Paraneoplastic cerebellar degeneration
|Paraneoplastic cerebellar degeneration|
|Classification and external resources|
Paraneoplastic cerebellar degeneration (PCD) is a paraneoplastic syndrome associated with lung, ovarian, breast, Hodgkin’s lymphoma and other cancers. PCD is a rare condition that occurs in less than 1% of cancer patients and usually occurs in middle-aged women.
As is the case with other paraneoplastic syndromes, PCD is believed to be due to an autoimmune reaction targeted against components of the central nervous system (in PCD, this is specifically Purkinje cells in the cerebellum, sometimes accompanied by a proliferation of Berg- mann astrocytes and microglia in the molecular layer of the cerebellum and a loss of granule cells ). It is thought to be triggered when tumor cells (in PCD, most commonly ovarian or breast cancer) express a protein normally expressed in the brain (in PCD, this is the Purkinje neuronal protein termed cdr2). This is believed to trigger an anti-tumor immune response that may be clinically significant, but also an anti-neuronal immune response. PCD patients harbor an anti-neuronal antibody known as anti-Yo (named after the first two letters of the index patient). PCD may be associated with onconeural antibodies directed against other intracellular antigens or against cell surface and with other tumors. When associated with small cell lung cancer, it is antibody termed "anti-Hu" (more commonly associated with paraneoplastic subacute sensory neuropathy and/or limbic encephalitis). The immune cells cross the blood–brain barrier, resulting in an autoimmune attack of Purkinje cells throughout the cerebellar cortex. Radiologic imaging occasionally reveals cerebellar atrophy. Other paraneoplastic antibodies may be associated with PCD symptoms, including anti-Tr and antibodies to glutamate receptor. Occasionally myoclonia and opsoclonus may occur.
Neurological symptoms present insidiously and progress rapidly for about 6 months to a severely disabled state followed by a variable plateau period that can last for months to years. The clinical cerebellar ataxia evident in patients with PCD are caused by Purkinje neuronal loss in the cerebellum. It is manifested by dysarthria, truncal, limb and gait ataxia, vertigo, nausea, vomiting, diplopia and nystagmus. Neurological symptoms precede the diagnosis of the underlying cancer in about 60% of cases. A cure of the cancer underlying PCD usually does not affect neurological symptoms, as cerebellar dysfunction stabilizes in the early stage after symptom onset before the cancer treatment has been initiated. There may be a role for high dose gammaglobulin therapy in the treatment PCD, but due to the rare occurrence of this disease, controlled trials of this therapy may be difﬁcult.
The anti-Purkinje cell antibodies originally described in PCD led to the hypothesis that the antibody might be pathogenic, much as earlier studies had demonstrated pathogenicity of anti-acetylcholine receptor antibodies in myasthenia gravis. However, when the antibody was used to clone the cDNA encoding the cdr2 antigen, it was found to be an intracellular protein. This led to the suggestion that there might be a cell-mediated component (T cell) in disease pathogenesis. cdr2 antigen-specific CD8+ T cells were subsequently described in all PCD patients, making them a hallmark of the disease, and likely components in both the anti-tumor immune response and in the neuronal degeneration.
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