Autoimmune central nervous system paraneoplastic disorders: mechanisms, diagnosis, and therapeutic options

The presence of specific antineuronal antibodies in some patients with paraneoplastic central nervous system (CNS) disorders supports the theory that these syndromes have an autoimmune etiology. The anti-Purkinje cell antibodies (APCAs) in some patients with paraneoplastic cerebellar degeneration and ovarian or breast carcinomas stain the cytoplasm of Purkinje cells. APCAs react with several distinct neuronal protein autoantigens, including proteins featuring a "leucine zipper" sequence motif, which suggests that they function in regulating DNA transcription. Type 1 anti-neuronal nuclear antibodies (ANNA-1) associated with paraneoplastic encephalomyelitis and small-cell lung carcinoma stain the nucleus and cytoplasm of all neurons, and react with a group of 35- to 40-kd proteins in neuronal immunoblots. The protein targets of ANNA-1 belong to a family of RNA-binding proteins that probably regulate posttranscriptional processing of RNA. Type 2 anti-neuronal nuclear antibodies (ANNA-2) associated with paraneoplastic opsoclonus-ataxia and breast carcinoma also produce a panneuronal immunocytochemical staining pattern, but react with a group of higher-molecular-mass proteins (53-61 kd and 79-84 kd); these autoantigens probably also function as RNA-binding proteins. Several patients with paraneoplastic stiff-man syndrome have antibodies against a 128-kd synaptic protein. These antineuronal antibodies are highly specific (but not infallible) diagnostic markers for the presence of a neoplasm in patients who present with neurological dysfunction. The actual role of these autoantibodies in the pathogenesis of neuronal damage and clinical disease remains to be determined. Current management options for patients with CNS neurological paraneoplastic syndromes are very limited. Only a small minority of patients with paraneoplastic cerebellar degeneration or encephalomyelitis show significant neurological improvement after successful tumor treatment and/or immunosuppressive treatments, while patients with paraneoplastic opsoclonus or stiff-man syndrome have a somewhat better outlook.