Hospital Medicine

Cerebellar degeneration

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Cerebellar degeneration

I. What every physician needs to know.

Cerebellar degeneration refers to cerebellar cell loss or damage with resulting neurologic findings. It is a descriptive term rather than a diagnosis unto itself. Traditionally, the term has referred to a group of heterogeneous, inherited, neurodegenerative cerebellar disorders that have recently become differentiated and categorized due to an expanded understanding of the underlying genetics.

Cerebellar degeneration can be autosomal recessive (such as in Friedrich’s ataxia), autosomal dominant (such as in the spinocerebellar ataxias), X-linked, or mitochondrial. However, acquired conditions (including infectious, metabolic, autoimmune, paraneoplastic, nutritional, toxic, or medication-related triggers) can lead to similar clinical findings and neuroimaging results as these genetic syndromes.

In this article, we will focus on the inherited and sporadic neurodegenerative cerebellar disorders, which typically present with subacute or chronic progressive cerebellar signs. Our discussion will include the initial evaluation of these patients, including the important historical, physical, and diagnostic considerations required to rule out an alternative systemic condition that can mimic a primary neurologic cerebellar condition.

II. Diagnostic Confirmation: Are you sure your patient has cerebellar degeneration?

Primary neurologic cerebellar degeneration is a diagnosis based on clinical features, including classic cerebellar findings (such as limb or truncal ataxia, dysmetria, or ocular findings), family history, subacute or chronic duration of symptoms, and progressive time course. Imaging is not necessary to confirm the diagnosis but can help confirm cerebellar atrophy and rule out other etiologies of cerebellar disease. Laboratory evaluation is crucial, both to exonerate systemic (and potentially reversible) triggers for cerebellar degeneration as well as to conduct genetic testing.

A. History Part I: Pattern Recognition:

The inherited cerebellar degenerative syndromes present as subacute or chronic neurologic symptoms, usually over months to years. Obtaining a thorough family history is important, and may identify a pattern of disease that is consistent with a genetic syndrome.

Most autosomal recessive ataxias begin in childhood or early adult life, though later onset symptoms are possible as well. Typically, parents do not manifest the condition because they are heterozygote for the mutation. Multiple children, both boys and girls, may have the condition if the parents have a large number of children. Friedrich’s ataxia is the most common inherited ataxia. Symptoms of gait difficult and clumsiness begin in adolescence and involvement of non-neurologic organ systems, such as musculoskeletal deformities, hypertrophic cardiomyopathy, and diabetes, may manifest as well.

Autosomal dominant cerebellar degeneration can be grouped into those conditions with progressive versus episodic features. Progressive cerebellar degeneration is seen in spinocerebellar ataxias (SCAs) whereas episodic ataxias (EA) are characterized by ataxia precipitated by stress, startle or exercise that wanes over minutes to days following the precipitant. Both types of autosomal dominant cerebellar degeneration are seen in all generations of a given family.

SCAs occur due to multiple different genetic mutations, but they have overlapping clinical features. Patients typically develop symptoms in early or middle adult life, but there is a wide range of age at onset. Patients exhibit progressive gait ataxia with associated dysmetria, dysdiadochokinesia (difficulty with rapid alternating movements), dysarthria, and nystagmus. Non-cerebellar signs may include bulbar deficits, upper motor neuron signs (such as brisk reflexes or spasticity), extrapyramidal signs, peripheral neuropathy, restless legs, sleep disturbance, and psychiatric comorbidities. The motor syndrome of SCA is always progressive, with loss of ambulation over 15 years.

Finally, sporadic cerebellar degeneration syndromes resemble inherited ataxias but have no defined genetic mutations. These patients may develop symptoms at any age and require a broad evaluation to rule out a previously defined genetic ataxia or acquired systemic trigger for their neurologic degeneration.

B. History Part 2: Prevalence:

Inherited cerebellar degeneration is not common though multiple different mutant gene loci have been identified. Friedrich’s ataxia is the most common inherited cerebellar degenerative syndrome with a prevalence of 1 in 50,000 Caucasians.

C. History Part 3: Competing diagnoses that can mimic cerebellar degeneration.

Cerebellar exam findings, such as ataxia, vertigo, and dysmetria, are associated with other forms of cerebellar insult besides inherited disorders. These other triggers include:

  • Vascular disorders, such as embolic or thrombotic stroke, dissection, vasculitis, or haemorrhage

  • Medications, such as anti-epileptic drugs (especially phenytoin, which can cause both an acute ataxia as well as a chronic cerebellar degeneration), benzodiazepines, and chemotherapy (e.g., cytarabine can cause an acute cerebellar syndrome and fluorouracil can cause a delayed ataxia)

  • Toxins, such as alcohol, heavy metals (especially mercury), and toluene

  • Nutritional deficiencies such as thiamine, vitamin B12, vitamin E, and copper

  • Infections, such as meningoencephalitis, HIV, progressive multifocal leukoencephalopathy, prion disease, Whipple’s disease

  • CNS demyelinating disorders such as multiple sclerosis

  • Primary or metastatic tumors or leptomeningeal carcinomatosis

  • Autoimmune conditions such as post-infectious cerebellitis, the Miller Fisher variant of Guillain-Barre syndrome, glutamic acid decarboxylase (ADA) antibody-associated ataxia (a sporadic ataxia seen in women, often with type 1 diabetes or other autoimmune conditions), celiac disease and gluten ataxia, and Hashimoto’s encephalopathy

  • Paraneoplastic cerebellar degeneration, which is most frequently seen in small-cell lung cancer (associated with anti-Hu antibodies), ovarian or breast cancer (anti-Yo antibodies), and Hodgkin’s disease (anti-Tr antibody)

It is important to also rule out conditions that mimic cerebellar ataxia. These include:

  • Sensory ataxia from large fiber sensory neuropathy and loss of proprioception

  • Normal pressure hydrocephalus

  • Obstructive hydrocephalus

  • Migraine headache with ataxia

  • Psychogenic ataxia

Finally, other neurodegenerative syndromes can present with cerebellar signs. Multiple system atrophy (MSA) is a neurodegenerative disorder that affects the brainstem, cerebellum, and basal ganglia. Patients with MSA develop symptoms in the fifth or sixth decade of life. They experience symmetric cerebellar signs as well as Parkinsonian features, autonomic dysfunction and urologic problems.

D. Physical Examination Findings.

Syndromes of cerebellar degeneration typically manifest as subacute or chronic cerebellar neurological signs. Certain neurologic findings can localize the pathologic process to the midline cerebellum (which includes the vermis) or cerebellar hemispheres, although there is often clinical overlap.

Midline cerebellar structures control motor execution, rapid and slow eye movements, balance, and vestibular function. A degenerative process in the midline cerebellum can thus result in the following findings:

  • Gait ataxia (especially difficulty with tandem gait)

  • Imbalance

  • Truncal ataxia

  • Dysmetria

  • Head bobbing

  • Vertigo

The cerebellar hemispheres deal with motor planning and coordination of complex tasks. An injury on one side leads to ipsilateral findings. Symptoms of cerebellar hemisphere injury include:

  • Dysdiadochokinesis (difficulty with rapid alternating movements)

  • Dysmetria of the hands and arm (lack of coordination or difficulty with measuring of distance using different muscle groups)

  • Limb ataxia (evaluated by finger-to-nose and heel-to-shin tests)

  • Intention tremor (occurs at end of purposeful movement)

  • Scanning speech (abnormal pauses between syllables of a word)

E. What diagnostic tests should be performed?

A thoughtful clinical approach to the patient with cerebellar signs will lead to an accurate diagnosis. The patient’s age, acuity of symptoms, pace of symptom progression, comorbid medical conditions, medications, associated neurological signs and family history are crucial in selection of appropriate diagnostic tests.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Laboratory studies for cerebellar degeneration serve two major purposes: 1) to rule out systemic conditions leading to cerebellar symptoms, and 2) to identify specific genetic mutations when an inherited neurodegenerative cerebellar syndrome is suspected. Evaluation of a patient with cerebellar symptoms should always include consultation with a neurologist.

As outlined above, many systemic conditions can lead to cerebellar symptoms and degeneration that mimic primary neurodegenerative disorders. Lab tests should be selected based on an individual patient’s exposures and risk factors. A broad serologic evaluation for a patient with progressive ataxia or other cerebellar symptoms could include: ESR, CRP, medication levels, toxicology panel, mercury and copper levels, vitamin E, vitamin B12, HIV, TSH, anti-gliadin antibodies (celiac disease), antiGAD antibodies (which can lead to low GABA levels in cerebellum and thus ataxia), paraneoplastic antibodies (such as anti-Hu and anti-Yo).

Cerebrospinal fluid samples may be useful as well, particularly to check for cell counts, protein level, infectious studies, oligoclonal bands, and 14-3-3 proteins.

Finally, genetic testing for inherited cerebellar degenerative syndromes is appropriate if the clinical history and negative systemic evaluation suggest a familial disorder. It is most appropriate to begin with testing for the more common conditions (such as Friedrich’s ataxia and spinocerebellar atrophy types 1-3), but testing should be discussed with neurology and genetics consultants.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

A non-contrast head CT is most appropriate for acute onset cerebellar symptoms to rule out ischemia or hemorrhage. For more subacute or chronic cerebellar symptoms, an MRI of the brain with contrast is the study of choice to identify masses, demyelinating lesions, vascular malformations, or cerebellar atrophy.

It is important to recognize, however, that cerebellar degeneration is not necessarily associated with demonstrable cerebellar atrophy or cerebellar signal changes on neuroimaging. The degenerative process may take place at a more microscopic level.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

While no single test for the work-up of cerebellar degeneration has an unacceptably poor yield unto itself, waste may occur when an expansive work-up is undertaken when unnecessary. For example, if a patient with a strong family history of breast cancer presents with cerebellar ataxia, initial focus should be on diagnosing paraneoplastic cerebellar degeneration as opposed to conducting a genotypic analysis for an inherited spinocerebellar ataxia.

III. Default Management.

A. Immediate management.

After getting diagnosed with an inherited cerebellar degenerative disorder, the patient should be managed in consultation with a neurologist. Most progressive, inherited syndromes have no cure, though specific management approaches will vary based on the clinical syndrome. For example, there is some evidence that idebenone (a synthetic derivative of coenzyme Q10) may improve cardiac and neurologic function in patients with Friedrich’s ataxia.

Supportive care remains the foundation of treatment. Physical therapy, occupational therapy, and speech and language pathology teams should assess patients’ functional status and provide optimal safety recommendations.

B. Physical Examination Tips to Guide Management.

Serial assessments may demonstrate a marked improvement in ataxia with appropriate management of reversible causes. In conditions without reversibility (such as the inherited cerebellar degenerative syndromes), it is important to clearly document initial exam findings, as these will tend to worsen over time as the disease progresses.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

There are no laboratory tests that are helpful to monitor inherited cerebellar degeneration.

D. Long-term management.

Long-term management of patients with inherited cerebellar degeneration involves a longitudinal relationship with a neurologist (typically a movement disorders specialist), supportive therapies (such as physical, occupational, and speech and language therapies), and improvements in the home environment (specifically handicap aids) to optimize safety.

Finally, genetic counselling should be provided both before and after genetic testing is done for the inherited neurodegenerative cerebellar syndromes.

E. Common Pitfalls and Side-Effects of Management

N/A

IV. Management with Co-Morbidities

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations while hospitalized.

N/A

B. Anticipated Length of Stay.

N/A

C. When is the Patient Ready for Discharge.

A patient with cerebellar degeneration should be discharged after reversible causes are excluded using laboratory and neuroimaging studies. Before leaving the acute care facility, the patient should receive physical therapy, occupational therapy, speech and language therapy, and home safety evaluations.

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

Clinic follow up should include primary care and neurology appointments. A genetics appointment is also helpful for patients with inherited cerebellar degeneration.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

MRI of the brain, CSF analysis (with specific studies noted above), and appropriate serologic elevation (HIV, TSH, etc.) should be completed prior to discharging a patient in order to rule out systemic etiologies of cerebellar degeneration.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

N/A

E. Placement Considerations.

Physical therapy and occupational therapy consultations should take place prior to discharge to evaluate the patient’s degree of disability. These evaluations may demonstrate that the patient requires rehabilitation following discharge, and, depending upon the prognosis, even long-term placement in a skilled nursing facility.

F. Prognosis and Patient Counseling.

Each specific inherited or sporadic disease that results in cerebellar degeneration carries its own prognosis, but most are progressive. Patients and families should meet with psychosocial and genetic counsellors to talk about next steps and implications on family dynamics.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Careful consideration of functional status and needs upon discharge are important. Functional assessment via physical therapy, occupational therapy, and speech and language pathology may help reduce readmission. Home services and respite care will also help family members cope with their relative’s progressive neurodegenerative condition.

VII. What's the evidence?

Subramony, SH, Xia, G, Bradley, W.G., Daroff, R.B., Fenichel, G.M., Jankovic, J.. "Disorders of the Cerebellum, Including the Degenerative Ataxias". Neurology in Clinical Practice. Elsevier. 2008. pp. 2123-2145.

(This textbook chapter summarizes acquired, inherited, and sporadic ataxias.)

Paulson, HL.. "The Spinocerebellar Ataxias". J Neuroophthal. vol. 29. 2009. pp. 227-237.

(This article reviews the spinocerebellar ataxias.)

Storey, E.. "Genetic cerebellar ataxias". Semin Neurol. vol. 34. 2014. pp. 280-92.

(This article reviews the most common genetic cerebellar ataxias, including SCAs and Friedrich’s ataxia.)

"Paraneoplastic syndromes of the CNS". Lancet Neurol. 2008.

(This article reviews paraneoplastic neurologic disorders and recent clinical and immunological developments.)

"Phenytoin toxicity: an easily missed cause of cerebellar syndrome". J Clin Pharm Ther. 2008.

(This case series of patients with phenytoin toxicity emphasizes that these patients can present with cerebellar signs.)

"Dietary treatment of gluten ataxia". J Neurol Neurosurg Psychiatry. 2003.

(This article discusses that immune-mediated gluten ataxia improves with strict gluten-free diet.)

"Cerebellar atrophy associated with HIV infection". Arch Neurol. 2010.

(This article reviews the clinical syndrome of cerebellar degeneration in HIV positive patients.)
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