Paraneoplastic encephalomyelitis (PEM)

Clinical features

The term PEM/SSN includes several neurologic syndromes characterized by pathologic changes of neuronal loss, microglial proliferation, and inflammatory infiltrates in the nervous system. The areas more frequently involved are the hippocampus, lower brainstem, spinal cord and dorsal root ganglia. The clinical picture reflects the variable anatomic involvement and includes: encephalopaty (limbic encephalitis), brainstem syndromes (bulbar encephalitis), autonomic dysfunction, myelitis, and subacute sensory neuronopathy. Although some patients may have a clinical involvement of only one of these areas through the whole clinical course, 75% of them present a multifocal disorder.

In 75% of PEM patients the underlying neoplasm is a small cell lung cancer (SCLC). Sensory neuronopathy is the most common clinical syndrome and in 20% of the patients, the neuropathy is the only clinical evidence of disease. The second most common clinical syndrome that may remain isolated throughout the clinical evolution is limbic encephalitis. Other common manifestations of PEM are, brainstem encephalitis, cerebellar symptoms, motor weakness, and autonomic dysfunction. The symptoms of brainstem encephalitis reflect the predominant involvement of the floor of the fourth ventricle and the inferior olives and include vertigo, nystagmus, oscillopsia, ataxia, diplopia, dysarthria, and dysphagia. The autonomic nervous system is affected in 30% of the patients; the most common symptoms are orthostatic hypotension, urinary retention, pupillary abnormalities, impotence and dry mouth. A few patients develop a chronic intestinal pseudoobstruction due to damage of the neurons of the myenteric plexus.

Associated antibodies
Most of the patients with PEM present anti-Hu antibodies. An exception would be patients who present an isolated limbic encephalitis throughout the complete clinical course. In this setting, anti-Hu antibodies are usually negative. Other antibodies less frequently associated with PEM are anti-CV2(CRMP5) and anti-amphiphysin.

Treatment
As in many paraneoplastic neurological syndromes of the central nervous system, PCD rarely improves with treatment. The best chance to at least stabilize the syndrome is to induce a complete response of the tumor. Immunotherapy rarely is effective but a trial with intravenous immunoglobulins, steroids or plasmapheresis is indicated because there are a few patient who improved.

Selected references

1. Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine 1992a; 71: 59-72.
2. Graus F, Keime-Guibert F, Reñé R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138-48.
3. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear antibodies. Neurology 1998; 50: 652-7.
4. Sillevis Smitt P, Grefkens J, de Leeuw B, et al. Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol 2002;249:745-53.
5. Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5 neuronal autoantibody: Marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001;49:146-54.