Paraneoplastic Neurological Disorders

Paraneoplastic syndromes are rare disorders that occur remote from a malignant neoplasm or metastases and can affect any organ system (Tarin D, Cancer Metastasis Rev, 32:707-721, 2013). Well-described paraneoplastic disorders include cancer cachexia, hypercalcemia, syndrome of inappropriate antidiuretic hormone secretion, and Lambert-Eaton myasthenic syndrome (Pelosof LC, Gerber DE, Mayo Clin Proc, 85:838-854, 2010). Collectively, paraneoplastic syndromes can affect up to 70% of cancer patients, with neurological paraneoplastic disorders affecting approximately 0.01-0.2%, though this is likely an underestimate (Dalmau J, Rosenfeld MR, Lancet Neurol, 7:327-340, 2008). In general, paraneoplastic disorders are the result of two main process: (1) synthesis and secretion of cytokines, hormones, or bioactive molecules and (2) immune reactions to tumor-related antigens (Pelosof LC, Gerber DE, Mayo Clin Proc, 85:838-854, 2010). Paraneoplastic neurological disorders (PNDs) predominately affect the nervous system and are almost all the product of an immune response to onconeural antigens of tumors that cross-react with the nervous system (Iorio R, Lennon VA, Immunol Rev, 248:104-121, 2012). PNDs are often the first sign of an asymptomatic or occult cancer and/or cancer relapse (Titulaer MJ, Soffietti R, Dalmau J, Gilhus NE, Giometto B, Graus F, Eur J Neurol, 18:19-e3, 2011). Neurological immune-related adverse events (nirAEs) following immune checkpoint inhibitor (ICI) treatment for cancer are similar in many respects to PNDs (Cuzzubbo S, Javeri F, Tissier M, Roumi A, Barlog C, Doridam J, Eur J Cancer, 73:1-8, 2017). Given the expanding use of ICI in the treatment of a variety of cancers and since PNDs can present at diagnosis, treatment, and relapse of cancer, it is crucial for both neurologists and oncologists to be familiar with the presentation and pathophysiology of PNDs. This chapter will review the presentation of PNDs, their association with specific autoantibodies and cancers, treatment, pathogenesis, and similarities with nirAEs following ICI therapy for cancer.