Review: Peripheral Nerves and Paraneoplasia
Abstract & Commentary
By Michael Rubin, MD Dr. Rubin is Professor of Clinical Neurology, New York-Presbyterian Hospital, Cornell Campus. Dr. Rubin is on the speaker's bureau for Athena Diagnostics, and does research for Pfizer and Merck.
Synopsis: Whole body fluorodeoxyglucose positron emission tomography scanning helps uncover the associated tumor, and recently proposed criteria may assist in the diagnosis. In many instances, prompt treatment of the tumor and immunotherapy result in symptom stabilization or neurologic improvement.
Source: Rudnicki SA, Dalmau J. Paraneoplastic Syndromes of the Peripheral Nerves. Curr Opin Neurol. 2005;18;598-603.
Paraneoplastic involvement of peripheral sensory or motor nerves, a rare complication of cancer, is the subject of this review. Acute inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, of either the axonal or demyelinating variety, has been associated, in 2% of cases, with Hodgkin's disease more so than with other malignancies. Non-small-cell lung cancer, leukemia, renal, esophageal, and vocal cord cancer have also been reported. Onconeural antibodies, paraneoplastic antibodies produced by the body as an immune response against a tumor antigen but often producing neural injury instead, were not found in 4 of 4 patients studied. Miller-Fisher syndrome, associated with anti-GQ1b antibody, has been reported following immunotherapy with MAGE-3 for melanoma. Steroid therapy resulted in neurological improvement. Chronic inflammatory demyelinating polyneuropathy, apart from plasma cell dyscrasias, is rarely associated with cancer, but has been reported with breast, pancreatic, colon, and liver cancer. Onconeural antibodies were absent.
Cancer is not associated with an increased incidence of motor neuron disease, but the latter may occur as a paraneoplastic manifestation of the former. Purely lower motor neuron disease was reported in a 72-year-old woman with breast cancer. Antibodies to axon initial segments and nodes of Ranvier were detected in her serum, and she improved neurologically following mastectomy, though not following immunotherapy administered prior to surgery. Renal cell carcinoma has been reported with a lower motor neuron syndrome that also improved postnephrectomy. Primary lateral sclerosis may rarely be associated with cancer of the breast, gall bladder, or duodenum. Multifocal motor neuropathy with conduction block and anti-GM1 and GD1b antibodies, was found in a patient with B-cell lymphoma, but treatment of the lymphoma resulted in symptomatic worsening despite lower antibody titers. Post mortem study supported a paraneoplastic origin of the motor neuropathy with axonal loss, intact anterior horn cells, and no evidence of lymphomatous infiltration of the peripheral nerves.
Subacute sensory neuronopathy (SSN), a paraneoplastic sensory ganglionitis most often associated with small-cell lung cancer and anti-Hu antibodies, but also reported with prostate, breast, pancreatic, neuroendocrine, bladder, and ovarian cancers, comprises the often asymmetric onset of pain and numbness affecting the face, trunk, and extremities. Sensory ataxia and pseudoathetosis may manifest as a consequence of the deafferentation. Motor, autonomic, and central nervous system involvement are also seen in these patients. Prognosis is poor, with a 20% 3-year survival, but neurologic symptoms and signs often improve with treatment of the underlying cancer. Combined sensorimotor neuropathy may be seen in association with the anti-CV2 (CRMP5) antibody, most often in small-cell lung cancer, with axonal or mixed axonal/demyelinating features.
Cramps-fasciculation syndrome, myokymia, continuous muscle fiber activity, Isaacs' syndrome, neuromyotonia, and Morvan's fibrillary chorea comprise a group of neuromuscular disorders sharing peripheral nerve hyperexcitability, any of which may be manifest as a paraneoplastic syndrome, usually with thymoma or small-cell lung cancer, but also with Hodgkin's lymphoma and plasmacytoma. Age over 40 and the presence of voltage-gated potassium-channel (VGKC) and acetylcholine receptor antibodies increase the likelihood of an underlying malignancy.
Mononeuropathy multiplex and painful sensorimotor neuropathy, either one as a manifestation of vasculitis, may be seen, more commonly in elderly men, as a paraneoplastic complication of small-cell lung cancer or, less often, cancer of the colon, bile duct, stomach, kidney, prostate, or tongue.
Peripheral neuropathy as a paraneoplastic syndrome complicates plasma cell dyscrasias, including multiple myeloma, Waldenstrom's macroglobulinemia, Castleman's disease (angiofollicular lymph node hyperplasia), and osteosclerotic myeloma, and may also be seen with monoclonal gammopathy of undetermined significance. Usually demyelinating in nature, and occasionally associated with GD1b or GM1 antibodies, axonal variants are also seen, and some demonstrate amyloid deposition on nerve biopsy.
Commentary
Paraneoplastic syndromes, immune-mediated remote effects of cancer, are rare (except for myasthenia gravis), yet capture attention far beyond their impact. Diagnosis of a paraneoplastic syndrome may be difficult, as it usually predates evidence of the cancer. Certain clues are helpful. Symptoms often develop abruptly, evolve rapidly over days and weeks, render the patient disabled, if not bedridden, and then stabilize within weeks to months (Posner JB. Ann N Y Acad Sci. 2003;998;178-186). When the syndrome affects the central nervous system (CNS), cerebrospinal fluid (CSF) is frequently abnormal, demonstrating lymphocytosis, oligoclonal banding, and IgG elevation, with titers of paraneoplastic antibodies, if present, higher in CSF than serum. Because some patients have antibodies in serum but not CSF, antibody studies in both are recommended. Though persons without paraneoplastic disease may have these antibodies, when encountered in a patient with undiagnosed neurologic disease, paraneoplasia must be suspected. If a patient with a paraneoplastic syndrome is antibody negative, a search for other serologic markers of cancer should include carcinoembryonic antigen (CEA), CA-125, CA-15-3, and prostate specific antigen (PSA). Additional work-up should encompass serum protein immunoelectrophoresis, skeletal survey, chest, abdomen, and pelvis computerized tomography, testicular ultrasound, magnetic resonance imaging, and [(18)F]flouro-2-deoxy-glucose-positron emission tomography (PET) scanning. If the cancer found is not usually associated with a paraneoplastic antibody, search for a second cancer is warranted, particularly if the tumor found does not express the target antigen of the paraneoplastic antibody (Rosenfeld MR, Dalmau J. Curr Treat Options Neurol. 2003;5:69-77).
Why do paraneoplastic syndromes develop? Apparently, they may be the ill-fated, immune-mediated byproduct of the body's attempt to destroy or contain the cancer. Some cancers share protein antigens with CNS tissue and, when they develop, the immune system recognizes them as foreign and may raise an antibody response, which in turn may injure CNS tissue while trying to eradicate the tumor. Several lines of evidence support this hypothesis. Serum antibodies in high titers are present in the serum of patients with paraneoplastic syndromes that react exclusively with antigens in the tumor and nervous tissue. Positive CSF antibody titers indicate they are synthesized within the CNS. They are also reported intraneuronally, but this remains open to question. Patients with paraneoplastic syndromes experience slower tumor growth than their non-paraneoplastic counterparts, and this has now been documented both in the clinic and laboratory. Paraneoplastic antibodies may be responsible for this phenomenon. Finally, blood, CSF, and brain tissue of paraneoplastic patients contain T-cells that are antigen-specific, suggesting that they play a role in etiopathogenesis.
It is worthwhile to note that neuromuscular disease in cancer patients is more common than appreciated, with abnormalities noted on electromyographic (EMG) examination in up to 40% of lung cancer patients, even in the absence of symptoms (Trojaborg W, et al. Brain. 1969;92:71-82). EMG demonstrates fasciculation potentials and myokymic discharges in 60-70% of patients with radiation-induced nerve injury, and chronic changes in the form of large amplitude, long-duration polyphasic motor unit potentials are seen in most patients with either radiation or carcinomatous plexopathy. Electrophysiologic studies, thus, have a central role in the diagnosis of these disorders.
Not to be overlooked is the fact that muscle wasting per se, cancer cachexia, is present in 50% of patients, and is directly responsible for 20% of cancer deaths (Muscaritoli M, et al. Curr Opin Clin Nutr Metab Care. 2004:7:459-466). Though often considered a late complication, it is frequently evident at the time of cancer diagnosis, including 80% of gastrointestinal malignancies and 60% of lung cancers. Actin and myosin hypercatabolism is the key feature, and cytokine-dependent calpain activation may be central to this process. ATP-ubiquitin-dependent proteolysis and ubiquitin mRNA over-expression, even prior to significant weight loss, suggest that the mechanisms of cancer cachexia are operative early. Attenuating muscle protein catabolism or stimulating anabolism remain challenging prospects in countering cachexia, but presently remain primarily at the experimental level.
Whole body fluorodeoxyglucose positron emission tomography scanning helps uncover the associated tumor, and recently proposed criteria may assist in the diagnosis. In many instances, prompt treatment of the tumor and immunotherapy result in symptom stabilization or neurologic improvement.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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