Neurologic Toxicity of Immune Checkpoint Inhibitors: A Review of Literature

Abstract

Immune checkpoint inhibitors have entailed a change of paradigm in the management of multiple malignant diseases and are acquiring a key role in an increasing number of clinical sceneries. However, since their mechanism of action is not limited to the tumor microenvironment, their systemic activity may lead to a wide spectrum of immune-related side effects. Although neurological adverse events are much less frequent than gastrointestinal, hepatic, or lung toxicity, with an incidence of <5%, their potential severity and consequent interruptions to cancer treatment make them of particular importance. Despite them mainly implying peripheral neuropathies, immunotherapy has also been associated with an increased risk of encephalitis and paraneoplastic disorders affecting the central nervous system, often appearing in a clinical context where the appropriate diagnosis and early management of neuropsychiatric symptoms can be challenging. Although the pathogenesis of these complications is not fully understood yet, the blockade of tumoral inhibitory signals, and therefore the elicitation of cytotoxic T-cell-mediated response, seems to play a decisive role. The aim of this review was to summarize the current knowledge about the pathogenic mechanisms, clinical manifestations, and therapeutic recommendations regarding the main forms of neurotoxicity related to checkpoint inhibitors.

A Systematic Review of Neurologic Toxicity and Psychiatric Adverse Events associated with Immune Checkpoint Inhibitors

“…The incidence of nAEs may be lower than that of other irAEs due to the unique anatomy of the nervous system, including the blood-brain and blood-nerve barriers, microglia, and other resident cells in the tumor microenvironment [8]. Additionally, most reported nAEs are low-grade, and the incidence of grade 3-4 nAEs increased after the use of anti-CTLA-4 treatment [12].…”

“…Additionally, most reported nAEs are low-grade, and the incidence of grade 3-4 nAEs increased after the use of anti-CTLA-4 treatment [12]. However, the exact mechanism by which ICIs cause neurotoxicity remains unknown [8]. Because various cells in the central nervous system express PD-1 and CTLA-4, they are also targeted by ICIs and may cause neuropsychiatric-related AEs [13].…”

“…Because various cells in the central nervous system express PD-1 and CTLA-4, they are also targeted by ICIs and may cause neuropsychiatric-related AEs [13]. Many studies have shown that molecular mimics, epitope spreading, paraneoplastic neurological syndrome, previous history of autoimmune diseases, and genetic differences among individuals may influence the occurrence of nAEs [8]. Herein, we will discuss nAEs of the central nervous system and the peripheral nervous system separately.…”

“…The incidence of neuropsychiatric irAEs is relatively low for ICIs. Neuropsychiatric irAEs can cause a variety of diseases in the central and peripheral nervous systems [8]. At present, studies of neuropsychiatric irAEs are rare.…”

“…At present, studies of neuropsychiatric irAEs are rare. A number of studies only focus on neurological irAEs (nAEs) highly associated with ICIs, and these have been systematically reviewed [8][9][10][11]. However, there is no comprehensive summary of the psychiatric irAEs (pAEs) associated with ICIs.…”