Diagnostic and Prognostic Biomarkers in Immune Checkpoint Inhibitor-Related Encephalitis: a Retrospective Cohort Study
Antonio Farina1, Macarena Villagran-Garcia1, Anne-Laurie Pinto1, Marie Benaiteau1, Cristina Birzu2, pauline dumez1, Dimitri Psimaras3, Marie Rafiq4, Géraldine Picard1, Virginie Desestret1, Jerome Honnorat1, Bastien Joubert1
1Hospices Civils de Lyon, 2AP-HP, Hospital Group Pitié-Salpêtrière, Neuro-oncology Department Paris, France, 3Hopital Salpetrière ; Service, 4Toulouse Purpan University Hospital Center
Objective:
We aimed to comprehensively characterise ICI-encephalitis and identify diagnostic biomarkers and outcome predictors.
Background:
Immune checkpoint inhibitor-related encephalitis (ICI-encephalitis) is not well characterised and diagnostic and prognostic biomarkers are lacking.
Design/Methods:
This retrospective study included all patients with ICI-encephalitis studied in a national reference center (2015–2023). Treatment response predictors, defined as a CTCAE v5.0 grade < 3 at any time after therapeutic intervention, were assessed by logistic regression analysis, and predictors of mortality by Cox regression analysis. NfL was measured by ELISA.
Results:
Of 67 patients with definite encephalitis (median age, 69 years; 66% male), 43/67 had a focal syndrome (64%; limbic encephalitis, cerebellar ataxia, and/or brainstem encephalitis), 24/67 (36%) had meningoencephalitis, a non-focal syndrome with altered mental status (22/24, 92%) and pleocytosis (24/24, 100%). Patients with focal encephalitis more frequently had abnormal brain MRI (26/42, 62% versus 8/24, 33%, p = 0.025), PNS-related antibodies (36/43, 84% versus 1/24, 4%, p < 0.001), and neuroendocrine cancers (22/43, 51% versus 1/24, 4%; p < 0.001) than patients with meningoencephalitis. PNS-related antibodies were associated with less treatment response, independently of age, sex, and baseline severity (adjusted OR 0.05; 95%CI [0.01; 0.19]; p < 0.001) as well as higher mortality, independently of age and cancer type (adjusted HR 5.07; 95% CI [2.12; 12.12]; p < 0.001). Serum NfL discriminated patients with definite ICI-encephalitis (n = 27) from cancer-matched controls (n = 16; optimal cut-off >273.5 pg/mL, sensitivity 81%, specificity 88%, AUC 0.87, 95% CI [0.76; 0.98]) and irAE treatment responders (n = 10) from non-responders (n = 17, optimal cut-off >645 pg/mL, sensitivity 90%, specificity 65%; AUC 0.75, 95% CI [0.55; 0.94]).
Conclusions:
ICI-encephalitis corresponds to a set of clinically-recognisable syndromes. Patients with focal encephalitis, PNS-related antibodies, and/or higher serum NfL have low treatment response rates. Research is needed on the underlying immunopathogenesis to foster therapeutic innovations.
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