K. Ray Chaudhuri

Non-motor symptoms of Parkinson's disease: diagnosis and management.

The clinical diagnosis of Parkinsons disease rests on the identification of the characteristics related to dopamine deficiency that are a consequence of degeneration of the substantia nigra pars compacta. However, non-dopaminergic and non-motor symptoms are sometimes present before diagnosis and almost inevitably emerge with disease progression. Indeed, non-motor symptoms dominate the clinical picture of advanced Parkinsons disease and contribute to severe disability, impaired quality of life, and shortened life expectancy. By contrast with the dopaminergic symptoms of the disease, for which treatment is available, non-motor symptoms are often poorly recognised and inadequately treated. However, attention is now being focused on the recognition and quantitation of non-motor symptoms, which will form the basis of improved treatments. Some non-motor symptoms, including depression, constipation, pain, genitourinary problems, and sleep disorders, can be improved with available treatments. Other non-motor symptoms can be more refractory and need the introduction of novel non-dopaminergic drugs. Inevitably, the development of treatments that can slow or prevent the progression of Parkinsons disease and its multicentric neurodegeneration provides the best hope of curing non-motor symptoms.

Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment

Several studies, including work from the Parkinsons disease (PD) non-motor group and others, have established that the non-motor symptoms of PD are common, occur across all stages of PD, are under-reported, and are a key determinant of quality of life. Research suggests that the non-motor symptoms of the disease are frequently unrecognised by clinicians and remain untreated. Even when identified, there is a common perception that many of these symptoms are untreatable. The role of dopaminergic drugs in treating the various non-motor problems of PD, although clinically recognised, has received little attention. In this Review, we investigate the dopaminergic basis of the range of non-motor symptoms that occur in PD such as depression, apathy, sleep disorders (including rapid-eye movement sleep behaviour disorder), and erectile dysfunction. We discuss the evidence that these symptoms are treatable, at least in part, with various dopaminergic strategies and, where relevant, we also refer to the use of deep-brain stimulation of appropriate targets in the brain. This Review provides a comprehensive overview of the management of this challenging aspect of PD.

The impact of non‐motor symptoms on health‐related quality of life of patients with Parkinson's disease

Non‐motor symptoms are detrimental to health‐related quality of life (HRQoL) of Parkinsons disease patients. In this study, the Non‐Motor Symptoms Scale (NMSS) was used to assess the impact of the non‐motor symptoms on HRQoL of Parkinsons disease patients.

Prevalence of nonmotor symptoms in Parkinson's disease in an international setting: study using nonmotor symptoms questionnaire in 545 patients

2006, there was, no single instrument (questionnaire or scale) for attempting a comprehensive assessment of the wide range of nonmotor symptoms (NMS) of Parkinsons disease (PD). The PD nonmotor group, a multidisciplinary group of experts including patient group representatives developed and validated the NMS screening questionnaire (NMSQuest) comprising 30 items. The NMSQuest is a self completed screening tool designed to draw attention to the presence of NMS. In this paper, we present the results gathered from 545 patients using the definitive version of the NMSQuest highlighting the prevalence of the wide range of NMS flagged in the NMSQuest from consecutive PD patients in an international setting.

The Nondeclaration of Nonmotor Symptoms of Parkinson's Disease to Health Care Professionals: An International Study Using the Nonmotor Symptoms Questionnaire

The nonmotor symptoms (NMS) of Parkinsons disease (PD) are less well recognised and can be more troublesome to patients and carers than classical motor features. NMS are frequently missed during routine consultations and such under‐recognition may have implications on quality of care given that many NMS are treatable. To determine the proportion of patients not declaring NMS to healthcare professional (HCP) as assessed by self completion of the NMS questionnaire (NMSQuest), a validated, self‐completing questionnaire with 30 items. Multicentre international study. The data was collected from PD patients across all age groups and stages attending outpatient clinics in specialist and care of the elderly settings. 242 patients recruited and undeclared NMS ranged from 31.8% (diplopia) to 65.2% (delusions). The most frequently nondeclared symptoms were delusions, daytime sleepiness, intense and vivid dreams, and dizziness. In many, appropriate treatments for undeclared NMS were started only after these were recognised following completion of NMSQuest. NMS of PD are frequently undeclared at routine hospital consultation and may be related to the fact that patients often do not link these symptoms with PD or may be too embarrassed to discuss these. Use of NMSQuest allows patients to flag symptoms which may be otherwise undeclared and remain untreated when potential treatments exist.

Intrajejunal levodopa infusion in Parkinson's disease: a pilot multicenter study of effects on nonmotor symptoms and quality of life.

Switching from oral medications to continuous infusion of levodopa/carbidopa gel reduces motor complications in advanced Parkinsons disease (PD), but effects on nonmotor symptoms (NMSs) are unknown. In this prospective open‐label observational study, we report the effects of intrajejunal levodopa/carbidopa gel infusion on NMS in PD based on standard assessments utilizing the nonmotor symptoms scale (NMSS) along with the unified Parkinsons disease rating scale (UPDRS 3 motor and 4 complications) and quality of life (QoL) using the Parkinsons disease questionnaire (PDQ‐8). Twenty‐two advanced PD patients (mean age 58.6 years, duration of disease 15.3 years) were followed for 6 months. A statistically significant beneficial effect was shown in six of the nine domains of the NMSS: cardiovascular, sleep/fatigue, attention/memory, gastrointestinal, urinary, and miscellaneous (including pain and dribbling) and for the total score of this scale (NMSST) paralleling improvement of motor symptoms (UPDRS 3 motor and 4 complications in “best on” state) and dyskinesias/motor fluctuations. In addition, significant improvements were found using the Parkinsons disease sleep scale (PDSS) and the PDQ‐8 (QoL). The improvement in PDQ‐8 scores correlated highly significantly with the changes in NMSST, whereas a moderately strong correlation was observed with UPDRS changes. This is the first demonstration that a levodopa‐based continuous dopaminergic stimulation is beneficial for NMS and health‐related quality of life in PD in addition to the reduction of motor fluctuations and dyskinesias.

Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial

BACKGROUND Continuous administration of a dopamine agonist could be used to treat patients with restless legs syndrome. Our aim was to investigate the efficacy of transdermal rotigotine in the treatment of idiopathic restless legs syndrome. METHODS In this randomised, double-blind, placebo-controlled trial, 458 patients with moderate-to-severe idiopathic restless legs syndrome (average baseline International Restless Legs Syndrome Study Group severity rating scale [IRLS] sum score of 28.1) were randomly assigned to receive transdermal rotigotine 1 mg over 24 h (n=115), 2 mg over 24 h (n=112), or 3 mg over 24 h (n=114), or to receive placebo (n=117). Study medication was delivered via patches, applied once a day for 6 months. Randomisation was done with a computer-generated randomisation list, stratified by centre. Primary efficacy outcomes were absolute change from baseline to end of maintenance in IRLS sum score and in the clinical global impressions (CGI) item 1 score, assessed by analysis of covariance in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00136045. FINDINGS Efficacy analyses were done on 112 patients in the 1 mg group, 109 in the 2 mg group, 112 in the 3 mg group, and 114 in the placebo group. Mean change in IRLS sum score from baseline at the end of the maintenance phase was -13.7 (SE 0.9) in the 1 mg group, -16.2 (0.9) in the 2 mg group, -16.8 (0.9) in the 3 mg group, and -8.6 (0.9) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Mean change in CGI item 1 score from baseline at the end of the maintenance phase was -2.09 (0.14) in the 1 mg group, -2.41 (0.14) in the 2 mg group, -2.55 (0.14) in the 3 mg group, and -1.34 (0.14) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Skin reactions, mostly mild or moderate, were seen in 145 (43%) of 341 patients who received rotigotine and in two (2%) of 117 who received placebo. Ten patients had serious adverse event that were deemed to be related to rotigotine: elevation of liver enzymes (one patient), worsening of tinnitus (one patient), non-response to anticoagulation (one patient), electrocardiogram changes (one patient), and application-site reactions (six patients). No admissions to hospital were needed for the application-site reactions, and they all resolved within a short time of patch removal without any other therapeutic intervention. The rate of typical dopaminergic side-effects in patients who received rotigotine was low; no signs of augmentation were noted. INTERPRETATION 24 h transdermal delivery of low-dose rotigotine could be used to relieve the night-time and daytime symptoms of restless legs syndrome. FUNDING Schwarz Biosciences.

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 (NMSOn) and off state (NMSOff) 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 ΔNMSOn/Off severities (defined as the differences of VAS scores between on and off). Severities of NMSon, NMSOff, and ΔNMSOn/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 Parkinsons 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.

Parkinson's disease is overdiagnosed clinically at baseline in diagnostically uncertain cases: a 3-year European multicenter study with repeat [123I]FP-CIT SPECT

Overdiagnosis of Parkinsons disease (PD) is suggested by specialist review of community diagnosis, and in postmortem studies. In specialist centers 4 to 15% of patients entered into clinical trials as early PD do not have functional imaging support for a PD diagnosis. In a European multicenter, prospective, longitudinal study, we compared clinical diagnosis with functional SPECT imaging using [123I]FP‐CIT (DaTSCAN™, GE Healthcare). Repeat observations were performed over 3 years in patients with tremor and/or parkinsonism in whom there was initial diagnostic uncertainty between degenerative parkinsonism and nondegenerative tremor disorders. Video‐recording of clinical features was scored independently of functional imaging results by two blinded clinicians at 36 months (= gold standard clinical diagnosis). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The main endpoint was the sensitivity and specificity of SPECT imaging at baseline compared with the gold standard. In 99 patients completing the three serial assessments, on‐site clinical diagnosis overdiagnosed degenerative parkinsonism at baseline in diagnostically uncertain cases compared with the gold standard clinical diagnosis (at 36 months), the latter giving a sensitivity of 93% and specificity of 46%. The corresponding baseline [123I]FP‐CIT SPECT results showed a mean sensitivity of 78% and a specificity of 97%. Inter‐reader agreement for rating scans as normal or abnormal was high (Cohens

Nocturnal subcutaneous apomorphine infusion in Parkinson's disease and restless legs syndrome

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