Better defined is subacute motor neuronopathy that occurs as a remote effect of bronchogenic carcinoma, Hodgkin disease, and other lymphomas as mentioned earlier in the discussion of encephalomyelitis (Schold et al). Some cases take the form of a relatively benign, purely motor weakness of the limbs, the course and severity of which are independent of the underlying neoplasm. Other cases are severe and progressive, causing respiratory failure and death, thus simulating amyotrophic lateral sclerosis (ALS); some of these will have the anti-Hu antibody (Verma et al; Forsyth et al). The basic neuropathologic change is a depletion of anterior horn cells; also seen are inflammatory changes and neuronophagia as in chronic poliomyelitis. The few autopsied cases have shown gliosis of the posterior columns, pointing to an asymptomatic affection of the primary sensory neuron, as well as a reduction in the number of Purkinje cells.
Forsyth and colleagues subdivided their cases of paraneoplastic motor neuron syndromes into three groups: (1) rapidly progressive amyotrophy and fasciculations with or without brisk reflexes—all of their 3 patients displayed anti-Hu antibodies, 2 with small cell lung cancer and 1 with prostate cancer; (2) a predominantly corticospinal syndrome that affected the oropharyngeal or limb musculature, without definite evidence of denervation, thus resembling primary lateral sclerosis—all were breast cancer patients and none showed antineuronal antibodies; and (3) a syndrome indistinguishable from ALS in 6 patients with breast or small cell lung cancer, Hodgkin disease, or ovarian cancer, none of whom had antineuronal antibodies. In the latter two groups one cannot be certain that the condition was not a chance occurrence of the idiopathic variety of motor neuron disease. Nevertheless, this is such a rare cause of motor neuron disease that an evaluation for tumor is not required in the typical case of ALS.
A rare paraneoplastic syndrome of spinal myoclonus with tonic spasms can occur and is assumed to be from inflammation of the spinal cord gray matter as discussed in Chaps. 4 and 42.
Several more recently discovered antibodies, such as CRMP-5 (collapsin-responsive mediator protein) and anti-Ma1 and -Ma2, have been detected in cases of brainstem encephalitis including with ophthalmoplegia but there have been associations with limbic and diencephalic syndromes as well and a hypokinetic parkinsonian appearance (Dalmau et al 2004). The anti-Ma antibodies cross-react with testicular antigens and a search for a testicular tumor is undertaken (Voltz et al). Although rare, the clinical syndromes associated with the anti-Ma antibody and testicular tumors are diverse: limbic, brainstem, or hypothalamic inflammation and an ataxic–opsoclonic syndrome that is more typical of anti-Ri antibody (see earlier).
The antibody to CRMP-5 is reported in some series to be second in frequency only to anti-Hu. Lung carcinoma has been the most common source in the series of Yu and colleagues, with thymoma, renal cell, and other neoplasms accounting for a few of the cases. The clinical features have been as diverse as for anti-Hu, including seizures, dementia, confusion, depression, as well as a variety of peripheral and cranial neuropathies and the Lambert-Eaton syndrome.
An illness similar to the one caused by anti-NMDA antibodies, under the name of Ophelia syndrome, has been reported as a paraneoplastic syndrome that is due to antibodies directed against the metabotropic glutamate receptor, mGluR5 (see Lancaster et al).