Progressive cerebellar degeneration

Progressive cerebellar degeneration is one of the most characteristic paraneoplastic syndromes encountered in adult neurological practice, but even this probably only occurs in less than 1 per cent of patients with cancer. The pathological appearances are of diffuse Purkinje cell loss throughout the cerebellum , astrocytic proliferation, some neuronal loss, and demyelination. The changes are usually confined to the peridentate regions, but similar changes may be seen elsewhere in the nervous system.

Neurological symptoms usually predate recognition of the associated malignancy and manifest as acute or subacute ataxia progressing rapidly to produce such severe loss of axial balance that affected individuals often cannot stand or sit unless fully supported (Brain et al. 1951; Anderson et al. 1988a). The selective disturbance of midline cerebellar function is followed by incoordination of the individual limbs, dysarthria, and disorders of eye movement, especially the presence of down-beating nystagmus, indicating diffuse damage to the brainstem cerebellar connections. In many cases, signs of more widespread disease are apparent, with cognitive decline, other signs of diffuse encephalomyelitis, and, less frequently, peripheral neuropathy. Symptomatic progression is rapid but the condition may arrest at an advanced stage, albeit with severe disability. Cerebellar degeneration may occur in association with other paraneoplastic disorders as part of the subacute sensory neuronopathy–encephalomyelitis syndrome.

Investigation of these patients shows the expected cerebrospinal fluid pleocytosis, elevated immunoglobulins, and presence of oligoclonal bands. Patients with paraneoplastic cerebellar degeneration usually have serum and cerebrospinal fluid antibodies directed against cerebellar Purkinje cells (Anderson et al. 1988b). Purkinje-cell antigens are selectively expressed in tumour tissue (Furneaux et al. 1990) and this is the usual specificity of anti-Yo, which serves as a marker for paraneoplastic cerebellar degeneration associated with carcinoma of the ovary, uterus, adnexa, or breast but also described in transitional cell carcinoma of the bladder (Greenlee et al. 1999) — generally a rare cause of paraneoplastic syndromes. Anti-Yo recognizes two groups of proteins, having molecular weights of 34–38 and 62–64 kDa, respectively (Furneaux et al. 1989). It stains the endoplasmic reticulum and Golgi complexes in Purkinje cells and their dendrites. The function of these proteins and the molecular basis of the disease have yet to be defined, although the gene encoding the smaller product is uniquely expressed in cerebellum and in tumour tissue from affected patients (Dropcho et al. 1987). In some cases, different antibody staining properties are seen in the presence of an otherwise typical clinical phenotype, but additional antibodies, recognizing different proteins extracted from neurons and not showing the same staining pattern, have also been identified in patients with mixed syndromes of cerebellar degeneration, encephalopathy, neuropathy, and autonomic failure. These seem not to occur in patients with breast or ovarian tumour without paraneoplastic neurological syndromes. Anti-Tr is associated with paraneoplastic cerebellar degeneration and Hodgkin's disease (Graus et al. 1997).

Most recently, Dalmau et al. (1999) identified anti-Ma, a novel auto-antibody, in 4/1705 samples, from patients in whom the phenotype was usually cerebellar degeneration due to extensive Purkinje-cell loss but with some variation in the clinical manifestations. In vitro studies showed widespread antineuronal nucleus and testis specificity, reacting against 37 and 40 kDa antigens which were also detected on the primary tumour in each case.

In a series of 47 patients with progressive cerebellar degeneration (Anderson et al. 1988a), 18 had typical anti-Purkinje-cell antibodies. These cases were all women with ovarian or breast carcinoma in whom cerebellar disease predated recognition of the tumour and tended to follow rapidly upon a systemic illness involving diarrhoea and vomiting. As is usually the case in paraneoplastic disorders of the central nervous system, removal of the primary tumour does not influence the neurological disorder, and treatment with plasmapheresis and immunosuppression are equally unrewarding, even though the antibody titre may fall for a while.

The clinical features of cancer-associated progressive cerebellar degeneration not associated with antineuronal antibodies differ from the antibody-positive cases, in that men are more commonly affected; the neurological symptoms more often complicate lung tumour and more commonly develop after recognition of the primary lesion; and the clinical symptomatology is broadly similar, as are the cerebrospinal fluid findings and the response to treatment.

Symptomatic treatment is generally unrewarding, although there may be some response to clonazepam. Albert et al. (2000) suggest that treatment with tacrolimus, which selectively inhibits the activated T cells present in the circulation and spinal fluid of patients with cerebellar degeneration, may benefit the paraneoplastic complication without risking tumour recurrence.

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