Paraneoplastic Cerebellar Degeneration 

  • Author: Abbas Mehdi, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA   more...
 
Updated: Feb 3, 2012
 

Background

Paraneoplastic syndromes are a group of rare disorders that are triggered by an abnormal immune system response to an underlying (usually undetected) malignant tumor. Patients with paraneoplastic neurological syndrome (PNS) most often present with neurologic symptoms before an underlying tumor is detected.

Paraneoplastic neurologic syndromes include many neurologic disorders including paraneoplastic cerebellar degeneration (PCD) caused by an immune-mediated mechanism other than a metastatic complication in patients with an underlying malignancy. Any part of the nervous system can be involved depending on the type of primary malignancy. These syndromes affect 1-3% of all cancer patients.[1] These syndromes are difficult to diagnose and respond poorly to treatment. However, the oncologic outcome of patients with antibody-associated paraneoplastic syndromes does not significantly differ from that of patients who do not have the antibodies or a paraneoplastic syndrome.

Paraneoplastic cerebellar degeneration is a rare nonmetastatic complication of a carcinoma, typically mediated by antibodies generated against tumor antigens (proteins). Similar proteins are also expressed on Purinje cells and possibly other cells within the cerebellum. The cancer-fighting antibodies mistakenly attack these normal protein cells in the cerebellum. This immune activation in the central nervous system (CNS) results in cerebellar injury and dysfunction defined as paraneoplastic cerebellar degeneration.

An association between paraneoplastic cerebellar degeneration and occult gynecologic cancers (breast or ovarian) was first identified in 1938, and the syndrome was described fully by Brain in 1951.[2] Posner found that patients with paraneoplastic cerebellar degeneration can be classified according to the presence or absence of an antibody that reacted with an antigen present in both the tumors and in cerebellar Purkinje neurons obtained from these patients.[3]

Paraneoplastic cerebellar degeneration is a syndrome that occurs predominantly in patients with cancer of the ovary, uterus, or adnexa; cancer of the breast; small-cell carcinoma of the lung; or Hodgkin lymphoma.

The onset of symptoms of cerebellar degeneration indicates the presence of an occult malignancy. Not all gynecologic cancers present as paraneoplastic neurologic syndrome; however, in a clinical presentation consistent with a paraneoplastic neurologic syndrome, the chances of underlying malignancy are very high.

The image below illustrates the workup of paraneoplastic cerebellar degeneration.

The workup of paraneoplastic cerebellar degeneratiThe workup of paraneoplastic cerebellar degeneration.
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Pathophysiology

Paraneoplastic cerebellar degeneration is caused by the secondary effects of cancer and is believed to be immune mediated. High titers in the patient's serum and cerebrospinal fluid (CSF) of autoantibodies directed against both neurons and tumor have been detected in some forms of this syndrome.[4, 5] These autoantibodies are considered the result of an immunologic response to tumor and may cross-react with cells of the nervous system, causing neuronal damage.

Specific forms of this syndrome often are associated with specific antineuronal antibodies and tumors. The onset of neurologic symptoms and detection of these antibodies precede diagnosis of the tumor more 60% of the time. Therefore, detection of these antibodies greatly assists the diagnosis of this syndrome and prompts investigations for the underlying tumor. Not all patients presenting with paraneoplastic cerebellar degeneration and its clinical features have recognizable antineuronal antibodies. However, this does not exclude the likelihood of occult malignancy.[6, 7] In approximately 40% of patients, no antibodies are identified.

The Yo antigen is a cytoplasmic protein (CDR2) that interacts with c-Myc. CDR2 is expressed mostly on the Purkinje cells of the cerebellum and can also be present in neurons of the brain stem. Studies suggest that CDR2 sequesters c-Myc in the neuronal cytoplasm and downregulates its activity. Disruption of this interaction by anti-Yo antibodies may increase c-Myc activity, leading to apoptosis of the Purkinje cells.[8, 9]

Antibodies could therefore play an initial pathogenic role in paraneoplastic cerebellar degeneration, although the T-cell immune response is believed to be the major effector of neuronal degeneration. In most of these syndromes, the antigens have been identified and the genes have been cloned.

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Epidemiology

Frequency

United States

In one study, paraneoplastic cerebellar degeneration was observed in 25% of paraneoplastic neurologic syndromes, occurring in 2 of every 1000 patients with cancer.[10]

Mortality/Morbidity

In the study cited above, median survival duration was 100 months for patients with breast cancer and 22 months for those with gynecologic cancer. Although paraneoplastic cerebellar degeneration led to the diagnosis of cancer in 63% of patients, cancer progression was the cause of death in 52%.[10]

Sex

Both sexes are affected, but paraneoplastic cerebellar degeneration is far more common in women than in men.

Age

  • Paraneoplastic cerebellar degeneration associated with anti-Yo antibody occurs in middle-aged women with occult ovarian or breast cancer that is usually indolent.
  • Paraneoplastic cerebellar degeneration associated with anti-Hu antibody occurs in middle-aged men and women or patients with risk factors for lung cancer.
  • When the condition is associated with Hodgkin lymphoma, patients are usually young men, and the cerebellar disease often follows the diagnosis of lymphoma.
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Contributor Information and Disclosures
Author

Abbas Mehdi, MD  Director, MDA Center of Central California; Consulting Staff, Department of Neurology, California Neurological Center, Inc

Abbas Mehdi, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, and American Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

David Y Ko, MD  Associate Professor of Clinical Neurology, Associate Director, USC Adult Epilepsy Program, Keck School of Medicine of the University of Southern California

David Y Ko, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and American Headache Society

Disclosure: GSK Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching; Lundbeck Consulting fee Consulting; Westward Consulting fee Consulting

Specialty Editor Board

Frederick M Vincent Sr, MD  Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine

Frederick M Vincent Sr, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Forensic Examiners, American College of Legal Medicine, American College of Physicians, and Michigan State Medical Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Jorge C Kattah, MD  Head, Associate Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria

Jorge C Kattah, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, and New York Academy of Sciences

Disclosure: Biogen Honoraria Consulting; Bayer Corporation Honoraria Consulting

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting

Chief Editor

Stephen A Berman, MD, PhD, MBA  Professor of Neurology, University of Central Florida College of Medicine

Stephen A Berman, MD, PhD, MBA is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, and Phi Beta Kappa

Disclosure: Nothing to disclose.

References

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The workup of paraneoplastic cerebellar degeneration.
MRI of a 29-year-old female with ARCA1. Sagittal T1 shows marked diffuse cerebellar atrophy with no atrophy of the cerebral cortex, midbrain, pons, or medulla. Image from National Institutes of Health.
Table. Antibodies Associated With Paraneoplastic Cerebellar Degeneration* (Adapted from Dalmau et al[22] )
Antibodies Predominantly Associated With PCDPredominant SyndromeAssociated Cancer
Anti-Yo (PCA-1) antibodiesPCDOvarian



Breast cancers



Anti-Tr antibodiesPCDHodgkin's lymphoma
Anti-mGluR1 antibodies**PCDHodgkin's lymphoma
Anti-Zic4 antibodies†PCDSmall-cell lung cancer
Sometimes Associated With PCD
Anti-VGCC antibodiesEaton-Lambert syndrome, PCDSmall-cell lung cancer



Lymphoma



Anti-Hu (ANNA-1) antibodiesEncephalomyelitis, PCD, sensory neuronopathySmall-cell lung cancer



Other cancers



Anti-Ri (ANNA-2) antibodiesPCD, brain-stem encephalitis, paraneoplastic opsoclonus-myoclonusBreast cancer



Gynecologic cancer



Small-cell lung cancer



Anti-CV2/CRMPS antibodiesEncephalomyelitis, PCD, chorea, peripheral neuropathy, uveitisSmall-cell lung cancer



Thymoma



Other cancers



Anti-Ma protein antibodies‡Limbic, hypothalamic, brain-stem encephalitis (infrequently PCD)Testicular cancer



Lung cancer



Other cancers



Anti-amphiphysin antibodiesStiff-person syndrome, encephalomyelitis, PCDBreast cancer



Small-cell lung cancer



*There is no uniform nomenclature for some of these antibodies; variant names appear in parentheses. mGluR1: metabotropic glutamate receptor 1, Zic4: zing finger of the cerebellum 4, and VCGG: voltage-gated calcium channel.



**Anti-mGluR1 antibodies have been identified in only 2 patients.



† Anti-Zic4 antibodies are predominantly associated with PCD only when no other paraneoplastic antibodies are detectable.



‡Ma proteins include Ma1 and Ma2. Patients with brain-stem and cerebellar dysfunction usually have antibodies against both MA1 and Ma2.



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