References for this Review were identified through searches of PubMed from 1966 to December 2007 with the terms “paraneoplastic”, “cerebellar degeneration”, “encephalitis, “limbic encephalitis”, “opsoclonus”, “cancer”, “antibodies”, “autoantigens”. Only papers published in English in peer-reviewed journals were selected. Articles were also identified through searches of the authors' own files.
ReviewParaneoplastic syndromes of the CNS
Introduction
In 1949, Guichard and Vignon1 used the term paraneoplastic in a discussion of the differential diagnosis of a patient with multiple cranial and radicular neuropathies caused by metastases of a neoplasm of the uterus. Guichard and colleagues2 subsequently studied three patients suspected of having similar metastatic neuropathies, the autopsies of whom did not reveal neoplastic cells in their spinal cords and nerve roots. These authors proposed that the term paraneoplastic was more appropriate than neoplastic to describe such polyneuropathies. The same term was later used to describe many complications that could not be attributed to identifiable mechanisms, such as direct invasion of the nervous system by the neoplasm, infections, coagulopathy, or side-effects of cancer treatment. Therefore, any symptom of unclear cause but associated with the presence of a neoplasm was considered paraneoplastic. Over the past 20 years, the discovery that many paraneoplastic neurological disorders (PND) are associated with antineuronal antibodies has resulted in tests that, along with recently defined clinical criteria, facilitate their diagnosis. Consequently, patients are diagnosed faster and treated earlier and more effectively than in the past. Patients whose symptoms do not conform to any of the classic PND or who do not have antineuronal antibodies have been studied further, resulting in the discovery of disorders that, in fact, are immune mediated and associated with new antibodies that are likely to be pathogenic.
In this Review, we focus on recent developments and new concepts in PND related to paraneoplastic cerebellar degeneration, opsoclonus-myoclonus, and encephalitides (table 1).3, 4, 5 Comprehensive reviews of PND of the peripheral nervous system have recently been reported in The Lancet Neurology and elsewhere;3, 4, 5, 6 we do not address these disorders or those affecting the spinal cord and visual system in this Review.
Section snippets
Epidemiology
Some researchers suggest that about one per 10 000 patients with cancer develop PND,7 although there are no data to support such a low prevalence. A report based on serological screening of patients with suspected PND without further selection criteria showed that among 60 000 consecutive cases examined in 4 years, 553 (0·9%) were positive for antibodies associated with PND.8 By contrast, a review of patients examined in a research laboratory in which most samples are preselected by use of
Immune responses and pathogenic mechanisms
Most PND of the CNS are probably immune mediated, the best evidence for which comes from the demonstration of antineuronal antibodies in the CSF and serum of patients (table 2). These antibodies react with neuronal proteins that are usually expressed by the patients' tumour, and their detection is the basis of useful diagnostic tests.
Diagnosis of PND
The initial diagnostic approach in patients with suspected PND of the CNS (figure 1) is straightforward for patients with a classic syndrome in association with well characterised paraneoplastic antibodies or a demonstrable tumour (Table 1, Table 2). However, not all patients have well characterised paraneoplastic antibodies, and other clinical scenarios are common, including patients with atypical syndromes or those whose tumour cannot be found. In such cases, a firm diagnosis of PND is
Paraneoplastic cerebellar degeneration
Cerebellar dysfunction is one of the most common paraneoplastic presentations of cancer. The tumours more commonly involved are small-cell lung cancer, gynaecological and breast tumours, and Hodgkin's lymphoma.34, 43, 44 Neurological deficits are sometimes preceded by prodromal symptoms, such as a viral-like illness, dizziness, nausea, or vomiting that might be attributed to a peripheral vestibular process.45 These symptoms are followed by gait unsteadiness that rapidly develops into ataxia,
Opsoclonus-myoclonus
Opsoclonus comprises involuntary, arrhythmic, chaotic, multidirectional saccades with horizontal, vertical, and torsional components, and is commonly accompanied by myoclonic jerks in the limbs and trunk, cerebellar ataxia, tremor, and encephalopathy. Although the circuitry and exact physiopathological mechanism of opsoclonus remain unclear, findings of recent pathological74 and functional MRI studies75 suggest that disinhibition of the fastigial nucleus of the cerebellum is involved. The
Limbic encephalitis and variants
Limbic encephalitis is an inflammatory process highly confined to structures of the limbic system. Patients develop mood and sleep disturbances, seizures, hallucinations, and short-term memory loss that can progress to dementia.89 Electroencephalography usually reveals foci of epileptic activity in one or both temporal lobes or focal or generalised slow activity.90 In 70–80% of patients, MRI fluid-attenuated inversion recovery (FLAIR) or T2 sequences show hyperintense signals in the medial
Additional considerations and future research
Progress in the study of PND is so rapid that recently defined clinical criteria already need expansion. For example, the discovery that SOX, a protein related to small-cell lung cancer, is the target of antibodies in 65% of patients with cancer-associated Lambert-Eaton myasthenic syndrome provides a potential test for differentiating paraneoplastic from non-paraneoplastic Lambert-Eaton myasthenic syndrome.134 Anti-SOX antibodies seem to have the same predictive value of a paraneoplastic cause
Search strategy and selection criteria
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