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.

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.

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.

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.

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.

Defining the Dorsal STN Border Using 7.0-T MRI: A Comparison to Microelectrode Recordings and Lower Field Strength MRI.

BACKGROUND: 7.0-T T2-weighted MRI offers excellent visibility of the subthalamic nucleus (STN), which is used as a target for deep brain stimulation (DBS) in Parkinson's disease (PD). A comparison of 7.0-T MRI to microelectrode recordings (MER) for STN border identification has not been performed. OBJECTIVE: To compare representation of STN borders on 7.0-T T2 MRI with the borders identified during MER in patients undergoing DBS for PD and to evaluate whether STN identification on 7.0-T T2 MRI leads to alterations in stereotactic target planning. DESIGN/METHODS: STN border identification was done using volumetric 7.0-T T2 MRI acquisitions. This was compared to the STN borders identified by MER. STN target planning was independently performed by 3 DBS surgeons on T2 imaging using 1.5-, 3.0-, and 7.0-T MRI. RESULTS: A total of 102 microelectrode tracks were evaluated in 19 patients. Identification of the dorsal STN border was well feasible on 7-T T2, whereas the ventral STN was un-distinguishable from the substantia nigra. The dorsal STN border on MRI was located more dorsal than MER in 73% of trajectories. The average distance from MRI to MER border was 0.9 mm (range -4.4 to +3.5 mm). STN target planning showed high correspondence between the 3 field strengths. CONCLUSION: 7.0-T T2 MRI offers the possibility of easy identification of the dorsal border of the STN. However, higher field strength MRI does not change the planning of the target. Compared to MER, the dorsal border on MRI was located more dorsal in the majority of cases, situating MER activity within STN representation.

Randomised controlled trial of escitalopram for cervical dystonia with dystonic jerks/tremor.

OBJECTIVE: Trials for additional or alternative treatments for cervical dystonia (CD) are scarce since the introduction of botulinum neurotoxin (BoNT). We performed the first trial to investigate whether dystonic jerks/tremor in patients with CD respond to the selective serotonin reuptake inhibitor (SSRI) escitalopram. METHODS: In a randomised, double-blind, crossover trial, patients with CD received escitalopram and placebo for 6 weeks. Treatment with BoNT was continued, and scores on rating scales regarding dystonia, psychiatric symptoms and quality of life (QoL) were compared. Primary endpoint was the proportion of patients that improved at least one point on the Clinical Global Impression Scale for jerks/tremor scored by independent physicians with experience in movement disorders. RESULTS: Fifty-threepatients were included. In the escitalopram period, 14/49 patients (29%) improved on severity of jerks/tremor versus 11/48 patients (23%) in the placebo period (P=0.77). There were no significant differences between baseline and after treatment with escitalopram or placebo on severity of dystonia or jerks/tremor. Psychiatric symptoms and QoL improved significantly in both periods compared with baseline. There were no significant differences between treatment with escitalopram and placebo for dystonia, psychiatric or QoL rating scales. During treatment with escitalopram, patients experienced slightly more adverse events, but no serious adverse events occurred. CONCLUSION: In this innovative trial, no add-on effect of escitalopram for treatment of CD with jerks was found on motor or psychiatric symptoms. However, we also did not find a reason to withhold patients treatment with SSRIs for depression and anxiety, which are common in dystonia. TRIAL REGISTRATION NUMBER: NTR2178.

Substituting the Target After Unsatisfactory Outcome of Deep Brain Stimulation in Advanced Parkinson's Disease: Cases From the NSTAPS Trial and Systematic Review of the Literature.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and the subthalamic nucleus (STN) are established treatment option in Parkinson's disease (PD). If DBS does not provide the desired effect, re-operation to the alternative target is a treatment option, but data on the effect of re-operation are scarce. OBJECTIVES: The objective of this study is to evaluate the clinical effect of re-operation the alternative target after failure of initial STN or GPi DBS for Parkinson's disease. MATERIALS AND METHODS: We descriptively analyzed the baseline characteristics, the effect of initial surgery and re-operation of eight NSTAPS (Netherlands SubThalamic and Pallidal Stimulation) patients and six previously published cases that underwent re-operation to a different target. RESULTS: In the NSTAPS cohort, two of the eight patients showed more than 30% improvement of off-drug motor symptoms after re-operation. The initial DBS leads of these patients were off target. In the cases from the literature, 30% off-drug motor improvement was seen in all three patients re-operated from GPi to STN and none of the three patients re-operated from STN to GPi. Only one of the three cases from the literature where any improvement was seen with the operation had a confirmed on target lead location after the first surgery, while the other two patients did not undergo post-operative imaging after the first surgery. CONCLUSIONS: Re-operation to a different target due to lack of effect appears to have a limited chance of leading to objective improvement if the leads were correctly placed during initial surgery.

Efficacy and safety of adjunctive oral therapy in Parkinson's disease with motor complications: a systematic review and network meta-analysis.

Background: The aim of this manuscript is to review the evidence and compare the efficacy and safety of catechol-O-methyltransferase inhibitors (COMT-Is), dopamine receptor agonists (DRAs) and monoamine-oxidase B inhibitors (MAOB-Is) as adjunctive treatment to levodopa in patients with Parkinson's disease (PD) experiencing motor complications. Methods: In this systematic review and network meta-analysis, literature searches were performed in MEDLINE and Embase to identify eligible randomised controlled trials (RCTs) with a minimal follow-up of at least 4 weeks published in English between 1980 and 2021. RCTs were included if either a COMT-I, DRA or MAOB-I was evaluated as an adjunctive therapy to levodopa in patients with PD experiencing motor complications and dyskinesia. The main outcomes included daily off-medication time, motor and non-motor examination scales, and adverse events including dyskinesia. Results: 74 RCTs reporting on 18 693 patients were included. All three studied drug classes decreased daily off-medication time compared with placebo (COMT-Is mean -0.8 hours (95% CI -1.0 to -0.6), DRAs -1.1 hours (95% CI -1.4 to -0.8), MAOB-Is -0.9 hours (95% CI -1.2 to -0.6)). Safety analysis showed an increased risk of dyskinesia for all three drug classes (COMT-Is OR 3.3 (95% CI 2.7 to 4.0), DRAs 3.0 (95% CI 2.5 to 3.5), MAOB-Is 1.6 (95% CI 1.2 to 2.2)). According to surface under the cumulative ranking curve scores, pramipexole IR was associated with the most favourable benefit-risk profile. Conclusions: COMT-Is, DRAs and MAOB-Is effectively reduce motor complications and increase incidence of dyskinesia. In the network meta-analysis, adjunctive use of DRAs appeared most effective.

How Information Affects Patients with Parkinson's Disease: A Scoping Review of the Literature.

Background: Patients with Parkinson's disease (PD) need to receive adequate information to manage their disease. However, little is known about how information provision affects patients. Objective: To conduct a scoping review of the literature on the relationship between content, timing, manner of delivery, and source of PD-specific information on the one hand, and patient outcomes on the other. Methods: All literature reporting about original data and published until April 2024 in peer-reviewed journals was searched in MEDLINE (Ovid), Embase (Ovid) and PsychInfo (Ovid). Subsequently, data were extracted and synthesized. Results: 40 publications describing the effects of information provision or patients' evaluation thereof were retrieved. Four categories of patient outcomes were described, namely 1) evaluation and experience of information provision; 2) physical functioning; 3) psychosocial well-being; and 4) quality of life. In intervention studies, patients generally valued the provided information. Findings from cross-sectional and qualitative studies showed the importance of tailoring information to individuals' needs and capabilities. Due to variation in study designs and outcomes, no unambiguous conclusions could be drawn regarding the relationship between information and outcomes. Conclusions: This scoping review identified how PD patients acquire information and revealed a lack of systematic research into the effect of information on patient outcomes. Future studies should assess 1) what information is currently provided by clinicians; 2) what additional information might be beneficial to provide; and 3) how information can be effectively aligned to benefit patients. This will eventually yield insight into how information might optimally empower PD patients.

Levodopa Response in Patients With Early Parkinson Disease: Further Observations of the LEAP Study.

BACKGROUND AND OBJECTIVES: The Levodopa in EArly Parkinson's Disease (LEAP) study enabled us to conduct post hoc analyses concerning the effects of levodopa in patients with early Parkinson disease. METHODS: The LEAP study was a double-blind, placebo-controlled, randomized, delayed-start trial in which patients with early Parkinson disease were randomized to receive levodopa/carbidopa 300/75 mg daily for 80 weeks (early-start group) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed-start group). We analyzed the effect of levodopa with the Unified Parkinson's Disease Rating Scale on bradykinesia, rigidity, and tremor. At week 80, participants answered 3 questions regarding motor response fluctuations. RESULTS: A total of 222 patients were randomized to the early-start group (mean ± SD age at baseline 64.8 ± 8.7 years; 71% male) and 223 to the delayed-start group (mean ± SD age at baseline 65.5 ± 8.8 years; 69% male). The difference between the early- and delayed-start groups in mean change from baseline to week 4, expressed as Hedges g effect size, was -0.33 for bradykinesia, -0.29 for rigidity, and -0.25 for tremor (for all symptoms indicating a small effect in favor of the early-start group); from baseline to week 22, respectively, -0.49, -0.36, and -0.44 (small to medium effect); and from baseline to week 40, respectively, -0.32, -0.19, and -0.27 (small effect). At 80 weeks, fewer patients in the early-start group (46 of 205 patients, 23%) experienced motor response fluctuations than patients in the delayed-start group (81 of 211, 38%; p < 0.01). DISCUSSION: In patients with early Parkinson disease, levodopa improves bradykinesia, rigidity, and tremor to the same order of magnitude. For all 3 symptoms, effects were larger at 22 weeks compared with 4 weeks. At 80 weeks, there were fewer patients with motor response fluctuations in the group that had started levodopa earlier. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the effect of levodopa on bradykinesia, rigidity, and tremor is larger after 22 weeks compared with 4 weeks of treatment. TRIAL REGISTRATION INFORMATION: ISRCTN30518857, EudraCT number 2011-000678-72.

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.

Combined and Sequential Treatment with Deep Brain Stimulation and Continuous Intrajejunal Levodopa Infusion for Parkinson's Disease.

(1) Background: Deep brain stimulation (DBS) and continuous intrajejunal levodopa infusion (CLI) are efficacious treatments of medication related motor response fluctuations in advanced Parkinson's disease (PD). Literature regarding the use of both advanced treatments within one patient is scarce. (2) Methods: We present a retrospective single center case series and a review of the literature. Patients with PD who were treated with both DBS and CLI in our tertiary referral center between 2005 and 2020 were identified and medical records were assessed. Additionally, literature on patients treated with both therapies was systematically searched for in Medline and Embase. (3) Results: Nineteen patients were included. Medication related motor response fluctuations were a major indication for the second therapy in all but one. Of nine patients initially treated with DBS, five reported improvement with CLI. Seven of ten patients initially treated with CLI experienced benefits from DBS. The systematic literature search resulted in fifteen previous publications comprising 66 patients. Of the 59 patients, for whom the effect of the second treatment was known, 57 improved. (4) Conclusions: PD patients, who have persisting medication related motor response fluctuations, despite DBS or CLI treatment, may benefit from an additional or alternative treatment with either CLI or DBS.

Advanced Care Planning in Parkinson's Disease: In-depth Interviews With Patients on Experiences and Needs.

Introduction: Advance care planning (ACP) is an iterative process of discussing the needs, wishes, and preferences of patients regarding disease-specific and end-of-life issues. There is ample evidence that ACP improves the quality of life and promotes the autonomy of patients with cancer and motor neuron disease who have a high disease burden and shortened life expectancy. In Parkinson's disease (PD) though, knowledge about the experiences and preferences of patients regarding ACP is scarce, despite the major disease burden associated with PD. Aim: This study aims to explore the experiences, needs, and preferences of PD patients regarding the content and timing of ACP. Methods: In-depth interviews were conducted with a purposively selected sample of patients diagnosed with PD. Using a semi-structured topic list, the participants were asked about their prospects for a future living with PD and with whom they wanted to discuss this. Qualitative analysis was performed in parallel with data collection using a data-driven constant comparative approach. The transcribed interviews were coded and analyzed by two researchers using MAXQDA software. Results: Of all 20 patients (13 males; age 47-82; disease duration 1-27 years), most expressed a wish to talk about ACP with a healthcare provider, enabling them to anticipate the uncertain future. The majority of patients preferred their healthcare provider to initiate the discussion on ACP, preferably at an early stage of the disease. Nearly all patients expressed the wish to receive more information regarding the long-term impact of PD, although, the preferred timing varied between patients. They also perceived that their neurologist was primarily focused on medication and had little time to address their need for a more holistic approach toward living with PD. Conclusion: Our results suggest that PD patients are in need of discussing ACP with their healthcare provider (HCP), even in the early stages of the disease. In addition, PD patients perceive a lack of information on their disease course and miss guidance on available supportive care. We recommend HCPs to inquire the information requirements and preferences of patients regarding ACP regularly, starting soon after diagnosis.

Evaluating and Optimizing Dentato-Rubro-Thalamic-Tract Deterministic Tractography in Deep Brain Stimulation for Essential Tremor.

BACKGROUND: Dentato-rubro-thalamic tract (DRT) deep brain stimulation (DBS) suppresses tremor in essential tremor (ET) patients. However, DRT depiction through tractography can vary depending on the included brain regions. Moreover, it is unclear which section of the DRT is optimal for DBS. OBJECTIVE: To evaluate deterministic DRT tractography and tremor control in DBS for ET. METHODS: After DBS surgery, DRT tractography was conducted in 37 trajectories (20 ET patients). Per trajectory, 5 different DRT depictions with various regions of interest (ROI) were constructed. Comparison resulted in a DRT depiction with highest correspondence to intraoperative tremor control. This DRT depiction was subsequently used for evaluation of short-term postoperative adverse and beneficial effects. RESULTS: Postoperative optimized DRT tractography employing the ROI motor cortex, posterior subthalamic area (PSA), and ipsilateral superior cerebellar peduncle and dentate nucleus best corresponded with intraoperative trajectories (92%) and active DBS contacts (93%) showing optimal tremor control. DRT tractography employing a red nucleus or ventral intermediate nucleus of the thalamus (VIM) ROI often resulted in a more medial course. Optimal stimulation was located in the section between VIM and PSA. CONCLUSION: This optimized deterministic DRT tractography strongly correlates with optimal tremor control. This technique is readily implementable for prospective evaluation in DBS target planning for ET.

General Anesthesia vs Local Anesthesia in Microelectrode Recording-Guided Deep-Brain Stimulation for Parkinson Disease: The GALAXY Randomized Clinical Trial.

Importance: It is unknown if there is a difference in outcome in asleep vs awake deep brain stimulation (DBS) of the subthalamic nucleus for advanced Parkinson disease. Objective: To determine the difference in adverse effects concerning cognition, mood, and behavior between awake and asleep DBS favoring the asleep arm of the study. Design, Setting, and Participants: This study was a single-center prospective randomized open-label blinded end point clinical trial. A total of 187 persons with Parkinson disease were referred for DBS between May 2015 to March 2019. Analysis took place from January 2016 to January 2020. The primary outcome follow-up visit was conducted 6 months after DBS. Interventions: Bilateral subthalamic nucleus DBS was performed while the patient was asleep (under general anesthesia) in 1 study arm and awake in the other study arm. Both arms of the study used a frame-based intraoperative microelectrode recording technique to refine final target placement of the DBS lead. Main Outcomes and Measures: The primary outcome variable was the between-group difference in cognitive, mood, and behavioral adverse effects as measured by a composite score. The secondary outcomes included the Movement Disorders Society Unified Parkinson's Disease Rating Scale, the patient assessment of surgical burden and operative time. Results: A total of 110 patients were randomized to awake (local anesthesia; n = 56; mean [SD] age, 60.0 (7.4) years; 40 [71%] male) or to asleep (general anesthesia; n = 54; mean [SD] age, 61.3 [7.9] years; 38 [70%] male) DBS surgery. The 6-month follow-up visit was completed by 103 participants. The proportion of patients with adverse cognitive, mood, and behavioral effects on the composite score was 15 of 52 (29%) after awake and 11 of 51 (22%) after asleep DBS (odds ratio, 0.7 [95% CI, 0.3-1.7]). There was no difference in improvement in the off-medication Movement Disorders Society Unified Parkinson's Disease Rating Scale Motor Examination scores between groups (awake group: mean [SD], -27.3 [17.5] points; asleep group: mean [SD], -25.3 [14.3] points; mean difference, -2.0 [95% CI, -8.1 to 4.2]). Asleep surgery was experienced as less burdensome by patients and was 26 minutes shorter than awake surgery. Conclusions and Relevance: There was no difference in the primary outcome of asleep vs awake DBS. Future large randomized clinical trials should examine some of the newer asleep based DBS technologies because this study was limited to frame-based microelectrode-guided procedures. Trial Registration: trialregister.nl Identifier: NTR5809.

Natural history and long-term testicular growth of acquired undescended testis after spontaneous descent or pubertal orchidopexy.

OBJECTIVE: To assess prospectively the natural history and long-term testicular growth of acquired undescended testis (UDT) after spontaneous descent or pubertal orchidopexy in case of nondescent. PATIENTS AND METHODS: From 1996 until 2008, 391 boys with 464 acquired UDT were included in the study. In accordance with Dutch consensus on non-scrotal testes, spontaneous descent at puberty was awaited; if this did not take place, orchidopexy was performed at puberty. Acquired UDT was defined as a testis previously residing in the scrotum that can no longer be manipulated into a stable scrotal (high scrotal) or nonscrotal (inguinal, impalpable) position. After referral, testis position, testis volume and puberty stage were monitored annually until adolescence. Testis volume was assessed using an orchidometer and compared with the Dutch standard. All investigations were carried out by the same physician (W.H.). Of these boys, 84 (mean age 12.9 years, range 6.4-21.3) were also clinically assessed by a second physician (J.G.), unaware of the results of the first examination. In addition, these boys were assessed with testicular ultrasonography, carried out by both physicians. RESULTS: Currently the mean (range) follow-up is 4.7 (0.1-12.0) years, and 253 acquired UDT have reached the scrotum. In 196 of these 253 cases (77.5%), there was spontaneous descent at puberty (mean age at descent 12.9 years, range 9.8-16.9); in the other 57 cases (22.5%), pubertal orchidopexy was required due to nondescent; five cases required orchidectomy. Of the 494 testis volume measurements after spontaneous descent, 458 (92.7%) were at ≥10th centile for age, of which 311 (63.0%) were ≥50th centile, and 107 (21.7%) ≥90th centile. After pubertal orchidopexy for nondescent, of the 85 measurements, 79 (92.9%) were at ≥10th centile, 53 (62.4%) ≥50th centile and 12 (14.1%) ≥90th centile. In unilateral cases, after spontaneous descent 174 of the 294 (59.2%) retained testes were found to be smaller than their counterpart and 90 of 294 (30.6%) were equal in size. After pubertal orchidopexy in unilateral cases, 40 of the 51 (78.4%) testes were smaller, and nine (17.6%) were equal in size. There was a strong correlation between both investigators for the measurement of testicular volume by orchidometer, and for the main investigator (W.H.) between his measurements by ultrasonography and the Prader orchidometer. CONCLUSION: Acquired UDT has a 77.5% tendency of spontaneous descent at puberty. In nearly all cases, after spontaneous descent as well as after pubertal orchidopexy, long-term testicular growth is within the normal range.