□ ORIGINAL ARTICLE □

The Risk Factors for the Wearing-off Phenomenon in

Parkinson’s Disease in Japan: A Cross-sectional,
Multicenter Study

Shinji Ouma 1, Jiro Fukae 1, Shinsuke Fujioka 1, Shosaburo Yamamoto 1, Taku Hatano 2,
Asako Yoritaka 3, Yasuyuki Okuma 4, Ken-ichi Kashihara 5,
Nobutaka Hattori 2 and Yoshio Tsuboi 1

Abstract

Objective Parkinson’s disease (PD) is a common, progressive, neurodegenerative disorder. With progression
of PD, the wearing-off phenomenon occurs more frequently as a motor complication, decreasing the patient’s
quality of life. The aim of this study was to investigate the risk factors for the wearing-off phenomenon in
Japanese PD patients.
Methods All of the study participants were clinically diagnosed as having PD. Each patient was assessed
for the wearing-off phenomenon based on the findings of clinical assessments and interviews that were con-
ducted during a single visit. The risk factors for wearing-off were analyzed by univariate and multivariate lo-
gistic regression analyses.
Results Wearing-off was observed in 101 of the 180 (56.1%) patients who were enrolled in this study. The
multivariate logistic regression analysis revealed that the onset of PD at !69 years of age (odds ratio [OR],
0.22; 95% confidence interval [CI], 0.05-0.88; p=0.032), female sex (OR, 6.49; 95% CI, 2.34-17.99; p<
0.001), catechol-O-methyltransferase (COMT) inhibitor treatment (OR, 19.59; 95% CI, 3.55-108.11; p<0.001)
and a high daily levodopa dosage (!600 mg/day) (OR, 7.69; 95% CI, 1.41-41.84; p=0.018) were independent
predictive factors for wearing-off in Japanese PD patients.
Conclusion Age at the symptomatic disease onset, female sex, COMT inhibitor treatment, and a high daily
levodopa dose were associated with the occurrence of wearing-off in Japanese PD patients. Physicians need
to consider the risk factors and carefully choose medications for PD patients to postpone the occurrence of
this phenomenon for as long as possible.

Key words: age of onset, daily levodopa dosage, Parkinson’s disease, female sex, wearing-off

(Intern Med 56: 1961-1966, 2017)

(DOI: 10.2169/internalmedicine.56.7667)

symptoms to non-motor symptoms (1, 2). Levodopa, which

Introduction is one of the anti-parkinsonian drugs, is used to treat PD pa-
tients throughout the world. Wearing-off (WO), a complica-
Parkinson’s disease (PD), which is one of the most com- tion that is frequently induced by levodopa, is defined as the
mon neurodegenerative disorders, mainly affects the nigros- predictable recurrence of motor and non-motor symptoms
triatal dopaminergic neurons (1). PD patients show various that precedes the administration of scheduled doses of levo-
combinations of clinical symptoms, ranging from motor dopa. Previous reports from Western countries have demon-

１
Department of Neurology, Fukuoka University School of Medicine, Japan, ２ Department of Neurology, Juntendo University School of Medicine,
Japan, ３ Department of Neurology, Juntendo Koshigaya Hospital, Japan, ４ Department of Neurology, Juntendo Shizuoka Hospital, Japan and ５ De-
partment of Neurology, Okayama Kyokuto Hospital, Japan
Received for publication May 1, 2016; Accepted for publication November 13, 2016
Correspondence to Dr. Yoshio Tsuboi, tsuboi@cis.fukuoka-u.ac.jp

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 Intern Med 56: 1961-1966, 2017 DOI: 10.2169/internalmedicine.56.7667

strated that approximately 40% of PD patients who were age at symptomatic disease onset, disease duration, duration
treated with levodopa for 4-6 years experienced WO (3-5). of anti-parkinsonian therapy, and duration of levodopa ther-
The occurrence of WO increases gradually, with almost all apy of all patients were divided into four groups (age at ex-
PD patients developing WO within 10 years after the initia- amination: <65 years, 66-69 years, 70-73 years, !74 years;
tion of levodopa therapy (5, 6). Since the occurrence of WO age at the symptomatic disease onset: <56 years, 56-62.4
is associated with a decreased quality of life (QOL) (5), it is years, 62.5-68 years, ! 69 years; disease duration: <3.5
important to identify the occurrence of WO and to start years, 3.5-5 years, 6-8 years, ! 9 years; duration of anti-
managing it immediately. To postpone the occurrence of parkinsonian therapy: <2 years, 2-4.4 years, 4.5-6 years, !7
WO as much as possible, it is crucial to clarify the potential years; duration of levodopa therapy: <1.3 years, 1.3-2 years,
risk factors for WO. 3-5 years, !6 years; daily dose of levodopa: <300 mg, 300-
Several risk factors related to WO have been reported by 349 mg, 350-500 mg, ! 600 mg). A univariate logistic re-
researchers from Western countries, including a young age gression was performed. Factors with p values of <0.05
at the time of symptomatic disease onset, high scores on the were included in a multivariate logistic regression analysis
parts II and III of the Unified Parkinson’s disease rating to determine the independent risk factors for WO. A multi-
scale (UPDRS), female sex, and being located in North variable logistic regression analysis was then performed to
America (7). To date, however, only a few reports related to determine the odds ratios (ORs and 95% confidence interval
this issue have been published from Asian countries includ- [CI]) for each group. All of the statistical analyses were per-
ing Japan. The aim of this study was to identify the risk fac- formed using the SAS software program (version 9.3.1; SAS
tors for WO in Japanese patients with PD; this study was a Institute, Cary, USA).
post hoc analysis of the data from the validation study of
the Japanese version of the 9-item Wearing-off Question- Results
naire (6).
The demographic characteristics of PD patients
Materials and Methods
The demographic characteristics of the participants have
The patients enrolled in this study were diagnosed accord- already been described elsewhere (6). Briefly, 180 PD pa-
ing to the United Kingdom PD Society Brain Bank criteria. tients (80 men and 100 women) were enrolled in the study.
Patients with severe dementia, uncontrolled psychiatric One hundred one of the 180 (56.1%) PD patients had symp-
comorbidities, and a history of previous neurosurgery for toms of WO. In comparison to PD patients without WO, the
PD were excluded from the study. This study was conducted PD patients with WO showed the following characteristics:
at five hospitals in Japan: Fukuoka University Hospital, Jun- younger age, a greater female predominance, an earlier age
tendo University Hospital, Juntendo Koshigaya Hospital, at the time of symptomatic disease onset, the administration
Juntendo Shizuoka Hospital, and Okayama Kyokuto Hospi- of dopamine agonists and COMT inhibitors, a longer dura-
tal. The study protocol was approved by the ethics commit- tion of anti-parkinsonian and levodopa treatment, and higher
tee of each hospital. All patients provided their written, in- daily doses of levodopa (Table 1).
formed consent before participating in the study.
The risk factors for WO
WO was defined as “the generally predictable recurrence
of motor and non-motor symptoms that precedes the admini- The results of univariate logistic regression analyses of
stration of scheduled doses of anti-parkinsonian medication the factors that were related to the occurrence of WO are
and which usually improves after these doses.” (6, 8) The shown in Table 2. The age at examination, disease duration,
physicians assessed each PD patient for WO based on the duration of anti-parkinsonian treatment, duration of levodopa
findings of clinical assessments and interviews during a sin- therapy, sex, HY stage, daily dose of levodopa, dopamine
gle visit. The clinical data, regarding the clinical course of agonist treatment, and COMT inhibitor treatment were
PD, were collected from all subjects. These included the age found to be significant risk factors for WO in the univariate
at examination, the age at the symptomatic disease onset, logistic regression analysis. Initially, a multivariate logistic
disease duration, duration of anti-parkinsonian therapy, dura- regression analysis could not be performed due to the large
tion of levodopa therapy, detailed anti-parkinsonian medica- number of categories; thus, the categories of duration of
tions, sex, Hoehn and Yahr stage (HY stage), initial symp- anti-parkinsonian therapy and HY stage were changed (dura-
tom, site of onset, and the daily levodopa dosage. All of the tion of anti-parkinsonian therapy: <4.5 years, 4.5-6 years, !7
physicians who participated in this study had more than 7 years; HY stage: 1-3, 4-5). The results of the multivariate
years of clinical experience in treating PD patients. logistic regression analysis, with adjustment for potential
confounders, are shown in Table 3. First, a younger age at
Statistical analysis
the time of symptomatic disease onset increased the risk of
The differences in the clinical and demographic character- developing WO. The OR for WO in the oldest onset group
istics were tested using Fisher’s exact test or a one-way (! 69 years) was 0.22 (95% CI, 0.05-0.88, p=0.032) in com-
analysis of variance, as appropriate. The age at examination, parison to the youngest onset group (<56 years). Second,

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 Intern Med 56: 1961-1966, 2017 DOI: 10.2169/internalmedicine.56.7667

Table 1. Demographic Characteristics of the PD Patients.

Overall Wearing-off Non-wearing-off p value

Number of patients 180 101 79
Male : female 80 : 100 38 : 63 42 : 37 p=0.049*
Age (y) 68.8±8.5 67.6±9.4 70.3±6.9 p=0.027*
Age of onset (y) 61.7±9.6 59.3±9.9 64.9±8.1 p<0.001**
Disease duration (y) 7.0±4.8 8.3±5.1 5.4±3.8 p<0.001**
Hoehn & Yahr stage 2.6±0.8 2.7±0.9 2.4±0.7 p=0.214
Medication
Anti-parkinsonian treatment duration (y) 5.5±5.0 7.0±5.6 3.7±3.5 p<0.001**
L-dopa treatment duration (y) 4.5±4.1 5.6±4.5 3.0±2.9 p<0.001**
Daily L-dopa dosage (mg) 441.9±237.4 520.8±273.0 341.1±124.2 p<0.001**
Dopamine agonist (n) 111 (61.7%) 64 (69.3%) 41 (51.9%) p=0.004**
MAOB inhibitor (n) 64 (35.6%) 39 (38.6%) 25 (31.6%) p=0.351
COMT inhibitor (n) 45 (25.0%) 43 (42.6%) 2 (2.5%) p<0.001**
Anticholinergic (n) 22 (12.2%) 15 (14.9%) 7 (8.9%) p=0.258
Amantadine (n) 21 (11.7%) 13 (12.9%) 8 (10.1%) p=0.645
Zonisamide (n) 26 (14.4%) 14 (13.9%) 12 (15.2%) p=0.833
Droxidopa (n) 4 (2.2%) 3 (3.0%) 1 (1.3%) p=0.632
(adapted from reference 6)

there was a sex difference in the risk factors for WO. The Neurology recommended that patients who are older (! 70-
OR for WO in female PD patients was 6.49 (95% CI, 2.34- 75 years) at the onset of PD should start treatment with
17.99, p<0.001) in comparison to male PD patients. Third, levodopa. The results of the present study provide further
the risk of WO was increased in a dose-dependent manner evidence that patients who are ! 70 years of age at the onset
according to the levodopa dosage. The OR for WO with a of PD should start levodopa treatment.
daily levodopa dosage of 600 mg/day was 7.69 (95% CI, The present study showed that the risk of WO in female
1.41-41.84, p=0.018) in comparison to a daily levodopa PD patients was higher than that in male patients. A previ-
dose of <300 mg/day. Furthermore, the OR for WO in pa- ous Japanese retrospective study demonstrated that the OR
tients receiving COMT inhibitor treatment was 19.59 (95% for WO in females was 2.13 in comparison to males (9).
CI, 3.55-108.11, p<0.001). The results of a multivariate analysis in the STRIDE-PD
study (a prospective study) also revealed that female sex
Discussion was associated with an increased risk of WO (7). Another
study indicated that female PD patients experienced more
Many studies have reported that young age at the onset of fluctuation in their motor and non-motor symptoms than
PD is a risk factor for the development of WO. Several pre- male patients (15). Taken together, these results suggest that
vious Japanese studies demonstrated that the hazard ratio for female PD patients are at high risk for experiencing WO.
WO was significantly lower in patients with old-onset PD Several causes for the increased risk of WO in female pa-
than it was in those with young-onset PD (9, 10). Ferguson tients have been discussed. Chen et al. analyzed the risk fac-
et al. compared 22 patients with autopsy-proven early-onset tors for WO in Chinese PD patients by a multivariate analy-
PD (age at onset: 21-50 years) with 44 patients with sis and concluded that a high levodopa dosage (adjusted to
autopsy-proven late-onset PD (age at onset: !65 years), and weight) was associated with WO (16). Because female pa-
found that early-onset PD was associated with a higher cu- tients generally have a lower body weight than male pa-
mulative incidence of dyskinesia, WO and on-off (11). Sev- tients, they tend to receive a higher daily levodopa dose per
eral other studies from Western countries also concluded kg of body weight than male patients. Second, other envi-
that patients with young-onset PD were more likely to de- ronmental factors may be associated with the occurrence of
velop WO and dyskinesia (3, 12-14). In the STRIDE-PD WO. Female hormones and uric acid (UA) may influence
study, several predictive factors for WO were identified by a the occurrence of WO, as well as the rate of PD progres-
multivariate analysis; among them, young age at the onset sion (17, 18). The neuroprotective effect of UA increases in
of PD was the strongest predictor (7). In the present study, a dose-dependent manner, and the serum UA concentration
when the ORs for WO in each group were divided by age, in female patients is generally lower than that in male pa-
the incidence of WO in the oldest onset patient group (! 69 tients; thus, the protective effect of UA is assumed to be
years) was significantly lower than that in the youngest on- weaker in female patients (17, 19, 20). Furthermore, estro-
set patient group (<56 year old). The PD treatment guide- gen changes after menopause, and its neuroprotective effect
lines (2011 version) published by the Japanese Society of may decrease (18).

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 Intern Med 56: 1961-1966, 2017 DOI: 10.2169/internalmedicine.56.7667

Table 2. Results of Univariate Logistic Regression Analysis.

Factor n WO (Percentage, %) Odds ratio 95% CI p value

Age at examination (y) <65 44 70.5% Reference -
66-69 41 48.8% 0.40 0.16-0.97 p=0.044*
70-73 43 53.5% 0.48 0.20-1.17 p=0.105
≥74 52 51.9% 0.45 0.19-1.06 p=0.067
Age of onset (y) <56 42 76.2% Reference -
56-62.4 48 60.4% 0.48 0.19-1.19 p=0.113
62.5-68 44 50.0% 0.31 0.12-0.79 p=0.014*
≥69 46 39.1% 0.20 0.08-0.51 p<0.001***
Disease duration (y) <3.5 45 31.1% Reference -
3.5-5.0 33 45.5% 1.85 0.73-4.68 p=0.197
6.0-8.0 53 66.0% 4.31 1.84-10.07 p<0.001***
≥9.0 49 75.5% 6.83 2.76-16.91 p<0.001***
Duration of anti-PD treatment (y) <2.0 34 29.4% Reference -
2-4.4 56 42.9% 1.80 0.73-4.46 p=0.204
4.5-6.0 37 64.9% 4.43 1.63-12.04 p<0.001***
≥7.0 53 81.1% 10.32 3.76-28.30 p<0.001***
Duration of levodopa treatment (y) <1.3 44 29.5% Reference -
1.3-2.0 27 48.1% 2.21 0.82-5.99 p=0.117
3.0-5.0 54 57.4% 3.21 1.38-7.47 p<0.001***
≥ 6.0 51 82.4% 11.13 4.23-29.30 p<0.001***
Sex male 80 47.5% Reference -
female 100 63.0% 1.88 1.04-3.42 p=0.038*
Hoehn and Yahr stage 1 16 43.8% Reference -
2 66 59.1% 1.86 0.62-5.60 p=0.271
3 81 48.1% 1.19 0.41-3.51 p=0.748
4, 5 17 94.1% 20.56 2.17-194.76 p<0.001***
Onset symptom
Akinesia negative 71 57.7% Reference -
positive 109 55.0% 0.90 0.49-1.64 p=0.721
Rigidity negative 6 50.0% Reference -
positive 174 56.3% 1.29 0.25-6.57 p=0.760
Tremor negative 98 56.1% Reference -
positive 82 56.1% 1.00 0.55-1.80 p=0.997
Daily levodopa dosage (mg) <300 18 50.0% Reference -
300-349 67 28.4% 0.40 0.14-1.15 p=0.088
350-599 48 66.7% 2.00 0.66-6.02 p=0.218
≥600 47 87.2% 6.83 1.94-24.09 p<0.001***
Dopamine agonist treatment negative 69 44.9% Reference -
positive 111 63.1% 2.09 1.14-3.86 p=0.018*
MAOB inhibitor treatment negative 116 53.4% Reference -
positive 64 60.9% 1.36 0.73-2.53 p=0.333
COMT inhibitor treatment negative 135 43.0% Reference -
positive 45 95.6% 28.54 6.64-122.68 p<0.001***
Anticholinergic drug treatment negative 158 54.4% Reference -
positive 22 68.2% 1.79 0.69-4.64 p=0.228
Amantadine treatment negative 159 55.3% Reference -
positive 21 61.9% 1.31 0.51-3.34 p=0.570
Zonisamide treatment negative 153 56.9% Reference -
positive 27 51.9% 0.82 0.36-1.85 p=0.629
Droxidopa treatment negative 176 55.7% Reference -
positive 4 75.0% 2.39 0.24-23.41 p=0.455
n: number, WO: wearing-off phenomenon, CI: confidence interval, MAOB inhibitor: monoamine oxidase B inhibitor, COMT inhibitor: cate-
chol-O-methyltransferase inhibitor

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 Intern Med 56: 1961-1966, 2017 DOI: 10.2169/internalmedicine.56.7667

Table 3. Results of Multivariate Logistic Regression Analysis.

n WO (Percentage, %) Odds ratio 95% CI p value

Age of onset (y) <56 42 76.2% Reference - -
56-62.4 48 60.4% 0.45 0.12-1.65 p=0.225
62.5-68 44 50.0% 0.29 0.07-1.16 p=0.080
≥69 46 39.1% 0.22 0.05-0.88 p=0.032*
Disease duration (y) <3.5 45 31.1% Reference - -
3.5-5.0 33 45.5% 0.7 0.18-2.75 p=0.607
6.0-8.0 53 66.0% 1.73 0.31-9.64 p=0.531
≥9.0 49 75.5% 0.28 0.03-2.55 p=0.259
Duration of anti-PD treatment (y) <4.5 90 37.8% Reference - -
4.5-6 37 64.9% 1.49 0.29-7.53 p=0.633
≥7 53 81.1% 6.7 0.42-106.66 p=0.178
Duration of levodopa treatment (y) <1.3 44 29.5% Reference - -
1.3-2.0 27 48.1% 1.86 0.49-7.03 p=0.362
3.0-5.0 54 57.4% 0.62 0.14-2.75 p=0.530
≥6.0 51 82.4% 0.93 0.10-9.09 p=0.953
Sex male 80 47.5% Reference - -
female 100 63.0% 6.49 2.34-17.99 p<0.001***
Hoehn and Yahr stage 1, 2, 3, 163 52.1% Reference - -
4, 5 17 94.1% 4.75 0.25-90.72 p=0.300
Daily levodopa dosage (mg) <300 18 50.0% Reference - -
300-349 67 28.4% 0.4 0.11-1.44 p=0.162
350-599 48 66.7% 1.49 0.36-6.14 p=0.582
≥600 47 87.2% 7.69 1.41-41.84 p=0.018*
Dopamine agonist treatment negative 69 44.9% Reference - -
positive 111 63.1% 1.15 0.43-3.08 p=0.784
COMT inhibitor treatment negative 135 43.0% Reference - -
positive 45 95.6% 19.59 3.55-108.11 p<0.001***
n: number, WO: wearing-off phenomenon, CI: confidence interval, COMT inhibitor: catechol-O-methyltransferase inhibitor

With regard to medications, levodopa treatment and compatible with the results of the present study.
COMT inhibitor treatment were independent risk factors for In conclusion, the present multicenter study identified
WO in Japanese PD patients in the present study. Previous four risk factors for WO in the Japanese PD population: a
reports demonstrated that the daily levodopa dose is a risk young age at the time of symptomatic disease onset, female
factor for WO. The Earlier versus Later Levodopa Therapy sex, COMT inhibitor treatment, and a high daily levodopa
in Parkinson’s disease (ELLDOPA) study showed that the dosage. The results of a number of previous studies show
incidence of WO increased in PD patients who received 600 that these risk factors for WO are common to various races.
mg of levodopa per day after only 40 weeks (21). The fre- To postpone the occurrence of WO as much as possible,
quency of another motor complication, dyskinesia, was also physicians need to keep in mind the risk factors for WO and
significantly increased in PD patients who received 600 mg carefully choose medications for PD patients.
of levodopa per day (21). The STRIDE-PD study, a large The present study is associated with several limitations.
and long-term prospective study, found that the risk of de- First, recent studies have demonstrated that the daily levo-
veloping WO increased in a dose-dependent manner (7). The dopa dose adjusted for body weight is an important factor
present study also showed that the risk of WO was signifi- for WO (7, 16). Unfortunately, the body weight information
cantly increased in patients who received more than 600 mg was not available for all of the PD patients in this study.
of levodopa per day. All of these reports suggest that a high Thus, we could not determine whether the increased risk of
daily levodopa dose is a risk factor for WO. Furthermore, WO in female PD patients was associated with their lower
the STRIDE-PD study demonstrated that the time to the on- body weight in comparison to male patients. Second, the
set of dyskinesia in patients receiving levodopa/carbidopa/ levodopa equivalent dose (LED) is a useful evaluation
entacapone (LCE) was a shorter than in patients who re- method, but the LED is not appropriate for non-
ceived levodopa/carbidopa (LC), and that the time to WO in dopaminergic drugs such as anticholinergic drugs, zon-
patients who received LCE tended to be shorter in compari- isamide, and droxidopa. Since the aim was to analyze the
son to patients who received LC (22). These findings are relationships between WO and non-dopaminergic drugs, the

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 Intern Med 56: 1961-1966, 2017 DOI: 10.2169/internalmedicine.56.7667

LED was not used in this study. Third, this study was retro- and risks. Parkinsonism Relat Disord 19: 725-731, 2013.
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