Article

The Unified Dyskinesia Rating Scale: Presentation and Clinimetric Profile

December 2008
Movement Disorders 23(16):2398-403

December 2008
23(16):2398-403

DOI:10.1002/mds.22341

Source
PubMed

Authors:

John Nutt

Oregon Health and Science University

Glenn T Stebbins

Rush University Medical Center

We developed and tested a rating scale aimed to capture the essential features of dyskinesia in Parkinson's disease (PD). Although several scales assess selected attributes of PD-dyskinesias, no comprehensive rating tool exists. Available rating scales were evaluated by the investigators and patient focus groups. Modifications were finalized into the Unified Dyskinesia Rating Scale (UDysRS). The UDysRS has four parts: I: Historical Disability (patient perceptions) of On-Dyskinesia impact (maximum 44 points); II: Historical Disability (patient perceptions) of Off-Dystonia impact (maximum 16 points); III: Objective Impairment (dyskinesia severity, anatomical distribution over seven body regions, and type (choreic or dystonic) based on four activities observed or video-recorded (28 points); IV: Objective Disability based on Part III activities (maximum 16 points). For clinimetric testing, 70 PD patients with all severities of dyskinesia were interviewed and videotaped. Twenty movement disorder experts rated the videotapes with the UDysRS. Internal consistency was examined with Cronbach's alpha. Inter- and intra-rater reliability was evaluated with generalized weighted and nonweighted Kappa coefficients, and intraclass correlation coefficients. Both subjective (Sections I and II) and objective (Sections III and IV) demonstrated high internal consistency (alpha: 0.915, 0.971). Interrater reliability for the objective sections was acceptable for all items and likewise for intrarater reliability except for right leg. Reliable factor structures were found for both subjective (six factors) and objective sections (five factors). The UDysRS is a clinimetrically sound rating scale for dyskinesia in PD, demonstrating acceptable levels of internal consistency and inter- and intra-rater reliability. Testing scale responsivity to treatment interventions is planned.

Clinically important change on the Unified Dyskinesia Rating Scale among patients with Parkinson's disease experiencing dyskinesia

Article

Full-text available

Oct 2022

Background The Unified Dyskinesia Rating Scale (UDysRS) evaluates dyskinesia in patients with Parkinson's disease (PD). A minimal clinically important change (MCIC)—the smallest change in a treatment outcome that a patient considers important—remains undefined for the UDysRS. Objective To utilize pivotal amantadine delayed-release/extended-release (DR/ER) trial data to derive MCICs for the UDysRS total score in patients with PD experiencing dyskinesia. Methods Pivotal trials included PD patients with ≥1 h daily ON time with troublesome dyskinesia and baseline scores ≥2 on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part IV, item 4.2. Patients randomized to amantadine DR/ER or placebo completed two consecutive 24-h diaries before each clinic visit and were evaluated during ON time with dyskinesia using the UDysRS, MDS-UPDRS, and Clinician Global Impression of Change (CGI-C). The UDysRS changes from baseline to week 12 were anchored to corresponding changes in MDS-UPDRS item 4.2 scores. A minimal clinically important improvement in the CGI-C and diary-reported ON time with troublesome dyskinesia (≥0.5 h) were supportive anchors. Receiver operating characteristic curves determined the UDysRS change values optimizing sensitivity and specificity to at least minimal improvement on each anchor. Results The analyses included 196 patients. Week 12 UDysRS total score reduction of ≥8 points corresponded to at least minimal MDS-UPDRS item 4.2 improvement. UDysRS reduction of ≥9 points corresponded to decreased ON time with troublesome dyskinesia of ≥0.5 h per patient diaries, and UDysRS reduction of ≥10 points corresponded to at least minimal improvement on the CGI-C. Conclusion Anchored to the MDS-UPDRS Part IV, item 4.2, an 8-point reduction in the UDysRS total score can be considered an MCIC for PD patients with dyskinesia.

Classification of neurodegenerative disorders using machine learning techniques

Chapter

Sep 2022

According to the World Health Organization, neurodegenerative diseases such as Huntington's disease, Parkinson's disease, progressive brain dysfunction, vascular dementia, cognitive impairment, Alzheimer's disease, and Amyotrophic Lateral Sclerosis account for more than seven million deaths and morbidity of one billion people worldwide, making research on a variety of neurodegenerative diseases particularly important. Several improvements in neuroimaging data acquisition approaches such as diffusion Magnetic Resonance and data mining from electroencephalogram are channeled toward classification of different neurodegenerative diseases and treatment options. Though, several challenges are encountered in the proper diagnosis, analysis, and classification of these neurodegenerative disorders such as increased dimensionality, nonlinearity, and nonstationarity. As a result, various machine learning approaches and algorithms such as reinforcement learning, semisupervised learning, unsupervised learning, supervised learning, deep learning, decision tree, BF tree, Bagging, Random Forest tree, RBF networks, and evolutionary learning are required to accurately classify and treat many of these neurodegenerative diseases. Several gait biomarkers, postural disorders, memory disorders, could be employed as quantitative assessment in early diagnosis and treatment strategies utilizing computer assisted diagnostic systems. Therefore, this chapter will focus on recent advances in the classification of neurodegenerative diseases utilizing machine learning algorithms.

A New Paradigm in Parkinson's Disease Evaluation With Wearable Medical Devices: A Review of STAT-ONTM

Article

Full-text available

Jun 2022

In the past decade, the use of wearable medical devices has been a great breakthrough in clinical practice, trials, and research. In the Parkinson's disease field, clinical evaluation is time limited, and healthcare professionals need to rely on retrospective data collected through patients' self-filled diaries and administered questionnaires. As this often leads to inaccurate evaluations, a more objective system for symptom monitoring in a patient's daily life is claimed. In this regard, the use of wearable medical devices is crucial. This study aims at presenting a review on STAT-ONTM, a wearable medical device Class IIa, which provides objective information on the distribution and severity of PD motor symptoms in home environments. The sensor analyzes inertial signals, with a set of validated machine learning algorithms running in real time. The device was developed for 12 years, and this review aims at gathering all the results achieved within this time frame. First, a compendium of the complete journey of STAT-ONTM since 2009 is presented, encompassing different studies and developments in funded European and Spanish national projects. Subsequently, the methodology of database construction and machine learning algorithms design and development is described. Finally, clinical validation and external studies of STAT-ONTM are presented.

Dyskinesia and Pain in Advanced Parkinson’s Disease: Post Hoc Analysis from the Phase 3b, Open-Label, Randomized DYSCOVER Study

Article

Full-text available

Feb 2024

The DYSCOVER study was a phase 3b, open-label, randomized trial (NCT02799381) that evaluated levodopa-carbidopa intestinal gel (LCIG) versus optimized medical treatment (OMT) in patients with Parkinson’s disease (PD) and a high burden of dyskinesia at baseline (defined as Unified Dyskinesia Rating Scale [UDysRS] total score ≥ 30). At week 12, patients receiving LCIG versus OMT experienced significant improvements in dyskinesia, pain, and health-related outcomes. The objective of this analysis was to examine correlations between dyskinesia, pain, and health-related outcomes in PD. This post hoc analysis assessed correlations between UDysRS, King’s Parkinson’s Disease Pain Scale (KPPS), 8-item Parkinson’s Disease Questionnaire (PDQ-8), Unified Parkinson’s Disease Rating Scale part II, Clinical Global Impression of Severity (CGI-S) or Change (CGI-C), and “On” time without troublesome dyskinesia at baseline and after 12 weeks of LCIG or OMT. Correlations were assessed by Pearson correlation coefficients (categorization: weak, r = 0.20–0.39; moderate, r = 0.40–0.59; strong, r ≥ 0.60). Among 61 patients, moderate-to-strong positive and significant correlations were observed between UDysRS and KPPS scores (baseline, r = 0.47; week 12 change from baseline [CFB], r = 0.63; all p < 0.001). UDysRS and KPPS scores had moderate-to-strong positive and highly significant correlations with PDQ-8 scores (baseline, r = 0.45 and 0.46, respectively; CFB, r = 0.54 and 0.64, respectively; all p < 0.001). Moderate positive and significant correlations were observed between UDysRS and CGI-S/CGI-C scores (baseline, r = 0.41; CFB, r = 0.47; all p < 0.001). In patients with high dyskinesia burden, positive correlations were observed between dyskinesia, pain, and health-related quality of life (HRQoL) at baseline. Improvements in dyskinesia and pain were associated with improvements in HRQoL, demonstrating the clinical burden of troublesome dyskinesia. Clinicaltrials.gov identifier NCT02799381.

Learning Spatio-Temporal Radon Footprints for Assessment of Parkinson’s Dyskinesia

Article

Full-text available

Feb 2024

Parkinson’s disease is a severe neurodegenerative disorder that leads to loss of control over various motor and mental functions. Its progression can be limited with medication, particularly through the use of levodopa. However, prolonged administration of levodopa often results in disorders independent of those caused by the disease. The detection of these disorders is based on the clinical examination of patients, through different type of activities and tasks, using the Unified Dyskinesia Rating Scale (UDysRS). In the present work, our aim is to develop a state-of-the-art assessment system for levodopa-induced dyskinesia (LID) using the joint coordinate data of a human skeleton body depicted on videotaped activities related to UDysRS. For this reason, we combine a robust mathematical method for encoding action sequences known as Spatio-temporal Radon Footprints (SRF) with a Convolutional Neural Network (CNN), in order to estimate dyskinesia’s ratings for six body parts. We introduce two different methodological approaches: Global SRF-CNN and Local SRF-CNN, based on the set of skeletal points used in the encoding scheme. A comparison between these approaches reveals that Local SRF-CNN demonstrates better performance than the Global one. Finally, Local SRF-CNN outperforms the state-of-the-art technique, on both tasks, for UDysRS dyskinesia assessment, using joint coordinate data of the human body, achieving an overall performance in mean RMSE value of 0.6198 for Drinking task and 0.4885 for Communication, compared to 0.6575 and 0.5175, respectively. This illustrates the ability of the proposed machine learning system to successfully assess LID.

Identification and quantitative assessment of motor complications in Parkinson’s disease using the Parkinson’s KinetiGraph™

Article

Full-text available

Aug 2023

Introduction Effective management and therapies for the motor complications of Parkinson’s disease (PD) require appropriate clinical evaluation. The Parkinson’s KinetiGraph™ (PKG) is a wearable biosensor system that can record the motion characteristics of PD objectively and remotely. Objective The study aims to investigate the value of PKG in identifying and quantitatively assessing motor complications including motor fluctuations and dyskinesia in the Chinese PD population, as well as the correlation with the clinical scale assessments. Methods Eighty-four subjects with PD were recruited and continuously wore the PKG for 7 days. Reports with 7-day output data were provided by the manufacturer, including the fluctuation scores (FS) and dyskinesia scores (DKS). Specialists in movement disorders used the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale-IV (MDS-UPDRS IV), the wearing-off questionnaire 9 (WOQ-9), and the unified dyskinesia rating scale (UDysRS) for the clinical assessment of motor complications. Spearman correlation analyses were used to evaluate the correlation between the FS and DKS recorded by the PKG and the clinical scale assessment results. Receiver operating characteristic (ROC) curves were generated to analyze the sensitivity and specificity of the FS and DKS scores in the identification of PD motor complications. Results The FS was significantly positively correlated with the MDS-UPDRS IV motor fluctuation (items 4.3–4.5) scores ( r = 0.645, p < 0.001). ROC curve analysis showed a maximum FS cut-off value of 7.5 to identify motor fluctuation, with a sensitivity of 74.3% and specificity of 87.8%. The DKS was significantly positively correlated with the UDysRS total score ( r = 0.629, p < 0.001) and the UDysRS III score ( r = 0.634, p < 0.001). ROC curve analysis showed that the maximum DKS cut-off value for the diagnosis of dyskinesia was 0.7, with a sensitivity of 83.3% and a specificity of 83.3%. Conclusion The PKG assessment of motor complications in the PD population analyzed in this study has a significant correlation with the clinical scale assessment, high sensitivity, and high specificity. Compared with clinical evaluations, PKG can objectively, quantitatively, and remotely identify and assess motor complications in PD, providing a good objective recording for managing motor complications.

Cross‐Cultural Differences in Patient Perceptions of Dyskinesia in Parkinson's Disease

Article

Jan 2023

Background: The prevalence of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) varies among geographical regions. Cultural differences in patient-based perceptions of LID have not been studied. Objective: We compared patient and clinician evaluations of LID severity across multiple cultures in patients with PD. Methods: The data set included the Unified Dyskinesia Rating (UDysRS) scores from 16 language translation programs (3566 patients). We defined the Perception Severity Index (PSI) as the ratio between normalized patient-based subjective ratings (UDysRS Part 1B) and normalized clinician examination (Parts 3 and 4) scores (Part 1B/Parts 3 + 4) and compared the PSI across languages. Results: The mean PSI for the Chinese language (2.16) was higher than those of all other languages, whereas the ratio for the Korean language (0.73) was lower than those for Japanese, German, Turkish, Greek, Polish, and Finnish languages (corrected P values <0.05). Conclusions: Culture, as represented by language, affects the subjective perception of LID and needs to be considered in multinational clinical PD trials on dyskinesia. © 2023 International Parkinson and Movement Disorder Society.

Doxycycline to treat levodopa-induced dyskinesias in Parkinson's disease: a preliminary study

Article

Full-text available

May 2023
ARQ NEURO-PSIQUIAT

Background: Levodopa-induced dyskinesia (LID) is a common motor complication of levodopa therapy in patients with Parkinson`s disease (PD). Doxycycline is a widely used and inexpensive tetracycline with anti-inflammatory properties. Objective: Evaluate the efficacy and safety of doxycycline in patients with PD and LID. Methods: This was an open-label, uncontrolled, single-arm, single-center, phase 2 proof-of-concept study in patients with PD with functional impact of dyskinesia, which used levodopa three times daily, in a movement disorders clinic in Brazil. Participants were treated with doxycycline 200 mg/day for 12 weeks, with evaluations at baseline, week 4, and week 12 of treatment. The primary outcome measure was the change from baseline in the Unified Dyskinesia Rating Scale (UDysRS) total score at week 12, evaluated by two blinded raters. Key secondary outcomes measures were OFF time and ON time with troublesome dyskinesia in the PD home diary. Results: Eight patients with PD were treated and evaluated. Doxycycline 200 mg/day reduced the UDysRS total score at week 12, compared with baseline (Friedman’s Χ2 = 9.6, p = 0.008). Further, doxycycline reduced the ON time with troublesome dyskinesia (Friedman’s Χ2 = 10.8, p = 0.004) without worsening parkinsonism. There were no severe adverse events, and dyspepsia was the commonest event. Conclusions: In this preliminary, open-label and uncontrolled trial, doxycycline was effective in reducing LID and safe after a 12-week treatment. Further well-designed placebo-controlled clinical trials with a longer duration and a larger number of participants are needed. Clinical Trial Registration: https://ensaiosclinicos.gov.br, identifier: RBR-1047fwbf

Altered domain-specific striatal functional connectivity in patients with Parkinson’s disease and urinary symptoms

Article

Full-text available

Apr 2024
J NEURAL TRANSM

Background In this study, we aimed at investigating the possible association of urinary symptoms with whole-brain MRI resting-state functional connectivity (FC) alterations from distinct striatal subregions in a large cohort of early PD patients. Methods Seventy-nine drug-naive PD patients (45 PD-urinary⁺/34 PD-urinary⁻) and 38 healthy controls (HCs) were consecutively enrolled. Presence/absence of urinary symptoms were assessed by means of the Nonmotor Symptom Scale - domain 7. Using an a priori connectivity-based domain-specific parcellation, we defined three ROIs (per each hemisphere) for different striatal functional subregions (sensorimotor, limbic and cognitive) from which seed-based FC voxel-wise analyses were conducted over the whole brain. Results Compared to PD-urinary⁻, PD-urinary⁺ patients showed increased FC between striatal regions and motor and premotor/supplementary motor areas as well as insula/anterior dorsolateral PFC. Compared to HC, PD-urinary⁺ patients presented decreased FC between striatal regions and parietal, insular and cingulate cortices. Conclusions Our findings revealed a specific pattern of striatal FC alteration in PD patients with urinary symptoms, potentially associated to altered stimuli perception and sensorimotor integration even in the early stages. These results may potentially help clinicians to design more effective and tailored rehabilitation and neuromodulation protocols for PD patients.

Fundamentals of deep brain stimulation for Parkinson's disease in clinical practice: part 1

Article

Full-text available

Apr 2024
ARQ NEURO-PSIQUIAT

Deep brain stimulation (DBS) is recognized as an established therapy for Parkinson's disease (PD) and other movement disorders in the light of the developments seen over the past three decades. Long-term efficacy is established for PD with documented improvement in the cardinal motor symptoms of PD and levodopa-induced complications, such as motor fluctuations and dyskinesias. Timing of patient selection is crucial to obtain optimal benefits from DBS therapy, before PD complications become irreversible. The objective of this first part review is to examine the fundamental concepts of DBS for PD in clinical practice, discussing the historical aspects, patient selection, potential effects of DBS on motor and non-motor symptoms, and the practical management of patients after surgery. Resumo Nas últimas três décadas, a estimulação cerebral profunda (ECP) se tornou um tratamento bem estabelecido para doença de Parkinson (DP) e outros transtornos do movimento. A eficácia a longo prazo na DP foi bem documentada para a melhora dos sintomas motores cardinais da DP e das complicações induzidas pelo uso do levodopa, como as flutuações motoras e as discinesias. O momento da seleção do paciente é crucial para se obter os benefícios ideais da ECP, antes que as complicações da DP se tornem irreversíveis. O objetivo desta primeira parte da revisão é examinar os conceitos fundamentais da ECP na prática clínica, discutindo os aspectos históricos, a seleção de pacientes, os potenciais efeitos da ECP nos sintomas motores e não motores da doença e o manejo prático dos pacientes após a cirurgia.

Efficacy of acupuncture (Jin’s three-needle) on motor symptoms and anxiety in patients with Parkinson’s disease: protocol for a multicentre, randomised, assessor-blinded clinical trial

Article

Full-text available

Mar 2024

Introduction Parkinson’s disease (PD) has a significant impact on a substantial number of individuals in China. Notably, 31% of patients with PD also grapple with the additional burden of anxiety. This dual challenge of managing both PD and anxiety underscores the complexity of the condition and the diverse range of symptoms patients may experience. Considering the circumstances, the cost and potential drawbacks associated with traditional antiparkinsonian drugs become increasingly relevant. Acupuncture emerges as a significant non-pharmacological adjunct therapy. Offering a potentially safer and more cost-effective option, acupuncture addresses the pressing need for holistic and complementary treatments that may alleviate both the motor symptoms of PD and the accompanying anxiety. Methods and analysis This is a multicentre, randomised controlled and assessor-blind trial. A total of 210 eligible patients with PD will be randomly assigned (1:1) to Jin’s three-needle (JTN) acupuncture group or waitlist (WL) group. Patients in the JTN group will receive acupuncture therapy three times per week for 4 weeks. Patients in the WL group will maintain their original dosage of antiparkinsonian drugs and receive acupuncture therapy after the observation period. The primary outcome measure will be the Unified Parkinson’s Disease Rating Scale score. The secondary outcome measures will be the scores of the Hoehn-Yahr Rating Scale, Unified Dyskinesia Rating Scale, Non-Motor Symptoms Scale, 39-item Parkinson’s Disease Questionnaire, Parkinson Anxiety Scale, Hamilton Anxiety Scale, Hamilton Depression Scale, Zarit burden interview and the level of cortisol and adrenocorticotropic hormone. The evaluation will be executed at baseline, the end of the treatment and a follow-up period. Ethics and dissemination The study was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (K[2023]014). All patients have to provide written, informed consent. The study will be disseminated through presentations in peer-reviewed international journals and at national and international conferences. Trial registration number Chinese Clinical Trial Registry; ChiCTR2300074675.

Role of zonisamide in advanced Parkinson's disease: a randomized placebo-controlled study

Article

Full-text available

Feb 2024
NEUROL SCI

Background Zonisamide (ZNS) has shown some efficacy in motor symptoms of PD; however, more evidence is lacking, and its effects on nonmotor symptoms (NMSs) and quality of life (QoL) remain to be investigated. This randomized double-blinded placebo-controlled crossover study investigated the effect of ZNS on motor and NMS symptoms and QoL in advanced PD. Methods PD patients with Hoehn and Yahr stage ≥ 2 (“On” state) and at least 2 h off time daily were randomized to groups: ZNS 25 mg, ZNS 50 mg and placebo. Groups were assessed at baseline and at the 1- and 3-month follow-ups. The primary endpoint was the change in the total MDS-UPDRS III “On”, while the secondary endpoint was the change in the total and parts I and IV MDS-UPDRS, Nonmotor Symptoms Scale and Parkinson’s disease questionnaire-39 at the final assessment. Results Sixty-nine patients were assessed for efficacy at the 1-month follow-up, and 58 patients were assessed at the 3-month follow-up. The primary endpoint showed significant improvement in the ZNS 25 mg group compared to the placebo group ( p = 0.009). At the final assessment, the ZNS 25 mg group showed significant improvement of total and part VI MDS-UPDRS, bradykinesia, tremor and functional impact of fluctuations compared to placebo. There was no change in dyskinesia, NMSs, QoL or side effects except for sedation. Conclusion ZNS has a favourable effect on motor symptoms in patients with wearing off as adjunctive therapy with other dopaminergic drugs, with no exacerbation of dyskinesia and a limited impact on NMSs and QoL. Trial registration Clinicaltrials.gov, NCT04182399, in 24/11/2019.

Comparison of dyskinesia profiles after L-DOPA dose challenges with or without dopamine agonist coadministration

Article

Full-text available

Dec 2023

Classification of long-term clinical course of Parkinson’s disease using clustering algorithms on social support registry database

Article

Full-text available

Sep 2023

Although Parkinson’s disease (PD) has a heterogeneous disease course, it remains challenging to establish subtypes. We described and clustered the natural course of Parkinson’s disease (PD) with respect to functional disability and mortality. This retrospective cohort study utilized the Korean National Health Insurance Service database, which contains the social support registry database for patients with PD. We extracted patients newly diagnosed with PD in 2009 and followed them up until the end of 2018. Functional disability was assessed based on the long-term care insurance (LTCI) and National Disability Registry data. Further, we measured all-cause mortality during the observation period. We included 2944 eligible patients. The surviving patients were followed up for 113.7 ± 3.3 months. Among the patients who died, patients with and without disability registration were followed up for 61.4 ± 30.1 and 43.2 ± 32.0 months, respectively. The cumulative survival rate was highest in cluster 1 and decreased from Cluster 1 to Cluster 6. In the multivariable Cox regression analysis, the defined clusters were significantly associated with increased long-term mortality (adjusted hazard ratio [aHR], 3.440; 95% confidence interval [CI], 3.233–3.659; p < 0.001). Further, age (aHR, 1.038; 95% CI, 1.031–1.045; p < 0.001), diabetes (aHR, 1.146; 95% CI, 1.037–1.267; p = 0.007), and chronic kidney disease (aHR, 1.382; 95% CI, 1.080–1.768; p = 0.010) were identified as independent risk factors for increased risk of long-term mortality. Contrastingly, the female gender (aHR, 0.753; 95% CI, 0.681–0.833; p < 0.001) and a higher LTCI grade (aHR, 0.995; 95% CI, 0.992–0.997; p < 0.001) were associated with a significantly decreased long-term mortality risk. We identified six clinical course clusters for PD using longitudinal data regarding the social support registry and mortality. Our results suggest that PD progression is heterogeneous in terms of disability and mortality.

Indicación de estimulación cerebral profunda en casos complejos de enfermedad de Parkinson. Experiencia en el Hospital Clínico Universidad de Chile

Article

Feb 2020

Introduction: Deep brain stimulation (DBS) is a standard surgical procedure for the treatment of advanced Parkinson Disease (PD) with motor complications that cannot be adequately managed by medical treatment. Currently available literature can guide physicians on basic aspects of patients’ selection and indications for DBS. However, there is a range of real-world clinical settings where the indications of DBS for Parkinson disease are debatable. Objective: to present the experience on PD patients with complex clinical manifestations treated with DBS in our hospital. Method: Report of four PD cases treated with DBS. Case 1: 63-year old woman with advanced PD and severe motor complications; Case 2: 60-year old man with 5 years of disease duration and mild motor complications; Case 3: 67-year old man with severe ventriculomegaly that may have precluded direct electrode passage to the surgical target; Case 4: 67- year-old woman with putative severe axial disability. Results: After one year of follow-up, all patients showed improvement on motor symptoms as well as quality of life. Discussion: We provide a brief rationale for the patient selection in each case to support the decision-making in the management of PD patients with complex clinical cases.

Multimodal Imaging of Substantia Nigra in Parkinson's Disease with Levodopa-Induced Dyskinesia

Article

Feb 2023
MOVEMENT DISORD

Background: Degeneration of the substantia nigra (SN) may contribute to levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), but the exact characteristics of SN in LID remain unclear. Objective: To further understand the pathogenesis of patients with PD with LID (PD-LID), we explored the structural and functional characteristics of SN in PD-LID using multimodal magnetic resonance imaging (MRI). Methods: Twenty-nine patients with PD-LID, 37 patients with PD without LID (PD-nLID), and 28 healthy control subjects underwent T1-weighted MRI, quantitative susceptibility mapping, neuromelanin-sensitive MRI, multishell diffusion MRI, and resting-state functional MRI. Different measures characterizing the SN were obtained using a region of interest-based approach. Results: Compared with patients with PD-nLID and healthy control subjects, the quantitative susceptibility mapping values of SN pars compacta (SNpc) were significantly higher (P = 0.049 and P = 0.00002), and the neuromelanin contrast-to-noise ratio values in SNpc were significantly lower (P = 0.012 and P = 0.000002) in PD-LID. The intracellular volume fraction of the posterior SN in PD-LID was significantly higher compared with PD-nLID (P = 0.037). Resting-state fMRI indicated that PD-LID in the medication off state showed higher functional connectivity between the SNpc and putamen compared with PD-nLID (P = 0.031), and the functional connectivity changes in PD-LID were positively correlated with Unified Dyskinesia Rating Scale total scores (R = 0.427, P = 0.042). Conclusions: Our multimodal imaging findings highlight greater neurodegeneration in SN and the altered nigrostriatal connectivity in PD-LID. These characteristics provide a new perspective into the role of SN in the pathophysiological mechanisms underlying PD-LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Expanded and Independent Spanish Validation of the MDS ‐Non Motor Rating Scale

Article

Full-text available

Jan 2023

Background: The Movement Disorder Society-sponsored Non-motor Rating Scale (MDS-NMS) assess the severity and disability caused by non-motor symptoms (NMS) in Parkinson's disease (PD). Objective: This article encapsulates the formal process for completing this program and the data on the first officially approved non-English version of the MDS-NMS (Spanish). Methods: The MDS-NMS translation program involves four steps: translation and back-translation; cognitive pre-testing to ensure that raters and patients understand the scale and are comfortable with its content; field testing of the finalized version; analysis of the factor structure of the tested version against the original English language version for the nine domains that could be analyzed in a confirmatory factor analysis. To be designated an "Official MDS translation," the confirmatory factor analysis Comparative Fit Index had to be ≥0.90. Results: The Spanish MDS-NMS was tested in 364 native-Spanish-speaking patients with PD from seven countries. For all subjects with fully computable data with all domains of the MDS-NMS (n = 349), the Comparative Fit Index was ≥0.90 for the nine eligible domains. Missing data were negligible and moderate floor effect (42.90%) was found for the Non-Motor Fluctuations subscale. Item homogeneity coefficient was adequate, and the correlation of the MDS-NMS domains with other measures for related constructs was acceptable (r s ≥ 0.50). Conclusions: The Spanish version of the MDS-NMS followed the IPMDS Translation Program protocol, reached the criterion to be designated as an Official Translation, and is now available on the MDS website.

How resistant are levodopa-resistant axial symptoms? Response of freezing, posture, and voice to increasing levodopa intestinal infusion rates in Parkinson disease

Article

Full-text available

Sep 2022

Background: Treatment of freezing of gait (FoG) and other Parkinson's disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily-ON therapeutic condition. Methods: We performed a pre-post interventional study including patients treated with levodopa/carbidopa-intestinal-gel-infusion (LCIG) with disabling FoG in daily-ON condition. Patients were evaluated at their usual LCIG infusion rate (T1), and one hour after 1.5x (T2) and 2x (T3) increase of the LCIG infusion rate by quantitative outcome measures. The number of FoG episodes (primary outcome), posture, speech, and gait features were objectively quantified during a standardized test by a blinded rater. Changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were also analyzed. Results: We evaluated sixteen patients with a mean age of 69±9.4 years and treated with LCIG for a mean of 2.2±2.1 years. FoG improved in 83.3% of patients by increasing the levodopa doses. The number of FoG episodes significantly decreased (mean 2.3 at T1, 1.7 at T2, 1.2 at T3; p:0.013). Posture and speech features did not show significant changes, while stride length (p:0.049), turn duration (p:0.001), and turn velocity (p:0.024) significantly improved doubling the levodopa infusion rate. Conclusions: In a short-term evaluation, the increase of LCIG dose can improve 'dopa-resistant' FoG and gait issues in most advanced PD patients with overall good control of motor symptoms in the absence of clinically significant dyskinesia.

Do we start too late? Insights from the real-world non-interventional BALANCE study on the present use of levodopa/carbidopa intestinal gel in advanced Parkinson's disease in Germany and Switzerland

Article

Aug 2022
PARKINSONISM RELAT D

Introduction Advanced Parkinson's disease is characterized by motor and non-motor fluctuations to oral dopamine replacement therapy. The BALANCE study evaluated the clinical practice in Germany and Switzerland, when patients eligible for levodopa/carbidopa intestinal gel (LCIG) therapy decided to either switch to LCIG or to stay on optimized standard of care (SoC) oral therapy as a non-randomized regular clinical decision. Methods In this non-interventional, multicenter, prospective observational study, patients were recruited between 2015 and 2020. We obtained comprehensive baseline characteristics in both groups. As primary endpoint, we evaluated whether LCIG led to higher quality-of-life (QoL) improvement than SoC after 12 months. As secondary endpoints, we studied several motor and non-motor outcomes. Results About half of the 137 patients decided for LCIG treatment (n = 73, 53.5%). Those were aged >70 years more often, had more advanced disease stage, higher burden of motor and neuropsychiatric symptoms, and cognitive impairment including dementia compared to SoC. QoL change after 12 months did not differ between groups (P = 0.286). The LCIG group improved in secondary outcomes, including the UPDRS III in ON, UPDRS IV, Unified Dyskinesia Rating Scale, and Non-Motor Symptoms Scale. Clinical Global Impression-Improvement scale improved in 78.0% and 19.5% of patients receiving LCIG and SoC, respectively. Caregiver burden remained stable in LCIG but worsened with SoC. Conclusion In current practice, patients and physicians delayed LCIG treatment and started substantially beyond the established indication criteria. This practice bears the risk to produce inferior results compared to the results from existing high-level evidence.

Parkinson's disease and iatrogenic impulsive-compulsive behaviors: A case/non-case study to build a complete model of individual vulnerability

Article

Full-text available

Aug 2022

Background and aims Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases. First-line medications consist of drugs that act by counteracting dopamine deficiency in the basal ganglia. Unfortunately, iatrogenic impulsive-compulsive behaviors (ICBs) can occur in up to 20% of PD patients over the course of their illness. ICBs must be considered multifactorial disorders that reflect the interactions of the medication with an individual's vulnerability and the underlying neurobiology of PD. We aimed to explore the predictive genetic, psychopathological and neurological factors involved in the development of ICBs in PD patients by building a complete model of individual vulnerability. Methods The PARKADD study was a case/non-case study. A total of 225 patients were enrolled (“ICB” group, N = 75; “no ICB” group, N = 150), and 163 agreed to provide saliva samples for genetic analysis. Sociodemographic, neurological and psychiatric characteristics were assessed, and genotyping for the characterization of polymorphisms related to dopaminergic and opioid systems was performed. Results Factors associated with “ICBs” were younger age of PD onset, personal history of ICB prior to PD onset and higher scores on the urgency and sensation seeking facets of impulsivity. No gene variant was significantly associated, but the association with the opioid receptor mu 1 (OPRM1) rs1799971 polymorphism was close to significance. Discussion and conclusions The influence of gene-environment interactions probably exists, and additional studies are needed to decipher the possible role of the opioid system in the development of ICBs in PD patients.

Retrospective Multicenter Study on Outcome Measurement for Dyskinesia Improvement in Parkinson’s Disease Patients with Pallidal and Subthalamic Nucleus Deep Brain Stimulation

Article

Full-text available

Aug 2022
BSRCCS

Deep brain stimulation (DBS) is an effective treatment for dyskinesia in patients with Parkinson’s disease (PD), among which the therapeutic targets commonly used include the subthalamic nucleus (STN) and the globus pallidus internus (GPi). Levodopa-induced dyskinesia (LID) is one of the common motor complications arising in PD patients on chronic treatment with levodopa. In this article, we retrospectively evaluated the outcomes of LID with the Unified Dyskinesia Rating Scale (UDysRS) in patients who underwent DBS in multiple centers with a GPi or an STN target. Meanwhile, the Med off MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS-Ⅲ) and the levodopa equivalent daily dose (LEDD) were also observed as secondary indicators. PD patients with a GPi target showed a more significant improvement in the UDysRS compared with an STN target (92.9 ± 16.7% vs. 66.0 ± 33.6%, p < 0.0001). Both the GPi and the STN showed similar improvement in Med off UPDRS-III scores (49.8 ± 22.6% vs. 52.3 ± 29.5%, p = 0.5458). However, the LEDD was obviously reduced with the STN target compared with the GPi target (44.6 ± 28.1% vs. 12.2 ± 45.8%, p = 0.006).

Altered functional connectivity of cerebellar dentate nucleus in peak-dose dyskinesia in Parkinson’s disease

Article

Full-text available

Aug 2022

The cerebellum is associated with the emergence of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD), yet the neural mechanism remains obscure. Our aim was to ascertain the role of functional connectivity (FC) patterns of the cerebellar dentate nucleus (DN) in the pathogenesis of peak-dose dyskinesia in PD. Twenty-three peak-dose dyskinetic PD patients, 27 non-dyskinetic PD patients, and 36 healthy controls (HCs) were enrolled and underwent T1-weighted and resting-state functional magnetic resonance imaging (rs-fMRI) scans after dopaminergic medication intake. We selected left and right DN as the regions of interest and then employed voxel-wise FC analysis and voxel-based morphometry analysis (VBM). The correlations between the altered FC pattern and clinical scores were also examined. Finally, receiver operating characteristic (ROC) curve analysis was performed to assess the potential of DN FC measures as a feature of peak-dose dyskinesia in PD. Dyskinetic PD patients showed excessively increased FC between the left DN and right putamen compared with the non-dyskinetic. When compared with controls, dyskinetic PD patients mainly exhibited increased FC between left DN and bilateral putamen, left paracentral lobule, right postcentral gyrus, and supplementary motor area. Additionally, non-dyskinetic PD patients displayed increased FC between left DN and left precentral gyrus and right paracentral lobule compared with controls. Meanwhile, increased FC between DN (left/right) and ipsilateral cerebellum lobule VIII was observed in both PD subgroups. However, no corresponding alteration in gray matter volume (GMV) was found. Further, a positive correlation between the z-FC values of left DN-right putamen and the Unified Dyskinesia Rating Scale (UDysRS) was confirmed in dyskinetic PD patients. Notably, ROC curve analyses revealed that the z-FC values of left DN-right putamen could be a potential neuroimaging feature identifying dyskinetic PD patients. Our findings demonstrated that the excessively strengthened connectivity of DN-putamen might contribute to the pathophysiological mechanisms of peak-dose dyskinesia in PD.

Forward and backward spatial recall in Parkinson's disease and matched controls: A 1-year follow-up study

Article

Apr 2022

Patients with Parkinson's disease (PD) exhibit a domain-general visuospatial dysfunction; however, no previous study has examined changes over time in forward and backward spatial recall in PD against controls. To evaluate changes in short-term (STM) and working memory (WM) dysfunction in PD, the current study assessed performance on a computer-modified version of the Corsi Block-Tapping Test (forward and backward recall) at two-time points 1 year apart, while simultaneously exploring associations with potentially relevant demographic and clinical variables. We enrolled 38 patients with PD and 38 controls matched for age, sex, and Montreal Cognitive Assessment (MoCA) total scores. Linear mixed-effects models analyzed the primary measured variables (forward and backward scores). At baseline, the dysfunction effect sizes were as follows: forward recall (-0.45, 95% CI [-0.90, 0.01]) and backward recall (-0.26, 95% CI [-0.71, 0.19]). At follow-up, patients exhibited substantially greater difficulties in backward recall (-0.65, 95% CI [-1.18, -0.13]) compared to the baseline assessment, whereas the forward dysfunction effect size remained almost the same (-0.43, 95% CI [-0.94, 0.09]). Age (p = .005, f = 0.35) and total scores on MoCA (p = .017, f = 0.18), irrespective of group and recall condition, were significant predictors of spatial block scores. The pattern of dysfunction effect sizes indicates that, in contrast to forward recall, backward recall dysfunction in PD worsened 1-year after the baseline assessment, presumably reflecting the progression of PD-related visuospatial WM dysfunction.

A Randomized, Double‐Blind, Controlled Phase II Study of Foliglurax in Parkinson's Disease

Article

Full-text available

Feb 2022

Background: Agents targeting the metabotropic glutamate receptor 4 have emerged as a potentially attractive new class of drugs for the treatment of Parkinson's disease (PD). Objective: The objective of this study was to evaluate the efficacy and safety of foliglurax in reducing off time and dyskinesia in patients with PD. Methods: This was a 28-day, multicenter, randomized, placebo-controlled, double-blind clinical trial of foliglurax 10 and 30 mg as adjunct to levodopa in 157 randomly assigned patients with PD and motor complications. Results: Although dose-dependent decreases in daily awake off time were apparent following treatment with foliglurax, the change from baseline to day 28 in off time (primary endpoint) and dyskinesia (secondary endpoint) did not improve significantly compared with placebo for either foliglurax dose. Treatment with foliglurax was generally safe, and there were no relevant safety signals. Conclusions: There was no evidence in this study that foliglurax has efficacy in improving levodopa-induced motor complications in PD. © 2022 International Parkinson and Movement Disorder Society.

Immediate-release/extended-release amantadine (OS320) to treat Parkinson's disease with levodopa-induced dyskinesia: Analysis of the randomized, controlled ALLAY-LID studies

Article

Feb 2022
PARKINSONISM RELAT D

Background Immediate Release (IR) amantadine has been used for treatment of levodopa induced dyskinesia (LID). The immediate-release/extended-release (IR/ER) amantadine formulation OS320 (OSMOLEX ER®) contains an IR outer layer and ER core for once-daily dosing. Objective Report individual and pooled results for the similarly designed double-blind, placebo-controlled ALLAY-LID I and II trials, assessing IR/ER-amantadine for LID. Methods PD patients with LID were randomized to IR/ER-amantadine 193 mg, 258 mg, or placebo. Primary endpoint was Unified Dyskinesia Rating Scale (UDysRS) score change from baseline to Day 98. Secondary outcome was ON time without troublesome dyskinesia based on diaries. Exploratory outcomes were other diary states (including OFF), MDS-UPDRS Parts II + III and Fatigue Severity Scale. Results Overall, 222 individuals enrolled (N = 87 ALLAY-LID I, N = 135 ALLAY-LID II); both trials terminated early for sponsor's decision. While ALLAY-LID I did not meet its primary endpoint, a significant reduction in UDysRS scores versus placebo was observed in ALLAY-LID II for both 193 mg and 258 mg doses. In the pooled analysis, placebo-adjusted UDysRS score differences were −5.5[−9.8,−1.2], p = 0.012 and −5.2[-9.5,-0.9], p = 0.017, respectively. IR/ER-amantadine 258 mg significantly increased time spent ON without troublesome dyskinesia in ALLAY-LID II and pooled analysis. Reductions in ON time with dyskinesia supported the primary outcome. There was no effect on OFF time or other outcomes. Overall, 13.3% (193 mg), 18.7% (258 mg) and 11.1% (placebo) discontinued for adverse events, most commonly hallucinations (4.0%, 10.7%, and 1.4%, respectively). Conclusions IR/ER-amantadine significantly reduced LID in ALLAY-LID II but not in ALLAY-LID I; post-hoc pooled data also indicated a positive treatment effect on LID.

Altered perivascular spaces in subcortical white matter in Parkinson’s disease patients with levodopa-induced dyskinesia

Article

Full-text available

Mar 2024

Dilated perivascular spaces (PVS) have emerged as a pathological hallmark in various neurological conditions, including Parkinson’s disease (PD). Levodopa-induced dyskinesia (LID), an intractable motor complication of PD, remains enigmatic regarding the distribution patterns of PVS. Our objective was to scrutinize the percent PVS (pPVS) changes within PD patients with LID (PD-LID). In total, 132 individuals were enrolled, including PD-LID ( n = 42), PD patients without LID (PD-nLID, n = 45), and healthy controls (HCs, n = 45). Employing an automated approach for PVS quantification based on structural magnetic resonance imaging, we comprehensively evaluated total pPVS in subcortical white matter globally and regionally. A significant increase in global pPVS was observed in PD patients versus HCs, particularly evident in PD-LID relative to HCs. Within the PD-LID group, elevated pPVS was discerned in the right inferior frontal gyrus region (rIFG) (pars opercularis), contrasting with PD-nLID and HCs. Moreover, PD patients exhibited increased pPVS in bilateral superior temporal regions compared to HCs. Notably, pPVS in the rIFG positively correlated with dyskinetic symptoms and could well identify LID. Our findings unveiled PVS alternations in subcortical white matter in PD-LID at both global and regional levels, highlighting the increased pPVS in rIFG as a prospective imaging marker for LID.

Short-Term Cannabidiol with Δ-9-Tetrahydrocannabinol in Parkinson's Disease: A Randomized Trial

Article

Mar 2024
MOVEMENT DISORD

Background Cannabis use is frequent in Parkinson's disease (PD), despite inadequate evidence of benefits and risks. Objective The aim is to study short‐term efficacy and tolerability of relatively high cannabidiol (CBD)/low Δ‐9‐tetrahydrocannabinol (THC) to provide preliminary data for a longer trial. Methods Persons with PD with ≥20 on motor Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) who had negative cannabis testing took cannabis extract (National Institute of Drug Abuse) oral sesame oil solution for 2 weeks, increasing to final dose of 2.5 mg/kg/day. Primary outcome was change in motor MDS‐UPDRS from baseline to final dose. Results Participants were randomized to CBD/THC (n = 31) or placebo (n = 30). Mean final dose (CBD/THC group) was 191.8 ± 48.9 mg CBD and 6.4 ± 1.6 mg THC daily. Motor MDS‐UPDRS was reduced by 4.57 (95% CI, −8.11 to −1.03; P = 0.013) in CBD/THC group, and 2.77 (−4.92 to −0.61; P = 0.014) in placebo; the difference between groups was non‐significant: −1.80 (−5.88 to 2.27; P = 0.379). Several assessments had a strong placebo response. Sleep, cognition, and activities of daily living showed a treatment effect, favoring placebo. Overall adverse events were mild and reported more in CBD/THC than placebo group. On 2.5 mg/kg/day CBD plasma level was 54.0 ± 33.8 ng/mL; THC 1.06 ± 0.91 ng/mL. Conclusions The brief duration and strong placebo response limits interpretation of effects, but there was no benefit, perhaps worsened cognition and sleep, and there was many mild adverse events. Longer duration high quality trials that monitor cannabinoid concentrations are essential and would require improved availability of research cannabinoid products in the United States. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Assessment and Treatment of Abnormal Involuntary Movements: A Clinically Focused Narrative Review

Article

Mar 2024
HARVARD REV PSYCHIAT

Learning Objectives After participating in this CME activity, the psychiatrist should be better able to: • Categorize and describe different types of abnormal involuntary movements (AIMs). • Identify assessment tools and treatment options for AIMs. Abstract Abnormal involuntary movements (AIMs) comprise a diverse group of movement disorders characterized by uncontrolled and unintended movements (e.g., tremors, tics, dystonia). AIMs can occur at any stage of life and pose significant challenges for clinicians. It is difficult to determine their underlying causes due to the complex neurobiological mechanisms involved. Therefore, it is crucial to quantify the severity and progression of AIMs using well-validated measurement scales, such as the Abnormal Involuntary Movement Scale (AIMS). By employing reliable assessment approaches, clinicians can objectively evaluate the motoric manifestations of AIMs and track them over time. Treatment of AIMs varies depending on their nature and etiology. While AIMs often respond to treatment, serious side effects can undermine treatment efficacy. In this clinically focused narrative review, we categorize different types of AIMs and discuss their neurobiological aspects. Further, we emphasize the importance of using well-validated measurement scales for accurate assessment and discuss available treatment modalities that target the specific AIMs manifestations. Additionally, we cover the need for comprehensive care to address the multifaceted nature of AIMs, accounting for their physical manifestations as well as their psychological, social, and functional toll on patients. By embracing a multidisciplinary approach, health care professionals can provide patient-centered care that promotes overall well-being and enhances the lives of patients coping with AIMs. Regular follow-up assessments are necessary to monitor treatment response, adjust medications when needed, and provide ongoing support for individuals affected by AIMs.

Using artificial intelligence to identify drugs for repurposing to treat l-DOPA-induced dyskinesia

Article

Feb 2024
NEUROPHARMACOLOGY

Bridging the gap between statistical significance and clinical relevance: A systematic review of minimum clinically important difference (MCID) thresholds of scales reported in movement disorders research

Article

Feb 2024

Background Minimum clinically important difference (MCID) is the smallest change in an outcome measure that is considered clinically meaningful. Using validated MCID thresholds for outcomes powers trials adequately to detect meaningful treatment effects, aids in their interpretation and guides development of new outcome measures. Objectives To provide a comprehensive summary of MCID thresholds of various symptom severity scales reported in movement disorder. Methods We conducted systematic review of the literature and included studies of one or more movement disorders, and reporting MCID scales. Results 2763 reports were screened. Final review included 32 studies. Risk of bias (RoB) assessment showed most studies were of good quality. Most commonly evaluated scale was Unified Parkinson's Disease Rating Scale (UPDRS) (11 out of 32). Four studies assessing MDS-UPDRS had assessed its different sub-parts, reporting a change of 2.64,3.05,3.25 and 0.9 points to detect clinically meaningful improvement and 2.45,2.51,4.63 and 0.8 points to detect clinically meaningful worsening, for the Part I, II, III and IV, respectively. For Parts II + III, I + II + III and I + II + III + IV, MCID thresholds reported for clinically meaningful improvement were 5.73, 4.9, 6.7 and 7.1 points respectively; while those for clinically meaningful worsening were 4.7, 4.2, 5.2 and 6.3 points, respectively. MCID thresholds reported for other scales included Abnormal Involuntary Movement Scale (AIMS), Toronto Western Spasmodic Torticollis Rating Scale (TWSRS), and Burke-Fahn-Marsden Dystonia Scale (BFMD). Conclusion This review summarizes all the MCID thresholds currently reported in Movement disorders research and provides a comprehensive resource for future trials, highlighting the need for standardized and validated MCID scales in movement disorder research.

Subtalamotomía por radiofrecuencia guiada por microrregistro multiunitario: Complicaciones tempranas en 130 procedimientos.Radiofrequency subthalamotomy guided by multi-unit microrecording: early complications in 130 procedures.

Article

Full-text available

Apr 2017

Objetivo. Describir las complicaciones tempranas (3 meses) observadas en 130 subtalamotomías realizadas en pacientes con diagnóstico de enfermedad de Parkinson (EP) idiopática en el Hospital Nacional Profesor Alejandro Posadas, entre enero del 2012 y diciembre del 2015.Material y métodos. Se analizaron 130 subtalamotomías realizadas en 110 pacientes con diagnóstico de EP avanzada de acuerdo a los criterios de la UK Parkinson´s Disease Brain Bank, evaluándose las complicaciones tempranas (hasta 3 meses) de la subtalamotomía por radiofrecuencia guiada por microrregistro.Resultados. Las complicaciones encontradas fueron hemorragia 2,3%, isquemia 0,7%, infección 1,5%. La incidencia de disquinesias fue de un 8,4% con resolución espontánea.Conclusión. La subtalamotomía constituye un recurso quirúrgico útil y efectivo para el tratamiento de los síntomas motores de la EP avanzada, presentando bajo índice de complicaciones tempranas.

A Double-Blind, Randomized, Placebo-Controlled Trial of Bumetanide in Parkinson's Disease

Article

Jan 2024
MOVEMENT DISORD

Background Acting on the main target of dopaminergic cells, the striatal γ‐aminobutyric acid (GABA)‐ergic cells, might be a new way to treat persons with Parkinson's disease (PD). Objective The objective of this study was to assess the efficacy of bumetanide, an Na–K–Cl cotransporter (NKCC1) inhibitor, to improve motor symptoms in PD. Methods This was a 4‐month double‐blind, randomized, parallel‐group, placebo‐controlled trial of 1.75 to 3 mg/day bumetanide as an adjunct to levodopa in 44 participants with PD and motor fluctuations. Results Compared to the baseline, the mean change in OFF Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III score after 4 months of treatment (primary endpoint) did not improve significantly compared with placebo. No changes between participants treated with bumetanide and those treated with placebo were observed for most other outcome measures. Despite no relevant safety signals, bumetanide was poorly tolerated. Conclusions There was no evidence in this study that bumetanide has efficacy in improving motor symptoms of PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Tardive Dyskinesia Impact Scale (TDIS), a novel patient-reported outcome measure in tardive dyskinesia: development and psychometric validation

Article

Full-text available

Jan 2024

Background Tardive dyskinesia (TD), a movement disorder in which patients experience abnormal involuntary movements, can have profound negative impacts on physical, cognitive, and psychosocial functioning. The Abnormal Involuntary Movement Scale (AIMS), a clinician-rated outcome, is considered the gold standard for evaluating treatment efficacy in TD clinical trials. However, it provides little information about the impacts of uncontrolled movements from a patient perspective and can be cumbersome to administer in clinical settings. The Tardive Dyskinesia Impact Scale (TDIS) was developed as a patient-reported outcome measure to fulfill the need for a disease-specific impact assessment in TD. The objective of the present study was to develop and evaluate the psychometric properties of the TDIS to determine whether it is fit-for-purpose to measure TD impact. Methods Data from qualitative studies and phase 3 trials of a VMAT2 inhibitor for the treatment of TD (KINECT3 and KINECT4) were used to determine the psychometric properties of the TDIS. Qualitative research included concept elicitation and cognitive debriefing interviews with TD patients and their caregivers in order to assess how well the TDIS captured key domains of TD impact. Quantitative analyses to examine the psychometric properties of the TDIS included assessing construct validity (factor structure, known groups, and predictive validity) and responsiveness to change. Results Qualitative results showed that the TDIS captures the key TD impacts reported by patients and caregivers and that the TDIS was interpreted as intended and relevant to patients’ experiences. Quantitative results found evidence of 2 underlying domains of the TDIS: physical and socioemotional (Comparative Fit Index > 0.9). Known groups and predictive validity indicated that, compared with the AIMS, the TDIS captures unique content (correlation between AIMS and TDIS = 0.2–0.28). The TDIS showed responsiveness to change in treatment, with TDIS scores improving over 48 weeks in the 2 phase 3 trials. Conclusions The TDIS captures relevant information about the impact of TD and is easily administered in a clinician’s office or patient’s home. It may be used longitudinally to show changes in TD burden over time. The TDIS complements the AIMS; using these assessments together provides a more holistic assessment of TD.

Microstructural and functional alterations of the ventral pallidum are associated with levodopa-induced dyskinesia in Parkinson's disease

Article

Nov 2023
EUR J NEUROL

Background and purpose The ventral pallidum (VP) regulates involuntary movements, but it is unclear whether the VP regulates the abnormal involuntary movements in Parkinson's disease (PD) patients who have levodopa‐induced dyskinesia (LID). To further understand the role of the VP in PD patients with LID (PD‐LID), we explored the structural and functional characteristics of the VP in such patients using multimodal magnetic resonance imaging (MRI). Methods Thirty‐one PD‐LID patients, 39 PD patients without LID (PD‐nLID), and 28 healthy controls (HCs) underwent T1‐weighted MRI, quantitative susceptibility mapping, multi‐shell diffusion MRI, and resting‐state functional MRI (rs‐fMRI). Different measures characterizing the VP were obtained using a region‐of‐interest‐based approach. Results The left VP in the PD‐LID group showed significantly higher intracellular volume fraction (ICVF) and isotropic volume fraction (IsoVF) compared with the PD‐nLID and HC groups. Rs‐MRI revealed that, compared with the PD‐nLID group, the PD‐LID group in the medication ‘off’ state had higher functional connectivity (FC) between the left VP and the left anterior caudate, left middle frontal gyrus and left precentral gyrus, as well as between the right VP and the right posterior ventral putamen and right mediodorsal thalamus. In addition, the ICVF values of the left VP, the FC between the left VP and the left anterior caudate and left middle frontal gyrus were positively correlated with Unified Dyskinesia Rating Scale scores. Conclusion Our multimodal imaging findings show that the microstructural changes of the VP (i.e., the higher ICVF and IsoVF) and the functional change in the ventral striatum–VP–mediodorsal thalamus–cortex network may be associated with pathophysiological mechanisms of PD‐LID.

Genetic meta-analysis of levodopa induced dyskinesia in Parkinson’s disease

Article

Full-text available

Aug 2023

The genetic basis of levodopa-induced-dyskinesia (LiD) is poorly understood, and there have been few well-powered genome-wide studies. We performed a genome-wide survival meta-analyses to study the effect of genetic variation on the development of LiD in five separate longitudinal cohorts, and meta-analysed the results. We included 2784 PD patients, of whom 14.6% developed LiD. We found female sex (HR = 1.35, SE = 0.11, P = 0.007) and younger age at onset (HR = 1.8, SE = 0.14, P = 2 × 10 ⁻⁵ ) increased the probability of developing LiD. We identified three genetic loci significantly associated with time-to-LiD onset. rs72673189 on chromosome 1 (HR = 2.77, SE = 0.18, P = 1.53 × 10 ⁻⁸ ) located at the LRP8 locus, rs189093213 on chromosome 4 (HR = 3.06, SE = 0.19, P = 2.81 × 10 ⁻⁹ ) in the non-coding RNA LINC02353 locus, and rs180924818 on chromosome 16 (HR = 3.13, SE = 0.20, P = 6.27 × 10 ⁻⁹ ) in the XYLT1 locus. Based on a functional annotation analysis on chromosome 1, we determined that changes in DNAJB4 gene expression, close to LRP8, are an additional potential cause of increased susceptibility to LiD. Baseline anxiety status was significantly associated with LiD (OR = 1.14, SE = 0.03, P = 7.4 × 10 ⁻⁵ ). Finally, we performed a candidate variant analysis of previously reported loci, and found that genetic variability in ANKK1 ( rs1800497 , HR = 1.27, SE = 0.09, P = 8.89 × 10 ⁻³ ) and BDNF ( rs6265 , HR = 1.21, SE = 0.10, P = 4.95 × 10 ⁻² ) loci were significantly associated with time to LiD in our large meta-analysis.

Dyskinesia and impulsive compulsive behaviour in Parkinson’s disease are not related: Insights from a study with wearable sensors

Article

Aug 2023
PARKINSONISM RELAT D

Introduction: Previous studies have suggested an association between Impulsive Compulsive Behaviour (ICB) and dyskinesia in Parkinson's disease (PD). However, none of these studies have employed an objective home-based measure of dyskinesia. Objectives: To evaluate in advanced PD the relationship between ICB and dyskinesia, objectively measured with a wearable device. Methods: In this cross-sectional study, ICB and other neuropsychiatric symptoms were assessed by means of structured clinical interview and specific screening instruments. Presence and severity of motor fluctuations and dyskinesia were rated with patient's and clinician's based rating instruments. Motor fluctuations and dyskinesia were also measured at home for 5-days using a validated wearable devise, the Parkinson's KinetiGraph™(PKG). Results: We included 89 subjects with PD (29 females, 62 ± 7 years, disease duration 10.3 ± 4.5), of whom 36 (40%) had ICB. Patients with and without ICB did not differ by presence and severity of dyskinesia measured by clinical scales and PKG. There was no association between the presence of ICB and dyskinesia in the whole sample. Conclusion: Our data suggest that ICB and dyskinesia are common but unrelated disorders in advanced PD.

Outcome Measures for Disease-Modifying Trials in Parkinson’s Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative

Article

Full-text available

Jul 2023

Background: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. Objective: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. Methods: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. Results: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. Conclusion: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.

Handicap as a Measure of Perceived‐Health Status in Parkinson's Disease

Article

Jun 2023

Background Handicap is a patient‐centered measure of health status that encompasses the impact of social and physical environment on daily living, having been assessed in advanced and late‐stage Parkinson's Disease (PD). Objective To characterize the handicap of a broader sample of patients. Methods A cross‐sectional study of 405 PD patients during the MDS‐UPDRS Portuguese validation study, using the MDS‐UPDRS, Unified Dyskinesias Rating Scale, Nonmotor symptoms questionnaire, PDQ‐8 and EQ‐5D‐3L. Handicap was measured using the London Handicap Scale (LHS). Results Mean age was 64.42 (±10.3) years, mean disease duration 11.30 (±6.5) years and median HY 2 (IQR, 2–3). Mean LHS was 0.652 (±0.204); “Mobility,” “Occupation” and “Physical Independence” were the most affected domains. LHS was significantly worse in patients with longer disease duration, older age and increased disability. In contrast, PDQ‐8 did not differentiate age groups. Handicap was significantly correlated with disease duration ( r = −0.35), nonmotor experiences of daily living (EDL) (MDS‐UPDRS‐I) ( r = −0.51), motor EDL (MDS‐UPDRS‐II) ( r = −0.69), motor disability (MDS‐UPDRS‐III) ( r = −0.49), axial signs of MDS‐UPDRS‐III ( r = −0.55), HY ( r = −0.44), presence of nonmotor symptoms ( r = −0.51) and PDQ‐8 index ( r = −0.64) (all P < 0.05). Motor EDL, MDS‐UPDRS‐III and PDQ‐8 independently predicted Handicap (adjusted R ² = 0.582; P = 0.007). Conclusions The LHS was easily completed by patients and caregivers. Patients were mild‐moderately handicapped, which was strongly determined by motor disability and its impact on EDL, and poor QoL. Despite correlated, handicap and QoL seem to differ in what they measure, and handicap may have an added value to QoL. Handicap seems to be a good measure of perceived‐health status in a broad sample of PD.

Objective measurement versus clinician-based assessment for Parkinson's disease

Article

Jun 2023

Introduction: Although clinician-based assessment through standardized clinical rating scales is currently the gold standard for quantifying motor impairment in Parkinson's disease (PD), it is not without limitations, including intra- and interrater variability and a degree of approximation. There is increasing evidence supporting the use of objective motion analyses to complement clinician-based assessment. Objective measurement tools hold significant potential for improving the accuracy of clinical and research-based evaluations of patients. Areas covered: The authors provide several examples from literature demonstrating how different motion measurement tools, including optoelectronics, contactless and wearable systems allow for both the objective quantification and monitoring of key motor symptoms (such as bradykinesia, rigidity, tremor, and gait disturbances), and the identification of motor fluctuations in PD patients. Furthermore, they discuss how, from a clinician's perspective, objective measurements can help in various stages of PD management. Expert opinion: In our opinion, sufficient evidence supports the assertion that objective monitoring systems enable accurate evaluation of motor symptoms and complications in PD. A range of devices can be utilized not only to support diagnosis but also to monitor motor symptom during the disease progression and can become relevant in the therapeutic decision-making process.

Comparison of dyskinesia profiles after L-DOPA dose challenges with or without dopamine agonist coadministration

Article

Jun 2023
NEUROPHARMACOLOGY

Many patients with Parkinson's disease (PD) experiencing l-DOPA-induced dyskinesia (LID) receive adjunct treatment with dopamine agonists, whose functional impact on LID is unknown. We set out to compare temporal and topographic profiles of abnormal involuntary movements (AIMs) after l-DOPA dose challenges including or not the dopamine agonist ropinirole. Twenty-five patients with PD and a history of dyskinesias were sequentially administered either l-DOPA alone (150% of usual morning dose) or an equipotent combination of l-DOPA and ropinirole in random order. Involuntary movements were assessed by two blinded raters prior and every 30 min after drug dosing using the Clinical Dyskinesia Rating Scale (CDRS). A sensor-recording smartphone was secured to the patients' abdomen during the test sessions. The two raters' CDRS scores were highly reliable and concordant with models of hyperkinesia presence and severity trained on accelerometer data. The dyskinesia time curves differed between treatments as the l-DOPA-ropinirole combination resulted in lower peak severity but longer duration of the AIMs compared with l-DOPA alone. At the peak of the AIMs curve (60-120 min), l-DOPA induced a significantly higher total hyperkinesia score, whereas in the end phase (240-270 min), both hyperkinesia and dystonia tended to be more severe after the l-DOPA-ropinirole combination (though reaching statistical significance only for the item, arm dystonia). Our results pave the way for the introduction of a combined l-DOPA-ropinirole challenge test in the early clinical evaluation of antidyskinetic treatments. Furthermore, we propose a machine-learning method to predict CDRS hyperkinesia severity using accelerometer data.

5-HT1A agonists for levodopa-induced dyskinesia in Parkinson's disease

Article

May 2023

Levodopa is the most effective agent for treating the symptoms of Parkinson's disease (PD). However, levodopa-induced dyskinesia remains a significant complication that manifests after few years of treatment, for which therapeutic options remain limited. Several agonists of the serotonin type 1A (5-HT1A) receptor with varying levels of efficacy and interaction at other sites, have been tested in the clinic. Clinical trials testing 5-HT1A agonists have yielded inconsistent results in alleviating dyskinesia, especially that the antidyskinetic benefit observed was often accompanied by an adverse effect on motor function. In this article, we summarize and analyze the various clinical trials performed with 5-HT1A agonists in PD patients with dyskinesia and offer perspectives on the future of this class of agents in PD.

Pharmacological and non-pharmacological treatments for impulsive-compulsive behaviors in Parkinson's disease

Article

Mar 2023
COCHRANE DB SYST REV

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: Primary objective To assess and compare the effects of pharmacological and non‐pharmacological treatments for ICBs in people with Parkinson's disease. Secondary objective To assess whether the effects of pharmacological and non‐pharmacological treatments for ICBs in people with Parkinson's disease differ according to ICB subtype.

Towards automated video-based assessment of dystonia in dyskinetic cerebral palsy: A novel approach using markerless motion tracking and machine learning

Article

Full-text available

Mar 2023

Introduction: Video-based clinical rating plays an important role in assessing dystonia and monitoring the effect of treatment in dyskinetic cerebral palsy (CP). However, evaluation by clinicians is time-consuming, and the quality of rating is dependent on experience. The aim of the current study is to provide a proof-of-concept for a machine learning approach to automatically assess scoring of dystonia using 2D stick figures extracted from videos. Model performance was compared to human performance. Methods: A total of 187 video sequences of 34 individuals with dyskinetic CP (8–23 years, all non-ambulatory) were filmed at rest during lying and supported sitting. Videos were scored by three raters according to the Dyskinesia Impairment Scale (DIS) for arm and leg dystonia (normalized scores ranging from 0–1). Coordinates in pixels of the left and right wrist, elbow, shoulder, hip, knee and ankle were extracted using DeepLabCut, an open source toolbox that builds on a pose estimation algorithm. Within a subset, tracking accuracy was assessed for a pretrained human model and for models trained with an increasing number of manually labeled frames. The mean absolute error (MAE) between DeepLabCut’s prediction of the position of body points and manual labels was calculated. Subsequently, movement and position features were calculated from extracted body point coordinates. These features were fed into a Random Forest Regressor to train a model to predict the clinical scores. The model performance trained with data from one rater evaluated by MAEs (model-rater) was compared to inter-rater accuracy. Results: A tracking accuracy of 4.5 pixels (approximately 1.5 cm) could be achieved by adding 15–20 manually labeled frames per video. The MAEs for the trained models ranged from 0.21 ± 0.15 for arm dystonia to 0.14 ± 0.10 for leg dystonia (normalized DIS scores). The inter-rater MAEs were 0.21 ± 0.22 and 0.16 ± 0.20, respectively. Conclusion: This proof-of-concept study shows the potential of using stick figures extracted from common videos in a machine learning approach to automatically assess dystonia. Sufficient tracking accuracy can be reached by manually adding labels within 15–20 frames per video. With a relatively small data set, it is possible to train a model that can automatically assess dystonia with a performance comparable to human scoring.

Subcutaneous, intranasal and transdermal dopamine agonists in the management of Parkinson's disease

Chapter

Mar 2016

Parkinson's disease is no longer considered only a motor disorder. It has become evident that the pathological changes are broad, the progression seems to follow a pattern suggesting transynaptic transmission via templation of proteins in a prion-like fashion, and that these pathological changes usually antedate the motor symptoms by decades. This book emphasizes treatment options for Parkinson's disease, critically assessing pharmacologic and surgical interventions for all aspects of the disease. Evidence from randomized controlled clinical trials is highlighted to develop practical recommendations for clinical practice. Lessons learnt from clinical trials – and controversies and future challenges – are all addressed. Readers will find the necessary clinical and scientific foundations for the understanding of the disease, the underpinnings of the pathological processes, the identification of disease biomarkers, and the basis for solid therapeutics. Chapters are authored by an international team of specialists who bring their expertise to improving the management of this disease.

Acoustic characteristics of speech in adolescents with suicidal attempt. Voice, speech and suicidal behaviour

Article

Full-text available

Sep 2022
J HEALTH SCI

Abstract Introduction: Suicide represents the second leading cause of death among adolescents. There are studies that link voice to suicidal risk. Methods: The research was conducted through a cross-sectional study, and the sample was selected through non-probability sampling, which included 40 adolescents between 16 and 19 years old from the city of Temuco. After the identification of suicidal attempts, the participants underwent voice and speech acoustic evaluation. Results: A parameter that showed differences was Jitter (p<0,05). As to the spontaneous speech tasks assessment, it was possible to observe differences in the formants concerning the vast majority of the vowels measured (p<0,05).Some voice and speech indicators differ depending on the group and the task requested. Conclusion: Therefore, these indicators might provide useful information for assessing suicidal behavior. Key words: Voice, suicidal attempt, suicide.

Tuberculosis infection trend over 6 years A retrospective analysis from 2011 to 2016

Article

Full-text available

Sep 2022

Introduction: Tuberculosis (TB) remains the leading cause of death from a single infectious agent and a major public health problem in Europe and worldwide. The present study pretends to characterize and evaluate the tendency of TB infections over a 6-year period. Methods: We performed a retrospective study on patients admitted to a tertiary hospital with tuberculosis, from 2011 to 2016, through electronic medical files’ data collection. Results: We included 591 patients with a peak in 2013, as well as a slight increase in male gender prevalence and length of stay over the 6 years. There was a spike of comorbidities in 2012. A decrease in prevalence in white patients, due to increase in African and Asian was also reported, besides a decline in HIV status, homelessness and IV drugs use. This coincided with an increase in laboratory changes and radiological changes, along with a rise in microbiological resistance. Discussion: Our data is in line with current health policy reports. It is of utmost importance the effort towards control and elimination of TB, through rapid diagnosis, prompt report and complete treatment.

AJHS 37 5

Article

Full-text available

Aug 2022

Angel Arturo López-González

DOXYCYCLINE TO TREAT LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON’S DISEASE: A PROOF-OF-CONCEPT STUDY

Preprint

Full-text available

May 2022

Background Levodopa-induced dyskinesia (LID) is a common motor complication of levodopa therapy in patients with Parkinson’s disease (PD). Doxycycline is a widely used and inexpensive tetracycline with anti-inflammatory properties. Objective Evaluate the efficacy and safety of doxycycline in patients with PD and LID. Methods This was an open-label, single-center, phase 2 proof-of-concept study in patients with PD with mild functional impact of dyskinesia, which used levodopa three times daily, in a movement disorders clinic in Brazil. Participants were treated with doxycycline 200 mg/day for 12 weeks, with evaluations in baseline, week 4, and week 12 of treatment. The primary outcome measure was the change from baseline in the Unified Dyskinesia Rating Scale (UDysRS) total score at week 12, evaluated by two blinded raters. Key secondary outcomes measures were OFF time and ON time with troublesome dyskinesia in the PD home diary. Results Eight patients with PD were treated and evaluated. Doxycycline 200 mg/day reduced the UDysRS total score in week 12, compared with baseline (Friedman’s X ² = 9.6, p = 0.008). Further, doxycycline reduced the ON time with troublesome dyskinesia (Friedman’s X ² = 10.8, p = 0.004) without worsening parkinsonism. There were no severe adverse events, and dyspepsia was the commonest event. Conclusions Doxycycline was effective in reducing LID and safe after a 12-week treatment. Further well-designed placebo-controlled clinical trials with a longer duration and a larger number of participants are needed.

BDNF rs6265 single-nucleotide polymorphism is involved in levodopa-induced dyskinesia in Parkinson’s disease via its regulation of the cortical thickness of the left postcentral gyrus

Article

Jan 2021

Background: Brain-derived neurotrophic factor (BDNF) gene rs6265 single-nucleotide polymorphism (SNP) is thought to be involved in neuroplasticity and influence the development of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). This study aimed to determine how the BDNF rs6265 SNP regulates cortical thickness and to investigate the association between BDNF and the pathological mechanisms of LID in PD. Methods: This cross-sectional study recruited 75 patients with PD, including 37 patients with LID and 38 patients without LID, and 33 healthy controls. All the participants underwent T1-weighted magnetic resonance imaging (MRI) scans, clinical evaluations, and BDNF rs6265 genotyping. Two-way factorial analysis of covariance (ANCOVA) was used to explore the primary effects of disease status, rs6265 genotype, and their interactions on cortical thickness. Associations between cortical thickness in the regions of the brain affected by disease status-genotype interactions and clinical symptoms were detected using Spearman's rank-order correlation. Receiver operating characteristic (ROC) curve analysis was used to test cortical thickness measurements as an indicator of LID. Results: The main effects of disease status were observed in the right pars orbitalis (F=4.229, P=0.017), medial orbitofrontal cortex (F=3.639, P=0.030), and left banks superior temporal sulcus (F=3.172, P=0.046). The left pars orbitalis (F=4.541, P=0.036) and lingual gyrus (F=4.307, P=0.041) were thicker in carriers of the CC genotype than in carriers of the TC/TT genotype. Interaction between disease status and genotype showed that in the LID group, carriers of the CC genotype had a thicker left postcentral gyrus (mean difference =0.103, 95% confidence interval, 0.036 to 0.107, Bonferroni-corrected P<0.005) than did carriers of the TC/TT genotype, whereas no difference was found in the non-LID and healthy control (HC) groups. In carriers of the CC genotype, the cortical thickness of the left postcentral gyrus could identify whether patients with PD had LID, with an area under the receiver operating curve (AUC) of 0.757 (P=0.033, optimal cut-off =2.102). The cortical thickness of the left postcentral gyrus was also positively correlated with the Unified Dyskinesia Rating Scale (UDysRS) score in the LID-CC subgroup (r=0.825, P=0.001). Conclusions: The BDNF rs6265 SNP might be associated with dyskinesia symptoms in patients with PD and LID through its regulation of cortical thickness in the left postcentral gyrus.

Case series investigating the differences between stimulation of rostral zona incerta region in isolation or in conjunction with the subthalamic nucleus on acute clinical effects for Parkinson’s disease

Article

Apr 2022

Background Subthalamic nucleus (STN) deep brain stimulation (DBS) is a highly effective therapy for movement disorders including Parkinson’s disease (PD). One focus of research has been to explore whether stimulation of the rostral zona incerta (rZI) region contributes to the efficacy observed in STN DBS therapy. Objective In this study, we conducted a case series to evaluate the clinical efficacy and adverse effects of stimulation to the rZI region in isolation and in conjunction with STN stimulation. Methods Volunteers with PD (N=5), treated with STN DBS, and determined to have a dorsal contact within the region of rZI were recruited to participate. Following evaluation of tolerability, each volunteer underwent routine motor assessments during three stimulation parameter conditions: STN, rZI, and co-stimulation STN + rZI. Both participant and clinical examiner were blinded to the condition. Efficacy was measured with the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and the Unified Dyskinesia Rating Scale (UDysRS). Volumes of tissue activation for all conditions were assessed for STN and rZI coverage. Results No significant differences between measures of MDS-UPDRS and UDysRS were observed for the three stimulation settings. Although not statistically significant, results showed that 2 participants preferred STN + rZI co- stimulation, 2 participants preferred STN stimulation, and 1 participant preferred rZI stimulation and 4/5 participant preferences were consistent with clinician preference. Conclusions Findings from this case series support further investigation into co-stimulation of the rZI region and STN for PD motor symptoms.

Motor complications associated with chronic levodopa therapy in Parkinson's disease

Article

Full-text available

Dec 1989

Fluctuations and dyskinesias are the 2 main motor complications associated with chronic levodopa therapy. Striatal denervation following degeneration of the substantia nigra dopaminergic projections is probably the major pathophysiologic mechanism underlying motor fluctuations. In addition, pathologic modification of striatal receptors, partially related to the nonphysiologic delivery of levodopa in a discontinuous pulsatile mode, may be responsible for the various types of dyskinesias and sudden "off" episodes. Drugs capable of providing a stable dopaminergic stimulation should be particularly useful for preventing the development of motor complications in patients not yet treated. At the other end of the clinical spectrum, patients with complex fluctuations are the least likely to improve with slow-release levodopa preparations.

Patient compliance with paper and electronic diaries

Article

Full-text available

May 2003
Contr Clin Trials

Paper diaries are commonly used in health care and clinical research to assess patient experiences. There is concern that patients do not comply with diary protocols, possibly invalidating the benefit of diary data. Compliance with paper diaries was examined with a paper diary and with an electronic diary that incorporated compliance-enhancing features. Participants were chronic pain patients and they were assigned to use either a paper diary instrumented to track diary use or an electronic diary that time-stamped entries. Participants were instructed to make three pain entries per day at predetermined times for 21 consecutive days. Primary outcome measures were reported vs actual compliance with paper diaries and actual compliance with paper diaries (defined by comparing the written times and the electronically-recorded times of diary use). Actual compliance was recorded by the electronic diary. Participants submitted diary cards corresponding to 90% of assigned times (+/-15 min). However, electronic records indicated that actual compliance was only 11%, indicating a high level of faked compliance. On 32% of all study days the paper diary binder was not opened, yet reported compliance for these days exceeded 90%. For the electronic diary, the actual compliance rate was 94%. In summary, participants with chronic pain enrolled in a study for research were not compliant with paper diaries but were compliant with an electronic diary with enhanced compliance features. The findings call into question the use of paper diaries and suggest that electronic diaries with compliance-enhancing features are a more effective way of collecting diary information.

CONSORT statement: extension to cluster randomised trials

Article

Full-text available

Apr 2004
Br Med J

The Consolidated Standards of Reporting Trials (CONSORT) statement was developed to improve the reporting of randomised controlled trials. It was initially published in 1996 and focused on the reporting of parallel group randomised controlled trials. The statement was revised in 2001, with a further update in 2010. A separate CONSORT statement for the reporting of abstracts was published in 2008. In earlier papers we considered the implications of the 2001 version of the CONSORT statement for the reporting of cluster randomised trial. In this paper we provide updated and extended guidance, based on the 2010 version of the CONSORT statement and the 2008 CONSORT statement for the reporting of abstracts. Many journals now require that reports of trials conform to the guidelines in the Consolidated Standards of Reporting Trials (CONSORT) statement, first published in 1996,1 revised in 2001,2 and revised most recently in 2010.3 The statement includes a checklist of items that should be included in the trial report. These items are evidence based whenever possible and are regularly reviewed.4 The statement also recommends including a flow diagram to show the progression of participants from group assignment through to the final analysis. An explanation and elaboration of the rationale for the checklist items is provided in an accompanying article.4 The standard CONSORT statement focuses on reporting parallel group randomised controlled trials in which individual participants are randomly assigned to study groups. However, in some situations it is preferable to randomly assign groups of people (such as communities, families, or medical practices) rather than individuals. Reasons include the threat of “contamination” (the unintentional spill-over of intervention effects from one treatment group to another) of some interventions if individual randomisation is used.5 6 Also, in certain settings, randomisation by group may be the only feasible method …

Core assessment program for surgical interventional therapies in Parkinson's disease (CAPSIT‐PD)

Article

Jul 1999
MOVEMENT DISORD

In 1992 the Core Assessment Program for Intracerebral Transplantations (CAPIT) was published providing the minimal requirements for a common patient evaluation protocol. Despite the intent, the program was thought to be too laborious to carry out in large scale trials, and it also lacked evaluations of cognitive functions and quality of life. Moreover, the CAPIT was designed for neural transplantation only and has not been revised since. Since then, pallidotomy and deep brain stimulation have emerged as additional treatment modalities but there exists no common tool for evaluation of, and between, the techniques. In 1996, within the framework of NECTAR (Network for European CNS Transplantation and Restoration), a dedicated program entitled “Neurosurgical Interventions in Parkinson's Disease” (NIPD) was funded by the European Union Biomed 2 program to develop a new Core Assessment Program for Surgical Interventional Therapies in PD (CAPSIT‐PD) and to establish an European registry for patients with PD subjected to functional neurosurgery. This article presents the recommendations of this new program.

ECDEU Assessment Manual for Psychopharmacology

Article

Jan 1976

W. Guy

Drug Insight: New drugs in development for Parkinson's disease

Article

Nov 2006
NAT CLIN PRACT NEURO

For many years, levodopa has given most patients with Parkinson's disease excellent symptomatic benefit. This agent does not slow down the progression of the disease, however, and it can induce motor fluctuations and dyskinesias in the long term. The other available antiparkinsonian agents also have drawbacks, and as a consequence research into antiparkinsonian drugs is expected to take new and different directions in the coming years. The most promising approaches include the development of 'neuroprotective' drugs that are capable of blocking or at least slowing down the degenerative process that is responsible for cellular death; 'restorative' strategies intended to restore normal brain function; more-effective agents for replacing dopamine loss; and symptomatic and antidyskinetic drugs that act on neurotransmitters other than dopamine or target brain areas other than the striatum. In this Review, we discuss the numerous drugs in development that target the primary motor disorder in Parkinson's disease.

Evaluation of Dyskinesias in a Pilot, Randomized, Placebo-Controlled Trial of Remacemide in Advanced Parkinson Disease

Article

Oct 2001
ARCH NEUROL-CHICAGO

Context: Long-term levodopa therapy for Parkinson disease commonly results in motor complications including "on-off" fluctuations and dyskinesias, but it is still unclear how best to assess treatment effects on dyskinesias in clinical trials. Objective: To compare several methods of rating levodopa-induced dyskinesias to evaluate the effect of remacemide hydrochloride treatment in patients with advanced Parkinson disease. Design: Two-week multicenter randomized, double-blind, placebo-controlled, parallel-group study. Setting: Five academic sites of the Parkinson Study Group. Patients: Thirty-nine subjects at least 30 years old with idiopathic Parkinson disease and disabling dyskinesias. Interventions: Randomly received daily doses of 150 mg, 300 mg, or 600 mg of remacemide hydrochloride or matching placebo for 2 weeks. Main outcome measures: The dyskinesia rating scales used were the Modified Goetz Dyskinesia Rating scale (MGDRS), a newly created Lang-Fahn Activities of Daily Living Dyskinesia scale (LFADLDS), and diary dyskinesia ratings. Results: Patient and investigator diaries showed excellent agreement in dyskinesia ratings. The MGDRS score correlated with clinic diary ratings of the percentage of "on" time with dyskinesias, and the LFADLDS score correlated with home and clinic diary assessments of percentage of on time with severe dyskinesias. The MGDRS score did not correlate highly with the LFADLDS score. This pilot study also validated previous results demonstrating the safety and tolerability of remacemide treatment for advanced Parkinson disease but did not result in any demonstrable improvement or worsening in dyskinesia measures. Conclusions: Diaries may provide a valid means of evaluating dyskinesias in clinical trials for Parkinson disease, but there remain other aspects of dyskinesias, as assessed by the MGDRS and LFADLDS, that are not reflected in diary ratings.

Practical Statistics For Medical Research

Article

Jun 1992

Practical Statistic for Medical Research

Article

Nov 1990

DG Altman

Core Assessment Program for Surgical Interventional Therapies in Parkinson's disease (CAPSIT-PD)

Article

Jul 1999
MOVEMENT DISORD

In 1992 the Core Assessment Program for Intracerebral Transplantations (CAPIT) was published providing the minimal requirements for a common patient evaluation protocol. Despite the intent, the program was thought to be too laborious to carry out in large scale trials, and it also lacked evaluations of cognitive functions and quality of life. Moreover, the CAPIT was designed for neural transplantation only and has not been revised since. Since then, pallidotomy and deep brain stimulation have emerged as additional treatment modalities but there exists no common tool for evaluation of, and between, the techniques. In 1996, within the framework of NECTAR (Network for European CNS Transplantation and Restoration), a dedicated program entitled “Neurosurgical Interventions in Parkinson's Disease” (NIPD) was funded by the European Union Biomed 2 program to develop a new Core Assessment Program for Surgical Interventional Therapies in PD (CAPSIT-PD) and to establish an European registry for patients with PD subjected to functional neurosurgery. This article presents the recommendations of this new program.

Idazoxan, an alpha-2 antagonist, and L-DOPA-induced dyskinesias in patients with Parkinson's disease

Article

Jul 2001
MOVEMENT DISORD

Dyskinesia is a frequent and disabling side effect in patients with Parkinson's disease treated with chronic dopatherapy. Preclinical data in the 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) monkey suggest that alpha-2 antagonists may reduce dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. We assessed, in a pilot randomised placebo-controlled study, the effects of single oral doses (10 mg, 20 mg, and 40 mg) of idazoxan, an alpha-2 antagonist, on motor parkinsonian disability and L-DOPA-induced dyskinesia following an acute oral challenge of L-DOPA in 18 patients with Parkinson's disease. The severity of L-DOPA-induced dyskinesia improved after 20 mg idazoxan pretreatment, while there was no concommittant deterioration in the antiparkinsonian response to L-DOPA. These results suggest that blocking alpha-2 receptors in patients with Parkinson's disease might improve L-DOPA-induced dyskinesia without the cost of a return of parkinsonian symptomatology. Further studies are required to assess whether this property could have potential therapeutic applications in the long-term management of dyskinetic patients with Parkinson's disease. © 2001 Movement Disorder Society.

Levodopa‐induced dyskinesias

Article

Jul 2007
MOVEMENT DISORD

Levodopa-induced dyskinesias (LID) are common and difficult to treat. This review focuses on three issues related to LID: clinical features, classification and rating, pathophysiology and pathogenesis, and management. The three primary clinical syndromes are OFF-period dystonia, peak-dose dyskinesia, and diphasic dyskinesia. Several other forms also occur, making the evaluation and choice of treatment complicated. A core component of the pathophysiology of LID is overactivity of the direct striatal output pathway. This pathway provides a direct GABAergic connection by which the striatum inhibits the output regions of the basal ganglia, i.e., the internal globus pallidus and the substantia nigra pars reticulata. Altering dopaminergic dosing and timing can abate dyskinesias, but usually impact the control of parkinsonism. Putative therapies to reduce the problem of dyskinesias could focus on the glutamatergic, GABAergic, 2 adrenergic, serotonergic (5HT1A, 5HT2A), opioid, histamine H3, adenosine A2A receptors, the monoamine transport or cannabinoid CB1 receptors systems. The only currently available drug with an evidence-based recommendation on efficacy for dyskinesia is amantadine. Therapy goals include the prevention of dyskinesia and treatment of dyskinesias that are troublesome clinically. New rating measures to assess severity and disability related to dyskinesia are in the process of development and clinimetric testing. © 2007 Movement Disorder Society

Core Assessment Program for Intrace-rebral Transplantation (CAPIT)

Article

Jan 1992

R 56865 Differentiates between Contractile Agents with Respect to the Nifedipine-Sensitive Component in the Isolated Rat Aorta

Article

Feb 1989

The interaction of the benzothiazolamine R 56865 with the nifedipine-sensitive component of the serotonin (5-HT)-, angiotensin II (AII)- and arginine-vasopressin (AVP)-induced contractions was studied in the isolated rat aorta. Nifedipine caused concentration-dependently (10(-9)-10(-6) mol/l) a slight rightward shift accompanied by a limited depression of the maximum of the concentration-response curves for 5-HT-, AII- and AVP-induced contractions. R 56865 (10(-5) mol/l) antagonized the contraction elicited by 5-HT and AII in a similar manner as nifedipine. The effect of R 56865 on 5-HT- and AII-induced contractions was no longer observed after pretreatment with nifedipine. The AVP-induced contraction was not affected by R 56865 (10(-5) mol/l). As shown previously, R 56865 is a weak inhibitor of potential-operated channels but inactive on Ca2+ channels activated by NA. In conclusion, R 56865 does not only differentiate between depolarization and receptor-stimulation, but also between the activation of Ca2+ channels by different types of receptors. We propose that R 56865 may interact with Ca2+ channels at a site which plays a role in their activation.

Taching tape for the motor section of the Unified Parkinson's Disease Rating Scale

Article

May 1995

We developed a teaching tape of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) to provide investigators with a visual document of three raters' interpretations of the scoring system for each item except rigidity. The rate of agreement for the selected samples was always significant, with Kendall's coefficient of concordance W ranging between 0.97 and 0.62. We also provided full UPDRS ratings on sample patients that may be used for training and for multicenter studies to assure uniformity of rating. The study identified several items of the UPDRS motor examination for which written instructions were vague, including speech, action tremor, finger taps, rapid alternating movements, and postural stability. Future versions of the scale should address these problems and correct ambiguities. This project offers the first attempt to provide a visual analog for the UPDRS.

Utility of an objective dyskinesia rating scale for Parkinson's disease: Inter- and intrarater reliability assessment

Article

Jul 1994

Although dyskinesia is a frequent and important problem in Parkinson's disease (PD), a reliable assessment measure has not been thoroughly developed and tested. We modified the Obeso dyskinesia scale to create an objective rating scale for dyskinesia assessment during activities of daily living. Thirteen physicians and 15 study coordinators involved in a clinical trial independently reviewed videotape segments of PD patients performing three tasks: walking, putting on a coat, and lifting a cup to the lips for drinking. Raters evaluated the severity of worst dyskinesia seen, the types of all dyskinesias seen, and the type of dyskinesia most associated with motoric disability. For all assessments, the total group showed statistically significant inter- and intrarater reliability. Physicians had a higher consistency than did coordinators, but for most measures the difference was not statistically significant. Physicians and coordinators found the scale easy to use and especially practical for rating dyskinesia severity and for identifying the most disabling dyskinesia. Dyskinesias can be assessed in clinical trials and warrant regular documentation.

Efficacy of a patient-training videotape on motor fluctuations for on-off diaries in Parkinson's disease

Article

Nov 1997

Patient on-off diaries are used in clinical trials, but a method to assure agreement between patient and examiner has never been developed. We tested whether a patient-teaching tape increased the rate of agreement between patient diary ratings and simultaneous neurologic assessment by a trained professional. A total of 32 consecutive patients who had Parkinson's disease with motor fluctuations independently completed a 4-h on-off diary (nine ratings) at the same time as an examiner. Those with < 80% agreement with the examiner (n = 20) were randomized to view either a training tape that showed motor fluctuations (experimental group) or-another videotape of general patient educational material (control group). All patients then underwent the same 4-h assessment of motor fluctuations. To test for long-term retention, they returned 1 month later and, without reviewing the videotape, underwent a final 4-h correlation assessment. After the training tape, the experimental group showed significant improvement, whereas the control group showed no improvement. Furthermore, another month later, the improvement in the experimental group was retained. Based on these findings, we suggest that future clinical trials assessing motor fluctuations incorporate this tape into their basic methodology.

Advantages of a modified scoring method for the Rush Video-Based Tic Rating Scale

Article

Jun 1999

Previously, we published a video-based objective rating scale of tics that met reliability and validity criteria for measurement of five domains of tic disability. In the original form, the scale's metric properties did not permit internal comparison of each of the five domains of impairment and did not provide a total score for use as a primary outcome measure. In this study, we retained the original scale and videotape protocol but tested whether a modified scoring system corrected these limitations. The new scoring method rated assigned tic data to ratings of 0-4 on five disability categories: number of body areas, frequency of motor tics, frequency of phonic tics, severity of motor tics, and severity of phonic tics. The sums of these ratings yielded a total score of overall tic disability (0-20). In a series of 31 patients with Gilles de la Tourette syndrome, we assessed Spearman correlation coefficients for the old and new scoring systems as well as the correlation of the new ratings with the objectively derived sections of the Yale Global Tic Severity Scale (YGTSS), another valid and reliable scale used in clinical practice and research. For each domain, the rank order for the scores on the original scale was well retained in the new scores. Likewise, for each domain, ranking with the new scoring system correlated well with scores on the comparable objective item from the YGTSS. The new total score accurately captured the rank order of the combined five domains from the original scale and correlated well with the total objective motor plus phonic tic score from the YGTSS and the YGTSS Tourette Syndrome Overall Impairment Rating. These data demonstrate that the modified videotape-based scoring system retains the essential information gathered in the original Rush scale. The modification provides comparisons among the five assessed domains and a total objectively based disability score that can be used as a single outcome measure for assessing tic disability.

A Unified Dyskinesia Rating Scale for L-dopa-induced dyskinesias?

Article

Feb 1999

John Nutt

Rating scales for dyskinesias in Parkinson's disease

Article

Feb 1999

Christopher G. Goetz

Bezard E, Brotchie JM, Gross CE. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci 2: 577-588

Article

Sep 2001
NAT REV NEUROSCI

Involuntary movements--or dyskinesias--are a debilitating complication of levodopa therapy for Parkinson's disease, and is experienced in most patients. Despite the importance of this problem, little was known about the cause of dyskinesia until recently; however, this situation has changed significantly in the past few years. Our increased understanding of levodopa-induced dyskinesia is not only valuable for improving patient care, but also in providing us with new insights into the functional organization of the basal ganglia and motor systems.

Motor fluctuations and dyskinesia in Parkinson’s disease

Article

Nov 2001
PARKINSONISM RELAT D

John Nutt

Motor fluctuations and dyskinesia are common complications of long-term levodopa therapy. The neural and molecular mechanisms underlying their development are partially understood. A variety of clinical strategies may reduce the unpredictability of motor fluctuations and reduce their impact. Prevention of these complications remains an elusive goal.

Clozapine improves dyskinesias in Parkinson disease: A double-blind, placebo-controlled study

Article

Mar 2004
NEUROLOGY

To investigate the efficacy and safety of clozapine in the treatment of levodopa-induced dyskinesias (LID) in patients with severe Parkinson disease (PD). Fifty patients were randomized to treatment in this 10-week, double-blind, parallel-group, placebo-controlled, multicenter trial. The principal measure of outcome was the diurnal change in the "on" time with LID assessed using a self-evaluation of the motor performance fluctuations performed every 2 weeks. An acute levodopa challenge was also performed at the beginning and end of the study. A reduction in the duration of "on" periods with LID was noted in favor of the clozapine group at the end of the study (placebo group day 0: 4.54 +/- 0.53 hours, end: 5.28 +/- 0.70 hours; clozapine group day 0: 5.68 +/- 0.66 hours, end: 3.98 +/- 0.57 hours; p = 0.003). The mean clozapine dosage was 39.4 +/- 4.5 (SEM) mg/day. The maximal LID score at rest during the levodopa challenge was significantly decreased under clozapine treatment, with a variation from day 0 to day 70 in the placebo group of +0.15 +/- 1.01 and in the clozapine group of -2.22 +/- 0.52 (p < 0.05). Five patients receiving clozapine and seven receiving placebo discontinued on account of adverse events. Among them, three patients in the clozapine group developed eosinophilia, which rapidly resolved after withdrawal of the drug. Clozapine is effective in the treatment of levodopa-induced dyskinesias in severe PD.

Drugs in development for Parkinson's disease

Article

Aug 2004
CURR OPIN INVEST DR

Pharmacological treatment of Parkinson's disease (PD) is entering a new and exciting era. Real promise now exists for the clinical application of a large range of molecules in development that will combat different aspects and stages of the condition. These include methyl- and ethyl-esterified forms of L-dopa (etilevodopa and melevodopa), inhibitors of enzymes such as monoamine oxidase type-B (eg, rasagiline), catechol-O-methyl transferase (eg, BIA-3202) and the monoamine re-uptake mechanism (eg, brasofensine). In addition, a range of full and partial dopamine agonists (eg, sumanirole, piribedil and BP-897) and their new formulations, for example, patch delivery systems (eg, rotigotine) are being developed. We also highlight non-dopaminergic treatments that will have wide ranging applications in the treatment of PD and L-dopa-induced dyskinesia. These include alpha2 adrenergic receptor antagonists (eg, fipamezole), adenosine A2A receptor antagonists (eg, istradefylline), AMPA receptor antagonists (eg, talampanel), neuronal synchronization modulators (eg, levetiracetam) and agents that interact with serotonergic systems such as 5-hydroxytryptamine (5-HT)1A agonists (eg, sarizotan) and 5-HT2A antagonists (eg, quetiapine). Lastly, we examine a growing number of neuroprotective agents that seek to halt or even reverse disease progression. These include anti-apoptotic kinase inhibitors (eg, CEP-1347), modulators of mitochondrial function (eg, creatine), growth factors (eg, leteprinim), neuroimmunophilins (eg, V-10367), estrogens (eg, MITO-4509), c-synuclein oligomerization inhibitors (eg, PAN-408) and sonic hedgehog ligands.

Parkinson's disease home diary: Further validation and implications for clinical trials

Article

Dec 2004

We provide further validation of a Parkinson's disease (PD) home diary and explore implications for practical use in clinical trials. We previously developed and published a home PD diary that includes the categories ASLEEP, off, on without dyskinesia, on with nontroublesome dyskinesia, and on with troublesome dyskinesia [Hauser et al., J Clin Neuropharmacol 2000;23:75-81] and demonstrated that patients generally consider off time and on time with troublesome dyskinesia "bad time" and on time without dyskinesia or with nontroublesome dyskinesia "good time". We suggested that that on time without dyskinesia or with nontroublesome dyskinesia would be an appropriate outcome measure in clinical trials of advanced PD patients. In the current study, PD patients with motor fluctuations and dyskinesia (present more than 25% of the awake day and at least moderately disabling) completed daily diaries on 3 consecutive days in each of 2 consecutive weeks. In addition, patients provided responses to five questions regarding dyskinesia and their motor response through the day on visual analog scales (VAS). Three hundred two patients from 10 countries participated. Eighty-three percent (n = 252) completed six diaries without missing or duplicate entries. Seventy-six percent of the missing or duplicate entries occurred after Day 3. Mean percent of the awake day on without dyskinesia or with nontroublesome dyskinesia ("good on", ONG%) was observed to be very stable over time (repeated measure analysis of variance, P = 0.99). Coefficients of reliability as calculated by Cronbach's alpha were as follows: 2 days, r = 0.806; 3 days, r = 0.868; 4 days, r = 0.918; 5 days, r = 0.934; 6 days, r = 0.946. The standard error of measurement (SEM) was calculated to be 10.75%. VAS responses to the question, "How much of the day today did you experience a good response?" more strongly correlated with ONG% (0.41) than ON% (0.24). The diary appears to be sufficiently simple and feasible. Test-retest reliability was good, and reliability increased with increasing number of diary days but compliance diminished beyond 3 days. Good on time (ONG = on time without dyskinesia or with nontroublesome dyskinesia) most strongly correlated with patients' perceived duration of a good response through the day and is an important outcome variable.

Drugs in development for Parkinson's disease: An update

Article

Feb 2006
CURR OPIN INVEST DR

The current development of emerging pharmacological treatments for Parkinson's disease (PD), front preclinical to launch, is summarized. Advances over the past year are highlighted, including the significant progress of several drugs through various stages of development. Several agents have been discontinued from development, either because of adverse effects or lack of clinical efficacy. The methyl-esterified form of L-DOPA (melevodopa) and the monoamine oxidase type B inhibitor rasagiline have both been launched. With regard to the monoamine re-uptake inhibitors, many changes have been witnessed, with new agents reaching preclinical development and pre-existing ones being discontinued or having no development reported. Of the dopamine agonists, many continue to progress successfully through clinical trials. Others have struggled to demonstrate a significant advantage over currently available treatments and have been discontinued. The field of non-dopaminergic treatments remains dynamic. The alpha2 adrenergic receptor antagonists and the adenosine A2A receptor antagonists remain in clinical trials. Trials of the neuronal' synchronization modulator levetiracetam are at an advanced stage, and there has also been a new addition to the class (ie, seletracetam). There has been a change in the landscape of neuroprotective agents that modulate disease progression. Candidates from the classes of growth factors and glyceraldehyde-3-phosphate dehydrogenase inhibitors have been discontinued, or no development has been reported, and the mixed lineage kinase inhibitor CEP-1347 has been discontinued for PD treatment. Other drugs in this field, such as neuroimmunophilins, estrogens and alpha-synuclein oligomerization inhibitors, remain in development.

Patient Evaluation of a Home Diary to Assess Duration and Severity of Dyskinesia in Parkinson Disease

Article

Nov 2006

To evaluate patient perceptions of a new home diary designed to assess the duration and severity of dyskinesia in patients with Parkinson disease (PD) and to investigate whether the use of a training video and pictograms aids patient understanding of PD terminology. Fifty advanced PD patients (Hoehn and Yahr stage 2.5-4.0; dyskinesia for >25% of the waking day) from the United States (n = 18), France (n = 12), and Germany (n = 20) were allocated alternately to 1 of 2 groups and shown a training video either with pictograms or without pictograms. The video explained the functional states "asleep," "OFF," "ON without dyskinesia," and "ON with dyskinesia," and how to complete the diary. Patients were given the corresponding version of the diary with or without pictograms to complete over a 24-hour period. Patients then participated in a second interview in which they were shown the alternate version of the video and diary for discussion only. Almost 95% of patients (47/50) reported that the video helped them to understand and clarify terms. Most patients [39/50 (78%)] preferred the diary with pictograms, but there was no evidence that pictograms improved the accuracy of diary completion. Overall, 80% of patients (40/50) completed the diaries correctly. Incorrect diary completion was usually because of confusion about the different functional states. Patients perceive diaries with pictograms as more helpful than those with words alone. Videos, in the patients' primary language, are considered valuable training aids that help patients complete daily diaries.

Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan

Article

Jan 2007

This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.

Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD

Article

Jun 2008
NEUROLOGY

Ten-year follow-up results from the Parkinson's Disease Research Group of the United Kingdom trial demonstrated that there were no long-term advantages to initiating treatment with bromocriptine compared with l-dopa in early Parkinson disease (PD). Increased mortality in patients on selegiline combined with l-dopa led to premature termination of this arm after 6 years. Between 1985 and 1990, 782 patients were recruited into an open pragmatic multicenter trial and were randomized to l-dopa/decarboxylase inhibitor (DDCI), l-dopa/DDCI plus selegiline, or bromocriptine. The main endpoints were mortality, disability, and motor complications. For final follow-up, health-related quality of life and mental function were also assessed. Median duration of follow-up at final assessment was 14 years in the 166 (21%) surviving participants who could be contacted. After adjustment for baseline characteristics, disability scores were better in the l-dopa than in the bromocriptine arm (Webster: 16.6 vs 19.8; p = 0.03; Northwestern University Disability: 34.3 vs 30.0, p = 0.05). Physical functioning (difference 20.8; 95% CI 10.0, 31.6; p < 0.001) and physical summary scores (difference 5.2; 95% CI 0.7, 9.7; p = 0.03) on the 36-item short-form health survey were also superior on l-dopa. Differences in mortality rates and prevalence of dyskinesias, motor fluctuations, and dementia were not significantly different. Initial treatment with the dopamine agonist bromocriptine did not reduce mortality or motor disability and the initially reduced frequency in motor complications was not sustained. We found no evidence of a long-term benefit or clinically relevant disease-modifying effect with initial dopamine agonist treatment.

Core assessment pro-gram for intracerebral transplantations (CAPIT) Intracerebral transplantation in movement disorders

Jan 1991
227-241

Langston Jw H Widner
Goetz
Cg

Langston JW, Widner H, Goetz CG, et al. Core assessment pro-gram for intracerebral transplantations (CAPIT). In: Lindvall O, Bjorklund A, Widner H, editors. Intracerebral transplantation in movement disorders. Amsterdam, The Netherlands: Elsevier; 1991. p 227–241.

Unified Parkinson's disease rating scale

Jan 1987
153-164

Elton S Rl Fahn
Committee Development
S Fahn
Marsden
Co
Calne Db
Goldsten

Fahn S, Elton RL, and members of the UPDRS Development Committee. Unified Parkinson's disease rating scale. In: Fahn S, Marsden CO, Calne DB, Goldsten M, editors. Recent develop-ment in Parkinson's disease, Vol.2. Florham Park, NJ: Macmillan Health Care Information; 1987. p 153–164.

Pathophysiology of levodopainduced dyskinesia: potential or new therapies

Jan 2001
NAT REV NEUROSCI
577-588

E Bézard
J M Brotchie
C E Gross

Bézard E, Brotchie JM, Gross CE. Pathophysiology of levodopainduced dyskinesia: potential or new therapies. Nat Rev Neurosci 2001;2:577-588.

Unified Parkinson's disease rating scale Fahn S Marsden CO Calne DB Goldsten M Recent development in Parkinson's disease 2 Florham Park, NJ Macmillan Health Care Information

Fahn S Elton

Pathophysiology of levodopa-induced dyskinesia: potential or new therapies

Jan 2001
577

Bézard

The Unified Dyskinesia Rating Scale: Presentation and Clinimetric Profile

Abstract

No full-text available

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