A total of 74 SCA3 patients(39 males and 35 females)with mean disease duration of 6.25 ± 6.24 years were recruited in the current study (Table 1). Up to 90.5% of the SCA3 patients had at least one type of abnormal eye movement (see Video). The frequency of each type of abnormal eye movement such as impaired smooth pursuit, increased SWJ, GEN, slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy was 28.4%, 13.5%, 78.4%, 41.9%, 23.0% and 5.4% respectively (Figure 1).
Table 1 Demographic and clinical features of the recruited SCA3 patients
Variable
|
Cross-sectional study
|
|
(n=74)
|
Sex (male,%)
|
39 (52.7%)
|
Mean age (years)
|
45.04±11.97
|
Age of onset (years)
|
38.79±12.53
|
Disease duration (years)
|
6.25±6.24
|
Educational year
|
10.53±4.52
|
BMI
|
23.69±21.46
|
Hyperreflexia (%)
|
33 (44.6%)
|
Vision loss
|
24 (32.4%)
|
ICARS-I
|
12.27±6.71
|
ICARS-II
|
15.69±8.97
|
ICARS-III
|
1.95±1.53
|
ICARS-IV
|
2.24±1.40
|
Total ICARS score
|
32.15±16.31
|
SARA score
|
11.01±5.73
|
MoCA score
|
23.58±4.68
|
HDRS-24 score
|
8.80±8.92
|
HARS score
|
6.82±7.04
|
ESS score
|
5.41±4.67
|
PSQI score
|
7.23±4.46
|
CAG repeat length
|
66.07±11.15
|
SCA3, spinocerebellar ataxia 3; BMI, body mass index; ICARS, International Cooperative Ataxia Rating Scale; SARA, Scale for the Assessment and Rating of Ataxia; MoCA , Montreal Cognitive Assessment; HDRS-24, Hamilton Depression Scale; HARS, Hamilton Anxiety Scale; ESS, Epworth Sleepiness Scale; PSQI, Pittsburgh sleep quality index.
Demographic and clinical characteristics of the SCA3 patients with and without each abnormal eye movement (impaired smooth pursuit, increased SWJ, GEN, slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy) are shown in Table 2. SCA3 patients with GEN had high scores of ICARS-IV and total ICARS, and longer length of CAG repeat than patients without GEN. SCA3 patients with slowing of saccades had a longer disease duration, a high score of ICARS-I, ICARS-II, total ICARS and SARA than patients without slowing of saccades. SCA3 patients with saccadic hypo/hypermetria had a high score of ICARS-III, ICARS-IV, and SARA than patients without saccadic hypo/hypermetria. The demographic and clinical characteristics did not differ significantly between SCA3 patients with and without impaired smooth pursuit, increased SWJ, or supranuclear gaze palsy.
Table 2 Demographic and clinical features of the SCA3 patients with and without each type of abnormal eye movement
|
Impaired smooth pursuits (horizontal or vertical)
|
Increased square-wave jerks
|
Gaze-evoked nystagmus (horizontal or vertical)
|
|
Yes
(n=21)
|
No
(n=53)
|
P value
|
Yes
(n=10)
|
No
(n=64)
|
P value
|
Yes
(n=58)
|
No
(n=16)
|
P value
|
Sex (male,%)c
|
10 (47.6%)
|
29 (54.7%)
|
0.693
|
2 (20.0%)
|
37 (57.8%)
|
0.727
|
31 (53.4%)
|
8 (50.0%)
|
0.807
|
Mean age (years)a
|
45.05±12.47
|
45.04±11.90
|
0.919
|
43.20±9.81
|
45.33±12.32
|
0.789
|
43.81±11.66
|
49.50±12.40
|
0.215
|
Age of onset (years)a
|
37.38±11.78
|
39.35±12.88
|
0.693
|
37.20±9.40
|
39.04±12.99
|
0.789
|
38.03±11.62
|
41.56±15.49
|
0.222
|
Disease duration (years)b
|
7.67±5.30
|
5.69±6.54
|
0.200
|
6.00±5.54
|
6.29±6.38
|
0.885
|
5.78±4.10
|
7.94±11.04
|
0.760
|
Educational yearb
|
10.00±4.04
|
10.74±4.72
|
0.688
|
9.20±3.36
|
10.73±4.66
|
0.789
|
11.03±4.57
|
8.69±3.93
|
0.089
|
BMIb
|
20.81±2.63
|
24.83±25.28
|
0.693
|
21.15±3.38
|
24.08±23.04
|
0.885
|
21.07±2.99
|
33.16±45.67
|
0.241
|
Hyperreflexiac
|
10 (47.6%)
|
23 (43.4%)
|
0.824
|
6 (60%)
|
27 (42.2%)
|
0.789
|
30 (51.7%)
|
3 (18.8%)
|
0.067
|
Vision lossc
|
9 (42.9%)
|
15 (28.3%)
|
0.429
|
6 (60.0%)
|
18 (28.1%)
|
0.727
|
22 (37.9%)
|
2 (12.5%)
|
0.133
|
ICARS-Id
|
14.91±7.25
|
11.23±6.24
|
0.223
|
11.20±4.37
|
12.44±7.01
|
0.789
|
12.93±6.30
|
9.88±7.74
|
0.055
|
ICARS-IId
|
19.38±10.12
|
14.23±8.12
|
0.165
|
13.00±8.54
|
16.11±9.03
|
0.789
|
16.38±8.75
|
13.19±9.59
|
0.067
|
ICARS-IIId
|
2.43±1.78
|
1.76±1.40
|
0.398
|
1.50±1.35
|
2.02±1.56
|
0.789
|
1.95±1.48
|
1.94±1.77
|
0.722
|
ICARS-IVd
|
3.05±1.43
|
1.93±1.27
|
0.060
|
2.90±1.60
|
2.14±1.36
|
0.727
|
2.55±1.27
|
1.13±1.31
|
0.020*
|
Total ICARS scored
|
39.76±18.04
|
29.13±14.68
|
0.113
|
28.60±14.14
|
32.70±16.65
|
0.789
|
33.81±15.39
|
26.13±18.58
|
0.040*
|
SARA scored
|
13.79±6.17
|
9.91±5.21
|
0.113
|
9.70±3.74
|
11.21±5.98
|
0.789
|
11.41±5.35
|
9.56±6.94
|
0.133
|
MoCA scoree
|
22.28±5.33
|
24.06±4.36
|
0.398
|
24.00±2.00
|
23.52±4.98
|
0.789
|
24.28±4.20
|
21.06±5.58
|
0.241
|
HDRS-24 scoreb
|
9.00±8.16
|
8.72±9.28
|
0.683
|
6.50±3.75
|
9.16±9.45
|
0.885
|
9.55±9.60
|
6.06±5.17
|
0.396
|
HARS scoreb
|
6.76±4.79
|
6.85±7.80
|
0.429
|
4.80±4.42
|
7.14±7.34
|
0.789
|
7.66±7.60
|
3.81±3.08
|
0.215
|
ESS scoreb
|
5.33±5.03
|
5.43±4.57
|
0.867
|
6.30±5.60
|
5.27±4.55
|
0.789
|
5.59±4.67
|
4.75±4.77
|
0.608
|
PSQI scoreb
|
8.33±4.09
|
6.79±4.56
|
0.280
|
6.00±2.98
|
7.42±4.64
|
0.789
|
7.36±4.57
|
6.75±4.14
|
0.722
|
CAG repeat lengthb
|
64.19±13.22
|
66.81±10.27
|
0.693
|
69.70±3.23
|
65.50±11.84
|
0.789
|
68.48±7.33
|
57.31±17.22
|
0.040*
|
|
Slowing of saccades (horizontal or vertical)
|
Saccadic hypo/hypermetria (horizontal or vertical)
|
Supranuclear gaze palsy (horizontal or vertical)
|
|
Yes
(n=31)
|
No
(n=43)
|
P value
|
Yes
(n=17)
|
No
(n=57)
|
P value
|
Yes
(n=4)
|
No
(n=70)
|
P value
|
Sex (male,%)c
|
19 (61.3%)
|
20 (46.5%)
|
0.523
|
13 (76.5%)
|
26 (45.6%)
|
0.100
|
3 (75.0%)
|
36 (51.4%)
|
0.840
|
Mean age (years)a
|
45.68±10.54
|
44.58±13.01
|
0.665
|
45.00±12.23
|
45.05±12.01
|
0.923
|
39.00±14.72
|
45.39±11.83
|
0.775
|
Age of onset (years)a
|
38.58±11.34
|
38.94±13.45
|
0.978
|
38.18±12.31
|
38.97±12.40
|
0.923
|
31.50±13.63
|
39.21±12.44
|
0.740
|
Disease duration (years)b
|
7.10±4.17
|
5.64±7.37
|
0.047*
|
6.82±5.09
|
6.08±6.58
|
0.620
|
7.50±8.96
|
6.18±6.13
|
0.893
|
Educational yearb
|
11.03±4.14
|
10.16±4.79
|
0.665
|
10.06±5.27
|
10.67±4.31
|
0.926
|
9.50±4.12
|
10.59±4.56
|
0.775
|
BMIb
|
20.85±2.61
|
25.74±28.03
|
0.665
|
20.32±2.74
|
24.69±24.37
|
0.442
|
21.65±1.94
|
23.80±22.07
|
0.791
|
Hyperreflexiac
|
16 (51.6%)
|
17 (39.5%)
|
0.604
|
9 (52.9%)
|
24 (42.1%)
|
0.662
|
3 (75.0%)
|
30 (42.9%)
|
0.775
|
Vision lossc
|
8 (25.8%)
|
16 (37.2%)
|
0.523
|
3 (17.6%)
|
21 (36.8%)
|
0.345
|
1 (25.0%)
|
23 (32.9%)
|
1.000
|
ICARS-Id
|
14.74±6.50
|
10.49±6.34
|
0.048*
|
14.71±5.58
|
11.54±6.88
|
0.260
|
10.50±5.92
|
12.37±6.77
|
0.775
|
ICARS-IId
|
18.97±8.91
|
13.33±8.34
|
0.048*
|
18.88±7.88
|
14.74±9.12
|
0.260
|
19.25±9.46
|
15.49±8.97
|
0.740
|
ICARS-IIId
|
2.19±1.49
|
1.77±1.56
|
0.665
|
2.94±1.03
|
1.65±1.54
|
0.020*
|
3.00±1.15
|
1.89±1.54
|
0.740
|
ICARS-IVd
|
2.61±1.45
|
1.98±1.32
|
0.247
|
3.24±1.35
|
1.95±1.29
|
0.020*
|
3.25±1.89
|
2.19±1.37
|
0.740
|
Total ICARS scored
|
38.52±15.25
|
27.56±15.64
|
0.047*
|
39.77±13.00
|
29.88±16.60
|
0.100
|
36.00±17.57
|
31.93±16.34
|
0.775
|
SARA scored
|
13.39±5.27
|
9.29±5.48
|
0.047*
|
14.32±4.54
|
10.02±5.71
|
0.033*
|
12.50±4.65
|
10.92±5.80
|
0.775
|
MoCA scoree
|
23.03±4.56
|
23.98±4.78
|
0.257
|
22.29±4.93
|
23.97±4.58
|
0.371
|
21.25±2.99
|
23.71±4.74
|
0.740
|
HDRS-24 scoreb
|
9.36±9.86
|
8.40±8.28
|
0.665
|
7.47±3.92
|
9.13±9.93
|
0.804
|
13.75±7.14
|
8.51±8.97
|
0.740
|
HARS scoreb
|
7.10±7.52
|
6.63±6.76
|
0.751
|
6.41±4.06
|
6.95±7.74
|
0.620
|
7.00±4.97
|
6.81±7.17
|
0.775
|
ESS scoreb
|
5.29±4.97
|
5.49±4.50
|
0.751
|
5.41±4.05
|
5.40±4.88
|
0.923
|
3.00±2.94
|
5.54±4.73
|
0.775
|
PSQI scoreb
|
6.84±4.58
|
7.51±4.40
|
0.665
|
6.94±4.72
|
7.32±4.42
|
0.827
|
7.50±2.52
|
7.21±4.56
|
0.840
|
CAG repeat lengthb
|
65.65±11.37
|
66.37±11.12
|
0.691
|
65.29±12.99
|
66.30±10.66
|
0.987
|
48.50±19.09
|
67.07±9.84
|
0.740
|
SCA3, spinocerebellar ataxia 3; BMI, body mass index; MoCA, Montreal Cognitive Assessment; ICARS, International Cooperative Ataxia Rating Scale; SARA, Scale for the Assessment and Rating of Ataxia; MoCA , Montreal Cognitive Assessment; HDRS-24, Hamilton Depression Scale; HARS, Hamilton Anxiety Scale; ESS, Epworth Sleepiness Scale; PSQI, Pittsburgh sleep quality index.
* Significant difference after false discovery rate (FDR) correction for multiple comparisons.
a Student's t-test; b Mann-Whitney U test; c Chi-squared test or Fisher's exact test; dAnalyses of covariance (ANCOVA) with adjustment for age and disease duration; eANCOVA with adjustment for age and educational years
Spearman’s rank correlation analyses showed that the SARA score was positively correlated with age (r = 0.205, p = 0.080), disease duration (r = 0.466, p < 0.001), HDRS-24 score (r = 0.234, p = 0.045), and number of abnormal eye movement (r = 0.435, p < 0.001), and negatively correlated with MoCA score (r = -0.266, p = 0.022). To investigate the correlation between abnormal eye movements and the severity of ataxia, we performed a multivariate stepwise linear regression analysis. Total SARA score was used to represent the severity of ataxia and acted as the dependent variable, while the 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) as the independent variable. Other covariables including age, disease duration, HDRS-24 score, MoCA score and CAG repeat length. All independent variables' tolerance was less than 0.2 and VIF was greater than 5, suggesting there was no multicollinearity in the model. The final model showed the number of type of abnormal eye movement (impaired smooth pursuit, increased SWJ, GEN, slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy) besides disease duration, HDRS-24 score, and CAG repeat length were positively correlated with the severity of ataxia in SCA, whereas MoCA score was negatively correlated with the severity of ataxia in SCA3 (Table 3). The residual plots of the multivariate linear regression model were shown in Figure 2. Scatter plots between SARA scores and the numbers of abnormal eye movement were drawn to demonstrate the relationship visually (Figure 3).
Table 3 Multivariate stepwise linear regression analysis of the total SARA score in patients with SCA3
Variable
|
Standardised
regression coefficient
|
Standard
error
|
P value
|
Disease duration
|
0.328
|
0.089
|
0.001*
|
HDRS-24 score
|
0.215
|
0.062
|
0.030*
|
CAG repeat length
|
0.243
|
0.050
|
0.015*
|
Number of abnormal eye movement
|
0.310
|
0.409
|
0.002*
|
MoCA score
|
-0.267
|
0.120
|
0.008*
|
SARA, Scale for the Assessment and Rating of Ataxia; SCA3, spinocerebellar ataxia 3; HDRS-24, Hamilton Depression Scale; MoCA, Montreal Cognitive Assessment.
* Significant difference. P value was calculated by a multivariate stepwise linear regression analysis, with age, disease duration, SARA score, CAG repeat length, number of abnormal eye movement, and HDRS-24 score were included as co-variables.