Approach Considerations
Consider a diagnosis of paraneoplastic cerebellar degeneration in patients who present with acute or subacute cerebellar degeneration and no risk factors for cerebellar disorders (eg, stroke, alcoholism, primary or metastatic neoplasms in the cerebellum, treatment with chemotherapeutic agents).
Once a diagnosis of paraneoplastic cerebellar degeneration is made, a thorough search for an underlying malignancy is warranted. Analysis of samples of serum and CSF for autoantibodies helps to determine the underlying primary malignancy.
Diagnosis and treatment of paraneoplastic cerebellar degeneration is important because the disability caused by the paraneoplastic cerebellar degeneration is severe; correct diagnosis can lead to early discovery of an occult tumor, which can improve the chance of recovery.
Laboratory Studies
Serum testing should include a basic metabolic and infectious workup to exclude other causes, including but not limited to:
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CBC, CMP, vitamin levels (especially thiamine and Vitamin E), alcohol level, and HIV
CSF analysis typically shows a mild pelocytosis, mild protein elevation, high IgG index, and oligoclonal bands. [14, 49]
In addition to the above studies, serum and CSF should also be tested for known onconeural antibodies.
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It is important to note that up to 40% of patients with PCD are seronegative. [50] Thus, negative antibody testing does not exclude the diagnosis.
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Since many of the paraneoplastic biomarkers are associated with specific types of cancer, the identification of one of these onconeural antibodies in serum or CSF can be very helpful in guiding the workup for an occult malignancy.
Imaging Studies
Magnetic resonance imaging (MRI) findings are normal early in the course of paraneoplastic cerebellar degeneration but can show cerebellar atrophy in advanced cases. [25]
MRI of the brain with contrast is recommended to exclude any structural, demyelinating, vascular, or infectious causes.
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.
PET (FDG-PET) may be useful to identify the underlying malignancy.
In paraneoplastic cerebellar degeneration with anti-Yo antibodies, perform radiography of the chest, mammography, and CT of the abdomen or chest to identify the primary malignancy.
In paraneoplastic cerebellar degeneration with anti-Hu antibodies, perform radiography and CT of the chest to identify a likely small-cell lung cancer. Also investigate other organs where small-cell cancers present, such as the cervix, esophagus, and prostate.
Other Tests
In addition to the imaging studies listed above, a thorough gynecologic examination should be performed in patients with paraneoplastic cerebellar degeneration with anti-Yo antibodies to identify the primary malignancy.
Whole body fluorodeoxyglucose positron emission tomography (FDG-PET) is useful in demonstrating occult neoplasms or small metastatic lesions.
If no primary mailignancy is identified, patients should have serial monitoring.
Procedures
If the initial workup of a patient who has paraneoplastic cerebellar degeneration with anti-Yo antibodies is nonrevealing, consider a total abdominal hysterectomy and a bilateral salpingo-oophorectomy in postmenopausal women. [26] If histologic examination reveals no malignancy and/or the patients are men or premenopausal women, periodic surveillance is necessary. At times, the primary malignancy is discovered up to 5 years after the initial onset of paraneoplastic cerebellar degeneration.
Tumor resection is necessary once the malignancy is identified.
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.
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The workup of paraneoplastic cerebellar degeneration.
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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.
Tables
Antibodies Predominantly Associated With PCD |
Predominant Syndrome |
Associated Cancer |
Anti-Yo (PCA-1) antibodies |
PCD |
Ovarian Breast cancers |
Anti-Tr antibodies |
PCD |
Hodgkin's lymphoma |
Anti-mGluR1 antibodies** |
PCD |
Hodgkin's lymphoma |
Anti-Zic4 antibodies† |
PCD |
Small-cell lung cancer |
Sometimes Associated With PCD |
|
|
Anti-VGCC antibodies |
Eaton-Lambert syndrome, PCD |
Small-cell lung cancer Lymphoma |
Anti-Hu (ANNA-1) antibodies |
Encephalomyelitis, PCD, sensory neuronopathy |
Small-cell lung cancer Other cancers |
Anti-Ri (ANNA-2) antibodies |
PCD, brain-stem encephalitis, paraneoplastic opsoclonus-myoclonus |
Breast cancer Gynecologic cancer Small-cell lung cancer |
Anti-CV2/CRMPS antibodies |
Encephalomyelitis, PCD, chorea, peripheral neuropathy, uveitis |
Small-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 antibodies |
Stiff-person syndrome, encephalomyelitis, PCD |
Breast 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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