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

Central nervous system adverse events of immune checkpoint inhibitors

“…We and others prefer this term to describe patients with a diffuse CNS dysfunction, as opposed to those with focal syndromes such as limbic, brainstem, or cerebellar encephalitis [13,14]; however, meningoencephalitis cases have been elsewhere defined as encephalitis, nonlimbic encephalitis, diffuse encephalitis or encephalopathy with inflammatory changes [5 && ,7,14,24 && ,25 & ]. In all cases, common features of post-ICI meningoencephalitis are: acute/subacute mental status alteration, isolated or accompanied by decreased vigilance, fever, seizures, meningism or, more rarely, language impairment, tremor or myoclonus [13,14,24 && ,25 & ]; CSF testing showing pleocytosis in nearly all patients, with higher cells counts and protein levels than in focal encephalitis [7,[12][13][14]; negative neural antibody tests, except for anti-GFAP antibodies in a subgroup of patients [12,13,14,24 && ,25 & ] (of note, unbiased antibody testing methods may reveal brain reactivities with unknown antigen specificity in some patients [14,26]); generally normal brain MRI, except for occasional leptomeningeal or pachymeningeal contrast enhancement and/or brain parenchymal patchy T2/FLAIR hyperintensities [7,7,13,14,26] (Fig. 1); more frequent concomitant nonneurological toxicities than in focal encephalitis [14,24 && ]; and mostly favourable outcomes (50-90%) after ICI discontinuation and immunomodulation [i.e., corticosteroids, intravenous immunoglobulins (IVIG)], plasma exchanges, ICI neurotoxicities may be an indirect or direct surrogate of effective ICI-induced immune system activation; however, evidence that neurotoxicities occurrence associates with improved oncological outcomes is still conflicting Tumour flare-up at other sites at the time of neurotoxicity is more likely to be associated with neoplastic invasion of the nervous system rather than an adverse event of ICI…”

“…We and others prefer this term to describe patients with a diffuse CNS dysfunction, as opposed to those with focal syndromes such as limbic, brainstem, or cerebellar encephalitis [13,14]; however, meningoencephalitis cases have been elsewhere defined as encephalitis, nonlimbic encephalitis, diffuse encephalitis or encephalopathy with inflammatory changes [5 ▪▪ ,7,14,24 ▪▪ ,25 ▪ ]. In all cases, common features of post-ICI meningoencephalitis are: acute/subacute mental status alteration, isolated or accompanied by decreased vigilance, fever, seizures, meningism or, more rarely, language impairment, tremor or myoclonus [13,14,24 ▪▪ ,25 ▪ ]; CSF testing showing pleocytosis in nearly all patients, with higher cells counts and protein levels than in focal encephalitis [7,12–14]; negative neural antibody tests, except for anti-GFAP antibodies in a subgroup of patients [12,13,14,24 ▪▪ ,25 ▪ ] (of note, unbiased antibody testing methods may reveal brain reactivities with unknown antigen specificity in some patients [14,26]); generally normal brain MRI, except for occasional leptomeningeal or pachymeningeal contrast enhancement and/or brain parenchymal patchy T2/FLAIR hyperintensities [7,7,13,14,26] (Fig.…”

“…1); more frequent concomitant nonneurological toxicities than in focal encephalitis [14,24 ▪▪ ]; and mostly favourable outcomes (50–90%) after ICI discontinuation and immunomodulation [i.e., corticosteroids, intravenous immunoglobulins (IVIG)], plasma exchanges, and, more rarely, immunosuppressants), despite usually high clinical severity at nadir [13,14]. ICI has been reintroduced in some cases, with systematic literature reviews and retrospective observational studies reporting relapses rates ranging between 0% and ∼30% [7,8 ▪ ,22,25 ▪ ]. Additionally, relapses at corticosteroids tapering have also been described [9,13].…”

“…Because even severe ICI neurotoxicities can recover on immune suppressive treatment, the possibility of restarting the ICIs should always be considered after resolution of the neurological toxicity, especially considering the high mortality related to tumour progression in these patients [8 ▪ ,24 ▪▪ ]. The risk of neurological relapse is still poorly defined, but appears low on the few retrospective data available [7,8 ▪ ,22,24 ▪▪ ]. Reintroduction of ICI should therefore only be considered after neurological improvement, weighed up against the risk of tumour recurrence, alternative anticancer therapies, and the patient's neurological functional reserve.…”

“…By activating the immune system in a nonspecific manner, ICI also trigger immune-related adverse events (irAEs) in 14-55% of patients [2], with possible involvement of any organ system, including the central nervous system (CNS-irAEs) [3]. CNS-irAEs are rare (1% of the patients, which might increase to up to 5% in case of combined PD(L)-1 and CTLA-4 inhibitor therapy [4,5 && ,6]), but are highly relevant to the neurologist due to the diagnostic challenges they pose, and their high disability burden and fatality rates (10-20% of post-ICI encephalitis patients [7,8 In this review, we will discuss the principles of diagnosis and management of CNS-irAEs, describe their clinical spectrum, and analyse their intersection with spontaneous CNS autoimmune disorders.…”