Subjective Perceived Motor Improvement after Acute Levodopa Challenge in Parkinson’s Disease

Abstract

Background: Previous studies found a poor association between parkinsonian patient’s reported subjective improvement after commencing dopaminergic treatment and improvements in objective measures of motor impairment by clinician.

Objective: To compare PD patient’s subjective perceived motor improvement after acute levodopa challenge test with objective motor improvement assessed by the clinician using the UPDRS part III. To analyze clinical characteristics, i.e. age, disease duration, cognitive performance or severity of axial features, that may have influenced patient’s perception.

Methods: Fifty-seven consecutive PD patients (23 women, 34 men; mean age, 63.4±7.7 years) (Hoehn and Yahr off score, 2.5±0.7; mean disease duration, 11.4±4.1 years) completed the acute levodopa challenge. The percentage of improvement in motor disability, i.e. objective motor improvement, was determined with respect to the off-drug condition.

Results: Bland & Altman visual analysis reveals a high degree of correlation between objective and subjective perceived motor improvement. Both the axial sub-scores in the off- and on-state (respectively, P = 0.006 and P = 0.024) and the presence of peak-dose dyskinesia (P = 0.043) significantly influence the difference between objective and subjective perceived motor improvement.

Conclusions: This is the first study reporting on how PD patients assessed their motor improvement after acute levodopa challenge. These findings suggest a strong correlation between objective motor improvement assessed by the clinician using the UPDRS part III and subjective perceived motor improvement reported by the patient.

Keywords

Parkinson’s disease subjective perception motor improvement acute levodopa challenge

INTRODUCTION

Parkinson’s disease (PD) is a progressive neurodegenerative disease that affects dopaminergic neurotransmission, resulting in bradykinesia, rigidity, and rest tremor. Diagnosis of PD is generally made based on clinical history and symptoms, together with laboratory test and imaging methods used mainly to rule out other diseases. Nevertheless, distinguishing PD from other parkinsonian syndromes remains often challenging [1], even for experienced neurologists because patients occasionally lack characteristic symptoms of the disease especially in the early stage [2]. Well-established diagnostic clinical criteria recommended by UK Parkinson’s Disease Society Brain Bank (UKPDSBB) require more than 24 months of levodopa-responsiveness to chronic levodopa treatment. In clinical practice, the response to antiparkinsonian medication is usually assessed by asking patients to rate subjectively their improvement. Unified Parkinson’s Disease Rating Scale (UPDRS) is a validated scale that allows objective motor assessment with a good intra rater reliability [3 –5]. The acute levodopa challenge test evaluates levodopa responsiveness in terms of UPDRS part III after a single oral dose of levodopa [6 –8]. It is also reported to be helpful to diagnose PD [9, 10] and to predict long lasting response to levodopa or dopaminergic agonists [7 , 12]. On the other hand, levodopa responsiveness appears as a key factor to select candidate for deep brain stimulation in more advanced stage of PD [13].

Previous studies found a poor association between the degree of patient reported subjective improvement after commencing treatment and improvements in objective measures of motor impairment [14]. To our knowledge, no studies have assessed how well the subjective perceived motor improvement by patients after acute levodopa challenge correlates with objectively measured improvement. Thus, the aim of this study was to compare PD patient’s subjective assessment of their response to single oral dose of levodopa with objective motor improvement assessed by the clinician using the UPDRS part III. Moreover, it focuses on clinical characteristics, such as age, disease duration, dyskinesia, cognitive performance or severity of axial features that may have influenced patient’s subjective perceived motor improvement.

MATERIALS AND METHODS

Patients

Fifty-seven consecutive patients (23 women, 34 men; mean age, 63.4±7.7 years) with idiopathic PD according to UKPDSBB criteria (Hoehn and Yahr off-score, 2.5±0.7; mean disease duration, 11.4±4.1 years), were enrolled in the Department of Neurology, University Hospital Rouen between January 2011 and March 2013. The patients were referred for medical treatment optimization (n = 15) or screening for deep brain stimulation eligibility (n = 42). All patients received a regular dopaminergic drug therapy.

Clinical evaluation

During the same visit, the following data were collected prospectively: age, sex, disease duration,levodopa medication duration, presence of non-motor fluctuations [15] (NMF) manifestations, i.e. dysautonomic, mental, and sensory symptoms, detailed dopaminergic treatment expressed in levodopa equivalent daily-dose (LEDD), severity of the disease evaluated by Hoehn & Yahr stage during “off” state, presence of co-morbid psychopathology including dopamine dysregulation syndrome [16] (DDS) and PD dementia (PDD) [17].

The motor state was assessed by the UPDRS part III. Axial motor features, i.e. speech, gait, walking and postural instability, were assessed separately using the corresponding UPDRS III sub-scores (items 18, 28, 29, and 30). Complications of levodopa therapy, i.e. dyskinesias (UPDRS part IVA score) and clinical fluctuations (UPDRS part IVB score), were also assessed. All the patients underwent standardized cognitive and psychiatric assessments, i.e. the Mattis Dementia Rating Scale (MDRS) score, the Montgomery & Åsberg Depression scale (MADRS) [18] or Hamilton Depression scale [19]. Depression was registered as: normal from 0 to 7 HAM D and MADRS, mild from 8 to 13 HAMD or 8 to 15 MADRS, moderate from 14 to 18 HAM D or 16 to 25 MADRS, severe from 19 to 22 HAM D or 26 to 31 MADRS and very severe over 23 HAM D or 32 MADRS.

Acute levodopa challenge

The acute levodopa challenge was conducted in all patients basically as described.

We pre-treated patients with the peripheral dopa-mine receptor blocker domperidone (Motilium®) with a total daily dose of 30 mg on the day before. The last application of 10 mg of domperidone was 30 min before the challenge test performance. Thus, we reduced the severity and appearance gastrointestinal side effects of levodopa.

Off-state was defined as motor impairment following at least 12 h absence of antiparkinsonian medication, while on-state was the patient’s best motor response to first L-dopa dose (1.5 times the individual morning dose) after the off-state. Long-acting dopamine agonists were stopped 72 h prior to off-examination. The percentage improvement in motor disability, i.e. objective motor improvement, was determined with respect to the off-drug condition.

Clinical evaluation was carried out at baseline (off-state) and at every 15 min, 30 and 60 min after levodopa intake, to assess the best motor response. Off-period dystonia and peak-dose dyskinesias were respectively recorded in off- and on-state. Peak-dose dyskinesias were defined as predominantlychoreodystonic movements occurring at the same time as the greatest degree of clinical improvement.

Subjective perceived motor improvement

Patients were blinded to the results of objective motor improvement. PD patient’s subjective assessment of their response to single oral dose of levodopa was assessed by asking them the following question immediately during the best on-state: ⪡ How much better do you feel since you have taken the L-dopa dose comparing with your state before (off-state)? Please estimate the percent of globalimprovement. ⪢

Statistical analysis

Statistical analysis was performed with the SPSS software. The different scores were expressed as mean value±SD. For all analyses, the level of significance was set to P < 0.05. Bland Altman plot was used to investigate the link between subjective and objective assessments. Normal distribution of the data was first tested with the Kolmogorov-Smirnov test. Then, Student test was conducted to assess the difference between the two measures. As recommended Bland Altman plot was built with the mean value of the two measures: the objective motor improvement (percentage improvement of UPDRS part III score) and the subjective perceived motor improvement (patient’s given percentage). The difference represented on ordinate was calculated as the relative difference between the objective and the subjective perceived motor improvement.

A Pearson correlation coefficient was calculated between the absolute value of differences between the objective and subjective perceived motor improvement and numeric data, i.e. age, disease duration, levodopa duration, LEDD, Hoehn & Yahr stage during off-state, axial sub-scores in the off- and on-state, UPDRS part IVA, UPDRS part IVB, MDRS and depression composite scores. Mann and Whitney test was used for ordinal data, i.e. gender, presence of NMF, DDS, PDD, off-period dystonia and peak-dose dyskinesias.

Subgroup analysis were performed to determine whether data correlate with under-or overestimation of the subjective perceived motor improvement using a Mann Whitney test for numeric data and the Fisher exact test for ordinal data.

RESULTS

Fifty-seven consecutive patients completed the acute levodopa challenge. The clinical characteristics are summarized in Table 1. Nine patients fulfilled criteria for probable PDD whereas 34 patients presented with NMF manifestations among which 22 patients suffered from sensory, 15 from autonomic and 7 from neuropsychiatric symptoms. Twenty two patients presented mild to severe depression and 12 patients fulfilled DDS diagnosis criteria. Fourteen patients had left lateralized predominant symptoms versus 36 right lateralized. The remaining 7 patients experienced symmetrical symptoms.

The mean acute improvement in UPDRS part III score, i.e. objective improvement, from off-state after acute levodopa challenge was 64% [range 7 to 92]. Similarly, off-axial motor sub-score improved by 59% [range 0 to 100% ] in the on-state. Meanwhile, the PD patient’s subjective perceived motor improvement was 64% [range 0 to 100]. In the off-state 36 patients experienced off-period dystonia whereas 24 experienced peak-dose dyskinesias in the on-state.

Correlation between objective and subjective perceived motor improvement

Bland & Altman visual analysis (Fig. 1) reveals a high degree of correlation between objective and the subjective perceived motor improvement with an average bias of 2.62. Furthermore the trend of repartition is confirmed with the linear regression test between relative difference (objective - subjective measures) and the mean value between objective and subjective perceived motor improvement (t: – 0,285, P 0,027). Thus, when the on-state improvement percentage increases, the relative difference between objective and subjective measures tends to lower. Moreover, when the on-state improvement is greatest, patient’s subjective perceived motor improvement tends to be equal or superior to clinician’s measure.

Factors influencing subjective perceived motor improvement

Both axial sub-scores in the off- and on-state (respectively, P = 0.006 and P = 0.024, Table 2) and the presence of peak-dose dyskinesia (P = 0.043, Table 3) influence significantly the difference between objective and subjective perceived motor improvement.

Post-hoc subgroup analysis

Firstly, post-hoc subgroup analysis were performed to determine whether axial sub-score in the off- state, axial sub-score in the on-state or the presence of peak-dose dyskinesia correlate with underestimation of the subjective perceived motor improvement. There was no correlation between underestimation of the subjective perceived motor improvement and each of these three factors.

Secondly, post-hoc subgroup analysis were performed to determine whether axial sub-score in the off- state, axial sub-score in the on-state or the presence of peak-dose dyskinesia correlate with overestimation of the subjective perceived motor improvement. There was no correlation between overestimation of the subjective perceived motor improvement and each of these three factors.

DISCUSSION

Although dopaminergic medication significantly improves motor symptoms and quality of life in PD, patient’s perception of motor improvement may differ from clinician objective measure. This discrepancy may draw attention to the inaccuracy of PD patient to weigh their treatment efficacy. In the current study, we find a strong correlation between objective motor improvement assessed by the clinician using the UPDRS part III and subjective perceived motor improvement reported by the patient, after acute levodopa challenge. Moreover, we report a significant influence of the axial sub-score both in the off- and on-state and of the presence of peak-dose dyskinesia on the so-called subjective perceived motorimprovement.

These results are in contrast with previous studies comparing patient rated treatment response with measured improvement in PD. In fact, a study shows that PD patients’ subjective ratings of their degree of improvement often do not accurately reflect the degree of objective change in parkinsonian disability measured by the UPDRS part III [14]. Consequently, almost 30% of patients whose motor UPDRS improved by more than 50% reported either no or only slight improvement. Several factors might account for the differences between this previous data and our results. Firstly, we assessed the levodopa responsiveness in series of PD patients with advanced form of the disease whereas Davidson et al., focused on newly treated patients in early stage of PD. Hence, naive and treated patients do not perceive equally levodopa effect [20]. Especially, patients identified as having motor fluctuations usually reported greater improvements from L-dopa compared to early PD. Secondly, we assessed both objective and subjective perceived motor improvement during the same time, after a single standardised acute levodopa challenge. This methodology, used in all patients, may have contributed to the slight difference between both objective and subjective evaluations. By contrast, Davidson et al., asked PD patients to give their perception of motor disability improvement by comparing two states with a 4 to 6 months interval [14]. Therefore, it is likely that discrepancies between objective and subjective responses may reflect difficulties of their patients to remember their previous disability. Thirdly, both studies may concern different perceptions of distinct response of levodopa. In fact, the therapeutic response to levodopa in PD consists of a short-duration response (SDR) and a long-duration response (LDR) [21]. The former is a clinical improvement that lasts some hours after a single levodopa dose while the latter is a sustained improvement in parkinsonian signs due to chronic levodopa therapy which’s lasts for some days after discontinuation of treatment. Therefore, we postulated that we assessed more specifically the SDR, whereas Davidson et al., focused on the LDR. Moreover, we assumed that PD patients may have a greater perception of the SDR compared to the LDR. Surprisingly, few patients were detected with a disappointing low dopa-sensitivity during the acute levodopa challenge. These results may have led to diagnostic doubt. Nevertheless long-term follow-up and chronic response to antiparkinsonian drugs plaid for PD. Then, we assume that these responses are false-negative.

Postural instability and gait disturbances are important motor symptoms in PD perceived by patients as having the most negative influence on their daily life [22 –24]. For this reason, we supposed that patient’s perception of motor improvement could be influenced by axial features severity. Especially, we anticipated that patients will underestimate the objective improvement when on axial sub-score remain severe. As expected, we find that axial sub-score both in the off- and on-state influences patient’s subjective response. This result is consistent with previous studies suggesting that impaired self-awareness of motor deficits was significantly associated with postural instability and gait difficulties [25]. Interestingly, there was no link between axial sub-score in the on-state and an under- or overestimation of the subjective perception. Since almost all studies have shown that dopaminergic medication improves gait speed, there is a mixed effect on freezing of gait. Indeed, some patients present less freezing on versus off medication, whereas some continue to freeze (and some become worse on medication). Therefore, axial sub-score in the on-state may have opposite influence on subjective perception.

Besides axial features, peak-dose dyskinesias also influence patient’s perception of motor improvement without evidence of under- or overestimation. Conversely, UPDRS IVA sub-score did not influence the patient’s perception. This discrepancy may be explained by the fact that UPDRS IVA integrates patient-derived information with the rater’s clinical observations and judgments whereas dyskinesias were notified by the sole clinician during the acute levodopa challenge. Several studies have suggested that PD patients may be partially or even completely unaware of the presence of levodopa-induced dyskinesia [26]. Hence, dopaminergic therapy may, by stimulating mesocortical–limbic pathways, exert a detrimental effect on the function of the orbitofrontal and cingulated frontal–subcortical loops, all of which are regions that play a role in the awareness of voluntary movements. We did not assess self-awareness of peak-dose dyskinesia observed during acute levodopa challenge. Then, we cannot conclude that peak-dose dyskinesia contribute to poor self-perception of movement improvement.

Mood elevation during on and mood decline in the off state, defining neuropsychiatric NMF have been documented in fluctuating PD patient. Moreover, Levodopa has a psychostimulant effect even after an acute intake [27, 28]. However, patient’s subjective perception was not impacted by either NMF or depressive mood in our study. These results, consistent with previous studies, may be partially explained by the fact that mood was not assessed immediately after the acute levodopa challenge. Another possible explanation is that the majority of patients did not suffer from depression. On the other hand, previous studies demonstrated that most cognitive measures did not change markedly after acute levodopa challenge in PD [29] and did not influence impaired awareness of severity [25]. Accordingly patient’s subjective perception was not impacted by global cognitive performance. Finally, several authors have reported that PD patients with predominant right hemisphere dysfunction (and therefore with predominant left hemi-body symptoms) display a greater lack of self-awareness of various motor symptoms [30]. Nevertheless, we observed no influence of body side predominant and motor features in our cohort.

Our findings may have important implications for daily clinical practice, especially for those centers which perform acute levodopa challenge in PD patients candidates for Continuous Dopaminergic Stimulation techniques. In fact, the patient’s perception is an indicator of treatment success and may be useful to choose the optimal dose of dopaminergic stimulation. Nevertheless, it remains crucial to evaluate levodopa responsiveness in terms of UPDRS part III. In fact, we found a strong correlation between objective and subjective perception of global improvement, but we did not specifically assess the subjective perception of the effect of treatment on each different symptoms (e.g. tremor) or set of symptoms (e.g. axial features). Another study will be interesting to achieve this purpose.

Several limitations of this study need to be pointed out. First, we asked the patient to assess their global improvement without focusing on the motor disability. Since levodopa can also improve certain non-motor aspects, especially in patients suffering from NMF, it may be argued that patient and clinician evaluated distinct improvements. However, we found no influence of NMF on the subjective perception. Therefore we concluded that patients have focused primarily on motor aspects. Second, the majority of patients were candidate for deep brain stimulation with a great expectation of improvement from the surgical therapy. As they were commonly aware that high levodopa response is a key selection criterion, we expected an inappropriate overestimation of motor improvement [31]. Thus, our results cannot be applied to all PD patients. Third, severity and body side predominant of peak-dose dyskinesia were not specifically assessed. Therefore, further research is needed to clarify mechanisms underlying influence of peak-dose dyskinesia. Finally, the small sample size may limit statistical results and power, especially regarding the absence of over- or underestimation factors.

CONCLUSIONS

This is the first study reporting on how PD patients assessed their motor improvement after acute levodopa challenge. These results suggest that fluctuating patients with advanced levodopa-responsive form of the disease have correct perception of the SDR of levodopa. Moreover, it emphasizes the influence of certain motor aspects, such as peak-dose dyskinesia and axial features, on motor improvement perception. Taken together, these findings might help to adjust levodopa medication, especially in PD patients who are potential candidates for Continuous Dopaminergic Stimulation techniques.

CONFLICTS OF INTEREST

The authors have no conflict of interest to report.

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