This study was conducted in agreement with the Ethics Committee of West China Hospital of Sichuan University. All recruited participants provided a written informed consent. A total of 74 genetically confirmed SCA3 patients (39 male) were consecutively recruited from the Department of Neurology, West China Hospital of Sichuan University between August 2015 and January 2020.
In the current study, we performed a cross-sectional study. After testing for trinucleotide repeat expansions of genes causing SCA1, SCA2, SCA3, SCA6 and SCA7 using short tandem repeat (STR) analysis, all patients received a genetically confirmed diagnosis of SCA3. The CAG repeat lengths of the expanded allele were collected. All the patients underwent a face-to-face interview in our department. The following demographic and clinical data were collected: sex, age, weight, height, educational years, age of onset, and disease duration. Body-mass index (BMI) was calculated by body weight (kg) divided by heights squared (m2). Global cognitive function was assessed using Montreal Cognitive Assessment (MoCA). Hamilton Depression Rating Scale-24 (HDRS-24) was used to screen depression. Hamilton Anxiety Rating Scale (HARS) was used to screen anxiety. Epworth Sleepiness Scale (ESS) was used to screen excessive daytime sleepiness. Pittsburgh sleep quality index (PSQI) was used to screen sleep problems.
Eye movement abnormalities were evaluated using accepted bedside techniques by neurologists who were experienced in movement disorders, including impaired smooth pursuit, increased SWJ, GEN, slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy. Impaired smooth pursuit, GEN, slowing of saccades, and saccadic hypo/hypermetria were evaluated following the International Cooperative Ataxia Rating Scale (ICARS) procedure. Pursuit was evaluated both in horizontal and vertical planes. SWJ were detected during central fixation, and increased SWJ were defined as SWJ ≥ 10 per minute. Saccades were evaluated both in horizontal and vertical planes for speed and accuracy. GEN was evaluated in eccentric gaze both in horizontal and vertical planes. Supranuclear gaze palsy was evaluated both in horizontal and vertical planes. Vision loss was also collected.
Ataxia severity was assessed using ICARS and SARA. ICARS is constituted by four symptomatologic compartments: postural and stance disorders, limb ataxia, dysarthria and oculomotor disorders. SARA is composed of eight items: gait, stance, sitting, speech disturbance, finger chase, nose-finger test, fast alternating hand movements and heel-shin slide. SARA has been proved to be a reliable and valid clinical scale measuring the severity of ataxia. In addition, oculomotor disorders are not included in the items of SARA, which is appropriate to avoid multicollinearity. Therefore, we chose SARA as the dependent variable to reflect the severity of ataxia in the multiple linear regression model.
All continuous variables were presented as the mean ± standard deviation and all categorical variables were presented as numbers or percentages. The demographic and clinical characteristics were compared between SCA3 patients with and without each type of abnormal eye movement (impaired smooth pursuit, increased SWJ, GEN, slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy) respectively. Continuous variables were compared using student's t-test if they accorded with normal distribution, and Mann-Whitney U test if they did not accord with normal distribution, and categorical variables using Chi-squared test or Fisher's exact test. ICARS-I, ICARS-II, ICARS-III, ICARS-IV, total ICARS scores, and SARA scores were compared using analyses of covariance (ANCOVA) with adjustment for age and disease duration. MoCA scores were compared using ANCOVA with adjustment for age and educational years. The p-values were false discovery rate (FDR)-corrected for multiple comparisons to avoid false positive significances following the Benjamini-Hochberg (BH) procedure: 1. Put the individual p-values in ascending order and label these p1, p2,...,pk,... pn; 2. The largest FDR p-value is equal to the largest p-value (pn); 3. The FDR pk-1 is the smaller one of the FDR pk and (pk-1/(k-1))n. Spearman’s rank correlation analyses were performed to assess the correlation between SARA scores with other variables, including sex, age, disease duration, BMI, CAG repeat length, HDRS-24 score, HARS score, PSQI score, MoCA score, and number of type of abnormal eye movement (0-6; impaired smooth pursuit, increased SWJ, GEN, slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy). Age, disease duration, CAG repeat length, and other variables with a P value less than 0.10 were entered into the next multivariate linear regression model to predict the severity of ataxia (SARA score) as covariables. Multicollinearity was diagnosed using tolerance and variance inflation factor (VIF). Tolerance less than 0.2 or VIF greater than 5 suggested the existence of multicollinearity. All analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 22.0. Two-tailed p values of < 0.05 were considered statistically significant.