Primary motor or encephalitic syndromes

Paraneoplastic cerebellar degeneration. This syndrome is caused by generalized loss of many cerebellar Purkinje cells, producing ataxia, which is also frequently accompanied by nystagmus and dysarthria. This is most commonly found in postmenopausal women with breast or ovarian carcinoma and less frequently with other adenocarcinomas. A few cases are associated with lung small cell carcinoma. About 5% of cases have no detectable cancer. Paraneoplastic cellular degeneration due to ovarian or breast cancer is accompanied in 50%-87% of patients by serum antibodies against Purkinje cell cytoplasm, known as Yo antibodies. In some cases appearance of the Purkinje cytoplasmic antibody may precede symptoms. Those cases due to lung small cell carcinoma are usually accompanied by antibodies against nuclei of CNS neurons called Hu antibodies. About one third of patients with Hu autoantibodies have CNS encephalopathy due to lung small cell carcinoma with or without cerebellar involvement. Hu and Yo antibodies are currently only available in some medical centers and large reference laboratories.

Antineuronal antibody associated with sensory or encephalitic disease. Besides cerebellar degeneration, another third of patients with Hu autoantibodies have sensory neuropathy without encephalopathy and about 10% of patients have a special type of encephalopathy that involves the CNS limbic area, with memory loss, behavioral abnormality, and partial seizures. A few cases with Hu antibodies have nonpulmonary neoplasms such as prostate carcinoma. However, the great majority of patients with Hu autoantibodies have lung small cell carcinoma.

Lambert-Eaton myasthenic syndrome (LEMS). Patients with Lambert-Eaton myasthenic syndrome (LEMS) have symptoms similar to those of MG; but weakness tends to be symmetrical in LEMS and asymmetrical in MG; weakness improves with exercise in LEMS and improves after rest in MG; tendon reflexes decrease in LEMS and increase in MG; ocular muscles often are not involved in LEMS but usually are involved in MG; and edrophonium test results are usually negative in LEMS but positive (correcting the weakness) in MG. The defect occurs presynaptically in LEMS and postsynaptically in MG. About 60% of patients with LEMS have a lung small cell carcinoma; therefore, LEMS is often considered a paraneoplastic disease. About 10%-15% of MG patients have a thymoma (which is a benign tumor) and another 60%-65% have benign thymus hyperplasia. Therefore, it is less certain that MG is a true paraneoplastic syndrome, at least in the way that the term “neoplastic” is ordinarily used. A test using Western blot technique has been described for LEMS antibody; this antibody attacks voltage-gated calcium channel antigen (myasthenia syndrome B antigen), which is used in the test in the form of recombinant antigen to assay LEMS antibody. About 45% of patients with LEMS have detectible LEMS antibody with this test method. LEMS antibody testing is only available in some research centers and a few large reference laboratories.

Cancer-associated retinopathy (CAR). Some patients with occult or overt malignancies have rapid worsening of vision. The most commonly associated (but not the only) tumor is lung small cell carcinoma. A test has been devised using a recombinant form of the retinal photoreceptor protein Recoverin as antigen to detect cancer-associated retinopathy (CAR) antibody. The test is only available in some research centers and a few large reference laboratories.

Paraneoplastic opsoclonus/myoclonus syndrome. The main clinical symptoms associated with this syndrome are opsoclonus (involuntary side-to-side eye motion) or truncal ataxia. There may also be myoclonus or motor weakness. Current diagnosis is based on detection of antibody to the Ri antigen, a neuron nuclear antigen. Most of the few patients to date found to have the Ri antibody had lung small cell carcinoma. The test is currently only available in a limited number of medical school research laboratories and a few large reference laboratories.

IgM motor neuropathies. Currently there are two syndromes in this category, both involved with carbohydrate antigens shared by neuron glycolipids and glycoproteins, and both diagnosed by detection of IgM antibodies against the carbohydrate-glycolipid antigens. The first is a syndrome characterized by antibodies against ganglioside monosialic acid (GM1), consisting of predominantly lower motor neuron disease and distal muscle weakness (although there may be combined sensory and motor abnormalities). Occasionally GM1 antibodies have also been reported in patients with SLE having CNS involvement and IgM monoclonal gammopathies with neuropathy. Only high antibody titers of GM1 are considered diagnostic because low titers of GM1 have been reported in some clinically normal persons, as well as some patients wtih MS or ALS. Unfortunately, at present only about 20% of patients with lower motor neuron disease or sensory neuropathy have diagnostic GM1 titer levels. The test is only available in large commercial laboratories and some university centers. The other syndrome is a demyelinating condition associated with antibody against myelin-associated glycoprotein (MAG). This syndrome can have either motor or sensory components or both together. Anti-MAG antibody elevation has been reported in up to 50% of patients with IgM monoclonal gammopathies associated wtih peripheral neuropathy. Only high antibody titers are considered diagnostic because low levels of MAG have been reported in some clinically normal persons and some patients with rheumatoid-collagen diseases. MAG antibody tests are available only in some large reference laboratories and university centers.