Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

Cognitive and psychiatric outcomes in the GALAXY trial: effect of anaesthesia in deep brain stimulation.

BACKGROUND: This study aims: (1) To compare cognitive and psychiatric outcomes after bilateral awake versus asleep subthalamic nucleus (STN) deep brain stimulation (DBS) surgery for Parkinson's disease (PD). (2) To explore the occurrence of psychiatric diagnoses, cognitive impairment and quality of life after surgery in our whole sample. (3) To validate whether we can predict postoperative cognitive decline. METHODS: 110 patients with PD were randomised to receive awake (n=56) or asleep (n=54) STN DBS surgery. At baseline and 6-month follow-up, all patients underwent standardised assessments testing several cognitive domains, psychiatric symptoms and quality of life. RESULTS: There were no differences on neuropsychological composite scores and psychiatric symptoms between the groups, but we found small differences on individual tests and cognitive domains. The asleep group performed better on the Rey Auditory Verbal Learning Test delayed memory test (f=4.2, p=0.04), while the awake group improved on the Rivermead Behavioural Memory Test delayed memory test. (f=4.4, p=0.04). The Stroop III score was worse for the awake group (f=5.5, p=0.02). Worse scores were present for Stroop I (Stroop word card) (f=6.3, p=0.01), Stroop II (Stroop color card) (f=46.4, p<0.001), Stroop III (Stroop color-word card) (f=10.8, p=0.001) and Trailmaking B/A (f=4.5, p=0.04). Improvements were seen on quality of life: Parkinson's Disease Questionnaire-39 (f=24.8, p<0.001), and psychiatric scales: Hamilton Depression Rating Scale (f=6.2, p=0.01), and Hamilton Anxiety Rating Scale (f=5.5, p=0.02). CONCLUSIONS: This study suggests that the choice between awake and asleep STN DBS does not affect cognitive, mood and behavioural adverse effects, despite a minor difference in memory. STN DBS has a beneficial effect on quality of life, mood and anxiety symptoms. TRIAL REGISTRATION NUMBER: NTR5809.

Bidirectional Interplay between Deep Brain Stimulation and Cognition in Parkinson's Disease: A Systematic Review.

BACKGROUND: Deep brain stimulation (DBS) is efficacious for treating motor symptoms in Parkinson's disease (PD). OBJECTIVES: The aim is to evaluate the evidence regarding DBS effectiveness after postoperative cognitive deterioration, the impact of preoperative cognition on DBS effectiveness, and the impact of DBS on cognition. METHODS: Literature searches were performed on MEDLINE, EMBASE, and CENTRAL (Cochrane library). Primary outcomes were OFF-drug Unified Parkinson Disease Rating Scale Part III score and cognitive test scores. RESULTS: DBS effectiveness did not differ in patients with postoperative declining compared to stable cognition (n = 5 studies). Preoperative cognition did not influence DBS effectiveness (n = 1 study). DBS moderately decreased verbal fluency compared to the best medical treatment (n = 24 studies), which may be transient. CONCLUSION: DBS motor effectiveness in PD does not appear to be influenced by cognition. DBS in PD seems cognitively safe, except for a moderate decline in verbal fluency. Further research is warranted. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Long-Term Follow-Up of the LEAP Study: Early Versus Delayed Levodopa in Early Parkinson's Disease.

BACKGROUND AND OBJECTIVE: The Levodopa in EArly Parkinson's disease study showed no effect of earlier versus later levodopa initiation on Parkinson's disease (PD) progression over 80 weeks. We now report the effects over 5 years. METHODS: The Levodopa in EArly Parkinson's disease study randomly assigned patients to levodopa/carbidopa 300/75 mg daily for 80 weeks (early start) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed start). Follow-up visits were performed 3 and 5 years after baseline. We assessed the between-group differences in terms of square root transformed total Unified Parkinson's Disease Rating Scale score at 3 and 5 years with linear regression. We compared the prevalence of dyskinesia, prevalence of wearing off, and the levodopa equivalent daily dose. RESULTS: A total of 321 patients completed the 5-year visit. The adjusted square root transformed total Unified Parkinson's Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07). At 5 years, 46 of 160 patients in the early-start group and 62 of 161 patients in the delayed-start group experienced dyskinesia (P = 0.06). The prevalence of wearing off and the levodopa equivalent daily dose were not significantly different between groups. CONCLUSIONS: We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Measurement properties of the childhood bladder and bowel dysfunction questionnaire.

OBJECTIVES: The childhood bladder and bowel dysfunction questionnaire (CBBDQ) was previously found feasible, structurally valid, with good internal consistency. The purpose of this study was to evaluate the remaining measurement properties according to the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). METHODS: A prospective cohort study among parents of children aged 5-12 years was conducted. Calculated were the area under the curve (AUC) (criterion validity, responsiveness, interpretability) and intra-class correlation coefficients (ICCagreement ) (construct validity and test-retest reliability). RESULTS: One hundred and seventy-two parents were included from March 2019 to April 2021. Correlating the bladder subscales of the CBBDQ with the Vancouver symptom score for dysfunctional elimination (VSSDES) and proxy-reported pediatric incontinence quality of life (p-PinQ) showed convergent validity (ICCsagreement : 0.76 and 0.74). Divergent validity was found when correlating the bowel subscales of the CBBDQ with the VSSDES (ICCagreement : 0.52). Excellent criterion validity (AUC: 0.98); excellent test-retest reliability (ICCagreement : 0.94) and, at 6 months, fair responsiveness (AUC: 0.74) were found. The minimal important change was 4.5, with cut-off value of 11. CONCLUSION: The CBBDQ has been developed according to COSMIN standards. The items were defined using the consensus-based ICCS standards and Rome-III criteria. The measurement properties were identified using enough participants. Although interpretability is not considered a measurement property, interpretability aspects are reported here as they refer to what instrument scores mean. The 18-item-CBBDQ met the measurement properties of validity, reliability, and responsiveness, as defined by COSMIN. The CBBDQ is suitable for self-administration by parents, and completion takes little time.

Surgical Complications in Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease: Experience in 800 Patients.

INTRODUCTION: We present our surgical complications resulting in neurological deficit or additional surgery during 25 years of DBS of the subthalamic nucleus (STN) for Parkinson's disease (PD). METHODS: We conducted a retrospective chart review of all PD patients that received STN DBS in our DBS center between 1998 and 2023. Outcomes were complications resulting in neurological deficit or additional surgery. Potential risk factors (number of microelectrode recording tracks, age, anesthesia method, hypertension, and sex) for symptomatic intracerebral hemorrhage (ICH) were analyzed. Furthermore, lead fixation techniques were compared. RESULTS: Eight hundred PD patients (507 men, 293 women) received unilateral (n = 11) or bilateral (n = 789) implantation of STN electrodes. Neurological deficit due to ICH, edema, delirium, or infarction was seen in 8.4% of the patients (7.4% transient, 1.0% permanent). Twenty-two patients (2.8%) had a symptomatic ICH following STN DBS, for which we did not find any risk factors, and five had permanent sequelae due to ICH (0.6%). Of all patients, 18.4% required additional surgery; the proportion was reduced from 27% in the first 300 cases to 13% in the last 500 cases (p < 0.001). The infection rate was 3.5%, which decreased from 5.3% in the first 300 cases to 2.2% in the last 500 cases. The use of a lead anchoring device led to significantly less lead migrations than miniplate fixation. CONCLUSION: STN DBS leads to permanent neurological deficit in a small number of patients (1.0%), but a substantial proportion needs some additional surgical procedure after the first DBS system implantation. The risk of revision surgery was reduced over time but remained significant. These findings need to be discussed with the patient in the preoperative informed consent process in addition to the expected health benefit.

Programming Algorithm for the Management of Speech Impairment in Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVES: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD) has an ambiguous relation to speech. Speech impairment can be a stimulation-induced side effect, and parkinsonian dysarthria can improve with STN-DBS. Owing to the lack of an up-to-date and evidence-based approach, DBS reprogramming for speech impairment is largely blind and greatly relies on the physician's experience. In this study, we aimed to establish an evidence- and experience-based algorithm for managing speech impairment in patients with PD treated with STN-DBS. MATERIALS AND METHODS: We performed a single-center retrospective study to identify patients with STN-DBS and speech impairment. Onset of speech impairment, lead localization, and assessment of DBS-induced nature of speech impairment were collected. When DBS settings were adjusted for improving speech, the magnitude and duration of effect were collected. We also performed a systematic literature review to identify studies describing the effects of parameter adjustments aimed at improving speech impairment in patients with PD receiving STN-DBS. RESULTS: In the retrospective study, 245 of 631 patients (38.8%) with STN-DBS had significant speech impairment. The probability of sustained marked improvement upon reprogramming was generally low (27.9%). In the systematic review, 23 of 662 identified studies were included. Only two randomized controlled trials have been performed, providing evidence for interleaving-interlink stimulation only. Considerable methodologic heterogeneity precluded the conduction of a meta-analysis. CONCLUSIONS: Speech impairment in STN-DBS for PD is frequent, but high-quality evidence regarding DBS parameter adjustments is scarce, and the probability of sustained improvement is low. To improve this outcome, we propose an evidence- and experience-based approach to address speech impairment in STN-DBS that can be used in clinical practice.

Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers.

OBJECTIVE: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. METHODS: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. RESULTS: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36-60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = -2.35 to -1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = -2.14 to -1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = -1.80 to -1.18). INTERPRETATION: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424-435.

Directional versus ring-mode deep brain stimulation for Parkinson's disease: protocol of a multi-centre double-blind randomised crossover trial.

BACKGROUND: The effectiveness of Deep Brain Stimulation (DBS) therapy for Parkinson's disease can be limited by side-effects caused by electrical current spillover into structures adjacent to the target area. The objective of the STEEred versus RING-mode DBS for Parkinson's disease (STEERING) study is to investigate if directional DBS for Parkinson's disease results in a better clinical outcome when compared to ring-mode DBS. METHODS: The STEERING study is a prospective multi-centre double-blind randomised crossover trial. Inclusion criteria are Parkinson's disease, subthalamic nucleus DBS in a 'classic' ring-mode setting for a minimum of six months, and optimal ring-mode settings have been established. Participants are categorised into one of two subgroups according to their clinical response to the ring-mode settings as 'responders' (i.e., patient with a satisfactory effect of ring-mode DBS) or 'non-responder' (i.e., patient with a non-satisfactory effect of ring-mode DBS). A total of 64 responders and 38 non-responders will be included (total 102 patients). After an optimisation period in which an optimal directional setting is found, participants are randomised to first receive ring-mode DBS for 56 days (range 28-66) followed by directional DBS for 56 days (28-66) or vice-versa. The primary outcome is the difference between ring-mode DBS and directional DBS settings on the Movement Disorders Society Unified Parkinson's Disease Rating Scale - Motor Evaluation (MDS-UPDRS-ME) in the off-medication state. Secondary outcome measures consist of MDS-UPDRS-ME in the on-medication state, MDS-UPDRS Activities of Daily Living, MDS-UPDRS Motor Complications-Dyskinesia, disease related quality of life measured with the Parkinson's Disease Questionnaire 39, stimulation-induced side-effects, antiparkinsonian medication use, and DBS-parameters. Participants' therapy preference is measured at the end of the study. Outcomes will be analysed for both responder and non-responder groups, as well as for both groups pooled together. DISCUSSION: The STEERING trial will provide insights into whether or not directional DBS should be standardly used in all Parkinson's disease DBS patients or if directional DBS should only be used in a case-based approach. TRIAL REGISTRATION: This trial was registered on the Netherlands Trial Register, as trial NL6508 ( NTR6696 ) on June 23, 2017.

Subthalamic and pallidal deep brain stimulation: are we modulating the same network?

The subthalamic nucleus and internal pallidum are main target sites for deep brain stimulation in Parkinson's disease. Multiple trials that investigated subthalamic versus pallidal stimulation were unable to settle on a definitive optimal target between the two. One reason could be that the effect is mediated via a common functional network. To test this hypothesis, we calculated connectivity profiles seeding from deep brain stimulation electrodes in 94 patients that underwent subthalamic and 28 patients with pallidal treatment based on a normative connectome atlas calculated from 1000 healthy subjects. In each cohort, we calculated connectivity profiles that were associated with optimal clinical improvements. The two maps showed striking similarity and were able to cross-predict outcomes in the respective other cohort (R = 0.37 at P < 0.001; R = 0.34 at P = 0.032). Next, we calculated an agreement map, which retained regions common to both target sites. Crucially, this map was able to explain an additional amount of variance in clinical improvements of either cohort when compared to the maps calculated on each cohort alone. Finally, we tested profiles and predictive utility of connectivity maps calculated from different motor symptom subscores with a specific focus on bradykinesia and rigidity. While our study is based on retrospective data and indirect connectivity metrics, it may deliver empirical data to support the hypothesis of a largely overlapping network associated with effective deep brain stimulation in Parkinson's disease irrespective of the specific target.

The effect of perturbation-based balance training on balance control and fear of falling in older adults: a single-blind randomised controlled trial.

BACKGROUND: Perturbation-based balance training (PBT) is an emerging intervention shown to improve balance recovery responses and reduce falls in everyday life in older adults. However, perturbation interventions were heterogeneous in nature and need improvement. This study aims to investigate the effects of a PBT protocol that was designed to address previously identified challenges of PBT, in addition to usual care, on balance control and fear of falling in older adults at increased risk of falling. METHODS: Community-dwelling older adults (age ≥ 65 years) who visited the hospital outpatient clinic due to a fall incident were included. Participants received PBT in addition to usual care (referral to a physiotherapist) versus usual care alone. PBT consisted of three 30-minute sessions in three weeks. Unilateral treadmill belt accelerations and decelerations and platform perturbations (shifts and tilts) were applied during standing and walking on the Computer Assisted Rehabilitation Environment (CAREN, Motek Medical BV). This dual-belt treadmill embedded in a motion platform with 6 degrees of freedom is surrounded by a 180° screen on which virtual reality environments are projected. Duration and contents of the training were standardised, while training progression was individualised. Fear of falling (FES-I) and balance control (Mini-BESTest) were assessed at baseline and one week post-intervention. Primary analysis compared changes in outcome measures between groups using Mann-Whitney U tests. RESULTS: Eighty-two participants were included (PBT group n = 39), with a median age of 73 years (IQR 8 years). Median Mini-BESTest scores did not clinically relevantly improve and were not significantly different between groups post-intervention (p = 0.87). FES-I scores did not change in either group. CONCLUSIONS: Participation in a PBT program including multiple perturbation types and directions did not lead to different effects than usual care on clinical measures of balance control or fear of falling in community-dwelling older adults with a recent history of falls. More research is needed to explore how to modulate PBT training dose, and which clinical outcomes are most suitable to measure training effects on balance control. TRIAL REGISTRATION: Nederlands Trial Register NL7680. Registered 17-04-2019 - retrospectively registered. https://www.trialregister.nl/trial/7680 .

Factors associated with an increased risk of developing postoperative symptomatic lumbar spondylolisthesis after decompression surgery: an explorative two-centre international cohort study.

PURPOSE: Symptomatic lumbar spinal stenosis can be treated with decompression surgery. A recent review reported that, after decompression surgery, 1.6-32.0% of patients develop postoperative symptomatic spondylolisthesis and may therefore be indicated for lumbar fusion surgery. The latter can be more challenging due to the altered anatomy and scar tissue. It remains unclear why some patients get recurrent neurological complaints due to postoperative symptomatic spondylolisthesis, though some associations have been suggested. This study explores the association between key demographic, biological and radiological factors and postoperative symptomatic spondylolisthesis after lumbar decompression. METHODS: This retrospective cohort study included patients who had undergone lumbar spinal decompression surgery between January 2014 and December 2016 at one of two Spine Centres in the Netherlands or Switzerland and had a follow-up of two years. Patient characteristics, details of the surgical procedure and recurrent neurological complaints were retrieved from patient files. Preoperative MRI scans and conventional radiograms (CRs) of the lumbar spine were evaluated for multiple morphological characteristics. Postoperative spondylolisthesis was evaluated on postoperative MRI scans. For variables assessed on a whole patient basis, patients with and without postoperative symptomatic spondylolisthesis were compared. For variables assessed on the basis of the operated segment(s), surgical levels that did or did not develop postoperative spondylolisthesis were compared. Univariable and multivariable logistic regression analyses were used to identify associations with postoperative symptomatic spondylolisthesis. RESULTS: Seven hundred and sixteen patients with 1094 surgical levels were included in the analyses. (In total, 300 patients had undergone multilevel surgery.) ICCs for intraobserver and interobserver reliability of CR and MRI variables ranged between 0.81 and 0.99 and 0.67 and 0.97, respectively. In total, 66 of 716 included patients suffered from postoperative symptomatic spondylolisthesis (9.2%). Multivariable regression analyses of patient-basis variables showed that being female [odds ratio (OR) 1.2, 95%CI 1.07-3.09] was associated with postoperative symptomatic spondylolisthesis. Higher BMI (OR 0.93, 95%CI 0.88-0.99) was associated with a lower probability of having postoperative symptomatic spondylolisthesis. Multivariable regression analyses of surgical level-basis variables showed that levels with preoperative spondylolisthesis (OR 17.30, 95%CI 10.27-29.07) and the level of surgery, most importantly level L4L5 compared with levels L1L3 (OR 2.80, 95%CI 0.78-10.08), were associated with postoperative symptomatic spondylolisthesis; greater facet joint angles (i.e. less sagittal-oriented facets) were associated with a lower probability of postoperative symptomatic spondylolisthesis (OR 0.97, 95%CI 0.95-0.99). CONCLUSION: Being female was associated with a higher probability of having postoperative symptomatic spondylolisthesis, while having a higher BMI was associated with a lower probability. When looking at factors related to postoperative symptomatic spondylolisthesis at the surgical level, preoperative spondylolisthesis, more sagittal orientated facet angles and surgical level (most significantly level L4L5 compared to levels L1L3) showed significant associations. These associations could be used as a basis for devising patient selection criteria, stratifying patients or performing subgroup analyses in future studies regarding decompression surgery with or without fusion.

Utilizing 7-Tesla Subthalamic Nucleus Connectivity in Deep Brain Stimulation for Parkinson Disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective surgical treatment for patients with advanced Parkinson disease (PD). Combining 7.0-Tesla (7T) T2- and diffusion-weighted imaging (DWI) sequences allows for selective segmenting of the motor part of the STN and, thus, for possible optimization of DBS. MATERIALS AND METHODS: 7T T2 and DWI sequences were obtained, and probabilistic segmentation of motor, associative, and limbic STN segments was performed. Left- and right-sided motor outcome (Movement Disorders Society Unified Parkinson's Disease Rating Scale) scores were used for evaluating the correspondence between the active electrode contacts in selectively segmented STN and the clinical DBS effect. The Bejjani line was reviewed for crossing of segments. RESULTS: A total of 50 STNs were segmented in 25 patients and proved highly feasible. Although the highest density of motor connections was situated in the dorsolateral STN for all patients, the exact partitioning of segments differed considerably. For all the active electrode contacts situated within the predominantly motor-connected segment of the STN, the average hemi-body Unified Parkinson's Disease Rating Scale motor improvement was 80%; outside this segment, it was 52% (p < 0.01). The Bejjani line was situated in the motor segment for 32 STNs. CONCLUSION: The implementation of 7T T2 and DWI segmentation of the STN in DBS for PD is feasible and offers insight into the location of the motor segment. Segmentation-guided electrode placement is likely to further improve motor response in DBS for PD. However, commercially available DBS software for postprocessing imaging would greatly facilitate widespread implementation.

The Fast Gray Matter Acquisition T1 Inversion Recovery Sequence in Deep Brain Stimulation: Introducing the Rubral Wing for Dentato-Rubro-Thalamic Tract Depiction and Tremor Control.

BACKGROUND: The dentato-rubro-thalamic tract (DRT) is currently considered as a potential target in deep brain stimulation (DBS) for various types of tremor. However, tractography depiction can vary depending on the included brain regions. The fast gray matter acquisition T1 inversion recovery (FGATIR) sequence, with excellent delineation of gray and white matter, possibly provides anatomical identification of rubro-thalamic DRT fibers. OBJECTIVE: This study aimed to evaluate the FGATIR sequence by comparison with DRT depiction, electrode localization, and effectiveness of DBS therapy. MATERIALS AND METHODS: In patients with DBS therapy because of medication-refractory tremor, the FGATIR sequence was evaluated for depiction of the thalamus, red nucleus (RN), and rubro-thalamic connections. Deterministic tractography of the DRT, electrode localization, and tremor control were compared. The essential tremor rating scale was used to assess (hand) tremor. Tremor control was considered successful when complete tremor suppression (grade 0) or almost complete suppression (grade 1) was observed. RESULTS: In the postoperative phase, we evaluated 14 patients who underwent DRT-guided DBS: 12 patients with essential tremor, one with tremor-dominant Parkinson disease, and one with multiple sclerosis, representing 24 trajectories. Mean follow-up was 11.3 months (range 6-19 months). The FGATIR sequence provided a clear delineation of a hypointense white matter tract within the hyperintense thalamus. In coronal plane, this tract was most readily recognizable as a "rubral wing," with the round RN as base and lateral triangular convergence. The deterministic DRT depiction was consistently situated within the rubral wing. The number of active contacts located within the DRT (and rubral wing) was 22 (92%), of which 16 (73%) showed successful tremor control. CONCLUSIONS: The FGATIR sequence offers visualization of the rubro-thalamic connections that form the DRT, most readily recognizable as a "rubral wing" in coronal plane. This sequence contributes to tractographic depiction of DRT and provides a direct anatomical DBS target area for tremor control.

Variability of Active Cervical Range of Motion Within and Between Days in Healthy Participants: A Prospective Observational Study.

OBJECTIVE: The purpose of this study was to determine the intraday and interday variability and systematic change over the day of active cervical range of motion (aCROM) measurements in asymptomatic persons using a clinically applicable measurement device. METHODS: A prospective observational study was performed. Sixteen adults (8 men and 8 women, median age 51 years) without neck pain in the last 3 months were recruited in 2 physiotherapy practices. Active cervical range of motion was estimated using the Apple iPhone application "3D Range of Motion." Measurements were performed 3 times a day for 7 days and spread over a period of 3 weeks. Mean values of aCROM were calculated. Intraday and interday variability was estimated by calculating limits of agreement. RESULTS: The limits of agreement for intraday variability ranged from ±12.1° for left rotation to ±15.5° for total rotation. For interday variability, the limits of agreement ranged from ±14.2° for right rotation to ±20.1° for total rotation. No systematic change over the day was found. CONCLUSION: This study showed substantial intraday and interday variability of aCROM measurements in asymptomatic people. No trend toward an increased or decreased aCROM was observed during the course of the day. When interpreting aCROM values, clinicians should consider the degree of variation in aCROM measurements over time.

Diving into the subcortex: The potential of chronic subcortical sensing for unravelling basal ganglia function and optimization of deep brain stimulation.

Subcortical structures are a relative neurophysiological 'terra incognita' owing to their location within the skull. While perioperative subcortical sensing has been performed for more than 20 years, the neurophysiology of the basal ganglia in the home setting has remained almost unexplored. However, with the recent advent of implantable pulse generators (IPG) that are able to record neural activity, the opportunity to chronically record local field potentials (LFPs) directly from electrodes implanted for deep brain stimulation opens up. This allows for a breakthrough of chronic subcortical sensing into fundamental research and clinical practice. In this review an extensive overview of the current state of subcortical sensing is provided. The widespread potential of chronic subcortical sensing for investigational and clinical use is discussed. Finally, status and future perspectives of the most promising application of chronic subcortical sensing -i.e., adaptive deep brain stimulation (aDBS)- are discussed in the context of movement disorders. The development of aDBS based on both chronic subcortical and cortical sensing has the potential to dramatically change clinical practice and the life of patients with movement disorders. However, several barriers still stand in the way of clinical implementation. Advancements regarding IPG and lead technology, physiomarkers, and aDBS algorithms as well as harnessing artificial intelligence, multimodality and sensing in the naturalistic setting are needed to bring aDBS to clinical practice.

Randomized Delayed-Start Trial of Levodopa in Parkinson's Disease.

BACKGROUND: Levodopa is the main treatment for symptoms of Parkinson's disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in the course of the disease the treatment with this drug should be initiated. METHODS: In a multicenter, double-blind, placebo-controlled, delayed-start trial, we randomly assigned patients with early Parkinson's disease to receive levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks (delayed-start group). The primary outcome was the between-group difference in the mean change from baseline to week 80 in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS; scores range from 0 to 176, with higher scores signifying more severe disease). Secondary analyses included the progression of symptoms, as measured by the UPDRS score, between weeks 4 and 40 and the noninferiority of early initiation of treatment to delayed initiation between weeks 44 and 80, with a noninferiority margin of 0.055 points per week. RESULTS: A total of 445 patients were randomly assigned: 222 to the early-start group and 223 to the delayed-start group. The mean (±SD) UPDRS score at baseline was 28.1±11.4 points in the early-start group and 29.3±12.1 points in the delayed-start group. The change in UPDRS score from baseline to week 80 was -1.0±13.1 points and -2.0±13.0 points, respectively (difference, 1.0 point; 95% confidence interval [CI], -1.5 to 3.5; P=0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect. Between weeks 4 and 40, the rate of progression of symptoms, as measured in UPDRS points per week, was 0.04±0.23 in the early-start group and 0.06±0.34 in the delayed-start group (difference, -0.02; 95% CI, -0.07 to 0.03). The corresponding rates between weeks 44 and 80 were 0.10±0.25 and 0.03±0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10); the difference in the rate of progression between weeks 44 and 80 did not meet the criterion for noninferiority of early receipt of levodopa to delayed receipt. The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups. CONCLUSIONS: Among patients with early Parkinson's disease who were evaluated over the course of 80 weeks, treatment with levodopa in combination with carbidopa had no disease-modifying effect. (Funded by the Netherlands Organization for Health Research and Development and others; LEAP Current Controlled Trials number, ISRCTN30518857 .).

Multicenter Validation of Individual Preoperative Motor Outcome Prediction for Deep Brain Stimulation in Parkinson's Disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) is an established therapy for Parkinson's disease (PD) patients suffering from motor response fluctuations despite optimal medical treatment, or severe dopaminergic side effects. Despite careful clinical selection and surgical procedures, some patients do not benefit from STN DBS. Preoperative prediction models are suggested to better predict individual motor response after STN DBS. We validate a preregistered model, DBS-PREDICT, in an external multicenter validation cohort. METHODS: DBS-PREDICT considered eleven, solely preoperative, clinical characteristics and applied a logistic regression to differentiate between weak and strong motor responders. Weak motor response was defined as no clinically relevant improvement on the Unified Parkinson's Disease Rating Scale (UPDRS) II, III, or IV, 1 year after surgery, defined as, respectively, 3, 5, and 3 points or more. Lower UPDRS III and IV scores and higher age at disease onset contributed most to weak response predictions. Individual predictions were compared with actual clinical outcomes. RESULTS: 322 PD patients treated with STN DBS from 6 different centers were included. DBS-PREDICT differentiated between weak and strong motor responders with an area under the receiver operator curve of 0.76 and an accuracy up to 77%. CONCLUSION: Proving generalizability and feasibility of preoperative STN DBS outcome prediction in an external multicenter cohort is an important step in creating clinical impact in DBS with data-driven tools. Future prospective studies are required to overcome several inherent practical and statistical limitations of including clinical decision support systems in DBS care.

Two-Compartment or 4-Compartment Fasciotomy for Lower Leg Chronic Exertional Compartment Syndrome: A Systematic Review.

Patients with lower leg chronic exertional compartment syndrome are impaired due to exercise-related pain. Fasciotomy is the surgical gold standard. However, it is unknown whether number of simultaneously opened compartments affects outcome. The purpose of this systematic review was to compare patient-reported outcomes of a 2-compartment fasciotomy with a 4-compartment fasciotomy. Controlled clinical trials (randomized/nonrandomized), cohort studies and case series reporting on outcome following either 2-compartment or 4-compartment fasciotomy for lower leg chronic exertional compartment syndrome were searched until May 31, 2021 in PubMed, EMBASE, and Cochrane. Results were qualitatively synthesized. Risk of bias and levels of evidence were determined. Seven studies reporting on altogether 194 athletes and military personnel (mean age 24 y) were included. Quality assessment revealed a high risk of bias in all studies. Both 2-compartment and 4-compartment fasciotomy were associated with a 50% to 100% "return to activity" rate (in studies reporting group results separately: 2-compartment 90%-100%; 4-compartment 50%-100%) and a 41% to 100% "return to previous activity" rate (in studies reporting group results separately: 2-compartment 82-100%; 4-compartment 50%-100%) without significant differences. Mean Marx activity score of 1 study found a small significant standardized mean difference (0.196 [0.524,0.916]) favoring 4-compartment fasciotomy. Rate of satisfaction (2-compartment 74%-89%; 4-compartment 75%-100%) and residual symptoms (2-compartment 0%-36%; 4-compartment 0%-50%) indicated no group differences. In conclusion, a 2-compartment fasciotomy or a 4-compartment fasciotomy for lower leg chronic exertional compartment syndrome appears to be equally successful. However, included studies were hampered by methodological shortcomings (low sample size, selection bias, heterogeneity and no uniform outcome measures).

Translating Evidence to Advanced Parkinson's Disease Patients: A Systematic Review and Meta-Analysis.

In the advanced stages of Parkinson's disease (PD), patients frequently experience disabling motor complications. Treatment options include deep brain stimulation (DBS), levodopa-carbidopa intestinal gel (LCIG), and continuous subcutaneous apomorphine infusion (CSAI). Choosing among these treatments is influenced by scientific evidence, clinical expertise, and patient preferences. To foster patient engagement in decision-making among the options, scientific evidence should be adjusted to their information needs. We conducted a systematic review from the patient perspective. First, patients selected outcomes for a treatment choice: quality of life, activities of daily living, ON and OFF time, and adverse events. Second, we conducted a systematic review and meta-analysis for each treatment versus best medical treatment using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Finally, the evidence was transformed into comprehensible and comparable information. We converted the meta-analysis results into the number of patients (per 100) who benefit clinically from an advanced treatment per outcome, based on the minimal clinically important difference and the cumulative distribution function. Although this approach allows for a comparison of outcomes across the three device-aided therapies, they have never been compared directly. The interpretation is hindered by the relatively short follow-up time in the included studies, usually less than 12 months. These limitations should be clarified to patients during the decision-making process. This review can help patients integrate the evidence with their own preferences, and with their clinician's expertise, to reach an informed decision. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.