Validation of a non-motor fluctuations questionnaire in Parkinson's disease

IntroductionNon-motor fluctuations (NMF) in Parkinson's disease (PD) remain poorly recognized but have a high impact on patients’ quality of life. The lack of assessment tools limits our understanding of NMF, compromising appropriate management. Our objective was to validate a hetero-questionnaire for NMF in PD patients at different stages of the disease: without treatment, without motor fluctuations, with motor fluctuations.MethodsWe included patients in 15 centers in France. Our questionnaire, NMF-Park, resulted from previous studies, allowing us to identify the more pertinent NMF for evaluation. Patients reported the presence (yes or no) of 22 selected NMF, and their link with dopaminergic medications. The assessment was repeated at one and two years to study the progression of NMF. We performed a metrological validation of our questionnaire.ResultsWe included 255 patients (42 without treatment, 88 without motor fluctuations and 125 with motor fluctuations). After metrological validation, three dimensions of NMF were found: dysautonomic; cognitive; psychiatric. The sensory/pain dimension described in the literature was not statistically confirmed by our study.DiscussionOur questionnaire was validated according to clinimetric standards, for different stages of PD. It was clinically coherent with three homogeneous dimensions. It highlighted a link between fatigue, visual accommodation disorder, and cognitive fluctuations; and the integration of sensory/pain fluctuations as part of dysautonomic fluctuations. It focused exclusively on NMF, which is interesting considering the described differences between non-motor and motor fluctuations.ConclusionOur study validated a hetero-questionnaire of diagnosis for NMF for different stages of PD.     

Patient diaries as a clinical endpoint in Parkinson's disease clinical trials

Parkinson's disease (PD) is the second most common neurodegenerative disorder with an estimated 4 million patients worldwide. L-dopa is standard, and often initial, therapy for patients with this condition; however, with continued dopaminergic treatment and as the disease progresses, the majority of patients experience complications such as "wearing-off" symptoms, dyskinesias, and other motor complications. These complications may become disabling and profoundly affect quality of life. Treatment modification and combination therapies with L-dopa, dopamine agonists, monoamine oxidase type B inhibitors, and catechol-O-methyltransferase inhibitors are commonly used to manage complications. In recent years regulatory agencies, clinical researchers, and sponsors have widely accepted and utilized changes in "ON" and "OFF" time measured by Patient Hauser Diaries as endpoints for measuring efficacy of therapeutics seeking approval for symptomatic treatment of PD. Successful antiparkinsonian medications have been associated with treatment effects of more than 1 h in either reduction of "OFF" time of increase in "ON" time. Accurate "ON" and "OFF" time registration during clinical studies requires rigorous patient training. Reduced compliance, recall bias and diary fatigue are common problems seen with patient diary reported measures. Electronic diaries may help reducing some of these problems but may be associated with other challenges in large, multicenter studies.     

Early treatment benefits of ropinirole prolonged release in Parkinson's disease patients with motor fluctuations

We performed a retrospective analysis of the Efficacy And Safety Evaluation in Parkinson's Disease (EASE‐PD) Adjunct Study, assessing the minimum time to symptom improvement after initiation of ropinirole prolonged release (2–24 mg/day) versus placebo in patients with moderate‐to‐advanced PD not optimally controlled with levodopa. Ropinirole prolonged release was superior to placebo at Week 2 for change from baseline in “off” time (adjusted mean treatment difference [AMTD] – 0.7 hours; 95% confidence interval [CI], –1.1, –0.2; P = 0.0029), and “on” time without troublesome dyskinesia (0.4 hours; 95%CI, 0.01, 0.88; P = 0.0444). At Week 4, improvements were seen in change from baseline in Unified Parkinson's Disease Rating Scale total motor score (AMTD, –3.1; 95%CI, –4.4, –1.8; P < 0.0001), activities of daily living score (AMTD, –1.1; 95%CI, –1.7, –0.5; P = 0.0004), and the cardinal symptoms of PD compared with placebo. These analyses indicate that once‐daily, adjunctive ropinirole prolonged release can offer PD symptom control 2 weeks after treatment initiation. © 2010 Movement Disorder Society     

ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with Parkinson's disease and motor response fluctuations: A randomized,placebo-controlled phase 2 study

IntroductionND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations.MethodsThis was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC. During Period-2, 16 patients were randomized to receive 7 days treatment with ND0612 or ND0612 plus oral entacapone. Reduction in OFF time was analyzed as an exploratory measure using a futility design with a predefined margin of 1.6 h.ResultsND0612 was well-tolerated; most patients experienced infusion site nodules (95% vs. 56% with placebo), which all resolved without sequelae. Patients treated with adjunct ND0612 during Period-1 avoided deep troughs in levodopa plasma levels and had a decreased fluctuation index versus placebo (1.6 ± 0.5 vs 3.1 ± 1.6 at end of Period-1, respectively). In Period-2, the coadministration of entacapone with continuous ND0612 SC infusion translated to an increase in mean levodopa AUC_0–10h compared to baseline. Exploratory efficacy analysis of Period 1 showed mean ± SD OFF time reductions of −2.13 ± 2.24 [90%CI: -2.8, ∞] hours (p = 0.84 using H₀ of μ₀ ≤-1.6).ConclusionLevodopa/carbidopa infusion with ND0612 was generally well-tolerated and resulted in reduced fluctuations in plasma levodopa concentrations when given with SoC oral levodopa. ND0612 met the efficacy endpoint for the futility design.     

Motor response to levodopa and the evolution of motor fluctuations in the first decade of treatment of Parkinson's disease.

Thirty-four patients with Parkinson's disease were followed for a mean period of 8 years from the time of initiation of levodopa medication. Levodopa response was charted from the starting point of pharmacological treatment to give a longitudinal point of view of the changes that evolve as the disease progresses. Objective measurements of the motor response to levodopa test-doses were made at approximately three yearly intervals. Motor fluctuations developed in 58% of the patient group after a mean treatment period of 35 months. Dyskinesia developed in parallel with fluctuations but appeared on average 7 months before symptomatic wearing-off effects of levodopa doses. The patients with motor fluctuations had significantly better responses to levodopa. By contrast, nonfluctuators were more prone to develop increasing midline motor disability affecting speech, gait and balance. Comparison of test-dose and pretreatment scores suggested that a substantial long-duration response to levodopa remains after many years of treatment, and that lateralized motor deficits show a stronger long duration response than midline ones. Motor fluctuations are a consequence of disease progression but their early development is, on balance, associated with better long-term functional ability because these patients have the greater capacity to respond to pharmacological treatment.     

Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations

The objective of this study was to evaluate the efficacy, safety, and tolerability of istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW‐6002) is an adenosine A_2A receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12‐week, multicenter, double‐blind, placebo‐controlled, randomized, Phase 3 study of istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti‐Parkinson's medications. Istradefylline‐treated subjects had significant placebo‐corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) istradefylline‐treated and 7 (6.1%) placebo‐treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with istradefylline than placebo. We conclude that istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations. © 2008 Movement Disorder Society     

Melevodopa/carbidopa effervescent formulation in the treatment of motor fluctuations in advanced Parkinson's disease

Melevodopa hydrochloride plus carbidopa in effervescent tablets (M/C) is a readily soluble antiparkinsonian tablet formulation. A total of 221 patients with Parkinson's disease and motor fluctuations entered a randomized, double‐blind, double‐dummy, controlled parallel group study, which compared the effectiveness of oral M/C effervescent tablets with standard oral formulation levodopa/carbidopa tablets (L/C; Sinemet) in reducing total daily OFF time. The difference of total daily OFF time (intention‐to‐treat population) between the two groups was not statistically significant (P = 0.07): ?39.4 minutes (95%CI: ?67.08 to ?11.73) in M/C group vs. +3.5 minutes (95%CI: ?36.19 to +43.26) in the L/C group. In the intragroup analysis, M/C significantly reduced the baseline daily OFF, which remained unchanged in the L/C group. There were no unexpected adverse events in either treatment arms, and discontinuation rates due to adverse events did not differ between the two groups [M/C: 2 patients (1.3%); L/C: 1 patient (1.4%)]. This study failed to meet the primary endpoint (P = 0.07); however, there was a trend in favour of the M/C preparation, which deserves further attention. © 2010 Movement Disorder Society     

Helicobacter pylori infection and motor fluctuations in patients with Parkinson's disease

To investigate whether Helicobacter pylori (HP) infection affects the clinical response to levodopa and whether its eradication could improve motor fluctuation in patients with Parkinson's disease (PD). Using the [¹³C] urea breath test, we monitored HP infection in 65 patients with PD and motor fluctuations of the “wearing‐off” or delayed “on” types, with or without dyskinesia. We compared the clinical features and response to L ‐dopa between HP noninfected (n = 30) and HP infected patients (n = 35) by reviewing home diaries kept for 72 hours. Among HP infected patients, we compared the differences in L ‐dopa “onset” time, “on‐time” duration, and scores on the motor examination section of the Unified PD Rating Scale (UPDRS‐III) during the medication “on” phase before and after HP eradication. There were no differences in the age, disease duration, Hoehn and Yahr stage, UPDRS‐III score, L ‐dopa daily dose, and frequency of dyskinesia between HP noninfected and HP infected groups. However, L ‐dopa “onset” time was longer and “on‐time” duration was shorter in HP infected patients than in HP noninfected patients (78.4 ± 28.2 vs. 56.7 ± 25.1 and 210.0 ± 75.7 vs. 257.7 ± 68.9 min, respectively, P < 0.05). HP eradication improved the delay L ‐dopa “onset” time and short “on‐time” duration (to 58.1 ± 25.6 and to 234.4 ± 66.5 min, respectively, P < 0.05). These data demonstrated that HP infection could interfere with the absorption of L ‐dopa and provoke motor fluctuations. HP eradication can improve the motor fluctuations of HP infected patients with PD. © 2008 Movement Disorder Society     

Longitudinal study of the motor response to levodopa in Parkinson's disease.

In this prospective study of 34 patients with Parkinson's disease, measurements of the short duration levodopa motor response have been performed in defined off states at 3 yearly intervals over a mean period of 11.4 years from the point of commencement of levodopa treatment. Twenty-two patients were still available for study; 10 had died and 2 were lost to follow-up. The levodopa motor response amplitude increases over the first 5 years of treatment, and thereafter, on and off scores worsen in parallel with conservation of the response. Patients who developed motor fluctuations within the first 5 years of treatment had, on average, a stronger response to levodopa with significantly better on phase motor function (P = 0.003). Although the proportion of "midline" motor disability (affecting gait, balance, and cranial motor function) increases with time, these deficits do not actually become unresponsive to levodopa. Patients who developed dementia had a significantly more rapid decline in motor function. The latest graph of serial scores for the whole cohort shows an upward curving or exponential increase in motor disability after the first decade of treatment. Applying a notional untreated disability line to this graph--an estimate of the disability that would have accrued if drugs had never been given--we suggest that the long-duration response to levodopa eventually runs down with disease progression.     

An acute and long-term study with a dispersible formulation of levodopa/benserazide (Madopar®) in Parkinson's disease

The clinical efficacy, tolerability and administration regimens of a dispersible formulation of levodopa/benserazide (DM) were investigated in 30 patients with idiopathic Parkinson's disease, complicated by motor fluctuations. All 30 patients showed delayed- “on” phenomenon after administration of the first morning dose of standard levodopa (SM), and 20 showed delayed- “on” phenomenon after the first afternoon dose. Patients were receiving standard formulations of levodopa as monotherapy or in combination. A double-dose study of the dispersible vs the standard formulation was performed in 30 patients, 24 of whom participated in a 36-month, follow-up clinical study. In the long-term study, SM was replaced with DM by substituting the first morning dose or the first morning and first afternoon doses. In the double-dose study, mean latency to “on” after the first morning dose was significantly shorter with DM than with SM (p < 0.001), whereas the duration of “on” was similar with the two preparations. The post-prandial delayed- “on” in the 14 patients who responded to therapy was significantly shorter for DM than for SM (p < 0.001). In the long-term study, the mean latency to “on” in all patients was significantly shorter than at baseline (p < 0.001). Time spent in “on” during the active day increased significantly, and remained stable during the 36-month study. No changes were apparent in the mean dosage of levodopa/day or the number of doses/day, and no acute or long-term adverse events were reported. In conclusion, these results confirm the long-term safety of the dispersible formulation, and its improved efficacy compared with standard levodopa formulations, as monotherapy and in association with slow-release formulations.     

Long-term safety and efficacy of apomorphine infusion in Parkinson's disease patients with persistent motor fluctuations: Results of the open-label phase of the TOLEDO study

IntroductionThe randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP).MethodsAll patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO.ResultsEighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of −3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (±SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (±674) and levodopa dose by 273 mg (±515).ConclusionsThe safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication.     

Premorbid exercise engagement and motor reserve in Parkinson's disease

BackgroundLife-long experiences of cognitive activity could enhance cognitive reserve, which may lead individuals to show less cognitive deficits in Alzheimer's disease, despite similar pathological changes. We performed this study to test whether premorbid physical activity may enhance motor reserve in Parkinson's disease (PD) (i.e., less motor deficits despite similar degrees of dopamine depletion).MethodsWe assessed engagement in premorbid leisure-time exercise among 102 drug naive PD patients who had been initially diagnosed at our hospital by dopamine transporter scanning. Patients were classified into tertile groups based on the frequency, duration, and intensity of the exercises in which they participated.ResultsAmong patients with mild to moderate reductions in striatal dopaminergic activity (above the median dopaminergic activity), the exercise group of the highest tertile showed significantly lower motor scores (i.e., fewer motor deficits, 15.53 ± 6.25), despite similar degrees of dopamine reduction, compared to the combined group of the middle and the lowest tertiles (21.57 ± 8.34, p = 0.01). Nonetheless, the highest tertile group showed a more rapid decline in motor function related to reductions in striatal dopaminergic activity than the other two groups (p = 0.002 with the middle tertile group and p = 0.001 with the lowest tertile group).ConclusionsThese results suggest that engagement in premorbid exercise acts as a proxy for an active reserve in the motor domain (i.e., motor reserve) in patients with PD.     

Effects of chronic subthalamic stimulation on nonmotor fluctuations in Parkinson's disease.

The aim of this study was to assess the outcome of nonmotor fluctuations (NMF) after chronic Subthalamic nucleus (STN) Deep Brain Stimulation (DBS) in Parkinson's disease(PD). Chronic stimulation of the STN has proved to be an effective treatment for advanced PD with motor complications. The outcome of NMF, which are also disabling, remains unknown. Forty-patients underwent bilateral STN stimulation. Each patient was interviewed before and after 1 yr of STN DBS with a structured questionnaire about their NMF. After 1 yr of chronic stimulation, the improvement in the motor score (UPDRS III) and dyskinesia amounted respectively to 67.4 and 76.3%. The decrease in motor fluctuations (MF) was 59% and 13 patients reported that their MF had disappeared. Comparatively, a reduction of the total number of NMF was also observed (mean number preoperatively: 15.6 per patient, postoperatively: 6.6). Most of the nonmotor fluctuating symptoms occurred in the "off" state preoperatively and no longer depended on the patient's motor state after surgery. The improvement in NMF was not identical for the different categories: pain/sensory fluctuations showed the best response to STN DBS (84.2%). Dysautonomic and cognitive fluctuations were also markedly improved (>60%) while psychic fluctuations remained the most frequent postoperative NMF observed. Some incapacitating manifestations such as drenching sweats and akathisia showed a remarkably good response to STN stimulation. In conclusion STN DBS alleviates NMF. It has strikingly successful effects on sensory, dysautonomic and cognitive fluctuations. However, psychic fluctuations respond less consistently to this treatment.     

Segmental progression of cardinal motor symptoms in Parkinson's disease: A pilot study suggesting a practical approach to rate disease course in the early stages

Little is known about the anatomical progression over the body segments of extrapyramidal signs in Parkinson's disease (PD); furthermore a great unmet need is the availability of instruments able to detect disease progression, even in the early phase.The purpose of this study is to demonstrate that assessing topographical distribution of the cardinal motor features of PD may significantly improve the evaluation of disease progression in the early stages.Forty-four drug-naïve PD patients were included in the study. Presence or absence of bradykinesia, rest tremor and rigidity was derived from Unified Parkinson's disease rating scale part III (UPDRS-III) in five different anatomical segments: axial, right and left upper- and lower-limbs. Based on this approach, four new scores were computed evaluating the anatomical spread of the cardinal motor symptoms of PD on the five body segments over a 18-month follow-up period. The four new scores included: the Bradykinesia Segmental Score, the Tremor Segmental Score, the Rigidity Segmental Score, measuring the occurrence of each motor symptom in different segments and the Combined Segmental Score evaluating the occurrence of any motor symptom in different anatomical regions. Data were analyzed using a repeated measures analysis of variance.The Combined Segmental Score showed a significant progression over time whereas the Hoehn and Yahr and the UPDRS-III scores did not.We suggest that a simple approach evaluating the anatomical distribution of motor symptoms and their progression over the body segments may be a useful complement to the classical rating tools to assess progression in early PD.     

Quality of life in early Parkinson's disease: impact of dyskinesias and motor fluctuations.

The impact of dyskinesias and motor fluctuations on quality of life (QOL) at various stages in the course of Parkinson's disease (PD) is not well understood. In 301 subjects with early PD enrolled in a clinical trial (CALM-PD), we quantified the impact of motor complications on QOL and investigated how this changes over time. We also compared QOL related to demographic and treatment characteristics. The presence of dyskinesias was associated with visual analogue scale (VAS) scores 3.0 of 100 points higher (better) than those without dyskinesias in years 1 to 2, even when adjusting for Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. The positive association between dyskinesias and QOL scores was more marked in older patients. In years 3 to 4, dyskinesias no longer had a significant relationship with QOL. Younger subjects had higher VAS scores. Gender, motor fluctuations, and treatment regimen had no significant association with QOL, although a trend was found toward a small negative effect of motor fluctuations on QOL. We conclude that motor complications that occur within the first 4 years of treatment of PD do not have a significant negative effect on quality of life as measured by a visual analogue scale for most patients.     

Association of Catechol-O-Methyltransferase and monoamine oxidase B gene polymorphisms with motor complications in parkinson's disease in a Chinese population

BackgroundCatechol-O-Methyltransferase (COMT) and Monoamine oxidase B (MAO-B) are the main enzymes that metabolize dopamine in the brain. The polymorphisms of the COMT gene and MAO-B gene are associated with high, intermediate and low levels of activity. This may influence the prevalence of motor complications in Parkinson's Disease (PD).MethodsThe study enrolled 1087 Chinese PD patients throughout the country. Sanger dideoxynucleotide chain termination methods were used for COMT and MAO-B genotyping. The researchers compared the association between presence of motor complications and COMT and MAO-B gene polymorphisms, both separately and in combination.ResultsComparison of the allele frequencies revealed that COMT (GG) was significantly more common among PD patients who exhibited wearing-off compared to PD patients without wearing-off (P < 0.05). A statistically higher frequency of the MAO-B (AG) genotype in PD patients with dyskinesias was found (P < 0.05). Although these differences were not significant after Bonferroni's correction. The combined haplotype of the MAO-B and COMT showed no increase (p < 0.05) in the risk of wearing-off and dyskinesias.ConclusionsOur findings suggest that polymorphisms in COMT and MAO-B may increase the risk of wearing-off and dyskinesias. COMT (GG) genotype may be the risk factor of wearing-off. While MAO-B (AG) genotype may be the risk factor of dyskinesias.     

Identification of motor and nonmotor wearing-off in Parkinson's disease: comparison of a patient questionnaire versus a clinician assessment.

This study compares the sensitivity of a Patient Questionnaire versus information gathered by clinicians at a routine clinic visit in recognizing symptoms of wearing-off in early Parkinson's disease (PD). This Patient Questionnaire, containing 32 items representing a wide spectrum of motor and nonmotor wearing-off symptoms, was administered to subjects attending two PD clinics. The Patient Questionnaire results were compared to the information gathered by the clinician from the Unified Parkinson's Disease Rating Scale (UPDRS) Part IV, Question 36 and from a specific Clinical Assessment Question regarding loss of medication efficacy, wearing-off, sleepiness, dyskinesias, psychiatric complications, morning akinesia, other dopaminergic side effects, or none of the above. Examiners were blinded to study hypothesis and survey contents. Three hundred consecutive subjects with PD of <5 years duration were evaluated; the mean subject age was 72 +/- 9.6 years and 60.2% were men. Subjects reporting wearing-off were significantly younger (69.9 vs. 74.7 years) and differed regarding duration of PD symptoms (3.7 vs. 3.1 years). Wearing-off was found in 181 subjects (62.6%) by one or more of the three measures. The most sensitive tool was the Patient Questionnaire, with 165 subjects (57.1%) indicating symptoms of wearing-off. Question 36 of the UPDRS was positive in 127 subjects (43.9%), and the Clinical Assessment Question identified 85 subjects (29.4%) as experiencing wearing-off. All of these results were found to differ significantly. The mean number of wearing-off symptoms reported by the 165 subjects indicating wearing-off on the clinical survey was 6.25, with tremor being the most common motor feature and tiredness the most common nonmotor feature.