Measurements on T1- and T2-weighted magnetic resonance images. 1 indicates anteroposterior diameter of the globus pallidus; 2, transverse diameter of the globus pallidus; 3, anteroposterior diameter of the midbrain; 4, transverse diameter of the midbrain; 5, width of the superior cerebellar peduncles; 6, width of the middle cerebellar peduncle; 7, diameter of the dentate nucleus; 8, diameter of the red nucleus; 9, anteroposterior diameter of the pons; 10, transverse diameter of the pons; 11, anteroposterior diameter of the fourth ventricle; 12, transverse diameter of the fourth ventricle; 13, anteroposterior diameter of the medulla oblongata; 14, transverse diameter of the medulla oblongata; 15, area of the cerebellar vermis; and 16, area of the cerebellar hemisphere.
T1-weighted magnetic resonance images of the brain in the midsagittal plane of a 52-year-old normal female subject (A) and a 47-year-old woman with spinocerebellar ataxia 6 (the duration of illness was 13 years in this patient) (B). The patient with spinocerebellar ataxia 6 shows severe cerebellar atrophy. The anteroposterior diameter of the pons was slightly reduced (2.16 cm) in this patient.
There were significant differences between the control and spinocerebellar ataxia 6 (SCA6) groups in the anteroposterior diameter of the pons (A), width of the middle cerebellar peduncle (B), diameter of the red nucleus (C), area of the cerebellar vermis (D), and hemisphere (E).
Murata Y, Kawakami H, Yamaguchi S, Nishimura M, Kohriyama T, Ishizaki F, Matsuyama Z, Mimori Y, Nakamura S. Characteristic Magnetic Resonance Imaging Findings in Spinocerebellar Ataxia 6. Arch Neurol. 1998;55(10):1348-1352. doi:10.1001/archneur.55.10.1348
To clarify the characteristic magnetic resonance imaging (MRI) findings in patients with spinocerebellar ataxia 6 (SCA6) diagnosed by genetic analysis.
Patients and Methods
Using MRI, we examined 10 patients genetically diagnosed as having SCA6 and 40 control subjects.
The mean (±SD) CAG repeat length in 10 patients with SCA6 was 22.9±1.3. There was a significant inverse correlation between the CAG repeat size and age at onset in the SCA6 group (r=−0.86, P =.003). In patients with SCA6, the areas of the cerebellar vermis and hemispheres in sagittal MRI were significantly smaller than those in the control subjects. In transaxial MRI, the anteroposterior diameter of the pons and the diameter of the middle cerebellar peduncle were mildly decreased and the red nucleus was slightly atrophied in patients with SCA6. There was no significant difference in the diameter of the midbrain, medulla oblongata, fourth ventricle, superior cerebellar peduncles, dentate nucleus, or globus pallidus between the SCA6 and control groups. A high-signal intensity in the transverse pontine fibers was not observed in any of the patients with SCA6 on T2-weighted and/or proton-weighted axial MRI.
The cerebellum and its afferent and efferent systems were affected in patients with SCA6. These results seem to distinguish the MRI findings of SCA6 from those of other forms of spinocerebellar ataxia.
AUTOSOMAL dominant cerebellar ataxias are a heterogeneous group of dominantly inherited disorders characterized by progressive ataxia that results from the degeneration of the cerebellum and its afferent and efferent connections. Spinocerebellar ataxia 6 (SCA6) is one of the autosomal dominant cerebellar ataxias and shows slowly progressive spinocerebellar degeneration.1 SCA6 occurs by the expansion of polymorphic CAG repeats in the gene of human α1A voltage-dependent calcium channel subunits.1,2 The clinical picture in SCA6 has been characterized by relatively late onset and prominent findings of gait and limb ataxia and dysarthria. Nystagmus is frequent, but other oculomotor findings are unusual.1- 3 Advances in genetic analysis have made it possible to diagnose SCA6 more accurately and to distinguish it from other types of spinocerebellar degeneration.1,2
The purpose of the present study is to clarify the characteristic magnetic resonance imaging (MRI) findings in patients with SCA6 diagnosed by genetic analysis.
We studied 10 patients with SCA6 (8 men and 2 women; mean±SD age, 55.4±12.5 years; duration of illness, 8.7±3.3 years; range of age at onset, 24-67 years) and 40 age-matched control subjects without neurologic deficits (19 men and 21 women; mean±SD age, 55.3±16.2 years). The condition of patients with SCA6 was diagnosed by genetic analysis2 and by symptoms and signs, including cerebellar ataxia, pyramidal tract signs, extrapyramidal symptoms, and amyotrophy. Informed consent for the genetic analysis and MRI examinations was obtained from all patients.
The subjects were examined using 1.5-T MRI. T1-weighted axial and sagittal images (repetition time, 450 milliseconds; echo time, 30 milliseconds), T2-weighted axial images (repetition time, 2000 milliseconds; echo time, 80 milliseconds), and proton-weighted axial images (repetition time, 2000 milliseconds; echo time, 30 milliseconds) were obtained in the transaxial and midsagittal planes (5-mm thickness and 2.5-mm gap). These measurements were performed separately and by 2 neuroradiologists (Y.M. and S.Y.) who did not know the clinical or genetic status of the subject and visually assessed the atrophy of the nuclei and fibers.
The anteroposterior and transverse diameters of the pons, midbrain, medulla oblongata, and fourth ventricle were measured on T1-weighted axial images. The width of the superior and middle cerebellar peduncles was also measured on T1-weighted axial images. Because it was difficult to measure the width of the superior cerebellar peduncle directly on the transaxial T1 MRI, we evaluated the diameter of the midbrain at the level of the superior cerebellar peduncle, which would indirectly reflect the width of the superior cerebellar peduncles. The diameters of the dentate nucleus, red nucleus, and globus pallidus was determined on T2-weighted axial images. The axial slice levels were selected with the use of sagittal and coronal MRI to standardize the horizontal level in each subject. The sagittal slice levels were also determined by coronal MRI. The area of the cerebellum was evaluated on T1-weighted sagittal images. The cerebellar vermis and cerebellar hemisphere were assessed on the midsagittal plane and on the parasagittal plane 5 mm lateral to the middle cerebellar peduncle, respectively. We tried to exclude the sulcus indentations in the marginal outline of the cerebellum using the computer software package MacSCOPE (Mitani Co, Fukui, Japan) (Figure 1). The threshold was determined to represent the edge of the cerebellum accurately, and the binary image was made. Thereafter, the pixel area of the cerebellum was counted, and the area of the cerebellum was measured. The degree of atrophy in the frontal, temporal, parietal, and occipital lobes was visually divided into 4 groups (0, none; 1, mild; 2, moderate; 3, severe) by observers (Y.M. and S.Y.) unaware of the subject's status. The appearance of the abnormal signal intensity of transverse pontine fibers was assessed on T2- and/or proton-weighted axial images.
All data were analyzed using the computer software package JMP 3.0 (SAS Institute Inc, Cary, NC). Differences between the 2 groups were examined by analysis of variance. Frontal, temporal, parietal, or occipital lobe atrophy was analyzed by the Wilcoxon rank sum test. Probability values less than .05 were accepted as significant.
There was no significant difference in any of the parameters measured between the male and female control subjects.
The mean CAG repeat length in 10 patients with SCA6 was 22.9±1.3 (5 patients with a CAG repeat size of 22, 3 with 23, 1 with 24, and 1 with 26). There was a significant inverse correlation between the CAG repeat size and age at onset in the SCA6 group (r=−0.86, P =.003). Table 1 summarizes the MRI findings of 10 patients with SCA6 and 40 control subjects. The SCA6 group had severe atrophy of the cerebellar vermis and hemispheres compared with the controls (Figure 2). Significant differences were observed between the 2 groups in the anteroposterior diameter of the pons, the diameter of the middle cerebellar peduncle, and the diameter of the red nucleus (P=.04, P =.03, and P=.04, respectively; Figure 3). The anteroposterior and transverse diameters of the midbrain, medulla oblongata, and globus pallidus were not significantly different between the SCA6 and control groups. We did not observe a significant enlargement of the fourth ventricle in patients with SCA6. A high signal intensity in the transverse pontine fibers was not observed in any of the patients with SCA6 on T2- and/or proton-weighted axial MRI. An acceptable level of interrater reliability was found for these measurements (κ>0.61).
In both the control and SCA6 groups, there were significant inverse correlations not only between age and the anteroposterior diameter of the pons (r=−0.32, P =.05 in the control group; r =−0.78, P=.009 in the SCA6 group) but also between age and the anteroposterior diameter of the midbrain (r=−0.46, P =.003 in the control group; r =−0.67, P=.03 in the SCA6 group). In the SCA6 group, there was no significant correlation between the duration of illness and any parameters measured. The expanded length of CAG repeats did not significantly influence the rate of abnormalities of MRI findings in patients with SCA6.
We examined the neuroradiologic features of 10 patients with SCA6 using 1.5-T MRI. There was severe atrophy of the cerebellar cortex and vermis in patients with SCA6. The middle cerebellar peduncle, pons, and red nucleus were also mildly atrophied. These results suggest that SCA6 affects the cerebellum and its afferent and efferent systems, including the pontocerebellar and dentatorubral pathways.
Severe cerebellar atrophy was observed in all 10 patients with SCA6, which is consistent with findings of a previous postmortem study.3 The cerebral cortex was relatively preserved. Subramony et al3 autopsied 2 genetically verified patients with SCA6 and observed a major loss of Purkinje cells, modest inferior olivary neuronal loss, moderate neuronal loss and gliosis in the dentate nucleus, and thinning of the granule cell layer in the cerebellum with sparing of the pons. However, we found no significant difference in the diameter of the dentate nucleus between patients with SCA6 and controls, although the mean value was smaller in patients with SCA6 (1.62 cm) than in controls (1.77 cm). The patients described by Suramony et al3 were older (>80 years) and had much more advanced disease (duration, about 30 years) than our patients (age, 55.4 years; duration, 8.7 years). Therefore, the neuropathologic changes in their study should be different from the topography of atrophy on the present MRI findings, and the cases studied here might produce similar changes in their end stages.
We previously reported the characteristic MRI findings in 31 patients with Machado-Joseph disease (MJD) and 20 patients with sporadic olivopontocerebellar atrophy (sOPCA).4 The MRIs of MJD disclosed remarkable small superior cerebellar peduncles and atrophy of the pons and globus pallidus. Decreased width of the middle cerebellar peduncle was also observed in MJD and sOPCA. On T2- and/or proton-weighted axial MRI, a high signal intensity in the transverse pontine fibers was observed in almost half of the patients (14 of 31) with MJD and all of the patients with sOPCA.4 In contrast, the patients with SCA6 in the present report showed no abnormal intensity in the transverse pontine fibers. In addition, the globus pallidus and the superior cerebellar peduncles were well preserved in patients with SCA6. These results seem to distinguish the MRI findings of SCA6 from those of MJD or sOPCA.
We found a significant inverse correlation between age at onset and the CAG repeat expansion (r=−0.86, P =.003). However, we found no relationship between the CAG repeat length and MRI findings, probably due to the limited number of patients: 5 patients with a CAG repeat length of 22, 3 with 23, 1 with 24, and 1 with 26. Matsuyama et al2 have revealed that patients with SCA6 with the same repeat length show a wide variety in the age of onset and in clinical symptoms, and they have suggested the influence of factors other than CAG repeat length. Further analysis is necessary with increased numbers of patients.
Human P-type α1A voltage-dependent calcium channel subunits, probably responsible for SCA6, are expressed in Purkinje cells in the cerebellar cortex, the periglomerular cells of the olfactory bulb, scattered neurons in the deep layer of the entorhinal and pyriform cortices, neurons in the brain stem, habenula, nucleus of the trapezoid body and inferior olive, and other regions.1,5- 7 Although the distribution of the α1A voltage-dependent calcium channel is ubiquitous in the brain, the channel is expressed most abundantly in the regions where patients who currently had SCA6 showed atrophy.
In conclusion, our results suggest that SCA6 affects the cerebellum and its afferent and efferent systems. Further study with larger numbers of subjects is necessary to elucidate the relationship between the CAG repeat length and atrophy or duration of illness.
Accepted for publication January 30, 1998.
This work was supported by a grant-in-aid from the Research Committee of Central Nervous System Degenerative Diseases, Ministry of Health and Welfare of Japan, Tokyo.
We thank Takahiko Saida, MD, National Utano Hospital, Kyoto, for the referral of patients, and Kaori Katayama, Third Department of Internal Medicine, Hiroshima University School of Medicine, for photography.
Reprints: Yoshio Murata, MD, Third Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.