Cancer, Paraneoplasia, and Peripheral Neuropathy
Abstract & Commentary
Source: Antoine JC, et al. Carcinoma associated paraneoplastic peripheral neuropathies in patients with and without anti-onconeural antibodies. J Neurol Neurosurg Psychiatry 1999;67:7-14.
Among 422 consecutive patients with periph-eral neuropathy, 26 were associated with carcinoma in the absence of tumor infiltration, drug toxicity, or malnutrition. Other known causes of polyneuropathy were excluded by blood studies including sedimentation rate, protein immunoelectrophoresis, thyroid function, vitamin B12, and folate levels. Cerebrospinal fluid analysis excluded leptomeningeal involvement. Nerve conduction studies and needle electromyogram were performed in all 26 patients, and 18 underwent superficial peroneal nerve biopsy. Screening for onconeural antibodies comprised standard anti-Hu, anti-Ri, anti-Yo, anti-amphyphysin, and anti-CV2 immunohistochemistry and western blotting on rat brain (Moll JW, et al. Neurology 1995;45:1937-1941).
Of the 26 patients with cancer-associated peripheral neuropathy, seven demonstrated onconeural antibodies: six showed anti-Hu antibodies with small cell cancer of lung or prostate, and the other had anti-CV2 antibodies and a mediastinal undifferentiated carcinoma. Neuropathy in these preceded the cancer by a mean of 10 months and, in the anti-Hu group, was generally disabling and predominantly sensory, with four patients also demonstrating paraneoplastic encephalomyelitis. Mild sensorimotor neuropathy and cerebellar ataxia characterized the anti-CV2 antibody patient. None of these seven patients demonstrated inflammatory changes pathologically and none responded to immunosuppression, including steroids, plasmapheresis, or intravenous immunoglobulin.
Of the 19 patients without onconeural antibodies, the neuropathies and cancer types were varied and diverse, the former comprising axonal sensory or sensorimotor polyneuropathy with upper motor neuron signs (n = 4), axonal sensorimotor polyneuropathy without upper motor neuron signs (n = 7), mononeuropathy multiplex (n = 2), or demyelinating neuropathy, most often chronic inflammatory demyelinating polyneuropathy. Cancer types included, among others, carcinoma of the stomach, colon, liver, pancreas, prostate, and melanoma.
Among this antibody negative group, those with more severe polyneuropathy (n = 14) were found to have cancer by a mean of 7.8 months following onset, their neuropathy was inflammatory in nature (11 of 14), and they responded to immunosuppression in the absence of central nervous system involvement. Those less disabled from neuropathy (n = 5) fell into a slowly progressive neuropathy group, with cancer diagnosed within a mean of 8.4 years, which may indeed have been coincidental. In the absence of onconeural antibodies, a cancer workup for inflammatory neuropathy is probably unwarranted unless associated with encephalomyelitis or vasculitis.
Commentary
Antiamphyphysin antibodies, first described in women with breast cancer and stiff man syndrome, react against the nerve terminal protein, amphyphysin, found in synaptic vesicles. Among 2800 serum samples tested for onconeural antibodies, Antoine and colleagues selected five samples with antiamphyphysin activity and found that its presence is nonspecific for either tumor type or neurological syndrome (Antoine JC, et al. Arch Neurol 1999;56:172-177). Two patients had Lambert Eaton myasthenic syndrome (LEMS) with small cell lung cancer, a third had small cell lung cancer discovered two years following limbic encephalitis, and two had encephalomyelitis, one with ovarian, and one with breast cancer, the latter also demonstrating sensory neuronopathy. None had stiff man syndrome and three had other antibodies, including antimitochondrial (n = 2), anti-voltage-gated calcium channel (n = 2), and anti-Hu antibodies (n = 1). Among the control groups, including: 1) various cancers (lung, colon, gynecologic) but without paraneoplastic illness subjects (n = 101); 2) small cell lung cancer with paraneoplastic illness (n = 8); 3) nonparaneoplastic neurologic illness (n = 40); and 4) normals (n = 30), only three of group 2 showed anti-amphyphysin antibodies.
Unlike the majority of CNS antibody-associated paraneoplastic syndromes that appear to have a cytotoxic T-cell pathogenic mechanism, stiff man syndrome, like LEMS and myasthenia gravis, is likely antibody mediated (Dalmau JO, Posner JB. Arch Neurol 1999;56:405-408). —mr
Which one of the following statements is true?
a. The peripheral paraneoplastic neurological syndromes likely have a cytotoxic T-cell mediated pathogenesis.
b. The central nervous system paraneoplastic neurological syndromes likely have an antibody-mediated pathogenesis.
c. Even in the absence of onconeural antibodies, a cancer workup is indicated in cases of acute inflammatory demyelinating polyneuropathy.
d. Antiamphyphysin antibodies are specific for stiff man syndrome and of an underlying lung cancer.
e. None of the above
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