Antibodies to neural cell surface and synaptic proteins in paraneoplastic neurologic syndromes

Among patients with paraneoplastic neurologic syndromes (PNS), emphasis has historically been placed on neural antibodies against intracellular proteins that have a strong association with malignancy. Because of the intracellular location of their antigenic targets, these antibodies are typically considered to be non-pathogenic surrogate markers of immune cell-mediated neural injury. Unfortunately, patients with these antibodies often have suboptimal response to immunotherapy and poor prognosis. Over the last two decades, however, dramatic advancements have been made in the discovery and clinical characterization of neural antibodies against extracellular targets. These antibodies are generally considered to be pathogenic, given their potential to directly alter antigen structure or function, and patients with these antibodies often respond favorably to prompt immunotherapy. These antibodies also associate with tumors and may thus occur as PNS, albeit more variably than neural antibodies against intracellular targets. The updated 2021 PNS diagnostic criteria, which classifies antibodies as high-risk, intermediate-risk, or lower-risk for an associated cancer, better clarifies how neural antibodies against extracellular targets relate to PNS. Using this recently created framework, the clinical presentations, ancillary test findings, oncologic associations, and treatment responses of syndromes associated with these antibodies are discussed.