Intraindividual Variability of Nonmotor Fluctuations in Advanced Parkinson's Disease.

Nonmotor symptoms (NMS) fluctuate in conjunction with motor oscillations in advanced Parkinson's disease (PD), though little is known about the variability of NMS fluctuations in individual patients. We aimed to assess within-patient variability in frequency and severity of NMS during a series of five patient-perceived motor On and Off periods in 38 fluctuating PD patients from the multicenter NonMotorFluctuations in PD study using a visual analogue scale. NMS frequency and severity appeared moderately variable in both motor states within individual patients. Symptom severity ranges between motor states showed high variability and were larger in motor Off states for most NMS.

Quantitative assessment of non-motor fluctuations in Parkinson's disease using the Non-Motor Symptoms Scale (NMSS).

Data on frequency, severity and correlations of NMS with motor complications are only available for a limited number of NMS. The NMS Scale (NMSS) is a validated tool to assess a broad range of NMS, which has not been used in NMS fluctuations. We assessed fluctuations of a broad range of non-motor symptom (NMS) for a 1-month time period in fluctuating Parkinson's disease (PD) in a multicenter cross-sectional study using the NMSS assessing NMS in motor On (NMSSOn) and Off state (NMSSOff) combined with clinical NMS and motor function scoring in 100 fluctuating PD patients. ΔNMSSOn/Off was defined as the differences of NMSS scores between On and Off. Complete NMSS datasets were available from 73 patients (53 % men; age: 68.2 ± 9.7 years) with mean total NMSS score in On state of 41.5 ± 37.6 and in Off state of 75.6 ± 42.3 (P < 0.001). Scores were higher in Off compared to On state for all domains except for domain "perceptual problems/hallucinations" (P = 0.608). Clinimetric properties of the NMSS were similar to those reported previously for NMS assessments independent of motor oscillations. NMSSOn, NMSSOff and ΔNMSSOn/Off showed weak to moderate correlations with demographics, indicators of motor symptom severity as well as with other measures of NMS, depression and quality of life. Correlations of NMSS items/domains with independent measures of related constructs were weak to moderate. In conclusion, when assessed with the NMSS, a broad range of NMS fluctuate with motor oscillations, but these fluctuations do neither correlate with motor function nor with measures of disease progression.

Influence of the nonergot dopamine agonist piribedil on vigilance in patients With Parkinson Disease and excessive daytime sleepiness (PiViCog-PD): an 11-week randomized comparison trial against pramipexole and ropinirole.

OBJECTIVES: The aim of this study was to investigate the effects of piribedil on vigilance and cognitive performance in patients with Parkinson disease experiencing excessive daytime sleepiness on pramipexole or ropinirole. METHODS: In this 11-week randomized, active-controlled, rater-blinded phase III study, eligible patients were randomly assigned to either receive piribedil or to continue on pramipexole or ropinirole. The primary outcome was the median reaction times during the second 15 minutes of the subtest "vigilance" of the Test battery for Attention Performances (TAP). Secondary outcomes included the Epworth Sleepiness Scale, Unified Parkinson's Disease Rating Scale, neuropsychological testing, and items of the Clinical Global Impression. RESULTS: Forty-four patients received piribedil; 36 continued on either pramipexole or ropinirole. There was no difference in the primary end point reaction time of the TAP subtest vigilance between piribedil and the comparator (996 vs 954 milliseconds, P = 0.68). Piribedil reduced daytime sleepiness with lower Epworth Sleepiness Scale scores at the end of treatment compared with the comparator (-4 vs -2 points; P = 0.01). The median Unified Parkinson's Disease Rating Scale III score at the end of treatment was comparable between the 2 groups. Neuropsychological tests revealed no significant between-treatment differences. A higher therapeutic effect and global improvement were shown by the Clinical Global Impression of piribedil-treated patients. CONCLUSIONS: This study shows that switching from pramipexole or ropinirole to piribedil has no effect on the reaction time of the TAP subtest vigilance but upholds the same therapeutic motor effect and reduces daytime sleepiness to a clinically relevant degree in patients with excessive daytime sleepiness.

Nonmotor fluctuations in Parkinson disease: severity and correlation with motor complications.

OBJECTIVE: To evaluate frequency, severity, and correlation of nonmotor symptoms (NMS) with motor complications in fluctuating Parkinson disease (PD). METHODS: The Multicenter NonMotor Fluctuations in PD cross-sectional study used clinical examination of 10 NMS (dysphagia, anxiety, depression, fatigue, excessive sweating, inner restlessness, pain, concentration/attention, dizziness, bladder urgency) quantified using a visual analogue scale (VAS) in motor-defined on (NMS(On)) and off state (NMS(Off)) combined with motor assessments and self-ratings at home in 100 patients with advanced PD. RESULTS: All NMS except dysphagia, excessive sweating, and bladder urgency fluctuated in conjunction to motor fluctuations with more frequent and severe symptoms in off compared to on state. The proportions of patients experiencing autonomic/sensory NMS in both motor states were similar to those with these NMS exclusively in off state (ratios 0.4-1.3), while for mental/psychic NMS the proportions with exclusive manifestation in off state were higher (ratios 1.8-3.1). Demographic and clinical characteristics correlated neither with NMS frequency patterns and severities nor with ΔNMS(On/Off) severities (defined as the differences of VAS scores between on and off). Severities of NMS(on), NMS(Off), and ΔNMS(On/Off) did not correlate with motor function. Presence of anxiety, depression, fatigue, and pain had negative impact on health-related quality of life (HRQOL) measured by Parkinson's Disease Questionnaire-8 scoring independent of their occurrence with respect to motor state. Fluctuations of these NMS but not of fatigue deteriorated HRQOL. CONCLUSION: Patterns of NMS fluctuations are heterogeneous and complex, but psychic NMS fluctuate more frequently and severely. Demographic parameters and motor function do not correlate with NMS or nonmotor fluctuation severities in fluctuating PD.

Reduced body mass index in Parkinson's disease: contribution of comorbid depression.

Courses of Parkinson's disease (PD) that are complicated by weight loss result in poorer overall treatment outcome and lower quality of life. To determine the contribution of depression, which has not yet been specified in the etiology of weight loss in PD, symptomatology and anamnesis from 215 outpatients diagnosed with PD were assessed using a comprehensive battery of neuropsychiatric scales. A percentage of 31 comorbid depressed patients and a comparison with a control population allowed an accurate characterization of effect sizes, sex differences, and patterns of the contribution of comorbid depression to weight loss. Our study showed that comorbid depression had a clinically relevant effect concerning reduced body mass index in male (0.3; Hedges' g) but not in female PD patients. Although some possible confounders are not controlled here, our results support the need of monitoring depressive symptoms in the courses of PD, particularly in male patients.

Requirements for Parkinson's disease pharmacotherapy from the patients' perspective: a questionnaire-based survey.

OBJECTIVE: Knowledge of patients' treatment needs is an important requirement for comprehensive long-term patient care. The objective of this investigation was to assess the requirements of patients with Parkinson's disease (PD) regarding pharmacotherapy. METHODS: A total of 17,500 members of the German Parkinson Association were given the opportunity to anonymously answer a questionnaire about their health-related quality of life, PD pharmacotherapy and their improvement suggestions for new PD medication. RESULTS: Answers from 6351 patients were available for analysis. The majority (87.2%) of patients were older than 60 years; 88.9% had been diagnosed with PD for longer than 3 years and 84.4% selected one of the three most severe categories (categories 1-3 on a 6-point scale) when rating the impact of PD on their quality of life. Symptoms that were regarded as very important for improvement with pharmacotherapy included motor fluctuations (66.3%), early morning akinesia (55.4%) and sleep disturbances (43.5%). Properties of a new PD medication that were rated as very important included continuous drug delivery over 24 hours (66.6%) and 24-hour symptom control (55.8%). The majority of patients used physicians (84.2%) and/or self-help groups (69.4%) to obtain information about PD. Topics of particular interest included comorbid diseases (78.3%), mobility and exercise (77.3%) and research (53%). CONCLUSION: PD has a major impact on patients' quality of life. From the patient's perspective, PD pharmacotherapy needs to address a range of symptoms including not only motor symptoms, but also non-motor symptoms such as sleep disturbances. In selecting the most appropriate treatment regimen, patient preference is an important consideration.

Treatment of dysautonomia in extrapyramidal disorders.

Although extrapyramidal diseases are commonly thought to solely affect the (extrapyramidal) motor system, non-motor symptoms such as behavioural abnormalities, dysautonomia, sleep disturbances and sensory dysfunctions are also frequently observed. Autonomic dysfunction is an important clinical component of extrapyramidal disease, but it is often not formally assessed, and thus frequently misdiagnosed. Symptoms of autonomic dysfunction can impact more on quality of life than motor symptoms. Appropriate symptom-oriented diagnosis and symptomatic treatment as part of an interdisciplinary approach can greatly benefit the patient. This review elaborates a limited overview on the treatment of cardiovascular, gastrointestinal, urogenital and sudomotor autonomic dysfunction in various extrapyramidal syndromes.

Utility of the WHO-Five Well-being Index as a screening tool for depression in Parkinson's disease.

Beck depression inventory (BDI-1A) is the gold standard screening tool for Parkinson's disease (PD) depression, but as a result of its complexity, it is of limited suitability as a quick and easy screening device. We, therefore, validate the 5-item WHO-Five Well-being Index (WHO-5) as a screening tool for PD depression. Two hundred thirteen of 215 recruited PD patients (99.1%) completed the WHO-5. Receiver operating characteristic plots were used to calculate sensitivity/specificity for all cut-off scores for the detection of depression and combined depression/dysthymia as assessed by an independent investigator using the Mini International Neuropsychiatric Interview (MINI). Internal consistency of the WHO-5 was good (Cronbach's alpha = 0.83). WHO-5 showed high validity with adequate detection of depression without differences in the validity indices compared to BDI-1A (P = 0.234). The optimal cut-off value for detection of depression was 12 of 13 points. WHO-5 is a useful, brief, and easy instrument for identifying PD subjects with depression in daily practice.

Lewy body dementia and Parkinson's disease with dementia.

Parkinson's disease (PD) is characterized by its motor impairment. However, non-motor symptoms such as psychiatric disorders, autonomic disturbances and sleep disorders frequently complicate the course of the disease. In particular, psychiatric disturbances including cognitive impairment, depression and psychosis impact these patients considerably. Approximately 31 % of PD patients suffer from cognitive impairment and dementia. Currently, two different clinical presentations are distinguished in PD patients, who present with dementia: Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), which are two different presentations of a single underlying disease process leading to the deposition of alpha-synuclein. Clinically, PDD is distinguished from DLB alone by the different temporal manifestations of extrapyramidal motor symptoms. Dementia is characterized by a subtle onset and progressive cognitive decline with a predominant dysexecutive syndrome, which can be accompanied by different behavioral symptoms such as hallucinations, depression, anxiety and sleep disorders. Dysregulation of different neurotransmitters has been associated with cognitive decline, but reduced cholinergic transmission is currently thought to be the pivotal mechanism in the development of cognitive dysfunction. Therefore, cholinesterase inhibitors are used in the treatment of dementia and accompanying behavioral symptoms in PDD and DLB. The occurrence of dementia impacts not only the patients themselves but also their care-givers and family.This article focuses on the clinical issues related to both disorders and is based on a meeting of experts which took place in April 2008 in Dresden.

Initial experience with ropinirole PR (prolonged release).

Ropinirole is a non-ergolinic dopamine agonist, which has been used for over 10 years for the treatment of Parkinson's disease. A new formulation (PR = prolonged release) has been developed, which allows the drug to be released slowly (continuously) so that it only has to be given once daily. Switching from the previous ropinirole immediate release ( ropinirole IR) to the prolonged release (ropinirole PR) formulation at the nearest equivalent total daily dose, can take place overnight and the acceptance and tolerability are good. The advantages are once-daily dosing, faster titration with good tolerability and more stable plasma levels. The new formulation is regarded as valuable addition to the currently available medications.

Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease.

BACKGROUND: Major hallmarks in the pathophysiology of Parkinson disease are cellular energy depletion and oxidative stress leading to cellular dysfunction and death. Coenzyme Q(10) (CoQ(10)) is an electron acceptor bridging mitochondrial complexes I and II/III and a potent antioxidant that consistently partially recovers the function of dopaminergic neurons. OBJECTIVE: To determine whether nanoparticular CoQ(10) is safe and displays symptomatic effects in patients with midstage Parkinson disease without motor fluctuations. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, stratified, parallel-group, single-dose trial. SETTING: Academic and nonacademic movement disorder clinics. PATIENTS: One hundred thirty-one patients with Parkinson disease without motor fluctuations and a stable antiparkinsonian treatment. Intervention Random assignment to placebo or nanoparticular CoQ(10) (100 mg 3 times a day) for a treatment period of 3 months. Stratification criterion was levodopa treatment. MAIN OUTCOME MEASURE: The subjects underwent evaluation with the Unified Parkinson's Disease Rating Scale (UPDRS) at each visit on a monthly basis. The primary outcome variable was the change of the sum score of the UPDRS parts II and III between the baseline and 3-month visits. RESULTS: One hundred thirty-one subjects were randomized according to the protocol. The mean changes of the sum UPDRS parts II/III score were -3.69 for the placebo group and -3.33 for the CoQ(10) group (P = .82). Statistical analysis according to the stratification did not result in significant changes of the primary outcome variable. No secondary outcome measure showed a significant change between the placebo group and the CoQ(10) group. The frequency and quality of adverse events were similar in both treatment groups. CONCLUSIONS: Nanoparticular CoQ(10) at a dosage of 300 mg/d is safe and well tolerated and leads to plasma levels similar to 1200 mg/d of standard formulations. Add-on CoQ(10) does not display symptomatic effects in midstage Parkinson disease.

Diagnostic aspects of early Parkinson's disease.

Insidious onset of mild, unspecific, sensitive, vegetative, psychopathological, cognitive and perceptive disturbances, i. e., visual and olfactory dysfunction, with a resulting change of personal behavior, i. e., reduced stress tolerance, precede the initially intermittently occurring motor symptoms in patients with Parkinson's disease (PD). Novel neuropathological findings suggest an expansion pattern of the neurodegenerative process beyond the nigral dopaminergic neurons with the initial event located outside the brain. This underlines the clinical concept of an initial premotor phase, which starts in nondopaminergic areas in PD. Moreover a more global general understanding of chronic neurodegeneration enables the performance of clinical trials on neuroprotection, since there is increasing evidence that diagnosis of PD at the threshold of onset of motor symptoms or cognitive symptoms in Alzheimer's disease is too late. Such an earlier diagnosis of chronic neurodegeneration will allow a more convincing demonstration of the efficacy of a neuroprotective or disease modifying compound. It will also support the concept of a clinically effective pharmacological intervention on a disease process, which is also more and more demanded by the health authorities for drug approval.

Decision-making impairments in patients with Parkinson's disease.

A high percentage of Parkinson's disease (PD) patients show cognitive impairments in addition to the cardinal motor symptoms. These deficits primarily concern executive functions most probably linked to dysfunctions in prefrontal regions due to decreased dopaminergic transmission in fronto-striatal loops. To investigate possible associations between decision-making and executive functions in PD, we examined 20 non-demented PD patients and 20 healthy control subjects with a neuropsychological test battery and the Game of Dice Task. In this computerised decision-making task, the rules for gains and losses and the winning probabilities are obvious and stable. Thus, strategic components besides feedback processing might influence decision-making in this task. We found that PD patients were impaired in the Game of Dice task performance and that the frequency of disadvantageous choices correlated with both executive functions and feedback processing. We suggest that decision-making deficits of PD patients in explicit gambling situations might be associated with dysfunctions in two different fronto-striatal loops: the limbic-orbitofrontal-striatal loop, involved in feedback processing, and the dorsolateral prefrontal-striatal loop, involved in executive functions.

Depression and Parkinson's disease.

Depression occurs in approximately 45% of all patients with Parkinson's disease (PD), reduces quality of life independent of motor symptoms and seems to be underrated and undertreated. Characteristics of symptoms differ from major depression. Because of overlapping clinical symptoms, diagnosis is based on subjectively experienced anhedonia and feeling of emptiness. Available rating scales for major depression may not be adequate to correctly measure severity of depression in PD. Anxiety and depression may manifest as first symptoms of PD many years before motor symptoms. Serotonergic, noradrenergic and dopaminergic mechanisms play key roles in the etiology of depression in PD. Tricyclic and newer, selective antidepressants including serotonin and noradrenaline reuptake inhibitors (SSRI, SNRI) appear to be effective in treating depression in PD. Selective reuptake inhibitors seem to have a favorable side effect profile. Recent controlled studies show antidepressant effects of pramipexole in bipolar II depression. New dopamine agonists pramipexole and ropinirole appear to ameliorate depressive symptoms in PD in addition to effects on motor symptoms. There is a lack of appropriate rating scales and controlled studies regarding depression in PD.

Dementia in idiopathic Parkinson's syndrome.

Approximately 25% of patients with idiopathic Parkinson's disease (IPD) later develop dementia, with the typical characteristics as detailed in ICD-10 and DSM-IV. Differential diagnosis has to exclude dementia due to Lewy bodies, subcortical vascular encephalopathy and subcortical dementia due to progressive supranuclear paralysis or corticobasal degeneration. Several studies showed promising results for cholinesterase inhibitors such as donepezile, rivastigmine and galantamine. The demented Parkinsonian patients then present with improvement in cognitive function while motor skills do not deteriorate.

Budipine provides additional benefit in patients with Parkinson disease receiving a stable optimum dopaminergic drug regimen.

BACKGROUND: The complex pharmacological profile of the antiparkinsonian drug budipine influences neurotransmission beyond the dopaminergic system. Previous studies have demonstrated the therapeutic efficacy of budipine on motor symptoms in insufficiently treated patients with Parkinson disease. OBJECTIVE: To demonstrate the efficacy of 20 mg of budipine, 3 times daily, in addition to a stable, prior, optimum-titrated dopaminergic substitution consisting of a combination of levodopa and a dopa decarboxylase inhibitor, bromocriptine mesylate, and optional selegiline hydrochloride in 99 patients with idiopathic Parkinson disease in a multicenter, double-blind, placebo-controlled trial. RESULTS: Budipine significantly (P<.001) decreased the Columbia University Rating Scale sum score (median, 15.0; 95% confidence interval, 11.3-17.0) compared with placebo (median, 4.3; 95% confidence interval, 3.0-7.5) at study end point. Budipine reduced Columbia University Rating Scale subscores for tremor, rigidity, and akinesia. CONCLUSION: The additional application of budipine provides further therapeutic benefit in subjects with Parkinson disease receiving a stable, prior, optimum-titrated dopaminergic drug regimen because of the hypothetical positive impact of budipine on altered nondopaminergic neurotransmission in patients with Parkinson disease.