Paraneoplastic Neurological Disorders (PND) are uncommon but important because they frequently present before a cancer is diagnosed and because they cause severe neurological disability. Current thinking is that they are caused by an autoimmune response to 'onconeural' antigens, shared by the tumour and the nervous system, although the precise immunopathogenic mechanism is unknown. It is likely that there is an important cellular immune response as evidenced by the presence of lymphocytic infiltration and activated cytotoxic T lymphocytes, found in the CSF of affected patients.
PND may affect any part of the nervous system either focally (e.g. cerebellar degeneration) or diffusely (e.g. encephalomyelitis). Both the Central and Peripheral Nervous System may be affected, with antigenic targets being either intracellular (both nuclear and cytoplasmic) or extracellular (receptors and ion channels). As a general rule, PND associated with antibodies against intracellular targets cause predominantly CNS disorders while those associated with antibodies against extracellular antigens cause predominantly neuromuscular disorders.
PND affecting the CNS are commonly associated with specific anti-neuronal antibodies, which are present in both serum and CSF. A suspected diagnosis of PND should prompt a search for what may be a very small tumour, sometimes not visible with conventional imaging techniques. Fluoro-deoxyglucose–Positron Emission Tomography (FDG-PET) scanning is helpful in this regard as it can visualise tumours down to a resolution of 6–8 mm anywhere in the body and is sometimes positive when chest X-ray and CT are negative. Current recommendations are that the search for cancer should continue for up to 5 years after diagnosis, except for Lambert Eaton Myasthenic Syndrome (LEMS) associated with Small cell Lung Cancer, where 2 years are sufficient.
Most CNS syndromes respond poorly to immunomodulatory treatment although occasional improvement is seen when the underlying tumour is treated. In contrast, disorders affecting the Neuromuscular Junction e.g. LEMS do improve with treatments that remove the relevant antibodies, directed against Voltage-Gated Calcium Channels.
Traditonally, PNS affect older patients with malignant tumours. Recently the spectrum of paraneoplasia has been broadened to include younger patients with benign tumours e.g. ovarian teratoma presenting with prodromal flu-like symptoms, psychiatric disturbance progressing to coma, movement disorders, autonomic instability and respiratory failure. These disorders are associated with antibodies directed against NMDA receptors in the hippocampi and improve with removal of the teratoma and plasma exchange.
The prognosis for the majority of PND is poor, even if the tumour is detected and treated, and patients may live in a severely disabled state for many years.
Original Article: http://jnnp.bmj.com/cgi/content/short/85/8/e3-d?rss=1
Júlio Pereira
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