The hallmarks of cerebellar ataxia are loss of balance, uncoordinated arm and hand use, staggering gait from a broadened base, as well as speaking, swallowing, fine motor control, cognition, and mood. Discoordinated eye movements and difficulty reading are often present in some types of cerebellar ataxia.

Cerebellar ataxia may be genetic, and autosomal dominant, termed neurodegenerative spinocerebellar ataxia (SCA); autosomal recessive; X-linked; and mitochondrial DNA inheritance patterns all occur. The most common forms of SCA are types 1, 2, 3, 6 and 7, which stem from CAG repeat and polyQ expansions that produce toxic forms (eg, aggregrates) of ataxin or, in the case of type 6, a calcium channel subunit. Most cause eventual damage to the Purkinje cells of the cerebellum.

Acquired forms of cerebellar ataxia may be treatable, and possible causes include immunologic or infectious responses, metabolic imbalances, or toxic exposures. Idiopathic cerebellar ataxia includes multisystem atrophy (MSA), which has a faster course with high 5-year mortality.

Diagnosis

Clinical Diagnosis

Often, no clear cause or gene will be identified. Many clinical features, including irregular saccadic pursuits, nystagmus, hyporeflexia, and eye movement velocity have different incidences in the different types of SCA, however, the variation is not enough to be diagnostically definitive for most SCA types.

In my clinic, we find that eye movement velocity can be helpful (Table), at least for differentiating types 1, 2, 3, and 6. People with cerebellar ataxia without cognitive impairment who have downbeat nystagmus most often have SCA6. Those with maculopathy most often have SCA7. It is important to recognize, however, that within each type there exists a great deal of heterogeneity.

Diagnostic Testing

Once ataxia has been localized to the cerebellum and identified as neurodegenerative, family history should be explored. If there is a clear family history, genetic testing is an appropriate next step. For individuals with SCA without a strong family history, it is important to also consider a diagnosis of MSA.

Some people have a very clear family history; for example, a person may say, “My mom had it, my grandfather, my aunt, my cousin, and so on.” In these cases, autosomal dominant SCA is likely and genetic testing is done to confirm the diagnosis. Others may have less clarity regarding family history; for example, a person who says, “My grandfather stumbled a lot, but we all thought that was because he drank too much.”

When no family history is present or when it is unclear, workup for reversible and treatable SCA is appropriate. It is essential to rule out congenital malformations or neoplasms with structural MRI. Findings from MRI, however, rarely differentiate types of SCA or provide clear information about nonstructural causes of SCA. Many times, the imaging findings do not reflect the severity of clinical symptoms and vice versa.

Other causes of SCA include infections or immunologic reactions, post-anoxia or post-stroke sequelae, metabolic derangements, epilepsy, or toxicity (environmental or medication related). Many of these can be identified or ruled out with laboratory testing, which can identify treatable causes of SCA and thus are also essential.

Unfortunately, it is not uncommon that laboratory tests do not provide a clear answer regarding the cause of SCA. When there is no family history and no cause identified with structural imaging or laboratory tests, the next question is whether or not the SCA is episodic. When SCA is episodic, testing for mutations in EA2 is most appropriate. For nonepisodic SCA, tests may include a full panel of genes known to be related to SCA, repeat expansion panels, and whole-exome sequencing (WES) for other genetic variations that may be causative.

Treatment

The focus of treatment today is to treat symptoms and improve quality of life for individuals with SCA.

Physical Therapy

Physical therapy can improve time to “up and go,” stride length, dynamic gait index, double support time, and walking speed. Exercises that people consider challenging (ie, the person doing the exercise feels it is difficult) correlate with larger gains in these measures. Physical therapists who specialize in treating people with neurodegenerative disorders are preferred. For all patients, exercise is an essential and mandatory part of treatment.

Medications

Although guidelines suggest specific medications for specific types of SCA and specific symptoms,1 response to medication is highly variable and individual due to the heterogeneity of SCA. For episodic ataxia, acetazolamide, verapamil, and 2,4-aminopyridine may reduce the frequency of attacks. For a number of different ataxia subtypes, riluzole has been shown in some studies to improve ataxia. In our practice, very few patients who start riluzole continue with this treatment. Lithium is probably not helpful and deferiprone possibly worsens ataxia. The potential benefits of medication should be weighed against risks and burden of treatment that may have limited efficacy.

For treating balance difficulties, fluoxetine can be beneficial and has the advantage of treating any comorbid depression, which is frequent and perhaps undertreated in SCA. For SCA type 3, citalopram has shown great benefit in animal studies, although results are not as dramatic in clinical practice. Citalopram also has the benefit of treating depression and irritability. Caution must be used with citalopram, however, because of QTc prolongation that can occur; the maximum daily dose is 40 mg and individuals over age 60 should not take more than 20 mg per day.

For spasticity, baclofen, tizanidine, or chlorzoxazone are helpful, and for those who can tolerate the combination, there is limited evidence that baclofen and chlorzoxazone in combination may be effective. Some patients with painful spasticity benefit from treatment with levodopa-carbidopa. Nystagumus can be treated with baclofen or 2,4-aminopyridine.

Future Directions

Antisense Oligonucleotide Therapy

Antisense oligonucleotides (ASOs) inactivate toxic mRNA and are in development for SCA3. Studies are planned for ASOs to treat SCA1 and SCA2. ATXN1-, ATXN2-, ATXN3- and ATXN7-specific ASOs have been developed. In animal models, treatment with these ASOs has reduced expression of mutant ataxin with CAG repeats, increased levels of functional ataxin, improved motor performance, and restored visual functions, depending on the type of SCA treated in the animal model.2-5

Troriluzole

In an 8-week randomized study (NCT02960893) of troriluzole for SCA1, 2, 3, 6, 7, 8, and 10, treatment with troriluzole showed improvement but not at a statistically significant difference compared with placebo. Recruitment is underway for a larger 48-week randomized trial (NCT03701399) of troriluzole. As part of the trial, individuals interested in enrolling who meet certain criteria will be tested genetically to confirm their diagnosis.

Biomarkers

Biomarkers are needed to make initial diagnosis more time- and cost-effective. Biomarkers will also provide more objective measures of disease progression and hopeful disease-modifying activity of potential therapies. Multiple studies of potential biomarkers including imaging measures, ataxin levels, and α-synuclein protein aggregates are all underway.

1. Zesiewicz TA, Wilmot G, Kuo SH, et al. Comprehensive systematic review summary: treatment of cerebellar motor dysfunction and ataxia: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(10):464-471.

2. Scoles DR, Meera P, Schneider MD, et al. Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature. 2017;544:362-366.

3. McLoughlin HS, Moore LR, Chopra R, et al. Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice. Ann Neurol. 2018 Jul;84(1):64-77.

4. Friedrich J, Kordasiewicz HB, O’Callaghan B, et al. Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. JCI Insight. 2018;3(21):123193.

5. Niu C, Prakash TP, Kim A, et al. Antisense oligonucleotides targeting mutant ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7. Sci Transl Med. 2018;10(465): eaap8677.