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Freezing of gait in Chinese patients with Parkinson Disease
JNS-13302; No of Pages 5 Journal of the Neurological Sciences xxx (2014) xxx–xxx
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Freezing of gait in Chinese patients with Parkinson Disease Ruwei Ou, Xiaoyan Guo, Wei Song, Bei Cao, Jing Yang, Qianqian Wei, Na Shao, Huifang Shang ⁎ Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
a r t i c l e
i n f o
Article history: Received 15 March 2014 Received in revised form 9 June 2014 Accepted 1 July 2014 Available online xxxx Keywords: Parkinson disease Gait disorder Freezing of gait Festination Non-motor symptoms Prevalence
a b s t r a c t A total of 474 Chinese Parkinson disease (PD) patients were evaluated to explore the prevalence and clinical correlates of freezing of gait (FOG) in this cross-sectional study. Two hundred and twenty-one PD patients (46.62%) reported FOG (freezers). FOG occurred more frequently in older patients and patients with low limbs as the site of onset, longer disease duration and higher Hoehn and Yahr (H&Y) stage (P b 0.05). After adjusting for confounding factors, the freezers had higher scores for the Unified PD Rating Scale (UPDRS) part III, NonMotor Symptoms Scale (NMSS), PD Questionnaire 39 (PDQ-39), Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA), and lower scores for the Mini-Mental status examination (MMSE), frontal assessment battery (FAB) and Montreal Cognitive Assessment (MoCA) compared with the non-freezers (P b 0.05). The binary logistic regression analysis indicated that festination, falls, a high daily dose of levodopa, the use of a dopamine receptor agonist, a high H&Y stage, the severity of urinary symptoms and a high HAMD score were associated with FOG. FOG is a relatively common disabling symptom in Chinese PD patients. Patients that were older, or reported a longer disease duration, low limbs as the site of onset and a more severe disability were more likely to experience FOG. Non-motor symptoms, especially urinary symptoms and depression, may also be related to FOG. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Gait disorder, a core symptom of Parkinson disease (PD), can consist of a variety of symptoms, such as slowness, shuffle, festination, falls, and freezing of gait (FOG) [1]. FOG is defined as a brief, episodic absence of or marked reduction in the forward progression of the feet despite the intention to walk [2]. FOG not only affects gait in the form of start hesitation, when turning or approaching a destination, or when walking in an open walkway [3], but it can also affect speech and writing [4]. It is a relatively common symptom of PD. In a previous retrospective study on 100 PD patients, sixty of the patients (60%) reported FOG [5]. In another retrospective study on 172 advanced PD patients, 53% PD patients reported FOG [6]. It has been reported that FOG is a disabling symptom and a cause of falls in PD patients [7]. It is important to investigate FOG more thoroughly because of the impact that FOG has on motor function and the quality of life (QoL) of PD patients. Previous studies have already reported a partial clinical profile on FOG in PD. A study on an American population found that FOG can occur as a result of disease progression or as a side effect of levodopa treatment [8]. Another study on an Italian population, however, found that FOG is not affected by levodopa treatment but that it is associated with a longer
⁎ Corresponding author at: Department of Neurology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China. Fax: +86 28 85423550. E-mail address: [email protected] (H. Shang).
PD duration and akinesia [5]. Other studies conducted on non-Asian populations found that there is a correlation between the severity of FOG and cognitive impairment [9,10]. The clinical symptoms of FOG in the Chinese PD population have yet to be reported. The aim of this study is to explore the prevalence and clinical correlates of FOG in a large cohort of Chinese PD patients. 2. Methods This study was approved by the Ethics Committee of West China Hospital of Sichuan University. A total of 474 PD patients from the Department of Neurology, West China Hospital of Sichuan University were consecutively recruited between May 2011 and April 2014 for this observational study. All of the participating PD patients were diagnosed according to the Unified Kingdom PD Society Brain Bank Clinical Diagnostic Criteria for PD [11]. Patients with atypical and secondary Parkinsonism were excluded from this study. Clinical data including age, onset age, gender, disease duration, diagnosis delay, family history of PD, type of motor symptoms, site of initial motor symptoms, years of education, handedness, treatment regimen and motor complications were collected by neurologists majoring in PD through in person interviews. Early-onset PD (EOPD) was defined as an onset age of PD younger than 50 years, and late-onset PD (LOPD) was defined as older than 50 years. PD patients were grouped into three subtypes including tremor-dominant, akinetic-rigid and mixed based on the criteria described in a previous study [12]. Unified PD Rating Scale (UPDRS) part III [13] and Hoehn and Yahr (H&Y) stage [14] were used to evaluate
http://dx.doi.org/10.1016/j.jns.2014.07.002 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Ou R, et al, Freezing of gait in Chinese patients with Parkinson Disease, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.07.002
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R. Ou et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
the severity of the motor symptoms. The QoL of PD patients was evaluated using PD Questionnaire 39 (PDQ-39), which contains 8 domains [15]. Non-motor symptoms (NMS) were assessed using the Non-Motor Symptoms Scale (NMSS), which contains 9 domains [16]. Cognitive function was evaluated using the Mini-Mental status examination (MMSE) [17], frontal assessment battery (FAB) [18] and Montreal Cognitive Assessment (MoCA), which contains 7 domains [19]. The severities of depression and anxiety were assessed using the Hamilton Depression Rating Scale (HAMD) (24 items) [20] and Hamilton Anxiety Rating Scale (HAMA), respectively [21]. All of the assessments were conducted at “on” state. Freezing episodes were observed by experienced neurologists during the visit and were reported by the patient, his or her family members or the caregiver when it occurred at home or anywhere outside of the hospital. Patients were identified as presented with FOG (freezers) based on the “yes” answer to the question “Do you feel that your feet get glued to the floor while walking, making a turn or when trying to initiate walking?”, which is based on item 1.3 of the FOG Questionnaire [22]. If patients and their family members could not understand the definition of FOG, a description or imitation of all of the subtypes of FOG would be performed by neurologists during the visit. The answer obtained from the patients was confirmed by their relatives or caregivers and by the clinical records to ensure the accuracy of data. 3. Statistical analyses All analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 19.0 for Windows. All of the continuous data, including age, age at onset, disease duration, diagnosis delay, years of education, daily levodopa dose, UPDRS part III score, the total scores and each domain score for the PDQ-39, NMSS and MoCA, and the total scores for the HAMD, HAMA, FAB and MMSE, are presented as the mean ± standard deviation (SD). The discontinuous data, including H&Y stage, is presented as the median value (quartile). Student's T test was used for the comparisons of the continuous data, including age, age at onset, disease duration, diagnosis delay and years of education, between the PD patients with and without FOG. The Chi-square test was used to evaluate the differences in the categorical variables between the PD patients with and without FOG. The Wilcoxon rank sum test was performed to compare the discontinuous data between the PD patients with and without FOG. Analyses of covariance (ANCOVA) adjusted for confounding factors were performed to compare the total scores from the UPDRS part III, PDQ-39, NMSS, FAB, MMSE, MoCA, HAMD and HAMA, as well as the scores of each domain from the PDQ-39, NMSS and MoCA between the PD patients with FOG and without FOG. A binary logistic regression model was used to explore potential factors related to FOG. The presence or absence of FOG was used as dependent variable. The parameters, including age, disease duration, onset age, low limbs as the site of onset, use of levodopa, dopamine receptor agonist or entacapone, daily dose of levodopa, H&Y stage, fluctuation, dyskinesia, festination, falls, as well as the scores for the sleep/fatigue, gastrointestinal, urinary, sexual dysfunction and miscellaneous subdomains in the NMSS, the scores for the visuospatial/executive abilities, naming, attention and orientation subdomains in the MoCA, and the total scores from the FAB, HAMD and HAMA, were used as covariables. All statistical tests were two-tailed, and P values b 0.05 were considered statistically significant (for multiple comparison of chi-square test, P values b 0.0125 were considered statistically significant). 4. Results In the current study, 221 PD patients (46.62%) reported FOG. FOG was more frequent in patients older than 65 years than in patients younger than 65 years (53.55% vs. 41.06%, P = 0.007), in patients
with lower limbs as the site of onset than in patients in which lower limbs were not the site of onset (52.17% vs. 43.32%, P = 0.033), and in patients with a disease duration greater than 5 years than in patients with a disease duration of less than 3 years or between 3 and 5 years (P b 0.0125) (Table 1). PD patients at a lower H&Y stage (1–2.5) demonstrated a significantly lower prevalence of FOG than patients at a higher H&Y stage (3 and 4–5) (P b 0.0125, Table 1). There was no significant difference in the prevalence of FOG between the male and female patients, between the EOPD and LOPD patients, between the patients with and without a family history of PD, or among the subtypes of PD patients (Table 1). The demographic and clinical features of the PD patients are listed in Table 2. The mean age, age of onset, disease duration and median H&Y stage were significantly greater for the freezers than the non-freezers (P b 0.05). The percentages of patients receiving treatment of levodopa, dopamine receptor agonist and entacapone, as well as the frequencies of motor fluctuation, dyskinesia, falls and festination were higher in the freezers than the non-freezers (P b 0.05). After adjusting for age and disease duration, the freezers had a higher mean UPDRS part III score and were taking a higher daily dose of levodopa than the non-freezers (P b 0.05). The percentages of patients treated with amantadine and benzhexol were not different between freezers and non-freezers. The PDQ-39 results for the PD patients with and without FOG are listed in Table 3. After adjusting for age, disease duration, H&Y stage and NMSS, the freezers had a significantly higher total score for the PDQ-39 and a higher score for the bodily discomfort subdomain compared with the non-freezers (P b 0.05). The NMSS results for the PD patients with and without FOG are listed in Table 4. After adjusting for age, disease duration and H&Y stage, the freezers had a significantly higher total score for the NMSS and higher scores for the sleep/fatigue, gastrointestinal, urinary, sexual dysfunction and miscellaneous domains compared with the non-freezers (P b 0.05). The cognitive function assessment results for the PD patients with and without FOG are presented in Table 5. After adjusting for age and disease duration, the freezers had lower total scores for the MMSE, FAB and MoCA, as well as lower scores for the visuospatial/executive abilities, naming, attention and orientation domains in the MoCA compared with the non-freezers (P b 0.05). No significant differences in the scores for the remaining domains of the PDQ-39, NMSS and MoCA were found between the freezers and non-freezers. The depression and anxiety severity results for the PD patients with and without FOG are listed in Table 6. After adjusting for age, disease duration and H&Y stage, the total scores for the HAMD and HAMA were significantly higher in the freezers compared with the non-freezers (P b 0.05). The potential factors related to FOG are presented in Table 7. The binary logistic regression model indicated a high H&Y stage, festination, falls, high daily dose of levodopa, use of a dopamine receptor agonist, a high score for the urinary domain in the NMSS and a higher score for the HAMD were associated with FOG (P b 0.005). No significant correlations were found between the remaining clinical factors and FOG. 5. Discussion To the best of our knowledge, this is the first study to investigate the prevalence of FOG and the clinical correlations between various factors and FOG in a large cohort of Chinese PD patients. We found that FOG is very common in the Chinese PD population (46.62%), which is consistent with other previous studies on nonAsian populations (range from 32% to 72%) [5,6,8,23–25]. Our patients at higher H&Y stages were more likely to report experiencing FOG, which is consistent with a previous study on an Israeli population [6]. Our findings that the PD patients who were older or who had a longer disease duration or low limbs as the site of onset were more likely to experience FOG have never been previously systematically reported. Additionally, we also found that there was no difference in the
Please cite this article as: Ou R, et al, Freezing of gait in Chinese patients with Parkinson Disease, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.07.002
R. Ou et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
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Table 1 Prevalence of FOG in patients with PD.
Total Gender Age Onset age Family history Low limbs as site of onset Type of motor symptom
Disease duration
H&Y stage
Groups
Freezers:total sample
Prevalence of FOG
Male Female b65 years old ≥65 years old EOPD LOPD Positive Negative Yes No Tremor-dominant Akinetic-rigid Mixed b3 years ≥3, but b5 years ≥5 years 1–2.5 3 4–5
221:474 117:257 104:217 108:263 113:211 47:116 174:358 18:45 203:429 108:207 113:267 1:10 148:307 72:157 57:191 51:108 113:175 115:343 74:94 32:35
46.62% 45.53% 47.93% 41.06% 53.55% 40.52% 48.60% 40.00% 47.32% 52.17% 43.32% 10.00% 48.21% 45.86% 29.84% 47.22% 64.57% 33.53% 78.72% 91.43%
Test
P-value
a
0.602
a
0.007a
a
0.129
a
0.349
a
0.033a
a
0.057
b1 b2 b3 c1 c2 c3
0.003a b0.001a 0.004a b0.001a b0.001a 0.058
FOG: freezing of gait. PD: Parkinson Disease. Freezers: PD patients with FOG. EOPD: early-onset PD. LOPD: late-onset PD. H&Y stage: Hoehn and Yahr stage. Test a: chi-square test. Test b1: comparison between patients with a disease duration less than 3 years and patients with a disease duration between 3 and 5 years using a chi-square test. Test b2: comparison between patients with a disease duration less than 3 years and patients with a disease duration greater than 5 years using a chi-square test. Test b3: comparison between patients with a disease duration between 3 and 5 years and patients with a disease duration greater than 5 years using a chi-square test. Test c1: comparison between patients with a H&Y stage 1–2.5 and patients with a H&Y stage 3 using a chi-square test. Test c2: comparison between patients with a H&Y stage 1–2.5 and patients with a H&Y stage 4–5 using a chi-square test. Test c3: comparison between patients with a H&Y stage 3 and patients with a H&Y stage 4–5 using a chi-square test. a Significant difference (for test a, P-values b 0.05 are considered statistically significant; for tests b and c, P-values b 0.0125 are considered statistically significant).
prevalence of FOG between the male and female patients, which is consistent with the finding from a previous study on English patients [25], but is inconsistent with the findings from two previous European studies [5,24]. For example, the study on an Italian population found that FOG was more prevalent in the female PD patients [5], whereas a study on a German population found that FOG was more prevalent in
the male PD patients [24]. The different sample sizes, inclusion criteria and genetic backgrounds among these study groups may account for these discrepancies. In the current study, after adjusting for age, disease duration, H&Y stage and NMSS, our PD patients with FOG had a lower QoL, especially in bodily discomfort, which is similar to the findings from a study
Table 2 Demographic and clinical features of PD patients.
Demographic features Use of left hand Education years (years) Mean age (years) Mean age at onset (years) Disease duration (years) Diagnosis delay (years) Drugs application Use of levodopa Daily dose of levodopa (mg/day) Use of dopamine receptor agonist Use of amantadine Use of benzhexol Use of entacapone Motor severity UPDRS part III H&Y stage Motor complication Fluctuation Dyskinesia Gait disorders Festination Falls
Total (n = 474)
Freezers (n = 221)
Non-freezers (n = 253)
Test
P-value
11 (2.32%) 9.20 ± 4.62 62.09 ± 10.55 57.32 ± 10.68 4.77 ± 4.04 1.89 ± 2.00
5 (2.26%) 9.00 ± 4.73 64.36 ± 10.16 58.39 ± 10.50 5.97 ± 4.24 2.08 ± 2.04
6 (2.37%) 9.36 ± 4.52 60.11 ± 10.50 56.39 ± 10.76 3.73 ± 3.55 1.73 ± 1.96
1 2 2 2 2 2
0.937 0.401 b0.001a 0.042a b0.001a 0.061
401 (84.60%) 292.30 ± 217.13 235 (49.58%) 128 (27.00%) 55 (11.60%) 44 (9.60%)
202 (91.40%) 370.36 ± 236.48 121 (54.75%) 65 (29.41%) 25 (10.48%) 32 (11.31%)
199 (78.66%) 224.11 ± 172.21 114 (45.06%) 63 (24.90%) 30 (11.97%) 12 (4.74%)
1 3 1 1 1 1
b0.001a b0.001a 0.035a 0.270 0.853 b0.001a
29.60 ± 13.80 2.0 (0.5)
35.90 ± 14.48 2.5 (1.0)
24.10 ± 10.45 2.0 (0.5)
3 4
b0.001a b0.001a
88 (18.57%) 46 (9.70%)
65 (29.41%) 29 (13.12%)
23 (9.09%) 17 (6.72%)
1 1
b0.001a 0.019a
137 (28.90%) 71 (14.98%)
110 (49.77%) 63 (28.51%)
27 (10.67%) 8 (3.16%)
1 1
b0.001a b0.001a
PD: Parkinson disease. Freezers: PD patients with freezing of gait. Non-freezers: PD patients without freezing of gait. UPDRS: Unified PD Rating Scale. H&Y stage: Hoehn and Yahr stage. Test1: Chi-square test. Test2: Student's T test. Test3: ANCOVA adjusted for age and disease duration. Test4: Wilcoxon rank sum test. a Significant difference.
Please cite this article as: Ou R, et al, Freezing of gait in Chinese patients with Parkinson Disease, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.07.002
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R. Ou et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
Table 3 PDQ-39 of PD patients with and without FOG.
Table 5 Cognitive function assessments of PD patients with and without FOG.
PDQ-39
Freezers (n = 221)
Non-freezers (n = 253)
P-valuea
Cognitive function
Freezers (n = 221)
Non-freezers (n = 253)
P-valuea
Total score Mobility Activities of daily life Emotional well-being Stigma Social support Cognitions Communication Bodily discomfort
49.11 11.30 6.21 6.64 3.95 0.89 4.08 1.69 3.26
26.34 9.00 5.62 6.17 3.15 0.83 3.92 1.40 2.78
b.001b 0.279 0.667 0.435 0.068 0.945 0.807 0.519 0.037b
MMSE FAB MoCA Visuospatial/executive abilities Naming Attention Language Abstraction Memory Orientation
26.03 14.60 21.53 2.97 2.12 4.92 1.50 1.13 2.83 5.33
27.21 15.82 23.69 3.46 2.35 5.31 1.70 1.20 3.22 5.67
0.016b b 0.001b 0.001b 0.008b 0.003b 0.016b 0.114 0.132 0.150 0.005b
± ± ± ± ± ± ± ± ±
25.74 11.83 6.00 5.91 4.55 1.74 3.18 2.27 2.65
± ± ± ± ± ± ± ± ±
19.92 10.03 5.43 5.45 3.88 1.83 3.13 1.88 2.65
PD: Parkinson disease. PDQ-39: PD Questionnaire 39. FOG: freezing of gait. Freezers: PD patients with FOG. Non-freezers: PD patients without FOG. a P-value is calculated from an ANCOVA adjusted for age, disease duration, H&Y stage and NMSS. b Significant difference.
on an Israeli population [26]. These findings demonstrate that FOG has a significant impact on the QoL of PD patients in addition to its effect on gait. Currently, there are very few studies that have investigated how the mechanism of FOG affects QoL. A previous study, however, suggested that the episodic characteristic of FOG may be involved in it [26]. Our patients with FOG demonstrated a more severe motor disability and more frequent motor complications, these findings are consistent with previous studies on Caucasian populations [5,6,8,23]. Additionally, we found an association between the H&Y stage and our patients with FOG, which is consistent with the findings from a study on an American population and another study on a German population [8, 24]. We also found no association between the disease duration and FOG, which is inconsistent with previous studies on Caucasian populations [5,6,8,23,24]. Rather, our findings suggest that there is an association between FOG and the severity of the disease. Furthermore, we also found that a high daily dose of levodopa and the use of a dopamine receptor agonist were also associated with FOG, which is consistent with the findings from previous studies [6,8,24]. However, we failed to find a correlation between receiving amantadine and entacapone treatments and FOG, which was reported in a previous study [24]. A high levodopa dose or dopamine receptor agonist treatment in patients with FOG may reflect a higher disease severity in patients with FOG. Based on the current finding, we cannot conclude that FOG is a side effect of the anti-Parkinson medicine. We found a correlation between FOG and festination and falls, and this association is also supported by previous studies [27–30]. Our findings indicate that FOG patients are
Table 4 NMS of PD patients with and without FOG. NMSS
Freezers (n = 221)
Non-freezers (n = 253)
P-valuea
Total score Cardiovascular Sleep/fatigue Mood/apathy Perceptual problems/hallucinations Attention/memory Gastrointestinal Urinary Sexual dysfunction Miscellaneous
60.01 1.26 12.21 11.76 1.08 4.76 5.85 8.36 7.49 6.63
33.49 0.80 6.96 7.33 0.66 3.10 2.40 3.41 4.59 4.24
b0.001b 0.092 b0.001b 0.169 0.687 0.093 b0.001b b0.001b 0.004b 0.006b
± ± ± ± ± ± ± ± ± ±
40.22 2.48 10.09 14.67 3.76 5.90 6.42 9.79 6.57 6.18
± ± ± ± ± ± ± ± ± ±
28.32 2.16 6.96 10.38 3.06 3.91 3.91 5.43 5.09 5.53
NMS: non-motor symptoms. PD: Parkinson disease. NMSS: Non-Motor Symptoms Scale. FOG: freezing of gait. Freezers: PD patients with FOG. Non-freezers: PD patients without FOG. a P-value is calculated from an ANCOVA adjusted for age, disease duration and H&Y stage. b Significant difference.
± ± ± ± ± ± ± ± ± ±
3.75 3.00 5.81 1.57 1.01 1.33 1.04 0.79 1.68 1.05
± ± ± ± ± ± ± ± ± ±
2.95 2.51 5.17 1.49 0.90 1.02 0.99 0.75 1.64 0.73
PD: Parkinson disease. FOG: freezing of gait. Freezers: PD patients with FOG. Non-freezers: PD patients without FOG. MMSE: Mini-Mental state examination. FAB: frontal assessment battery. MoCA: Montreal Cognitive Assessment. a P-value is calculated from an ANCOVA adjusted for age and disease duration. b Significant difference.
more likely to experience other types of gait disorders, such as festination and falls. In addition, we also found that the PD patients with FOG had more severe NMS than the PD patients without FOG. Furthermore, we also found that urinary symptoms and depression were also associated with FOG in this study, which is consistent with a study on an Israeli population [31]. These findings indicate that our focus should extend beyond the treatment of motor symptoms when treating NMS in PD patients with FOG. Although our PD patients with FOG demonstrated a poor cognitive performance compared with the PD patients without FOG, no association was found between FOG and cognitive dysfunction. This finding is inconsistent with previous studies on a non-Asian population [9,10,32, 33], which found that FOG is associated with executive dysfunction and visuospatial deficits. The pathogenesis of FOG remains unclear. A resting-state fMRI study [34] found that the connectivity disruption of “executive-attention” and visual neural networks may be associated with FOG in PD. One voxel-based morphometry study found an association between FOG and posterior gray matter atrophy [35]. Another voxel-based morphometry study found that PD patients with FOG had frontal and parietal atrophy, indicating that FOG may be involved in executive dysfunction and perception deficits [36]. Our findings from this cross-sectional study do not resolve these discrepancies. Further longitudinal studies using a combination of imaging techniques and neuropsychological assessments are needed to clarify this potential association. There were some limitations of the present study that should be discussed. First, FOG is experienced more commonly at home, and it is hard to evaluate FOG in the clinical setting or research laboratory. Therefore, recall bias may have affected the results of this study. Second, the results may have been affected by some unpredictable factors, which were unknown at the time of the study. Third, we did not find a difference in the frequency of FOG among the different patient
Table 6 Depression and anxiety of PD patients with and without FOG.
HAMD HAMA
Freezers (n = 221)
Non-freezers (n = 253)
P-valuea
14.73 ± 9.82 9.64 ± 7.50
9.61 ± 7.81 6.21 ± 5.92
b0.001b b0.001b
PD: Parkinson disease. FOG: freezing of gait. Freezers: PD patients with FOG. Non-freezers: PD patients without FOG. HAMD: Hamilton Depression Rating Scale. HAMA: Hamilton Anxiety Rating Scale. a P-value is calculated from an ANCOVA adjusted for age, disease duration and H&Y stage. b Significant difference.
Please cite this article as: Ou R, et al, Freezing of gait in Chinese patients with Parkinson Disease, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.07.002
R. Ou et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx Table 7 Correlative clinical factors of FOG in PD patients.
Age Disease duration Age at onset Low limbs as site of onset Use of levodopa Daily dose of levodopa Use of dopamine receptor agonist Use of entacapone H&Y stage Fluctuation Dyskinesia Festination Falls NMSS Sleep/fatigue Gastrointestinal Urinary Sexual dysfunction Miscellaneous MoCA Visuospatial/executive abilities Naming Attention Orientation FAB HAMD HAMA
OR
95%CI
P-valuea
1.003 1.011 1.206 1.450 0.929 1.002 1.820 0.926 2.868 2.235 1.351 4.921 3.433
0.962–1.046 0.879–1.041 0.466–3.123 0.879–2.392 0.387–2.231 1.001–1.004 1.130–2.930 0.354–2.424 1.852–4.441 0.982–5.087 0.497–3.671 2.830–8.556 1.433–8.225
0.891 0.300 0.699 0.146 0.869 0.001b 0.014b 0.876 b 0.001b 0.055 0.556 b 0.001b 0.006⁎
1.019 1.015 1.039 1.023 1.017
0.980–1.058 0.957–1.076 1.003–1.077 0.975–1.074 0.969–1.066
0.346 0.622 0.034b 0.349 0.498
1.007 0.800 1.062 0.898 0.986 1.038 1.046
0.812–1.250 0.591–1.082 0.802–1.405 0.647–1.247 0.883–1.102 1.039–1.069 0.897–1.038
0.947 0.147 0.676 0.521 0.809 0.010b 0.333
PD: Parkinson disease. FOG: freezing of gait. H&Y stage: Hoehn and Yahr stage. NMSS: Non-Motor Symptoms Scale. MoCA: Montreal Cognitive Assessment. HAMD: Hamilton Depression Rating Scale. HAMA: Hamilton Anxiety Rating Scale. a P-value is calculated from binary logistic regression analysis. b Significant difference.
subtypes, and this finding may be because the number of tremor subtype patients was too low. 6. Conclusions FOG is a relatively common disabling symptom of PD in Chinese patients. Patients that are older, or who reported longer disease duration, low limbs as the site of onset and a more severe motor disability were more likely to experience FOG. NMS, especially urinary symptoms and depression, may also be associated with FOG. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgments The authors thank the patients and their families for their participation in the study. References [1] Rogers MW. Disorders of posture, balance, and gait in Parkinson's disease. Clin Geriatr Med 1996;12(4):825–45. [2] Giladi N, Nieuwboer A. Understanding and treating freezing of gait in parkinsonism, proposed working definition, and setting the stage. Mov Disord 2008;23(Suppl. 2): S423–5. [3] Stern GM, Lander CM, Lees AJ. Akinetic freezing and trick movements in Parkinson's disease. J Neural Transm Suppl 1980;16:137–41. [4] Bartels AL, Balash Y, Gurevich T, Schaafsma JD, Hausdorff JM, Giladi N. Relationship between freezing of gait (FOG) and other features of Parkinson's: FOG is not correlated with bradykinesia. J Clin Neurosci 2003;10(5):584–8.
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Freezing of gait in Chinese patients with Parkinson Disease Ruwei Ou, Xiaoyan Guo, Wei Song, Bei Cao, Jing Yang, Qianqian Wei, Na Shao, Huifang Shang ⁎ Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
a r t i c l e
i n f o
Article history: Received 15 March 2014 Received in revised form 9 June 2014 Accepted 1 July 2014 Available online xxxx Keywords: Parkinson disease Gait disorder Freezing of gait Festination Non-motor symptoms Prevalence
a b s t r a c t A total of 474 Chinese Parkinson disease (PD) patients were evaluated to explore the prevalence and clinical correlates of freezing of gait (FOG) in this cross-sectional study. Two hundred and twenty-one PD patients (46.62%) reported FOG (freezers). FOG occurred more frequently in older patients and patients with low limbs as the site of onset, longer disease duration and higher Hoehn and Yahr (H&Y) stage (P b 0.05). After adjusting for confounding factors, the freezers had higher scores for the Unified PD Rating Scale (UPDRS) part III, NonMotor Symptoms Scale (NMSS), PD Questionnaire 39 (PDQ-39), Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA), and lower scores for the Mini-Mental status examination (MMSE), frontal assessment battery (FAB) and Montreal Cognitive Assessment (MoCA) compared with the non-freezers (P b 0.05). The binary logistic regression analysis indicated that festination, falls, a high daily dose of levodopa, the use of a dopamine receptor agonist, a high H&Y stage, the severity of urinary symptoms and a high HAMD score were associated with FOG. FOG is a relatively common disabling symptom in Chinese PD patients. Patients that were older, or reported a longer disease duration, low limbs as the site of onset and a more severe disability were more likely to experience FOG. Non-motor symptoms, especially urinary symptoms and depression, may also be related to FOG. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Gait disorder, a core symptom of Parkinson disease (PD), can consist of a variety of symptoms, such as slowness, shuffle, festination, falls, and freezing of gait (FOG) [1]. FOG is defined as a brief, episodic absence of or marked reduction in the forward progression of the feet despite the intention to walk [2]. FOG not only affects gait in the form of start hesitation, when turning or approaching a destination, or when walking in an open walkway [3], but it can also affect speech and writing [4]. It is a relatively common symptom of PD. In a previous retrospective study on 100 PD patients, sixty of the patients (60%) reported FOG [5]. In another retrospective study on 172 advanced PD patients, 53% PD patients reported FOG [6]. It has been reported that FOG is a disabling symptom and a cause of falls in PD patients [7]. It is important to investigate FOG more thoroughly because of the impact that FOG has on motor function and the quality of life (QoL) of PD patients. Previous studies have already reported a partial clinical profile on FOG in PD. A study on an American population found that FOG can occur as a result of disease progression or as a side effect of levodopa treatment [8]. Another study on an Italian population, however, found that FOG is not affected by levodopa treatment but that it is associated with a longer
⁎ Corresponding author at: Department of Neurology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China. Fax: +86 28 85423550. E-mail address: [email protected] (H. Shang).
PD duration and akinesia [5]. Other studies conducted on non-Asian populations found that there is a correlation between the severity of FOG and cognitive impairment [9,10]. The clinical symptoms of FOG in the Chinese PD population have yet to be reported. The aim of this study is to explore the prevalence and clinical correlates of FOG in a large cohort of Chinese PD patients. 2. Methods This study was approved by the Ethics Committee of West China Hospital of Sichuan University. A total of 474 PD patients from the Department of Neurology, West China Hospital of Sichuan University were consecutively recruited between May 2011 and April 2014 for this observational study. All of the participating PD patients were diagnosed according to the Unified Kingdom PD Society Brain Bank Clinical Diagnostic Criteria for PD [11]. Patients with atypical and secondary Parkinsonism were excluded from this study. Clinical data including age, onset age, gender, disease duration, diagnosis delay, family history of PD, type of motor symptoms, site of initial motor symptoms, years of education, handedness, treatment regimen and motor complications were collected by neurologists majoring in PD through in person interviews. Early-onset PD (EOPD) was defined as an onset age of PD younger than 50 years, and late-onset PD (LOPD) was defined as older than 50 years. PD patients were grouped into three subtypes including tremor-dominant, akinetic-rigid and mixed based on the criteria described in a previous study [12]. Unified PD Rating Scale (UPDRS) part III [13] and Hoehn and Yahr (H&Y) stage [14] were used to evaluate
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Please cite this article as: Ou R, et al, Freezing of gait in Chinese patients with Parkinson Disease, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.07.002
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the severity of the motor symptoms. The QoL of PD patients was evaluated using PD Questionnaire 39 (PDQ-39), which contains 8 domains [15]. Non-motor symptoms (NMS) were assessed using the Non-Motor Symptoms Scale (NMSS), which contains 9 domains [16]. Cognitive function was evaluated using the Mini-Mental status examination (MMSE) [17], frontal assessment battery (FAB) [18] and Montreal Cognitive Assessment (MoCA), which contains 7 domains [19]. The severities of depression and anxiety were assessed using the Hamilton Depression Rating Scale (HAMD) (24 items) [20] and Hamilton Anxiety Rating Scale (HAMA), respectively [21]. All of the assessments were conducted at “on” state. Freezing episodes were observed by experienced neurologists during the visit and were reported by the patient, his or her family members or the caregiver when it occurred at home or anywhere outside of the hospital. Patients were identified as presented with FOG (freezers) based on the “yes” answer to the question “Do you feel that your feet get glued to the floor while walking, making a turn or when trying to initiate walking?”, which is based on item 1.3 of the FOG Questionnaire [22]. If patients and their family members could not understand the definition of FOG, a description or imitation of all of the subtypes of FOG would be performed by neurologists during the visit. The answer obtained from the patients was confirmed by their relatives or caregivers and by the clinical records to ensure the accuracy of data. 3. Statistical analyses All analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 19.0 for Windows. All of the continuous data, including age, age at onset, disease duration, diagnosis delay, years of education, daily levodopa dose, UPDRS part III score, the total scores and each domain score for the PDQ-39, NMSS and MoCA, and the total scores for the HAMD, HAMA, FAB and MMSE, are presented as the mean ± standard deviation (SD). The discontinuous data, including H&Y stage, is presented as the median value (quartile). Student's T test was used for the comparisons of the continuous data, including age, age at onset, disease duration, diagnosis delay and years of education, between the PD patients with and without FOG. The Chi-square test was used to evaluate the differences in the categorical variables between the PD patients with and without FOG. The Wilcoxon rank sum test was performed to compare the discontinuous data between the PD patients with and without FOG. Analyses of covariance (ANCOVA) adjusted for confounding factors were performed to compare the total scores from the UPDRS part III, PDQ-39, NMSS, FAB, MMSE, MoCA, HAMD and HAMA, as well as the scores of each domain from the PDQ-39, NMSS and MoCA between the PD patients with FOG and without FOG. A binary logistic regression model was used to explore potential factors related to FOG. The presence or absence of FOG was used as dependent variable. The parameters, including age, disease duration, onset age, low limbs as the site of onset, use of levodopa, dopamine receptor agonist or entacapone, daily dose of levodopa, H&Y stage, fluctuation, dyskinesia, festination, falls, as well as the scores for the sleep/fatigue, gastrointestinal, urinary, sexual dysfunction and miscellaneous subdomains in the NMSS, the scores for the visuospatial/executive abilities, naming, attention and orientation subdomains in the MoCA, and the total scores from the FAB, HAMD and HAMA, were used as covariables. All statistical tests were two-tailed, and P values b 0.05 were considered statistically significant (for multiple comparison of chi-square test, P values b 0.0125 were considered statistically significant). 4. Results In the current study, 221 PD patients (46.62%) reported FOG. FOG was more frequent in patients older than 65 years than in patients younger than 65 years (53.55% vs. 41.06%, P = 0.007), in patients
with lower limbs as the site of onset than in patients in which lower limbs were not the site of onset (52.17% vs. 43.32%, P = 0.033), and in patients with a disease duration greater than 5 years than in patients with a disease duration of less than 3 years or between 3 and 5 years (P b 0.0125) (Table 1). PD patients at a lower H&Y stage (1–2.5) demonstrated a significantly lower prevalence of FOG than patients at a higher H&Y stage (3 and 4–5) (P b 0.0125, Table 1). There was no significant difference in the prevalence of FOG between the male and female patients, between the EOPD and LOPD patients, between the patients with and without a family history of PD, or among the subtypes of PD patients (Table 1). The demographic and clinical features of the PD patients are listed in Table 2. The mean age, age of onset, disease duration and median H&Y stage were significantly greater for the freezers than the non-freezers (P b 0.05). The percentages of patients receiving treatment of levodopa, dopamine receptor agonist and entacapone, as well as the frequencies of motor fluctuation, dyskinesia, falls and festination were higher in the freezers than the non-freezers (P b 0.05). After adjusting for age and disease duration, the freezers had a higher mean UPDRS part III score and were taking a higher daily dose of levodopa than the non-freezers (P b 0.05). The percentages of patients treated with amantadine and benzhexol were not different between freezers and non-freezers. The PDQ-39 results for the PD patients with and without FOG are listed in Table 3. After adjusting for age, disease duration, H&Y stage and NMSS, the freezers had a significantly higher total score for the PDQ-39 and a higher score for the bodily discomfort subdomain compared with the non-freezers (P b 0.05). The NMSS results for the PD patients with and without FOG are listed in Table 4. After adjusting for age, disease duration and H&Y stage, the freezers had a significantly higher total score for the NMSS and higher scores for the sleep/fatigue, gastrointestinal, urinary, sexual dysfunction and miscellaneous domains compared with the non-freezers (P b 0.05). The cognitive function assessment results for the PD patients with and without FOG are presented in Table 5. After adjusting for age and disease duration, the freezers had lower total scores for the MMSE, FAB and MoCA, as well as lower scores for the visuospatial/executive abilities, naming, attention and orientation domains in the MoCA compared with the non-freezers (P b 0.05). No significant differences in the scores for the remaining domains of the PDQ-39, NMSS and MoCA were found between the freezers and non-freezers. The depression and anxiety severity results for the PD patients with and without FOG are listed in Table 6. After adjusting for age, disease duration and H&Y stage, the total scores for the HAMD and HAMA were significantly higher in the freezers compared with the non-freezers (P b 0.05). The potential factors related to FOG are presented in Table 7. The binary logistic regression model indicated a high H&Y stage, festination, falls, high daily dose of levodopa, use of a dopamine receptor agonist, a high score for the urinary domain in the NMSS and a higher score for the HAMD were associated with FOG (P b 0.005). No significant correlations were found between the remaining clinical factors and FOG. 5. Discussion To the best of our knowledge, this is the first study to investigate the prevalence of FOG and the clinical correlations between various factors and FOG in a large cohort of Chinese PD patients. We found that FOG is very common in the Chinese PD population (46.62%), which is consistent with other previous studies on nonAsian populations (range from 32% to 72%) [5,6,8,23–25]. Our patients at higher H&Y stages were more likely to report experiencing FOG, which is consistent with a previous study on an Israeli population [6]. Our findings that the PD patients who were older or who had a longer disease duration or low limbs as the site of onset were more likely to experience FOG have never been previously systematically reported. Additionally, we also found that there was no difference in the
Please cite this article as: Ou R, et al, Freezing of gait in Chinese patients with Parkinson Disease, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.07.002
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Table 1 Prevalence of FOG in patients with PD.
Total Gender Age Onset age Family history Low limbs as site of onset Type of motor symptom
Disease duration
H&Y stage
Groups
Freezers:total sample
Prevalence of FOG
Male Female b65 years old ≥65 years old EOPD LOPD Positive Negative Yes No Tremor-dominant Akinetic-rigid Mixed b3 years ≥3, but b5 years ≥5 years 1–2.5 3 4–5
221:474 117:257 104:217 108:263 113:211 47:116 174:358 18:45 203:429 108:207 113:267 1:10 148:307 72:157 57:191 51:108 113:175 115:343 74:94 32:35
46.62% 45.53% 47.93% 41.06% 53.55% 40.52% 48.60% 40.00% 47.32% 52.17% 43.32% 10.00% 48.21% 45.86% 29.84% 47.22% 64.57% 33.53% 78.72% 91.43%
Test
P-value
a
0.602
a
0.007a
a
0.129
a
0.349
a
0.033a
a
0.057
b1 b2 b3 c1 c2 c3
0.003a b0.001a 0.004a b0.001a b0.001a 0.058
FOG: freezing of gait. PD: Parkinson Disease. Freezers: PD patients with FOG. EOPD: early-onset PD. LOPD: late-onset PD. H&Y stage: Hoehn and Yahr stage. Test a: chi-square test. Test b1: comparison between patients with a disease duration less than 3 years and patients with a disease duration between 3 and 5 years using a chi-square test. Test b2: comparison between patients with a disease duration less than 3 years and patients with a disease duration greater than 5 years using a chi-square test. Test b3: comparison between patients with a disease duration between 3 and 5 years and patients with a disease duration greater than 5 years using a chi-square test. Test c1: comparison between patients with a H&Y stage 1–2.5 and patients with a H&Y stage 3 using a chi-square test. Test c2: comparison between patients with a H&Y stage 1–2.5 and patients with a H&Y stage 4–5 using a chi-square test. Test c3: comparison between patients with a H&Y stage 3 and patients with a H&Y stage 4–5 using a chi-square test. a Significant difference (for test a, P-values b 0.05 are considered statistically significant; for tests b and c, P-values b 0.0125 are considered statistically significant).
prevalence of FOG between the male and female patients, which is consistent with the finding from a previous study on English patients [25], but is inconsistent with the findings from two previous European studies [5,24]. For example, the study on an Italian population found that FOG was more prevalent in the female PD patients [5], whereas a study on a German population found that FOG was more prevalent in
the male PD patients [24]. The different sample sizes, inclusion criteria and genetic backgrounds among these study groups may account for these discrepancies. In the current study, after adjusting for age, disease duration, H&Y stage and NMSS, our PD patients with FOG had a lower QoL, especially in bodily discomfort, which is similar to the findings from a study
Table 2 Demographic and clinical features of PD patients.
Demographic features Use of left hand Education years (years) Mean age (years) Mean age at onset (years) Disease duration (years) Diagnosis delay (years) Drugs application Use of levodopa Daily dose of levodopa (mg/day) Use of dopamine receptor agonist Use of amantadine Use of benzhexol Use of entacapone Motor severity UPDRS part III H&Y stage Motor complication Fluctuation Dyskinesia Gait disorders Festination Falls
Total (n = 474)
Freezers (n = 221)
Non-freezers (n = 253)
Test
P-value
11 (2.32%) 9.20 ± 4.62 62.09 ± 10.55 57.32 ± 10.68 4.77 ± 4.04 1.89 ± 2.00
5 (2.26%) 9.00 ± 4.73 64.36 ± 10.16 58.39 ± 10.50 5.97 ± 4.24 2.08 ± 2.04
6 (2.37%) 9.36 ± 4.52 60.11 ± 10.50 56.39 ± 10.76 3.73 ± 3.55 1.73 ± 1.96
1 2 2 2 2 2
0.937 0.401 b0.001a 0.042a b0.001a 0.061
401 (84.60%) 292.30 ± 217.13 235 (49.58%) 128 (27.00%) 55 (11.60%) 44 (9.60%)
202 (91.40%) 370.36 ± 236.48 121 (54.75%) 65 (29.41%) 25 (10.48%) 32 (11.31%)
199 (78.66%) 224.11 ± 172.21 114 (45.06%) 63 (24.90%) 30 (11.97%) 12 (4.74%)
1 3 1 1 1 1
b0.001a b0.001a 0.035a 0.270 0.853 b0.001a
29.60 ± 13.80 2.0 (0.5)
35.90 ± 14.48 2.5 (1.0)
24.10 ± 10.45 2.0 (0.5)
3 4
b0.001a b0.001a
88 (18.57%) 46 (9.70%)
65 (29.41%) 29 (13.12%)
23 (9.09%) 17 (6.72%)
1 1
b0.001a 0.019a
137 (28.90%) 71 (14.98%)
110 (49.77%) 63 (28.51%)
27 (10.67%) 8 (3.16%)
1 1
b0.001a b0.001a
PD: Parkinson disease. Freezers: PD patients with freezing of gait. Non-freezers: PD patients without freezing of gait. UPDRS: Unified PD Rating Scale. H&Y stage: Hoehn and Yahr stage. Test1: Chi-square test. Test2: Student's T test. Test3: ANCOVA adjusted for age and disease duration. Test4: Wilcoxon rank sum test. a Significant difference.
Please cite this article as: Ou R, et al, Freezing of gait in Chinese patients with Parkinson Disease, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.07.002
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Table 3 PDQ-39 of PD patients with and without FOG.
Table 5 Cognitive function assessments of PD patients with and without FOG.
PDQ-39
Freezers (n = 221)
Non-freezers (n = 253)
P-valuea
Cognitive function
Freezers (n = 221)
Non-freezers (n = 253)
P-valuea
Total score Mobility Activities of daily life Emotional well-being Stigma Social support Cognitions Communication Bodily discomfort
49.11 11.30 6.21 6.64 3.95 0.89 4.08 1.69 3.26
26.34 9.00 5.62 6.17 3.15 0.83 3.92 1.40 2.78
b.001b 0.279 0.667 0.435 0.068 0.945 0.807 0.519 0.037b
MMSE FAB MoCA Visuospatial/executive abilities Naming Attention Language Abstraction Memory Orientation
26.03 14.60 21.53 2.97 2.12 4.92 1.50 1.13 2.83 5.33
27.21 15.82 23.69 3.46 2.35 5.31 1.70 1.20 3.22 5.67
0.016b b 0.001b 0.001b 0.008b 0.003b 0.016b 0.114 0.132 0.150 0.005b
± ± ± ± ± ± ± ± ±
25.74 11.83 6.00 5.91 4.55 1.74 3.18 2.27 2.65
± ± ± ± ± ± ± ± ±
19.92 10.03 5.43 5.45 3.88 1.83 3.13 1.88 2.65
PD: Parkinson disease. PDQ-39: PD Questionnaire 39. FOG: freezing of gait. Freezers: PD patients with FOG. Non-freezers: PD patients without FOG. a P-value is calculated from an ANCOVA adjusted for age, disease duration, H&Y stage and NMSS. b Significant difference.
on an Israeli population [26]. These findings demonstrate that FOG has a significant impact on the QoL of PD patients in addition to its effect on gait. Currently, there are very few studies that have investigated how the mechanism of FOG affects QoL. A previous study, however, suggested that the episodic characteristic of FOG may be involved in it [26]. Our patients with FOG demonstrated a more severe motor disability and more frequent motor complications, these findings are consistent with previous studies on Caucasian populations [5,6,8,23]. Additionally, we found an association between the H&Y stage and our patients with FOG, which is consistent with the findings from a study on an American population and another study on a German population [8, 24]. We also found no association between the disease duration and FOG, which is inconsistent with previous studies on Caucasian populations [5,6,8,23,24]. Rather, our findings suggest that there is an association between FOG and the severity of the disease. Furthermore, we also found that a high daily dose of levodopa and the use of a dopamine receptor agonist were also associated with FOG, which is consistent with the findings from previous studies [6,8,24]. However, we failed to find a correlation between receiving amantadine and entacapone treatments and FOG, which was reported in a previous study [24]. A high levodopa dose or dopamine receptor agonist treatment in patients with FOG may reflect a higher disease severity in patients with FOG. Based on the current finding, we cannot conclude that FOG is a side effect of the anti-Parkinson medicine. We found a correlation between FOG and festination and falls, and this association is also supported by previous studies [27–30]. Our findings indicate that FOG patients are
Table 4 NMS of PD patients with and without FOG. NMSS
Freezers (n = 221)
Non-freezers (n = 253)
P-valuea
Total score Cardiovascular Sleep/fatigue Mood/apathy Perceptual problems/hallucinations Attention/memory Gastrointestinal Urinary Sexual dysfunction Miscellaneous
60.01 1.26 12.21 11.76 1.08 4.76 5.85 8.36 7.49 6.63
33.49 0.80 6.96 7.33 0.66 3.10 2.40 3.41 4.59 4.24
b0.001b 0.092 b0.001b 0.169 0.687 0.093 b0.001b b0.001b 0.004b 0.006b
± ± ± ± ± ± ± ± ± ±
40.22 2.48 10.09 14.67 3.76 5.90 6.42 9.79 6.57 6.18
± ± ± ± ± ± ± ± ± ±
28.32 2.16 6.96 10.38 3.06 3.91 3.91 5.43 5.09 5.53
NMS: non-motor symptoms. PD: Parkinson disease. NMSS: Non-Motor Symptoms Scale. FOG: freezing of gait. Freezers: PD patients with FOG. Non-freezers: PD patients without FOG. a P-value is calculated from an ANCOVA adjusted for age, disease duration and H&Y stage. b Significant difference.
± ± ± ± ± ± ± ± ± ±
3.75 3.00 5.81 1.57 1.01 1.33 1.04 0.79 1.68 1.05
± ± ± ± ± ± ± ± ± ±
2.95 2.51 5.17 1.49 0.90 1.02 0.99 0.75 1.64 0.73
PD: Parkinson disease. FOG: freezing of gait. Freezers: PD patients with FOG. Non-freezers: PD patients without FOG. MMSE: Mini-Mental state examination. FAB: frontal assessment battery. MoCA: Montreal Cognitive Assessment. a P-value is calculated from an ANCOVA adjusted for age and disease duration. b Significant difference.
more likely to experience other types of gait disorders, such as festination and falls. In addition, we also found that the PD patients with FOG had more severe NMS than the PD patients without FOG. Furthermore, we also found that urinary symptoms and depression were also associated with FOG in this study, which is consistent with a study on an Israeli population [31]. These findings indicate that our focus should extend beyond the treatment of motor symptoms when treating NMS in PD patients with FOG. Although our PD patients with FOG demonstrated a poor cognitive performance compared with the PD patients without FOG, no association was found between FOG and cognitive dysfunction. This finding is inconsistent with previous studies on a non-Asian population [9,10,32, 33], which found that FOG is associated with executive dysfunction and visuospatial deficits. The pathogenesis of FOG remains unclear. A resting-state fMRI study [34] found that the connectivity disruption of “executive-attention” and visual neural networks may be associated with FOG in PD. One voxel-based morphometry study found an association between FOG and posterior gray matter atrophy [35]. Another voxel-based morphometry study found that PD patients with FOG had frontal and parietal atrophy, indicating that FOG may be involved in executive dysfunction and perception deficits [36]. Our findings from this cross-sectional study do not resolve these discrepancies. Further longitudinal studies using a combination of imaging techniques and neuropsychological assessments are needed to clarify this potential association. There were some limitations of the present study that should be discussed. First, FOG is experienced more commonly at home, and it is hard to evaluate FOG in the clinical setting or research laboratory. Therefore, recall bias may have affected the results of this study. Second, the results may have been affected by some unpredictable factors, which were unknown at the time of the study. Third, we did not find a difference in the frequency of FOG among the different patient
Table 6 Depression and anxiety of PD patients with and without FOG.
HAMD HAMA
Freezers (n = 221)
Non-freezers (n = 253)
P-valuea
14.73 ± 9.82 9.64 ± 7.50
9.61 ± 7.81 6.21 ± 5.92
b0.001b b0.001b
PD: Parkinson disease. FOG: freezing of gait. Freezers: PD patients with FOG. Non-freezers: PD patients without FOG. HAMD: Hamilton Depression Rating Scale. HAMA: Hamilton Anxiety Rating Scale. a P-value is calculated from an ANCOVA adjusted for age, disease duration and H&Y stage. b Significant difference.
Please cite this article as: Ou R, et al, Freezing of gait in Chinese patients with Parkinson Disease, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.07.002
R. Ou et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx Table 7 Correlative clinical factors of FOG in PD patients.
Age Disease duration Age at onset Low limbs as site of onset Use of levodopa Daily dose of levodopa Use of dopamine receptor agonist Use of entacapone H&Y stage Fluctuation Dyskinesia Festination Falls NMSS Sleep/fatigue Gastrointestinal Urinary Sexual dysfunction Miscellaneous MoCA Visuospatial/executive abilities Naming Attention Orientation FAB HAMD HAMA
OR
95%CI
P-valuea
1.003 1.011 1.206 1.450 0.929 1.002 1.820 0.926 2.868 2.235 1.351 4.921 3.433
0.962–1.046 0.879–1.041 0.466–3.123 0.879–2.392 0.387–2.231 1.001–1.004 1.130–2.930 0.354–2.424 1.852–4.441 0.982–5.087 0.497–3.671 2.830–8.556 1.433–8.225
0.891 0.300 0.699 0.146 0.869 0.001b 0.014b 0.876 b 0.001b 0.055 0.556 b 0.001b 0.006⁎
1.019 1.015 1.039 1.023 1.017
0.980–1.058 0.957–1.076 1.003–1.077 0.975–1.074 0.969–1.066
0.346 0.622 0.034b 0.349 0.498
1.007 0.800 1.062 0.898 0.986 1.038 1.046
0.812–1.250 0.591–1.082 0.802–1.405 0.647–1.247 0.883–1.102 1.039–1.069 0.897–1.038
0.947 0.147 0.676 0.521 0.809 0.010b 0.333
PD: Parkinson disease. FOG: freezing of gait. H&Y stage: Hoehn and Yahr stage. NMSS: Non-Motor Symptoms Scale. MoCA: Montreal Cognitive Assessment. HAMD: Hamilton Depression Rating Scale. HAMA: Hamilton Anxiety Rating Scale. a P-value is calculated from binary logistic regression analysis. b Significant difference.
subtypes, and this finding may be because the number of tremor subtype patients was too low. 6. Conclusions FOG is a relatively common disabling symptom of PD in Chinese patients. Patients that are older, or who reported longer disease duration, low limbs as the site of onset and a more severe motor disability were more likely to experience FOG. NMS, especially urinary symptoms and depression, may also be associated with FOG. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgments The authors thank the patients and their families for their participation in the study. References [1] Rogers MW. Disorders of posture, balance, and gait in Parkinson's disease. Clin Geriatr Med 1996;12(4):825–45. [2] Giladi N, Nieuwboer A. Understanding and treating freezing of gait in parkinsonism, proposed working definition, and setting the stage. Mov Disord 2008;23(Suppl. 2): S423–5. [3] Stern GM, Lander CM, Lees AJ. Akinetic freezing and trick movements in Parkinson's disease. J Neural Transm Suppl 1980;16:137–41. [4] Bartels AL, Balash Y, Gurevich T, Schaafsma JD, Hausdorff JM, Giladi N. Relationship between freezing of gait (FOG) and other features of Parkinson's: FOG is not correlated with bradykinesia. J Clin Neurosci 2003;10(5):584–8.
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Please cite this article as: Ou R, et al, Freezing of gait in Chinese patients with Parkinson Disease, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.07.002