Keywords:
Parkinson disease - quality of life - activities of daily living
Palavras-chave:
doença de Parkinson - qualidade de vida - atividades cotidianas
Motor fluctuations in Parkinson's disease (PD) have been extensively studied[1],[2]. Conversely, less is known about the behavior of non-motor symptoms in relation
to the “on” and “off” periods. While some authors have suggested that these non-motor
fluctuations correlate closely with motor fluctuations[3],[4],[5], the heterogeneity of study designs and differences in sample populations complicate
the generalization of these results. In addition, non-motor symptoms have an important
impact on quality of life[6] and, in some cases, their burden can be more disabling when compared with motor
symptoms[7].
Wearing-off is defined as a predictable recurrence of motor and non-motor symptoms
preceding scheduled doses of antiparkinsonian medication[8]. The underlying pathophysiology of wearing-off is thought to be multi-factorial[9].
Motor wearing-off includes the recurrence of motor symptoms like tremor, rigidity,
and bradykinesia; while non-motor wearing-off includes the recurrence of symptoms
such as anxiety, fatigue, or depressed mood[10].
Different scales have been specifically developed to assess wearing-off in patients
with PD[11]. The Wearing-Off Questionnaire (WOQ-19) has been used in several studies as a screening
tool to identify patients with wearing-off phenomena[12].
The objective of this study was to assess the impact of motor and non-motor wearing-off
on activities of daily living and quality of life of patients with PD.
METHODS
A cross-sectional study was performed on consecutive patients with PD, based on the
UK Parkinson's Disease Society Brain Bank Criteria[13], attending the Movement Disorders outpatient clinic at the National Institute of
Neurology and Neurosurgery in Mexico City. All the participating patients agreed to
take part in the study and gave full consent as dictated by the National Institute
of Neurology and Neurosurgery local ethics committee. Since the study included several
self-administered questionnaires to be completed by a respondent without intervention
of the researchers, patients with cognitive decline (Montreal Cognitive Assessment
< 26) or any medical or psychiatric comorbidity that would hinder an adequate assessment
were not included.
Clinical and demographic data collected included age, gender, years of education and
disease duration. In addition, the levodopa equivalent daily dose (LEDD) was calculated[14].
Patients were evaluated in their “on” state by a neurologist with expertise in movement
disorders using the Movement Disorders Society Unified Parkinson's Disease Rating
Scale (MDS-UPDRS), Part IA (non-motor experiences of daily living), Part III (motor
examination) and Part IV (treatment complications)[15]. Part IV was not included in the analysis as it mainly evaluates the presence of
fluctuations along with dyskinesia. Disease severity was assessed using the Hoehn
and Yahr (HY) staging.
Patient-reported outcomes, including activities of daily living and quality of life,
were evaluated using the Spanish version of the MDS-UPDRS Part IB (non-motor experiences
of daily living) and Part II (motor experiences of daily living). These two parts
are designed as self-administered questionnaires and could be completed either alone
or with their caregivers.
For the study purposes, it is important to highlight that in the MDS-UPDRS Part IA
the patient had to choose the best answer that describes how he/she had felt “most
of the time during the past week”. On the other hand, Parts IB and II required the
patient to mark the answer that best describes what he/she could do “most of the time”.
Quality of life was assessed using the Parkinson's Disease Questionnaire-8 (PDQ-8).
The PDQ-8 is a disease-specific and self-administered instrument addressing aspects
of functioning and well-being in the past month. The scale comprises eight questions,
scored by frequency of problems (0 = never to 4 = always). A PDQ-8 single index is
calculated resulting in a score ranging from 0 to 100 (0 = no problem at all; 100
= maximum level of problem)[16].
In addition, the WOQ-19 was applied. The WOQ-19 is a disease-specific and self-administered
instrument addressing aspects of motor and non-motor symptoms related to the wearing-off
phenomenon. The WOQ-19 assesses the following motor symptoms: tremor, difficulty with
speech, weakness, problems with balance, slowness, reduced dexterity, general stiffness
and difficulty getting out of the chair. On the other hand, non-motor features assessed
include: anxiety, sweating, mood changes, numbness, panic attacks, cloudy mind/dullness
of thinking, abdominal discomfort, muscle cramping, experiencing hot and cold, pain
and aching.
Patients marked the presence/absence of selected symptoms as well as the improvement
after the next dose of medication. The presence of wearing-off was considered if the
symptom is reported to improve after the following dose of medication[12]. For the study purposes, patients were classified in the following groups: patients
without wearing-off (Non-WO), patients with exclusively motor wearing-off symptoms
(M-WO), patients with exclusively non-motor wearing-off symptoms (NMS-WO), and patients
with both with motor and non-motor wearing-off symptoms (Mixed-WO).
Statistical analysis
Demographic data were reported in terms of percentage, mean and standard deviation.
Data distribution was assessed using the Shapiro-Wilk test.
The analysis of quantitative variables between the groups was performed using one-way
ANOVA with Tukey's Honest Significant Difference post hoc test for normally distributed data. If nonparametric comparison was needed, a Kruskal-Wallis
test with pairwise comparisons using the Dunn-Bonferroni approach were performed.
Differences in proportions of categorical variables were analyzed using Chi-square
or Fisher's test as needed. The 95% confidence interval is reported through-out. A
level of p < 0.05 was set for statistical significance. All statistical analyses were
performed with SPSS software version 17.
RESULTS
A total of 271 patients (148 males and 123 females) with PD were included. The mean
age was 65.4 ± 12.4 years, and the mean disease duration was 9.0 ± 5.5 years. According
to the HY stage, 60.4% had mild disease (HY stages 1–2), 25.9% had moderate disease
(HY stage 3), and 13.7% had severe disease (HY stage 4–5). Two hundred and forty-six
patients (90.8%) were on levodopa in monotherapy or polytherapy, and 166 patients
were treated with a dopaminergic agonist (61.3%).
The complete sociodemographic characteristics of the study sample are summarized in
[Table 1].
Table 1
Clinical and demographic data of the study sample.
|
Variable
|
Mean ± Standard deviation
|
|
Male gender*
|
148 (54.6%)
|
|
Current age (years)
|
65.41 ± 12.43
|
|
Disease duration (years)
|
8.98 ± 5.48
|
|
Years of education
|
8.98 ± 5.45
|
|
Levodopa equivalent daily dose
|
797.38 ± 427.29
|
|
MDS-UPDRS Part I
|
10.35 ± 6.74
|
|
MDS-UPDRS Part II
|
15.20 ± 11.03
|
|
MDS-UPDRS Part III
|
30.53 ± 15.85
|
|
MDS-UPDRS Part IV
|
2.75 ± 3.98
|
MDS-UPDRS: Movement Disorders Society Unified Parkinson's Disease Rating Scale; Part
I: non-motor experiences of daily living; Part II: motor experiences of daily living;
Part III: motor examination; Part IV: treatment complications.
A total of 199 patients (73.4%) had a wearing-off phenomenon. After categorizing patients
according to the type of wearing-off phenomena, 63.8% had Mixed-WO, 32.7% had M-WO,
and 3.5% had NMS-WO. The comparison of the main demographic and clinical variables
between groups is shown in [Table 2].
Table 2
Comparison of the main demographic and clinical variables between different groups.
|
Variable
|
Non-WO n = 72
|
M-WO n = 65
|
NMS-WO n = 7
|
Mixed-WO n = 127
|
p-value
|
|
Male gender **
|
38 (52.7%)
|
35 (52.2%)
|
2 (28.5%)
|
73 (57.4%)
|
0.460
|
|
Current age (years)*
|
68.04 ± 11.59
|
66.60 ± 11.20
|
69.85 ± 6.96
|
63 ± 13.35
|
0.077
|
|
Disease duration*
|
8.78 ± 6.24
|
8.22 ± 4.29
|
6.85 ± 4.14
|
9.60 ± 5.57
|
0.131
|
|
MDS-UPDRS I*
|
10.71 ± 6.60
|
8.51 ± 6.14
|
17.14 ± 5.78
|
10.72 ± 6.90
|
0.004
|
|
MDS-UPDRS Item 1.3 (depressed mood)*
|
0.56 ± 0.85
|
0.49 ± 0.77
|
1.57 ±1.13
|
0.50 ± 0.80
|
0.214
|
|
MDS-UPDRS II*
|
14.13 ± 10.87
|
13.37 ± 10.61
|
11 ± 7.37
|
16.98 ± 11.31
|
0.043
|
|
MDS-UPDRS III*
|
31.52 ± 15.31
|
28.83 ± 14.65
|
27.71 ± 10.76
|
31.02 ± 17.03
|
0.704
|
|
MDS-UPDRS IV*
|
1.17 ± 2.76
|
2.03 ± 3.64
|
2.14 ± 3.38
|
4.02 ± 4.35
|
< 0.001
|
|
PDQ-8*
|
25.31 ± 19.57
|
23.32 ± 21.37
|
37.05 ± 15.24
|
31.27 ± 22.61
|
0.016
|
|
Use of dopamine agonist**
|
47 (65.2%)
|
48 (73.8%)
|
2 (28.5%)
|
99 (77.9%)
|
0.019
|
|
Use of levodopa**
|
59 (81.9%)
|
59 (90.7%)
|
7 (100%)
|
122 (96%)
|
0.007
|
|
LEDD (mg)*
|
581.66 ± 421.77
|
748.81 ± 445.94
|
502.50 ± 346.99
|
865.41 ± 423.97
|
< 0.001
|
Non-WO: Non-wearing-off; M-WO: Motor wearing-off; NMS-WO: Non-motor wearing-off; Mixed-WO:
Mixed wearing-off; MDS-UPDRS: Movement Disorder Society – Unified Parkinson's Disease
Rating Scale; PDQ-8: Parkinson's Disease Quality of Life; LEDD: Levodopa Equivalent
Daily Dose.
*Kruskal-Wallis test. Mean ± standard deviation.
**Fisher's test.
Statistically significant differences between groups were found for the MDS-UPDRS
I total score (p = 0.004), MDS-UPDRS II total score (p = 0.043), use of levodopa (p
= 0.007), use of dopamine agonists (p = 0.019), LEDD (p < 0.001), and the PDQ-8 score
(p = 0.016).
The MDS-UPDRS part I score was higher in the NMS-WO group compared with the M-WO group
(mean difference of 8.64 ± 2.64, 95% CI 1.82-15.45, p = 0.007). There was a trend
toward significance between the NMS-WO group and Mixed-WO group (mean difference of
6.48 ± 2.57, 95% CI −0.23-13.07, p = 0.086).
The MDS-UPDRS part II score showed a trend between the M-WO and Mixed-WO groups (mean
difference of 3.62 ± 1.67, 95% CI −0.70-7.93, p = 0.091), but no statistical significant
differences were found after the post hoc analysis.
In regard to treatment, patients with NMS-WO were less frequently on a dopamine agonist
compared with those in the Mixed-WO and M-WO groups (28.5% vs. 77.9%, p = 0.010 and
28.5% vs. 73.8%, p=0.025, respectively). Also, patients in the Mixed-WO group were
more commonly on levodopa compared with those in the Non-WO group (96% vs. 81.9%,
p = 0.001). After post hoc analysis, patients in the Mixed-WO group had a higher LEDD compared with the Non-WO
group (mean difference of 283.75 ± 63.02, 95% CI 120.81-446.67, p < 0.001). No other
statistical significant differences were found.
Regarding the quality of life, the post hoc analysis did show a statistically significant difference between groups. The Mixed-WO
group had a worse quality of life compared with the M-WO group (mean difference of
7.96 ± 3.26, 95% CI 0.48-16.40, p = 0.047).
DISCUSSION
Motor and non-motor wearing-off are frequent in patients with PD receiving dopaminergic
replacement therapy. Non-motor wearing-off has been less studied; consequently, this
type of complication may be overlooked in clinical practice. Moreover, non-motor fluctuations
may be confused with anxiety or depression.
Non-motor wearing-off prevalence varies widely between studies ranging from 17% to
100% depending on the clinical tools used for assessment[3],[4],[10],[16],[17]. In our study, a prevalence of 49.4% was found (127 patients with mixed wearing-off
and seven patients with non-motor wearing-off). This finding can be explained by the
relatively long disease duration of almost nine years, due to the fact that a longer
disease duration has been clearly associated with a higher prevalence of treatment
complications[18].
It has been reported that motor and non-motor fluctuations tend to be present concomitantly,
although the latter can appear without motor fluctuations[19]. Brun et al.[4] found that the presence of motor fluctuations was an independent predictor for non-motor
fluctuations, while Witjas et al.[10] reported that all patients with motor wearing-off in their cohort also had non-motor
fluctuations. In our study, the prevalence of non-motor wearing-off in combination
with motor fluctuations was 46.8%. In fact, only seven patients with exclusively non-motor
wearing-off were found. On the other hand, less than 27% of the patients had no wearing-off
phenomena. This group had less exposure to levodopa than the patients with motor or
mixed wearing-off, which is in line with previous reports[10],[16]. It should also be noted that patients in the NMS-WO group received a lower LEDD
compared with those groups with motor fluctuation (M-WO and Mixed-WO). Overall, patients
in the Mixed-WO group were more frequently on a dopamine agonist and levodopa, as
well as on a higher dose. This may suggest that motor wearing-off is more related
to the dopaminergic treatment dosage than the non-motor fluctuations.
The MDS-UPDRS part I total score, assessing non-motor aspects of daily living, was
higher in the NMS-WO group compared with patients in the M-WO group. No difference
was found between patients with mixed wearing-off and those patients without the wearing-off
phenomenon. This finding suggests that patients with motor wearing-off may have a
lower overall burden of non-motor symptoms; while patients with mixed or no wearing-off
have similar burdens, as measured by the MDS-UPDRS part I. Conversely, patients with
non-motor fluctuations also have a higher burden of non-motor symptoms.
On the other hand, no differences were found between groups in the MDS-UPDRS part
II scores (motor experiences of daily living). Lack of statistical difference in the
MDS-UPDRS part II may suggest that the total score of this subscale does not relate
to the presence of motor and non-motor wearing-off symptoms.
Regarding the motor state, Seki et al.[16] reported that patients with both motor and non-motor wearing-off had more severe
motor symptoms as assessed by the MDS-UPDRS part III. In our sample, we did not find
any differences between groups. While the management of motor symptoms as measured
by motor evaluation was not related to the wearing-off phenomena, the type of dopaminergic
replacement treatment and its dose did show some association, as mentioned before.
The MDS-UPDRS part IV score was higher in the Mixed-WO group; this finding was expected
since three of the six items comprising this part address motor fluctuations.
Wearing-off symptoms have implications in health-related quality of life. Non-motor
symptoms have been clearly associated with a decrease in the quality of life[20],[21]. Nonetheless, there is less evidence regarding the impact of non-motor fluctuations
and quality of life. In our study, PD patients in the NMS-WO group had the worst score
in the PDQ-8, followed by patients in the Mixed-WO group. On the other hand, patients
with no wearing-off and those with only motor wearing-off had a better quality of
life. This finding suggests that, in fact, non-motor fluctuations may yield a higher
impact on the quality of life than motor wearing-off symptoms.
Our study has several limitations. First, by study design, we did not analyze individual
non-motor fluctuations. Nonetheless, the objective of our study was to assess the
overall impact of non-motor wearing-off phenomena. Second, we evaluated only the frequencies
of motor and non-motor fluctuations, but we did not assess their severity. Lastly,
due to the small size of the NMS-WO group, our results should be interpreted with
caution; other independent studies confirming our findings are required.
In conclusion, the present study shows that both motor and non-motor fluctuations
have an impact on activities of daily living and quality of life. However, the presence
of non-motor fluctuations did significantly worsen the quality of life. The identification
and assessment of non-motor fluctuations in the day-to-day clinical practice could
result in the improvement of the quality of life of patients with PD.
