A Screening Tool to Quickly Identify Movement Disorders in Patients with Inborn Errors of Metabolism.

BACKGROUND: Movement disorders are frequent in patients with inborn errors of metabolism (IEMs) but poorly recognized, particularly by nonmovement disorder specialists. We propose an easy-to-use clinical screening tool to help recognize movement disorders. OBJECTIVE: The aim is to develop a user-friendly rapid screening tool for nonmovement disorder specialists to detect moderate and severe movement disorders in patients aged ≥4 years with IEMs. METHODS: Videos of 55 patients with different IEMs were scored by experienced movement disorder specialists (n = 12). Inter-rater agreements were determined on the presence and subtype of the movement disorder. Based on ranking and consensus, items were chosen to be incorporated into the screening tool. RESULTS: A movement disorder was rated as present in 80% of the patients, with a moderate inter-rater agreement (κ =0.420, P < 0.001) on the presence of a movement disorder. When considering only moderate and severe movement disorders, the inter-rater agreement increased to almost perfect (κ = 0.900, P < 0.001). Dystonia was most frequently scored (27.3%) as the dominant phenotype. Treatment was mainly suggested for patients with moderate or severe movement disorders. Walking, observations of the arms, and drawing a spiral were found to be the most informative tasks and were included in the screening tool. CONCLUSIONS: We designed a screening tool to recognize movement disorders in patients with IEMs. We propose that this screening tool can contribute to select patients who should be referred to a movement disorder specialist for further evaluation and, if necessary, treatment of the movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Preoperative Electroencephalography-Based Machine Learning Predicts Cognitive Deterioration After Subthalamic Deep Brain Stimulation.

BACKGROUND: Subthalamic deep brain stimulation (STN DBS) may relieve refractory motor complications in Parkinson's disease (PD) patients. Despite careful screening, it remains difficult to determine severity of alpha-synucleinopathy involvement which influences the risk of postoperative complications including cognitive deterioration. Quantitative electroencephalography (qEEG) reflects cognitive dysfunction in PD and may provide biomarkers of postoperative cognitive decline. OBJECTIVE: To develop an automated machine learning model based on preoperative EEG data to predict cognitive deterioration 1 year after STN DBS. METHODS: Sixty DBS candidates were included; 42 patients had available preoperative EEGs to compute a fully automated machine learning model. Movement Disorder Society criteria classified patients as cognitively stable or deteriorated at 1-year follow-up. A total of 16,674 EEG-features were extracted per patient; a Boruta algorithm selected EEG-features to reflect representative neurophysiological signatures for each class. A random forest classifier with 10-fold cross-validation with Bayesian optimization provided class-differentiation. RESULTS: Tweny-five patients were classified as cognitively stable and 17 patients demonstrated cognitive decline. The model differentiated classes with a mean (SD) accuracy of 0.88 (0.05), with a positive predictive value of 91.4% (95% CI 82.9, 95.9) and negative predictive value of 85.0% (95% CI 81.9, 91.4). Predicted probabilities between classes were highly differential (hazard ratio 11.14 [95% CI 7.25, 17.12]); the risk of cognitive decline in patients with high probabilities of being prognosticated as cognitively stable (>0.5) was very limited. CONCLUSIONS: Preoperative EEGs can predict cognitive deterioration after STN DBS with high accuracy. Cortical neurophysiological alterations may indicate future cognitive decline and can be used as biomarkers during the DBS screening. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Differential response to pallidal deep brain stimulation among monogenic dystonias: systematic review and meta-analysis.

OBJECTIVE: Genetic subtypes of dystonia may respond differentially to deep brain stimulation of the globus pallidus pars interna (GPi DBS). We sought to compare GPi DBS outcomes among the most common monogenic dystonias. METHODS: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines. We searched PubMed for studies on genetically confirmed monogenic dystonia treated with GPi DBS documenting pre-surgical and post-surgical assessments using the Burke-Fahn-Marsden Dystonia Rating Scale Motor Score (BFMMS) and Burke-Fahn-Marsden Disability Score (BFMDS). We performed (i) meta-analysis for each gene mutation; (ii) weighted ordinary linear regression analyses to compare BFMMS and BFMDS outcomes between DYT-TOR1A and other monogenic dystonias, adjusting for age and disease duration and (iii) weighted linear regression analysis to estimate the effect of age, sex and disease duration on GPi DBS outcomes. Results were summarised with mean change and 95% CI. RESULTS: DYT-TOR1A (68%, 38.4 points; p<0.001), DYT-THAP1 (37% 14.5 points; p<0.001) and NBIA/DYT-PANK2 (27%, 21.4 points; p<0.001) improved in BFMMS; only DYT-TOR1A improved in BFMDS (69%, 9.7 points; p<0.001). Improvement in DYT-TOR1A was significantly greater than in DYT-THAP1 (BFMMS -31%), NBIA/DYT-PANK2 (BFMMS -35%; BFMDS -53%) and CHOR/DYT-ADCY5 (BFMMS -36%; BFMDS -42%). Worse motor outcomes were associated with longer dystonia duration and older age at dystonia onset in DYT-TOR1A, longer dystonia duration in DYT/PARK-TAF1 and younger age at dystonia onset in DYT-SGCE. CONCLUSIONS: GPi DBS outcomes vary across monogenic dystonias. These data serve to inform patient selection and prognostic counselling.

Relative Contribution of Magnetic Resonance Imaging, Microelectrode Recordings, and Awake Test Stimulation in Final Lead Placement during Deep Brain Stimulation Surgery of the Subthalamic Nucleus in Parkinson's Disease.

INTRODUCTION: For deep brain stimulation (DBS) surgery of the subthalamic nucleus (STN) in Parkinson's disease (PD), many centers employ visualization of the nucleus on magnetic resonance imaging (MRI), intraoperative microelectrode recordings (MER), and test stimulation in awake patients. The value of these steps is a subject for ongoing debate. In the current study, we determined the relative contribution of MRI targeting, multitrack MER, and awake test stimulation in final lead placement during STN DBS surgery for PD. METHODS: Data on PD patients undergoing MRI-targeted STN DBS surgery with three-channel MER and awake test stimulation between February 2010 and January 2014 were analyzed to determine in which MER trajectory final leads were implanted and why this tract was chosen. RESULTS: Seventy-six patients underwent implantation of 146 DBS leads. In 92% of the STN, the final leads were implanted in one of the three planned channels. In 6%, additional channels were needed. In 2%, surgery was aborted before final lead implantation due to anxiety or fatigue. The final leads were implanted in the channels with the longest STN MER signal trajectory in 60% of the STN (38% of the bilaterally implanted patients). This was the central channel containing the MRI target in 39% of the STN (18% bilaterally). The most frequently noted reasons why another channel than the central channel was chosen for final lead placement were (1) a lower threshold for side effects (54%) and (2) no or a too short trajectory of the STN MER signal (40%) in the central channel. The latter reason correlated with larger 2D (x and y) errors in our stereotactic method. CONCLUSIONS: STN DBS leads were often not implanted in the MRI-planned trajectory or in the trajectory with the longest STN MER signal. Thresholds for side effects during awake test stimulation were decisive for final target selection in the majority of patients.

Khodakarami, H., et al., Prediction of the Levodopa Challenge Test in Parkinson's Disease Using Data from a Wrist-Worn Sensor. Sensors 2019, 19, 5153.

The authors wish to make the following erratum to this paper [...].

A systematic review of MEG-based studies in Parkinson's disease: The motor system and beyond.

Parkinson's disease (PD) is accompanied by functional changes throughout the brain, including changes in the electromagnetic activity recorded with magnetoencephalography (MEG). An integrated overview of these changes, its relationship with clinical symptoms, and the influence of treatment is currently missing. Therefore, we systematically reviewed the MEG studies that have examined oscillatory activity and functional connectivity in the PD-affected brain. The available articles could be separated into motor network-focused and whole-brain focused studies. Motor network studies revealed PD-related changes in beta band (13-30 Hz) neurophysiological activity within and between several of its components, although it remains elusive to what extent these changes underlie clinical motor symptoms. In whole-brain studies PD-related oscillatory slowing and decrease in functional connectivity correlated with cognitive decline and less strongly with other markers of disease progression. Both approaches offer a different perspective on PD-specific disease mechanisms and could therefore complement each other. Combining the merits of both approaches will improve the setup and interpretation of future studies, which is essential for a better understanding of the disease process itself and the pathophysiological mechanisms underlying specific PD symptoms, as well as for the potential to use MEG in clinical care.

Botulinum neurotoxin treatment in jerky and tremulous functional movement disorders: a double-blind, randomised placebo-controlled trial with an open-label extension.

OBJECTIVE: To study the effect of botulinum neurotoxin (BoNT) treatment in jerky and tremulous functional movement disorders (FMD). METHODS: Patients with invalidating, chronic (>1 year) symptoms were randomly assigned to two subsequent treatments with BoNT or placebo every 3 months with stratification according to symptom localisation. Improvement on the dichotomised Clinical Global Impression-Improvement scale (CGI-I) (improvement vs no change or worsening) at 4 months, assessed by investigators blinded to the allocated treatment was the primary outcome. Subsequently all patients were treated with BoNT in a ten month open-label phase. RESULTS: Between January 2011 and February 2015 a total of 239 patients were screened for eligibility of whom 48 patients were included. No difference was found on the primary outcome (BoNT 16 of 25 (64.0%) vs Placebo 13 of 23 patients (56.5%); proportional difference 0.075 (95% CI -0.189 to 0.327; p=0.77). Secondary outcomes (symptom severity, disease burden, disability, quality of life and psychiatric symptoms) showed no between-group differences. The open-label phase showed improvement on the CGI-I in 19/43 (44.2%) of remaining patients, with a total of 35/43 (81.4%) improvement compared with baseline. CONCLUSIONS: In this double-blind randomised controlled trial of BoNT for chronic jerky and tremulous FMD, we found no evidence of improved outcomes compared with placebo. Motor symptoms improved in a large proportion in both groups which was sustained in the open-label phase. This study underlines the substantial potential of chronic jerky and tremulous FMD patients to recover and may stimulate further exploration of placebo-therapies in these patients. TRIAL REGISTRATION NUMBER: NTR2478.

Prediction of the Levodopa Challenge Test in Parkinson's Disease Using Data from a Wrist-Worn Sensor.

The response to levodopa (LR) is important for managing Parkinson's Disease and is measured with clinical scales prior to (OFF) and after (ON) levodopa. The aim of this study was to ascertain whether an ambulatory wearable device could predict the LR from the response to the first morning dose. The ON and OFF scores were sorted into six categories of severity so that separating Parkinson's Kinetigraph (PKG) features corresponding to the ON and OFF scores became a multi-class classification problem according to whether they fell below or above the threshold for each class. Candidate features were extracted from the PKG data and matched to the class labels. Several linear and non-linear candidate statistical models were examined and compared to classify the six categories of severity. The resulting model predicted a clinically significant LR with an area under the receiver operator curve of 0.92. This study shows that ambulatory data could be used to identify a clinically significant response to levodopa. This study has also identified practical steps that would enhance the reliability of this test in future studies.

A post hoc study on gene panel analysis for the diagnosis of dystonia.

BACKGROUND: Genetic disorders causing dystonia show great heterogeneity. Recent studies have suggested that next-generation sequencing techniques such as gene panel analysis can be effective in diagnosing heterogeneous conditions. The objective of this study was to investigate whether dystonia patients with a suspected genetic cause could benefit from the use of gene panel analysis. METHODS: In this post hoc study, we describe gene panel analysis results of 61 dystonia patients (mean age, 31 years; 72% young onset) in our tertiary referral center. The panel covered 94 dystonia-associated genes. As comparison with a historic cohort was not possible because of the rapidly growing list of dystonia genes, we compared the diagnostic workup with and without gene panel analysis in the same patients. The workup without gene panel analysis (control group) included theoretical diagnostic strategies formulated by independent experts in the field, based on detailed case descriptions. The primary outcome measure was diagnostic yield; secondary measures were cost and duration of diagnostic workup. RESULTS: Workup with gene panel analysis led to a confirmed molecular diagnosis in 14.8%, versus 7.4% in the control group (P = 0.096). In the control group, on average 3 genes/case were requested. The mean costs were lower in the gene panel analysis group (€1822/case) than in the controls (€2660/case). The duration of the workup was considerably shorter with gene panel analysis (28 vs 102 days). CONCLUSIONS: Gene panel analysis facilitates molecular diagnosis in complex cases of dystonia, with a good diagnostic yield (14.8%), a quicker diagnostic workup, and lower costs, representing a major improvement for patients and their families. © 2016 International Parkinson and Movement Disorder Society.

Thalamic deep brain stimulation for orthostatic tremor: A multicenter international registry.

BACKGROUND: We report the accumulated experience with ventral intermediate nucleus deep brain stimulation for medically refractory orthostatic tremor. METHODS: Data from 17 patients were reviewed, comparing presurgical, short-term (0-48 months), and long-term (≥48 months) follow-up. The primary end point was the composite activities of daily living/instrumental activities of daily living score. Secondary end points included latency of symptoms on standing and treatment-related complications. RESULTS: There was a 21.6% improvement (P = 0.004) in the composite activities of daily living/instrumental activities of daily living score, which gradually attenuated (12.5%) in the subgroup of patients with an additional long-term follow-up (8 of 17). The latency of symptoms on standing significantly improved, both in the short-term (P = 0.001) and in the long-term (P = 0.018). Three patients obtained no/minimal benefit from the procedure. CONCLUSIONS: Deep brain stimulation of the ventral intermediate nucleus was, in general, safe and well tolerated, yielding sustained benefit in selected patients with medically refractory orthostatic tremor. © 2017 International Parkinson and Movement Disorder Society.

Safety and feasibility of faecal microbiota transplantation for patients with Parkinson's disease: a protocol for a self-controlled interventional donor-FMT pilot study.

INTRODUCTION: Experimental studies suggest a role of gut microbiota in the pathophysiology of Parkinson's disease (PD) via the gut-brain axis. The gut microbiota can also influence the metabolism of levodopa, which is the mainstay of treatment of PD. Therefore, modifying the gut microbiota by faecal microbiota transplantation (FMT) could be a supportive treatment strategy. METHODS AND ANALYSIS: We have developed a study protocol for a single-centre, prospective, self-controlled, interventional, safety and feasibility donor-FMT pilot study with randomisation and double-blinded allocation of donor faeces. The primary objectives are feasibility and safety of FMT in patients with PD. Secondary objectives include exploring whether FMT leads to alterations in motor complications (fluctuations and dyskinesias) and PD motor and non-motor symptoms (including constipation), determining alterations in gut microbiota composition, assessing donor-recipient microbiota similarities and their association with PD symptoms and motor complications, evaluating the ease of the study protocol and examining FMT-related adverse events in patients with PD. The study population will consist of 16 patients with idiopathic PD that use levodopa and experience motor complications. They will receive FMT with faeces from one of two selected healthy human donors. FMT will be administered via a gastroscope into the duodenum, after treatment with oral vancomycin, bowel lavage and domperidone. There will be seven follow-up moments during 12 months. ETHICS AND DISSEMINATION: This study was approved by the Medical Ethical Committee Leiden Den Haag Delft (ref. P20.087). Study results will be disseminated through publication in peer-reviewed journals and international conferences. TRIAL REGISTRATION NUMBER: International Clinical Trial Registry Platform: NL9438.

Functional Movement Disorders and Deep Brain Stimulation: A Multi-Center Study.

Background: Functional movement disorders (FMD) are a commonly under-recognized diagnosis in patients with underlying neurodegenerative diseases. FMD have been observed in patients undergoing deep brain stimulation (DBS) for Parkinson's disease (PD) and other movement disorders. The prevalence of coexisting FMD among movement disorder-related DBS patients is unknown, and it may occur more often than previously recognized. Methods: We retrospectively assessed the relative prevalence and clinical characteristics of FMD occurring post-DBS, in PD and dystonia patients (FMD+, n = 29). We compared this cohort with age at surgery-, sex-, and diagnosis-matched subjects without FMD post-DBS (FMD-, n = 29). Results: Both the FMD prevalence (0.2%-2.1%) and the number of cases/DBS procedures/year varied across centers (0.15-3.65). A total of nine of 29 FMD+ cases reported worse outcomes following DBS. Although FMD+ and FMD- manifested similar features, FMD+ showed higher psychiatric comorbidity. Conclusions: DBS may be complicated by the development of FMD in a subset of patients, particularly those with pre-morbid psychiatric conditions.

Predicting Motor Outcome and Quality of Life After Subthalamic Deep Brain Stimulation for Parkinson's Disease: The Role of Standard Screening Measures and Wearable-Data.

BACKGROUND: Standardized screening for subthalamic deep brain stimulation (STN DBS) in Parkinson's disease (PD) patients is crucial to determine eligibility, but its utility to predict postoperative outcomes in eligible patients is inconclusive. It is unknown whether wearable data can contribute to this aim. OBJECTIVE: To evaluate the utility of universal components incorporated in the DBS screening, complemented by a wearable sensor, to predict motor outcomes and Quality of life (QoL) one year after STN DBS surgery. METHODS: Consecutive patients were included in the OPTIMIST cohort study from two DBS centers. Standardized assessments included a preoperative Levodopa Challenge Test (LCT), and questionnaires on QoL and non-motor symptoms including cognition, psychiatric symptoms, impulsiveness, autonomic symptoms, and sleeping problems. Moreover, an ambulatory wearable sensor (Parkinson Kinetigraph (PKG)) was used. Postoperative assessments were similar and also included a Stimulation Challenge Test to determine DBS effects on motor function. RESULTS: Eighty-three patients were included (median (interquartile range) age 63 (56-68) years, 36% female). Med-OFF (Stim-OFF) motor severity deteriorated indicating disease progression, but patients significantly improved in terms of Med-ON (Stim-ON) motor function, motor fluctuations, QoL, and most non-motor domains. Motor outcomes were not predicted by preoperative tests, including covariates of either LCT or PKG. Postoperative QoL was predicted by better preoperative QoL, lower age, and more preoperative impulsiveness scores in multivariate models. CONCLUSION: Data from the DBS screening including wearable data do not predict postoperative motor outcome at one year. Post-DBS QoL appears primarily driven by non-motor symptoms, rather than by motor improvement.

Cognition and psychopathology in myoclonus-dystonia.

OBJECTIVE: (1) To study the neuropsychological and psychopathological profile in myoclonus-dystonia (M-D) patients with and without a mutation in the DYT11 gene. (2) To explore whether cognitive and psychiatric impairments are related to severity and duration of motor symptoms. Herewith, this study may help to clarify whether neuropsychological and psychiatric symptoms are associated with the DYT11 mutation or are secondary to the burden of motor impairments that originated in early childhood. METHODS: Extensive batteries of neuropsychological tests and psychiatric questionnaires were administered to DYT11 gene mutation-carrying (MC) M-D patients (n=31), non-mutation-carrying (NMC) M-D patients (n=20) and a healthy control group (n=36). RESULTS: MC M-D patients demonstrated mild impairments in executive functions. On the contrary, with the exception of one type of verbal fluency, no evident cognitive impairments were found in NMC M-D patients. Further, increased rates of anxiety disorders were found only in MC M-D patients, whereas increased rates of depressive symptoms were observed in both M-D groups. Correlation analyses yielded modest associations between severity of myoclonus and executive functions. No relationships were found between neuropsychological test performance and scores on the psychiatric assessments. CONCLUSIONS: The findings of this study suggest that anxiety disorders and executive dysfunctions may be part of the phenotype of M-D patients with a DYT11 mutation, whereas depressive symptoms and semantic fluency impairments may be secondary to suffering from a chronic movement disorder, regardless of DYT11 gene mutation.

Assessment of Parkinson's Disease Severity From Videos Using Deep Architectures.

Parkinson's disease (PD) diagnosis is based on clinical criteria, i.e., bradykinesia, rest tremor, rigidity, etc. Assessment of the severity of PD symptoms with clinical rating scales, however, is subject to inter-rater variability. In this paper, we propose a deep learning based automatic PD diagnosis method using videos to assist the diagnosis in clinical practices. We deploy a 3D Convolutional Neural Network (CNN) as the baseline approach for the PD severity classification and show the effectiveness. Due to the lack of data in clinical field, we explore the possibility of transfer learning from non-medical dataset and show that PD severity classification can benefit from it. To bridge the domain discrepancy between medical and non-medical datasets, we let the network focus more on the subtle temporal visual cues, i.e., the frequency of tremors, by designing a Temporal Self-Attention (TSA) mechanism. Seven tasks from the Movement Disorders Society - Unified PD rating scale (MDS-UPDRS) part III are investigated, which reveal the symptoms of bradykinesia and postural tremors. Furthermore, we propose a multi-domain learning method to predict the patient-level PD severity through task-assembling. We show the effectiveness of TSA and task-assembling method on our PD video dataset empirically. We achieve the best MCC of 0.55 on binary task-level and 0.39 on three-class patient-level classification.

Patient-Related Factors Influencing Caregiver Burden in Parkinson's Disease Patients: Comparison of Effects Before and After Deep Brain Stimulation.

BACKGROUND: Caregivers of Parkinson's disease (PD) patients provide important support during the pre- and postoperative phase of deep brain stimulation (DBS). High levels of caregiver burden have been reported after DBS. However, a comparison between preoperative and postoperative burden and associated factors has been insufficiently studied. OBJECTIVE: To investigate the influence of DBS on caregiver burden, and to identify the differential impact of patient-related factors on caregiver burden before and after DBS. METHODS: Consecutive patients referred for DBS eligibility screening or during one-year follow-up assessments were included. Caregiver burden was measured with the short Zarit Burden Interview (ZBI-12). Inverse Probability Weighting (IPW) was used to compare caregiver burden between preoperative and postoperative assessments. RESULTS: We included 47 patients (24 screening, 23 follow-up) (median age 65 years, 29.4% female sex). DBS did not impact caregiver burden (screening: median ZBI-12 9.5 (IQR 3.25, 16.75); follow-up median ZBI-12 6 (IQR 4, 14); IPW-coefficient 0.57 (95% CI -2.75, 3.89)). Worse caregiver burden during DBS screening was associated with worse patient-related scores on depressive symptoms, anxiety, QoL, and impulsiveness. Worse scores on depressive symptoms, anxiety, apathy, postural-instability-gait-disorder, and QoL were associated with worse caregiver burden at one-year follow-up. CONCLUSION: DBS appears not associated with changes in caregiver burden. Various symptoms are valued differently between screening and follow-up assessments in terms of caregiver burden. Early recognition of caregivers "at risk" may improve guidance of patient-caregiver dyads throughout the DBS process.