Paraneoplastic Cerebellar Degeneration

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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, such as paraneoplastic cerebellar degeneration (PCD), and are caused by an immune-mediated mechanism, rather than a metastatic complication or medication effect, in patients with an underlying malignancy. Any malignancy can cause a paraneoplastic syndrome and 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.[4, 5]

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.



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The workup of paraneoplastic cerebellar degeneration.

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.[6, 7] 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.[8, 9] 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.[10, 11]

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.

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.[12]

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%.[12]

Sex

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

Age

See the list below:

History

The development of paraneoplastic cerebellar degeneration is quite rapid and patients are severely disabled in days to weeks.

Since most of the patients have occult malignancy, patients are less likely to develop symptoms of paraneoplastic cerebellar degeneration if they have a known history of malignancy.

Neoplasms associated with paraneoplastic cerebellar degeneration are adult onset and more prevalent in females. A common clinical presentation is middle age female with or without comorbid condition presents typically with mild dizziness and nausea followed by vertigo and nystagmus that may suggest a peripheral vestibular problem. These symptoms are followed by ataxia of the limbs and midline, oscillopsia, dysarthria, tremor, and sometimes dysphagia and blurry vision.

The ocular motor and bulbar abnormalities suggests some degree of brain stem involvement.

Mild memory and cognitive deficits as well as affective symptoms can occur in about 20% of patients with paraneoplastic cerebellar degeneration. This is known as cerebellar cognitive affective syndrome.[13]

Initially, patients can be misdiagnosed with cerebrovascular disease, demyelinating disease, infectious diseases, vitamin deficiency, toxic exposure, sarcoidosis, autoimmune diseases (eg, SLE, Sjogren syndrome), and alcohol-induced cerebellar degeneration.

Other diseases that can mimic this condition include late-onset spinocerebellar ataxia with or without a family history, olivopontocerebellar degeneration, and other degenerative diseases of the brain seen in elderly patients.

History, examination, and diagnostic testing help to differentiate paraneoplastic cerebellar degeneration from other conditions that are statistically more likely to occur than paraneoplastic cerebellar degeneration. Early diagnosis of paraneoplastic cerebellar degeneration can lead to early diagnosis and treatment of the occult malignancy.

Physical

See the list below:

Findings that are inconsistent with a diagnosis of paraneoplastic cerebellar degeneration include the following:

Causes

Two major patterns of antibody response have been described: anti-Hu (type IIa, antineuronal nuclear antibodies type 1) and anti-Yo (type 1, anti-Purkinje cell antibodies [APCA]). Both anti-Yo and anti-Hu antibodies label patient tumors and are believed to be elicited by tumor antigens that are cross-reactive with neuronal antigens.

Table. Antibodies Associated With Paraneoplastic Cerebellar Degeneration* (Adapted from Dalmau et al[24] )



View Table

See Table

Laboratory Studies

See the list below:

Imaging Studies

See the list below:

Other Tests

See the list below:

See the image below for an illustration of the workup of paraneoplastic cerebellar degeneration.



View Image

The workup of paraneoplastic cerebellar degeneration.

Procedures

See the list below:

Histologic Findings

The hallmark of paraneoplastic cerebellar degeneration is severe loss of Purkinje cells diffusely throughout the cerebellar cortex. These cells are completely absent on specimens. Other cell loss is observed but is rare. Occasionally, Purkinje cell loss is patchy. Inflammatory changes are also observed with lymphocytic infiltration. Atrophy of the granular and molecular layers is demonstrated, with microglial proliferation and astrocytosis but relative sparing of basket cells. The deep cerebellar nuclei and the cerebellar connections to the brain stem are normal. Patients with APCA-1/anti-Yo antibody tend to demonstrate more inflammatory changes and characteristic immunofluorescence patterns with coarse granular staining of Purkinje cell cytoplasm as well as proximal axons and dendrites; nuclei and systemic tissues are not stained. In paraneoplastic cerebellar degeneration associated with anti-Hu, the cortical and cerebellar neuronal nuclei are stained.

Medical Care

Two approaches can be used to treat paraneoplastic neurologic syndrome. The first treatment is directed toward the underlying tumor, while the second approach is toward the autoimmune disease causing the cerebellar dysfunction.

Since neurologic paraneoplastic syndromes are immune-mediated, 2 distinct approaches to therapy have been reported: removal of the antigen source by treatment of the underlying tumors and suppression of the immune response. Immunosuppression can be beneficial for some conditions.[27]

Surgical Care

Surgical care is required for patients who undergo tumor resection.

Consultations

A team approach is required in treating patients with paraneoplastic cerebellar degeneration.

Diet

The patient may require nutritional support in severe cases of nausea and vomiting.

Activity

Bed rest is usual because patients with severe cerebellar dysfunction are at high risk of falls.

Further Outpatient Care

See the list below:

Prognosis

Prognosis greatly depends on early detection of the underlying neoplasm and its stage at the time of detection.

Author

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

Disclosure: Nothing to disclose.

Coauthor(s)

David Y Ko, MD, Associate Professor of Clinical Neurology, Loma Linda University School of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: SK<br/>Serve(d) as a speaker or a member of a speakers bureau for: Eisai, Lundbeck, Sunovion, Supernus, UCB.

Specialty Editors

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

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

Disclosure: Nothing to disclose.

Chief Editor

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

Disclosure: Nothing to disclose.

Additional Contributors

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

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.

The workup of paraneoplastic cerebellar degeneration.

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.

Antibodies Predominantly Associated With PCD Predominant Syndrome Associated 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.