Continuing Education Activity

Paraneoplastic cerebellar degeneration, also known as paraneoplastic cerebellar ataxia is one of the most commonly occurring paraneoplastic neurological syndromes. The symptoms of paraneoplastic cerebellar degeneration can be rapidly progressive and very debilitating. They can also precede the diagnosis of the underlying malignancy. Thus, prompt recognition and treatment of this disease are crucial to the prevention of significant disability. This activity reviews the diagnosis and treatment of paraneoplastic cerebellar degeneration and highlights the importance of interdisciplinary coordination between healthcare teams to manage patients with this condition.

Objectives:

• Review the pathophysiology of paraneoplastic cerebellar degeneration.
• Summarize the pertinent history and physical examination findings in patients with paraneoplastic cerebellar degeneration.
• Outline the diagnostic tests for patients with paraneoplastic cerebellar degeneration.
• Describe interprofessional team strategies for improving care coordination and communication to diagnose paraneoplastic cerebellar degeneration and improve patients outcomes.

Introduction

Paraneoplastic syndromes constitute a group of uncommon manifestations that are noted in patients with different types of malignancies.[1] The underlying mechanism is not a direct spread but could be hormonal, caused by active proteins or peptides secreted by malignant cells such as antidiuretic hormone (ADH), parathyroid hormone-related peptide (PTHrP) or adrenocorticotrophic hormone (ACTH). They also can be autoimmune, caused by crossreacting antibodies or immune cells produced in the human body in response to malignant tumors, such as Lambert Eaton syndrome, paraneoplastic cerebellar degeneration, and limbic encephalitis. They can also be related to cytokines produced by tumor cells or the immune system. Paraneoplastic syndromes can occur with multiple types of malignancies, including but not limited to breast cancer, small cell lung cancer, squamous cell lung cancer, Hodgkin lymphoma, mesothelioma, renal cell carcinoma, and multiple other malignancies.[2] 

Clinicians need to be familiar with the presentations of paraneoplastic syndromes as they can be the first presenting symptoms of an underlying malignancy.[3] Failure to identify these syndromes may result in delayed diagnosis of cancer and poor clinical outcomes. These syndromes are not directly related to tumor invasion, metastatic disease symptoms, or due to adverse treatment effects.

Paraneoplastic neurological syndromes (PNS) are a unique subset of paraneoplastic syndromes. Caused by cross-reactive antibodies called onconeural antibodies, these are antibodies produced by the immune system in response to malignant tumors. These onconeural antibodies can attack different parts of the nervous system resulting in various neurological manifestations.[4]

Paraneoplastic cerebellar degeneration (PCD) is one of the more commonly seen paraneoplastic neurological syndromes.[5] It is caused by immune-mediated injury to cerebellar Purkinje cells. It is associated with multiple malignancies but, most commonly, breast and pelvic malignancies.[6] PCD has also been reported in patients with Hodgkin lymphoma, gastric cancer, prostate cancer, and small cell lung cancer.[7][8] PCD can progress rapidly over a few weeks and can result in severe disability.

Etiology

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.[9]

Epidemiology

Paraneoplastic cerebellar degeneration is very rare and is thought to affect less than 1% of patients with cancer.[6] Due to the rarity of the condition, available epidemiological data is limited. Paraneoplastic cerebellar degeneration is presumed to be more frequent in females. This hypothesis has been made due to the high prevalence of anti-yo antibodies in these patients [10]; these antibodies are mainly associated with breast and gynecological malignancies.[11]

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.[12] 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.[13] The rate of injury varies between patients, with some presenting with acute symptoms versus a more subacute slow-progressing process.[11] 

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.[14] 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.[15] Histopathological examination of cerebellar tissues of patients with paraneoplastic cerebellar degeneration revealed widespread inflammation, gliosis, and loss of Purkinje cells.[16]

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.[10] 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.[17] The onset of cerebellar symptoms can precede the diagnosis of malignancy by months to years.[18][7] Personal or family history of cancer or autoimmune disease in patients presenting with cerebellar ataxia must raise suspicion towards paraneoplastic cerebellar degeneration.

Evaluation

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.[19] 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

• Anti-Yo (PCA-1): this is the most commonly detected onconeural antibody in PCDand is commonly associated with breast cancer and ovarian cancer.
• Anti-Hu:  small-cell lung cancer, prostate cancer, and seminoma testicular cancer. 
• Anti-Ri: breast, ovarian and small cell lung cancers
• Anti-Tr: Hodgkin lymphoma
• Anti VGCC: small cell lung cancer and lymphoma
• Anti- Ma2: small cell lung cancer and testicular cancer
• Anti- CRMP5 (Anti- CV2): small cell lung cancer and thymoma
• 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.[20]

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.[9] Patients with high clinical suspicion and no identifiable underlying malignancy should be placed on regular surveillance. 

Treatment / Management

Management of paraneoplastic cerebellar degeneration mainly relies on early identification and treatment of the underlying malignancy.[21] Immunotherapy has also been recommended, including systemic corticosteroids, intravenous immunoglobulins, plasma exchange, cyclophosphamide, tacrolimus, and rituximab with variable degrees of response.[22][23] Patients who underwent treatment of their primary malignancy had better outcomes regardless of the use of immunotherapy.[21] 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.

Differential Diagnosis

In patients presenting with central ataxia, it is important to rule out more common etiologies, namely, space-occupying lesions and vascular insults affecting the cerebellum. It is also important to differentiate paraneoplastic cerebellar degeneration from other neurological disorders than can present in a similar way. These can be classified into:

1. Demyelinating disorders, such as multiple sclerosis
2. Autoimmune disorders such as glutamic-acid-decarboxylase-associated cerebellar degeneration, sarcoidosis, systemic lupus erythematosus, and Behcet disease
3. Atypical central nervous system infections: Creutzfeldt-Jakob disease, progressive multifocal leukoencephalopathy.
4. Metabolic disorders: vitamin B12 deficiency, alcohol-related Wernicke encephalopathy, celiac disease

Prognosis

Paraneoplastic cerebellar degeneration has a poor prognosis, Patients with PCD experience progressive symptoms for weeks to months, most patients' symptoms will stabilize after 6 months of onset, by this time the majority of the patients are significantly disabled and are either wheelchair or bed-bound. Patients with anti-yo antibodies and anti-Hu antibodies were noted to have more severe symptoms and are more resistant to treatment and were noted to have worse overall survival compared to patients with anti-Tr antibodies and anti-Ri-antibodies.[21]

Complications

Delayed recognition and treatment of paraneoplastic cerebellar degeneration can result in severe disability. The damage to the cerebellum is irreversible once the disease has reached the burnout state. The delay in the diagnosis of underlying malignancy can result in cancer progression with significant morbidity and mortality.

Deterrence and Patient Education

Cerebellar diseases cause unsteady gait, frequent falls, and can lead to injuries and significant disabilities. PCD is a rare condition with no evidence-based treatment guidelines. There are no known preventive measures, and the treatment outcomes are not consistent.[21] As in any neurological condition, early recognition of symptoms and seeking professional help is key to early diagnosis and better outcomes. 

Enhancing Healthcare Team Outcomes

The diagnosis and management of paraneoplastic cerebellar degeneration can pose a challenge and requires an interprofessional approach with close coordination between healthcare professionals in different specialties. Patients typically present to their primary care provider or the emergency provider at the onset of symptoms, and their rule is essential in excluding the more common causes of cerebellar symptoms, mainly ischemic strokes, and space-occupying lesions. Patients with normal brain imaging should be referred to a neurologist for further workup.

High suspicion of a paraneoplastic syndrome should warrant an oncological evaluation for prompt identification of the underlying malignancy. Once a malignancy is identified, the patient may need surgical intervention. This interprofessional approach is crucial to achieving better outcomes in patients with PCD. One should also acknowledge the role of physical therapy and rehabilitation medicine in managing patients with PCD.[24] [Level 5]