Pembrolizumab‑induced aseptic meningitis in a patient with non‑small cell lung cancer: A case report and literature review of aseptic meningitis as an immune‑related adverse event

Inui,Genki; Funaki,Yoshihiro; Makino,Haruhiko; Touge,Hirokazu; Arai,Katsunori; Kuroda,Keisuke; Hirayama,Yuuki; Kato,Ryohei; Nonaka,Takafumi; Yamane,Kohei; Teruya,Yasuhiko; Sueda,Yuriko; Sakamoto,Tomohiro; Yamaguchi,Kosuke; Kodani,Masahiro; Kawase,Shinya; Umekita,Yoshihisa; Horie,Yasushi; Nosaka,Kanae; Yamasaki,Akira

doi:10.3892/mco.2022.2553

Pembrolizumab‑induced aseptic meningitis in a patient with non‑small cell lung cancer: A case report and literature review of aseptic meningitis as an immune‑related adverse event

Authors:
- Genki Inui
- Yoshihiro Funaki
- Haruhiko Makino
- Hirokazu Touge
- Katsunori Arai
- Keisuke Kuroda
- Yuuki Hirayama
- Ryohei Kato
- Takafumi Nonaka
- Kohei Yamane
- Yasuhiko Teruya
- Yuriko Sueda
- Tomohiro Sakamoto
- Kosuke Yamaguchi
- Masahiro Kodani
- Shinya Kawase
- Yoshihisa Umekita
- Yasushi Horie
- Kanae Nosaka
- Akira Yamasaki
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Affiliations: Department of Multidisciplinary Internal Medicine, Division of Respiratory Medicine and Rheumatology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8503, Japan, Department of Respiratory Medicine, Yonago Medical Center, Yonago, Tottori 683‑0006, Japan, Department of Brain and Neurosciences, Division of Neurology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8503, Japan, Department of Pathology, Division of Pathology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8503, Japan
Published online on: June 1, 2022 https://doi.org/10.3892/mco.2022.2553
Article Number: 120
Copyright: © Inui et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Aseptic meningitis is a rare immune‑related adverse event (irAE), which occurs during treatment with immune checkpoint inhibitors (ICIs). This condition has non‑specific symptoms and exhibits no clear signs on magnetic resonance imaging (MRI). There are only a few reports of aseptic meningitis caused by pembrolizumab treatment for non‑small cell lung cancer (NSCLC). The present study includes a report of such a case and a review of the related literature. A 67‑year‑old Japanese man received first‑line pembrolizumab treatment for NSCLC and subsequently developed severe nausea and vomiting. No significant findings were observed following a computed tomography (CT) scan, MRI of the brain and upper gastrointestinal tract, or upper gastrointestinal endoscopy. Cerebrospinal fluid analysis revealed lymphocyte infiltration and elevation of the IgG index, without indications of metastasis or infection, which suggested the presence of aseptic meningitis. The symptoms immediately improved following prednisolone treatment, and aseptic meningitis was diagnosed as an irAE related to pembrolizumab treatment. Given that aseptic meningitis can cause non‑specific symptoms, including headache and nausea, the possibility of an irAE should be considered in patients with non‑specific symptoms who are receiving ICIs, and a cerebrospinal fluid examination should be performed.

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1	Ettinger DS, Wood DE, Aggarwal C, Aisner DL, Akerley W, Bauman JR, Bharat A, Bruno DS, Chang JY, Chirieac LR, et al: NCCN guidelines insights: Non-small cell lung cancer, version 1.2020. J Natl Compr Canc Netw. 17:1464–1472. 2019.PubMed/NCBI View Article : Google Scholar
2	Dalakas MC: Neurological complications of immune checkpoint inhibitors: What happens when you ‘take the brakes off’ the immune system. Ther Adv Neurol Disord. 11(1756286418799864)2018.PubMed/NCBI View Article : Google Scholar
3	Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, et al: 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. 36:1714–1768. 2018.PubMed/NCBI View Article : Google Scholar
4	Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 375:1823–1833. 2016.PubMed/NCBI View Article : Google Scholar
5	Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodriguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, et al: Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 378:2288–2301. 2018.PubMed/NCBI View Article : Google Scholar
6	Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 378:2078–2092. 2018.PubMed/NCBI View Article : Google Scholar
7	Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, et al: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 377:1919–1929. 2017.PubMed/NCBI View Article : Google Scholar
8	Ready N, Farago AF, de Braud F, Atmaca A, Hellmann MD, Schneider JG, Spigel DR, Moreno V, Chau I, Hann CL, et al: Third-line nivolumab monotherapy in recurrent SCLC: CheckMate 032. J Thorac Oncol. 14:237–244. 2019.PubMed/NCBI View Article : Google Scholar
9	Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, et al: First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 379:2220–2229. 2018.PubMed/NCBI View Article : Google Scholar
10	Waghdhare S, Kalantri A, Joshi R and Kalantri S: Accuracy of physical signs for detecting meningitis: A hospital-based diagnostic accuracy study. Clin Neurol Neurosurg. 112:752–757. 2010.PubMed/NCBI View Article : Google Scholar
11	Blackmon JT, Viator TM and Conry RM: Central nervous system toxicities of anti-cancer immune checkpoint blockade. J Neurol Neuromedicine. 1:39–45. 2016.
12	Fujiwara S, Mimura N, Yoshimura H, Fujimoto D, Ito M, Mori R, Ito J, Tomii K, Kawamoto M and Kohara N: Elevated adenosine deaminase levels in the cerebrospinal fluid in immune checkpoint inhibitor-induced autoimmune encephalitis. Intern Med. 58:2871–2874. 2019.PubMed/NCBI View Article : Google Scholar
13	Tuon FF, Higashino HR, Lopes MI, Litvoc MN, Atomiya AN, Antonangelo L and Leite OM: Adenosine deaminase and tuberculous meningitis-a systematic review with meta-analysis. Scand J Infect Dis. 42:198–207. 2010.PubMed/NCBI View Article : Google Scholar
14	Yonenobu Y, Ishijima M, Toyooka K and Fujimura H: A case of meningoencephalitis associated with pembrolizumab treated for squamous cell lung cancer. Rinsho Shinkeigaku. 59:105–108. 2019.PubMed/NCBI View Article : Google Scholar : (In Japanese).
15	Thwaites GE and Hien TT: Tuberculous meningitis: Many questions, too few answers. Lancet Neurol. 4:160–170. 2005.PubMed/NCBI View Article : Google Scholar
16	Akaishi T, Narikawa K, Suzuki Y, Mitsuzawa S, Tsukita K, Kuroda H, Nakashima I, Fujihara K and Aoki M: Importance of the quotient of albumin, quotient of immunoglobulin G and Reibergram in inflammatory neurological disorders with disease-specific patterns of blood-brain barrier permeability. Neurol Clin Neurosci. 3:94–100. 2015.
17	Leitinger M, Varosanec MV, Pikija S, Wass RE, Bandke D, Weis S, Studnicka M, Grinzinger S, McCoy MR, Hauer L and Sellner J: Fatal necrotizing encephalopathy after treatment with nivolumab for squamous non-small cell lung cancer: Case report and review of the literature. Front Immunol. 9(108)2018.PubMed/NCBI View Article : Google Scholar
18	Glantz MJ, Cole BF, Glantz LK, Cobb J, Mills P, Lekos A, Walters BC and Recht LD: Cerebrospinal fluid cytology in patients with cancer: Minimizing false-negative results. Cancer. 82:733–739. 1998.PubMed/NCBI View Article : Google Scholar
19	Spain L, Walls G, Julve M, O'Meara K, Schmid T, Kalaitzaki E, Turajlic S, Gore M, Rees J and Larkin J: Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: A single centre experience and review of the literature. Ann Oncol. 28:377–385. 2017.PubMed/NCBI View Article : Google Scholar
20	Bot I, Blank CU, Boogerd W and Brandsma D: Neurological immune-related adverse events of ipilimumab. Pract Neurol. 13:278–280. 2013.PubMed/NCBI View Article : Google Scholar
21	Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, Bergmann T, Bockmeyer CL, Eigentler T, Fluck M, 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. 8(e53745)2013.PubMed/NCBI View Article : Google Scholar
22	Bompaire F, Mateus C, Taillia H, De Greslan T, Lahutte M, Sallansonnet-Froment M, Ouologuem M, Renard JL, Gorochov G, Robert C and Ricard D: Severe meningo-radiculo-neuritis associated with ipilimumab. Invest New Drugs. 30:2407–2410. 2012.PubMed/NCBI View Article : Google Scholar
23	Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, Suri KB, Levy C, Allen T, Mavroukakis S, et al: Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 30:825–830. 2007.PubMed/NCBI View Article : Google Scholar
24	Takamatsu D, Furubayashi N, Negishi T, Ieiri K, Inoue T, Tsukino K and Nakamura M: Relapse of aseptic meningitis induced by ipilimumab and nivolumab therapy for metastatic renal cell carcinoma: A case report. Mol Clin Oncol. 11:590–594. 2019.PubMed/NCBI View Article : Google Scholar
25	Cordes LM, Davarpanah NN, Reoma LB, Gasmi B, Quezado M, Khan OI, Nath A and Apolo AB: Neurotoxicities associated with checkpoint inhibitors: Two case reports and a review of the literature. Clin Case Rep. 8:24–32. 2019.PubMed/NCBI View Article : Google Scholar
26	Toyozawa R, Haratake N, Toyokawa G, Matsubara T, Takamori S, Miura N, Yamaguchi M, Takenoyama M and Seto T: Atezolizumab-induced aseptic meningitis in patients with NSCLC. JTO Clin Res Rep. 1(100012)2020.PubMed/NCBI View Article : Google Scholar
27	Lima G, Kahn A, Sama S and Savage J: Aseptic meningitis as an immune-related adverse event after pembrolizumab. Case Rep Oncol Med. 2019(7183747)2019.PubMed/NCBI View Article : Google Scholar
28	Tadano H and Torigoe T: Immune-related adverse events of immune checkpoint inhibitors. Nihon Rinsho Meneki Gakkai Kaishi. 40:102–108. 2017.PubMed/NCBI View Article : Google Scholar : (In Japanese).
29	Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, Carvajal RD, Dickson MA, D'Angelo SP, Woo KM, et al: 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. J Clin Oncol. 33:3193–3198. 2015.PubMed/NCBI View Article : Google Scholar
30	Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, et al: A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 354:899–910. 2006.PubMed/NCBI View Article : Google Scholar
31	Hottinger AF, de Micheli R, Guido V, Karampera A, Hagmann P and Du Pasquier R: Natalizumab may control immune checkpoint inhibitor-induced limbic encephalitis. Neurol Neuroimmunol Neuroinflamm. 5(e439)2018.PubMed/NCBI View Article : Google Scholar
32	Teraoka S, Fujimoto D, Morimoto T, Kawachi H, Ito M, Sato Y, Nagata K, Nakagawa A, Otsuka K, Uehara K, et al: Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: A prospective cohort study. J Thorac Oncol. 12:1798–1805. 2017.PubMed/NCBI View Article : Google Scholar
33	Niki M, Nakaya A, Kurata T, Nakahama K, Yoshioka H, Kaneda T, Kibata K, Ogata M and Nomura S: Pembrolizumab-induced autoimmune encephalitis in a patient with advanced non-small cell lung cancer: A case report. Mol Clin Oncol. 10:267–269. 2019.PubMed/NCBI View Article : Google Scholar
34	Simonaggio A, Michot JM, Voisin AL, Le Pavec J, Collins M, Lallart A, Cengizalp G, Vozy A, Laparra A, Varga A, et al: Evaluation of readministration of immune checkpoint inhibitors after immune-related adverse events in patients with cancer. JAMA Oncol. 5:1310–1317. 2019.PubMed/NCBI View Article : Google Scholar