Correspondence *Department of Neurology, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095, USA

Email sperlman@mednet.ucla.edu

The case

An 83-year-old man was referred to a tertiary care ataxia center with a 5-year history of difficulty in walking and balance problems. He also had a history of hypertension, hyperlipidemia, and a basal cell carcinoma that had been treated successfully with minor surgery 2 years previously. At the onset of his balance problems at the age of 78 years, he had begun to stumble and was unsteady on his feet. These symptoms worsened progressively, and by a year later his speech had also started to become dysarthric. When the symptoms had first become noticeable, the patient was evaluated in a local emergency department and, on the basis of his clinical findings, was diagnosed with a mild stroke. An MRI scan, however, showed no evidence of ischemia but instead showed isolated cerebellar atrophy. As the patient's condition continued to worsen he was referred to a neurologist, who initiated an evaluation for a paraneoplastic condition because of the patient's previous history of cancer. Investigations included CT scans of the chest, abdomen, and pelvis; all results were found to be unremarkable, and laboratory test results for prostate-specific antigen, carcinoembryonic antigen, and the Hu, Ri, Ma, and Ta serum neuronal antibodies were negative. In addition, serum electrolytes, renal and liver functions, and complete blood count were all normal. Gliadin and glutamic acid decarboxylase 65 autoantibodies were negative, and rapid plasma reagin was nonreactive. Serum protein electrophoresis, alpha-fetoprotein, vitamin B₁₂, folate, parathyroid hormone, thyroid-stimulating hormone, and vitamin E levels were all within normal limits. MRI scans showed only cerebellar degeneration. The patient was followed clinically, but over time he began to experience falls and dysphagia, which eventually prompted his referral to the ataxia center.

The patient reported no family history of ataxia or other neurological conditions, and he had no history of excessive alcohol or drug use, or exposure to toxic substances. On neurological examination, he demonstrated saccadic smooth pursuit without nystagmus, mild ocular dysmetria, scanning dysarthria, and moderate appendicular and truncal ataxia. He also had dysdiadochokinesia and a wide-based unstable gait. Cognitive testing was normal and there was no evidence of pyramidal or extrapyramidal signs, or any disturbances of sensation. An MRI scan of the brain showed severe diffuse cerebellar atrophy, which was most pronounced in the midline vermis, without any involvement of the brainstem or spinal cord (Figure 1).

Figure 1 T1-weighted MRI brain scans of the patient demonstrating diffuse atrophy isolated to the cerebellum.

(A) Coronal view. (B) Sagittal view. The diffuse cerebellar atrophy is most severe in the midline vermis (arrow).

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On the basis of the patient's clinical presentation and neurological examination findings as well as his previous neuroimaging and diagnostic studies, a genetic ataxia syndrome was considered. Given his lack of a family history of ataxia, genetic evaluation was directed towards a sporadic hereditary ataxic condition. This testing was positive for a disease-associated CAG repeat expansion in the gene for autosomal dominant spinocerebellar ataxia (SCA) type 6, with 11 repeats on the normal allele and an abnormal 22 repeats on the affected allele.

The patient was treated empirically with buspirone 5 mg twice daily, which was slowly titrated to 15 mg twice daily over 4 weeks, resulting in a mild subjective improvement in his balance after 3 months. He was referred to physical, occupational, and speech therapy clinics for gait retraining, assessment for an assistive device, home safety, and management of his dysarthria and dysphagia. Genetic counseling was also offered to the patient and other family members who were considered to be at risk.

Discussion of diagnosis

The patient in this case presented with what was essentially a pure cerebellar phenotype without additional associated features. His medical and family histories were both unremarkable, and although the presence of a history of cancer raised the specter of a paraneoplastic syndrome, evaluation for this condition was also unilluminating. Additional screening studies for acquired causes were also unremarkable. As the patient had a negative family history for ataxic disorders, a sporadic genetic mutation was considered; because of the patient's age and clinical examination, directed genetic screening was initially confined to SCA6. A previously published algorithm based on an analysis of 127 patients with SCA1–8 suggests a predictive value of 59% for SCA6 in similar patients.¹ It is important to note, however, that in the general population of ataxic patients, additional, currently undescribed hereditary conditions are likely to exist; clinical studies examining patients presenting with an idiopathic late-onset pure cerebellar ataxia indicate that up to 70% may have no currently identifiable genetic mutation.² Fortunately, in this case, genetic testing yielded a positive result and the diagnostic evaluation was able to be successfully concluded.

SCA6 is a pure cerebellar ataxic syndrome associated with a CAG repeat expansion within the _1A subunit of the voltage-gated calcium channel encoded by the CACNA1A gene on chromosome 19p13.^{3, 4, 5} Pathogenic alleles typically contain more than 21 CAG repeats.^{3, 5, 6} The disease is characterized by a clinical phenotype consisting primarily of cerebellar dysfunction with gait and limb ataxia, dysarthria, and nystagmus. Other findings such as neuropathy, or pyramidal or extrapyramidal signs, are less common but are occasionally seen.^{3, 6} The age of onset is approximately 50 years^{3, 6} and the initial cerebellar symptoms can be episodic. Evidence suggests that affected patients have a normal lifespan.³ A family history of ataxia is often not reported in cases of SCA6, because the onset of symptoms occurs later in life and symptoms are often attributed to other medical conditions.³ Although not yet proven conclusively, there is evidence that SCA6 might be a channelopathy. As such, this disorder would be pathogenically distinct from the majority of autosomal dominant spinocerebellar ataxias, which appear to be polyglutamate gain-of-function diseases.³ Recently, SCA13 was identified as a channelopathy arising from point mutations in the gene encoding a cerebellar-enriched voltage-gated potassium channel, KCNC3.⁷ SCA13 is an autosomal dominant syndrome characterized by either adult-onset cerebellar ataxia or early-onset ataxia and mental retardation.⁷ Once genetic testing is available, SCA13 will also be another important consideration in the differential diagnosis of adult-onset ataxia. The distinction between polyglutamate gain-of-function diseases and channelopathies could, in addition, be important in the design of future treatment strategies.^{7, 8}

Differential diagnosis

The clinical finding of an insidious-onset progressive cerebellar ataxia, as seen in the present patient, can pose a significant diagnostic challenge. Ataxia as a general symptom can be seen in a variety of diverse conditions—both hereditary and acquired. Obtaining a detailed description of the onset and progression of symptoms is an important initial step in differentiation. In an adult, this process should include an in-depth discussion of the patient's previous activity levels and coordination skills, because a slowly progressive ataxia can manifest itself subtly by way of a reduction in a patient's previous abilities, before the onset of overt clinical symptoms. It is also essential to obtain a detailed family history, and it can often be useful to determine the patient's ethnic origin if possible, because some hereditary ataxias have been found to show an increased prevalence in certain geographic regions.^{3, 9}

The key features of cerebellar dysfunction include dysmetric and saccadic eye movements with nystagmus, dysarthria, a coarse kinetic tremor, impaired coordination of targeted and rapid-alternating movements (dysdiadochokinesia), and a wide-based unstable gait.^{9, 10} The presence of additional features such as dementia, behavioral changes, retinopathy, extrapyramidal features, upper motor neuron signs, peripheral neuropathy, autonomic dysfunction, and seizures, can be useful for differentiating ataxic etiologies.^{9, 10}

The initial diagnostic evaluation of an ataxic patient should include an in-depth assessment for potential acquired causes.⁸ This screening should always be performed—even in the setting of a suspected hereditary ataxia—because acquired and hereditary causes can coexist. In the older ataxic patient, multifactorial disease is relatively common and is often the rule. In rare instances multiple genetic mutations can even coexist, and, if suspected, these should be given consideration. An algorithm for a focused screening evaluation is proposed in Tables 1–3. Such screening should always include neuroimaging of the brain—ideally with MRI—as this can rapidly identify confounding entities such as stroke, neoplasm, demyelinating disease, trauma, or cerebellar anomalies. Some hereditary or acquired ataxic conditions such as Wilson's disease, leukodystrophies, or prion disease can also demonstrate characteristic degenerative features on MRI scans. The predominant MRI finding in patients with spinocerebellar ataxia is atrophy of the cerebellum or olivopontocerebellar structures.³ After the initial screening evaluation (Table 1), the need for additional studies (Table 2) can be determined on the basis of the patient's clinical history and neurological examination findings.

Table 1 Recommended primary clinical evaluation for acquired causes of ataxia in an adult patient.

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Table 2 Recommended secondary clinical evaluation for acquired causes of ataxia in an adult patient.

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If a detailed screening for acquired causes is found to be negative, the diagnostic evaluation can then be directed towards hereditary or sporadic genetic etiologies (Table 3, and Supplementary Table 1 online). Various flowcharts have been developed to guide directed gene testing, particularly for the autosomal dominant spinocerebellar ataxias, which allow differentiation on the basis of predominant clinical features.³ For the most common autosomal dominant SCAs—types 1–8—a clinically based mathematical algorithm has recently been developed to direct gene testing,¹ which can be useful in initial screening for a hereditary condition. Because of the rapid pace of molecular genetic research, new genetic tests frequently become available, so patients with unidentified but suspected hereditary ataxia should be periodically re-evaluated with updated genetic screening. At least 24 autosomal dominant hereditary ataxias have been described,^{3, 4} in addition to at least half as many autosomal recessive disorders.^{4, 11} Age of symptom onset can be a key distinguishing feature of the two types, as most recessive ataxic syndromes are early-onset and tend to present before the age of 20 years,¹¹ and most dominant ataxias typically present later in life.³ This distinction is not absolute, however, and some patients with Friedreich's ataxia or Tay–Sachs disease, for example, can present clinically much later then expected.^{12, 13} It has been suggested that late-onset ataxia should be defined as that occurring after the age of 40 years.² Although there is much overlap, this distinction can be useful diagnostically, since of all the known hereditary ataxias only SCA6, a predominantly cerebellar syndrome, and fragile X-associated tremor–ataxia syndrome, have a clear mean age of onset well beyond 40 years of age.^{3, 4, 11, 14} In the older male (and occasional female) without an obvious family history, the late-onset phenotype of fragile X-associated tremor–ataxia syndrome consisting of gait ataxia, tremor, parkinsonism, and cognitive dysfunction, could be misdiagnosed as another more common neurological illness, such as dementia, essential tremor, Parkinson's disease, or stroke.¹⁴

Table 3 Recommended genetic considerations for ataxia in an adult patient.^a

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Multiple system atrophy (MSA) is an important consideration in a patient presenting with a late-onset ataxic phenotype. MSA is a sporadic progressive neurodegenerative condition characterized primarily by cerebellar dysfunction, parkinsonism, autonomic dysfunction, and pyramidal signs.¹⁵ Diagnostic guidelines are currently based on clinical evaluation, because other investigative studies can be equivocal early in the disease course.¹⁵ Studies such as MRI, functional imaging, anal sphincter electromyogram, or autonomic studies can be useful in specific cases to differentiate MSA from other neurodegenerative diseases.¹⁵ Prion diseases are another important consideration in patients with a late-onset ataxic phenotype. These neurodegenerative spongiform encephalopathies can be sporadic, acquired, or familial.¹⁶ Clinically, most patients exhibit a rapidly progressive dementia with additional neurological signs, but some cases—particularly those with sporadic Creutzfeldt–Jakob disease or familial Gerstmann–Sträussler–Scheinker disease—can present with a late-onset ataxic phenotype.¹⁶ A definitive diagnosis is achieved only by laboratory pathology investigations, although electroencephalogram and cerebrospinal fluid studies can support a diagnosis,¹⁶ and MRI—in particular diffusion-weighted and fluid-attenuated inversion recovery images—can also be helpful.

In sporadic cases of late-onset cerebellar ataxia that are found to lack a specific acquired or genetic etiology after detailed evaluation, a diagnosis of idiopathic late-onset cerebellar ataxia can also be considered.¹⁷ In one large study that assessed over 100 such patients for likely alternative etiologies, fewer than 30% met the criteria for MSA—even after 4 years of disease symptoms—and fewer than 15% were ultimately found to have an identifiable genetic cause, leaving nearly 60% diagnosed as idiopathic.¹⁷ Continued surveillance and periodic re-evaluation of these patients could be warranted, however, as it remains possible that at least some patients might have an as-yet-undetermined genetic cause.^{2, 17}

Therapeutic management

Much of the treatment currently available for late-onset hereditary ataxia is unfortunately only symptomatic. The most prominent feature, ataxia, is notoriously difficult to manage, and to date there are no clearly effective treatments available,³ and no medications have received FDA approval for use in the US in this capacity.⁸ A number of small clinical trials have studied various medications for the symptomatic treatment of ataxia and the associated features seen in hereditary ataxic conditions,⁸ in addition to antioxidants for their potential as neuroprotectants.⁸ Medications that have previously been reported to be of benefit for the therapeutic management of the most common cerebellar symptoms are indicated in Table 4, along with suggestions for their use (see also Supplementary Reference List 1 online). It is hoped that future studies will uncover more effective medical therapies, and more novel therapeutic strategies such as RNA interference could soon become feasible.¹⁸ For now, patients will benefit most from a comprehensive plan that addresses both the neurological and practical symptoms of their disease.⁸ For falls and ambulation difficulties, physical and occupational therapies can provide assistance in strengthening muscles that support the trunk, and also provide gait and balance retraining. Assistive devices that maximize functional independence and home safety are other important considerations. Speech therapy can be used to improve dysarthria and dysphagia if present. Social workers, genetic counselors, psychologists, and psychiatrists can also be instrumental in helping patients and their families to cope with issues surrounding their progressively worsening condition.

Table 4 Potential therapeutic treatments for various symptoms of cerebellar dysfunction.

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Conclusion

The patient presenting with a late-onset progressive ataxic phenotype poses a diagnostic challenge to the clinician, which can be addressed by means of a thorough medical history and physical examination, as well as a focused and directed diagnostic evaluation for acquired and hereditary etiologies. In a patient over the age of 40 years with sporadic progressive ataxia, SCA6 is an important consideration. Treatment of hereditary ataxia is generally symptomatic and should be focused on maximizing the patient's functionality while preventing physical, social, and psychological complications.

References

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Supplementary information

Supplementary Table 1 (doc 26 KB)

Internet resources: internet sites that may be useful for the differential diagnosis of hereditary ataxias.

Supplementary Reference List 1 (doc 27 KB)

Supplementary references for Table 4.

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