A 3-year cohort study of the natural history of spinocerebellar ataxia type 6 in Japan

The present study was performed at 8 centers (Hokkaido University, Niigata University, Chiba University, National Hospital Organization Chiba-East-Hospital, Tokyo Metropolitan Neurological Hospital, Shinsyu University, Nagoya University, and Tottori University) belonging to the Research Committee for Ataxic Disease. This committee is part of the Ministry of Health, Labour, and Welfare of Japan. The written informed consent form, which was approved by the institutional review board of all centers and by the Ethics Committee of the Tottori University Hospital, was signed by all study participants. Patients with SCA6 who were being treated at any of the 8 centers were consecutively recruited between 2007 and 2008. A linkable, anonymizing registration system was used to register all patients.

Registration and follow-up evaluations were performed from April to July during the annual registration period of the Japan IDR registry; therefore, follow-up investigations were performed at the same time each year. As part of the prospective study, all patients were assessed with the SARA and the BI each year. The SARA was used to assess the degree of ataxia. The SARA consists of 8 items: gait, stance, sitting, speech, finger chase, nose-to-finger test, fast alternating hand movements, and heel-to-shin slide. Each item has its own subscore. The SARA grades ataxia on a scale of 0 to 40, with 0 indicating the absence of ataxia and 40 indicating the most severe degree of ataxia. The Japanese SARA is well validated and can be administered quickly [14],[15]. The BI was used to assess how well a patient performs the activities of daily living (ADL). The BI grades activity on a scale of 0 to 100, with 0 indicating that a person cannot care for him/herself and 100 indicating that a person can care for him/herself. All investigators were board-certified neurologists and were experienced in the use of the applied scales.

The IDR inquiry sheet for patients with an SCA includes 5 items from the ICARS (walking, standing with eyes open, body sway with feet together and eyes closed, knee-tibia test of the worse foot, and finger-to-nose test of the worse hand [decomposition and dysmetria]) and 6 items from the BI (feeding, bathing, grooming, dressing, mobility, and stairs) [11]-[13]. The total number of points obtained from the IDR inquiry sheet for the 5 items from the ICARS and the 6 items from the BI was referred to as the IDR-ICARS and IDR-BI scores, respectively. The IDR-ICARS grades ataxia on a scale of 0 to 26, with 0 indicating the least impaired condition. The IDR-BI grades activity on a scale of 0 to 55, with 0 indicating the most impaired condition. The 5 items of the IDR-ICARS were selected because these subscores correlated well with disease duration in Japanese patients with cerebellar ataxia [10].

The IDR inquiry sheet was last modified in 2003. For the retrospective portion of the IDR registry study, we collected the IDR inquiry sheets from 2003 onwards. The inquiry sheets were collected from the patients’ medical records, starting in the year they registered for the study. IDR data collection continued prospectively each year. The utility of the IDR registry was evaluated by analyzing a total of 7 years’ worth of data.

The differences between the scores obtained at registration and those obtained at each year’s evaluation were referred to as the ∆ scores, and the differences between the scores obtained at registration and the scores obtained at the last evaluation were referred to as the total ∆ scores. The total ∆/year was calculated by dividing the total ∆ score by the number of follow-up years.

Statistical analyses were performed with IBM SPSS Statistics software version 19 (SPSS Inc., Chicago, IL). The test results were considered significant at the .05 level. The Mann–Whitney test was used to compare the clinical characteristics of the male and female patients. Correlations between clinical scores and covariates were tested by using the Pearson correlation test. Data for disease progression were analyzed by using the Friedman test followed by post hoc Wilcoxon signed rank tests. The rate at which patients became wheelchair dependent was calculated from the data of the 7-year IDR registry study by using the Kaplan-Meier method. The CAG repeat length of the normal CACNA1A allele of each patient could not be collected in this study; therefore, we analyzed the repeat lengths of the expanded alleles, with the exception of the repeat lengths of the 3 patients who are homozygous for the expanded allele. For the cross-sectional study, an analysis of covariance at registration was performed with the SARA score as the dependent variable and sex, age at onset, disease duration, and CAG repeat length of the expanded CACNA1A allele as independent variables. For the prospective study, an analysis of covariance was performed with the total ∆SARA/year as the dependent variable and sex, age at onset, disease duration, CAG repeat length of the expanded CACNA1A allele, and SARA score at registration as independent variables. Age at registration was not included in the model, as age at registration was recorded as the sum of age at onset and disease duration. The test results were considered significant at the .01 level for the multivariate analysis.

The study population consisted of 46 patients with SCA6 who belonged to 44 families. The SARA and IDR-ICARS scores of female patients were significantly lower than those of male patients. Although the age at onset, age at registration, and disease duration tended to be lower in female patients than in male patients, the differences were not statistically significant. Similarly, although the BI and IDR-BI scores of female patients tended to be higher than those of male patients, the differences were not statistically significant (Table 1).

A patient’s age at the time of registration and the duration of his/her disease were correlated with clinical scores; however, a patient’s age at the time of disease onset and the CAG repeat length of the expanded CACNA1A allele were not correlated with those scores (Table 2).

The patients’ IDR-ICARS and IDR-BI scores correlated well with their SARA and BI scores, respectively (Figure 1A, B). The correlation coefficients of the SARA and IDR-ICARS scores and the BI and IDR-BI scores were 0.89 and 0.93, respectively (P < .001). The BI scores were inversely correlated with the SARA scores (R = −0.83, P < .001). Patients with a SARA score of less than 10 points maintained a high BI score. Conversely, among patients with a SARA score of more than 10 points, those with a higher SARA score had a lower BI score (Figure 1C).

The results of multivariate analysis of the patients’ SARA scores at the time of registration are presented in Table 3. An analysis of covariance with the SARA score as the dependent variable and clinical factors as independent variables produced multivariate models that explained 39.5% of the variance of the SARA scores. The SARA scores were influenced by sex, age at onset, disease duration, and CAG repeat length of the expanded CACNA1A allele.

The data obtained from the prospective study were used to obtain information on disease progression. This information is presented in Table 4 (5 right most columns). During the 3-year follow-up period, 2 patients died and 1 patient dropped out. The causes of the 2 deaths were suffocation and aplastic anemia. One untraceable patient could not continue to visit because of his disability. The follow-up rate of the third year was 93%. The total number of evaluations for the prospective study was 177. The SARA scores worsened significantly each year. The ∆SARA/year at the 1-, 2-, and 3-year follow-up evaluations was 1.35 ± 1.70 (mean ± SD), 1.39 ± 1.39, and 1.24 ± 1.06 points/year, respectively. The total ∆SARA/year was 1.33 ± 1.40 points/year. The ∆SARA/year was 1.08 ± 0.92 points/year for male patients and 1.56 ± 1.71 points/year for female patients. The difference of the ∆SARA/year between genders was not significant. Each year, the SARA scores of patients who scored between 0 and 24.5 points changed by similar amounts (∆SARA/year = 1.48 ± 1.86 points/y), but the amount of change was smaller for patients with scores of more than 25 points (∆SARA/year = 0.48 ± 1.42 points/y).

Among the subscores of the SARA scale, the subscores for gait (∆/year = 0.27 points/y), stance (∆/year = 0.22 points/y), and fast alternating hand movements (∆/year = 0.24 points/y) were worse than the 5 other subscores (sitting: ∆/year = 0.10 points/y, speech: ∆/year = 0.16 points/y, finger chase: ∆/year = 0.06 points/y, nose-to-finger test: ∆/year = 0.10 points/y, heel-to-shin slide: ∆/year = 0.10 points/y) at the third year. The results of multivariate analysis for the decline in the SARA score were not significant.

The data from the 7-year IDR registry study were used to analyze disease progression. The results of this analysis are presented in Table 4 (last 4 rows). The ∆IDR-ICARS/year of the prospective portion of the study (absolute value 0.66 ± 1.28 points/y) was similar to that of the retrospective portion (absolute value 0.60 ± 1.59 points/y). The IDR-ICARS scores changed linearly in the retrospective and prospective portions of the study. The regression coefficient of the linear regression analysis was 0.63. Among the subscores of the IDR-ICARS scale, the subscore for walking (∆/year = 0.23 points/y) was worse than the 4 other subscores (standing: ∆/year = 0.12 points/y, body sway: ∆/year = 0.11 points/y, knee-tibia test: ∆/year = 0.05 points/y, and finger-to-nose test: ∆/year = 0.07 points/y) at the third year.

Among the 46 patients with SCA6 who participated in this study, 9 already used a wheelchair when they filed their first IDR inquiry sheet. During the 7-year study period of the IDR registry, 12 of the remaining 37 patients became wheelchair dependent. Figure 2 panels A and B show the rates at which patients became wheelchair dependent. These rates are based on disease duration and age, respectively. All patients with a disease duration of less than 8 years and patients who were younger than 51 years could walk during the entire study. During the course of the study, patients with a disease duration of more than 9 years and patients who were older than 52 years gradually became wheelchair dependent. The medians of disease duration and age in patients who needed to use a wheelchair were 24.0 years (95% confidence interval [95% CI], 12.8 - 35.2 y) and 77.0 years (95% CI, 71.6 - 82.4 y), respectively. The 9 patients who were wheelchair dependent when they filed their first IDR inquiry sheet had a disease duration of more than 11 years and an IDR-ICARS score of more than 17 points, and all were older than 56 years.