatic melanoma. Cancer Immunol Res. 2016;4(3):175–8. doi:.
  25. Kazandjian D, Suzman DL, Blumenthal G, Mushti S, He K, Libeg M, et al. FDA approval summary: nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist. 2016;21(5):634–42. doi:.
  26. Carl D, Grüllich C, Hering S, Schabet M. Steroid responsive encephalopathy associated with autoimmune thyroiditis following ipilimumab therapy: a case report. BMC Res Notes. 2015;8(1):316. doi:.
  27. Richard K, Weslow J, Porcella SL, Nanjappa S. A case report of steroid responsive nivolumab-induced encephalitis. Cancer Contr. 2017;24(5):1073274817729069. doi:.
  28. Matsuoka H, Kimura H, Koba H, Tambo Y, Ohkura N, Hara J, et al. Nivolumab-induced limbic encephalitis with anti-Hu antibody in a patient with advanced pleomorphic carcinoma of the lung. Clin Lung Cancer. 2018;19(5):e597–9. doi:.
  29. 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. J Thorac Oncol. 2017;12(11):1626–35. doi:.
  30. Strik H, Keber U, Hammoud WA, Riera-Knorrenschild J, Carl B, Dodel R, et al. Immune checkpoint inhibitor-associated CNS autoimmune disorder (ICICAD) following nivolumab treatment: A new entity of drug-induced autoimmune encephalitis? Eur J Cancer. 2017;87:205–8. doi:.
  31. Chaucer B, Stone A, Demanes A, Seibert SM. Nivolumab-Induced Encephalitis in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome. Case Rep Oncol Med. 2018;2018:4273231. doi:.
  32. Leitinger M, Varosanec MV, Pikija S, Wass RE, Bandke D, Weis S, et al. Fatal necrotizing encephalopathy after treatment with nivolumab for squamous non-small cell lung cancer: case report and review of the literature. Front Immunol. 2018;9:108. doi:.
  33. Zurko J, Mehta A. Association of immune-mediated cerebellitis with immune checkpoint inhibitor therapy. Mayo Clin Proc Innov Qual Outcomes. 2018;2(1):74–7. doi:.
  34. Kopecký J, Kubeček O, Geryk T, Slováčková B, Hoffmann P, Žiaran M, et al. Nivolumab induced encephalopathy in a man with metastatic renal cell cancer: a case report. J Med Case Reports. 2018;12(1):262. doi:.
  35. De la Hoz A, Foolad F, Gallegos C, Kornblau S, Kontoyiannis DP. Nivolumab-induced encephalitis post allogeneic stem cell transplant in a patient with Hodgkin’s disease. Bone Marrow Transplant. 2019;54(5):749–51. doi:.
  36. Shibaki R, Murakami S, Oki K, Ohe Y. Nivolumab-induced autoimmune encephalitis in an anti-neuronal autoantibody-positive patient. Jpn J Clin Oncol. 2019;49(8):793–4. doi:.
  37. Zafar Z, Vogler C, Hudali T, Bhattarai M. Nivolumab-Associated Acute Demyelinating Encephalitis: A Case Report and Literature Review. Clin Med Res. 2019;17(1-2):29–33. doi:.
  38. Gill A, Perez MA, Perrone CM, Bae CJ, Pruitt AA, Lancaster E. A case series of PD-1 inhibitor-associated paraneoplastic neurologic syndromes. J Neuroimmunol. 2019;334:576980. doi:.
  39. Hottinger AF, de Micheli R, Guido V, Karampera A, Hagmann P, Du Pasquier R. Natalizumab may control immune checkpoint inhibitor-induced limbic encephalitis. Neurol Neuroimmunol Neuroinflamm. 2018;5(2):e439. doi:.
  40. Buttgereit F, da Silva JA, Boers M, Burmester GR, Cutolo M, Jacobs J, et al. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann Rheum Dis. 2002;61(8):718–22. doi:.
  41. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al.; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32. doi:.
  42. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. doi:.
  43. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob J-J, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56. doi:.
  44. Gozzard P, Maddison P. Which antibody and which cancer in which paraneoplastic syndromes? Pract Neurol. 2010;10(5):260–70. doi:.
  45. Connolly C, Bambhania K, Naidoo J. Immune-Related Adverse Events: A Case-Based Approach. Front Oncol. 2019;9:530. doi:.
  46. Oncology NCPGi. Management of Immunotherapy‐Related Toxicities, Version 1.2020. 2019 December 16. Available at:
  47. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al.; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714–68. doi:.
  48. Gresa-Arribas N, Titulaer MJ, Torrents A, Aguilar E, McCracken L, Leypoldt F, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13(2):167–77. doi:.
  49. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–68. doi:.
  50. Haanen J, Carbonnel F, Robert C, Kerr K, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv119–42. doi:.
  51. Hottinger AF. Neurologic complications of immune checkpoint inhibitors. Curr Opin Neurol. 2016;29(6):806–12. doi:.

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