Paraneoplastic Cerebellar Degeneration (PCD) is one of the more commonly seen paraneoplastic neurological syndromes. It is caused by immune-mediated injury to cerebellar Purkinje cells. It is associated with multiple malignancies but, most commonly, breast and pelvic malignancies.[rx] PCD has also been reported in patients with Hodgkin lymphoma, gastric cancer, prostate cancer, and small cell lung cancer.[rx][rx] PCD can progress rapidly over a few weeks and can result in severe disability.
Pathophysiology
Paraneoplastic cerebellar degeneration is an inflammatory autoimmune process that occurs due to the destruction of cerebellar Purkinje cells by onconeural antibodies; these antibodies are produced by the immune system in response to a protein that is expressed by tumor cells. This protein is known as cerebellar degeneration-related protein 2.[rx] These antibodies cross-react with a similar protein present in the cerebellar Purkinje cells causing their death. This frequently starts as a localized process. However, it gradually spreads to involve the entire cerebellum. There is also evidence of brain stem involvement.[rx] The rate of injury varies between patients, with some presenting with acute symptoms versus a more subacute slow-progressing process.[rx]
Multiple onconeural antibodies were detected in patients with paraneoplastic cerebellar degeneration and are thought to the culprit in the cerebellar Purkinje cells injury. These antibodies include anti-Yo (PCA-1), anti-Hu, anti-Ri, anti-Tr, anti-VGCC, anti-Ma, anti-CRMP5 (anti-CV2), and anti-mGluR.[rx] Anti-Yo antibody, also known as anti-Purkinje cell cytoplasmic antibody type 1, is the most commonly detected and is usually associated with breast and gynecological malignancies.[rx] Histopathological examination of cerebellar tissues of patients with paraneoplastic cerebellar degeneration revealed widespread inflammation, gliosis, and loss of Purkinje cells.[rx]
The anti-Purkinje cell antibodies originally described in PCD led to the hypothesis that the antibody might be pathogenic, much as earlier studies had demonstrated pathogenicity of anti-acetylcholine receptor antibodies in myasthenia gravis. However, when the antibody was used to clone the cDNA encoding the cdr2 antigen, it was found to be an intracellular protein. This led to the suggestion[rx] that there might be a cell-mediated component (T cell) in disease pathogenesis. cdr2 antigen-specific CD8+ T cells were subsequently described[rx] in more anti-Yo-positive PCD patients,.[rx] These T cells are likely components in both the anti-tumor immune response and in the neuronal degeneration.
Causes of Paraneoplastic Cerebellar Degeneration
Paraneoplastic cerebellar degeneration is caused by onconeural antibodies produced by the immune system in response to a malignant tumor; these onconeural antibodies attack Purkinje cells in the cerebellum, causing acute to subacute cerebellar dysfunction.[rx]
Antibodies in paraneoplastic syndromes involving the brain (not all of these are cerebellar)
| Antibody Name | Tumor type | Reacts with | Symptoms |
| Hu | Small cell lung | Anti-neuronal nuclear antibody-1 | Sensory neuropathy, encephalo myeloneuropathy, gastrointestinal dysmotility. Not useful in following persons with paraneoplastic syndromes. |
| 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, opsoclonus, stiff-man syndrome. |
| 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 |
| NMDAR | ovarian teratomas | anti-NMDA receptor on cells | Encephalitis |
| Kelch | Seminoma | antibody for Kelch | vertigo, tinnitus, hearing loss, and ataxia in the context of seminoma or “testicular microlithiasis” |
Symptoms of Paraneoplastic Cerebellar Degeneration
Neurological symptoms may include, among others, dysarthria, truncal, limb and gait ataxia and nystagmus.[rx] Symptoms often develop subacutely and progress rapidly over a period of weeks or months to a plateau period that can last for months to years and which often reflects the complete loss of Purkinje cells.
Diagnosis of Paraneoplastic Cerebellar Degeneration
History and Physical
Patients with paraneoplastic cerebellar degeneration can present initially with mild symptoms such as unsteady gait, double vision, and difficulty with fine hand movements. These symptoms usually progress to limb and truncal ataxia. Brain stem related symptoms have also been reported, including nystagmus, dysarthria, dysphagia.[rx] In some patients, the symptoms can progress slowly over a few weeks or months, but rapidly progressing symptoms over days have also been reported. Some patients will experience a prodrome of flu-like illness, with low-grade fever, malaise, nausea, and vomiting before the onset of motor symptoms.[rx] The onset of cerebellar symptoms can precede the diagnosis of malignancy by months to years.[rx][rx] Personal or family history of cancer or autoimmune disease in patients presenting with cerebellar ataxia must raise suspicion towards paraneoplastic cerebellar degeneration.
Imaging Studies
Patients suspected to have paraneoplastic cerebellar degeneration should undergo brain imaging with computed tomography scans (CT) and magnetic resonance imaging (MRI) to rule out hemorrhagic strokes, primary and secondary brain tumors, and ischemic strokes as part of their initial workup. MRI of the brain in PCD is usually normal but can show cerebellar atrophy as the disease progresses. Fluorodeoxyglucose-positron emission tomography scan can show increased activity early in the disease.[rx] Positron emission tomography-computed tomography (PET/CT) is essential to detect the underlying malignancy.
CSF Analysis
Patients with paraneoplastic neurological syndromes often have mild pleocytosis, protein elevation, and/or oligoclonal bands. These findings are neither sensitive nor specific.
Paraneoplastic Antibody Assay
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Anti-Yo (PCA-1): this is the most commonly detected onconeural antibody in PCDand is commonly associated with breast cancer and ovarian cancer.
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Anti-Hu: small-cell lung cancer, prostate cancer, and seminoma testicular cancer.
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Anti-Ri: breast, ovarian and small cell lung cancers
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Anti-Tr: Hodgkin lymphoma
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Anti VGCC: small cell lung cancer and lymphoma
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Anti- Ma2: small cell lung cancer and testicular cancer
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Anti- CRMP5 (Anti- CV2): small cell lung cancer and thymoma
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Anti-mGluR1: Hodgkin lymphoma.
To diagnose a patient with definitive PCD, the patient must have severe cerebellar symptoms for less than 12 weeks with a normal brain MRI, and the patient must also have a moderate disability with at least a score of 3 on the Modified Rankin Scale (MRS), Clinical evidence of both appendicular and truncal ataxia must be present in addition to an established diagnosis of cancer within 5 years of symptoms onset. Patients with cerebellar symptoms and detectable onconeural antibodies are also considered to have definitive PCD.[rx]
Patients who have the classic symptoms without onconeural antibodies are considered to have probable PCD and should undergo further imaging to detect underlying malignancy, and should have repeat paraneoplastic antibody assay.[rx] Patients with high clinical suspicion and no identifiable underlying malignancy should be placed on regular surveillance.
Treatment of Paraneoplastic Cerebellar Degeneration
Management of paraneoplastic cerebellar degeneration mainly relies on early identification and treatment of the underlying malignancy.[rx] Immunotherapy has also been recommended, including systemic corticosteroids, intravenous immunoglobulins, plasma exchange, cyclophosphamide, tacrolimus, and rituximab with variable degrees of response.[rx][rx] Patients who underwent treatment of their primary malignancy had better outcomes regardless of the use of immunotherapy.[rx] To our knowledge, there were no randomized controlled clinical trials for the treatment of PCD, and this is probably due to the very low prevalence of the disease.
References