Deep Brain Stimulation and Responsive Neurostimulation Implantation for Medically Refractory Epilepsy: A Case Report Study of a Single-Center's Experience

Background and PurposeImplantation of deep brain stimulation (DBS) electrodes in the anterior nucleus of the thalamus (ANT) or the centromedian nucleus (CM), for the treatment of refractory epilepsy, is technically demanding. To enhance the accuracy of electrode placement within the ANT and CM, we analyzed our experience with electrode revision surgery in ANT and CM DBS and investigated the cause of misplacement and verifying methods for accurate placement.MethodsA retrospective analysis of the medical records of 23 patients who underwent DBS for refractory epilepsy during the period from 2013 to 2016 was performed.ResultsMisplacement of the electrode occurred in 1 (25%) of 4 ANT DBS and 2 (14.3%) of 14 patients with CM DBS performed in our institute, and revision surgery was performed in three patients. During this period, we performed three revision surgeries for misplaced electrodes in ANT DBS that were performed at another hospital. Therefore, we performed six revision surgeries (four in ANT, two in CM) for mistargeted DBS electrodes for thalamic DBS. Transventricular lead placement and an anatomical targeting of the ANT was the cause of misplacement in the ANT and intraoperative brain shift was found to be the cause in the CM. For verification of the location of lead placement, magnetic resonance imaging (MRI) was superior to computed tomography and electroencephalography (EEG).ConclusionsTo reduce the rate of electrode misplacement for refractory epilepsy, image-based targeting of the ANT according to individual anatomical variation, and efforts to minimize intraoperative brain shift are essential. To verify the location of the electrode, MRI examination is mandatory in DBS for refractory epilepsy.

There are three neurostimulation devices available to treat generalized epilepsy: vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). However, the choice between them is unclear due to lack of head-to-head comparisons. A systematic comparison of neurostimulation outcomes in generalized epilepsy has not been performed previously. The goal of this meta-analysis was to determine whether one of these devices is better than the others to treat generalized epilepsy. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic review of PubMed, Embase, and Web of Science was performed for studies reporting seizure outcomes following VNS, RNS, and DBS implantation in generalized drug-resistant epilepsy between the first pivotal trial study for each modality through August 2022. Specific search criteria were used for VNS ("vagus", "vagal", or "VNS" in the title and "epilepsy" or "seizure"), DBS ("deep brain stimulation", "DBS", "anterior thalamic nucleus", "centromedian nucleus", or "thalamic stimulation" in the title and "epilepsy" or "seizure"), and RNS ("responsive neurostimulation" or "RNS" in the title and "epilepsy" or "seizure"). From 4409 articles identified, 319 underwent full-text reviews, and 20 studies were included. Data were pooled using a random-effects model using the meta package in R. Sufficient data for meta-analysis were available from seven studies for VNS (n= 510) and nine studies for DBS (n= 87). Data from RNS (five studies, n= 18) were insufficient for meta-analysis. The mean (SD) follow-up durations were as follows: VNS, 39.1 (23.4) months; DBS, 23.1 (19.6) months; and RNS, 22.3 (10.6) months. Meta-analysis showed seizure reductions of 48.3% (95% confidence interval [CI] = 38.7%-57.9%) for VNS and 64.8% (95% CI=54.4%-75.2%) for DBS (p= .02). Our meta-analysis indicates that the use of DBS may lead to greater seizure reduction than VNS in generalized epilepsy. Results from RNS use are promising, but further research is required.

Pediatric drug-resistant epilepsy (DRE) is defined as epilepsy that is not controlled by two or more appropriately chosen and dosed anti-seizure medications (ASMs). When alternative therapies or surgical intervention is not viable or efficacious, advanced options like deep brain stimulation (DBS) or responsive neurostimulation (RNS) may be considered. Describe the Stanford early institutional experience with DBS and RNS in pediatric DRE patients. Retrospective chart review of seizure characteristics, prior therapies, neurosurgical operative reports, and postoperative outcome data in pediatric DRE patients who underwent DBS or RNS placement. Nine patients had DBS at 16.0 ± 0.9 years and 8 had RNS at 15.3 ± 1.7 years (mean ± SE). DBS targets included the centromedian nucleus of the thalamus (78% of DBS patients), anterior nucleus of the thalamus (11%), and pulvinar (11%). RNS placement was guided by stereo-EEG and/or intracranial monitoring in all RNS patients (100%). RNS targets included specific seizure onset zones (63% of RNS patients), bilateral hippocampi (25%) and bilateral temporal lobes (12%). Only DBS patients had prior trials of ketogenic diet (56%) and VNS therapy (67%). Four DBS patients (44%) had prior neurosurgical interventions, including callosotomy (22%) and focal resection (11%). One RNS patient (13%) and one DBS patient (11%) required revision surgery. Two DBS patients (22%) developed postoperative complications. Three RNS patients (38%) underwent additional resections; one RNS patient had electrocorticography recordings for seizure mapping before surgery. For patients with a follow-up of at ≥1 year (n = 7 for DBS and n = 5 for RNS), all patients had reduced seizure burden. Clinical seizure freedom was achieved in 80% of RNS patients and 20% had a >90% reduction in seizure burden. The majority (71%) of DBS patients had a ≥50% reduction in seizures. No patients experienced no change or worsening of seizure frequency. In the early Stanford experience, DBS was used as a palliatively for generalized or mixed DRE refractory to other resective or modulatory approaches. RNS was used for multifocal DRE with a clear seizure focus on stereo-EEG and no prior surgical interventions. Both modalities reduced seizure burden across all patients. RNS offers the additional benefit of providing data to guide future surgical planning.

Neuromodulation has been proven to be a promising alternative treatment for adult patients with drug-resistant epilepsy (DRE). Deep brain stimulation (DBS) and responsive neurostimulation (RNS) were approved by many countries for the treatment of DRE. However, there is a lack of systematic studies illustrating the differences between them. This meta-analysis is performed to assess the efficacy and clinical characteristics of DBS and RNS in adult patients with DRE. PubMed, Web of Science, and Embase were retrieved to obtain related studies including adult DRE patients who accepted DBS or RNS. The clinical characteristics of these patients were compiled for the following statistical analysis. A total of 55 studies (32 of DBS and 23 of RNS) involving 1,568 adult patients with DRE were included in this meta-analysis. There was no significant difference in seizure reduction and responder rate between DBS and RNS for DRE. The seizure reduction of DBS and RNS were 56% (95% CI 50-62%, p > 0.05) and 61% (95% CI 54-68%, p > 0.05). The responder rate of DBS and RNS were 67% (95% CI 58-76%, p > 0.05) and 71% (95% CI 64-78%, p > 0.05). Different targets of DBS did not show significant effect on seizure reduction (p > 0.05). Patients with DRE who accepted DBS were younger than those of RNS (32.9 years old vs. 37.8 years old, p < 0.01). The mean follow-up time was 47.3 months for DBS and 39.5 months for RNS (p > 0.05). Both DBS and RNS are beneficial and alternative therapies for adult DRE patients who are not eligible to accept resection surgery. Further and larger studies are needed to clarify the characteristics of different targets and provide tailored treatment for patients with DRE.

<h3>Objective:</h3> We aim to compare effects of thalamic Deep Brain Stimulator (DBS) and responsive neurostimulator (RNS) device therapy on seizure burden in drug-resistant epilepsy patients. <h3>Background:</h3> Intractable epilepsy unamenable to cortical resection is often treated with a device, either RNS or DBS provides intracranial stimulation. The devices are thought to reduce seizure frequency by reducing synchronization of cortical activity. The RNS provides more localized stimulation while the DBS does this by stimulating the anterior nucleus of the thalamus. At our institution a small number of patients have also undergone thalamic stimulation by using the RNS. <h3>Design/Methods:</h3> We performed retrospective analysis on seizure frequency pre-implant and at most recent follow-up for our cohort, 12 DBS and 6 RNS patients. <h3>Results:</h3> Average age of RNS implantation was 30 years (range 19–41) vs 42 years (range 18–66) for DBS. Thirteen (9 DBS, 4 RNS) of the 18 patients had stereo-EEG (SEEG) evaluation before device placement, SEEG ictal onset was broad or multifocal in all (DBS: 7 – bilateral and 2 – unilateral, RNS: 3 bilateral, 1 unilateral). Three out of five patients who did not have invasive EEG evaluation before device placement had suspected (2) or confirmed (1) genetic etiology, all five had non-localizing, non-lateralizing scalp ictal EEG. The electrodes were placed to the anterior nucleus of thalamus bilaterally in all DBS and four RNS patients, two RNS patients had centromedian nucleus of thalamus sampling. Twelve of our 18 patients (8 out of 12 DBS and 4 out of 6 RNS) were shown to be responders, achieving 50% or greater reduction in seizure frequency. The average follow-up duration for RNS was 22 months (range 3–36), for DBS 13.5 months (range 2–29). <h3>Conclusions:</h3> This analysis demonstrates the potency of thalamic neuromodulation, both RNS and DBS, as therapies capable of seizure relief in wide breadths of epilepsy presentations. <b>Disclosure:</b> Dr. Das has received personal compensation for serving as an employee of Concentra. Dr. Das has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for janicek. The institution of an immediate family member of Dr. Das has received research support from NIH. irina podkorytova has nothing to disclose. Chijindu Iheanacho has nothing to disclose. Dr. Alick-Lindstrom has nothing to disclose. Dr. Agostini has nothing to disclose. Dr. Doyle has nothing to disclose. The institution of Dr. Ding has received research support from National Institute of Aging. The institution of Dr. Ding has received research support from NINDS. Dr. Hays has nothing to disclose. Dr. Perven has nothing to disclose. Dr. Dieppa has nothing to disclose. Dr. Zepeda Garcia has nothing to disclose.

We sought to perform a systematic review and individual participant data meta-analysis to identify predictors of treatment response following thalamic neuromodulation in pediatric patients with medically refractory epilepsy. Electronic databases (MEDLINE, Ovid, Embase, and Cochrane) were searched, with no language or data restriction, to identify studies reporting seizure outcomes in pediatric populations following deep brain stimulation (DBS) or responsive neurostimulation (RNS) implantation in thalamic nuclei. Studies featuring individual participant data of patients with primary or secondary generalized drug-resistant epilepsy were included. Response to therapy was defined as >50% reduction in seizure frequency from baseline. Of 417 citations, 21 articles reporting on 88 participants were eligible. Mean age at implantation was 13.07 ± 3.49 years. Fifty (57%) patients underwent DBS, and 38 (43%) RNS. Sixty (68%) patients were implanted in centromedian nucleus and 23 (26%) in anterior thalamic nucleus, and five (6%) had both targets implanted. Seventy-four (84%) patients were implanted bilaterally. The median time to last follow-up was 12 months (interquartile range = 6.75-26.25). Sixty-nine percent of patients achieved response to treatment. Age, target, modality, and laterality had no significant association with response in univariate logistic regression. Until thalamic neuromodulation gains widespread approval for use in pediatric patients, data on efficacy will continue to be limited to small retrospective cohorts and case series. The inherent bias of these studies can be overcome by using individual participant data. Thalamic neuromodulation appears to be a safe and effective treatment for epilepsy. Larger, prolonged prospective, multicenter studies are warranted to further evaluate the efficacy of DBS over RNS in this patient population where resection for curative intent is not a safe option.

Introduction: Neuromodulation is an important treatment modality for patients with drug-resistant epilepsy who are not candidates for resective or ablative procedures. However, randomized controlled trials and real-world studies reveal that a subset of patients will experience minimal reduction or even an increase in seizure frequency after neuromodulation. We describe our experience with patients who undergo a second intracranial neuromodulation procedure after unsatisfactory initial response to intracranial neuromodulation. Methods: We performed a retrospective chart review to identify all patients who had undergone deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) or responsive neurostimulation (RNS), followed by additional intracranial neuromodulatory procedures, with at least 12 months of follow-up. Demographic and clinical data, including seizure frequencies, were collected. Results: All patients had temporal lobe epilepsy. Six patients were treated with concurrent ANT DBS and temporal lobe RNS, and 3 patients transitioned between neuromodulation systems. Of the patients treated concurrently with ANT DBS and temporal lobe RNS, 5 of the 6 patients experienced additional reduction in seizure frequency after adding a second neuromodulation system. Of the patients who switched between neuromodulation modalities, all patients experienced further reduction in seizure frequency. Conclusions: For patients who do not experience adequate benefit from initial therapy with ANT DBS or temporal lobe RNS, the addition of a neuromodulation system or switching to a different form of neuromodulation may allow for additional reduction in seizure frequency. Larger studies will need to be performed to understand whether the use of multiple systems concurrently leads to improved clinical results in patients who are initially treatment resistant to neuromodulation.

Introduction: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) and responsive neurostimulation (RNS) of the hippocampus are the predominant approaches to brain stimulation for treating mesial temporal lobe epilepsy (MTLE). Both are similarly effective at reducing seizures in drug-resistant patients, but the underlying mechanisms are poorly understood. In rare cases where it is clinically indicated to use RNS and DBS simultaneously, ambulatory electrophysiology from RNS may provide the opportunity to measure the effects of ANT DBS in the putative seizure onset zone and identify biomarkers associated with clinical improvement. Here, one such patient became seizure free, allowing us to identify and compare the changes in hippocampal electrophysiology associated with ANT stimulation and seizure freedom. Methods: Ambulatory electrocorticography and clinical history were retrospectively analyzed for a patient treated with RNS and DBS for MTLE. DBS artifacts were used to identify ANT stimulation periods on RNS recordings and measure peri-stimulus electrographic changes. Clinical history was used to determine the chronic electrographic changes associated with seizure freedom. Results: ANT stimulation acutely suppressed hippocampal gamma (25–90Hz) power, with minimal theta (4–8Hz) suppression and without clear effects on seizure frequency. Eventually, the patient became seizure free alongside the emergence of chronic gamma increase and theta suppression, which started at the same time as clobazam was introduced. Both seizure freedom and the associated electrophysiology persisted after inadvertent DBS discontinuation, further implicating the clobazam relationship. Unexpectedly, RNS detections and long episodes increased, although they were not considered to be electrographic seizures, and the patient remained clinically seizure free. Conclusion: ANT stimulation and seizure freedom were associated with distinct, dissimilar spectral changes in RNS-derived electrophysiology. The time course of these changes supported a new medication as the most likely cause of clinical improvement. Broadly, this work showcases the use of RNS recordings to interpret the effects of multimodal therapy. Specifically, it lends additional credence to hippocampal theta suppression as a biomarker previously associated with seizure reduction in RNS patients.

In children with drug-resistant epilepsy (DRE), resective, ablative, and disconnective surgery may not be feasible or may fail. Neuromodulation in the form of deep brain stimulation (DBS) and responsive neurostimulation (RNS) may be viable treatment options, however evidence for their efficacies in children is currently limited. This systematic review aimed to summarize the literature on DBS and RNS for the treatment of DRE in the pediatric population. Specifically, the authors focused on currently available data for reported indications, neuromodulation targets, clinical efficacy, and safety outcomes. PRISMA guidelines were followed throughout this systematic review (PROSPERO no. CRD42020180669). Electronic databases, including PubMed, Embase, Cochrane Library, OpenGrey, and CINAHL Plus, were searched from their inception to February 19, 2021. Inclusion criteria were 1) studies with at least 1 pediatric patient (age < 19 years) who underwent DBS and/or RNS for DRE; and 2) retrospective, prospective, randomized, or nonrandomized controlled studies, case series, and case reports. Exclusion criteria were 1) letters, commentaries, conference abstracts, and reviews; and 2) studies without full text available. Risk of bias of the included studies was assessed using the Cochrane ROBINS-I (Risk of Bias in Non-randomised Studies - of Interventions) tool. A total of 35 studies were selected that identified 72 and 46 patients who underwent DBS and RNS, respectively (age range 4-18 years). Various epilepsy etiologies and seizure types were described in both cohorts. Overall, 75% of patients had seizure reduction > 50% after DBS (among whom 6 were seizure free) at a median (range) follow-up of 14 (1-100) months. In an exploratory univariate analysis of factors associated with favorable response, the follow-up duration was shorter in those patients with a favorable response (18 vs 33 months, p < 0.05). In the RNS cohort, 73.2% of patients had seizure reduction > 50% after RNS at a median (range) follow-up of 22 (5-39) months. On closer inspection, 83.3% of patients who had > 50% reduction in seizures actually had > 75% reduction, with 4 patients being seizure free. Overall, both DBS and RNS showed favorable response rates, indicating that both techniques should be considered for pediatric patients with DRE. However, serious risks of overall bias were found in all included studies. Many research needs in this area would be addressed by conducting high-quality clinical trials and establishing an international registry of patients who have undergone pediatric neuromodulation, thereby ensuring robust prospective collection of predictive variables and outcomes.

Objective: Surgical site infection (SSI) is the most common serious complication of deep brain stimulation (DBS) implantation surgery. Here, we report a single-surgeon experience on the efficacy of topical, intrawound vancomycin powder (VP) in reducing SSI for DBS surgery and present the first systematic review and meta-analysis examining the effect of topical vancomycin on SSI in patients after DBS surgery. Methods: For the retrospective review, all unique patients undergoing DBS surgery at UCSF for new hardware implantation or internal pulse generator (IPG) replacement by a single surgeon from September 2013 to March 2019, with at least 1 year of follow-up data, were included. For the meta-analysis, we included all primary studies that compared SSIs with and without application of topical vancomycin in DBS surgeries. Results: 368 unique patients met inclusion criteria; 195 patients received topical VP (VP group) and 173 did not (control). 99/195 patients in the VP group underwent new DBS implantation and 96/195 had IPG replacement. 71/173 patients in the control group had new DBS implantation and 102/173 had IPG replacement. There were 10 total cases of SSI: 4 patients from the VP group (3 new implants and 1 IPG replacement) and 6 patients from the control group (3 new implants and 3 IPG replacements), resulting in SSI rates of 2.1 and 3.5%, respectively (p value = 0.337). Including our retrospective analysis, 6 studies met inclusion criteria for the systematic review and meta-analysis. In the 4 studies that examined primary DBS implants, 479 total patients received topical VP and 436 did not; mean odds ratio for SSI with topical vancomycin was 0.802 (95% confidence interval [CI] 0.175–3.678). Across the 5 studies that examined IPG implantations or replacements, 606 total patients received topical VP while 1,173 patients did not; mean odds ratio for SSI with topical vancomycin was 0.492 (95% CI 0.164–1.475). In either case, topical VP application did not significantly decrease risk of SSI. Conclusion: Surgical infections after DBS surgery are uncommon events, with studies demonstrating mixed results on whether topical vancomycin reduces this risk. Our single-institution retrospective analysis and systematic review of prior studies both demonstrated no significant SSI rate reduction with topical VP. This is likely due to low baseline SSI rates, resulting in a small effect size for prevention. Given the cost-effectiveness, simplicity, and low risk, topical, intrawound VP remains a treatment option to further reduce risk of SSI, particularly in settings with higher baseline infection rates.

Effect of deep brain stimulation on the severity of seizures and the quality of life in patients with multifocal drug-resistant epilepsy in Iran: A pilot review of local experience.

Neuromodulation is a viable option for patients with drug-resistant epilepsies. We reviewed the management of patients with two deep brain neurostimulators. In addition, patients implanted with a device targeting the centromedian-parafascicular (CM-Pf) nuclear complex supplements this report to provide an illustrative case to implantation and programming a patient with three active devices. A narrative review using PubMed and Embase identified patients with drug-resistant epilepsy implanted with more than one neurostimulator was performed. Combinations of vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) were identified. We provide a background of a newly reported case of an adult with a triple implant eventually responding to CM-Pf DBS as the third implant following suboptimal benefit from VNS and RNS. In review of the literature, dual-device therapy is increasing in reports of use with combinations of VNS, RNS, and DBS to treat patients with drug-resistant epilepsy. We review dual-device implants with thalamic DBS device combinations, functional neural networks, and programming patients with dual devices. CM-Pf is a new target for DBS and has shown a variable response in focal epilepsy. We report the unique case of 28-year-old male with drug-resistant focal epilepsy who experienced a 75% seizure reduction with CM-Pf DBS as his third device after suboptimal responses to VNS and RNS. After 9 months, he also experienced seizure freedom from recurrent focal to bilateral tonic-clonic seizures. No medical or surgical complications or safety issues were encountered. We demonstrate safety and feasibility in an adult combining active VNS, RNS, and CM-Pf DBS. Patients with dual-device therapy who experience a suboptimal response to initial device use at optimized settings should not be considered a neuromodulation "failure." Strategies to combine devices require a working knowledge of brain networks.

In this paper, the authors' aim was to examine reasons underpinning decisions to undergo, or alternatively forgo, a second-sided deep brain stimulation (DBS) implantation in patients with Parkinson disease (PD). Fifty-two patients with Parkinson disease (PD) were randomized to receive DBS to the subthalamic nucleus or globus pallidus internus (GPi) as part of the COMPARE trial. Forty-four patients had complete data sets. All patients were offered a choice at 6 months after unilateral implantation whether to receive a contralateral DBS implant. All patients had advanced PD. The mean patient age was 59.8 years (range 43-76 years), and the mean duration of disease was 12.2 years (range 5-21 years). The mean baseline Unified Parkinson's Disease Rating Scale (UPDRS)-III motor score was 42.7. The main outcome measures used in this study were the UPDRS-III Motor Scale and the UPDRS-IV Dyskinesia Scale. Twenty-one (48%) of the 44 patients in the cohort did not undergo bilateral implantation and have been successfully treated for an average of 3.5 years; of these, 14 (67%) had a GPi target. The most common reason for adding a second side was inadequacy to address motor symptoms. Patient satisfaction with motor outcomes after unilateral DBS implantation was the most common reason for not undergoing bilateral implantation. Those who chose a second DBS procedure had significantly higher baseline UPDRS-III motor and ipsilateral UPDRS-III scores, and a significantly lower asymmetrical index. The logistic regression analysis revealed that the odds of proceeding to bilateral DBS was 5.2 times higher for STN than for GPi DBS. For every 1% increase in asymmetry, the odds of bilateral DBS decreased [corrected] by 0.96. Unilateral DBS is an effective treatment for a subset of patients with PD. Baseline asymmetry is an important factor in the effectiveness and decision-making process between unilateral and bilateral DBS. Patients with GPi DBS in this cohort were more likely to choose to remain with unilateral implantation.

Lesser-Known Aspects of Deep Brain Stimulation for Parkinson's Disease: Programming Sessions, Hardware Surgeries, Residential Care Admissions, and Deaths

Putting it all together: Options for intractable epilepsy: An updated algorithm on the use of epilepsy surgery and neurostimulation