Vagus Nerve Stimulation Device Research Articles

Ultrasound-driven piezoelectret-based nanogenerator stimulates vagus nerve for myocardial infarction treatment

Myocardial infarction (MI) stands as the predominant cause of morbidity and mortality within the spectrum of cardiovascular diseases, with an unfavorable long-term prognosis. Vagus nerve stimulation (VNS) emerges as a potential clinically significant intervention for alleviating myocardial remodeling after MI, offering promise as a therapeutic approach. However, challenges persist in addressing the fundamental issues of flexibility, miniaturization, and the long-term use of VNS devices. Here, we devised an implantable ultrasound-driven piezoelectret-based nanogenerator (UPN) as a wireless-powered and battery-free vagus nerve stimulator. The UPN with the features of flexibility and lightweight exhibited a maximum output of 10.68 V and 261 μA (peak to peak) under an ultrasonic probe setup at 700 mW cm−2. In the in vivo efficacy study, VNS therapy resulted in a notable improvement in cardiac function with the treatment of UPN, a 20.42 % enhancement in left ventricular ejection fraction and an 11.76 % increase in fractional shortening on the 28th day were realized. Concomitantly, inflammatory responses, myocardial fibrosis, and sympathetic nerve remodeling witnessed a significant reduction. Particularly noteworthy is the observed therapeutic effect linked to the inhibition of the IL-17 and TNF signaling pathways. In summary, this study introduces a novel strategy for nerve stimulation, offering a potential avenue for treating chronic inflammatory diseases.

Characterizing the safety profile of vagus nerve stimulation devices for epilepsy from 21,448 manufacturer and user reports.

This study summarizes medical device reports (MDRs) associated with adverse events for vagus nerve stimulation (VNS) devices indicated for epilepsy as reported by the Manufacturer and User Facility Device Experience (MAUDE) database of the US Food and Drug Administration. The MAUDE database was surveyed for MDRs from November 2013 to September 2022 regarding VNS devices for epilepsy. Event descriptions, device problems, correlated patient consequences, and device models were grouped and analyzed in Python. Based on event description, revision surgeries and other unique events were identified. Revenue from VNS device sales was used to approximate growth in their use over time. A total of 21,448 MDRs met the inclusion criteria. High VNS impedance, the most prevalent device malfunction overall (17.0% of MDRs), was the most common factor for 18 of the 102 encountered patient problems and led to 1001 revision surgeries (3371 total revisions). Included in those 18 device malfunctions were 3 of the top 6 occurring patient problems: seizure recurrence (9.9% associated with high impedance; encompassed focal, absence, and grand mal subtypes), death (1.3%), and generalized pain (7.9%). The next 4 top cited device malfunctions-lead fracture (13.7% of MDRs), operational issue (6.6%), battery problem holding charge (4.2%), and premature end-of-life indicator (2.9%)-differed widely in their percentage of cases that did not impact patients (77.4%, 57.3%, 48.9%, and 92.2%, respectively), highlighting differing malfunction severities. Seizure recurrence, the most prevalent patient impact, was the outcome most associated with 32 of the 68 encountered device problems, including high impedance (12.8%), lead fracture (12.2%), operational issue (18.4%), battery problem holding charge (31.2%), and premature end-of-life indicator (8.9%), which comprised the top 5 occurring device problems. In general, MDRs spanned a diverse range including device age, hardware, software, and surgeon or manufacturer error. Trends were seen over time with declining annual MDRs coupled with a rise in the use of VNS devices as gauged by revenue growth. Shifting device and patient problem profiles were also seen in successive models, reflecting engineering updates. This study characterizes the most common and consequential side effects of VNS devices for epilepsy while clarifying likely causes. In addition, the outcomes of 68 distinct device malfunctions were identified, including many not ubiquitously present in literature, lending critical perspective to clinical practice.

Effect of vagus nerve stimulation on emergency department utilization in children with drug-resistant epilepsy: a retrospective cohort study.

Epilepsy affects approximately 470,000 children in the United States. The estimated median incidence is 50.4 cases per 100,000 persons per year. There are approximately 3.1 million seizure-related emergency department (ED) visits per year among children. Vagus nerve stimulation (VNS) is a treatment option for drug-resistant epilepsy (DRE). While its primary goal is to decrease seizure burden, VNS may decrease seizure intensity and improve quality of life. The authors assessed whether VNS decreased the number of seizure-related ED visits in a cohort of children with DRE. The authors performed a retrospective chart review of pediatric patients (aged 0-21 years) who underwent implantation of a vagus nerve stimulator between January 2009 and January 2020 at the University of Pittsburgh Medical Center Children's Hospital of Pittsburgh. They used paired t-tests to assess differences in the number of ED visits 2 years before versus 2 years after VNS device implantation. Univariable linear regression analyses were used to test associations of preoperative characteristics with change in the number of ED visits following vagus nerve stimulator insertion. This study included 240 patients. Compared with patients without seizure-related ED visits before VNS, patients with ≥ 1 ED visits were younger in age at first VNS surgery (9.5 vs 10.8 years), had a shorter epilepsy duration before VNS surgery (5.8 vs 7.4 years), had a later year of device implantation (2014 vs 2012), and on average took more antiseizure medications (ASMs; 2.4 vs 2.1). There was no significant difference between the total number of seizure-related ED visits pre- versus post-VNS surgery (1.72 vs 1.59, p = 0.50), and no difference in status epilepticus-related visits (0.59 vs 0.46, p = 0.17). Univariable linear regression analyses revealed a mean change in ED visits of +0.3 for each year prior to 2022 and -0.5 for each additional ASM that patients took before vagus nerve stimulator insertion. This single-institution analysis demonstrated no significant change in the number of seizure-related ED visits within 2 years following VNS device implantation. Earlier VNS surgery was associated with more seizure-related ED visits after device insertion, suggesting that medical management and center experience may play a role in decreasing seizure-related ED visits. A greater number of ASMs was associated with fewer seizure-related ED visits after VNS device insertion, suggesting the role of medical management, patient baseline seizure threshold, and caregiver comfort with at-home seizure management.

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study's initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. NCT04539964; August 31, 2020.

Compatibility of Standard Vagus Nerve Stimulation and Investigational Microburst Vagus Nerve Stimulation Therapy with fMRI.

Vagus nerve stimulation devices are conditionally approved for MR imaging with stimulation turned off, and the requirement to modify the stimulation settings may be a barrier to scanning in some radiology practices. There is increasing interest in studying the effects of stimulation during MR imaging/fMRI. This study evaluated the safety of standard and investigational microburst vagus nerve stimulation therapies during MR imaging/fMRI. A prospective, multicenter study was conducted in patients with an investigational vagus nerve stimulation device that delivered either standard or investigational microburst vagus nerve stimulation. Thirty participants underwent sequential MR imaging and fMRI scans, encompassing 188 total hours of scan time (62.7 hours with standard vagus nerve stimulation and 125.3 hours with investigational microburst vagus nerve stimulation). No adverse events were reported with active stimulation during MR imaging or during 12 months of follow-up. Our results support the safety of standard and investigational microburst vagus nerve stimulation therapy during MR imaging and fMRI scans.

A retrospective, naturalistic study of deep brain stimulation and vagal nerve stimulation in young patients.

Invasive neuromodulation interventions such as deep brain stimulation (DBS) and vagal nerve stimulation (VNS) are important treatments for movement disorders and epilepsy, but literature focused on young patients treated with DBS and VNS is limited. This retrospective study aimed to examine naturalistic outcomes of VNS and DBS treatment of epilepsy and dystonia in children, adolescents, and young adults. We retrospectively assessed patient demographic and outcome data that were obtained from electronic health records. Two researchers used the Clinical Global Impression scale to retrospectively rate the severity of neurologic and psychiatric symptoms before and after patients underwent surgery to implant DBS electrodes or a VNS device. Descriptive and inferential statistics were used to examine clinical effects. Data from 73 patients were evaluated. Neurologic symptoms improved for patients treated with DBS and VNS (p<.001). Patients treated with DBS did not have a change in psychiatric symptoms, whereas psychiatric symptoms worsened for patients treated with VNS (p=.008). The frequency of postoperative complications did not differ between VNS and DBS groups. Young patients may have distinct vulnerabilities for increased psychiatric symptoms during treatment with invasive neuromodulation. Child and adolescent psychiatrists should consider a more proactive approach and greater engagement with DBS and VNS teams that treat younger patients.

Vagus nerve stimulation: Potential for treating chronic wounds.

Vagus nerve stimulation (VNS) has been approved as a treatment for various conditions, including drug-resistant epilepsy, migraines, chronic cluster headaches and treatment-resistant depression. It is known to have anti-inflammatory, anti-nociceptive and anti-adrenergic effects, and its therapeutic potential for diverse pathologies is being investigated. VNS can be achieved through invasive (iVNS) or non-invasive (niVNS) means, targeting different branches of the vagus nerve. iVNS devices require surgical implantation and have associated risks, while niVNS devices are generally better tolerated and have a better safety profile. Studies have shown that both iVNS and niVNS can reduce inflammation and pain perception in patients with acute and chronic conditions. VNS devices, such as the VNS Therapy System and MicroTransponder Vivistim, have received Food and Drug Administration approval for specific indications. Other niVNS devices, like NEMOS and gammaCore, have shown effectiveness in managing epilepsy, pain and migraines. VNS has also demonstrated potential in autoimmune disorders, such as rheumatoid arthritis and Crohn's disease, as well as neurological disorders like epilepsy and migraines. In addition, VNS has been explored in cardiovascular disorders, including post-operative atrial fibrillation and myocardial ischemia-reperfusion injury, and has shown positive outcomes. The mechanisms behind VNS's effects include the cholinergic anti-inflammatory pathway, modulation of cytokines and activation of specialised pro-resolving mediators. The modulation of inflammation by VNS presents a promising avenue for investigating its potential to improve the healing of chronic wounds. However, more research is needed to understand the specific mechanisms and optimise the use of VNS in wound healing. Ongoing clinical trials may support the use of this modality as an adjunct to improve healing.

Epilepsy first aid awareness among healthcare workers in Saudi Arabia: A cross-sectional study.

Epilepsy is a neurological disorder affecting more than 50 million human lives of all ages, its social, physical and psychological implications is of huge concern. The current study and as a continuation of epilepsy knowledge assessment projects conducted by our research team is aimed to assess the knowledge of healthcare workers regarding epilepsy first aid in Saudi Arabia. A cross-sectional questionnaire-based study was carried out from 2020 to 2021. During the study period, 272 healthcare workers were recruited; participants were males and females from different nationalities in various Saudi Arabian cities, possess diverse qualifications, and belong to several healthcare-related professions. The question, "Did you witness an epileptic seizure"? was answered as "Yes" by 42% of participants, and in response to the question "If you know that this patient struggles during seizure attacks," 58% of respondents stated that they would not call an ambulance. Moreover, the question "Put something in his/her mouth to prevent tongue biting" was incorrectly answered as "Yes" by 42% of respondents, and the question "Try to catch him/her and stop his/her movement" in order to control the attack was answered "Yes" by 21% of respondents. Furthermore, almost 90% of healthcare participants do not know how to use the Vagus Nerve Stimulation device. The mean knowledge score among participants was 23.7; sex, as well as type of higher qualification obtained, was found to be significantly associated with the score of knowledge. Knowledge toward epilepsy and epilepsy first aid among healthcare workers in Saudi Arabia was found fragile. Further research is appreciated to support the current findings.

Identification of metabolic biomarkers of chronic vagus nerve stimulation (VNS) in subjects with drug-resistant epilepsy (DRE).

Neuromodulation by means of vagus nerve stimulation (VNS) therapy, reduces seizure frequency and improves quality of life in subjects with drug-resistant epilepsy (DRE), yet its molecular mechanism remains unclear. This study investigates the impact of chronic VNS on lipid bioactive metabolites and fatty acids (FA) in the plasma and red blood cells of seven subjects with DRE. By measuring expression levels of peroxisome proliferator-activated receptor α (PPARα) and sirtuin1 (SIRT1) genes-key regulators in energy and lipid metabolism-and lipid profiles before and after various stages of VNS, this study identifies potential mechanisms by which VNS may reduce seizure frequency. Blood samples collected before VNS device implantation, after acute VNS stimulus, and following gradual intensity increments up to therapeutic levels revealed that VNS increases SIRT1 and PPARα expression and erythrocyte concentrations of PPARα ligands. Additionally, we observe reduced de novo lipogenesis biomarkers in erythrocytes, indicating that VNS may influence systemic lipid and energy metabolism. Our findings suggest that VNS could enhance neuronal function by modulating energy metabolism, thus potentially reducing seizure frequency in subjects with DRE. Future research targeting SIRT1 and PPARα may provide innovative therapeutic strategies for managing DRE. Plain Language Summary: The exact mechanism of VNS is still unknown. This study investigated the effects of VNS Therapy on energetic metabolism, suggesting possible novel biomarkers for DRE subjects and neuromodulation therapies.

Vagus nerve stimulation and acetylcholinesterase inhibitor donepezil provide cardioprotection against trastuzumab-induced cardiotoxicity in rats by attenuating mitochondrial dysfunction

Trastuzumab (Trz) is a targeted anticancer drug for human epidermal growth factor receptor 2 (HER2)-positive tumors, as Trz-induced cardiotoxicity (TIC) is commonly observed in Trz-treated patients. Since cardiac autonomic modulation with electrical vagus nerve stimulation (VNS) and acetylcholinesterase (AChE) inhibitors exerts cardioprotection against various heart diseases, the comparative effects of electrical VNS and an AChE inhibitor (donepezil) on cardiac and mitochondrial functions and programmed cell death pathways in TIC are not known. VNS devices were implanted in thirty-two male Wistar rats and were divided into 4 groups: (i) Control-Sham (CSham), (ii) Trz-Sham (TSham), (iii) Trz-VNS (TVNS), and (iv) Trz-donepezil (TDPZ). Rats in the Trz-treated groups were intraperitoneally injected with Trz (4 mg/kg/day) for 7 days, while CSham rats were injected with NSS. VNS devices were activated in the TVNS rats during the 7-day Trz treatment, but not in the sham rats. Rats in the TDPZ group received donepezil orally (5 mg/kg/day) for 7 days. At the end, left ventricular (LV) function and heart rate variability were evaluated, and heart tissue was collected for biochemical and histological analysis. Trz rats showed LV dysfunction and cardiac sympathovagal imbalance. In addition, mitochondrial function and dynamics were impaired in TIC rats. Trz also increased cardiomyocyte death by inducing apoptosis, pyroptosis, and ferroptosis. Electrical VNS and donepezil had similar efficacy in alleviating cardiac mitochondrial dysfunction, dynamic imbalances, and cardiomyocyte death, leading to improved LV function. These findings suggested that parasympathetic activation via either VNS or an AChE inhibitor could be a promising therapeutic intervention against TIC.

Histopathological changes in tissues surrounding vagal nerve stimulation generators: A retrospective analysis of revision surgeries.

Vagal nerve stimulation (VNS) is an effective treatment for patients with epilepsy, depression, and other neuropsychiatric conditions. Understanding the tissue changes associated with VNS devices is crucial for optimizing patient outcomes and device development. This study aimed to investigate the histopathological changes in the tissues surrounding the VNS generator and explore potential correlations with clinical factors and battery performance. A total of 23 patients who underwent VNS generator revision surgery owing to battery depletion were included. Tissue samples from the areas surrounding the VNS generator were obtained and analyzed for histopathological changes. Demographic and device-related variables were also recorded. Capsule formation was observed in all patients. Acute inflammation were not detected in any case. Perivascular lymphocytic infiltration, foreign-body giant cell reaction (FBGCR), and calcification were observed in 8.7%, 26.1%, and 43.5% of patients, respectively. Crystalloid foreign body appearance was noted in 4 patients. The median output current of the generator was higher in patients with lymphocytic infiltration than in those without lymphocytic infiltration. The median off time was higher in patients with skin retraction than in those without skin retraction. Moreover, discomfort was associated with the presence of FBGCR. Our study provides insights into the tissue changes associated with the VNS generator, with capsule formation being a common response. Crystalloid foreign body appearance was not reported previously. Further research is needed to understand the relationship between these tissue changes and VNS device performance, including the potential impact on battery life. These findings may contribute to VNS therapy optimization and device development.

1019 New onset OSA after long term Vagus Nerve Stimulator implantation in a patient with Lennox-Gastaut syndrome: A case report

Abstract Introduction Implantable vagus nerve stimulation (VNS) is an established treatment for drug resistant epilepsy. New onset obstructive sleep apnea (OSA) is a rare side effect of VNS. There are few studies describing VNS induced sleep apnea in adults. [1-2] A study of 16 patients with drug-refractory epilepsy found 5 patients with normal AHI develop mild OSA after VNS treatment for 3 months. [2] However, no literature exists regarding OSA after long term VNS implantation. Untreated OSA in patients with epilepsy can impact epilepsy outcomes. We report a case of new onset OSA after long term VNS implantation, refractory to PAP therapy. Report of case(s) A 36 year-old man with Lennox-Gastaut syndrome presented with gasping during sleep and daytime hypersomnolence. He underwent VNS implantation at the age of 12. A prior PSG in 2018 showed no sleep apnea. Repeat PSG showed VNS-induced OSA (AHI 10.1/hour). After failed CPAP titration, BPAP-S at 25/16 cm H2O improved OSA. Review of therapy data on follow up showed AHI of 13.7/hour and CAI of 10.9/hour, which is concerning for treatment induced central sleep apnea on BPAP. Diagnostic study with VNS turned off revealed mild OSA (AHI 5.8/hour). A multidisciplinary approach involving ENT for drug-induced sleep endoscopy to optimize VNS stimulation parameters along with neurology and sleep involvement is planned. The optimized VNS setting could be used during planned sleep times using a VNS device with dual-programming capability. Conclusion To our knowledge, there is no literature on development of sleep apnea after long term VNS implantation. Although the exact mechanism is unknown, VNS can cause sleep apnea or worsen sleep apnea in patients with a preexisting diagnosis. [1] This case demonstrates need for continuous monitoring and screening for sleep apnea in patients who have been implanted with VNS, even if baseline and follow up PGSs are normal. Current literature suggests discontinuation of VNS to resolve VNS-induced OSA, but we describe a case here where VNS is needed for ongoing management of epilepsy. Further studies are needed to identify treatment options for patients that cannot discontinue VNS therapy who also cannot be successfully treated with PAP if they develop VNS-induced OSA. Support (if any)

Management of vagus nerve simulation therapy in the peri-operative period: Guidelines from the Association of Anaesthetists: Guidelines from the Association of Anaesthetists.

Vagus nerve stimulation is a well-established treatment option for patients with drug-resistant epilepsy and has an expanding range of other clinical indications. Side effects of vagus nerve stimulation therapy include: cough; voice changes; vocal cord adduction; rarely, obstructive sleep apnoea; and arrhythmia. Patients with implanted vagus nerve stimulation devices may present for unrelated surgery and critical care to clinicians who are unfamiliar with their function and safe management. These guidelines have been formulated by multidisciplinary consensus based on case reports, case series and expert opinion to support clinicians in the management of patients with these devices. The aim is to provide specific guidance on the management of vagus nerve stimulation devices in the following scenarios: the peri-operative period; peripartum period; during critical illness; and in the MRI suite. Patients should be aware of the importance of carrying their personal vagus nerve stimulation device magnet with them at all times to facilitate urgent device deactivation if necessary. We advise that it is generally safer to formally deactivate vagus nerve stimulation devices before general and spinal anaesthesia. During periods of critical illness associated with haemodynamic instability, we also advise cessation of vagus nerve stimulation and early consultation with neurology services.

Abstract 150: Vagus Nerve Stimulation (VNS) Paired With Upper Extremity Rehabilitation In Chronic Stroke: Improvements In Wrist And Hand Impairment And Function

Introduction: In the VNS-REHAB trial, vagus nerve stimulation (VNS) paired with task-specific arm and hand rehabilitation (Paired VNS) led to clinically meaningful improvements in both impairment and function of the upper extremity in people with chronic ischemic stroke. In this post hoc analysis of trial data, we assessed whether improvements were driven by proximal (shoulder and elbow) and/or distal (wrist and hand) components of the Upper Extremity Fugl-Meyer Assessment (FMA-UE). We also wanted to determine whether FMA-UE improvements correlated with improvements in functional outcome. Methods: Chronic stroke participants (n=108) with moderate-severe UE impairment (FMA-UE 35.1±8) were implanted with the VNS device and randomized to Paired VNS (n=53) or Controls (n=55). Participants underwent 6 weeks of in-clinic therapy followed by 90 days of a home exercise program. Outcomes, including the FMA-UE and Wolf Motor Function Test (WMFT), were collected after in-clinic therapy (Post-1) and 90 days of home therapy (Post-90). Results: Distal FMA-UE change was significantly greater after Paired VNS compared to Controls, both at Post-1 (2.43±2.52 vs. 0.64±2.33; 95% CI 0.87-2.72, p&lt;0.001, Cohen’s d=0.74) and Post-90 (2.58±2.88 vs. 0.93±3.16; 95% CI 0.5-2.81, p=0.005, Cohen’s d=0.55). Proximal FMA-UE change was also greater after Paired VNS compared to Controls but did not reach statistical significance at either timepoint. At Post-90, both proximal (r=0.50, p&lt;0.0001) and distal (r=0.42, p=0.001) FMA-UE change significantly correlated with WMFT change after Paired VNS, but not in Controls (proximal: r=0.24, p=0.06; distal: r=0.14, p=0.24). Conclusions: The data suggest that Paired VNS leads to greater improvement in the distal upper extremity compared to rehabilitation alone and that improvements in FMA-UE scores are correlated with improvements in function. These findings suggest that the improvements seen with Paired VNS are of functional importance. A greater understanding of region-specific arm and hand recovery after Paired VNS therapy will facilitate planning and implementation of a personalized neurorehabilitation approach based on patient-specific impairments.

An economic evaluation of vagus nerve stimulation as an adjunctive treatment to anti-seizure medications for the treatment of drug resistant epilepsy in the United States

IntroductionPeople with recurrent epileptic seizures are typically treated with anti-seizure medications (ASMs). Around a third of epilepsy patients fail to achieve an adequate response to ASMs and may be eligible to receive vagus nerve stimulation (VNS) therapy for their drug-resistant epilepsy (DRE) if they are unsuited to surgery. VNS received approval from the United States (US) Food and Drug Administration agency. However, there has to date been no comprehensive cost effectiveness evaluation of VNS within the US setting. This study was designed, using a US Medicare perspective, to estimate costs and quality-adjusted life years (QALYs) associated with VNS as an adjunct to ongoing ASM therapy, compared to ASMs alone.MethodsWe developed a cohort state transition model in Microsoft Excel, with four health states defined by different percentage reductions in seizure frequency, with a 3-month cycle and transition probabilities derived from published clinical trials and registry data. Sensitivity analyses were conducted to understand the impact of parameter uncertainty. Costs included the VNS device, placement, programming, battery changes, and removal; ASM therapy; adverse events associated with VNS (dyspnea, hoarseness, and cough); and costs associated with seizure burden (i.e. hospitalizations, emergency department visits, neurologist visits).ResultsUnder base case assumptions, treatment with VNS was associated with a 0.385 QALY gain and a $109,678 saving per patient, when compared with ASM therapy alone. The incremental net monetary benefit (iNMB) was $128,903 at a threshold of $50,000 per QALY, with the positive iNMB indicating that VNS is a highly cost effective treatment. This result is explained by the modeled reduction in relative seizure frequency and associated reduction in healthcare resource use that the VNS group experienced. Sensitivity analyses supported this conclusion.ConclusionsVNS was evaluated as a cost effective addition to the current standard of care in the treatment of DRE in the US Medicare context.

Satisfying outcome of vagus nerve stimulation applied in the treatment of a patient with drug-resistant epilepsy caused by periventricular nodular heterotopia

Introduction. Periventricular nodular heterotopia (PNH) is a developmental malformation of the cerebral cortex characterized by abnormal migration of neurons into the cortical plate and is often associated with drug-resistant focal epilepsy. Case report. A 33-year-old female patient suffered from drug-resistant epilepsy, which was predominantly characterized by focal seizures, with occasional seizures that had a focal onset and progressed into bilateral tonic-clonic seizures. Magnetic resonance imaging showed bilateral heterotopic nodules in the occipital horns of the lateral brain ventricles. 18-Fluoro-deoxyglucose positron emission tomography ? FDG-PET scan demonstrated a zone of reduced glucose metabolism on the right temporal region. Electroencephalogram suggested focal electrocortical activity on the temporo-parieto-occipital regions, predominantly on the right temporal side. The woman was treated with polytherapy (valproic acid, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, clobazam, and lacosamide), but it did not affect the seizure frequency. Due to the bilateral localization of the heterotopic nodules, surgical treatment was not recommended. After a multidisciplinary assessment, we decided on vagus nerve stimulation (VNS) and achieved satisfying seizure control. Conclusion. Patients with PNH require multidisciplinary assessment and treatment, while in this report we have a case of a patient in whom satisfying control of drug-resistant epilepsy was achieved after the implantation of the VNS device.

Abstract 11205: Pharmacological and Non-Pharmacological Parasympathomimetic Interventions Prevent Trastuzumab-Induced Cardiotoxicity Through Attenuating Impaired Mitochondrial Function

Introduction: Although the use of trastuzumab (Trz) has effectively reduced the mortality rate in breast cancer patients, Trz-induced cardiotoxicity (TIC) has become a serious complication. Parasympathetic activations via either electrical vagus nerve stimulation (VNS) device or acetylcholinesterase inhibitor donepezil (DPZ), have been shown to exert cardioprotection in various heart diseases. However, the cardioprotective effects of VNS and DPZ on left ventricular (LV) function, autonomic function, and mitochondrial function in TIC rats are unknown. Hypothesis: Both VNS and DPZ protect the heart against TIC by reducing LV dysfunction, sympathovagal imbalance, and mitochondrial dysfunction. A combination of VNS and DPZ treatment exerts a better benefit than either single intervention. Methods: Adult male Wistar rats (N=25) were subjected to VNS device implantation. Then, rats were assigned into five groups (N=5/group), including (i) control without VNS (C), (ii) Trz (4 mg/kg/day, I.P., 7 days), (iii) Trz+DPZ (5 mg/kg/day, P.O., 7 days) (TrzD), (iv) Trz with VNS (TrzV), and (v) Trz+DPZ with VNS (TrzVD). LV function and heart rate variability (HRV) were performed. All hearts were collected to determine mitochondrial reactive oxygen species (ROS) levels and mitochondrial morphology. Results: Trz rats had a reduced LV ejection fraction, impaired HRV as shown by increased LF/HF ratio, and mitochondrial dysfunction shown by increased ROS levels and dysmorphology (Figures 1A-D). Treatment with either DPZ, VNS, or the combined treatment exerted similar cardioprotection via reducing sympathovagal imbalance and mitochondrial injury, leading to improved LV function, (Figures 1A-D). Conclusions: Promoting parasympathetic activity using VNS, DPZ, or the combined treatment similarly protected the heart against TIC via improving HRV, mitochondrial function, and mitochondrial morphology, suggesting a novel potential strategy for patients receiving Trz.

Vagus Nerve Stimulation in Treatment-Resistant Depression: A Case Series of Long-Term Follow-up.

Vagus nerve stimulation (VNS) has been shown to be effective for treatment-resistant depression (TRD). However, long-term (>5 years) studies on the efficacy and tolerability of this treatment have been lacking. Here, we report a long-term clinical follow-up of 5 patients with severe and long-standing TRD, who received a VNS implant. Of the initial 6 patients with TRD implanted with VNS at our center, 5 of them were followed for 6 to 12 years after implantation. Primary efficacy outcomes were clinical response and improved functioning at follow-up visits. The primary safety outcome was all-cause discontinuation, and the secondary safety outcomes were the number and the severity of adverse events. The VNS implant was associated with a sustained response (>10 years) in terms of clinical response and social, occupational, and psychological functioning in 3 patients. Two patients dropped out after 6 and 7 years of treatment, respectively. Vagus nerve stimulation was well tolerated by all patients, who reported only mild adverse effects. One patient, who discontinued concomitant drug treatment, had a hypomanic episode in the 10th year of treatment. The parameters of the VNS device were fine-tuned when life stressors or symptom exacerbation occurred. Our case series showed that VNS can have long-term and durable effectiveness in patients with severe multiepisode chronic depression, and this could be associated with its neuroplastic effects in the hippocampus. In light of good general tolerability, our findings support VNS as a viable treatment option for TRD.

Auriküler Vagus Sinir Stimülasyonunun İnsan Ses Özelliklerine Etkileri

Vagus nerve stimulation (VNS) has been used in the treatment of epilepsy and depression for more than 20 years. Although the invasive cervical method is the most preferred application, side effects such as cough, voice change and hoarseness can be seen due to negative effects on the recurrent laryngeal nerve (a branch of the vagus nerve). Auricular VNS has been preferred recently due to its non-invasiveness, but uncertainty about the stimulation parameters continues. We tested the hypothesis that auricular VNS can affect voice and its features indirectly via afferent nerve connections reaching the nucleus tractus solitarius. Two patients previously using auricular VNS device for different diseases were requested to record their voices before and after the stimulation. Their devices (Vagustim) were changed with new version to check the usage of the patients. Sound recordings at different VNS frequencies (1-150 Hz) were collected by a mobile phone and analyzed with Praat and our MATLAB algorithm. Fundamental frequency (f0), jitter, shimmer, and harmonic to noise ratio (HNR) owere evaluated. The alteration was highest at 100 Hz and 30 Hz VNS for the male and female patients respectively. Audio recordings before and after 30 Hz (for female) and 100 Hz (for male) VNS at different durations (5-30 min) on different days were repeated and compared by Praat and our algorithm. Some discrepancy between the parameters jitter, shimmer, and HNR are detected between the algorithms, which is accounted to the fact that it is not standardized whether the algorithm uses only a specific part of the input signal or the whole signal. However, when the ratio of change of these parameters are considered, fundamental frequency and the HNR were found to be highly consistent for developing an algorithm to govern the stimulation parameters in an automated way. Furthermore, the same ratios for jitter and shimmer are also promising after some improvement to be included in such an algorithm. These results suggest that auricular VNS can affect voice and its parameters, but this change is related with stimulation parameters. It seems necessary to develop specific software and algorithms that can detect this change well.

Vagus Nerve Stimulation as a Potential Therapy in Early Alzheimer's Disease: A Review.

Cognitive dysfunction in Alzheimer’s disease (AD) is caused by disturbances in neuronal circuits of the brain underpinned by synapse loss, neuronal dysfunction and neuronal death. Amyloid beta and tau protein cause these pathological changes and enhance neuroinflammation, which in turn modifies disease progression and severity. Vagal nerve stimulation (VNS), via activation of the locus coeruleus (LC), results in the release of catecholamines in the hippocampus and neocortex, which can enhance synaptic plasticity and reduce inflammatory signalling. Vagal nerve stimulation has shown promise to enhance cognitive ability in animal models. Research in rodents has shown that VNS can have positive effects on basal synaptic function and synaptic plasticity, tune inflammatory signalling, and limit the accumulation of amyloid plaques. Research in humans with invasive and non-invasive VNS devices has shown promise for the modulation of cognition. However, the direct stimulation of the vagus nerve afforded with the invasive procedure carries surgical risks. In contrast, non-invasive VNS has the potential to be a broadly available therapy to manage cognitive symptoms in early AD, however, the magnitude and specificity of its effects remains to be elucidated, and the non-inferiority of the effects of non-invasive VNS as compared with invasive VNS still needs to be established. Ongoing clinical trials with healthy individuals and patients with early AD will provide valuable information to clarify the potential benefits of non-invasive VNS in cognition and AD. Whether invasive or non-invasive VNS can produce a significant improvement on memory function and whether its effects can modify the progression of AD will require further investigation.