Paraneoplastic cerebellar degeneration

Overview

Paraneoplastic cerebellar degeneration (PCD) is a rare and serious neurological disorder that occurs as a remote effect of cancer. It is classified as a paraneoplastic syndrome, meaning it results from the body's immune response to an underlying malignancy rather than direct tumor invasion or metastasis. PCD specifically affects the cerebellum—the part of the brain responsible for coordination, balance, and fine motor control. The condition leads to a rapid onset of cerebellar dysfunction, often resulting in significant disability. PCD can precede the diagnosis of cancer and may be the first indication of an occult malignancy, making early recognition crucial for initiating prompt cancer screening and treatment.

Causes

Paraneoplastic cerebellar degeneration is caused by an autoimmune reaction in which the body’s immune system mistakenly attacks cerebellar neurons, particularly Purkinje cells, in response to an underlying tumor. This occurs because of the production of autoantibodies that cross-react with both tumor antigens and antigens present in the cerebellum.

The most common cancers associated with PCD include:

• Small cell lung carcinoma (SCLC)

• Breast cancer

• Ovarian cancer

• Hodgkin lymphoma

• Uterine or other gynecologic cancers

Several specific onconeural antibodies have been identified in PCD, including:

• Anti-Yo (PCA-1): Most commonly seen in breast and gynecologic cancers.

• Anti-Hu (ANNA-1): Typically associated with small cell lung cancer.

• Anti-Tr: Found in patients with Hodgkin lymphoma.

• Anti-Ri (ANNA-2): Also associated with breast cancer and SCLC.

Symptoms

Symptoms of paraneoplastic cerebellar degeneration develop rapidly over weeks to a few months and are primarily related to cerebellar dysfunction. Common clinical features include:

• Ataxia: Unsteady gait, poor coordination, and difficulty walking.

• Dysmetria: Inability to judge distance or scale of movement (e.g., overshooting or undershooting a target).

• Dysarthria: Slurred or slowed speech due to impaired coordination of the speech muscles.

• Nystagmus: Rapid, involuntary eye movements, often horizontally oriented.

• Vertigo: A sensation of spinning or dizziness.

• Tremor: Intention tremor that worsens with purposeful movement.

• Cognitive or mood changes: In some cases, mild memory loss or personality changes may occur.

The symptoms are usually bilateral and progressive, and they can severely affect a person's ability to perform daily tasks and maintain independence.

Diagnosis

Diagnosing PCD involves identifying the characteristic clinical presentation, confirming cerebellar dysfunction, detecting associated antibodies, and searching for an underlying malignancy. Diagnostic steps include:

• Neurological examination: Reveals signs of cerebellar ataxia, tremor, and coordination deficits.

• MRI of the brain: May show cerebellar atrophy or signal abnormalities in the cerebellum. However, MRI findings can be normal in early stages.

• Cerebrospinal fluid (CSF) analysis: Often shows elevated protein and lymphocytic pleocytosis; oligoclonal bands may be present.

• Serologic testing: Detection of onconeural antibodies such as anti-Yo, anti-Hu, anti-Ri, or anti-Tr supports the diagnosis.

• Cancer screening: Full-body imaging (CT, PET scan) and specific tumor markers are essential to identify the underlying neoplasm. In women, gynecological exams and mammograms are critical; in men, testicular and prostate evaluations may be indicated.

Diagnosis is often made clinically in the context of cerebellar symptoms, supportive antibody tests, and evidence of an associated malignancy.

Treatment

Treatment of paraneoplastic cerebellar degeneration involves managing the underlying cancer and modulating the immune response to reduce neurological damage. Key treatment approaches include:

1. Cancer Therapy

• Surgical removal: If the tumor is localized and operable.

• Chemotherapy and radiation: Often required for systemic cancers such as SCLC or breast cancer.

• Prompt treatment of cancer: Can sometimes halt or reverse neurological decline if initiated early.

2. Immunotherapy

• Corticosteroids: High-dose intravenous steroids may reduce inflammation and immune activity.

• Intravenous immunoglobulin (IVIG): Used to modulate immune responses, particularly in early-stage disease.

• Plasmapheresis: May be helpful in removing circulating autoantibodies.

• Immunosuppressants: Agents like cyclophosphamide or rituximab may be considered in resistant cases.

3. Supportive Care

• Physical and occupational therapy: Helps patients retain mobility and functional independence.

• Speech therapy: Beneficial for dysarthria and swallowing difficulties.

• Assistive devices: May include walkers, canes, or wheelchairs depending on the degree of ataxia.

Prognosis

The prognosis of paraneoplastic cerebellar degeneration is generally poor, especially if diagnosis and treatment are delayed. Neurological deficits often progress rapidly and may become irreversible, even if the underlying tumor is treated successfully. Early detection of the associated cancer and prompt initiation of treatment may halt progression and, in rare cases, lead to partial improvement. However, most patients are left with significant cerebellar dysfunction. The presence and type of onconeural antibodies (e.g., anti-Yo is associated with a worse prognosis) can also influence outcomes. Long-term supportive care is essential to manage chronic symptoms and improve quality of life.