Paraneoplastic Neurological Syndromes and Beyond Emerging With the Introduction of Immune Checkpoint Inhibitor Cancer Immunotherapy

Abstract

Paraneoplastic neurological syndromes are more commonly seen with malignancies such as small cell lung cancer, thymoma, gynecological malignancies, and breast cancer as well as seminoma. With the introduction of immune checkpoint inhibitor (ICI) cancer immunotherapy we see an increase of autoimmune neurological complications in patients with malignancies not traditionally associated with paraneoplastic neurological syndromes, such as melanoma and renal cell carcinoma. Immune checkpoint inhibitors enhance antitumor immune responses resulting often in immune-related adverse effects that can affect any organ, including the central and peripheral nervous system, neuromuscular junction and muscle. Neurological complications are rare; neuromuscular complications are more common than central nervous system ones but multifocal neurological presentations are often encountered. The vast majority of neurological complications appear within 3 months of ICI initiation, but have been described even after ICI cessation. Neural autoantibody testing reveals autoantibodies in approximately half of the patients with CNS complications. Early suspicion and diagnosis is critical to avoid worsening and improve outcomes. Therapeutic strategies depend on the severity of the symptoms and initially typically involve discontinuation of ICI and high dose steroids. Further immunosuppression might be necessary. Outcomes are dependent on patient's characteristics and clinical presentations.

Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis

“…The advent of immune checkpoint inhibitors as treatments for advanced malignancy has been accompanied by the unintended induction of several categories of autoimmune neurological disease including meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome, and myositis (114). In addition, the use of these agents has resulted in cases of disorders classically considered paraneoplastic, including sensory neuronopathy, limbic encephalitis, and cerebellar syndrome (115)(116)(117)(118)(119)(120). The major antibodies detected have been anti-Hu, and anti-Ma2, although single cases have been associated with anti-Ri, anti-CRMP5, anti-PCA-2, anti-GAD65, and other antibodies (119,(121)(122)(123)(124)(125)(126).…”

Immunotherapy in Ovarian Cancer

“…Those disorders may include, for instance, dermatomyositis and paraneoplastic neurological syndromes (Requena et al 2014;Zaborowski et al 2015). It has already been observed that immunotherapy may also induce those conditions (Valencia-Sanchez and Zekeridou, 2021). For example, severe encephalitis affected a patient with recurrent clear cell ovarian cancer treated with nivolumab (anti-PD1 immunotherapy) (Burke et al 2018).…”

Plasma exchange for severe immune-related adverse events from checkpoint inhibitors: an early window of opportunity?

“…There are many other neurological syndromes that may be mediated by autoantibodies, including paraneoplastic disorders such as limbic encephalitis or subacute cerebellar ataxia. Commercially available antibody testing only detects a known antibody in approximately half of the patients, raising the possibility of unidentified antibodies driving pathogenesis [ 73 ]. There are several cases of severe irAE encephalitis that have been successfully managed with PLEX, and in some cases, IVIG [ 58 , 59 ].…”