Paraneoplastic sensory-motor neuropathies

The association of cancer and peripheral neuropathy is not unusual and it has long been underlined that a careful follow up of patients with peripheral neuropathy of unknown origin may eventually result in the diagnosis of cancer providing an aetiology to the neuropathy. However, such an association does not necessarily indicates that the neuropathy is paraneoplastic as it may result from chance. The problem is particularly crucial with sensory-motor neuropathies and cancer for which less than 30% of patients have onconeural antibodies (ab). The following commentary does not take into account the specific problem of neuropathy and malignant monoclonal gammopathies.

Definite sensory-motor peripheral neuropathies

These neuropathies occur with anti-Hu or anti-CV2 ab, some patients having both. With anti-Hu ab, subacute sensory neuronopathy (SSN) is responsible for the sensory manifestations and motor symptoms usually result from motor neurone degeneration. About 15%-30% of patients with anti-Hu ab and peripheral neuropathy present with a sensory and motor neuropathy, one third having an equal proportion of sensory and motor involvement. As the distribution of symptoms is frequently asymmetrical or multifocal, the disorder can be misdiagnosed as mononeuritis multiplex or polyradiculopathy. An acute and severe evolution in the four limbs may mimic a Guillain-Barré syndrome. There is indications that in patients with SSN, inflammatory lesions may extend into the peripheral nerves. Vasculitis or demyelinating lesions have both been reported on nerve biopsy. The pathophysiology of these nerve changes is unclear as the Hu proteins are not normally expressed in the peripheral nerve.

Peripheral neuropathy occurs in 60% of patients with anti-CV2 ab. In two third of cases it is a sensory-motor neuropathy affecting preferentially the lower limbs. Pain is less frequent than with anti-Hu ab. Electrophysiological and pathological studies indicate an axonal or axonal and demyelinating process. Patients with both anti-Hu and anti-CV2 ab may combine SSN and nerve lesion. About 65% of patients simultaneously have central nervous system disorder, autonomic neuropathy or eye involvement.

Possible paraneoplastic peripheral neuropathies

Different forms of neuropathy fall in this group. Contrary to the neuropathies associated with onconeural antibodies, the disorders are usually restricted to the peripheral nervous system and the associated tumours are varied. The neuropathies include Guillain-Barré syndrome, chronic or relapsing sensory-motor neuropathies some of which fulfilling the diagnostic criteria of chronic inflammatory demyelinating polyneuropathy, neuropathies with vasculitis, chronic axonal neuropathies, and brachial plexopathy. There is indication that neuropathies occurring within a short delay with cancer are frequently of an inflammatory type. However, whether the tumour is responsible for the disorder is still unknown. Rare cases of patients with melanoma, peripheral neuropathy, and antibodies reacting with gangliosides common to both the tumour and the peripheral nerve suggest that a crossed immunological process may occur in some neuropathies.

Paraneoplastic neuropathies and vasculitis.

The clinical presentation is mononeuritis multiplex or symmetrical sensorimotor axonal neuropathy. High ESR and high CSF protein concentration are frequent laboratory findings. Extra-neurological manifestations are absent. Some patients improve with the treatment of the tumour and others with immunosuppressants. In fact, paraneoplastic vasculitic neuropathies correspond to at least two different nosological situations.

• 1- In a first group of patient, vasculitis is a satellite of subacute sensory neuropathy either confirmed by autopsy or highly probable on clinical and electrophysiological data. These patients have small cell lung cancer and, when tested, anti-Hu ab are detected. In one case, vasculitis was also present in muscle biopsy.
• 2- In a second group of patients, peripheral neuropathy is the only clinical manifestation. The cancers in this group of patients are various including lymphoma, Hodgkin’s disease, uterus, stomach and non small cell lung cancer. The frequency of cancer in patients with nerve vasculitis has been estimated from 5.5% to 14% which appears to be higher than in the general population. Controlled epidemiological studies are needed to confirm these results.

Selected references

1. Rudnicki SA, Dalmau J. Paraneoplastic syndromes of the spinal cord, nerve, and muscle.. Muscle Nerve. 2000;23:1800-18.

2. Smitt PS, Posner JB. Paraneoplastic peripheral neuropathy. In Latov N, Wokke JH, Kelly JJ, eds. Immunological and infectious diseases of the peripheral nerves. Cambridge: Cambridge University Press, 1998:208-24.

3. Antoine JC, Mosnier JF, Absi L, et al. Carcinoma associated paraneoplastic peripheral neuropathies in patients with and without anti-onconeural antibodies. J Neurol Neurosurg Psychiatry 1999; 67:7-14.

4. Antoine JC, Honnorat J, Camdessanche JP, et al. Paraneoplastic anti-CV2 antibodies react with peripheral nerve and are associated with a mixed axonal and demyelinating peripheral neuropathy. Ann Neurol 2001; 49: 214-21.

5. Kloos L, Sillevis Smitt P, Ang C W, et al. Paraneoplastic ophthalmoplegia and subacute motoraxonal neuropathy associated with anti-GQ1b antibodies in a patient with malignant melanoma. J Neurol Neurosurg Psychiatry 2003; 74:507–9

6. Younger DS, Dalmau J, Inghirami G, ET AL. Anti-Hu-associated peripheral nerve and muscle microvasculitis. Neurology 1994 ; 44: 181-3.
7. Vincent D, Dubas F, Haw JJ, et al. Nerve and muscle microvasculitis. J Neurol Neurosurg Psychiatry 1986; 49:1007-10.
8. Oh SJ. Paraneoplastic vasculitis of the peripheral nervous system. Vasculitis and the nervous system, Neurologic Clinics Vol 15, number 1997 ; 4: 849-63.