Paraneoplastic Neurological Syndromes of the Central Nervous System: Pathophysiology, Diagnosis, and Treatment

Abstract

Paraneoplastic neurological syndromes (PNS) include any symptomatic and non-metastatic neurological manifestations associated with a neoplasm. PNS associated with antibodies against intracellular antigens, known as "high-risk" antibodies, show frequent association with underlying cancer. PNS associated with antibodies against neural surface antigens, known as "intermediate- or low-risk" antibodies, are less frequently associated with cancer. In this narrative review, we will focus on PNS of the central nervous system (CNS). Clinicians should have a high index of suspicion with acute/subacute encephalopathies to achieve a prompt diagnosis and treatment. PNS of the CNS exhibit a range of overlapping "high-risk" clinical syndromes, including but not limited to latent and overt rapidly progressive cerebellar syndrome, opsoclonus-myoclonus-ataxia syndrome, paraneoplastic (and limbic) encephalitis/encephalomyelitis, and stiff-person spectrum disorders. Some of these phenotypes may also arise from recent anti-cancer treatments, namely immune-checkpoint inhibitors and CAR T-cell therapies, as a consequence of boosting of the immune system against cancer cells. Here, we highlight the clinical features of PNS of the CNS, their associated tumors and antibodies, and the diagnostic and therapeutic strategies. The potential and the advance of this review consists on a broad description on how the field of PNS of the CNS is constantly expanding with newly discovered antibodies and syndromes. Standardized diagnostic criteria and disease biomarkers are fundamental to quickly recognize PNS to allow prompt treatment initiation, thus improving the long-term outcome of these conditions.

Keywords: CAR T-cell therapies; ataxia; central nervous system; epilepsy; immune suppressants; immune-checkpoint inhibitors; movement disorders; neurology; oncology; paraneoplastic neurological syndromes.

Figure 1

Main classes of antibodies, their associated cancer risk, and response to therapies. The figure schematizes the two main classes of antibodies found in paraneoplastic syndromes.

Figure 2

PD1/PD-L1 interaction and immune-checkpoint inhibitors for cancer treatment. In the absence of immune-checkpoint inhibitors, the binding between PD1 and PD-L1 on T-cells and cancer cells, respectively, prevents the activation of T-cells. In presence of anti-PD1 antibodies (ICIs), the T-cell is activated against cancer cells and promotes their death through different immune-mediated pathways. These may generate immune-mediated adverse events.

Figure 3

CAR T-cell therapies for cancer treatment. CAR T interacts with cancer cell’s antigen (1); it then activates a co-stimulatory signal which stimulates the synthesis, transcription, and translation of perforins and granzymes (2, 3) that ultimately kill the cancer cell (4).

Figure 4

Main paraneoplastic syndromes and related antibodies. The figure illustrates the main paraneoplastic syndromes, their associated antibodies, and their risk of associated malignancy.