Paraneoplastic Neurological Syndromes

Paraneoplastic neurological syndromes (PNS) are immune-mediated disorders triggered by cancer that may affect any level of the nervous system and often associated with autoantibodies targeting either intracellular or extracellular neural antigens. Recently, the diagnostic criteria for PNS have been updated in order to highlight the need for a clear causal relationship with cancer to confirm PNS, as well as the relevance of congruent clinical-immunological-oncological associations. Such updated diagnostic criteria are consequently based on the so-labeled PNS-Care score, which comprises three axes: neurological phenotype, antibody status, and cancer; three levels of risk (high, intermediate, and low) were proposed for the phenotypes and the antibodies according to the strength of their association with cancer. High-risk phenotypes include those that, despite not being pathognomonic, are highly suggestive of a paraneoplastic etiology, whereas intermediate-risk phenotypes consist of syndromes that are usually immune-mediated but less often related to cancer. Similarly, high-risk antibodies are strongly associated with cancer (>70%), while the frequency of underlying tumors is lower for intermediate-risk antibodies (30–70%). Another notable difference is that high-risk antibodies generally target intracellular antigens and, therefore, have no direct pathogenic role; they constitute, however, very useful biomarkers for PNS diagnosis. Conversely, intermediate-risk antibodies recognize cell surface antigens and are thought to play a direct role in the pathogenesis. Finally, both low-risk phenotypes and low-risk antibodies include those with no epidemiological association with cancer. PNS diagnosis largely relies on neural antibody detection, which must be conducted using the right specimens and techniques. Similarly, appropriate tumor screening should be undertaken, since most PNS are diagnosed before the underlying cancer is known. PNS physiopathology is so far poorly understood, but novel findings in certain types of PNS support that genetic alterations in the tumors may play an important role, leading to an abnormal expression of neural antigens followed by a crossed immune reaction between the nervous system and cancer. This hypothesis is further suggested by the development of PNS-like complications after the use of immune-checkpoint inhibitors as enhancers of the anti-tumor immune response during cancer treatment. The treatment of PNS principally consists of tumor removal and immunotherapy. Despite early interventions being able to achieve good outcomes in PNS associated with intermediate-risk antibodies, most of those related to high-risk antibodies usually carry an ominous prognosis.