What Is "Advanced" Parkinson's Disease? Defining What Determines Medicare Coverage for Deep Brain Stimulation in the USA.

BACKGROUND: The National Coverage Determination (NCD) by the Centers for Medicare and Medicaid Services (CMS) for deep brain stimulation requires that a patient have "advanced idiopathic Parkinson's disease (PD) as determined by Hoehn and Yahr (HY) stage or the Unified Parkinson's Disease Rating Scale part III motor subscale (UPDRS III)." How to apply the HY or UPDRS III scales to define "advanced" PD is unclear. SUMMARY: There is an ongoing recovery audit by the CMS of deep brain stimulation cases that were covered by Medicare but are deemed not to have met the NCD requirements and therefore not to have been medically necessary. Whether a hospital is asked to refund Medicare often hinges upon whether medical documentation supports the diagnosis of advanced PD. However, neither the HY nor the UPDRS III scales use "advanced" to define or describe stages of PD. The NCD has an accompanying National Coverage Analysis that reviews the studies that inform the NCD. These studies use "advanced" as well as the HY and UPDRS III scales. This review identifies how the HY and UPDRS III scales were used to categorize advanced PD in the studies that were cited in the National Coverage Analysis. KEY MESSAGES: In the studies used for the NCD for deep brain stimulation for PD, an HY score ≥3 or a UPDRS III score ≥30 was used to describe patient cohorts considered to have advanced PD.

Feasibility of interprofessional partnerships between neurologists and dentists for oral health management of Parkinson's disease.

This dental student-led study aimed to explore the extent to which an interprofessional intervention can be incorporated within the management of Parkinson's Disease (PD) to address the oral health needs of those living with the condition. Existing integrated or interprofessional (IP) care models lack the inclusion of oral health to improve clinical outcomes. We conducted key informant interviews with five neurologists and four dentists to ascertain their willingness, and the process needed, to facilitate collaborative referral management for patients with PD. We conducted a focus group composed of eight patients living with PD to understand their oral health needs and perspective on an integrated oral health management care team. Both neurologists and dentists were receptive IP the idea of integrating oral health into the overall management of patients, with the expectation of improved communication and collaboration. Patients commonly expressed a need for their oral health to be addressed by both neurologists and dentists. These results reveal an opportunity for an IP care model that includes oral health management in the care for patients with PD. It also provides clues on how to incorporate care for PD into a dental education curriculum.

An Artificial Neural Network Predicts Gender Differences of Motor and Non-Motor Symptoms of Patients with Advanced Parkinson's Disease under Levodopa-Carbidopa Intestinal Gel.

Background and Objectives: Currently, no tool exists to predict clinical outcomes in patients with advanced Parkinson's disease (PD) under levodopa-carbidopa intestinal gel (LCIG) treatment. The aim of this study was to develop a novel deep neural network model to predict the clinical outcomes of patients with advanced PD after two years of LCIG therapy. Materials and Methods: This was a longitudinal, 24-month observational study of 59 patients with advanced PD in a multicenter registry under LCIG treatment from September 2019 to September 2021, including 43 movement disorder centers. The data set includes 649 measurements of patients, which make an irregular time series, and they are turned into regular time series during the preprocessing phase. Motor status was assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) Parts III (off) and IV. The NMS was assessed by the NMS Questionnaire (NMSQ) and the Geriatric Depression Scale (GDS), the quality of life by PDQ-39, and severity by Hoehn and Yahr (HY). Multivariate linear regression, ARIMA, SARIMA, and Long Short-Term Memory-Recurrent NeuralNetwork (LSTM-RNN) models were used. Results: LCIG significantly improved dyskinesia duration and quality of life, with men experiencing a 19% and women a 10% greater improvement, respectively. Multivariate linear regression models showed that UPDRS-III decreased by 1.5 and 4.39 units per one-unit increase in the PDQ-39 and UPDRS-IV indexes, respectively. Although the ARIMA-(2,0,2) model is the best one with AIC criterion 101.8 and validation criteria MAE = 0.25, RMSE = 0.59, and RS = 0.49, it failed to predict PD patients' features over a long period of time. Among all the time series models, the LSTM-RNN model predicts these clinical characteristics with the highest accuracy (MAE = 0.057, RMSE = 0.079, RS = 0.0053, mean square error = 0.0069). Conclusions: The LSTM-RNN model predicts, with the highest accuracy, gender-dependent clinical outcomes in patients with advanced PD after two years of LCIG therapy.

Treatment Detection and Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Part III Estimation Using Finger Tapping Tasks.

The validation of objective and easy-to-implement biomarkers that can monitor the effects of fast-acting drugs among Parkinson's disease (PD) patients would benefit antiparkinsonian drug development. We developed composite biomarkers to detect levodopa/carbidopa effects and to estimate PD symptom severity. For this development, we trained machine learning algorithms to select the optimal combination of finger tapping task features to predict treatment effects and disease severity. Data were collected during a placebo-controlled, crossover study with 20 PD patients. The alternate index and middle finger tapping (IMFT), alternative index finger tapping (IFT), and thumb-index finger tapping (TIFT) tasks and the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III were performed during treatment. We trained classification algorithms to select features consisting of the MDS-UPDRS III item scores; the individual IMFT, IFT, and TIFT; and all three tapping tasks collectively to classify treatment effects. Furthermore, we trained regression algorithms to estimate the MDS-UPDRS III total score using the tapping task features individually and collectively. The IFT composite biomarker had the best classification performance (83.50% accuracy, 93.95% precision) and outperformed the MDS-UPDRS III composite biomarker (75.75% accuracy, 73.93% precision). It also achieved the best performance when the MDS-UPDRS III total score was estimated (mean absolute error: 7.87, Pearson's correlation: 0.69). We demonstrated that the IFT composite biomarker outperformed the combined tapping tasks and the MDS-UPDRS III composite biomarkers in detecting treatment effects. This provides evidence for adopting the IFT composite biomarker for detecting antiparkinsonian treatment effect in clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Automatic Assessments of Parkinsonian Gait with Wearable Sensors for Human Assistive Systems.

The rehabilitation evaluation of Parkinson's disease has always been the research focus of human assistive systems. It is a research hotspot to objectively and accurately evaluate the gait condition of Parkinson's disease patients, thereby adjusting the actuators of the human-machine system and making rehabilitation robots better adapt to the recovery process of patients. The rehabilitation evaluation of Parkinson's disease has always been the research focus of rehabilitation robots. It is a research hotspot to be able to objectively and accurately evaluate the recovery of Parkinson's disease patients, thereby adjusting the driving module of the human-machine collaboration system in real time, so that rehabilitation robots can better adapt to the recovery process of Parkinson's disease. The gait task in the Unified Parkinson's Disease Rating Scale (UPDRS) is a widely accepted standard for assessing the gait impairments of patients with Parkinson's disease (PD). However, the assessments conducted by neurologists are always subjective and inaccurate, and the results are determined by the neurologists' observation and clinical experience. Thus, in this study, we proposed a novel machine learning-based method of automatically assessing the gait task in UPDRS with wearable sensors as a more convenient and objective alternative means for PD gait assessment. In the design, twelve gait features, including three spatial-temporal features and nine kinematic features, were extracted and calculated from two shank-mounted IMUs. A novel nonlinear model is developed for calculating the score of gait task from the gait features. Twenty-five PD patients and twenty-eight healthy subjects were recruited for validating the proposed method. For comparison purpose, three traditional models, which have been used in previous studies, were also tested by the same dataset. In terms of percentages of participants, 84.9%, 73.6%, 73.6%, and 66.0% of the participants were accurately assigned into the true level with the proposed nonlinear model, the support vector machine model, the naive Bayes model, and the linear regression model, respectively, which indicates that the proposed method has a good performance on calculating the score of the UPDRS gait task and conformance with the rating done by neurologists.

Ambiental Factors in Parkinson's Disease Progression: A Systematic Review.

Background and Objectives: So far, there is little evidence of the ambient effect on motor and non-motor symptoms of Parkinson's Disease (PD). This systematic review aimed to determine the association between ambiental factors and the progression of PD. Materials and Methods: A systematic literature search of PubMed, Cochrane, Embase, and Web of Science was conducted up to 21 December 2021 according the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Eight articles were used in the analyses. Long-term exposure to fine particles (particulate matter ≤ 2.5 µm; PM2.5) was positively associated with disease aggravation in two studies. Short-term PM2.5 exposure was positively associated with disease aggravation in three studies. Significant associations were found between PD aggravation and NO2, SO2, CO, nitrate and organic matter (OM) concentrations in two studies. Associations were more pronounced, without reaching statistical significance however, in women, patients over 65 years old and cold temperatures. A 1% increase in temperature was associated with a significant 0.18% increase in Levodopa Equivalent Dose (LED). Ultraviolet light and humidity were not significantly associated with an increase in LED. There was no difference in hallucination severity with changing seasons. There was no evidence for seasonal fluctuation in Unified Parkinson's Disease Rating Scale (UPDRS) scores. Conclusions: There is a link between air pollutants and temperature for PD progression, but this has yet to be proven. More longitudinal studies are warranted to confirm these findings.

Self-Report versus Clinician Examination in Early Parkinson's Disease.

BACKGROUND: Evaluating the discrepancies between patient-reported measures and clinician examination has implications for formulating individual treatment regimens. OBJECTIVE: This study investigated the association between health outcomes and level of self-reported motor-related function impairment relative to clinician-examined motor signs. METHODS: Recently diagnosed PD patients were evaluated using the Parkinson's Progression Marker Initiative (PPMI, N = 420) and the PASADENA phase II clinical trial (N = 316). We calculated the average normalized difference between each participant's part II and III MDS-UPDRS (Movement Disorder Society Unified Parkinson's Disease Rating Scale) scores. Individuals with score differences <25th or >75th percentiles were labeled as low- and high-self-reporters, respectively (those between ranges were labeled intermediate-self-reporters). We compared a wide range of clinical/biomarker readouts among these three groups, using Kruskal-Wallis nonparametric and Pearson's χ2 tests. Spearman's correlations were tested for associations between MDS-UPDRS subscales. RESULTS: In both cohorts, high-self-reporters reported the largest impairment/symptom experience for most motor and nonmotor patient-reported variables. By contrast, these high-self-reporters were similar to or less impaired on clinician-examined and biomarker measures. Patient-reported nonmotor symptoms on MDS-UPDRS part IB showed the strongest positive correlation with self-reported motor-related impairment (PPMI rs  = 0.54, PASADENA rs  = 0.52). This correlation was numerically stronger than the part II and clinician-examined MDS-UPDRS part III correlation (PPMI rs  = 0.38, PASADENA rs  = 0.28). CONCLUSION: Self-reported motor-related impairments reflect not only motor signs/symptoms but also other self-reported nonmotor measures. This may indicate (1) a direct impact of nonmotor symptoms on motor-related functioning and/or (2) the existence of general response tendencies in how patients self-rate symptoms. Our findings suggest further investigation into the suitability of MDS-UPDRS II to assess motor-related impairments. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinical correlates of serum 25-hydroxyvitamin D in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) patients have lower levels of serum 25-hydroxyvitamin D (25(OH)D) than the general population. Previous studies have suggested a negative association between 25(OH)D and clinical features of PD, but the data are inconsistent. MATERIALS AND METHODS: We conducted a cross-sectional, observational study. Serum 25(OH)D, disease (Hoehn-Yahr stage [HY]) and clinical symptom (Unified Parkinson Disease Rating Scale [UPDRS]) severity and global cognitive functions (Mini-Mental State Examination [MMSE]) were studied in 500 consecutive PD patients not using vitamin D supplements. Information on sunlight exposure and dietary intakes (using a 66-item food frequency questionnaire) were also collected. A convenient sample of age and sex-matched community healthy controls (N = 100) was included as a control group. RESULTS: PD patients had lower 25(OH)D serum levels than controls. Deficiency status (<20 ng/mL) was found in 65.6% of patients. 25(OH)D levels were independently correlated to sunlight exposure (P = .002) and vitamin D intake (P = .009). In multivariate models, using a Mendelian randomization approach, lower serum 25(OH)D was associated with more severe disease (HY, P = .035), worse clinical symptoms (UPDRS Part-III total score [P = .006] and dopaminergic [P = .033] and non-dopaminergic subscores [P = .001]) and greater global cognitive function impairment (P = .041). Neither cognitive functions nor clinical features were associated with reduced intake of vitamin D and sunlight exposure. CONCLUSION: : Serum 25(OH)D was negatively correlated with disease and symptoms severity, as well as with global cognitive functions. Our study adds to the evidence that low 25(OH)D may affect the progression of PD negatively. Intervention studies in this area are required.

Migraine, Tension-Type Headache and Parkinson's Disease: A Systematic Review and Meta-Analysis.

Background and Objectives: The relationship between migraine and tension-type headache (TTH) with Parkinson's disease (PD) is controversial, while a common pathophysiological link remains obscure. The aim of this systematic review is to investigate the association between PD, migraine and TTH. Materials and Methods: Following PRISMA, we searched MEDLINE, WebofScience, Scopus, CINAHL, Cochrane Library and ClinicalTrials.gov up to 1 July 2022 for observational studies examining the prevalence and/or associations of PD with migraine and TTH. We pooled proportions, standardized mean differences (SMD) and odds ratios (OR) with random effects models. The risk of bias was assessed with the Newcastle-Ottawa scale (PROSPERO CRD42021273238). Results: Out of 1031 screened studies, 12 were finally included in our review (median quality score 6/9). The prevalence of any headache among PD patients was estimated at 49.1% (760 PD patients; 95% CI 24.8-73.6), migraine prevalence at 17.2% (1242 PD patients; 95% CI 9.9-25.9), while 61.5% (316 PD patients; 95% CI 52.6-70.1) of PD patients with migraine reported headache improvement after PD onset. Overall, migraine was not associated with PD (302,165 individuals; ORpooled = 1.11; 95% CI 0.72-1.72).However, cohort studies demonstrated a positive association of PD among lifetime migraineurs (143,583 individuals; ORpooled = 1.54, 95% CI 1.28-1.84), while studies on 12-month migraine prevalence yielded an inverse association (5195 individuals; ORpooled = 0.64, 95% CI 0.43-0.97). Similar findings were reported by 3 studies with data on the TTH-PD relationship (high prevalence, positive association when examined prospectively and an inverse relationship on 12-month prevalence). These data were not quantitatively synthesized due to methodological differences among the studies. Finally, PD patients suffering from any headache had a lower motor unified Parkinson's disease rating scale (UPDRS) score (503 PD patients; SMD -0.39; 95% CI -0.57 to -0.21) compared to PD patients not reporting headache. There is an unclear association of headaches in genetic PD cohorts. Conclusions: Observational data suggest that migraine and TTH could be linked to PD, but the current literature is conflicting.

Modelling item scores of Unified Parkinson's Disease Rating Scale Part III for greater trial efficiency.

AIMS: The multipart Unified Parkinson's Disease Rating Scale is the standard instrument in clinical trials. A sum of scores for all items in 1 or more parts of the instrument is usually analysed. Without accounting for relative importance of individual items, this sum of scores conceivably does not optimize the power of the instrument. The aim was to compare the ability to detect drug effect in slowing down motor function deterioration, as measured by Part III of the Scale-motor examinations-between the item scores and the sum of scores. METHODS: We used data from 423 patients in a Parkinson's disease progression trial to estimate the symptom severity by item response modelling; modelled symptom progression using the severity and the sum of scores; and conducted simulations to compare the sensitivity of detecting a broad range of hypothetical drug effects on progression using the severity and the sum of scores. RESULTS: The severity endpoint was far more sensitive than the sum of scores for detecting treatment effects, e.g. requiring 275 vs. 625 patients per arm to achieve 60% probability of trial success for detecting a range of potential effects in a 2-year trial. Nontremor items related to the left side of the body seemed most informative. The domain relevance of tremor items appeared questionable. CONCLUSION: This analysis generated clear evidence that longitudinal modelling of item scores can enhance trial efficiency and success. It also called for reassessing the placement of the tremor items in the instrument.

Ropinirole Patch Versus Placebo, Ropinirole Extended-Release Tablet in Advanced Parkinson's Disease.

BACKGROUND: A dopamine agonist patch is an important treatment option for PD. OBJECTIVES: A randomized, double-blind, parallel-group, placebo-controlled trial was conducted to evaluate superiority of ropinirole hydrochloride patch over placebo and noninferiority to ropinirole hydrochloride extended-release tablet. METHODS: PD patients using levodopa received ropinirole patch (up to 64 mg/d), ropinirole tablets (up to 16 mg/d), or placebo once-daily (double-dummy technique). The primary endpoint was the change from baseline in the total score for the UPDRS Part III (on state) at week 16. RESULTS: The change of the least squares mean (95% confidence interval) in the UPDRS Part III total score was -9.8 (-10.8 to -8.7) with ropinirole patch, -4.3 (-5.8 to -2.8) with placebo, and -10.1 (-11.2 to -9.1) with ropinirole tablet. The difference between the ropinirole patch and placebo groups was -5.4 (-7.3 to -3.6), demonstrating superiority of the patch over placebo. The difference between the ropinirole patch and tablet groups was 0.3 (-1.2 to 1.8). The upper limit of the 95% confidence interval was smaller than the noninferiority limit of 2.5, demonstrating noninferiority of ropinirole patch to ropinirole tablet. In all three groups, most adverse events were mild or moderate and there were no serious safety concerns. CONCLUSIONS: Once-daily ropinirole patch was effective in advanced PD patients, having demonstrated superiority over placebo and noninferiority to ropinirole tablet, without causing serious safety problems. Ropinirole patch can be an alternative option for PD patients. © 2020 International Parkinson and Movement Disorder Society.

Clinical, pathophysiological and genetic features of motor symptoms in autosomal dominant Alzheimer's disease.

Owing to an early and marked deposition of amyloid-ß in the basal ganglia, autosomal dominant Alzheimer's disease could distinctly involve motor symptoms. Therefore, we aimed to assess the prevalence and characteristics of motor signs in autosomal dominant Alzheimer's disease. Baseline Unified Parkinson Disease Rating Scale part three scores (UPDRS-III) from 433 participants of the Dominantly Inherited Alzheimer's Network observational study were analysed. Motor symptoms were scrutinized with respect to associations with mutation carrier status, mutation site within PSEN1, basal ganglia amyloid-ß as measured by Pittsburgh compound B PET, estimated years to symptom onset and Clinical Dementia Rating Scale-Sum of Boxes. Motor findings in mutation carriers were compared to patients with sporadic Alzheimer's disease using data of the National Alzheimer's Coordination Center. Mutation carriers showed motor findings at a higher frequency (28.4% versus 12.8%; P < 0.001) and severity (mean UPDRS-III scores 2.0 versus 0.4; P < 0.001) compared to non-carriers. Eleven of the 27 UPDRS-III items were statistically more frequently affected in mutation carriers after adjustment for multiple comparisons. Ten of these 11 items were subscale components of bradykinesia. In cognitively asymptomatic mutation carriers, dysdiadochokinesia was more frequent compared to non-carriers (right hand: 3.8% versus 0%; adjusted P = 0.023; left: 4.4% versus 0.6%; adjusted P = 0.031). In this cohort, the positive predictive value for mutation carrier status in cognitively asymptomatic participants (50% a priori risk) of dysdiadochokinesia was 100% for the right and 87.5% for the left side. Mutation carriers with motor findings more frequently were basal ganglia amyloid-ß positive (84% versus 63.3%; P = 0.006) and showed more basal ganglia amyloid-ß deposition (Pittsburgh compound B-standardized uptake value ratio 2.472 versus 1.928; P = 0.002) than those without. Frequency and severity of motor findings were greater in post-codon 200 PSEN1 mutations (36%; mean UPDRS-III score 3.03) compared to mutations pre-codon 200 PSEN1 (19.3%, P = 0.022; 0.91, P = 0.013). In mutation carriers, motor symptom severity was significantly positively correlated with basal ganglia amyloid-ß deposition, Clinical Dementia Rating scores and estimated years to symptom onset. Mutation carriers with a Clinical Dementia Rating global score of 2 exhibited more pronounced motor symptoms than sporadic Alzheimer's disease patients with the same Clinical Dementia Rating global score (mean UPDRS-III scores 20.71 versus 5.96; P < 0.001). With a prevalence of approximately 30% and increasing severity with progression of dementia, motor symptoms are proven as a clinically relevant finding in autosomal dominant Alzheimer's disease, in particular in advanced dementia stages, that correlates with deposition of amyloid-ß in the basal ganglia. In a very small per cent of cognitively asymptomatic members of families with autosomal dominant Alzheimer's disease, dysdiadochokinesia may increase the chance of an individual's status as mutation carrier.

Base-peak assessment of levodopa response and detection of fluctuating patients in Parkinson's disease.

OBJECTIVES: This study aims to evaluate the base-peak difference in levodopa response for detecting patients with motor fluctuations in Parkinson's disease (PD). METHODS: Two independent PD samples were evaluated at baseline and 2 h after the administration of the usual morning dose of levodopa using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III). The presence of motor fluctuations was defined by the UPDRS-IV. We quantified the magnitude of motor variation as absolute (Δ) and percentage (Δ%) change in UPDRS-III scores. Optimal cut-offs for each index distinguishing patients with or without fluctuations were calculated on the exploratory population. The accuracy of the identified cut-offs was then verified in a testing population. RESULTS: In the exploratory population (N = 26), the optimal cut-off for detecting fluctuations was a Δ of 6 points and a Δ% of 18.4%. When we applied the identified thresholds to the testing population (N = 139), we found a sensitivity of 93.8% (95% CI: 89.7 to 97.8) and a specificity of 91.2% (95% CI: 86.5 to 95.9) for Δ, 83.3% (95% CI: 77.1 to 89.5) and 86.8% (95% CI: 81.2 to 92.4) for Δ%, respectively. CONCLUSIONS: The assessment of levodopa usual morning dose response through the base-peak evaluation represents an accurate method for detecting parkinsonian patients with motor fluctuations, and for defining the Minimal Important Difference (MID) in levodopa response suggesting the presence of motor fluctuations in PD patients demanding further therapeutic interventions.

Does the M.D. Anderson Dysphagia Inventory correlate with dysphagia-limit and the Unified Parkinson Disease Rating Scale in early-stage Parkinson's disease?

BACKGROUND: Dysphagia is a common and critical condition that occurs in Parkinson's disease (PD), and it may appear in early stages. However, few reliable swallowing-related questionnaires are currently available. Therefore, finding efficient questionnaires for surveying dysphagia during the early stages of PD is necessary. PURPOSE: This prospective study aimed to identify the correlations between the M.D. Anderson Dysphagia Inventory (MDADI) with dysphagia limit (DL) and the Unified Parkinson Disease Rating Scale (UPDRS) in early-stage PD. METHODS: Forty-two patients with early-stage PD were recruited from a medical center. Data were collected for analysis of swallowing-related quality of life using the MDADI, symptom severity using the UPDRS, and DL using a noninvasive swallowing-respiration assessment system. RESULTS: Our results showed that the MDADI, including its composite and subscales, was not correlated with DL. The composite scores of the MDADI were moderately correlated with the total score of the UPDRS (r = -0.504; p < 0.05) as well as with the second and third sections of the UPDRS scores (r = -0.453 to -0.478; p < 0.05). These results indicated that the impaired MDADI score can predict symptom severity (UPDRS), especially in activities of daily life and motor function. CONCLUSION: The impaired MDADI for early-stage PD was determined, and decreased DL as a presentation of dysphagia could not be reflected by the MDADI. The MDADI may be used as a quick and convenient questionnaire for predicting the severity of early-stage PD, but not for the screening of early or subclinical dysphagia.

A double-blind randomized controlled trial to assess efficacy of bromocriptine in cirrhotic patients with hepatic parkinsonism.

BACKGROUND: Parkinsonism like features can be seen in cirrhotics, possibly related to alterations in brain dopamine metabolism, transport and receptor integrity at basal ganglia. Hepatic parkinsonism is often not suspected and only ammonia-reducing therapies are given to such patients. We investigated the efficacy and safety of bromocriptine, a dopaminergic agent, in patients with hepatic parkinsonism. PATIENTS AND METHODS: Cirrhotics were screened for the presence of extrapyramidal symptoms and were diagnosed as hepatic parkinsonism if any two of tremor, bradykinesia and/or rigidity were present, supported by MRI brain showing T1 hyperintensities in basal ganglia and substantia nigra. Patients were randomized to receive placebo (Gr A, n = 22) or bromocriptine (Gr B, n = 24) for 12 weeks. Complete, partial and non-response were defined as 30%, 10%-30% and <10% reduction,respectively, in Unified Parkinson's Disease Rating Scale motor score. RESULTS: Of 1016 cirrhotics, 50 (4.9%) had hepatic parkinsonism. Patients in two treatment groups were comparable for MELD score, arterial NH3 and frequency of portosystemic shunts. Bromocriptine therapy for 12 weeks resulted in improvement in rigidity, tremors, bradykinesia and gait compared to placebo with complete and partial response in seven vs none (29.1%, 0%, P < 0.01) and 12 vs one (50%, 4.5%, P < 0.01) patients. Prolonged and more severe motor symptoms were associated with non-response to bromocriptine therapy. There were no major side effects in either treatment group. CONCLUSIONS: Hepatic parkinsonism is seen in ~5% cirrhotics. Bromocriptine is a safe and effective therapy for these patients and is more effective in mild to moderate hepatic parkinsonism.

Item Response Model Adaptation for Analyzing Data from Different Versions of Parkinson's Disease Rating Scales.

PURPOSE: The aim of this work was to allow combination of information from recent and historical trials in Parkinson's Disease (PD) by developing bridging methodology between two versions of the clinical endpoint. METHODS: A previously developed Item Response Model (IRM), that described longitudinal changes in Movement Disorder Society (MDS) sponsored revision of Unified Parkinson's Disease Rating Scale (UPDRS) [MDS-UPDRS] data from the De Novo PD cohort in Parkinson's Progression Markers Initiative, was first adapted to describe baseline UPDRS data from two clinical trials, one in subjects with early PD and another in subjects with advanced PD. Assuming similar IRM structure, items of the UPDRS version were mapped to those in the MDS-UPDRS version. Subsequently, the longitudinal changes in the placebo arm of the advanced PD study were characterized. RESULTS: The parameters reflecting differences in the shared items between endpoints were successfully estimated, and the model diagnostics indicated that mapping was better for early PD subjects (closer to De Novo cohort) than for advanced PD subjects. Disease progression for placebo in advanced PD patients was relatively shallow. CONCLUSION: An IRM able to handle two variants of clinical PD endpoints was developed; it can improve the utilization of data from diverse sources and diverse disease populations.

Improved accuracy using a modified registration method of ROSA in deep brain stimulation surgery.

OBJECTIVE The aim of this study was to determine whether a modified registration method could reduce registration error and postoperative electrode vector error and to analyze the method's clinical significance in deep brain stimulation (DBS) surgery. METHODS The first part of the study involved a skull model, in which three registration methods were tested using the ROSA (robotic stereotactic assistance) system. In the second part, four registration methods were clinically tested in patients undergoing DBS surgery using the ROSA system. Thirty-three patients (65 sides, group I) underwent the conventional registration method 2E, and registration errors were recorded. Thirty-eight patients (75 sides, group II) underwent four types of modified registration methods including 2A, 2B, 2C, and 2D. Registration and electrode vector errors, intraoperative electrophysiological signal length (IESL), and DBS power-on voltage were recorded. The primary measure of efficacy was the change in the Unified Parkinson's Disease Rating Scale (UPDRS) and UPDRS Part III scores from baseline to 10 weeks after surgery. RESULTS In the skull model, the registration error (mean ± SD) was 0.56 ± 0.11 mm for method 1A, 0.35 ± 0.11 mm for method 1B (vs. 1A, p < 0.001), and 0.90 ± 0.15 mm for method 1C (vs. 1A, p < 0.001). In the clinical study, method 2C was selected for DBS surgery in group II since it had the smallest registration error among the four methods tested. The registration error was 0.62 ± 0.22 mm (mean ± SD) for group I and 0.27 ± 0.07 mm for group II (p < 0.001). Postoperative electrode vector error was 0.97 ± 0.31 mm for group I and 0.65 ± 0.23 mm for group II (p < 0.001). There was a positive correlation between registration error and electrode vector error in both groups (group I: r = 0.69, p < 0.001; group II: r = 0.71, p < 0.001). The mean IESL was 5.0 ± 0.9 mm in group I and 5.8 ± 0.7 mm in group II (p < 0.001). The mean DBS power-on voltage was 1.63 ± 0.44 V in group I and 1.48 ± 0.38 V in group II (p = 0.027). In the UPDRS score, group I showed 50% ± 16% improvement and group II showed 52% ± 18% improvement (p = 0.724); there was no statistically significant difference in improvement on the UPDRS. CONCLUSIONS In DBS surgery assisted by the ROSA system, registration error and electrode vector error showed a positive correlation. The modified registration method could reduce the registration error and electrode vector error, but the long-term effects need to be further observed and evaluated.

High-intensity focused ultrasound: past, present, and future in neurosurgery.

Since Lynn and colleagues first described the use of focused ultrasound (FUS) waves for intracranial ablation in 1942, many strides have been made toward the treatment of several brain pathologies using this novel technology. In the modern era of minimal invasiveness, high-intensity focused ultrasound (HIFU) promises therapeutic utility for multiple neurosurgical applications, including treatment of tumors, stroke, epilepsy, and functional disorders. Although the use of HIFU as a potential therapeutic modality in the brain has been under study for several decades, relatively few neuroscientists, neurologists, or even neurosurgeons are familiar with it. In this extensive review, the authors intend to shed light on the current use of HIFU in different neurosurgical avenues and its mechanism of action, as well as provide an update on the outcome of various trials and advances expected from various preclinical studies in the near future. Although the initial technical challenges have been overcome and the technology has been improved, only very few clinical trials have thus far been carried out. The number of clinical trials related to neurological disorders is expected to increase in the coming years, as this novel therapeutic device appears to have a substantial expansive potential. There is great opportunity to expand the use of HIFU across various medical and surgical disciplines for the treatment of different pathologies. As this technology gains recognition, it will open the door for further research opportunities and innovation.

Preliminary experience with a transcranial magnetic resonance-guided focused ultrasound surgery system integrated with a 1.5-T MRI unit in a series of patients with essential tremor and Parkinson's disease.

OBJECTIVE Transcranial magnetic resonance-guided focused ultrasound surgery (tcMRgFUS) is one of the emerging noninvasive technologies for the treatment of neurological disorders such as essential tremor (ET), idiopathic asymmetrical tremor-dominant Parkinson's disease (PD), and neuropathic pain. In this clinical series the authors present the preliminary results achieved with the world's first tcMRgFUS system integrated with a 1.5-T MRI unit. METHODS The authors describe the results of tcMRgFUS in a sample of patients with ET and with PD who underwent the procedure during the period from January 2015 to September 2017. A monolateral ventralis intermedius nucleus (VIM) thalamic ablation was performed in both ET and PD patients. In all the tcMRgFUS treatments, a 1.5-T MRI scanner was used for both planning and monitoring the procedure. RESULTS During the study period, a total of 26 patients underwent tcMRgFUS thalamic ablation for different movement disorders. Among these patients, 18 were diagnosed with ET and 4 were affected by PD. All patients with PD were treated using tcMRgFUS thalamic ablation and all completed the procedure. Among the 18 patients with ET, 13 successfully underwent tcMRgFUS, 4 aborted the procedure during ultrasound delivery, and 1 did not undergo the tcMRgFUS procedure after stereotactic frame placement. Two patients with ET were not included in the results because of the short follow-up duration at the time of this study. A monolateral VIM thalamic ablation in both ET and PD patients was performed. All the enrolled patients were evaluated before the treatment and 2 days after, with a clinical control of the treatment effectiveness using the graphic items of the Fahn-Tolosa-Marin tremor rating scale. A global reevaluation was performed 3 months (17/22 patients) and 6 months (11/22 patients) after the treatment; the reevaluation consisted of clinical questionnaires, neurological tests, and video recordings of the tests. All the ET and PD treated patients who completed the procedure showed an immediate amelioration of tremor severity, with no intra- or posttreatment severe permanent side effects. CONCLUSIONS Although this study reports on a small number of patients with a short follow-up duration, the tcMRgFUS procedure using a 1.5-T MRI unit resulted in a safe and effective treatment option for motor symptoms in patients with ET and PD. To the best of the authors' knowledge, this is the first clinical series in which thalamotomy was performed using tcMRgFUS integrated with a 1.5-T magnet.

Comparison of Awake vs. Asleep Surgery for Subthalamic Deep Brain Stimulation in Parkinson's Disease.

BACKGROUND: Deep brain stimulation (DBS) surgery for Parkinson's disease (PD) is usually performed as awake surgery allowing sufficient intraoperative testing. Recently, outcomes after asleep surgery have been assumed comparable. However, direct comparisons between awake and asleep surgery are scarce. OBJECTIVE: To investigate the difference between awake and asleep surgery comparing motor and nonmotor outcome after subthalamic nucleus (STN)-DBS in a large single center PD population. METHODS: Ninety-six patients were retrospectively matched pairwise (48 asleep and 48 awake) and compared regarding improvement of Unified PD Rating Scale Motor Score (UPDRS-III), cognitive function, Levodopa-equivalent-daily-dose (LEDD), stimulation amplitudes, side effects, surgery duration, and complication rates. Routine testing took place at three months and one year postoperatively. RESULTS: Chronic DBS effects (UPDRS-III without medication and with stimulation on [OFF/ON]) significantly improved UPDRS-III only after awake surgery at three months and in both groups one year postoperatively. Acute effects (percentage UPDRS-III reduction after activation of stimulation) were also significantly better after awake surgery at three months but not at one year compared to asleep surgery. UPDRS-III subitems "freezing" and "speech" were significantly worse after asleep surgery at three months and one year, respectively. LEDD was significantly lower after awake surgery only one week postoperatively. The other measures did not differ between groups. CONCLUSIONS: Overall motor function improved faster in the awake surgery group, but the difference ceased after one year. However, axial subitems were worse in the asleep surgery group suggesting that worsening of axial symptoms was risked improving overall motor function. Awake surgery still seems advantageous for STN-DBS in PD, although asleep surgery may be considered with lower threshold in patients not suitable for awake surgery.