Neurological adverse events of immune checkpoint inhibitors: An update of clinical presentations, diagnosis, and management

Immune checkpoints are negative regulators of T cells that may be hijacked by cancer cells to evade immune surveillance [1]. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies targeting these molecules, namely cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand programmed death-ligand 1 (PDL-1) [1]. While CTLA-4 is expressed by activated T cells and interferes with T cell priming in lymph nodes; PD1 is expressed by effector T cells and the interaction with its ligand PD-L1, expressed under inflammatory conditions by many somatic- and tumor-cells, leads to suppression of effector T cell responses in the periphery [1]. By overcoming immune system inhibition, ICIs induce an efficient anti-tumor response with well-demonstrated therapeutic efficacy [1], [2]. The downside is the occurrence of immune-related adverse events (irAEs) in up to 60% of patients, potentially involving any organ system but especially the skin, gastrointestinal tract, endocrine system, and liver [2]. The severity of irAEs is graded by the Common Terminology Criteria for Adverse Events (CTCAE); that ranges from 1.0 (mild: symptoms interfering with activity daily or instrumental life) to 5.0 (death due to the symptoms) [3]. Although rarer than other toxicities, severe (CTCAE grade > 2) neurological irAEs (n-irAEs) occur in a not negligible proportion of treated patients (1–3%) [4], [5], and they represent, together with cardiac toxicity, the deadliest adverse events of ICIs [6]. This review aims to provide an updated illustration of the most reported and best characterized n-irAEs. We also discuss the essential parts of the diagnostic approach, and we provide general recommendations for the management of these disorders.

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