Magali Fernandez, MD
DESCRIPTION
Ataxia is defined as incoordination of movements, especially voluntary movements. Gait, limb movements, balance, speech, eye movements, and tone can be involved. Ataxia may be of sudden or insidious onset. Irregular movements are especially prominent with directed movements of the limbs and become more pronounced closer to the target (hypermetria, intention tremor). Gait is wide based and unsteady. Speech may be hesitant or explosive. Nystagmus and irregular eye movements may be seen.
EPIDEMIOLOGY
Incidence
No reports available.
Prevalence
- The National Ataxia Foundation estimates that there are 150,000 individuals affected by either a hereditary or sporadic ataxia in the US.
- Prevalence of the autosomal dominant cerebellar ataxias (ADCAs) in Europe is estimated to be between 1 and 3 per 100,000 Europeans (1).
RISK FACTORS
- Acquired ataxias:
- Excessive alcohol consumption, drug or toxin exposure, nutritional deficiencies.
Genetics
- The hereditary ataxias progress slowly and can be classified by type of inheritance.
- In autosomal-dominant ataxias, risk to offspring (of being affected) is 50%.
- In autosomal-recessive forms, risk to siblings is a 25% chance of being affected, 50% of being an unaffected carrier, and 25% chance of being unaffected and not a carrier. Offspring of an affected individual are obligate carriers.
- In X-linked recessive inheritance, all daughters of an affected male are carriers; sons are not affected. For siblings, if the mother of the affected individual is a carrier, brothers are at 50% risk of being affected; sisters have a 50% chance to be carriers and unaffected.
- Mitochondrial disorders are transmitted by maternal inheritance. Males do not transmit mitochondrial DNA mutations. A female with a mitochondrial (mt) DNA mutation may transmit a variable amount of mutant mtDNA to her offsprings, which results in clinical variability among siblings in the same family.
GENERAL PREVENTION
- There are no specific treatments, prophylaxis, or vaccines available for sporadic or hereditary ataxia, with the exception of:
- Vitamin E therapy for ataxia with vitamin E deficiency (AVED).
PATHOPHYSIOLOGY
Varies depending on the specific cause of ataxia. Ataxia is most commonly related to disruption of cerebellar pathways. However, coordinated movements require synchronization of multiple sensory and motor pathways, and injury to the spinal cord, brainstem, cortex or peripheral nervous system can also cause ataxia.
ETIOLOGY
COMMONLY ASSOCIATED CONDITIONS
- Mitochondrial disorders are frequently associated with other manifestations: Seizures, diabetes mellitus, cardiomyopathy, short stature, retinopathy, and deafness.
- Ataxia telangiectasia is associated with recurrent infections and susceptibility to malignancies.
HISTORY
Age of onset, family history, and drug, alcohol, or toxin exposure should be elicited. Determine if the ataxia is static or progressive and if the symptoms are intermittent or permanent. Association with acute headache, nausea, vomiting, and/or diplopia may be a sign of acute cerebellar infarct or hemorrhage and should be treated as potentially life threatening. In older males with recent onset ataxia and tremor inquire about grandchildren with mental retardation to assess for the fragile X-associated tremor/ataxia syndrome.
PHYSICAL EXAM
Ataxia may be cerebellar or sensory in origin or both. The brainstem, basal ganglia, spinal cord, retina, or peripheral nervous system are often involved. There is great overlap in the phenotype of the hereditary SCAs. There are a few distinguishing features for some types. Molecular diagnosis is needed for definitive classification.
- Distinguishing features of some autosomal-dominant hereditary ataxias:
- SCA2: Slow saccadic eye movements, hyporeflexia, or areflexia
- SCA4: Sensory axonal neuropathy
- SCA6: Sometimes episodic ataxia is present
- SCA7: Visual loss with retinopathy
- SCA10: May be associated with seizures
- SCA12: Early tremor, late dementia
- SCA13: Mild mental retardation and short stature
- SCA14: Early axial myoclonus
- SCA16: Head and hand tremor
- DRPLA: Chorea, seizures, and myoclonus
- EA1: Episodic ataxia lasting seconds/minutes, myokymia
- EA2: Episodic ataxia lasting minutes to hours, nystagmus (2,3)
- Distinguishing features of the autosomal-recessive disorders:
- Friedreich ataxia (FA): Hyporeflexia or areflexia, extensor plantars, depressed vibratory/proprioceptive sense, and cardiac involvement
- AVED: Similar to FA, plus head titubation and dystonia
- Ataxia telangiectasia: Telangiectasia, immunodeficiency, cancer and endocrine abnormalities
- Ataxia with oculomotor apraxia: Oculomotor apraxia, choreoathetosis, and mental retardation
- Spastic ataxia autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS): Pyramidal signs, peripheral neuropathy, and retinal striations
- X-linked disorder:
- Fragile X-associated tremor/ataxia syndrome
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
- Serum levels of vitamin B12, thyroid-stimulating hormone (TSH), and vitamin E should be checked. Heavy metal screening in cases of suspected exposure should be performed. Plasma amino acids and urine organic acids are helpful when an inherited metabolic cause is suspected. If the Miller-Fisher variant of Guillain–Barré syndrome is suspected (ataxia with areflexia and ophthalmoplegia), lumbar puncture for cell count and protein level and nerve conduction studies should be considered.
- Molecular genetic testing for patients with a family history.
Follow-Up & Special Considerations
- DNA testing is commercially available for SCA1, 2, 3, 5–8, 10–15, 17–18, 23, 27, 28, DRPLA, EA1, 2, 5, and 6, FA, ataxia-telangiectasia, and other autosomal recessive ataxias (3). These tests are expensive. Genetic counseling prior to testing is advised.
- A premutation (an increased number of CGG repeats under the full mutation range) in the fragile X (FMR1) gene on the X chromosome may result in fragile X-associated tremor/ataxia syndrome. Specific tests for this are available.
Imaging
Initial Approach
Cranial MRI may identify structural abnormalities including infarcts, hemorrhage, tumors, and demyelination. Atrophy of involved structures in the brain or spinal cord can be found in some neurodegenerative disorders.
Follow-Up & Special Considerations
MRI may be repeated in patients with no initial findings.
Diagnostic Procedures/Other
Antigliadin antibodies and glutamic acid decarboxylase antibodies (GAD-Abs) should be searched in all patients with cerebellar ataxia of unknown etiology. Paraneoplastic cerebellar syndrome is associated with anti-Yo, -Hu -Ri, -Ta, -Ma, or -CV2. Paraneoplastic symptoms may be the first sign of an occult cancer. In ataxia-telangiectasia, serum electrophoresis shows decreased concentrations of immunoglobulin A (IgA) and immunoglobulin G (IgG), while serum α-fetoprotein levels are elevated. Cultured cells show cytogenetic abnormalities and increased sensitivity to ionizing radiation. The percentage of sporadic ataxia patients with no apparent acquired cause who test positive for a genetic test is about 13% (4C).
Pathological Findings
Muscle biopsy may confirm a mitochondrial disorder.
DIFFERENTIAL DIAGNOSIS
- Vascular: Infarcts, hemorrhage, vasculitis
- Structural: Tumors, abscess, arteriovenous malformations, Chiari malformations
- Multiple sclerosis
- Infectious: Postinfectious cerebellitis, Gerstmann–Sträussler syndrome, Creutzfeldt–Jakob disease (CJD)
- Toxins: Alcohol, anticonvulsants, heavy metals, toluene, cytarabine (ara-C), cyclosporine
- Endocrine: Hypothyroidism
- Nutritional: Vitamin E deficiency, vitamin B12 deficiency, Wernicke–Korsakoff disease
- Immune: Gluten sensitivity and glutamic acid decarboxylase antibodies, Miller-Fisher variant of Guillain–Barré syndrome
- Paraneoplastic cerebellar degeneration
- Sporadic neurodegenerative diseases: Cerebellar cortical atrophy, multiple system atrophy
- Hereditary:
- Autosomal dominant: SCA 1-31 and 36, DRPLA, episodic ataxia types 1–6. Autosomal dominant spastic ataxia.
- Autosomal recessive: FA, ataxia telangiectasia, AVED, infantile-onset spinocerebellar ataxia, ataxia with oculomotor apraxia, Marinesco–Sjögren, spastic ataxia (ARSACS), myoclonus-ataxia syndromes, ataxia with hypogonadism
- X-linked: X-linked ataxia with spasticity, X-linked ataxia with sideroblastic anemia, X-linked ataxia with deafness and blindness and fragile X-associated tremor/ataxia syndrome
- Mitochondrial: Neuropathy, ataxia, and retinitis pigmentosa (NARP), myoclonic epilepsy and ragged-red fiber disease (MERRF)
- Metabolic: Abetalipoproteinemia, hexosaminidase deficiency, Refsum disease
MEDICATION
First Line
- In most cases, no effective medications are available.
- Adults with vitamin E deficiency: Replace with 60–75 IU PO or IM. Adjust dosage to normal plasma levels.
- Thiamine deficiency in chronic alcoholics and malnourished patients: Thiamine 50 mg PO daily. In Wernicke encephalopathy, thiamine 50–100 mg IV and IM immediately, 50 mg/day IM for 3 days, and then 50 mg PO daily. Higher dosages may be necessary at times.
- Vitamin B12 deficiency: Cyanocobalamin 1,000 µg IM daily for 5–7 days, then weekly for a month and then monthly for life.
- For episodic ataxia: Acetazolamide (3).
Second Line
Stroke prevention, multiple sclerosis, or cancer treatment as indicated.
ADDITIONAL TREATMENT
General Measures
Protect from fall risks; acute-onset ataxia needs to be treated as a possible neurosurgical emergency. Cerebellar hemorrhages and large infarcts are associated with a high risk of swelling and may compromise brainstem respiratory centers leading to death—rapid imaging needed.
Issues for Referral
Patient and families with a diagnosed hereditary ataxia should receive genetic counseling.
Additional Therapies
Physical, occupational, and speech therapy.
COMPLEMENTARY AND ALTERNATIVE THERAPIES
- Antiemetics for nausea and vomiting; eye patching for diplopia.
- Antispastic medications for those with spasticity.
- Patients with GAD-Abs and the Miller-Fisher variant of Guillain–Barré syndrome may respond to IV immunoglobulin.
SURGERY/OTHER PROCEDURES
Decompression of hematomas or infarcts associated with edema compressing the cerebellum, brainstem, and fourth ventricle, surgical removal of tumors.
IN-PATIENT CONSIDERATIONS
Initial Stabilization
Assess patient condition and look for signs of increased intracranial pressure and brainstem compromise.
Admission Criteria
Acute ataxia associated with inability to walk generally requires admission and evaluation.
IV Fluids
Avoid hypotonic fluids.
Nursing
Protect from fall risks.
Discharge Criteria
Discharge criteria include assurance of safety from falls.
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
In ataxia secondary to acute cerebellar stroke or hemorrhage, patients are followed closely (often in the ICU for cerebral edema and brainstem compromise).
DIET
- Gluten-free diet may benefit patients with antigliadin antibodies.
PATIENT EDUCATION
- National Ataxia Foundation
- International Network of Ataxia Friends
PROGNOSIS
Prognosis depends on the underlying etiology.
COMPLICATIONS
Acute cerebellar conditions may present with increased intracranial pressure such as in vascular events and structural lesions.
Ataxia may be acquired or genetic: Percentage of sporadic ataxia patients with a positive genetic test is about 13%.
