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.
View Image | The workup of paraneoplastic cerebellar degeneration. |
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.
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In one study, paraneoplastic cerebellar degeneration was observed in 25% of paraneoplastic neurologic syndromes, occurring in 2 of every 1000 patients with cancer.[12]
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]
Both sexes are affected, but paraneoplastic cerebellar degeneration is far more common in women than in men.
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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.
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Findings that are inconsistent with a diagnosis of paraneoplastic cerebellar degeneration include the following:
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 |
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View Image | 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.... |
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See the image below for an illustration of the workup of paraneoplastic cerebellar degeneration.
View Image | The workup of paraneoplastic cerebellar degeneration. |
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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.
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]
A team approach is required in treating patients with paraneoplastic cerebellar degeneration.
Bed rest is usual because patients with severe cerebellar dysfunction are at high risk of falls.
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Prognosis greatly depends on early detection of the underlying neoplasm and its stage at the time of detection.
Antibodies Predominantly Associated With PCD Predominant Syndrome Associated Cancer Anti-Yo (PCA-1) antibodies PCD Ovarian
Breast cancersAnti-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
LymphomaAnti-Hu (ANNA-1) antibodies Encephalomyelitis, PCD, sensory neuronopathy Small-cell lung cancer
Other cancersAnti-Ri (ANNA-2) antibodies PCD, brain-stem encephalitis, paraneoplastic opsoclonus-myoclonus Breast cancer
Gynecologic cancer
Small-cell lung cancerAnti-CV2/CRMPS antibodies Encephalomyelitis, PCD, chorea, peripheral neuropathy, uveitis Small-cell lung cancer
Thymoma
Other cancersAnti-Ma protein antibodies‡ Limbic, hypothalamic, brain-stem encephalitis (infrequently PCD) Testicular cancer
Lung cancer
Other cancersAnti-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.