Faculty Bibliography

Lance Adams Syndrome (LAS), or chronic post-hypoxic myoclonus (PHM), is a rare and disabling condition which occurs in the aftermath of a diffuse hypoxic brain injury, usually when patient regains consciousness. Due to its refractoriness to antiepileptics, deep brain stimulation (DBS) has been attempted over the past fifteen years. We describe three patients who underwent Globus Pallidus interna (GPi)-DBS at the NYU Langone Department of Neurosurgery. Despite varying stimulation parameters and contact combinations, none achieved substantial improvement of action and negative myoclonus or regained the ability to ambulate unassisted. We compared our results with previous reports. Our literature review identified ten cases of LAS treated with DBS since 2010. The target was GPi in 8/10 patients, the ventralis intermedius (VIM) nucleus in one, and the subtalamic nucleus (STN) in one. Varying degrees of improvement were reported, with some evidence suggesting that long pulse width and lower frequency might be more effective. However, most reports provided only partial Unified Myoclonus Rating Scale (UMRS) scores, with missing information on rest and reflex myoclonus as well as negative myoclonus. Due to the paucity of prior reports and the limited generalizability of existing evidence, the efficacy of DBS in LAS has yet to be demonstrated. Further case reports, both positive and negative, supported by neurophysiological measures, may help bridge this knowledge gap.

BACKGROUND:Parkinson's disease management is often complicated by motor fluctuations and dyskinesia. Although deep brain stimulation addresses these symptoms, its use is limited by invasiveness, potential device failure, and the need for ongoing maintenance. Magnetic resonance-guided focused ultrasound (MRgFUS) provides incisionless, image-guided ablation as an alternative. However, the benefits and harms of staged, bilateral MRgFUS pallidothalamic tractotomy have not been evaluated systematically in prospective multicentre studies. METHODS:In this prospective, multicentre, single-arm study, adults with idiopathic, levodopa-responsive Parkinson's disease and motor complications (Movement Disorders Society Unified Parkinson's Disease Rating Scale [MDS-UPDRS] part IV item 4.2 or 4.4 score ≥2) were enrolled at nine investigational centres (six in the USA, two in Spain, and one in Taiwan). Participants underwent unilateral MRgFUS pallidothalamic tractotomy to the symptom-dominant side. Contralateral pallidothalamic tractotomy followed a minimum of 6 months later for participants meeting prespecified criteria. The primary efficacy endpoint was percent change from baseline to 3 months after the second procedure in the summed MDS-UPDRS part III off-medication upper and lower extremity (ULE) motor scores. Safety outcomes were incidence, severity, and persistence of treatment-related adverse events in the 12 months after each procedure. Safety and efficacy of unilateral treatment were evaluated in the unilateral intention-to-treat (ITT) and safety populations, defined as all patients receiving one or more sonications during the first procedure. The primary outcome and safety of bilateral treatment were evaluated in the bilateral modified ITT (mITT) and safety populations, which required one or more sonications during the second procedure, a baseline motor assessment, and at least one post-bilateral motor assessment. This trial is registered at ClinicalTrials.gov, NCT04728295 and is active, not recruiting. FINDINGS/RESULTS:Between July 12, 2021, and Nov 1, 2023, 54 patients received unilateral treatment and 40 proceeded to bilateral treatment (63 [67%] were male and 31 [33%] were female) and were included in the primary analysis; 36 completed 12-month follow-up after the second procedure. Median bilateral ULE motor scores decreased from 33·0 points (IQR 28·0-40·5) at baseline to 21·0 points (15·0-25·5) at month 3 post-bilateral treatment, a median within-patient change of 10·5 points (5·7-20·0), representing a 32% (18-52) improvement (p<0·0001). Benefits became apparent within 1 month of the first procedure and lasted through to 12 months after the second procedure. Treatment-related adverse events occurred in 21 (39%) of 54 patients after unilateral treatment; one (2%) had a persistent moderate adverse event at 6 months. After bilateral treatment, 22 (55%) of 40 patients had treatment-related adverse events; ten (25%) had persistent moderate or severe adverse events at 12 months, mainly affecting speech, gait, and balance. One (3%) patient developed severe persistent anarthria. INTERPRETATION/CONCLUSIONS:Unilateral MRgFUS pallidothalamic tractotomy demonstrated safety and efficacy for Parkinson's disease motor complications; however, bilateral treatment offered small motor gains while increasing persistent moderate or severe adverse events. Post-bilateral treatment complications in speech, gait, and balance are consistent with historical data for bilateral ablative procedures for movement disorders. Although unilateral MRgFUS pallidothalamic tractotomy was beneficial in our study, bilateral procedures demand rigorous patient selection and counselling regarding cumulative risks. FUNDING/BACKGROUND:Insightec.

UNLABELLED:<p>Introduction: Tremor-predominant Parkinson's disease (TPPD) generally responds favorably to deep brain stimulation (DBS) targeting the subthalamic nucleus (STN). However, traditional stereotactic targeting of the STN does not universally yield the anticipated intraoperative improvement, prompting exploration of additional targets to achieve optimal results prior to permanent implantation of electrodes. The posterior subthalamic area (PSA), including the caudal zona incerta (cZI), have been associated with tremor suppression and can be easily compared to the neighboring STN intraoperatively. METHODS:We retrospectively compared intraoperative and clinical outcomes in tremor-dominant PD patients who prospectively underwent dual trajectory microelectrode monitor targeting the STN and PSA/cZI. We compared the neurophysiology and tremor response of both the central (STN) and posterior (PSA) trajectories in 22 patients and analyzed outcomes in those who ultimately received traditional STN (16) or PSA/cZI lead implantation (12). RESULTS:While both groups achieved substantial overall motor improvement under chronic stimulation, intraoperative test stimulation through the posterior path produced more consistent tremor arrest compared with STN. These findings suggest that positioning the DBS lead further posteriorly to engage the PSA can augment tremor suppression in select cases of TPPD without compromising other parkinsonian symptom relief. CONCLUSION/CONCLUSIONS:Our results emphasize the value of intraoperative physiological feedback in trajectory selection in tremor-predominant patients and are consistent with emerging literature that PSA/cZI DBS is an effective and potentially superior target for management of tremor in PD. </p>.

BACKGROUND:Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an established treatment for medication-refractory tremor with limited evidence in patients aged >80 years. OBJECTIVE:To retrospectively compare safety and efficacy of MRgFUS in under-80 versus over-80 patients without prior balance disturbances or unstable comorbidities. METHODS:One hundred thirty five consecutive patients with essential tremor or tremor-predominant Parkinson's disease underwent unilateral MRgFUS thalamotomy. Patients were stratified into under-80 (n: 97, median age 71 years) and over-80 (n: 38, median age 82 years). Tremor severity was scored with the Fahn-Tolosa-Marin Clinical Rating Scale. Outcomes included intraoperative tremor suppression and SE occurrence, resolution, and improvement. RESULTS:Older patients showed higher baseline tremor severity (U: 383.5; p: 0.02). Tremor reduction >50% occurred in 95.6% of cases, with complete resolution in 77.0%. Higher target temperature predicted better tremor control (OR [95% CI]: 4.03 [1.39-11.65]; p: 0.01), whereas greater baseline tremor (OR [95% CI]: 0.90 [0.83-0.99]; p: 0.02) and SDR <0.4 (OR [95% CI]: 0.14 [0.02-0.85]; p: 0.03) predicted poorer outcomes. Age ≥ 80 did not affect intraprocedural tremor control (OR [95% CI]: 0.83 [0.15-4.70]; p: 0.83) and longitudinal mixed-effects analysis confirmed sustained 1-year tremor control, unaffected by advanced age. SEs occurred in 71.1%, mostly balance disturbances. After a mean follow-up of 43.7 weeks, 60.4% improved and 46.9% fully resolved, with only 1.5% severe persistent SEs. Age ≥ 80 did not influence SE rates (OR [95% CI]: 0.60 [0.27-1.33]; p: 0.20), resolution (OR [95% CI]: 0.56 [0.25-1.26]; p: 0.16), or improvement (OR [95% CI]: 0.60 [0.28-1.30]; p: 0.19). CONCLUSIONS:MRgFUS thalamotomy yields comparable outcomes in carefully selected patients aged >80 years and in younger individuals.

The management of drug-resistant epilepsy (DRE) in the pediatric population using neurostimulation of the centromedian (CM) nucleus of the thalamus (CMN) has been reported to be effective and safe. We present a case series of pediatric patients treated with responsive neurostimulation (RNS) and report on contact localization in relation to preliminary outcomes, specifically seizure reduction rates. Thirteen pediatric patients treated with RNS underwent direct targeting of the CMN based on Magnetization-Prepared 2 Rapid Gradient-Echo (MP2RAGE) scans, using ClearPoint neuronavigation. The implanted electrodes were co-registered to a probabilistic anatomical model of the thalamic nuclei (Freesurfer) for secondary confirmation of contact localization. Ten out of the 12 patients with extra-temporal multifocal or generalized DRE (83.3%) had over 50% reduction in seizures, benefiting from an 80.4% seizure reduction rate. The average follow-up interval was 25.2 months, with no patients experiencing stimulation-related side effects. The analysis of post-operative images revealed that out of the 24 CM-processed electrodes, 23 (95.8%) had at least two contacts in the nucleus, based on patient-specific segmentation of the thalamus. The preliminary outcomes suggest a robust response to central neurostimulation and no stimulation-related side effects in pediatric patients suffering from multifocal or generalized DRE when implementing high-accuracy direct targeting. PLAIN LANGUAGE SUMMARY: We are reporting our experience in the management of the most challenging types of pediatric epilepsy, involving seizures originating from multiple and/or poorly defined brain areas. We surgically implanted a responsive neurostimulation device (RNS) in central areas of the brain that function as connection hubs between different brain regions. These devices are designed to detect early signs of abnormal brain activity, and respond with electrical pulses to prevent progression to clinical seizures. Using our approach, we reduced the seizure rates by an average of 80% in 83% of the pediatric patients who received this treatment.

BACKGROUND AND PURPOSE/OBJECTIVE:Accurate localization of the ventral intermediate nucleus (VIM) within the dentatorubrothalamic tract (DRTT) is critical for effective neurosurgical treatment of essential tremor (ET). This study evaluated the feasibility and anatomical specificity of quantitative susceptibility mapping (QSM) for direct VIM/DRTT visualization, comparing it with conventional diffusion tractography-based reconstructions. MATERIALS AND METHODS/METHODS:Twenty-seven participants (10 healthy controls, 17 ET patients) were enrolled across two institutions and imaged on 3T MRI systems. QSM-defined VIM/DRTT regions were manually segmented based on characteristic hypointense susceptibility contrast. Whole-brain diffusion tractography was performed to reconstruct the DRTT, pyramidal tract (PT), and medial lemniscus (ML) tracts. Spatial overlap between QSM-and tractography-defined VIM/DRTT regions was calculated, as well as overlap with neighboring PT and ML tracts to assess specificity. RESULTS:Two participants were excluded due to insufficient VIM/DRTT streamlines in tractography reconstruction. In healthy controls, QSM-and tractography-defined VIM/DRTT showed high spatial correspondence (left: 87.6 ± 5.1%; right: 85.3 ± 6.5%). ET patients exhibited slightly lower overlap (mean range: 71.5 - 85.1%). Overlap with neighboring PT and ML tracts was minimal (<3.3%), confirming high anatomical specificity of QSM-derived VIM/DRTT regions. CONCLUSIONS:QSM enables direct visualization of the VIM/DRTT with high spatial agreement to conventional tractography-based approaches while demonstrating minimal overlap with adjacent tracts. These findings support QSM as a complementary or standalone imaging modality for improved, patient-specific neurosurgical targeting in ET. ABBREVIATIONS/BACKGROUND:DBS = deep brain stimulation; DRTT = dentatorubrothalamic tract; ET = essential tremor; ML = medial lemniscus; MRgFUS = MR-guided focused ultrasound; VIM = ventral intermediate nucleus; PT = pyramidal tract; QSM = quantitative susceptibility mapping; WM = white matter.

IMPORTANCE/UNASSIGNED:The Implantable Neurostimulator for the Treatment of Parkinson's Disease (INTREPID) trial was a randomized, double-blind, sham-controlled study of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of Parkinson disease (PD). OBJECTIVE/UNASSIGNED:To evaluate the long-term (5-year) outcomes and safety of STN-DBS for PD. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This was a prospective, randomized (3:1), 12-week double-blind sham-controlled study at 23 movement disorder centers across the US with an open-label 5-year follow-up. Patients were implanted and followed up with the Vercise DBS system from May 2013 to December 2022. Eligibility required diagnosis of bilateral idiopathic PD with more than 5 years of motor symptoms, more than 6 hours per day of poor motor function, modified Hoehn and Yahr Scale scores higher than 2, Unified Parkinson's Disease Rating Scale (UPDRS-III) score of 30 or higher (medication-off state), and 33% or higher improvement in UPDRS-III medication-on score. INTERVENTION/UNASSIGNED:Bilateral STN-DBS for moderate to advanced PD. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Primary outcomes included changes in UPDRS and dyskinesia scores, quality-of-life measures, and safety assessments. Exploratory analyses included medication reduction and DBS association with motor signs. RESULTS/UNASSIGNED:A total of 313 patients were enrolled with 191 receiving the DBS system, and 137 participants (72%) completed the study. The study population had a mean (SD) age of 60 (7.9) years, with 139 (73%) male participants. Motor function without medication as measured by UPDRS-III improved from a mean (SD) of 42.8 (9.4) to 21.1 (10.6) at year 1 (51%; 95% CI, 49%-53%; P < .001) and 27.6 (11.6) at year 5 (36%; 95% CI, 33%-38%; P < .001). Activities of daily living without medication as measured by UPDRS-III improved from a mean (SD) of 20.6 (6.0) to 12.4 (6.1) at year 1 (41%; 95% CI, 38%-42%; P < .001) and 16.4 (6.5) at year 5 (22%; 95% CI, 18%-23%; P < .001). Dyskinesia scores decreased from 4.0 (5.1) to 1.0 (2.1) at year 1 (75%; 95% CI, 73%-75%; P < .001) and to 1.2 (2.1) at year 5 (70%; 95% CI, 63%-75%; P < .001). The levodopa equivalent dose was reduced by 28% at year 1, remaining stable at year 5 (28%; 95% CI, 26%-31%; P < .001). The most common serious adverse event was infection (9 participants). Ten deaths were reported, none related to the study. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Although STN-DBS outcomes declined slightly, possibly due to the progressive nature of the disease, patients with PD sustained significant improvement in motor and activities of daily living scores, along with a stable reduction in anti-parkinsonian medication over the 5-year follow-up period.

OBJECTIVE:Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) has been investigated clinically for treatment-resistant depression (TRD). Although the initial BROADEN study, a randomized controlled trial, was halted after an interim futility analysis, observation of long-term follow-up (LTFU) data from this and other cohorts demonstrated sustained improvement in depressive symptoms, prompting further investigation of DBS as a therapeutic option. METHODS:Data from 5 studies, including BROADEN, were used to evaluate the long-term safety and effectiveness of SCC DBS for TRD. Effectiveness measures included percent change in HDRS-17 and MADRS, response and partial response rate, and remission rate. Outcomes were assessed through five years post-implant, with primary analyses focused on the first 24 months due to attrition after this point. Sensitivity analyses were performed to evaluate robustness of the results, and adverse events were summarized. RESULTS:172 subjects were implanted in 5 studies across 5 countries. Average age was 47.9 years, 8.1 years in the current depressive episode, and 88 % had received electroconvulsive therapy (ECT). Effectiveness outcomes were analyzed through 24 months; additional data through five years are available in the supplement. Average MADRS reduction was 43 % at 12 months and 53 % at 24 months post-device activation, with response rates of 46 % and 55 %, and partial response rates of 13.3 % and 15.5 %, respectively. Observed case and sensitivity analyses for both MADRS and HDRS-17 showed a significant reduction in depressive symptoms at each follow-up visit. Safety data from four studies included 151 implanted subjects with 523 patient-years. Incidence of suicide was 0.55 per 100 patient-years. CONCLUSIONS:Active SCC DBS shows continuous and sustained improvement in depressive symptomatology from the first year onward. While several limitations may impact the validity of these findings, SCC DBS has the possibility to provide a safe and durable treatment for TRD.

BACKGROUND/UNASSIGNED:High intensity focused ultrasound (HiFU) is a relatively new incisionless intervention used for treatment of essential tremor and Parkinson's disease tremor. Understanding the indications, benefits, risks and limitations of HiFU, as well as how it compares to deep brain stimulation (DBS), is important in guiding appropriate recommendations for prospective patients. METHODS/UNASSIGNED:Current literature on efficacy and safety of HiFU in essential tremor and Parkinson's disease was reviewed. We additionally reviewed data on the patients who presented to our center for HiFU consultation, including outcomes of patients with low skull density ratios, and distances traveled for the procedure. RESULTS/DISCUSSION/UNASSIGNED:HiFU is an effective and generally well-tolerated treatment for tremor. Adverse events, especially gait instability, are typically temporary but should be discussed with patients. The risk of tremor recurrence in certain patients with Parkinson's disease is also of note. Identifying appropriate candidates for either intervention remains crucial and involves considering each patient's circumstances and preferences, potential adverse effects, and practical aspects like access to follow-up and expectations. Data on bilateral HiFU lesioning, use of HiFU in patients with low skull density ratios, and emerging targets like the pallidothalamic tract are discussed as well.