Central nervous system adverse events of immune checkpoint inhibitors

Abstract

Purpose of review Immune checkpoint inhibitors (ICI) may trigger immune-related adverse events which rarely affect the central nervous system (CNS-irAEs). Over the past few years, cumulative data have led to the characterization of well defined syndromes with distinct cancer and antibody associations as well as different outcomes. Recent findings The most frequent CNS-irAE is encephalitis, which includes three main groups: meningoencephalitis, a nonfocal syndrome usually responsive to corticosteroids; limbic encephalitis, associated with high-risk paraneoplastic neurological syndromes (PNS) antibodies (e.g. anti-Hu, anti-Ma2) and neuroendocrine cancers, characterized by poor treatment response and outcomes; and cerebellar ataxia, with variable outcomes (worse when high-risk PNS antibodies are detected). Additionally, a diffuse encephalopathy without inflammatory findings, with poor response to corticosteroids and high mortality has been described. The spectrum of CNS-irAEs also includes meningitis, myelitis, and rarer presentations. A subset of CNS-irAEs (i.e. limbic encephalitis and/or rapidly progressive cerebellar ataxia) is undistinguishable from ICI-naïve PNS. Summary The clinical and outcomes diversity of CNS-irAEs suggests different pathogenic mechanisms, which need to be understood to establish more effective and specific treatment modalities. It is crucial to identify biomarkers able to predict which patients will experience severe CNS-irAEs, to anticipate their diagnosis, and to predict long-term outcomes.

Neurological Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors

“…Currently, myositis, sometimes with concurrent myasthenic symptoms and myocarditis, and neuropathies, including GBS and variants, are the most common clinical presentations. Although CNS involvement is less frequently seen, it carries a significant risk of long-lasting disability and mortality [ 43 , 52 , 87 , 95 ].…”

“…Unfavorable treatment outcomes are reported in about 30% of cases, and the risk factors include advanced age, aggressive malignancy, high severity of symptoms at onset, concurrent myocarditis, CNS involvement (particularly, focal encephalitis), presence of antineuronal antibodies targeting intracellular antigens, and ICI administration in individuals with previous paraneoplastic autoantibodies and/or autoimmune disorders [ 66 , 73 , 86 , 87 , 88 , 89 ]. In case of corticosteroid resistance (lack of response within 10–14 days of treatment), and in individuals with negative prognostic factors, as well as in all cases of GBS and MG, rapid escalation to intravenous immunoglobulins (IVIG) (2 mg/kg/day for 3–5 days) or plasmapheresis (5–7 sessions) is advocated [ 47 ].…”

“…In refractory or relapsing cases, escalation to second-line therapies is prudent and includes options such as abatacept, mycophenolate mofetil, tacrolimus, azathioprine, cyclophosphamide, rituximab, bortezomib, infliximab, tocilizumab, and natalizumab. The optimal choice should be guided by the presumed pathophysiological mechanism of the disorder and an individual’s comorbidities [ 87 ]. Figure 4 and Figure 5 summarize the recommended management of common neurological irAEs.…”