Characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis: A retrospective multicentre cohort study.

Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis. In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre. Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43). ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.

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Déclaration de conflit d'intérêts

Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LMJ, JMV, WB, PH, RM, AC, TH, FM, LR, PB, JAS, TE, MT, CH, LvB, THu, declare no conflicts of interest. SZ declares speaker's fees or travel grants from Bristol-Myers Squibb (BMS), Sun Pharma and Merck Sharp & Dohme (MSD). ME received funding from DFG under Germany's Excellence Strategy – EXC-2049 – 390688087, BMBF, DZNE, DZHK, EU, Corona Foundation, and Foundation Leducq. ME reports grants from Bayer and fees paid to the Charité from AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Amgen, GSK, Sanofi, Covidien, Novartis, Pfizer, all outside the submitted work. CUB received compensation (all paid to the institute except TRV) for advisory roles for BMS, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, Pierre Fabre Pharmaceuticals, Third Rock Ventures, received research funding (all paid to the institute) from BMS, Novartis, NanoString, and declares stockownership in Immagene BV, where he is co-founder. AG received speaker's honoraria from Allmiral, BMS, MSD and Roche; AG has intermittent advisory board relationships with Amgen, BMS, Novartis, MSD, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from BMS, MSD, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, BMS, GSK, Novartis, Merck, MSD, Pfizer, and Roche. MS received speaker's honoraria and travel grants from Abbvie, BMS, Merck, MSD, Novartis, Pfizer, and Sanofi. JCH has served as a consultant for GSK, MSD, Pierre Fabre Pharmaceuticals, Sunpharma (personal) and BMS, Immunocore, Nektar, Novartis, Philogen (institution); received speaker's honoraria from Almirall, Amgen, BMS, GSK, MSD, Novartis, Pfizer, Pierre Fabre Pharmaceuticals, Roche, Sanofi (personal); a scientific grant from BMS and Sunpharma (institution) and clinical trial honoraria for BioNTech, BMS, Genentech, Immunocore, Iovance, MSD, Novartis, Philogen, Pierre Fabre Pharmaceuticals, Regeneron, Roche, Sanofi, 4SC (institution). SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, MSD, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, MSD, and Pierre Fabre Pharmaceuticals. LZ served as consultant and/or has received honoraria from BMS, MSD, Novartis, Pierre-Fabre Pharmaceuticals, Sunpharma and Sanofi; Research funding to institution: Novartis; travel support from MSD, BMS, Amgen, Pierre-Fabre Pharmaceuticals, Sunpharma, Sanofi and Novartis, outside the submitted work. LS declares advisory and speaker honoraria from Bristol Myers Squibb. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre Pharmaceuticals, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre Pharmaceuticals, Medac and Novartis. RSB has served as consultant for and/or received honoraria from Amgen, AstraZeneca, BMS, Celgene, Jansen-Cilag, MSD, Merck Seono, Novartis, Pfizer, and Roche. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim, BMS, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, MSD, Novartis Pharma AG, OncoSec, PHMR Limited, Pierre Fabre Pharmaceuticals, Provectus, Qbiotics, Regeneron. FS has received an honorarium from Gilead for an advisory board meeting. MS received speaker's honoraria and participated in advisory boards of BMS, Novartis, MSD, Roche, Pierre Fabre Pharmaceuticals, Kyowa Kirin, Immunocore, Recordati and Sanofi-Genzyme. MS received travel accommodation and expenses by Novartis, Pierre Fabre Pharmaceuticals, and Sun Pharma. LEF has served as consultant for Galderma, Janssen, Leo Pharma, Eli Lilly, Almirall, Union Therapeutics, Regeneron, Novartis, Amgen, Abbvie, UCB, Biotest, and InflaRx. SK received compensation for advising roles for Biogen. LH has served as consultant for Amgen, BMS, Biome-dx, EMA, Immunocore, Kyowa Kirin, MSD, Novartis, Pierre Fabre Pharmaceuticals, Roche, and Sanofi.