British Journal of Radiology (2005) 78, 694-696
© 2005 British Institute of Radiology
doi: 10.1259/bjr/73834093
Radiological characterization of spinocerebellar ataxia type 6
D Butteriss, BSc, MBBS, FRCR1,
P Chinnery, MBBS, FRCP, PhD2 and
D Birchall, FRCR, FRCP, MD1
Departments of 1 Neuroradiology and 2 Neurology, Regional Neurosciences Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK
Correspondence: Dr D Birchall
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Abstract
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Spinocerebellar ataxia type 6 (SCA-6) is a rare, autosomal dominant neurodegenerative condition characterized by adult onset cerebellar ataxia and ocular movement disorders. The presentation is non-specific, and radiological characterization would be of diagnostic benefit. There is little published on the radiological appearances of SCA-6, and there are conflicting reports in the literature. We report the radiological findings in a group of 10 patients with SCA-6.
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Introduction
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Spinocerebellar ataxia type 6 (SCA-6) is an uncommon autosomal dominant disorder that is characterized by a slowly progressive cerebellar ataxia, dysarthria and nystagmus [1–3]. The overall prevalence of autosomal dominant ataxia is estimated to be approximately 1:100 000 [3], but the proportion of these that is SCA-6 is highly variable between different geographical areas, as low as 1–2% in France and Spain, and as high as 31% in Japan [4]. Clinical manifestations of SCA-6 are reasonably uniform, but are not specific, so that genetic testing is currently required to confirm the diagnosis. Onset is gradual, often with an initially episodic course, with mean age of onset 43–52 years. Patients usually present with slowly progressive dysarthria and subsequently with gait ataxia, upper limb incoordination and intention tremor. Visual changes including diplopia, horizontal gaze-evoked nystagmus, vertical nystagmus and fixation difficulties [5, 6]. Lifespan is preserved.
The clinical features of SCA-6 are non-specific and clinically indistinguishable from other causes of late-onset cerebellar ataxia. In part due to its late onset there may be no convincing family history to suggest a genetic cause. Although genetic testing for the causative CACNA1A gene abnormalities is widely available, because of these factors formal diagnosis may be delayed. If it is possible to identify imaging features of the condition that are highly suggestive of the diagnosis then confirmatory genetic testing can be performed without undue delay, allowing for prognostic and genetic counselling of the patient and their family.
Few morphological studies of SCA-6 have been performed due to the rarity of the condition, and consist of small numbers of patients [7–10]. Atrophy of the cerebellar vermis and hemispheres has been reported. There is conflicting evidence regarding pontine involvement. The object of the present study is to characterize the radiological findings in a group of western European patients with SCA-6.
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Materials and methods
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We studied 10 patients with a genetic diagnosis of SCA-6 (6 male, 4 female subjects between 44 years and 70 years of age), along with 8 age- and sex-matched controls, who had no clinical evidence of cerebellar disease. The subjects were examined using a 1.5 T MR scanner (Philips Intera, Best, Netherlands). Imaging included axial and sagittal T2 and coronal T1 scans. The sizes of the cerebellar vermis, ventral pons, middle cerebellar peduncles and cerebellar hemispheres were analysed in the following way.
Area measurements were made of the cerebellar vermis and ventral pons on the mid-sagittal images, relative to the area of the posterior fossa, in keeping with previously established methodology [8]. The measurements were performed by a single neuroradiologist using the "Scion image" software package to measure the number of pixels within each area of interest. The cerebellar vermis was divided into a superior segment, comprising the lingula (lobule I), central lobule (II), culmen (III), declive (VI), folium (VII) and tuber (VII), and an inferior segment, comprising the pyramis (VIII), uvula (IV) and nodulus (X). Ratios of the area of interest to the entire posterior fossa area were made, to eliminate any differences arising from image magnification and patient size (Figures 1 and 2
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Figure 1. Sagittal T2 weighted image of subject with spinocerebellar ataxia type 6 with the area of the posterior fossa outlined.
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Figure 2. Sagittal T2 weighted MR image of a subject with spinocerebellar ataxia type 6 showing the pontine and vermian regions outlined for area measurement in a patient with moderate cerebellar atrophy.
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Using axial images, the maximum width of the middle cerebellar peduncles was measured in centimetres, perpendicular to the long axis of the peduncle (Figure 3).
Evaluation of cerebellar hemisphere volume was made using a qualitative scale, with severity of atrophy estimated as normal (0), mild (1), moderate (2) or severe (3).
The data were analysed with the Minitab computer statistics package, using two-sample t-tests with a 95% confidence interval and a p-value of less than 0.05 taken as significant.
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Results
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Figures 4–6 show boxplots comparing the areas of the whole, superior and inferior vermis for affected patients compared with control subjects. Statistically significant differences were found between affected patients and normal controls for the superior vermis (p=0.0018), whole vermis (p=0.002), and to a lesser extent for the inferior vermis (p=0.013). No significant correlation between the degree of cerebellar hemisphere atrophy and vermian atrophy was found.
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Figure 4. Boxplots of the area of the entire cerebellar vermis for control and affected subjects. Means are indicated by solid circles.
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Figure 5. Boxplots of the area of the superior cerebellar vermis for control and affected subjects. Means are indicated by solid circles.
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Figure 6. Boxplots of the area of the inferior cerebellar vermis for control and affected subjects. Means are indicated by solid circles.
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No significant differences were demonstrated between the ventral pontine or middle cerebellar peduncle values between affected and control subjects (p=0.72 and p=0.75, respectively).
No correlation was demonstrated between the degree of cerebellar hemispheric atrophy and the other parameters in the affected subjects.
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Discussion
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Our results have shown that there is significant cerebellar vermian atrophy in patients with SCA-6 in comparison with normal subjects, particularly affecting the superior cerebellar vermis. Cerebellar hemispheric atrophy was less marked, and was mild or normal in the majority of cases. We did not find any evidence of statistically significant atrophy of the ventral pons or of the middle cerebellar peduncles.
The limited data available in the literature studies describe variable morphological findings in SCA-6 [7–9]. Cerebellar vermian atrophy has been reported, and one paper that estimated cerebellar hemispheric area in affected patients also found a reduction compared with normal controls [7]. The findings with respect to extracerebellar structures are more variable. Murata et al [7] described mild ventral pontine and middle cerebellar peduncular atrophy, and Nagaoka et al [8] found mild ventral pontine atrophy with no evidence of dorsal pontine changes. The variability of features within different study samples of people with the same condition is hard to explain. It may be that the phenotypic manifestation of disease is different in western European population as opposed to the Japanese patients reported in the above papers, the main difference being the lack of evidence of pontine atrophy in our patient cohort. This may indicate that genetic factors are also involved in determining variable patterns of atrophy in this condition. Certainly genotyping of our cohort has demonstrated significant genetic homogeneity and suggests that all the cases are probably descended from a common founder, a greater genetic heterogeneity in other cohorts may explain the variability of the imaging findings.
The group of superior cerebellar folia that show the greatest degree of atrophy includes the anatomical anterior lobe and part of the posterior lobe, which are involved in trunk muscle tone and movement, and the initiation and fine control of movement. Lobuli VI and VII comprise the oculomotor vermis and are involved in the control of eye movements [10], and the involvement of these regions may account for the visual signs that are associated with SCA-6. The reason for preferential superior vermian atrophy in SCA-6 is unknown, but it has also been described in cases of acquired cerebellar degeneration following alcohol abuse, phenytoin and cytotoxic therapy, and thallium and toluene poisoning. It has been theorized that the superior folia are more susceptible to damage by a variety of insults that primarily affect the cerebellum, although a mechanism has not been described [11].
In spinocerebellar ataxias (SCA) other than type 6, there appears to be a lesser degree of cerebellar atrophy and more marked atrophy of extracerebellar structures. Nagaoka et al [8] described general pontine atrophy in SCA-1 and SCA-3, resulting in a "flat pons" appearance on MRI. Burk et al [12] and Klockgether et al [13] studied SCA-1, SCA-2 and SCA-3 and found brainstem atrophy to be present in all but most marked in SCA-2, with varying degrees of cerebellar vermis and hemisphere atrophy. The morphological differences between the various types of SCA are explained by the degeneration of different neuronal populations and their connections, and may be diagnostic [12].
In summary, we have found that an MRI study of English patients with SCA-6 demonstrates significant cerebellar vermian and less marked cerebellar hemispheric atrophy. Our finding of more marked superior vermian atrophy has not previously been emphasised in SCA-6. We did not find statistically significant evidence of atrophy of the ventral pons or the middle cerebellar peduncles. These features may be helpful in the diagnosis of this condition.
Received for publication June 4, 2004.
Revision received January 4, 2005.
Accepted for publication January 28, 2005.
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Abstract
Introduction
