Wearing off: A complex phenomenon often poorly recognized in Parkinson's disease. A study with the WOQ-19 questionnaire
Background: 'Wearing off' refers to the phenomenology of movement disorders in Parkinson's disease (PD) that appears early and is much commoner than generally believed. It may be present in the form of either motor symptoms or non-motor symptoms.
Keywords: Motor symptoms, non-motor symptoms, Parkinson's disease, Wearing-off questionnaire-19
Parkinson's disease (PD) is a neurodegenerative disorder secondary to the progressive loss of dopaminergic neurons of the substantia nigra, pars compacta. Oxidative stress, which points to a possible involvement of free radicals, could also play an important role in the genesis of PD. Furthermore, several studies have focused on the genetic causes of PD.,,,
Levodopa (LD) is the most effective treatment; however, the global care of patients, especially in a younger age group in whom the disease may be prevalent for a prolonged period, often requires the integration of multiple combinations of medications including dopamine agonists (DA) and monoamine oxidase B inhibitors (MAOBI).,
The long-term treatment of PD sufferers with dopaminergic therapy is frequently associated with motor fluctuations, which may significantly impact their quality of life. The wearing-off (WO) phenomenon is an early indicator of a poor overall medication-related control of the evolving symptomatology of patients suffering from PD.
The incidence of motor complications related to PD recorded in the literature is variable; however, 50–80% of patients with PD develop motor complications within 5–10 years of LD therapy. More recent studies have reported that approximately 50% of subjects may develop both motor and non-motor complications as well as the wearing-off phenomenon within 2 years of commencement of therapy., This condition frequently remains under-recognized because of the heterogeneity of signs and symptoms, which are often labelled as mood disorders. An early and accurate recognition of motor and non-motor fluctuations could determine an optimal treatment that has been adjusted to reduce the wearing-off phenomenon and to improve the additional symptoms that have developed as a result of administration of therapy. Recent evidence has suggested that even in individuals with PD not considered to be having fluctuating motor symptoms, the better dosage optimization of the dopaminergic therapy may significantly influence their perceived quality of life.
The Movement Disorder Society (MDS) Task Force has recommended the wearing-off questionnaire-19 (WOQ-19), developed by Stacy et al., as a diagnostic tool for screening patients, to enable an early detection of the presence of the wearing-off phenomenon in subjects suffering from PD; the systematic utilization of the WOQ-19 helps in the early identification of symptoms that develop due to the wearing-off phenomenon more frequently than is possible using the standard assessment conducted by physicians., In addition, a recent study has demonstrated a close association between the frequency of the wearing-off phenomenon and its impact on the quality of life.
In our study, we used the validated Italian version of the 19-item wearing-off questionnaire for wearing-off detection in PD.,, The WOQ-19 includes nine motor symptoms and ten non-motor symptoms; hence, the systematic utilization of this tool in clinical practice can help detect and clinically manage both motor and non-motor fluctuations seen in PD.
The WOQ-19 consists of nine items assessing fluctuations in the motor symptoms, including the presence of tremors, difficulty in speech, presence of motor weakness, problems with balance, slowness of movements, reduced dexterity of movements, presence of generalized stiffness alongside muscle cramps, and difficulty in getting up from a chair; as well as ten items assessing fluctuations in the non-motor symptoms, including anxiety, sweating, mood changes, numbness, panic attacks, clouded mind/dullness of thinking, abdominal discomfort, hot and cold sensations, localized pain, and generalized body ache.,, For each item, the patient was asked to select if a symptom had been present, and whether or not it improved after the dose of anti-Parkinson medication/s had been administered. A recent study has also estimated the presence of motor and non-motor symptoms using the Italian version of WOQ-19.
The objective of our study, therefore, was to detect the existence of motor and non-motor symptoms using the WOQ-19 and to correlate the scores obtained using this scale with the severity of the disease and the effectiveness of treatment in ameliorating the clinical symptomatology and the wearing-off phenomenon that is often an associated feature. The assessment of the wearing-off phenomenon, its correlation with the medication given, and the efficacy of the WOQ-19 in effectively evaluating its severity have never been investigated in the previously reported studies.
Seventy-three consecutive patients with Parkinson's disease were recruited from the Santorso Hospital and San Martino Hospital from September 2012 to March 2014. All patients provided a written informed consent to participate in the study. The patients in whom the disease had been detected in a time duration of less than one year, as well as those subjects who were not on levodopa therapy were excluded from the study. The patients with associated dementia, diagnosed by the neurologists using the DSM-IV (The Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorders) criteria, were also excluded from the study.
The diagnosis of PD was made according to the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria. Further exclusion criteria included an age <18 years; inability to read or understand the questionnaire; the presence of diphasic dyskinesia; and the presence of any comorbidity, sequelae or disorder that could interfere with the objective clinical assessment of the recruited patients.
The primary objective of our study was to determine the presence of a correlation between the motor and non-motor symptoms and the disease severity through evaluation carried out using the WOQ-19. The patients, therefore, underwent a uniform clinical assessment with standardized questions being asked during their disability evaluation. The clinical features originally present in these patients were also directly collated from their clinical documentation.
Our survey included collection of data on the gender and age status at assessment, the age of symptom onset as well as the disease duration, the details of pharmacological treatment, the Hoehn and Yahr stage (H&Y), and the Unified Parkinson's Disease Rating Scale (UPDRS) part III with related sub-scores. The patients were clinically evaluated in the daytime during their ON and OFF condition. The H and Y and the UPDRS-III scores reported in this study are related to the ON phase (that is, after the dose of LD had been administered). We selected patients with an early-stage PD to reduce the selection bias. This may be related to those patients with an advanced disease who were suffering from several non-motor and motor symptoms, in whom it may be impossible to distinguish the additional symptoms that develop due to the wearing-off phenomenon. Records obtained from the patients' regularly maintained clinical diary were also collected. Therefore, it was possible to retrieve the exact timing of introduction of the LD therapy, and the DA and MAOBI treatments as well as when the LD therapy was introduced in the MAOB-I and DA groups [Table 1]. The patients were asked to indicate whether or not they had experienced any of the 19 symptoms indicated in the WOQ-19 questionnaire during the day and if these symptoms improved after an additional dose of LD had been administered. The WOQ-19 was filled out by the patients themselves; , they were asked to describe the symptoms which they had experienced in the time span between the end of the previous dose of LD and the subsequent administration of the next dose (regardless of the DA or MAOB-I treatment that was also being given). They were also asked to record if the additional symptoms that they developed following the administration of the previous dosage of LD improved after the administration of the next LD dosage.
The secondary objective of this study was the estimation of the wearing-off symptoms (based on the WOQ-19 questionnaire Italian version) among the PD patients who were treated with levodopa, levodopa and DA, levodopa/rasagiline, levodopa/selegiline, or a combination therapy consisting of levodopa/DA/MAOBI. The total daily dosage was 1 mg of rasagiline, and 10 mg of selegiline.
The questionnaire was designed to be self-rated. The recruited patients indicated if one or more of the referred symptoms of PD listed in the questionnaire improved after taking an additional dose of LD, and if the symptom variations were present routinely. Therefore, if the symptoms improved after the LD intake, these manifestations were considered as being evidence of the wearing-off phenomena. The patients were also asked to record which symptoms were the ones that were more disturbing to them and particularly hampering their daily life activities.
The WOQ questionnaire was administered to all the included patients during the 'on' phase (after the dose of LD had been administered), who recorded at least two stages of the symptoms that they had developed, both after the administration of the initial LD dose and prior to the administration of the subsequent LD dose.
The patients' characteristic features were recorded utilizing frequency tables for categorical variables, and the minimum and maximum values, as well as the median, mean and standard deviation for continuous variables.
The presentation of the patients' continuous variables was performed using box-and-whisker plots (minimum, median, maximum), while bar graphs were used to show the categorical variables.
The significance evaluation of intergroup differences, for the values obtained from the WOQ-19, UPDRS motor section, and H&Y, along with age, education, and disease onset, was performed with the Kruskal–Wallis test. The degree of correlation between the presence of motor and non-motor symptoms (estimated through the WOQ subscores), with the degree of motor impairment (assessed using the UPDRS motor section and the H&Y scale), and the anti-Parkinsonian therapy administered were analyzed by the nonparametric Spearman correlation (bivariate analysis). All analyses were performed using the statistical software Statistical Package for the Social Sciences (SPSS) version 21.0 (SPSS, Chicago, IL, USA).
Seventy-three patients (58% male and 42% female) were enrolled in the study. The mean (±standard deviation) age at diagnosis was 69.01 ± 7.67 years, with an age range of 44–75 years; the motor UPDRS and H&Y scores were 18.06 ± 7.09 and 1.84 ± 0.72, respectively.
The mean score of the educational level of the interviewed patients was 6.00 ± 2.44 and there was a significant difference between the groups, especially in the group of patients treated with levodopa/rasagiline, where the score was 1.75 ± 0.46. However, we do not believe that this difference may have affected our results.
In our patients, the average time from the onset of Parkinson's disease to the presentation for treatment was 5.46 ± 3.33 years, and the average time from the onset of Parkinson's disease to the beginning of dopaminergic therapy was 4.40 ± 3.31 years.
The majority of patients were treated with LD and DA (38.3%), followed by only LD (22%), LD and rasagiline (12.3%), and finally, LD and selegiline (8.2%) [Table 1] and [Table 2].
Pharmacological treatment detail
The mean duration of treatment was 7.16 ± 3.31 years with levodopa and selegiline; 7.15 ± 3.73 years with levodopa along with DA and MAOBI; 5.48 ± 3.57 years with levodopa and DA; 4.33 ± 2.22 years with levodopa; and 3.75 ± 2.12 years with levodopa and rasagiline. The correct comparison of the therapy between different subgroups should also be considered according to the duration of intake of levodopa (there are notes pertaining to the beneficial and side effects of long-term levodopa therapy). In particular, the levodopa/selegiline group (6.16 ± 3.12) showed a longer illness history than all the others, followed by the levodopa group, the dopamine agonist and MAOB inhibitor group (6.07 ± 3.66), and the levodopa/dopamine agonist group (4.48 ± 3.58). The levodopa/rasagiline group presented with a lower score of motor impairment and had a shorter disease history than the other subjects. Therefore, the comparison between the groups provided a reliable analysis regarding the motor and non-motor symptoms that manifested during the best therapy for each enrolled patient.
Data analysis was carried out for the entire sample and in the individual subgroups undergoing treatment.
The analysis of the entire sample showed significant differences (P < 0.05) between the motor UPDRS and H&Y scores related to the years of disease history and therapy duration.
Estimating the correlation between disease severity and motor UPDRS and H&Y scores, the report indicated the presence of a significant correlation between the motor and non-motor symptoms with disease severity. Specifically, the statistical significant (P < 0.05) correlation in the analyzed sample was observed for motor weakness, experience of panic attacks, abdominal discomfort, muscle cramping, thermal disturbances, pain, and aching. Regarding motor symptoms, a remarkably significant association with balance abnormalities, difficulty in getting up from the chair, and tremors was observed.
The subgroup investigation estimated a prevalence measure of the main disorders reported.
In the patients treated with only levodopa, the mean motor UPDRS and H&Y scores were 17.40 ± 6.36 and 1.66 ± 0.55, respectively; the duration of the disease was 4.33 ± 2.22 years with the duration of therapy from the onset being 3.26 ± 2.25 years. There was a significant correlation with 5 of 9 motor symptoms and with 4 of 10 non-motor symptoms (P < 0.05). After the medication dose had been administered, there was a significant improvement of motor symptoms such as balance and weakness; whereas, there was a non-significant improvement of non-motor symptoms such as cramping tremor, reduced dexterity, sweating, pain, ache, and thermal disturbances [Figure 1].
In the patients treated with levodopa and rasagiline, the motor UPDRS and H and Y scores were 16.37 ± 7.79 and 2.00 ± 0.49, respectively, and time to PD onset was 3.75 ± 2.12 years with commencement of levodopa therapy taking place 2.50 ± 1.69 years prior to the conduction of this study. The most common and significant correlation (P < 0.05) was obtained with five non-motor symptoms and four motor symptoms. Following the levodopa dosage, improvement occurred in both motor and non-motor symptoms (anxiety, weakness, slowness of movements, difficulty getting up out of the chair, general stiffness, abdominal discomfort, and balance disorders) [Figure 2].
In the patients treated with levodopa and selegiline, the motor UPDRS and H and Y scores were 26.33 ± 7.44 and 2.91 ± 1.02, respectively, and the latency period was 7.16 ± 3.31 years with therapy duration from PD onset being 6.16 ± 3.12 years. The disturbances complained of concerned several items of the questionnaire (there was significant correlation with five motor symptoms and five non-motor symptoms).
Following the levodopa dosage, we noticed a slight improvement in weakness, slowness of movements, and balance disorders [Figure 3].
Levodopa/dopamine agonist group
The motor UPDRS and H&Y scores in the patients treated with levodopa and DA were 18.44 ± 6.31 and 1.77 ± 0.72, respectively, and the time-to-onset of the disease was 5.48 ± 3.57 years with the duration of therapy from onset being 4.48 ± 3.58 years. Referred symptoms and significant correlation (P < 0.05) were observed for 7 of 9 motor symptoms and 6 of 10 non-motor symptoms with the levodopa dose administered. A mild improvement occurred only in weakness, slowness of movements, and abdominal discomfort [Figure 4].
Levodopa/dopamine agonist/IMAO group
In the patients treated with a combination of levodopa, MAOBI, and DA, the motor UPDRS and H and Y scores were 17.76 ± 8.52 and 1.76 ± 0.80, respectively, and the time to onset of disease was 7.15 ± 3.73 years with the duration of therapy from the onset being 6.07 ± 3.66 years. These patients complained of several symptoms in most of the items of the questionnaire, although the pharmacological response was distributed among several items (motor symptoms and non-motor symptoms; P < 0.05).
After levodopa administration, we noticed some improvement in weakness, difficulty in speech, stiffness, balance disorders, slowness of movement, and thinking. Moreover, in most of the remaining items, an improvement in both motor and non-motor symptoms was recorded, although without a significant statistically significant correlation [Figure 5].
The main objective of our study was to evaluate the usefulness of the WOQ-19 questionnaire in routine daily clinical practice; furthermore, our purpose was also to determine the presence of the less common symptoms, mostly subjective, that are, therefore, less investigated. Finally, our goal was to understand which pharmacological approach could more strongly influence the main referred symptoms. We considered the 'wearing off' phenomenon to be present when at least one of the patient's listed symptoms improved after taking a new dose of dopaminergic medication.
To obtain this information, we used the WOQ-19 questionnaire. This validated instrument in Italian was reported in a recent study, and so far, a few papers have been published about its usefulness in everyday clinical practice. For investigating these fluctuations, only patients taking at least levodopa were selected. We confirmed the results of the previously reported studies using the WOQ-19 where the self-assessment of their symptomatology by PD patients indicated a higher percentage of 'wearing-off' symptoms than was seen on the evaluation by clinicians.
The patients who experienced 'wearing off' were younger and with a longer disease duration.
It is also important to highlight that non-motor symptoms represent an important proportion of the 'wearing off' phenomenon in levodopa-treated PD patients.
Although it is difficult to objectively assess these symptoms, there is no doubt that they significantly affect PD patients. The original paper by Stacy et al., described an increased ability to detect fluctuations by using such a questionnaire.
Most of the patients reported more non-motor symptoms than motor symptoms and the former symptoms most frequently referred to: tremor, slowness of movements, balance disorders, muscle cramps, pain and aching, abdominal discomfort, and thermal disturbances. In our opinion, these data are very significant because they demonstrate that non-motor symptoms manifest themselves in, and accompany Parkinson's disease; they are perceived as disturbing features affecting the quality of life and are often treated with inappropriate therapies. Some differences between the groups were also found.
It should be emphasized that it was not possible to judge the different UPDRS scores in the various groups, because the latter had not been homogeneously stratified at the beginning of recruitment. We observed the difference in motor impairment and noticed that the levodopa/rasagiline group had a lower UPDRS-III score (16.37 ± 7.79) than all the other groups; it was also the only group to achieve a significant improvement in symptoms such as feeling hot or cold, panic attacks, and mood swings; and, it was the only group to show some improvement in such symptoms as pain and aching. Conversely, the group that recorded the major motor impairment in the UPDRS III score and H&Y stage was the levodopa/selegiline group.
The group of patients treated with levodopa/DA/MAOBI showed a moderate motor impairment in the UPDRS III score and H&Y stage with a homogeneous and moderate impairment observed in both motor and non-motor symptoms (unlike that seen in other therapy groups). This group obtained an improvement in almost all the symptoms experienced (with minor differences between various symptomatology) before taking the next dose of levodopa.
Finally, the patients on the combination of levodopa and dopamine agonists achieved improvement in symptoms related to slowness, reduced dexterity, sweating, and abdominal discomfort.
There was an apparent discrepancy between the relatively low score obtained on the H&Y scale and the high incidence of symptoms recorded on the WOQ-19 questionnaire. This could be attributed to the misconception about the majority of non-motor symptoms amongst the physician who recorded the H&Y scale, which is more focused on assessing the motor symptoms while overlooking the subtle non-motor symptoms; the high incidence of symptoms recorded on the WOQ-19 questionnaire was because the questionnaire was self-administered by the patients who could focus on their symptoms other than the motor ones also.
The significant correlation between the onset of disease, the years of therapy, and the H&Y and motor UPDRS scores is interesting and provides evidence that disease and therapy duration directly correlate with the motor impairment. An important finding of the study was that the next levodopa dose predominantly improves motor symptoms.
Panic attacks, abdominal discomfort, thermal disturbances, pain, and aching were the major non-motor symptoms reported that had the maximum potential to adversely affected the patients' quality of life. Among the different therapeutic subgroups, the patients treated with levodopa, dopamine agonists, and MAOBI, experienced a generalized symptomatic improvement in their motor symptoms after the subsequent dopaminergic medication.
The differences between the groups may be a positive consequence of differential restoration of the striatal dopaminergic imbalance, suggesting a possible neuroprotective effect. In fact, data showed a significant improvement in the motor and non-motor symptoms within the levodopa/dopamine agonist/MAOI group, when the longest history of disease and time of drug treatment was considered.
The early detection of dose-cycle related symptoms might help the physicians to optimize treatment for a single patient because it may indicate underdosage or inappropriate dosage intervals. In clinical practice, this simplified and easily administered wearing-off patient questionnaire may be useful for the early detection of fluctuations. As it is very easy to use, even for the patient, this question sheet may be administered in routine consultation as a tool to improve the quality of the interview. The WOQ-19 is brief and its simple format permits its rapid completion by the patient. Thus, it may optimize the amount of time the clinician spends with a patient. Further, careful explanation of the WOQ-19 questionnaire accompanied by an improved awareness of the non-motor symptoms of the wearing-off phenomenon are strongly suggested.
We observed that the WOQ-19 helps to diagnose the wearing-off phenomena in PD patients. Interestingly, in addition to the traditional motor symptom disorders such as tremor, fatigue, and muscle cramps that are already part of the expected motor disturbances, it is apparent that many typical and atypical non-motor symptoms are also likely to appear in the not-so-well compensated disease; in fact, together with the classic non-motor symptoms such as pain, sweating and anxiety, other symptoms such as abdominal pain and disequilibrium emerged as potential indicators of the wearing off phenomenon. In our daily experience, we observed that some patients, who were not compliant with their medication and in an advanced stage of the disease, complained of a cramp-like abdominal sensation, along with pain and aching, which was sometimes associated with motor deterioration. We believe that certain important non-motor symptoms may be indicators of an inadequately managed disease. Thus, these unusual non-motor symptoms when additionally looked for, along with the traditional motor and non-motor symptoms that have already been recognized as diagnostic markers of the disease, can help physicians tailor the best treatment plan for each patient.
The use of the WOQ-19 has proven to be particularly useful for the global care of the parkinsonian patients in different stages of the disease. More specifically, the adoption of this tool has allowed for the detection of certain symptoms that usually remain uninvestigated and sometimes are not referred to by the patient at the time of the medical examination. Obviously, such symptoms are those mainly linked to the non-motor arena of manifestations of PD, which also negatively influence the quality of life.
It should be stressed that the data we obtained from the WOQ-19 was not spontaneously reported by the patients; as a consequence, the validity and reliability of this procedure in revealing symptoms (e.g., pain, aching, abdominal discomfort, muscle cramping, thermal disturbances, abnormal sensation of hot and cold, and other non-motor symptoms insensitive to other medical therapies) is apparent; the correction and consideration of these symptoms are crucial from the therapeutic point of view. This fact is frequently underestimated.
Our results emphasize that a combination of various dopaminergic therapies permitted us to address to the greatest possible extent, the symptoms reported. Particularly, the combination of levodopa, DA and MAOBI permitted the achievement of an overall better therapeutic outcome, especially in the realm of non-motor symptoms; another striking feature was that the longer the disease duration, the lesser was the extent of treatment. The significance of this fact in the comprehensive care of patient suffering from PD suggests that a different and more aggressive therapeutic approach be adopted in detecting the underlying symptom complex and in treating them effectively with the plethora of medication combinations available.
This study has some limitations that are mainly related to the small sample size as well as the lack of standardization of groups. The disease duration and the sample size are related to the methodology of collecting data from a clinical study in the outpatient department. It had the advantage of providing a survey of patients suffering from PD in a small rural community.
Further studies are necessary to determine which pharmacological approach can produce an objective and prolonged amelioration, especially of the non-motor symptoms, and improve the quality of life in PD. This study represents an attempt to study the multidimensional symptomatology and the early complications arising during the treatment of PD using a simple, short and reliable test that effectively improves the global care of patients suffering from PD.
San Martino Hospital (Belluno, Italy); Santorso Hospital (Santorso, Vicenza, Italy).
The authors would thank Maria Grazia Pavei for the English language revisions done in the article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]