Pathogenesis Most PNDs are mediated by immune responses triggered by neuronal proteins (onconeuronal antigens) expressed by tumors. In PNDs of the central nervous system (CNS), many antibody-associated immune responses have been identified (Table 97-2). These antibodies usually react with the patient's tumor, and their detection in serum or cerebrospinal fluid (CSF) strongly predicts the presence of cancer. The target antigens are usually intracellular proteins with roles in neuronal development and function. Some of the antibodies react with epitopes located in critical protein domains, disrupting protein function and leading to neuronal apoptosis. In addition to onconeuronal antibodies, most PNDs of the. | Chapter 097. Paraneoplastic Neurologic Syndromes Part 2 Pathogenesis Most PNDs are mediated by immune responses triggered by neuronal proteins onconeuronal antigens expressed by tumors. In PNDs of the central nervous system CNS many antibody-associated immune responses have been identified Table 97-2 . These antibodies usually react with the patient s tumor and their detection in serum or cerebrospinal fluid CSF strongly predicts the presence of cancer. The target antigens are usually intracellular proteins with roles in neuronal development and function. Some of the antibodies react with epitopes located in critical protein domains disrupting protein function and leading to neuronal apoptosis. In addition to onconeuronal antibodies most PNDs of the CNS are associated with infiltrates of CD4 and CD8 T cells microglial activation gliosis and variable neuronal loss. The infiltrating T cells are often in close contact with neurons undergoing degeneration suggesting a primary pathogenic role. T cell-mediated cytotoxicity may contribute directly to cell death in these PNDs. Thus both humoral and cellular immune mechanisms participate in the pathogenesis of many PNDs. This complex immunopathogenesis may underlie the resistance of many of these conditions to therapy. Table 97-2 Paraneoplastic Antineuronal Antibodies Associated Syndromes and Cancers Antibody Syndrome Associated Cancers Anti-Hu ANNA-1 PEM including cortical limbic brainstem encephalitis cerebellar dysfunction myelitis PSN autonomic dysfunction SCLC other neuroendocrine tumors Anti-Y o PCA-1 PCD Ovary and other gynecologic cancers breast Anti-Ri ANNA-2 PCD brainstem encephalitis opsoclonus- myoclonus Breast gynecological SCLC Anti-Tr PCD Hodgkin s lymphoma Anti-Zic PCD encephalomyelitis SCLC and other neuroendocrine tumors Anti- CV2 CRMP5 PEM PCD chorea peripheral neuropathy uveitis SCLC thymoma other Anti-Ma proteins Limbic hypothalamic brainstem encephalitis infrequently PCD Germ-cell tumors of testis lung
