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Background: Non-motor symptoms such as sleep disturbance, cognitive decline, fatigue, anxiety, and depression in Parkinson’s disease (PD) impact quality of life. Increased levels of pro-inflammatory cytokines in individuals with PD have been reported, which may contribute to non-motor symptoms. A mind-body exercise, Qigong, has demonstrated benefits across different medical conditions. However, a lack of evidence causes clinicians and patients to be uncertain about the effects of Qigong in individuals with PD. This study will examine the effects of Qigong on non-motor symptoms and inflammatory status in individuals with PD. Methods: Sixty individuals with PD will be recruited. Qigong and sham Qigong group (n = 30 for each) will receive a 12-week intervention. Participants will practice their assigned exercise at home (2×/day) and attend routinely group exercise meetings. Results: Clinical questionnaires and neuropsychological tests will measure non-motor symptoms including sleep quality (primary outcome). Biomarker assays will measure inflammatory status. A two-way mixed-design analysis of variance (ANOVA) will be utilized. Conclusions: This study may generate evidence for the benefits of Qigong on non-motor symptoms of PD and the effect on inflammatory status. Findings may lead to the development of a novel, safe, and cost-effective rehabilitation approach for individuals with PD.

Postural instability is a major unmet need in the treatment of Parkinson's disease (PD) and its progression is not well understood. This study examined compensatory stepping taken in response to a backwards waist pull in participants with moderate PD (H&Y III) compared to age-range matched healthy controls (HC). The first step in the response was quantified in terms of strategy, temporal, kinematic, and center of pressure (COP) parameters previously observed to be significantly different in mild PD (H&Y II) compared to HC. Patients with moderate PD, compared to HC, utilized more steps to regain balance, had a longer weight-shift-time, and utilized a base-width neutral step to regain balance. However, there were no differences in ankle angle or COP location at landing as observed in mild PD, possibly due to the use of the base-width neutral step. These results suggest that moderate PD significantly impairs the compensatory response to a backwards pull. Further study should examine the progression of impairment in compensatory responses across PD severity levels, and the correlation with fall risk.

Rotigotine transdermal system is a nonergot, 24-hour dopamine agonist approved for the treatment of early and advanced Parkinson's disease (PD). Recent studies have demonstrated significant improvements with rotigotine in motor function in early PD and significant improvements in daily off-time and motor function in advanced PD. In addition to motor improvements, nonmotor symptoms have been shown to be improved with rotigotine in both early and advanced PD. Rotigotine has been shown in large, controlled studies to be safe and efficacious for the treatment of motor and some nonmotor symptoms of early and advanced PD.

Aim: The aim of this study was to identify mild cognitive deficits in Parkinson's disease (PD) prior to extensive neurodegeneration and to evaluate the extent to which dopamine depletion and other disease-related predictors can explain cognitive profiles. Methods: Neuropsychological performances of 40 nondemented early-stage PD patients and 42 healthy controls were compared across on or off dopaminergic medications. Stepwise regression evaluated cognitive predictors of early-stage PD and disease-related predictors of PD cognition (levodopa dose, disease duration, Unified Parkinson's Disease Rating Scale score, sleep, quality of life, and mood) across on and off states. Results: Neuropsychological performance was lower in PD patients across cognitive domains with significant memory, naming, visuomotor, and complex attention/executive deficits, but with intact visuospatial, simple attention, and phonemic fluency functions. However, medication effects were absent except for simple attention. Regression analyses revealed age, working memory, and memory recall to be the best cognitive predictors of PD, while age, quality of life, disease duration, and anxiety predicted PD cognition in the off state. Conclusion: Nondemented early-stage PD patients presented with extensive mild cognitive deficits including prominent memory impairment. The profile was inconsistent with expected isolated frontostriatal dysfunction previously attributed to dopamine depletion and this highlights the need to further characterize extranigral sources of mild cognitive impairment in PD.

Parkinson's disease (PD) is a progressive, neurodegenerative neurological disorder of unknown etiology. Loss of dopaminergic cells in the substantia nigra of the brain is responsible for motor, affective and cognitive changes observed. No cure is available. Common motor symptoms are tremor, rigidity, and bradykinesia, as well as postural instability in later stages of the disease (Weiner, Shulman, & Lang, 2001). As the disease progresses medication induced motor symptoms, such as dyskinesia--involuntary gross motor wiggling or dance-like movement affecting upper and lower extremities--may emerge (Weiner et al, 2001). Awareness of the importance and impact of nonmotor symptoms has grown with clinical and research experience indicating cognitive and behavioral components substantially contributing to impaired quality of life and increased severity of motor symptoms. Yet, anxiety remains unrecognized and under treated among PD patients. (O'Sullivan, Williams, & Gallagher, 2008; Schulman, Taback, Rabinstein & Weiner, 2002). Anxiety disorders are the most common psychological disorder in the general population (Thyer et al., 1985), while anxiety disorders among older adults often co-occur with medical and neurological disorders (Raj et al., 1993). PD and comorbid anxiety have been documented repeatedly with estimates of 40-75% (Schiffer, et al., 1988; Shulman et al., 2002; Stein, Heuser, Juncos, Uhde, 1990). Clinical treatment, when provided, is primarily pharmacological with anxiolytics, benzodiazepines or antidepressants used. Pathological neurodegenerative changes in noradrenergic mechanisms may be responsible for anxiety experienced by patients with PD (Marsh, 2000). No experimental studies have examined the efficacy of medication in this population. The effects of anxiety on functioning of PD are formidable and further diminish quality of life (Marinus, Leentjens, Visser, Striggelbout & Van Hilten, 2002). Comorbid anxiety results in increased motor dysfunction including more severe tremor, "freezing" (sudden inability to move), dyskinesia and situational anxiety. Indeed, anxiety may produce excess disability than that observed solely due to PD. Treatment of motor and non motor symptoms of PD focuses on maintaining and improving quality of life. Addressing comorbid anxiety is an important target in this process and relaxation training has been suggested (Marsh, 2000). Despite the wide spread occurrence of comorbid anxiety and PD, few reports of relaxation training with PD patients are available. Schumaker (1980) examined the effect of frontal electromyographic (EMG) biofeedback and progressive muscle relaxation training on manual motor performance of PD patients. No effect of intervention on motor performance was observed. Behavioral Relaxation Training (BRT) has been used to successfully manage tremor of two older adults; one with essential tremor (ET) and another with ET and PD (Chung et al., 1995). Chung et al reported decreased tremor severity and improved performance in activities of daily. Improved psychological adjustment was anecdotally reported. Lundervold (1997) reported that BRT and coping self-instructions were effective with an ET patient in reducing tremor severity related to negative arousal (anger in specific social situations). Decreased emotional distress and EMG activity among four muscle groups was observed. More recently, Lundervold, Pahwa and Lyons (2009) reported using behavioral intervention that included BRT for management of PD and comorbid general anxiety. Two contemporary behavioral accounts describe anxiety and distress among movement disorder patients (Lundervold & Poppen, 2004; Macht & Ellgring, 1998). These reports describe a three component behavioral model. From a behavioral perspective, identification of current maintaining contextual variables, (i.e., setting events, antecedents and consequences) is critical in selection appropriate interventions (Speigler & Guevremont, 2003). …

Carbidopa/levodopa enteral suspension (CLES; Duopa) is a suspension or gel formulation of carbidopa/levodopa that is approved by the USA Food and Drug Administration for the treatment of advanced Parkinson's disease patients with motor fluctuations. CLES is delivered at a constant rate continuously throughout the day into the jejunum through an infusion pump via a PEG-J tube implanted surgically. The efficacy of CLES was established in the USA based on a randomized, double-blind, double-dummy, active controlled, parallel group and 12-week study, in which mean daily OFF time was reduced by 4.0 h, compared to 1.9 h with oral immediate release carbidopa/levodopa. The CLES hardware consists of a cassette containing the drug, a pump to deliver the drug and tubing to connect the PEG-J to the pump. It is critical to understand the appropriate conversion of the carbidopa/levodopa daily dosages to the CLES dosage and how to program the pump and titrate CLES to achieve the most effective dose. We describe one methodology for patient selection, outpatient titration and pump programming.

The International Parkinson and Movement Disorder Society established a task force on tremor that reviewed the use of transducer-based measures in the quantification and characterization of tremor. Studies of accelerometry, electromyography, activity monitoring, gyroscopy, digitizing tablet-based measures, vocal acoustic analysis, and several other transducer-based methods were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and responsiveness were reviewed for each measure using the following criteria: (1) used in the assessment of tremor; (2) used in published studies by people other than the developers; and (3) adequate clinimetric testing. Accelerometry, gyroscopy, electromyography, and digitizing tablet-based measures fulfilled all three criteria. Compared to rating scales, transducers are far more sensitive to changes in tremor amplitude and frequency, but they do not appear to be more capable of detecting a change that exceeds random variability in tremor amplitude (minimum detectable change). The use of transducer-based measures requires careful attention to their limitations and validity in a particular clinical or research setting. © 2016 International Parkinson and Movement Disorder Society.

Background Dopamine agonist therapy and deep brain stimulation (DBS) of the subthalamic nucleus (STN) are antiparkinsonian treatments that act on a different part of the basal ganglia-thalamocortical motor circuitry, yet produce similar symptomatic improvements. Objective/Hypothesis The purpose of this study was to identify common and unique brain network features of these standard treatments. Methods We analyzed images produced by H 2 15 O positron emission tomography (PET) of patients with Parkinson’s disease (PD) at rest. Nine patients were scanned before and after injection of apomorphine, and 11 patients were scanned while bilateral stimulators were off and while they were on. Results Both treatments produced common deactivations of the neocortical sensorimotor areas, including the supplementary motor area, precentral gyrus, and postcentral gyrus, and in subcortical structures, including the putamen and cerebellum. We observed concomitant activations of the superior parietal lobule and the midbrain in the region of the substantia nigra/STN. We also detected unique, treatment-specific changes with possible motor-related consequences in the basal ganglia, thalamus, neocortical sensorimotor cortex, and posterolateral cerebellum. Unique changes in nonmotor regions may reflect treatment-specific effects on verbal fluency and limbic functions. Conclusions Many of the common effects of these treatments are consistent with the standard pathophysiologic model of PD. However, the common effects in the cerebellum are not readily explained by the model. Consistent deactivation of the cerebellum is interesting in light of recent reports of synaptic pathways directly connecting the cerebellum and basal ganglia, and may warrant further consideration for incorporation into the model.

Object The goal of this study was to evaluate short- and long-term benefits in quality of life (QOL) after unilateral deep brain stimulation (DBS) for essential tremor (ET). Methods Patients who received unilateral DBS of the ventral intermediate nucleus of the thalamus between 1997 and 2010 and who had at least 1 follow-up evaluation at least 1 year after surgery were included. Their QOL was assessed with the Parkinson Disease Questionnaire-39 (PDQ-39), and ET was measured with the Fahn-Tolosa-Marin tremor rating scale (TRS) prior to surgery and then postoperatively with the stimulation in the on mode. Results Ninety-one patients (78 at 1 year; 42 at 2–7 years [mean 4 years]; and 22 at > 7–12 years [mean 9 years]) were included in the analysis. The TRS total, targeted tremor, and activities of daily living (ADL) scores were significantly improved compared with presurgical scores up to 12 years. The PDQ-39 ADL, emotional well-being, stigma, and total scores were significantly improved up to 7 years after surgery compared with presurgical scores. At the longest follow-up, only the PDQ-39 stigma score was significantly improved, and the PDQ-39 mobility score was significantly worsened. Conclusions Unilateral thalamic stimulation significantly reduces ET and improves ADL scores for up to 12 years after surgery, as measured by the TRS. The PDQ-39 total score and the domains of ADL, emotional well-being, and stigma were significantly improved up to 7 years. Although scores were improved compared with presurgery, other than stigma, these benefits did not remain significant at the longest (up to 12 years) follow-up, probably related in part to changes due to aging and comorbidities.

Defined as the transient state between standing and walking, gait initiation is negatively affected in Parkinson's disease (PD), which often results in significant disability. Although deep brain stimulation (DBS) is the most common surgical procedure for PD, the long-term effects of DBS on gait initiation are not well studied. The present study evaluated the long-term effects of subthalamic nucleus (STN) DBS on the preparation phase of gait initiation using principal component (PC) analysis. Six patients with PD who had undergone STN DBS and 24 healthy control subjects were evaluated. PD subjects were assessed 11.3 ± 10.3 (P1) and 78.9 ± 10.6 (P2) months after surgery. PD subjects were tested with STN DBS in two conditions: without medication and with medication. PC analysis was applied separately for the vertical, anterior–posterior and medial–lateral components of ground reaction force (GRF) recorded during gait initiation. Three PC scores were chosen by the scree test for each GRF component and all these PC scores were used for calculating a standard distance between healthy controls and PD subjects. The Friedman test showed a significant difference in standard distance among conditions ( P = 0.004), with the post-hoc test recognizing differences among P1 conditions and P2 medication-on condition. The eigenvector loading factors pointed to major differences between PD conditions surrounding the maximum amplitude of vertical and anterior–posterior GRF. For the studied sample, all distances increased in the follow-up evaluation (P2) with and without medications, indicating a worsening in gait initiation after seven years.

Summary Background The effects of constant-current deep brain stimulation (DBS) have not been studied in controlled trials in patients with Parkinson's disease. We aimed to assess the safety and efficacy of bilateral constant-current DBS of the subthalamic nucleus. Methods This prospective, randomised, multicentre controlled trial was done between Sept 26, 2005, and Aug 13, 2010, at 15 clinical sites specialising in movement disorders in the USA. Patients were eligible if they were aged 18–80 years, had Parkinson's disease for 5 years or more, and had either 6 h or more daily off time reported in a patient diary of moderate to severe dyskinesia during waking hours. The patients received bilateral implantation in the subthalamic nucleus of a constant-current DBS device. After implantation, computer-generated randomisation was done with a block size of four, and patients were randomly assigned to the stimulation or control group (stimulation:control ratio 3:1). The control group received implantation without activation for 3 months. No blinding occurred during this study, and both patients and investigators were aware of the treatment group. The primary outcome variable was the change in on time without bothersome dyskinesia (ie, good quality on time) at 3 months as recorded in patients' diaries. Patients were followed up for 1 year. This trial is registered with ClinicalTrials.gov, number NCT00552474. Findings Of 168 patients assessed for eligibility, 136 had implantation of the constant-current device and were randomly assigned to receive immediate (101 patients) or delayed (35 patients) stimulation. Both study groups reported a mean increase of good quality on time after 3 months, and the increase was greater in the stimulation group (4·27 h vs 1·77 h, difference 2·51 [95% CI 0·87–4·16]; p=0·003). Unified Parkinson's disease rating scale motor scores in the off-medication, on-stimulation condition improved by 39% from baseline (24·8 vs 40·8). Some serious adverse events occurred after DBS implantation, including infections in five (4%) of 136 patients and intracranial haemorrhage in four (3%) patients. Stimulation of the subthalamic nucleus was associated with dysarthria, fatigue, paraesthesias, and oedema, whereas gait problems, disequilibrium, dyskinesia, and falls were reported in both groups. Interpretation Constant-current DBS of the subthalamic nucleus produced significant improvements in good quality on time when compared with a control group without stimulation. Future trials should compare the effects of constant-current DBS with those of voltage-controlled stimulation. Funding St Jude Medical Neuromodulation Division.

Purpose The primary purpose was to demonstrate the feasibility of executing treatment tasks focused on increasing loudness in a group format for individuals with Parkinson's disease (PD). A second purpose was to report preliminary pre-to-post treatment outcomes for individuals with PD immediately after they complete the group program. Methods The group intervention is described. Fifteen adults with PD who participated in the group and three clinicians leading the group provided feedback about the execution of the intervention. The participants also provided voice samples and self-ratings of voice handicap once before completing the 8-week voice group and once immediately after completing the voice group. Outcome measures included voice intensity, fundamental frequency (F0) mean, standard deviation and range, maximum phonation time, and listener judgment of loudness. Results Feedback from the clinicians suggested that many, but not all, of the voice activities could be executed within a group setting. Participants with PD indicated they understood the focus of the group and that subjectively they felt the group was helpful for increasing loudness. Statistically significant increases occurred for voice intensity, F0 maximum, and F0 range. Voice handicap scores decreased significantly and 80% of the participants were judged louder post intervention. Conclusions Clinician and participant feedback indicated that it was feasible to execute most LSVT ® tasks in a group format with some modifications. The preliminary outcome data indicate that the targeted behavior (voice dB and loudness) did change in the predicted direction as did several other measures. Future studies comparing outcomes of group intervention to the gold standard LSVT ® , and exploring retention of treatment gains over time, are needed. Learning outcomes: After reading the manuscript, readers will be able to: (1) Describe previous attempts at group intervention to improve voice for individuals with Parkinson's disease. (2) List three ways that the group intervention tried in this study differed from LSVT ® . (3) Identify three limitations to this study that must be addressed before advocating implementation of the group approach in clinical situations.

Health-related quality of life is an im- portant patient-reported outcome used in intervention tri- als and for monitoring the consequences of health status on physical, mental, and social domains. Parkinson's dis- ease is a complex disorder that strongly affects patients' quality of life. Several health-related quality of life tools have been used in Parkinson's disease. A Movement Disorder Society Task Force was commissioned to rate the psychometric quality of available health-related qual- ity of life scales as applied to Parkinson's disease. Fol- lowing the methodology adopted by previous work of the Movement Disorder Society Task Force, a review of generic and specific health-related quality of life scales applied in studies on Parkinson's disease was com- pleted. Considering the scales from 3 perspectives—use in Parkinson's disease, use by multiple research groups, and clinimetric properties—a final classification as ''rec- ommended,'' ''suggested,'' or ''listed'' was applied to each reviewed instrument. Four generic scales (EuroQoL, Nottingham Health Profile, 36-Item Short-Form Health Survey, and Sickness Impact Profile) and 5 specific scales (39-Item Parkinson's Disease Questionnaire, Par- kinson's Disease Questionnaire Short Form, Parkinson's Disease Quality of Life Questionnaire, Parkinson's Impact Scale, and Scales for Outcomes in Parkinson's Disease- Psychosocial) reached the level of ''recommended.'' The 39-item Parkinson's Disease Questionnaire is the most thoroughly tested and applied questionnaire. Three other generic measures (Quality of Life Questionnaire 15D, Schedule for the Evaluation of Individual Quality of Life- Direct Weighting, and World Health Organization Quality of Life Assessment Short Version) and the specific Parkin- son's Disease Quality of Life Scale are ''suggested.'' With a little additional effort in completing the stipulated require- ments, they could reach the ''recommended'' level. At present there is a wide variety of health-related quality of life measures for application in the Parkinson's disease setting, and the task force does not recommend the devel- opment of a new scale. Selection of the most appropriate instrument for a particular objective requires consideration of the characteristics of each scale and the goals of the assessment. V C 2011 Movement Disorder Society

Item does not contain fulltext OBJECTIVES: To explore current practices and opinions regarding hospital management of Parkinson disease (PD) patients in specialized PD Centers. METHODS: Fifty-one out of 54 National Parkinson Foundation (NPF) Centers worldwide completed an online survey regarding hospitalization of PD patients. RESULTS: Many Centers were concerned about the quality of PD-specific care provided to their patients when hospitalized. Primary concerns were adherence to the outpatient medication schedule and poor understanding by hospital staff of medications that worsen PD. Few Centers had a policy with their primary hospital that notified them when their patients were admitted. Rather, notification of hospitalization came often from the patient or a family member. Several Centers (29%) reported not finding out about a hospitalization until a routine clinic visit after discharge. Quick access to outpatient PD care following discharge was a problem in many Centers. Elective surgery, fall/fracture, infection, and mental status changes, were identified as common reasons for hospitalization. CONCLUSIONS: There is a perceived need for PD specialists to be involved during hospitalization of their patients. Improvement in communication between hospitals and PD Centers is necessary so that hospital clinicians can take advantage of PD specialists' expertise. Education of hospital staff and clinicians regarding management of PD, complications of PD, and medications to avoid in PD is critical. Most importantly, outpatient access to PD specialists needs to be improved, which may prevent unnecessary hospitalizations in these patients.

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component., T.G. serves as an editorial board member of Movement Disorders and Parkinsonism and Related Disorders and is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society) and the European Community (MeFoPa, Medndelian Forms of Parkinsonism). T.G. received speakers honoraria from Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim and Valeant Pharma and royalties for his consulting activities from Cefalon Pharma and Merck-Serono. T.G. holds a patent concerning the LRRK2 gene and neurodegenerative disorders. J.H. is consulting for Merck Serono and Eisai. I.Litvan is the founder of the Litvan Neurological Research Foundation, whose mission is to increase awareness, determine the cause/s and search for a cure for neurodegenerative disorders presenting with either parkinsonian or dementia symptoms (501c3).

Purpose Adequate velopharyngeal control is essential for speech, but may be impaired in Parkinson's disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on velopharyngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of velopharyngeal control, and whether these changes were correlated with limb function and stimulation settings. Methods Seventeen PD participants with bilateral STN DBS were tested within a morning session after a minimum of 12 h since their most recent dose of anti-PD medication. Testing occurred when STN DBS was on, and again 1 h after STN DBS was turned off, and included aerodynamic measures during syllable production, and standard neurological ratings of limb function. Results We found that PD participants exhibited changes with STN DBS, primarily consistent with increased intraoral pressure ( n = 7) and increased velopharyngeal closure ( n = 5). These changes were modestly correlated with measures of limb function, and were correlated with stimulation frequency. Conclusion Our findings suggest that STN DBS may change velopharyngeal control during syllable production in PD, with greater benefit associated with low frequency stimulation. However, DBS demonstrates a more subtle influence on speech-related velopharyngeal control than limb motor control. This distinction and its underlying mechanisms are important to consider when assessing the impact of STN DBS on PD. Learning outcomes: As a result of this activity, the participant will be able to (1) describe the effects of deep brain stimulation on limb and speech function; (2) describe the effects of deep brain stimulation on velopharyngeal control; and (3) discuss the possible reasons for differences in limb outcomes compared with speech function with deep brain stimulation of the subthalamic nucleus.

Evaluation of: Olanow CW, Kieburtz K, Odin P et al. Continuous intrajejunal infusion of levodopa–carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol . 13(2), 141–149 (2014). Levodopa-induced motor complications, including motor fluctuations and dyskinesia, can be a major source of disability for Parkinson’s disease patients. The development of levodopa-induced motor complications has been attributed to the pulsatile dopaminergic stimulation characteristic of conventional oral levodopa regimens. This is a review of a 12-week, randomized, controlled, double-blind, double-dummy study of continuous jejunal infusion of levodopa–carbidopa intestinal gel to determine if the continuous infusion of levodopa reduces motor complications in Parkinson’s disease. Results demonstrated that levodopa–carbidopa intestinal gel significantly reduced off-time without increasing troublesome dyskinesia compared with standard oral levodopa therapy. Adverse effects were common in both the levodopa–carbidopa intestinal gel and placebo groups and were related primarily to the infusion hardware.

While the use of deep brain stimulation (DBS) for the treatment of neurological disorders has risen substantially over the last decade, it is often difficult to compare the results from different studies due to the lack of consistent reporting of key study parameters. We present guidelines to standardize the reporting of clinical studies of DBS for Parkinson's disease (PD). These guidelines provide a minimal set of required data elements to facilitate the interpretation and comparison of results across published clinical studies. The guidelines, summarized in the format of a checklist, may also have utility in the planning of clinical studies of DBS for PD as well as other neurological and psychiatric disorders.

The objective of this study was to examine the experience with and safety of brain 1.5 Tesla (T) magnetic resonance imaging (MRI) in deep brain stimulation (DBS) patients. This was a retrospective review of brain MRI scanning performed on DBS patients at the University of Kansas Medical Center between January 1995 and December 2007. A total of 249 DBS patients underwent 445 brain 1.5 T MRI scan sessions encompassing 1,092 individual scans using a transmit-receive head coil, representing the cumulative scanning of 1,649 DBS leads. Patients with complete implanted DBS systems as well as those with externalized leads underwent brain imaging. For the majority of scans, specific absorption rates localized to the head (SAR(H)) were estimated and in all cases SAR(H) were higher than that specified in the present product labeling. There were no clinical or hardware related adverse events secondary to brain MRI scanning. Our data should not be extrapolated to encourage MRI scanning beyond the present labeling. Rather, our data may contribute to further defining safe MRI scanning parameters that might ultimately be adopted in future product labeling as more centers report in detail their experiences.

Deep brain stimulation of the subthalamic nucleus (DBS-STN) is an approved treatment for advanced Parkinson disease (PD) patients; however, there is a need to further evaluate its effect on gait. This study compares logistic regression (LR), probabilistic neural network (PNN) and support vector machine (SVM) classifiers for discriminating between normal and PD subjects in assessing the effects of DBS-STN on ground reaction force (GRF) with and without medication. Gait analysis of 45 subjects (30 normal and 15 PD subjects who underwent bilateral DBS-STN) was performed. PD subjects were assessed under four test conditions: without treatment (mof-sof), with stimulation alone (mof-son), with medication alone (mon-sof), and with medication and stimulation (mon-son). Principal component (PC) analysis was applied to the three components of GRF separately, where six PC scores from vertical, one from anterior-posterior and one from medial-lateral were chosen by the broken stick test. Stepwise LR analysis employed the first two and fifth vertical PC scores as input variables. Using the bootstrap approach to compare model performances for classifying GRF patterns from normal and untreated PD subjects, the first three and the fifth vertical PCs were attained as SVM input variables, while the same ones plus the first anterior-posterior were selected as PNN input variables. PNN performed better than LR and SVM according to area under the receiver operating characteristic curve and the negative likelihood ratio. When evaluating treatment effects, the classifiers indicated that DBS-STN alone was more effective than medication alone, but the greatest improvements occurred with both treatments together.

Rotigotine is a highly lipophilic dopamine-receptor agonist and the first transdermally delivered agent to demonstrate efficacy and safety as monotherapy in early Parkinson's disease and to reduce "off" hours in levodopa-treated patients with advanced Parkinson's disease. The rotigotine pharmacophore is nonergolinic and demonstrates high affinity for dopamine D(2) and D(3) receptors. With once-daily application, the patch matrix provides continuous, nonfluctuating plasma drug levels at steady state, resulting in continuous and steady plasma and brain levels and striatal dopamine-receptor stimulation. In early Parkinson's disease, doses of rotigotine up to 8 mg/24 hours demonstrate comparable efficacy to ropinirole (at doses up to 12 mg/day); in advanced Parkinson's disease, doses of rotigotine up to 16 mg/24 hours demonstrate comparable efficacy and tolerability to pramipexole (at doses up to 4.5 mg/day). In the registration trials for early and advanced Parkinson's disease, the adverse effects most commonly observed with rotigotine were minor application site reactions, dizziness, nausea, and somnolence. Doses of transdermal rotigotine can be titrated to a maintenance dose within 2-3 weeks, and the once-daily regimen minimizes complexity of therapy. The transdermal delivery system is also an advantage when nonoral administration is desired, and the 24-hour, continuous, nonfluctuating drug levels can improve early morning and nocturnal symptoms of Parkinson's disease. Thus, transdermally delivered rotigotine is a clinically innovative and useful addition to the dopamine-receptor agonist class. This review summarizes the key pharmacologic and clinical data for rotigotine and provides a focused clinical context for its use in early-to-advanced Parkinson's disease, as well as a brief summary for its role in restless legs syndrome.

Background—Purkinje cell axonal swellings (“torpedoes”), described in several cerebellar disorders as well as essential tremor (ET), have not been quantified in common neurodegenerative conditions.

As no comprehensive assessment instrument for impulse control disorders (ICDs) in Parkinson's disease (PD) exists, the aim of this study was to design and assess the psychometric properties of a self-administered screening questionnaire for ICDs and other compulsive behaviors in PD. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) has 3 sections: Section 1 assesses four ICDs (involving gambling, sexual, buying, and eating behaviors), Section 2 other compulsive behaviors (punding, hobbyism, and walkabout), and Section 3 compulsive medication use. For validation, a convenience sample of 157 PD patients at 4 movement disorders centers first completed the QUIP, and then was administered a diagnostic interview by a trained rater blinded to the QUIP results. A shortened instrument (QUIP-S) was then explored. The discriminant validity of the QUIP was high for each disorder or behavior (receiver operating characteristic area under the curve [ROC AUC]: gambling = 0.95, sexual behavior = 0.97, buying = 0.87, eating = 0.88, punding = 0.78, hobbyism = 0.93, walkabout = 0.79). On post hoc analysis, the QUIP-S ICD section had similar properties (ROC AUC: gambling = 0.95, sexual behavior = 0.96, buying = 0.87, eating = 0.88). When disorders/behaviors were combined, the sensitivity of the QUIP and QUIP-S to detect an individual with any disorder was 96 and 94%, respectively. Scores on the QUIP appear to be valid as a self-assessment screening instrument for a range of ICDs and other compulsive behaviors that occur in PD, and a shortened version may perform as well as the full version. A positive screen should be followed by a comprehensive, clinical interview to determine the range and severity of symptoms, as well as need for clinical management.

Controlled-release carbidopa and levodopa (CL-CR) and the combination of carbidopa, levodopa, and entacapone (CLE) are used for extending levodopa (L-dopa) effects. In a randomized, open-label crossover study of 17 PD subjects with wearing-off responses, we compared 8-hour L-dopa pharmacokinetics (PK) and clinical effects after two doses of CL-CR (50 and 200 mg, respectively) and CLE (37.7, 150, 200 mg, respectively). PK analysis revealed the anticipated near-equivalent mean L-dopa area-under-the-concentration-curve values (639,490 ng min/mL for two doses of CLE, and 662,577 for CL-CR, P = 0.86). The mean hourly fluctuation index for L-dopa concentration was 235% for CLE and 196% for CL-CR (P = 0.004). The mean maximal concentration for the first CLE dose was 1,926 +/- 760 ng/mL and for CL-CR, 1,840 +/- 889 (P = 0.33). During the PK studies, the mean time that L-dopa concentration was > or =1,000 ng/mL for CLE was 291 +/- 88 minutes and for CL-CR, 306 +/- 86 (P = 0.33). The mean percent-time in "off" state was 18% for CLE and 28% for CL-CR (P = 0.017), "on state without dyskinesia" was 64% for CLE and 65% for CL-CR (P = 0.803), and "on state with nontroublesome dyskinesia" was 18% for CLE and 7% for CL-CR (P = 0.03). Despite less "off" time with CLE, both formulations demonstrated similar mean PK values and marked intersubject PK variability.

Muhammad M Nashatizadeh, Kelly E Lyons, Rajesh PahwaDepartment of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USAAbstract: Ropinirole prolonged release is a once-daily, 24-hour formulation of ropinirole, a non-ergot dopamine agonist. It is approved as monotherapy and as an adjunct to levodopa in the treatment of Parkinson’s disease (PD). Several potential advantages of ropinirole prolonged release compared to the immediate release formulation include maintaining more consistent dopaminergic activity with steadier plasma levels, increased tolerability, greater compliance from a simpler once-daily dosing regimen and ease in dose titration. In a randomized, double-blind, non-inferiority, crossover study, ropinirole prolonged release was shown to have comparable efficacy and tolerability to immediate release ropinirole in early PD patients, with significantly greater compliance. Subjects were converted overnight between ropinirole formulations without loss of efficacy and with good tolerability. In a randomized, double-blind, placebo-controlled study in advanced PD, daily “off” time was reduced by an average of 2.1 hours with ropinirole prolonged release compared to 0.4 hours with placebo. Patients on ropinirole prolonged release were also more likely to require less daily levodopa. Ropinirole prolonged release is well tolerated with a similar adverse effect profile to other non-ergot dopamine agonists. The most common adverse effects include dyskinesia, nausea, dizziness, hallucinations, somnolence, abdominal pain or discomfort and orthostatic hypotension. Ropinirole prolonged release is a safe and effective treatment option for both early and advanced PD. This manuscript briefly reviews the current pharmacological treatment options for PD and provides a more detailed review of the currently available data regarding ropinirole prolonged release as a treatment option for PD.Keywords: ropinirole prolonged release, ropinirole PR, dopamine agonist, Parkinson’s disease, once-daily treatment

The objective of this study was to evaluate the safety, tolerability, and preliminary efficacy of intravenous glutathione in Parkinson's disease (PD) patients. This was a randomized, placebo-controlled, double-blind, pilot trial in subjects with PD whose motor symptoms were not adequately controlled with their current medication regimen. Subjects were randomly assigned to receive intravenous glutathione 1,400 mg or placebo administered three times a week for 4 weeks. Twenty-one subjects were randomly assigned, 11 to glutathione and 10 to placebo. One subject who was assigned to glutathione withdrew from the study for personal reasons prior to undergoing any postrandomization efficacy assessments. Glutathione was well tolerated and there were no withdrawals because of adverse events in either group. Reported adverse events were similar in the two groups. There were no significant differences in changes in Unified Parkinson's Disease Rating Scale (UPDRS) scores. Over the 4 weeks of study medication administration, UPDRS ADL + motor scores improved by a mean of 2.8 units more in the glutathione group (P = 0.32), and over the subsequent 8 weeks worsened by a mean of 3.5 units more in the glutathione group (P = 0.54). Glutathione was well tolerated and no safety concerns were identified. Preliminary efficacy data suggest the possibility of a mild symptomatic effect, but this remains to be evaluated in a larger study.

The management of early Parkinson’s disease (PD) involves the treatment of motor symptoms and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews motor symptom efficacy data for the newest PD treatment options, as well as for established therapies. Safety and tolerability data are also reviewed. Part 2 of the article reviews key findings relevant to the assessment of potential neuroprotective therapies and the treatment of non-motor symptoms.

A multiple-baseline, across-behaviors experimental design was used to evaluate the effects of a multicomponent behavioral intervention for anxiety secondary to Parkinson's disease (PD). A 67-year-old man with an 18-year history of PD, a 13-year history of anxiety, and meeting DSM-IV-TR criteria for general anxiety disorder (GAD) took part in the study. Dependent variables were the Clinical Anxiety Scale (CAS), Subjective Unit of Discomfort (SUD) ratings, and the Behavioral Relaxation Scale, a direct observation measure of relaxed behavior. Systematic increases in relaxed behavior with corresponding reductions in SUD ratings and CAS scores were obtained following Behavioral Relaxation Training (BRT). Further decreases in SUD ratings occurred following BRT + Imagery and BRT + Coping. Generalization assessment of relaxed behavior in the home environment indicated 78% relaxed. Social validity ratings, obtained by a “blinded” rater during neuropsychological assessment, indicated the patient was as “calm as oth...

Despite its being one of the most commonly observed neurological disorders, neuropathological studies of essential tremor (ET) are rare. There have been surprisingly few autopsy studies and even fewer case-control comparisons. The primary objective was to describe and quantify the pathological changes in 33 ET and 21 control brains. A secondary objective was to correlate clinical and pathological features. We examined autopsy tissue from the Essential Tremor Centralized Brain Repository. Eight (24.2%) of the 33 ET brains had Lewy bodies in the brainstem, mainly in the locus ceruleus. However, the majority of ET brains (25/33, 75.8%) had no Lewy bodies, but had pathological changes in the cerebellum. The mean number of Purkinje cells per 100x field was reduced in ET cases without Lewy bodies (6.6 +/- 2.4 versus 9.6 +/- 3.4, P0.01), and there were approximately 7x more Purkinje cell torpedoes per section (12.6 +/- 7.9 versus 1.7 +/- 1.4, P0.001) compared to controls. ET cases without Lewy bodies also had degeneration of the dentate nucleus (two cases). Other findings in ET cases were Purkinje cell heterotopias and dendrite swellings. Lewy body ET cases were older than ET cases without Lewy bodies. Several trends were observed in ET cases without Lewy bodies, including a younger age of onset of tremor and higher proportions with gait difficulty and family history of ET. The pathological changes of ET seem to be heterogeneous and degenerative. The majority have cerebellar changes without Lewy bodies; a smaller proportion has brainstem Lewy bodies. The clinical differences between cases with versus without Lewy bodies require additional study.

Background: In patients experiencing motor fluctuations, a major treatment challenge is the reduction of “off” time, particularly upon awakening. Rotigotine (Neupro) is a novel dopaminergic agonist with 24-hour transdermal delivery. Methods: A randomized, double-blind, placebo-controlled trial (PREFER Study) was performed to assess efficacy and safety with two targeted transdermal doses of rotigotine in subjects with advanced Parkinson disease with ≥2.5 hours of daily “off” time. Subjects were randomized to receive placebo patches (n = 120) or rotigotine up to either 8 mg/24 hours (n = 120) or 12 mg/24 hours (n = 111). The primary efficacy measures compared changes from baseline to the end of week 24 in the number of daily hours “off” and responder rates for subjects achieving ≥30% reduction in “off” time. Results: Compared to placebo, there were significant decreases in mean “off” time of 1.8 hours/day for the rotigotine 8 mg/24 hours group and 1.2 hours/day for the 12 mg/24 hours group. For rotigotine 8 and 12 mg/24 hours groups, ≥30% responder rates were 56.6% and 55.1% compared to the 34.5% placebo response. “On” time without dyskinesia after awakening was more than doubled in both rotigotine treatment groups vs placebo. Drug-related adverse effects included typical dopaminergic side effects, which were generally mild/moderate in intensity. Patch application site reactions including erythema and pruritus were mild to moderate and transient in the majority of instances. Conclusions: Transdermal rotigotine significantly improved “off” time in subjects with Parkinson disease not optimally controlled with levodopa and was safe and well tolerated, with typical dopaminergic side effects and occasional application site reactions.

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

Levodopa responsiveness has been shown to be the best predictor of improvement after subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson’s disease (PD). The objective of this study was to assess the effect of STN DBS on PD patients intolerant to levodopa due to severe acute side effects such as intolerable nausea. There were 10 patients in the study who received STN DBS for PD. Five patients who were intolerant to levodopa were matched based on age, disease duration, sex and presurgical disease severity to 5 patients taking levodopa and demonstrating a good levodopa response. Both groups had a significant improvement in Unified Parkinson’s Disease Rating Scale activities of daily living and motor subscales as well as tremor, rigidity and bradykinesia scores at 3, 6 and 12 months after surgery compared to baseline, and these improvements were equivalent between the two groups. Patient global ratings also indicated significant improvements at all follow-up visits. There were no differences in stimulator settings between the two groups at the 3-, 6- or 12-month follow-up visits. In conclusion, although levodopa responsiveness is the best predictor for outcome after STN DBS, carefully selected PD patients intolerant to levodopa can have significant improvement.

This introductory chapter gives a brief overview of the book Deep Brain Stimulation Management, touching on the key topics pertaining to use of deep brain stimulation (DBS) for clinicians. DBS has evolved as an important and established treatment for movement disorders, and new indications for DBS in the treatment of neurological and psychiatric disorders are emerging. It uses a device with three implantable components: quadripolar brain lead(s), neurostimulator(s), and extension wire(s). There are three major movement disorders for which DBS is indicated: essential tremor, Parkinson's disease, and dystonia. DBS is a chronic neuromodulation therapy and not a surgical treatment. The chapter also gives an overview of how other chapters in this book are organized. This book serves as a practical reference, a "go to" guide to be kept in the clinic and consulted in the course of managing patients being considered for or treated with DBS.

To determine if the non-motor sections of the Movement Disorder Society's (MDS) version of the Unified Parkinson's Disease Rating Scale (UPDRS) could supplement the original UPDRS as a patient completed assessment of changes in non-motor symptoms in Parkinson's disease (PD) patients after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS).Thirty PD patients who underwent bilateral STN DBS were assessed using the total UPDRS and the non-motor sections of the MDS-UPDRS prior to surgery and one year following surgery. This study focuses on non-motor symptoms as assessed by Part I of the UPDRS and Part 1A and 1B of the MDS-UPDRS.One year following surgery, no individual non-motor symptoms or the total mentation score of the UPDRS were significantly changed. In comparison, the MDS-UPDRS showed significant improvements in sleep and urinary problems and a trend towards improvement in anxiety, constipation, daytime sleepiness, fatigue and pain.This study provides evidence that the MDS-UPDRS non-motor sections, when completed by the patients, can supplement the original version of the UPDRS as an effective method of measuring changes in non-motor symptoms after DBS. It also reinforces the benefits of bilateral STN DBS on non-motor symptoms of PD.

Contains fulltext : 153006.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To determine (1) the relationship between assisted timed Up and Go (TUG) performance and the Parkinson's Disease Questionnaire-39 (PDQ-39), and (2) whether adjusting the TUG score (adding time) improves the relationship between TUG performance and the PDQ-39 in persons with Parkinson disease (PD) who use assistive devices or push off, or both. DESIGN: Cross-sectional. SETTING: Twenty participating National Parkinson Foundation Centers of Excellence. PARTICIPANTS: Data were obtained from participants (N=6624) without exclusion at the 20 participating sites. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The relationship between TUG scores and PDQ-39 mobility scores was determined using the method of linear least squares. Adjusted scores were determined through minimizing the sum of the squared error. RESULTS: The correlation between assisted TUG scores and PDQ-39 mobility scores was slightly lower (R(2)=.384) compared with the correlation between nonassisted TUG scores and PDQ-39 mobility scores (R(2)=.409). Adjusting assisted TUG performance scores for push off and for use of an assistive device resulted in a modest increase in correlation (R(2)=.399). CONCLUSIONS: Applying adjustments to assisted TUG may provide clinically important information for evaluating balance, mobility, and falls, and for determining the most effective therapeutic strategies for persons with PD.

© 2015 The Authors. The proceedings of the 2nd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, and computational work on DBS for the treatment of neurological and neuropsychiatric disease and represent the insights of a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers and members of industry. Presentations and discussions covered a broad range of topics, including advocacy for DBS, improving clinical outcomes, innovations in computational models of DBS, understanding of the neurophysiology of Parkinson's disease (PD) and Tourette syndrome (TS) and evolving sensor and device technologies.

This study evaluates the effects of sequential tui na massage, acupuncture, and instrument-delivered qigong for patients with Parkinson disease (PD) over a 6-month period.Patients received weekly treatments, which included tui na massage prior to acupuncture followed by instrument-delivered qigong. Each patient was assessed at baseline and at 6 months.The setting was an outpatient research/academic clinic for patients with PD and nonacademic acupuncture clinic.Twenty-five (25) patients with idiopathic PD were the subjects.Before and after treatment patients were evaluated with the Unified Parkinson Disease Rating Scale (UPDRS), Hoehn and Yahr Staging (HY), Schwab and England Activities of Daily Living (SE), Beck Depression Inventory (BDI), Parkinson's Disease Questionnaire (PDQ-39) quality of life assessment, and patient global assessments.There were no significant improvements in treatment measures; however, there was a 2.4-point worsening in UPDRS motor scores (24.0 versus 26.4, p = 0.018). There was a 16% improvement in the PDQ- 39 total score (23.2 versus 19.6, p = 0.044) and a 29% improvement in the BDI (9.6 versus 6.8, p = 0.006). Sixteen (16) patients reported moderate to marked improvement. There were no adverse effects.Acupuncture is safe and well tolerated in patients with PD. Most patients reported subjective improvement. The BDI and PDQ-39 total score, measuring depression and quality of life, demonstrated some improvement, but UPDRS motor scores worsened.

Objective: To make evidence-based treatment recommendations for the medical and surgical treatment of patients with Parkinson disease (PD) with levodopa-induced motor fluctuations and dyskinesia. To that end, five questions were addressed. 1. Which medications reduce off time? 2. What is the relative efficacy of medications in reducing off time? 3. Which medications reduce dyskinesia? 4. Does deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus interna (GPi), or ventral intermediate (VIM) nucleus of the thalamus reduce off time, dyskinesia, and antiparkinsonian medication usage and improve motor function? 5. Which factors predict improvement after DBS?Methods: A 10-member committee including movement disorder specialists and general neurologists evaluated the available evidence based on a structured literature review including MEDLINE, EMBASE, and Ovid databases from 1965 through June 2004.Results, Conclusions, and Recommendations: 1. Entacapone and rasagiline should be offered to reduce off time (Level A). Pergolide, pramipexole, ropinirole, and tolcapone should be considered to reduce off time (Level B). Apomorphine, cabergoline, and selegiline may be considered to reduce off time (Level C). 2. The available evidence does not establish superiority of one medicine over another in reducing off time (Level B). Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C). 3. Amantadine may be considered to reduce dyskinesia (Level C). 4. Deep brain stimulation of the STN may be considered to improve motor function and reduce off time, dyskinesia, and medication usage (Level C). There is insufficient evidence to support or refute the efficacy of DBS of the GPi or VIM nucleus of the thalamus in reducing off time, dyskinesia, or medication usage, or to improve motor function. 5. Preoperative response to levodopa predicts better outcome after DBS of the STN (Level B).

Subthalamic nucleus (STN) deep brain stimulation (DBS) is currently the most common therapeutic surgical procedure for patients with Parkinson's disease (PD) who have failed medical management. However, a recent summary of clinical evidence on the effectiveness of STN DBS is lacking. We report the results of such a systematic review and meta-analysis. A comprehensive review of the literature using Medline and Ovid databases from 1993 until 2004 was conducted. Estimates of change in absolute Unified Parkinson's Disease Rating Scale (UPDRS) scores after surgery were generated using random-effects models. Sources of heterogeneity were explored with meta-regression models, and the possibility of publication bias was evaluated. Patient demographics, reduction in medication requirements, change in dyskinesia, daily offs, quality of life, and a ratio of postoperative improvement from stimulation compared to preoperative improvement by medication from each study were tabulated and average scores were calculated. Adverse effects from each study were summarized. Thirty-seven cohorts were included in the review. Twenty-two studies with estimates of standard errors were included in the meta-analysis. The estimated decreases in absolute UPDRS II (activities of daily living) and III (motor) scores after surgery in the stimulation ON/medication off state compared to preoperative medication off state were 13.35 (95% CI: 10.85-15.85; 50%) and 27.55 (95% CI: 24.23-30.87; 52%), respectively. Average reduction in L-dopa equivalents following surgery was 55.9% (95% CI: 50%-61.8%). Average reduction in dyskinesia following surgery was 69.1% (95% CI: 62.0%-76.2%). Average reduction in daily off periods was 68.2% (95% CI: 57.6%-78.9%). Average improvement in quality of life using PDQ-39 was 34.5% +/- 15.3%. Univariable regression showed improvements in UPDRS III scores were significantly greater in studies with higher baseline UPDRS III off scores, increasing disease duration prior to surgery, earlier year of publication, and higher baseline L-dopa responsiveness. Average baseline UPDRS III off scores were significantly lower (i.e., suggesting milder disease) in later than in earlier studies. In multivariable regression, L-dopa responsiveness, higher baseline motor scores, and disease duration were independent predictors of greater change in motor score. No evidence of publication bias in the available literature was found. The most common serious adverse event related to surgery was intracranial hemorrhage in 3.9% of patients. Psychiatric sequelae were common. Synthesis of the available literature indicates that STN DBS improves motor activity and activities of daily living in advanced PD. Differences between available studies likely reflect differences in patient populations and follow-up periods. These data provide an estimate of the magnitude of the treatment effects and emphasize the need for controlled and randomized studies.

A total of 956 individuals with Parkinson's disease (PD) from 430 multiplex PD pedigrees were screened for 12 previously reported, pathogenic LRRK2 mutations: R793M, L1114L, I1371V, R1441C, R1441G, R1441H, Y1699C, M1869T, I2012T, I2020T, G2385R, and IVS31 +3G > A. Previous screening identified the LRRK2 G2019S mutation in 5% of our families. Only 1 of the 12 newly screened mutations, R1441C, was detected in a single family in our patient cohort. These results indicate that, although the G2019S mutation remains the most common mutation identified in familial PD patients, other mutations in LRRK2 are infrequent.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective for the treatment of advanced Parkinson's disease. Most studies have evaluated the effectiveness of DBS of the STN using clinical motor scores or simple timed tests of motor function. There have been few studies that quantitatively assessed the outcome of STN DBS using multiple testing paradigms. In the current study, 11 patients who had bilateral STN DBS were quantitatively evaluated under four conditions using gait, postural control, and gait initiation. The four conditions included the medication on/stimulation on (M_on/S_on), medication on/stimulation off (M_on/S_off), medication off/stimulation on (M_off/S_on), and medication off/stimulation off (M_off/S_off) conditions. DBS of the STN significantly increased walking speed with and without levodopa, but had no influence on the cadence. The addition of levodopa had a minimal additional effect on walking speed. The effect of STN DBS on gait initiation approached the significant level. The mean values of lateral body sway during quiet standing increased moderately with medication and/or DBS, but the changes were not statistically significant. Future studies need to determine whether or not there is a potential negative effect of STN DBS on the postural control.

Background/Objective Essential tremor (ET) can diminish functioning and quality of life (QOL) but generic QOL measures may be relatively insensitive to ET and its therapies. We sought to develop an ET-specific measure that might be more sensitive, acceptable to patients, relatively brief, and easily used. Design/Methods A sample of 200 patients (average age 70 years, range 30–91; average disease duration 15 years) rated the extent to which tremor impacts a function or state, tremor severity in various body parts, perceived health, and overall QOL. Responses to this initial questionnaire were subjected to principal components analysis (PCA). Inspection of factor coordinates, Eigenvalues, variance accounted for, and correlation matrices were used to select items for confirmatory PCA. Final scale reliability was assessed using Cronbach's α. Validity was evaluated by correlations between QOL scales and self-rated tremor severity. Results PCA of 65 initial items yielded 11 factors accounting for 71% of variance. Six factors were discarded. Two items were eliminated for not loading on a factor and 33 for perceived redundancy. Confirmatory PCA of the retained 30 items yielded an almost identical factor structure (six factors, 70% of variance accounted for, and similar item loadings). Because two factors had very few items loading on them, these two factors were combined into one scale. The final measure has five scales: Physical, Psychosocial, Communication, Hobbies/Leisure, and Work/Finance. Reliability was excellent for the whole instrument and four scales (≥0.89), and good for the Work/Finance scale (0.79). Severity of voice and head tremor were the best correlates of Communication (0.70 and 0.35), while the Physical scale was related to right and left upper extremity tremor (0.59 and 0.56). Scales correlated more highly with patients' rating of their overall QOL than their health perception. Conclusions A brief, 30-item, ET-specific QOL scale with excellent reliability was developed. Preliminary validity data are encouraging. The Quality of Life in Essential Tremor Questionnaire (QUEST) promises to facilitate QOL measurement in ET.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which dopaminergic neurons are lost from the substantia nigra, causing basal ganglia dysfunction [1]. Resting tremor, bradykinesia, rigidity, and postural instability are the cardinal symptoms [2]. Levodopa is the most efficacious medication for PD [3]. Early in the course of PD, levodopa controls the primary motor symptoms and provides relief for nearly all patients. Initially, the effects of a single dose of levodopa last more than 4 hours. Over time, however, the drug eventually ceases to provide these relatively long and predictable symptom-free periods [4–6]. In addition, patients develop periods of involuntary choreic (twisting or turning) movements known as levodopainduced dyskinesias. Motor fluctuations and dyskinesias can become more disabling than the original PD symptoms. In moderate to advanced disease, patients may be afflicted by tremor, loss of mobility, dystonias, choreiform dyskinesias, episodes of ‘‘freezing,’’ and other motor symptoms [7]. Managing motor fluctuations and dyskinesias represents one of the major challenges of the long-term treatment of PD [7]. Recent research has led to many treatment innovations and strategies that provide patients with more

Throughout the past decade, there has been a marked increase in surgical therapies, primarily deep brain stimulation (DBS), for the treatment of advanced Parkinson's disease (PD). DBS of the thalamus has been shown to be effective in reducing parkinsonian tremor; however, it is not the treatment of choice for PD given the progression of other symptoms such as rigidity and bradykinesia. Stimulation of the globus pallidus or the subthalamic nucleus is safe and efficacious in the long-term treatment of all cardinal symptoms of PD, and they are currently the surgeries of choice. Serious adverse events with DBS can occur in 1% to 2% of patients, infection in 5% to 8% of patients, and hardware complications in approximately 25% of patients. Complications associated with DBS are related to the experience of the surgical center. Referring physicians and patients should be aware of the number of surgical procedures and complication rates of any prospective surgical center.

Ropinirole (Requip, GlaxoSmithKline) is a novel nonergoline dopamine D2 agonist indicated for the treatment of early and advanced Parkinson's disease. It is mainly metabolized by the liver and its elimination half-life is approximately 5.8 h. When used as monotherapy in early Parkinson's disease, ropinirole improves signs and symptoms of the disorder. When used as an adjunct to levodopa in advanced Parkinson's disease patients with motor fluctuations, ropinirole reduces off time and allows a reduction of levodopa dose. The initial use of ropinirole in early Parkinson's disease to which levodopa is added when necessary, has been demonstrated to lead to a lower incidence of dyskinesias compared with treatment with levodopa alone. An 18F-dihydroxyphenylalanine positron emission tomography study suggested the possibility that ropinirole could slow the progression of loss of dopamine neurons compared with treatment with levodopa but this remains to be proven. Side effects of ropinirole include nausea, somnolence, edema, orthostatic hypotension, hallucinations and dyskinesia. A once-daily formulation of ropinirole is currently in development that has the potential for greater convenience, improved tolerability and greater efficacy.

Parkinson's disease (PD) is a common neurodegenerative disorder in humans with wide variability in the age of disease onset. Although the disease has been thought previously to occur sporadically in most patients, there is increasing evidence of a genetic contribution to the disorder. Recently, a polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with sporadic and familial PD. In an effort to identify susceptibility genes for PD, we have collected 783 PD patients from 372 families and 397 healthy controls from 217 families. PD patients and healthy controls were genotyped for the intron 6 insertion polymorphism by BseRI restriction endonuclease digestion. No significant difference in either homozygosity or heterozygosity for the 7048G7049 (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as compared with the panel of healthy controls. Moreover, direct sequencing of exon 1 of the Nurr1 gene in PD patients failed to detect either of the two recently reported Nurr1 mutations identified in a small subset of a PD patient cohort. Taken together, these data suggest that genetic alteration at the Nurr1 locus is not a significant risk factor for the development of Parkinson's disease in our large sample of familial PD patients.

Background: Manganese is known to cause a parkinsonian syndrome similar clinically to Parkinson disease (PD). l-Dopa responsiveness is a hallmark of PD; however, l-dopa’s effect on manganese-induced parkinsonism is not well defined. Objective: To access the efficacy and safety of l-dopa therapy in a double-blind, randomized, placebo-controlled trial. Methods: Thirteen patients with manganese-induced parkinsonism were evaluated in a cross-over study with a modified Unified PD Rating Scale (UPDRS), timed walk test, tapping, and global clinical impression scores. Adverse reactions were assessed. Results: There was no significant difference between placebo and l-dopa for any measure: motor UPDRS, 27.4 vs 28.8; walk time, 16.6 seconds vs 17.7 seconds; tapping right hand, 69.5 vs 64.7; and tapping left hand, 66.8 vs 64.4. There were no differences in the global impression scores. Adverse reactions occurred similarly in the two groups, including headaches, drowsiness, and diarrhea. Conclusions: l-Dopa therapy is not effective for the management of parkinsonism in welders. l-dopa unresponsiveness may be useful to distinguish manganese-induced parkinsonism from Parkinson disease.