Paraneoplastic Cerebellar Degeneration

Last edited: 11/22/2001 by Timothy C. Hain, MD, Chicago IL. Click here to return to index. Please read our disclaimer

Paraneoplastic cerebellar degenerations are disorders of the cerebellum, the part of the brain responsible for coordination, which are associated with tumors (neoplasms). They arise when tumors express proteins that are normally found only in neurons, and it is believed that the immune system, in its attempt to kill the tumor, also damages the cerebellum. Although antibodies occasionally useful for diagnosis, they do not appear to be the cause of the cerebellar damage. Rather, current thought is that "killer T-cells", or cytotoxic CD8+ T lymphocytes, are the most likely mediator of neuronal injury. Treatments to reduce the antibodies are ineffective, and attempts to reproduce disease by transfer of antibodies into animals have been unsuccessful

Certain tumors are more common than others. These include cancer of the ovary, uterus or adnexa, cancer of the breast, and especially small cell carcinoma of the lung. The condition frequently begins before the tumor is diagnosed.

Examination of patients with anti-Purkinje cell antibodies, especially anti-Yo, is usually dominated by a rapidly progressive unsteadiness, and downbeating nystagmus. Pathological examination often reveals profound loss of Purkinje cells, which are the output cells for the cerebellum. The MRI scan of the brain may be normal. The single most useful clinical test is usually a chest X-ray. In situations where a paraneoplastic syndrome is suspected, but antibodies have not yet been done, a chest-X ray is also generally the most useful clinical test.

Antibody Name Tumor type Reacts with Symptoms
Hu Small cell lung Anti-neuronal nuclear antibody-1 Sensory neuropathy, encephalomyeloneuropathy, gastrointestinal dysmotility
Yo Gynecological Anti-Purkinje Cell Cerebellar ataxia, sensory or motor neuropathy
PCA-2 Small cell lung Anti-Purkinje Cell (cytoplasmic) Mixed Neurological presentations -- limbic encephalitis, cerebellar ataxia, Eaton Lambert myasthenic, autonomic neuropathy, motor neuropathy
Tr Hodgkin's Lymphoma Anti-Purkinje Cell Subacute cerebellar ataxia
Ri Breast Anti-neuronal nuclear antibody-2 Opsoclonus
amphiphysin breast and lung (small cell lung) neuronal cytoplasmic antigens. encephalomyeloradiculoneuritides
CRMP (anti-CV2)   peripheral nerve peripheral neuropathy (collapsin response-mediator protein-5 antibody)
ANNA-3 small-cell lung mainly anti-neuronal nuclear antibody-3 Neuropathy, ataxia, encephalopathy

 

At this writing there are 8 described anti-neuronal antibodies associated with paraneoplastic syndromes. Certain types of antibodies are correlated with certain disorders-- examples are anti-Hu and Yo. Anti-Hu is an type IIa, ANNA (anti-neuronal nuclear antibody) type I antibody. Small cell lung carcinoma is found in more than 80% of patients with anti-Hu.

Anti-Yo is an anti Purkinje cell antibody. Anti-Hu reacts with nearly all neurons, but anti-Yo reacts only with Purkinje cells. Patients with anti-Yo have a gynecological cancer, usually ovarian or breast, 90% of the time. A second anti-Purkinje cell antibody (PCA-2) was described by Vernino and Lennon (2000).

Anti-Ri, or ANNA-2, was first described in women with paraneoplastic opsoclonus and encephalitus associated with breast carcinoma. It also is found in men (about 1/3 of patients) and in association with lung cancer.

Recent work has suggested that cytotoxic T cells are responsible for the damage to the cerebellar Purkinje cells (Albert et al, 2000). In this same study, a treatment with tacrolimus, a specific inhibitory of activated T cells, elminated cytotoxic specific T cells from the circulating blood.

Antibody name Associations Reacts with Neurological symptoms
GAD Diabetes, Stiff-person syndrome Glutamine dehydrogenase Various, including cerebellar
Gliadin Celiac Disease   Cerebellar
Ma Tumors, testicular cancer Ma protein Brainstem encephalitis, cerebellar degeneration

 

Other types of antibodies such as anti-GAD, and anti-gliadin antibodies found in Celiac disease (Pellechia et al, 1999), are also associated with cerebellar disease. Anti-Ma antibodies (Ma is a protein expressed in neurons, tumors and the testis) have also been associated with paraneoplastic brainstem encephalitis (Ma1 and Ma2), while immunity to Ma2 is predominantly associated with limbic and brainstem encephalitis (Rosenfeld et al, 2001).

Paraneoplastic cerebellar degeneration must be separated from numerous other causes of cerebellar damage.

 

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