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.

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.

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.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Despite the well-established efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's Disease (PD), there remains a subset of patients with only a moderate improvement in symptoms even with appropriate lead placement and optimal programming. In patients with persistent tremor or dyskinesias, one consideration is the addition of a second "rescue lead" to provide dual stimulation to primary and secondary targets to address the refractory component. This study aimed to assess all "rescue lead" cases from our institution and characterize the patients and their outcomes. METHODS:Records of all patients with PD treated at our institution between 2005 and 2023 were retrospectively reviewed. Clinical data of all patients treated with a second rescue lead to supplement a positive but inadequate initial DBS response were collected and reviewed. RESULTS:Of 670 patients with PD treated at our institution during the study period, 7 were managed with a rescue lead. All 7 were initially treated with STN DBS with a partial improvement in underlying symptoms, had confirmed appropriate lead placement, and underwent thorough programming. Four patients underwent rescue with a globus pallidus interna lead for persistent dyskinesias, all with subsequent improvement in their dyskinesias. Three patients had persistent tremors that were treated with a rescue ventrointermediate thalamus stimulation with subsequent improvement in tremor scores. There were no operative complications, and all patients tolerated dual stimulation. CONCLUSION/CONCLUSIONS:For a small subset of patients with PD with persistent dyskinesias or tremors after STN DBS despite optimized lead parameters and adequate lead placement, rescue lead placement offers an effective treatment option.

INTRODUCTION:Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD), but its efficacy is tied to DBS programming, which is often time consuming and burdensome for patients, caregivers, and clinicians. Our aim is to test whether the Mobile Application for PD DBS (MAP DBS), a clinical decision support system, can improve programming. METHODS:We conducted an open-label, 1:1 randomized, controlled, multicenter clinical trial comparing six months of SOC standard of care (SOC) to six months of MAP DBS-aided programming. We enrolled patients between 30 and 80 years old who received DBS to treat idiopathic PD at six expert centers across the United States. The primary outcome was time spent DBS programming and secondary outcomes measured changes in motor symptoms, caregiver strain and medication requirements. RESULTS:We found a significant reduction in initial visit time (SOC: 43.8 ± 28.9 min n = 37, MAP DBS: 27.4 ± 13.0 min n = 35, p = 0.001). We did not find a significant difference in total programming time between the groups over the 6-month study duration. MAP DBS-aided patients experienced a significantly larger reduction in UPDRS III on-medication scores (-7.0 ± 7.9) compared to SOC (-2.7 ± 6.9, p = 0.01) at six months. CONCLUSION:MAP DBS was well tolerated and improves key aspects of DBS programming time and clinical efficacy.

The subthalamic nucleus (STN) is theorized to globally suppress movement through connections with downstream basal ganglia structures. Current theories are supported by increased STN activity when subjects withhold an uninitiated action plan, but a critical test of these theories requires studying STN responses when an ongoing action is replaced with an alternative. We perform this test in subjects with Parkinson's disease using an extended reaching task where the movement trajectory changes mid-action. We show that STN activity decreases during action switches, contrary to prevalent theories. Furthermore, beta oscillations in the STN local field potential, which are associated with movement inhibition, do not show increased power or spiking entrainment during switches. We report an inhomogeneous population neural code in STN, with one sub-population encoding movement kinematics and direction and another encoding unexpected action switches. We suggest an elaborate neural code in STN that contributes to planning actions and changing the plans.

Deep brain stimulation may be an effective therapy for select cases of severe, treatment-refractory Tourette syndrome; however, patient responses are variable, and there are no reliable methods to predict clinical outcomes. The objectives of this retrospective study were to identify the stimulation-dependent structural networks associated with improvements in tics and comorbid obsessive-compulsive behaviour, compare the networks across surgical targets, and determine if connectivity could be used to predict clinical outcomes. Volumes of tissue activated for a large multisite cohort of patients (n = 66) implanted bilaterally in globus pallidus internus (n = 34) or centromedial thalamus (n = 32) were used to generate probabilistic tractography to form a normative structural connectome. The tractography maps were used to identify networks that were correlated with improvement in tics or comorbid obsessive-compulsive behaviour and to predict clinical outcomes across the cohort. The correlated networks were then used to generate 'reverse' tractography to parcellate the total volume of stimulation across all patients to identify local regions to target or avoid. The results showed that for globus pallidus internus, connectivity to limbic networks, associative networks, caudate, thalamus, and cerebellum was positively correlated with improvement in tics; the model predicted clinical improvement scores (P = 0.003) and was robust to cross-validation. Regions near the anteromedial pallidum exhibited higher connectivity to the positively correlated networks than posteroventral pallidum, and volume of tissue activated overlap with this map was significantly correlated with tic improvement (P < 0.017). For centromedial thalamus, connectivity to sensorimotor networks, parietal-temporal-occipital networks, putamen, and cerebellum was positively correlated with tic improvement; the model predicted clinical improvement scores (P = 0.012) and was robust to cross-validation. Regions in the anterior/lateral centromedial thalamus exhibited higher connectivity to the positively correlated networks, but volume of tissue activated overlap with this map did not predict improvement (P > 0.23). For obsessive-compulsive behaviour, both targets showed that connectivity to the prefrontal cortex, orbitofrontal cortex, and cingulate cortex was positively correlated with improvement; however, only the centromedial thalamus maps predicted clinical outcomes across the cohort (P = 0.034), but the model was not robust to cross-validation. Collectively, the results demonstrate that the structural connectivity of the site of stimulation are likely important for mediating symptom improvement, and the networks involved in tic improvement may differ across surgical targets. These networks provide important insight on potential mechanisms and could be used to guide lead placement and stimulation parameter selection, as well as refine targets for neuromodulation therapies for Tourette syndrome.