Paraneoplastic neurologic disorders (PNDs) are cancer-related syndromes that can affect any part of the nervous system (Table 50-1). They are caused by mechanisms other than metastasis or by any of the complications of cancer such as coagulopathy, stroke, metabolic and nutritional conditions, infections, and side effects of cancer therapy. In 60% of patients, the neurologic symptoms precede the cancer diagnosis. Clinically disabling PNDs occur in 0.5–1% of all cancer patients, but they affect 2–3% of patients with neuroblastoma or small-cell lung cancer (SCLC) and 30–50% of patients with thymoma or sclerotic myeloma.
| CLASSIC SYNDROMES: USUALLY OCCUR WITH CANCER ASSOCIATION | NONCLASSIC SYNDROMES: MAY OCCUR WITH AND WITHOUT CANCER ASSOCIATION |
|---|---|
Encephalomyelitis Limbic encephalitis Cerebellar degeneration (adults) Opsoclonus-myoclonus Subacute sensory neuronopathy Gastrointestinal paresis or pseudo-obstruction Dermatomyositis (adults) Lambert-Eaton myasthenic syndrome Cancer- or melanoma-associated retinopathy | Brainstem encephalitis Stiff-person syndrome Necrotizing myelopathy Motor neuron disease Guillain-Barré syndrome Subacute and chronic mixed sensory-motor neuropathies Neuropathy associated with plasma cell dyscrasias and lymphoma Vasculitis of nerve Pure autonomic neuropathy Acute necrotizing myopathy Polymyositis Vasculitis of muscle Optic neuropathy BDUMP |
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 50-2). These antibodies react with the patient’s tumor, and their detection in serum or cerebrospinal fluid (CSF) usually predicts the presence of cancer. When the antigens are intracellular, most syndromes are associated with extensive 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.
| ANTIBODY | ASSOCIATED NEUROLOGIC SYNDROME(S) | TUMORS |
|---|---|---|
| Anti-Hu (ANNA1) | Encephalomyelitis, subacute sensory neuronopathy | SCLC |
| Anti-Yo (PCA1) | Cerebellar degeneration | Ovary, breast |
| Anti-Ri (ANNA2) | Cerebellar degeneration, opsoclonus, brainstem encephalitis | Breast, gynecologic, SCLC |
| Anti-Tr | Cerebellar degeneration | Hodgkin’s lymphoma |
| Anti-CRMP5 (CV2) | Encephalomyelitis, chorea, optic neuritis, uveitis, peripheral neuropathy | SCLC, thymoma, other |
| Anti-Ma proteins | Limbic, hypothalamic, brainstem encephalitis | Testicular (Ma2), other (Ma) |
| Anti-amphiphysin | Stiff-person syndrome, encephalomyelitis | Breast, SCLC |
| Recoverin, bipolar cell antibodies, othersa | Cancer-associated retinopathy (CAR) Melanoma-associated retinopathy (MAR) | SCLC (CAR), melanoma (MAR) |
| Anti-GAD | Stiff-person, cerebellar syndromes, limbic encephalitis | Infrequent tumor association (thymoma) |
In contrast to the disorders associated with immune responses against intracellular antigens, those associated with antibodies to antigens expressed on the neuronal cell surface of the CNS or at the neuromuscular junction are more responsive to immunotherapy (Table 50-3, Fig. 50-1). These disorders occur with and without a cancer association and may affect children and young adults, and there is increasing evidence that they are mediated by the antibodies.
| ANTIBODY | NEUROLOGIC SYNDROME | TUMOR TYPE WHEN ASSOCIATED |
|---|---|---|
| Anti-AChR (muscle)a | Myasthenia gravis | Thymoma |
| Anti-AChR (neuronal)a | Autonomic ganglionopathy | SCLC |
| Anti-VGCCb | LEMS, cerebellar degeneration | SCLC |
| Anti-NMDARa | Anti-NMDAR encephalitis | Teratoma in young women (children and men rarely have tumors) |
| Anti-LGI1c | Limbic encephalitis, hyponatremia, faciobrachial tonic or dystonic seizures | Rarely thymoma |
| Anti-Caspr2c | Morvan’s syndrome, neuromyotonia | Thymoma, prostate cancer |
| Anti-GABABRd | Limbic encephalitis, seizures | SCLC, neuroendocrine |
| Anti-GABAARd | Encephalitis with prominent seizures and status epilepticus; less often opsoclonus and stiff-person syndrome | Rarely thymoma |
| Anti-AMPARd | Limbic encephalitis with relapses | SCLC, thymoma, breast |
| Glycine receptord | Encephalomyelitis with rigidity, stiff-person syndrome | Rarely, thymoma, lung cancer |
| Anti-DPPXd | Agitation, myoclonus, tremor, seizures, hyperekplexia, encephalomyelitis with rigidity | No cancer, but frequent diarrhea or cachexia suggesting paraneoplasia |
FIGURE 50-1
Antibodies to the GluN1 subunit of the N-methyl-d-aspartate (NMDA) receptor in a patient with anti-NMDA receptor encephalitis and ovarian teratoma. (A) Coronal section of rat brain immunolabeled (green fluorescence) with the patient’s antibodies. The reactivity predominates in the hippocampus, which is highly enriched in NMDA receptors. (B) This image shows the antibody reactivity with cultures of rat hippocampal neurons; the intense green immunolabeling is due to the antibodies against the GluN1 subunit of NMDA receptors. (C–E) Images of HEK cells (a human kidney cell line) transfected to express NMDA receptors, showing reactivity with patient’s antibodies (C) and with a commercial monoclonal antibody against NMDA receptors (E); the patient’s antibody reactivity co-labels only the cells that express NMDA receptors (D). (From J Dalmau et al: Lancet Neurol 7:1091, 2008; with permission.)
Other PNDs are likely immune-mediated, although their antigens are unknown. These include several syndromes of inflammatory neuropathies and myopathies. In addition, many patients with typical PND syndromes are antibody-negative.
For still other PNDs, the cause remains quite obscure. These include, among others, several neuropathies that occur in the terminal stages of cancer and a number of neuropathies associated with plasma cell dyscrasias or lymphoma without evidence of inflammatory infiltrates or deposits of immunoglobulin, cryoglobulin, or amyloid.
Approach to the Patient: Paraneoplastic Neurologic Disorders
Three key concepts are important for the diagnosis and management of PNDs. First, it is common for symptoms to appear before the presence of a tumor is known; second, the neurologic syndrome usually develops rapidly, producing severe deficits in a short period of time; and third, there is evidence that prompt tumor control improves the neurologic outcome. Therefore, the major concern of the physician is to recognize a disorder promptly as paraneoplastic and to identify and treat the tumor.
PND OF THE CENTRAL NERVOUS SYSTEM AND DORSAL ROOT GANGLIAWhen symptoms involve brain, spinal cord, or dorsal root ganglia, the suspicion of PND is usually based on a combination of clinical, radiologic, and CSF findings. Presence of antineuronal antibodies (Tables 50-2 and 50-3) may help in the diagnosis, but only 60–70% of PNDs of the CNS and less than 20% of those involving the peripheral nervous system have neuronal or neuromuscular junction antibodies that can be used as diagnostic tests.
Magnetic resonance imaging (MRI) and CSF studies are important to rule out neurologic complications due to the direct spread of cancer, particularly metastatic and leptomeningeal disease. In most PNDs, the MRI findings are nonspecific. Paraneoplastic limbic encephalitis is usually associated with characteristic MRI abnormalities in the mesial temporal lobes (see below), but similar findings can occur with other disorders (e.g., nonparaneoplastic autoimmune limbic encephalitis and human herpesvirus type 6 [HHV-6] encephalitis) (Fig. 50-2). The CSF profile of patients with PND of the CNS or dorsal root ganglia typically consists of mild to moderate pleocytosis (<200 mononuclear cells, predominantly lymphocytes), an increase in the protein concentration, and a variable presence of oligoclonal bands. There are no specific electrophysiologic tests that are diagnostic of PND. Moreover, a biopsy of the affected tissue is often difficult to obtain, and although useful to rule out other disorders (e.g., metastasis) the pathologic findings are not specific for PND.
PND OF NERVE AND MUSCLEIf symptoms involve peripheral nerve, neuromuscular junction, or muscle, the diagnosis of a specific PND is usually established on clinical, electrophysiologic, and pathologic grounds. The clinical history, accompanying symptoms (e.g., anorexia, weight loss), and type of syndrome dictate the studies and degree of effort needed to demonstrate a neoplasm. For example, the frequent association of Lambert-Eaton myasthenic syndrome (LEMS) with SCLC should lead to a chest and abdomen computed tomography (CT) or body positron emission tomography (PET) scan and, if negative, periodic tumor screening for at least 3 years after the neurologic diagnosis. In contrast, the weak association of polymyositis with cancer calls into question the need for repeated cancer screenings in this situation. Serum and urine immunofixation studies should be considered in patients with peripheral neuropathy of unknown cause; detection of a monoclonal gammopathy suggests the need for additional studies to uncover a B cell or plasma cell malignancy. In paraneoplastic neuropathies, diagnostically useful antineuronal antibodies are limited to anti-CV2/CRMP5 and anti-Hu.
For any type of PND, if antineuronal antibodies are negative, the diagnosis relies on the demonstration of cancer and the exclusion of other cancer-related or independent neurologic disorders. Combined CT and PET scans often uncover tumors undetected by other tests. For germ cell tumors of the testis and teratomas of the ovary, ultrasound and CT or MRI of the abdomen and pelvis may reveal tumors undetectable by PET.
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