Chapter 097. Paraneoplastic Neurologic Syndromes (Part 2) potx

Paraneoplastic Neurologic Syndromes Part 2 Pathogenesis Most PNDs are mediated by immune responses triggered by neuronal proteins onconeuronal antigens expressed by tumors.. These ant

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

Cancers

Anti-Hu

(ANNA-1)

PEM (including cortical, limbic, brainstem encephalitis, cerebellar dysfunction, myelitis), PSN, autonomic dysfunction

SCLC, other neuroendocrine tumors

Anti-Yo

(PCA-1)

gynecologic cancers, breast

Anti-Ri

(ANNA-2)

encephalitis, opsoclonus-myoclonus

Breast, gynecological, SCLC

lymphoma

Anti-Zic PCD, encephalomyelitis SCLC and other

neuroendocrine tumors

Anti-CV2/CRMP5

PEM, PCD, chorea, peripheral neuropathy, uveitis

SCLC, thymoma, other

Anti-Ma

proteinsa

Limbic, hypothalamic, brainstem encephalitis (infrequently PCD)

Germ-cell tumors

of testis, lung cancer, other solid tumors

Anti-NR1/NR2subunits of

Encephalitis with prominent psychiatric symptoms,

Ovarian teratoma

NMDA receptor

seizures, hypoventilation

Anti-amphiphysin

Stiff-person syndrome, PEM

Breast, SCLC

Anti-VGKCb Peripheral nerve

hyperexcitability (neuromyotonia), limbic encephalitis

Thymoma, SCLC, others

Anti-recoverin Cancer-associated

retinopathy (CAR)

SCLC and other

Anti-bipolar

cells of the retina

Melanoma-associated retinopathy (MAR)

Melanoma

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-voltage-gated

potassium channel; SCLC, small-cell lung cancer; NMDA, N-methyl-D-aspartate