Search

Objective: Short-term outcomes of deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) were reported for people with drug-resistant focal epilepsy (PwE). Because long-term data are still scarce, the Medtronic Registry for Epilepsy (MORE) evaluated clinical routine application of ANT-DBS., Methods: In this multicenter registry, PwE with ANT-DBS were followed up for safety, efficacy, and battery longevity. Follow-up ended after 5 years or upon study closure. Clinical characteristics and stimulation settings were compared between PwE with no benefit, improvers, and responders, that is, PwE with average monthly seizure frequency reduction rates of ≥50%., Results: Of 170 eligible PwE, 104, 62, and 49 completed the 3-, 4-, and 5-year follow-up, respectively. Most discontinuations (68%) were due to planned study closure as follow-up beyond 2 years was optional. The 5-year follow-up cohort had a median seizure frequency reduction from 16 per month at baseline to 7.9 per month at 5-year follow-up (p < .001), with most-pronounced effects on focal-to-bilateral tonic-clonic seizures (n = 15, 77% reduction, p = .008). At last follow-up (median 3.5 years), 41% (69/170) of PwE were responders. Unifocal epilepsy (p = .035) and a negative history of epilepsy surgery (p = .002) were associated with larger average monthly seizure frequency reductions. Stimulation settings did not differ between response groups. In 179 implanted PwE, DBS-related adverse events (AEs, n = 225) and serious AEs (n = 75) included deterioration in epilepsy or seizure frequency/severity/type (33; 14 serious), memory/cognitive impairment (29; 3 serious), and depression (13; 4 serious). Five deaths occurred (none were ANT-DBS related). Most AEs (76.3%) manifested within the first 2 years after implantation. Activa PC depletion (n = 37) occurred on average after 45 months., Significance: MORE provides further evidence for the long-term application of ANT-DBS in clinical routine practice. Although clinical benefits increased over time, side effects occurred mainly during the first 2 years. Identified outcome modifiers can help inform PwE selection and management., (© 2024 Medtronic and The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Objectives: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice., Methods: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes., Results: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years ( p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years ( p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported., Discussion: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation., Classification of Evidence: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy., Trial Registration Information: MORE ClinicalTrials.gov Identifier: NCT01521754, first posted on January 31, 2012., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Deep brain stimulation (DBS) has been proposed for severe, chronic, treatment-refractory obsessive-compulsive disorder (OCD) patients. Although serious adverse events can occur, only a few studies report on the safety profile of DBS for psychiatric disorders. In a prospective, open-label, interventional multi-center study, we examined the safety and efficacy of electrical stimulation in 30 patients with DBS electrodes bilaterally implanted in the anterior limb of the internal capsule. Safety, efficacy, and functionality assessments were performed at 3, 6, and 12 months post implant. An independent Clinical Events Committee classified and coded all adverse events (AEs) according to EN ISO14155:2011. All patients experienced AEs (195 in total), with the majority of these being mild (52% of all AEs) or moderate (37%). Median time to resolution was 22 days for all AEs and the etiology with the highest AE incidence was 'programming/stimulation' (in 26 patients), followed by 'New illness, injury, condition' (13 patients) and 'pre-existing condition, worsening or exacerbation' (11 patients). Sixteen patients reported a total of 36 serious AEs (eight of them in one single patient), mainly transient anxiety and affective symptoms worsening (20 SAEs). Regarding efficacy measures, Y-BOCS reduction was 42% at 12 months and the responder rate was 60%. Improvements in GAF, CGI, and EuroQol-5D index scores were also observed. In sum, although some severe AEs occurred, most AEs were mild or moderate, transient and related to programming/stimulation and tended to resolve by adjustment of stimulation. In a severely treatment-resistant population, this open-label study supports that the potential benefits outweigh the potential risks of DBS.

Background: The Medtronic Registry for Epilepsy (MORE; Medtronic Inc, Dublin, Ireland) is an open label observational study evaluating the long-term effectiveness, safety, and performance of deep brain stimulation (DBS) of the anterior nucleus of thalamus (ANT) for the treatment of refractory epilepsy., Objective: To compare the difference in success rate of placing contacts at ANT-target region (ANT-TR) between transventricular (TV) and extraventricular (EV) lead trajectories in 73 ANT-DBS implants in 17 European centers participating in the MORE registry., Methods: The success rate of placing contacts at ANT-TR was evaluated using a screening method combining both individual patient imaging information and stereotactic atlas information to identify contacts at ANT-TR., Results: EV lead trajectory was used in 53% of the trajectories. Approximately, 90% of the TV lead trajectories had at least 1 contact at ANT-TR, vs only 71% of the EV lead trajectories. The success rate for placing at least 1 contact at ANT-TR bilaterally was 84% for TV implants and 58% for EV implants (P < .05; Fisher's exact). No intracranial bleedings were observed, but 1 cortical infarct was reported following EV lead trajectory., Conclusion: The results of this registry support the use of TV lead trajectories for ANT-DBS as they have a higher probability in placing contacts at ANT-TR, without appearing to compromise procedural safety. Follow-up data collection is continuing in the MORE registry. These data will provide outcomes associated with TV and EV trajectories.

The aim of this review was to provide strong clinical evidence of the efficacy of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in isolated inherited or idiopathic dystonia. Eligible studies were identified after a systematic literature review of the effects of bilateral GPi-DBS in isolated dystonia. Absolute and percentage changes from baseline in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor and disability scores were pooled, and associations between treatment effect and patient characteristics were explored using meta-regression. In total, 24 studies were included in the meta-analysis, comprising 523 patients. The mean absolute and percentage improvements in BFMDRS motor score at the last follow-up (mean 32.5 months; 24 studies) were 26.6 points [95% confidence interval (CI), 22.4-30.8] and 65.2% (95% CI, 59.6-70.7), respectively. The corresponding changes in disability score at the last follow-up (mean 32.9 months; 14 studies) were 6.4 points (95% CI, 5.0-7.8) and 58.6% (95% CI, 50.3-66.9). Multivariate meta-regression of absolute scores indicated that higher BFMDRS motor and disability scores before surgery, together with younger age at time of surgery, were the main factors associated with significantly better DBS outcomes at the latest follow-up. Reporting of safety data was frequently inconsistent and could not be included in the meta-analysis. In conclusion, patients with isolated inherited or idiopathic dystonia significantly improved after GPi-DBS. Better outcomes were associated with greater dystonia severity at baseline. These findings should be taken into consideration for improving patient selection for DBS., (© 2017 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: In preparation for a multicenter study, a protocol was written on how to perform surgical targeting of the bed nucleus of the stria terminalis, based on the lead implantation experience in patients with treatment-refractory obsessive-compulsive disorder (OCD) at the Universitaire Ziekenhuizen Leuven (UZ Leuven). When analyzing the postoperative images, we were struck by the fact that the difference between the postoperative position of the leads and the planned position seemed larger than expected., Methods: The precision of targeting in four patients with severe OCD who received bilateral model 3391 leads (Medtronic) was compared with the precision of targeting in the last seven patients who underwent surgery at UZ Leuven for movement disorders (four with Parkinson disease and three with essential tremor; all received bilateral leads). Because the leads implanted in six of the seven patients with movement disorders were model 3387 leads (Medtronic), targeting precision was also analyzed in four patients with OCD in whom model 3387 leads were implanted in the same target as the other patients with OCD., Results: In the patients with OCD, every implanted lead deviated at least 1.3 mm from its intended position in at least one of three directions (lateral, anteroposterior, and depth), whereas in the patients with movement disorders, the maximal deviation of any of all implanted leads was 1.3 mm. The deviations in lead placement were comparable in patients with OCD who received a model 3387 implant and patients who received a model 3391 implant. In the patients with OCD, all leads were implanted more posteriorly than planned., Conclusions: The cause of the posterior deviation could not be determined with certainty. The most likely cause was an increased mechanical resistance of the brain tissue along the trajectory when following the targeting protocol compared with the trajectories classically used for subthalamic nucleus or ventral intermediate nucleus of the thalamus stimulation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Sonic hedgehog (Shh) signaling controls many aspects of ontogeny, orchestrating congruent growth and patterning. During brain development, Shh regulates early ventral patterning while later on it is critical for the regulation of precursor proliferation in the dorsal brain, namely in the neocortex, tectum and cerebellum. We have recently shown that Shh also controls the behavior of cells with stem cell properties in the mouse embryonic neocortex, and additional studies have implicated it in the control of cell proliferation in the adult ventral forebrain and in the hippocampus. However, it remains unclear whether it regulates adult stem cell lineages in an equivalent manner. Similarly, it is not known which cells respond to Shh signaling in stem cell niches. Here we demonstrate that Shh is required for cell proliferation in the mouse forebrain's subventricular zone (SVZ) stem cell niche and for the production of new olfactory interneurons in vivo. We identify two populations of Gli1+ Shh signaling responding cells: GFAP+ SVZ stem cells and GFAP- precursors. Consistently, we show that Shh regulates the self-renewal of neurosphere-forming stem cells and that it modulates proliferation of SVZ lineages by acting as a mitogen in cooperation with epidermal growth factor (EGF). Together, our data demonstrate a critical and conserved role of Shh signaling in the regulation of stem cell lineages in the adult mammalian brain, highlight the subventricular stem cell astrocytes and their more abundant derived precursors as in vivo targets of Shh signaling, and demonstrate the requirement for Shh signaling in postnatal and adult neurogenesis.

TGF-beta1 is a key regulator of diverse biological processes in many tissues and cell types, but its exact function in the developing and adult mammalian CNS is still unknown. We report that lack of TGF-beta1 expression in neonatal Tgfb1(-/-) mice results in a widespread increase in degenerating neurons accompanied by reduced expression of synaptophysin and laminin and a prominent microgliosis. Lack of TGF-beta1 also strongly reduces survival of primary neurons cultured from Tgfb1(-/-) mice. TGF-beta1 deficiency in adult Tgfb1(-/+) mice results in increased neuronal susceptibility to excitotoxic injury, whereas astroglial overexpression of TGF-beta1 protects adult mice against neurodegeneration in acute, excitotoxic and chronic injury paradigms. This study reveals a nonredundant function for TGF-beta1 in maintaining neuronal integrity and survival of CNS neurons and in regulating microglial activation. Because individual TGF-beta1 expression levels in the brain vary considerably between humans, this finding could have important implications for susceptibility to neurodegeneration.

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of Abeta deposition, but the cause or significance of this cellular response is unclear. Here we show that cultured adult mouse astrocytes migrate in response to monocyte chemoattractant protein-1 (MCP-1), a chemokine present in AD lesions, and cease migration upon interaction with immobilized Abeta(1-42). We also show that astrocytes bind and degrade Abeta(1-42). Astrocytes plated on Abeta-laden brain sections from a mouse model of AD associate with the Abeta deposits and reduce overall Abeta levels in these sections. Our results suggest a novel mechanism for the accumulation of astrocytes around Abeta deposits, indicate a direct role for astrocytes in degradation of Abeta and implicate deficits in astroglial clearance of Abeta in the pathogenesis of AD. Treatments that increase removal of Abeta by astrocytes may therefore be a critical mechanism to reduce the neurodegeneration associated with AD.