Clinical Neurology and Neurosurgery 134 (2015) 110–115
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Utility of the Japanese version of the 9-item Wearing-off Questionnaire Jiro Fukae a , Masa-aki Higuchi a , Shosaburo Yanamoto a , Kosuke Fukuhara a , Jun Tsugawa a , Shinji Ouma a , Taku Hatano b , Asako Yoritaka c , Yasuyuki Okuma d , Kenichi Kashihara e , Nobutaka Hattori b , Yoshio Tsuboi a,∗ a
Department of Neurology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan c Department of Neurology, Juntendo Koshigaya Hospital, Koshigaya, Japan d Department of Neurology, Juntendo Shizuoka Hospital, Izunokuni, Japan e Department of Neurology, Okayama Kyokuto Hospital, Okayama, Japan b
a r t i c l e
i n f o
Article history: Received 3 November 2014 Received in revised form 21 April 2015 Accepted 26 April 2015 Available online 5 May 2015 Keywords: Parkinson’s disease Wearing-off Questionnaire Motor symptom Non-motor symptom
a b s t r a c t Background and purpose: The 9-item Wearing-off Questionnaire (WOQ-9) is a useful tool for screening of wearing-off. We performed a validation study of the Japanese version of the WOQ-9 (JWOQ-9) using a cross-sectional design in Japanese Parkinson’s disease (PD) patients diagnosed with sporadic PD and treated with levodopa. Methods: Subjects with severe dementia, uncontrolled psychiatric comorbidities, and previous PD neurosurgery were excluded. The wearing-off phenomenon was detected according to the JWOQ-9, and the results were compared with independent evaluations of wearing-off conducted by PD specialists blinded to the JWOQ-9 results. To validate the JWOQ-9, a sample size of at least 70 patients with wearing-off and 70 patients without wearing-off was required. Therefore, a total of 180 patients (101 patients with wearing-off and 79 patients without wearing-off) were enrolled. Results: The sensitivity, specificity, positive predictive value, and negative predictive value of the JWOQ-9 were 94.1%, 39.2%, 66.4%, and 83.8%, respectively. Motor symptom questions demonstrated both moderate sensitivity (58.1–87.3%) and specificity (60.4–87.5%). In contrast, non-motor symptom questions demonstrated fair to moderate sensitivity (51.5–64.6%), with high specificity (80.0–94.1%). Like the original WOQ-9, the JWOQ-9 exhibits significant value for detecting possible wearing-off. Conclusions: The JWOQ-9 is a useful screening tool for detecting wearing-off of both motor and non-motor symptoms. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Parkinson’s disease (PD) is a neurodegenerative disorder involving nigrostriatal dopaminergic neurons. The introduction of levodopa therapy dramatically improves the quality of life and prognosis of PD patients, at least for the first several years [1]. However, motor complications, including “wearing-off” and “dyskinesia,” frequently develop during treatment with levodopa [1–3]. While wearing-off has a great impact on the patient’s quality of
∗ Corresponding author at: Department of Neurology, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. Tel.: +81 92 801 1011; fax: +81 92 865 7900. E-mail address: [email protected] (Y. Tsuboi). http://dx.doi.org/10.1016/j.clineuro.2015.04.021 0303-8467/© 2015 Elsevier B.V. All rights reserved.
life [4], the ability to detect this phenomenon is sometimes difficult, as the symptoms are varied and include both motor and non-motor symptoms [3–7]. In particular, non-motor symptoms of wearing-off are less well recognized by physicians and PD patients. Specific questionnaires have been developed to screen for wearing-off in PD patients. In 2005, a 32-item Wearing-off Questionnaire (WOQ-32) was developed and validated by Stacy et al., allowing for effective identification of wearing-off symptoms in PD patients [6]. However, a potential limitation of the WOQ-32 is the time required to complete the many questions, such that screening cannot be completed rapidly [6]. Accordingly, a 9-item Wearingoff Questionnaire (WOQ-9) and 19-item Wearing-off Questionnaire (WOQ-19) were developed as more user-friendly screening tools [8,9]. Stacy et al. subsequently demonstrated sensitivity and specificity of the WOQ-9 to be 96.2% and 40.9%, respectively, and
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Fig. 1. A, Japanese version of the 9-item Wearing-off Questionnaire (JWOQ-9). B, JWOQ-9 back-translated into English.
concluded that the WOQ-9 is a useful screening tool for detecting wearing-off [9]. WOQ-19 and WOQ-9 have previously been translated into Japanese and validated linguistically (Fig. 1) [10]. However, the Japanese language is somewhat unique and it has not been clarified whether the Japanese version of the WOQ-9 (JWOQ9) displays equivalent usefulness and validity to the English version. Thus, the aim of this multi-center study was to assess sensitivity and specificity of the JWOQ-9 in Japanese PD patients receiving antiparkinsonian medications, compared with findings of assessments conducted by neurologists.
2. Materials and methods 2.1. Subjects This cross-sectional study was performed at five clinical hospitals from January to December 2012 (Fukuoka University Hospital, Juntendo University Hospital, Juntendo Koshigaya Hospital, Juntendo Shizuoka Hospital, and Okayama Kyokuto Hospital). The study protocol was approved by the ethics committee of each hospital. A diagnosis of PD was made based on the United Kingdom PD Society Brain Bank criteria [11]. Key inclusion criteria were: 0.60 (substantial), or a higher level of agreement, was proposed as the threshold for acceptable reliability of the questionnaire [15].
3. Results 3.1. Demographic characteristics of PD patients From January to December 2012, 201 patients with PD were enrolled in this study. Of the 201 PD patients, 21 interpreted the questionnaire incorrectly; for example, only checking a box in the second column of the item(s) without checking a box in the first column. These patients were excluded, and the final per-protocol population included a total of 180 PD patients. The mean age of the patients was 68.7 ± 8.4 years. The participants of the study included 80 males and 100 females. The average duration since PD diagnosis was 7.0 ± 4.9 years, and the PD patients had been receiving PD medications for an average of 5.5 ± 5.0 years. The HY stage distribution was: stage 1, 8.9%; stage 2, 36.7%; stage 3, 45.0%; stage 4, 8.3%; and stage 5, 1.1%. All patients were currently receiving levodopa at a mean daily dose of 441.9 ± 237.4 mg/day. Treatment duration with levodopa was 4.5 ± 4.1 years (Table 1). Patients with mild cognitive impairment, controlled depression, and controlled psychiatric symptoms were also included in the study. Of those, 12.2% and 6.1% were
administrated antidepressants and antipsychotics, respectively. Moreover, PD patients receiving antidepressants had significantly chance to having wearing-off (Table 1). Of the 180 PD patients, 101 (56.1%) had wearing-off symptoms, as judged by a physician. Compared with PD patients without wearing-off symptoms, they were younger (67.6 ± 9.4 versus 70.3 ± 6.9 years, p = 0.027) and had an earlier age of onset (59.3 ± 9.9 versus 64.9 ± 8.1 years, p = 0.0001) (Table 1). In addition, females were more likely to experience wearing-off (62.4% versus 46.8%, p = 0.049). The duration of antiparkinsonian and levodopa treatment was longer in patients with wearing-off than in those without (7.0 ± 5.6 versus 3.7 ± 3.5 years, p = 0.0001; 5.6 ± 5.6 versus 3.0 ± 2.9 years, p = 0.0001, respectively) (Table 1), and patients with wearing-off received larger daily doses of levodopa than those without (520.8 ± 273.0 mg/day versus 341.1 ± 124.2 mg/day, p = 0.0001) (Table 1).
3.2. Sensitivity and specificity of the JWOQ-9 With more than one positive response, the JWOQ-9 showed 94.1% sensitivity, 39.2% specificity, and 70.0% accuracy for detecting wearing-off (Table 2). The corresponding AUC was 0.78, and the kappa value was 0.35. With more than two positive responses, the sensitivity of the JWOQ-9 decreased from 94.1% to 87.1%, while specificity increased from 39.2% to 72% (Table 2). Accuracy for detecting wearing-off also increased from 70.0% to 81.4%, and the kappa value increased to 0.60.
3.3. Sensitivity and specificity of each question item The prevalence of motor symptoms was: tremors, 61.1%; slowness, 87.2%; reduced dexterity, 77.8%; stiffness, 73.9%; and muscle cramping, 56.7% (Table 3). The frequency of non-motor symptoms was: cloudy/thinking, 56.7%; pain/aching, 35.6%; mood changes, 45.0%; and anxiety/panic, 35.6% (Table 3). The sensitivity of motor symptoms ranged from 58.1% to 87.3%, whereas specificity ranged from 60.4% to 87.5%. In contrast, the sensitivity of non-motor symptoms ranged from 51.5% to 64.6%, while specificity ranged from 80.0% to 94.1% (Table 3).
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Table 2 Quality attributes of the JWOQ-9. Patientsreported benefit after medication
Physicianreported ‘wearing-off’
Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
Accuracy
Agreementa
Total (N = 180) ≥1 positive
143 (79.4%)
101 (56.1%)
≥2 positive
110 (61.1%)
101 (56.1%)
94.1% (89.2–97.1) 87.1% (81.6–91.5)
39.2% (33.0–43.1) 72.2% (65.0–77.7)
66.4% (63.0–68.6) 80.0% (74.9–84.0)
83.8% (70.5–92.1) 81.4% (73.4–87.7)
70.0 (64.6–73.4) 0.81 (0.74–0.87)
0.35 (0.24–0.43) 0.60 (0.47–0.70)
Reported symptom
a
Agreement with the criterion (kappa value). 95% confidence intervals are provided in parentheses.
3.4. Prevalence difference in symptom fluctuation between the WOQ-9 and JWOQ-9
initiation of levodopa therapy was 50.0%, 59.0%, 67.7% and 80.4%, respectively (Fig. 3).
According to the original version of the WOQ-9, Stacy et al. reported that the prevalence of motor and non-motor symptoms fluctuates [9]. To examine cultural differences, we compared prevalence of motor and non-motor symptom fluctuation between the original WOQ-9 and the JWOQ-9. Differences in each symptom fluctuation frequency were assessed using Fisher’s exact test. There were no significant differences in any item between the English and Japanese WOQ-9, apart from the item “cloudy/thinking”. Interestingly, there was a tendency for patients from the United States (US) to show more motor symptom fluctuation, while more nonmotor symptom fluctuation was observed in Japanese patients (Fig. 2).
4. Discussion
3.5. Wearing-off frequency Association between duration of levodopa treatment and wearing-off development is shown (Fig. 3). For a diagnosis of wearing-off by a physician, the percentage of Japanese PD patients who developed wearing-off by the end of the second, fourth, sixth, and more than 6 years after initiation of levodopa therapy was 29.2%, 47.7%, 66.7%, and 82.4%, respectively (Fig. 3). For a diagnosis of wearing-off according to the JWOQ-9 (one positive response), the percentage of Japanese PD patients who developed wearing-off by the end of the second, fourth, sixth, and more than 6 years after
Several studies have evaluated the ability of short questionnaires to identify PD patients with wearing-off [9,13]. Generally, questionnaires for wearing-off serve two potential functions: screening and diagnosing wearing-off. For screening purposes, sensitivity of ≥90% is required as the minimal acceptable level [9,12]. For diagnostic purposes, a questionnaire must fulfill two requirements: (1) sensitivity, specificity, and accuracy of ≥75%, and (2) a level of agreement (kappa value) between the questionnaire and physician’s diagnosis of >0.60 [13,14]. In the present study, the JWOQ-9 with one positive response showed high sensitivity (94.1%), low specificity (39.2%), and reasonable accuracy (70.0%) for diagnosing wearing-off. These results are similar to the original study of the WOQ-9, which reported sensitivity of 96.2% and specificity of 40.9% [9]. After translation into Japanese, the JWOQ-9 maintained a high capacity for detecting possible wearing-off, suggesting that the JWOQ-9 with one positive response is also a useful tool for screening of wearing-off. However, the JWOQ-9 with one positive response may not be used as a diagnostic tool for detecting wearing-off because its specificity, accuracy, and agreement are not adequate to fulfill the expected requirements. Alternatively, the sensitivity, specificity, and accuracy of the JWOQ-9 with two positive responses were 87.1%, 72.2%, and 0.81, respectively, in this
Table 3 Sensitivity and specificity of each symptom. Patientsreported benefit after medication
Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
Accuracy
Agreementa
Total (N = 180) Motor Tremor (N = 132) (73.3%)
90 (68.2%)
Slowness (N = 157) (87.2%)
88 (56.1%)
Reduced dexterity (N = 140) (77.8%) Stiffness (N = 133) (73.9%)
59 (42.1%)
Muscle cramping (N = 102) (56.7%)
43 (42.2%)
87.3% (81.1–92.2) 82.1% (76.7–86.1) 57.5% (51.5–61.9) 80.2% (74.6–84.4) 58.1% (50.7–63.3)
60.4% (51.1–67.6) 83.9% (75.6–90.0) 83.0% (73.2–90.2) 80.9% (70.5–88.5) 82.5% (71.1–90.6)
76.7% (71.2–80.9) 88.6% (82.8–92.9) 84.7% (75.9–91.2) 88.5% (82.3–93.1) 83.7% (73.2–91.3)
76.2% (64.5–85.3) 75.4% (67.9–80.9) 54.3% (47.9–59.0) 69.1% (60.3–75.6) 55.9% (0.48–0.61)
0.77 (0.69–0.82) 0.83 (0.76–0.88) 0.67 (0.60–0.73) 0.81 (0.73–0.86) 0.68 (0.59–0.74)
0.49 (0.33–0.62) 0.65 (0.51–0.75) 0.37 (0.22–0.47) 0.59 (0.44–0.70) 0.37 (0.20–0.50)
51.5% (45.9–53.6) 64.6% (57.9–67.5) 64.6% (59.3–67.6) 63.6% (55.6–68.8)
94.1% (83.0–98.3) 87.5% (67.4–96.4) 81.3% (59.7–93.2) 80.0% (62.3–91.4)
94.6% (84.4–98.5) 93.9% (84.2–98.3) 93.3% (85.7–97.6) 87.5% (76.4–94.6)
49.2% (43.4–51.4) 45.2% (34.8–49.8) 36.1% (26.5–41.4) 50.0% (38.9–57.1)
0.66 (0.58–0.69) 0.70 (0.60–0.75) 0.68 (0.59–0.73) 0.69 (0.58–0.76)
0.37 (0.24–0.42) 0.40 (0.19–0.49) 0.31 (0.13–0.41) 0.38 (0.15–0.52)
Reported symptom
Non-motor Cloudy/slow thinking (N = 102) (56.7%) Pain/aching (N = 64) (35.6%) Mood changes (N = 81) (45.0%) Anxiety/panic (N = 64) (35.6%) a
78 (58.6%)
37 (36.3%) 33 (51.6%) 45 (55.6%) 32 (50.0%)
Agreement with the criterion (kappa value). 95% confidence intervals are in parentheses.
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J. Fukae et al. / Clinical Neurology and Neurosurgery 134 (2015) 110–115
Fig. 2. Prevalence differences in motor and non-motor symptom fluctuation between the English WOQ-9 and Japanese WOQ-9. Prevalence differences were compared by Fisher’s exact test. *p < 0.05, **p < 0.01, ***p < 0.001.
study. In addition, the level of agreement between the JWOQ-9 with two positive responses and the physician’s diagnosis of wearing-off was moderate (kappa value = 0.60). This specificity and agreement do not fulfill the requirements for using the JWOQ-9 as the sole diagnostic tool for identifying wearing-off. The JWOQ-9 consists of questions regarding five motor and four non-motor symptoms of wearing-off (Fig. 1) [9,10]. We subsequently evaluated the sensitivity and specificity of each of these items. For the motor symptoms, almost all of the items showed moderate to high sensitivity and specificity. In particular, the “slowness” item exhibited high sensitivity and specificity with moderate agreement. The developing effective and efficient care pathways for patients with chronic pain (DEEP) study showed “slowness” to be
Fig. 3. Association between wearing-off frequency and duration of levodopa.
the most frequent wearing-off symptom identified with the WOQ19 questionnaire [3]. These results suggest that motor symptom fluctuation can be recognized by both physicians and PD patients. In contrast, sensitivity of the non-motor symptom items was lower than the motor symptom items, suggesting that in our study, the majority of PD patients diagnosed as having wearing-off by a physician felt that their non-motor symptoms were unresponsive to treatment, even after taking levodopa. The reason for this point may be partially because not all non-motor symptoms are responsive to levodopa therapy. We also found that non-motor symptom items showed high specificity for wearing-off. Although non-motor symptoms are common and occur in patients without PD, the obvious response of non-motor symptoms to levodopa may be characteristic of wearing-off in PD patients. We found only one significant frequency difference between the English WOQ-9 and JWOQ-9, that of “cloudy/thinking” symptom fluctuation. This suggests that the meaning of “cloudy/thinking” is somewhat different between English and Japanese. Our study showed that US PD patients felt a greater levodopa response to motor symptoms than Japanese patients. Moreover, US PD patients were more concerned about wearing-off than dyskinesia [16]. These results suggest that US PD patients should be more careful than Japanese patients in observing the effect of levodopa on motor symptoms. Conversely, we also found that Japanese patients tend to experience more non-motor symptom fluctuation than US patients. While US patients were concerned about long-term side effects of their medication, Japanese patients worried about experiencing hallucinations [16], suggesting there are cultural differences between Japan and the US. Our findings indicate that Japanese patients are more sensitive to non-motor symptoms than US patients. Previous studies have shown that approximately 10% of PD patients per year develop wearing-off after initiation of levodopa treatment [2]. Therefore, up to 40% of patients exhibit wearingoff within 4–6 years of treatment, with almost all PD patients experiencing fluctuating symptoms after 10 years [17,18]. In the present study, the percentage of Japanese PD patients who developed wearing-off by the second, fourth, and sixth years from the start of levodopa treatment was 29.2%, 47.7%, and 67.7%, respectively. This suggests that the onset of wearing-off occurs earlier than indicated by previous reports [19]. Furthermore, the largest discrepancy between the physician’s assessment and JWOQ-9 evaluation was identified in PD patients treated with levodopa for less than 2 years. Bareˇs et al. reported that the biggest discrepancy between physician’s assessment and the JWOQ-9 is noted in the first years of levodopa therapy, suggesting that PD patients treated with levodopa therapy for less than 2 years do not feel that antiparkinsonian drugs are adequate for symptom control [20]. Moreover, this discrepancy occurred because the WOQ-9 questionnaire does not distinguish wearing-off symptoms limited to the morning [20]. Our study has several limitations. First, only PD patients were assessed using the JWOQ-9, and we enrolled no control subjects. As also observed in the validation study of a Chinese version of the WOQ-9, 10.4% of PD patients misinterpreted the questionnaire, and consequently completed the questionnaire incorrectly [21]. If control subjects had been enrolled, we may have identified why incorrect completion occurs in patients versus control subjects. Second, there was a difference in our inclusion criteria with respect to the original validation studies of the WOQ-9 and JWOQ-9. In the original studies, the enrolled subjects had a diagnosis of PD for less than 5 years [9]. In contrast, we did not limit disease duration. One reason for our choice is that wearing-off may occur whenever PD patients receive antiparkinsonian drugs. Therefore, we examined utility of the JWOQ-9 and estimated frequency of wearing-off at all stages of PD.
J. Fukae et al. / Clinical Neurology and Neurosurgery 134 (2015) 110–115
5. Conclusion We performed a multi-center study to validate the JWOQ-9 in Japanese PD patients. Our results suggest that the JWOQ-9 is a reliable tool for screening for wearing-off in Japanese PD patients, with usefulness and validity equivalent to the original WOQ-9.
[8]
[9]
[10]
Sources of funding None. Conflicts of interest/Disclosures
[11]
[12]
None.
[13]
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©2015 Elsevier
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Utility of the Japanese version of the 9-item Wearing-off Questionnaire Jiro Fukae a , Masa-aki Higuchi a , Shosaburo Yanamoto a , Kosuke Fukuhara a , Jun Tsugawa a , Shinji Ouma a , Taku Hatano b , Asako Yoritaka c , Yasuyuki Okuma d , Kenichi Kashihara e , Nobutaka Hattori b , Yoshio Tsuboi a,∗ a
Department of Neurology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan c Department of Neurology, Juntendo Koshigaya Hospital, Koshigaya, Japan d Department of Neurology, Juntendo Shizuoka Hospital, Izunokuni, Japan e Department of Neurology, Okayama Kyokuto Hospital, Okayama, Japan b
a r t i c l e
i n f o
Article history: Received 3 November 2014 Received in revised form 21 April 2015 Accepted 26 April 2015 Available online 5 May 2015 Keywords: Parkinson’s disease Wearing-off Questionnaire Motor symptom Non-motor symptom
a b s t r a c t Background and purpose: The 9-item Wearing-off Questionnaire (WOQ-9) is a useful tool for screening of wearing-off. We performed a validation study of the Japanese version of the WOQ-9 (JWOQ-9) using a cross-sectional design in Japanese Parkinson’s disease (PD) patients diagnosed with sporadic PD and treated with levodopa. Methods: Subjects with severe dementia, uncontrolled psychiatric comorbidities, and previous PD neurosurgery were excluded. The wearing-off phenomenon was detected according to the JWOQ-9, and the results were compared with independent evaluations of wearing-off conducted by PD specialists blinded to the JWOQ-9 results. To validate the JWOQ-9, a sample size of at least 70 patients with wearing-off and 70 patients without wearing-off was required. Therefore, a total of 180 patients (101 patients with wearing-off and 79 patients without wearing-off) were enrolled. Results: The sensitivity, specificity, positive predictive value, and negative predictive value of the JWOQ-9 were 94.1%, 39.2%, 66.4%, and 83.8%, respectively. Motor symptom questions demonstrated both moderate sensitivity (58.1–87.3%) and specificity (60.4–87.5%). In contrast, non-motor symptom questions demonstrated fair to moderate sensitivity (51.5–64.6%), with high specificity (80.0–94.1%). Like the original WOQ-9, the JWOQ-9 exhibits significant value for detecting possible wearing-off. Conclusions: The JWOQ-9 is a useful screening tool for detecting wearing-off of both motor and non-motor symptoms. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Parkinson’s disease (PD) is a neurodegenerative disorder involving nigrostriatal dopaminergic neurons. The introduction of levodopa therapy dramatically improves the quality of life and prognosis of PD patients, at least for the first several years [1]. However, motor complications, including “wearing-off” and “dyskinesia,” frequently develop during treatment with levodopa [1–3]. While wearing-off has a great impact on the patient’s quality of
∗ Corresponding author at: Department of Neurology, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. Tel.: +81 92 801 1011; fax: +81 92 865 7900. E-mail address: [email protected] (Y. Tsuboi). http://dx.doi.org/10.1016/j.clineuro.2015.04.021 0303-8467/© 2015 Elsevier B.V. All rights reserved.
life [4], the ability to detect this phenomenon is sometimes difficult, as the symptoms are varied and include both motor and non-motor symptoms [3–7]. In particular, non-motor symptoms of wearing-off are less well recognized by physicians and PD patients. Specific questionnaires have been developed to screen for wearing-off in PD patients. In 2005, a 32-item Wearing-off Questionnaire (WOQ-32) was developed and validated by Stacy et al., allowing for effective identification of wearing-off symptoms in PD patients [6]. However, a potential limitation of the WOQ-32 is the time required to complete the many questions, such that screening cannot be completed rapidly [6]. Accordingly, a 9-item Wearingoff Questionnaire (WOQ-9) and 19-item Wearing-off Questionnaire (WOQ-19) were developed as more user-friendly screening tools [8,9]. Stacy et al. subsequently demonstrated sensitivity and specificity of the WOQ-9 to be 96.2% and 40.9%, respectively, and
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Fig. 1. A, Japanese version of the 9-item Wearing-off Questionnaire (JWOQ-9). B, JWOQ-9 back-translated into English.
concluded that the WOQ-9 is a useful screening tool for detecting wearing-off [9]. WOQ-19 and WOQ-9 have previously been translated into Japanese and validated linguistically (Fig. 1) [10]. However, the Japanese language is somewhat unique and it has not been clarified whether the Japanese version of the WOQ-9 (JWOQ9) displays equivalent usefulness and validity to the English version. Thus, the aim of this multi-center study was to assess sensitivity and specificity of the JWOQ-9 in Japanese PD patients receiving antiparkinsonian medications, compared with findings of assessments conducted by neurologists.
2. Materials and methods 2.1. Subjects This cross-sectional study was performed at five clinical hospitals from January to December 2012 (Fukuoka University Hospital, Juntendo University Hospital, Juntendo Koshigaya Hospital, Juntendo Shizuoka Hospital, and Okayama Kyokuto Hospital). The study protocol was approved by the ethics committee of each hospital. A diagnosis of PD was made based on the United Kingdom PD Society Brain Bank criteria [11]. Key inclusion criteria were: 0.60 (substantial), or a higher level of agreement, was proposed as the threshold for acceptable reliability of the questionnaire [15].
3. Results 3.1. Demographic characteristics of PD patients From January to December 2012, 201 patients with PD were enrolled in this study. Of the 201 PD patients, 21 interpreted the questionnaire incorrectly; for example, only checking a box in the second column of the item(s) without checking a box in the first column. These patients were excluded, and the final per-protocol population included a total of 180 PD patients. The mean age of the patients was 68.7 ± 8.4 years. The participants of the study included 80 males and 100 females. The average duration since PD diagnosis was 7.0 ± 4.9 years, and the PD patients had been receiving PD medications for an average of 5.5 ± 5.0 years. The HY stage distribution was: stage 1, 8.9%; stage 2, 36.7%; stage 3, 45.0%; stage 4, 8.3%; and stage 5, 1.1%. All patients were currently receiving levodopa at a mean daily dose of 441.9 ± 237.4 mg/day. Treatment duration with levodopa was 4.5 ± 4.1 years (Table 1). Patients with mild cognitive impairment, controlled depression, and controlled psychiatric symptoms were also included in the study. Of those, 12.2% and 6.1% were
administrated antidepressants and antipsychotics, respectively. Moreover, PD patients receiving antidepressants had significantly chance to having wearing-off (Table 1). Of the 180 PD patients, 101 (56.1%) had wearing-off symptoms, as judged by a physician. Compared with PD patients without wearing-off symptoms, they were younger (67.6 ± 9.4 versus 70.3 ± 6.9 years, p = 0.027) and had an earlier age of onset (59.3 ± 9.9 versus 64.9 ± 8.1 years, p = 0.0001) (Table 1). In addition, females were more likely to experience wearing-off (62.4% versus 46.8%, p = 0.049). The duration of antiparkinsonian and levodopa treatment was longer in patients with wearing-off than in those without (7.0 ± 5.6 versus 3.7 ± 3.5 years, p = 0.0001; 5.6 ± 5.6 versus 3.0 ± 2.9 years, p = 0.0001, respectively) (Table 1), and patients with wearing-off received larger daily doses of levodopa than those without (520.8 ± 273.0 mg/day versus 341.1 ± 124.2 mg/day, p = 0.0001) (Table 1).
3.2. Sensitivity and specificity of the JWOQ-9 With more than one positive response, the JWOQ-9 showed 94.1% sensitivity, 39.2% specificity, and 70.0% accuracy for detecting wearing-off (Table 2). The corresponding AUC was 0.78, and the kappa value was 0.35. With more than two positive responses, the sensitivity of the JWOQ-9 decreased from 94.1% to 87.1%, while specificity increased from 39.2% to 72% (Table 2). Accuracy for detecting wearing-off also increased from 70.0% to 81.4%, and the kappa value increased to 0.60.
3.3. Sensitivity and specificity of each question item The prevalence of motor symptoms was: tremors, 61.1%; slowness, 87.2%; reduced dexterity, 77.8%; stiffness, 73.9%; and muscle cramping, 56.7% (Table 3). The frequency of non-motor symptoms was: cloudy/thinking, 56.7%; pain/aching, 35.6%; mood changes, 45.0%; and anxiety/panic, 35.6% (Table 3). The sensitivity of motor symptoms ranged from 58.1% to 87.3%, whereas specificity ranged from 60.4% to 87.5%. In contrast, the sensitivity of non-motor symptoms ranged from 51.5% to 64.6%, while specificity ranged from 80.0% to 94.1% (Table 3).
J. Fukae et al. / Clinical Neurology and Neurosurgery 134 (2015) 110–115
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Table 2 Quality attributes of the JWOQ-9. Patientsreported benefit after medication
Physicianreported ‘wearing-off’
Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
Accuracy
Agreementa
Total (N = 180) ≥1 positive
143 (79.4%)
101 (56.1%)
≥2 positive
110 (61.1%)
101 (56.1%)
94.1% (89.2–97.1) 87.1% (81.6–91.5)
39.2% (33.0–43.1) 72.2% (65.0–77.7)
66.4% (63.0–68.6) 80.0% (74.9–84.0)
83.8% (70.5–92.1) 81.4% (73.4–87.7)
70.0 (64.6–73.4) 0.81 (0.74–0.87)
0.35 (0.24–0.43) 0.60 (0.47–0.70)
Reported symptom
a
Agreement with the criterion (kappa value). 95% confidence intervals are provided in parentheses.
3.4. Prevalence difference in symptom fluctuation between the WOQ-9 and JWOQ-9
initiation of levodopa therapy was 50.0%, 59.0%, 67.7% and 80.4%, respectively (Fig. 3).
According to the original version of the WOQ-9, Stacy et al. reported that the prevalence of motor and non-motor symptoms fluctuates [9]. To examine cultural differences, we compared prevalence of motor and non-motor symptom fluctuation between the original WOQ-9 and the JWOQ-9. Differences in each symptom fluctuation frequency were assessed using Fisher’s exact test. There were no significant differences in any item between the English and Japanese WOQ-9, apart from the item “cloudy/thinking”. Interestingly, there was a tendency for patients from the United States (US) to show more motor symptom fluctuation, while more nonmotor symptom fluctuation was observed in Japanese patients (Fig. 2).
4. Discussion
3.5. Wearing-off frequency Association between duration of levodopa treatment and wearing-off development is shown (Fig. 3). For a diagnosis of wearing-off by a physician, the percentage of Japanese PD patients who developed wearing-off by the end of the second, fourth, sixth, and more than 6 years after initiation of levodopa therapy was 29.2%, 47.7%, 66.7%, and 82.4%, respectively (Fig. 3). For a diagnosis of wearing-off according to the JWOQ-9 (one positive response), the percentage of Japanese PD patients who developed wearing-off by the end of the second, fourth, sixth, and more than 6 years after
Several studies have evaluated the ability of short questionnaires to identify PD patients with wearing-off [9,13]. Generally, questionnaires for wearing-off serve two potential functions: screening and diagnosing wearing-off. For screening purposes, sensitivity of ≥90% is required as the minimal acceptable level [9,12]. For diagnostic purposes, a questionnaire must fulfill two requirements: (1) sensitivity, specificity, and accuracy of ≥75%, and (2) a level of agreement (kappa value) between the questionnaire and physician’s diagnosis of >0.60 [13,14]. In the present study, the JWOQ-9 with one positive response showed high sensitivity (94.1%), low specificity (39.2%), and reasonable accuracy (70.0%) for diagnosing wearing-off. These results are similar to the original study of the WOQ-9, which reported sensitivity of 96.2% and specificity of 40.9% [9]. After translation into Japanese, the JWOQ-9 maintained a high capacity for detecting possible wearing-off, suggesting that the JWOQ-9 with one positive response is also a useful tool for screening of wearing-off. However, the JWOQ-9 with one positive response may not be used as a diagnostic tool for detecting wearing-off because its specificity, accuracy, and agreement are not adequate to fulfill the expected requirements. Alternatively, the sensitivity, specificity, and accuracy of the JWOQ-9 with two positive responses were 87.1%, 72.2%, and 0.81, respectively, in this
Table 3 Sensitivity and specificity of each symptom. Patientsreported benefit after medication
Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
Accuracy
Agreementa
Total (N = 180) Motor Tremor (N = 132) (73.3%)
90 (68.2%)
Slowness (N = 157) (87.2%)
88 (56.1%)
Reduced dexterity (N = 140) (77.8%) Stiffness (N = 133) (73.9%)
59 (42.1%)
Muscle cramping (N = 102) (56.7%)
43 (42.2%)
87.3% (81.1–92.2) 82.1% (76.7–86.1) 57.5% (51.5–61.9) 80.2% (74.6–84.4) 58.1% (50.7–63.3)
60.4% (51.1–67.6) 83.9% (75.6–90.0) 83.0% (73.2–90.2) 80.9% (70.5–88.5) 82.5% (71.1–90.6)
76.7% (71.2–80.9) 88.6% (82.8–92.9) 84.7% (75.9–91.2) 88.5% (82.3–93.1) 83.7% (73.2–91.3)
76.2% (64.5–85.3) 75.4% (67.9–80.9) 54.3% (47.9–59.0) 69.1% (60.3–75.6) 55.9% (0.48–0.61)
0.77 (0.69–0.82) 0.83 (0.76–0.88) 0.67 (0.60–0.73) 0.81 (0.73–0.86) 0.68 (0.59–0.74)
0.49 (0.33–0.62) 0.65 (0.51–0.75) 0.37 (0.22–0.47) 0.59 (0.44–0.70) 0.37 (0.20–0.50)
51.5% (45.9–53.6) 64.6% (57.9–67.5) 64.6% (59.3–67.6) 63.6% (55.6–68.8)
94.1% (83.0–98.3) 87.5% (67.4–96.4) 81.3% (59.7–93.2) 80.0% (62.3–91.4)
94.6% (84.4–98.5) 93.9% (84.2–98.3) 93.3% (85.7–97.6) 87.5% (76.4–94.6)
49.2% (43.4–51.4) 45.2% (34.8–49.8) 36.1% (26.5–41.4) 50.0% (38.9–57.1)
0.66 (0.58–0.69) 0.70 (0.60–0.75) 0.68 (0.59–0.73) 0.69 (0.58–0.76)
0.37 (0.24–0.42) 0.40 (0.19–0.49) 0.31 (0.13–0.41) 0.38 (0.15–0.52)
Reported symptom
Non-motor Cloudy/slow thinking (N = 102) (56.7%) Pain/aching (N = 64) (35.6%) Mood changes (N = 81) (45.0%) Anxiety/panic (N = 64) (35.6%) a
78 (58.6%)
37 (36.3%) 33 (51.6%) 45 (55.6%) 32 (50.0%)
Agreement with the criterion (kappa value). 95% confidence intervals are in parentheses.
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J. Fukae et al. / Clinical Neurology and Neurosurgery 134 (2015) 110–115
Fig. 2. Prevalence differences in motor and non-motor symptom fluctuation between the English WOQ-9 and Japanese WOQ-9. Prevalence differences were compared by Fisher’s exact test. *p < 0.05, **p < 0.01, ***p < 0.001.
study. In addition, the level of agreement between the JWOQ-9 with two positive responses and the physician’s diagnosis of wearing-off was moderate (kappa value = 0.60). This specificity and agreement do not fulfill the requirements for using the JWOQ-9 as the sole diagnostic tool for identifying wearing-off. The JWOQ-9 consists of questions regarding five motor and four non-motor symptoms of wearing-off (Fig. 1) [9,10]. We subsequently evaluated the sensitivity and specificity of each of these items. For the motor symptoms, almost all of the items showed moderate to high sensitivity and specificity. In particular, the “slowness” item exhibited high sensitivity and specificity with moderate agreement. The developing effective and efficient care pathways for patients with chronic pain (DEEP) study showed “slowness” to be
Fig. 3. Association between wearing-off frequency and duration of levodopa.
the most frequent wearing-off symptom identified with the WOQ19 questionnaire [3]. These results suggest that motor symptom fluctuation can be recognized by both physicians and PD patients. In contrast, sensitivity of the non-motor symptom items was lower than the motor symptom items, suggesting that in our study, the majority of PD patients diagnosed as having wearing-off by a physician felt that their non-motor symptoms were unresponsive to treatment, even after taking levodopa. The reason for this point may be partially because not all non-motor symptoms are responsive to levodopa therapy. We also found that non-motor symptom items showed high specificity for wearing-off. Although non-motor symptoms are common and occur in patients without PD, the obvious response of non-motor symptoms to levodopa may be characteristic of wearing-off in PD patients. We found only one significant frequency difference between the English WOQ-9 and JWOQ-9, that of “cloudy/thinking” symptom fluctuation. This suggests that the meaning of “cloudy/thinking” is somewhat different between English and Japanese. Our study showed that US PD patients felt a greater levodopa response to motor symptoms than Japanese patients. Moreover, US PD patients were more concerned about wearing-off than dyskinesia [16]. These results suggest that US PD patients should be more careful than Japanese patients in observing the effect of levodopa on motor symptoms. Conversely, we also found that Japanese patients tend to experience more non-motor symptom fluctuation than US patients. While US patients were concerned about long-term side effects of their medication, Japanese patients worried about experiencing hallucinations [16], suggesting there are cultural differences between Japan and the US. Our findings indicate that Japanese patients are more sensitive to non-motor symptoms than US patients. Previous studies have shown that approximately 10% of PD patients per year develop wearing-off after initiation of levodopa treatment [2]. Therefore, up to 40% of patients exhibit wearingoff within 4–6 years of treatment, with almost all PD patients experiencing fluctuating symptoms after 10 years [17,18]. In the present study, the percentage of Japanese PD patients who developed wearing-off by the second, fourth, and sixth years from the start of levodopa treatment was 29.2%, 47.7%, and 67.7%, respectively. This suggests that the onset of wearing-off occurs earlier than indicated by previous reports [19]. Furthermore, the largest discrepancy between the physician’s assessment and JWOQ-9 evaluation was identified in PD patients treated with levodopa for less than 2 years. Bareˇs et al. reported that the biggest discrepancy between physician’s assessment and the JWOQ-9 is noted in the first years of levodopa therapy, suggesting that PD patients treated with levodopa therapy for less than 2 years do not feel that antiparkinsonian drugs are adequate for symptom control [20]. Moreover, this discrepancy occurred because the WOQ-9 questionnaire does not distinguish wearing-off symptoms limited to the morning [20]. Our study has several limitations. First, only PD patients were assessed using the JWOQ-9, and we enrolled no control subjects. As also observed in the validation study of a Chinese version of the WOQ-9, 10.4% of PD patients misinterpreted the questionnaire, and consequently completed the questionnaire incorrectly [21]. If control subjects had been enrolled, we may have identified why incorrect completion occurs in patients versus control subjects. Second, there was a difference in our inclusion criteria with respect to the original validation studies of the WOQ-9 and JWOQ-9. In the original studies, the enrolled subjects had a diagnosis of PD for less than 5 years [9]. In contrast, we did not limit disease duration. One reason for our choice is that wearing-off may occur whenever PD patients receive antiparkinsonian drugs. Therefore, we examined utility of the JWOQ-9 and estimated frequency of wearing-off at all stages of PD.
J. Fukae et al. / Clinical Neurology and Neurosurgery 134 (2015) 110–115
5. Conclusion We performed a multi-center study to validate the JWOQ-9 in Japanese PD patients. Our results suggest that the JWOQ-9 is a reliable tool for screening for wearing-off in Japanese PD patients, with usefulness and validity equivalent to the original WOQ-9.
[8]
[9]
[10]
Sources of funding None. Conflicts of interest/Disclosures
[11]
[12]
None.
[13]
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