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Chapter 097. Paraneoplastic Neurologic Syndromes (Part 2)

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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...

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  1. 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
  2. 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 PEM (including cortical, SCLC, other (ANNA-1) limbic, brainstem encephalitis, neuroendocrine tumors cerebellar dysfunction, myelitis), PSN, autonomic dysfunction Anti-Yo PCD Ovary and other (PCA-1) gynecologic cancers, breast
  3. Anti-Ri PCD, brainstem Breast, (ANNA-2) encephalitis, opsoclonus- gynecological, SCLC myoclonus Anti-Tr PCD Hodgkin's lymphoma Anti-Zic PCD, encephalomyelitis SCLC and other neuroendocrine tumors Anti- PEM, PCD, chorea, SCLC, thymoma, CV2/CRMP5 peripheral neuropathy, uveitis other Anti-Ma Limbic, hypothalamic, Germ-cell tumors proteinsa brainstem encephalitis of testis, lung cancer, (infrequently PCD) other solid tumors Anti- Encephalitis with Ovarian teratoma NR1/NR2 subunits of prominent psychiatric symptoms,
  4. NMDA receptor seizures, hypoventilation Anti- Stiff-person syndrome, Breast, SCLC amphiphysin PEM Anti-VGCCb LEMS, PCD SCLC, lymphoma Anti-AChRb MG Thymoma Anti-VGKCb Peripheral nerve Thymoma, hyperexcitability SCLC, others (neuromyotonia), limbic encephalitis Anti-recoverin Cancer-associated SCLC and other retinopathy (CAR) Anti-bipolar Melanoma-associated Melanoma cells of the retina retinopathy (MAR)
  5. a Patients with antibodies to Ma2 are usually men with testicular cancer. Patients with additional antibodies to other Ma proteins are men or women with a variety of solid tumors. b These antibodies can occur with or without a cancer association. Note: PEM: paraneoplastic encephalomyelitis; PCD, paraneoplastic cerebellar degeneration; PSN, paraneoplastic sensory neuronopathy; LEMS, Lambert-Eaton myasthenic syndrome; MG, myasthenia gravis; VGCC, voltage- gated calcium channel; AChR, acetylcholine receptor; VGKC, voltage-gated potassium channel; SCLC, small-cell lung cancer; NMDA, N-methyl-D-aspartate.
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