Vagus Nerve Stimulation In Patients Research Articles

Label-free functional imaging of vagus nerve stimulation-evoked potentials at the cortical surface

Vagus nerve stimulation (VNS) is an FDA-approved stimulation therapy to treat patients with refractory epilepsy. In this work, we use a coherent holographic imaging system to characterize vagus nerve-evoked potentials (VEPs) in the cortex in response to VNS stimulation paradigms without electrode placement or any genetic, structural, or functional labels. We analyze stimulation amplitude up to saturation, pulse width up to 800 μs, and frequency from 10 Hz to 30 Hz, finding that stimulation amplitude strongly modulates VEPs response magnitude (effect size 0.401), while pulse width has a moderate modulatory effect (effect size 0.127) and frequency has almost no modulatory effect (effect size 0.009) on the evoked potential magnitude. We find mild interactions between pulse width and frequency. This non-contact label-free functional imaging technique may serve as a non-invasive rapid-feedback tool to characterize VEPs and may increase the efficacy of VNS in patients with refractory epilepsy.

Outcomes of surgical resection and vagus nerve stimulation in patients with medically refractory epilepsy and glutamic acid decarboxylase 65 antibody positivity.

Epilepsy associated with high-titer glutamic acid decarboxylase 65 (GAD65) IgG is often refractory to immunotherapies and antiseizure medication. This study sought to determine the efficacy of vagus nerve stimulation (VNS) and surgical resection in patients with drug-resistant epilepsy associated with GAD65-IgG. We retrospectively identified 15 patients with drug-resistant epilepsy and high serum GAD65 antibody titers (>20 nmol·L-1) who underwent VNS implantation (n = 6), surgical resection (n = 7), or both (n = 2). A responder to VNS was defined as someone with a ≥50% reduction in seizure frequency, and a favorable surgical outcome was defined as Engel I-II. Of the eight patients who underwent VNS implantation, three (37.5%) were initially responders, but this was not sustained in two. Of the nine patients who underwent surgical resection, three (33.3%) had a favorable outcome; however, only one patient was seizure-free at last follow-up. Pathology was available in six patients, and only one had evidence of inflammation; this patient had seizure onset 1 year prior to surgery. Favorable seizure outcome correlated with older age at time of resective surgery, with a trend favoring later age of seizure onset. Taken together, surgical resection and VNS implantation may have limited efficacy in this patient population but can be considered in carefully selected cases.

Complex executive functions assessed by the trail making test (TMT) part B improve more than those assessed by the TMT part A or digit span backward task during vagus nerve stimulation in patients with drug-resistant epilepsy.

There is a paucity of clinical studies examining the long-term effects of vagus nerve stimulation (VNS) on cognition, although a recent study of patients with drug-resistant epilepsy (DRE) treated with VNS therapy demonstrated significant improvement in executive functions as measured by the EpiTrack composite score. The present study aimed to investigate performance variability in three cognitive tests assessing executive functions and working memory in a cohort of DRE patients receiving VNS therapy during a follow-up duration of up to 5 years. The study included 46 DRE patients who were assessed with the Trail Making Test (TMT) (Parts A and B) and Digit Span Backward (DB) task prior to VNS implantation, 6 months and 12 months after implantation, and yearly thereafter as a part of the clinical VNS protocol. A linear mixed-effects (LME) model was used to analyze changes in test z scores over time, accounting for variations in follow-up duration when predicting changes over 5 years. Additionally, we conducted descriptive analyses to illustrate individual changes. On average, TMT-A z scores improved by 0.024 units (95% confidence interval (CI): 0.006 to 0.042, p = 0.009), TMT-B z scores by 0.034 units (95% CI: 0.012 to 0.057, p = 0.003), and DB z scores by 0.019 units per month (95% CI: 0.011 to 0.028, p < 0.001). Patients with psychiatric comorbidities achieved the greatest improvements in TMT-B and DB z scores among all groups (0.0058 units/month, p = 0.036 and 0.028 units/month, p = 0.003, respectively). TMT-A z scores improved the most in patients taking 1-2 ASMs as well as in patients with psychiatric comorbidities (0.042 units/month, p = 0.002 and p = 0.003, respectively). Performance in all three tests improved at the group level during the follow-up period, with the most robust improvement observed in TMT-B, which requires inhibition control and set-switching in addition to the visuoperceptual processing speed that is crucial in TMT-A and working-memory performance that is essential in DB. Moreover, the improvement in TMT-B was further enhanced if the patient had psychiatric comorbidities.

Analysis of factors influencing the efficacy of vagus nerve stimulation for the treatment of drug-resistant epilepsy in children and prediction model for efficacy evaluation.

Vagus nerve stimulation (VNS) has been widely used in the treatment of drug-resistant epilepsy (DRE) in children. We aimed to explore the efficacy and safety of VNS, focusing on factors that can influence the efficacy of VNS, and construct a prediction model for the efficacy of VNS in the treatment of DRE children. Retrospectively analyzed 45 DRE children who underwent VNS at Qilu Hospital of Shandong University from June 2016 to November 2022. A ≥50% reduction in seizure frequency was defined as responder, logistic regression analyses were performed to analyze factors affecting the efficacy of VNS, and a predictive model was constructed. The predictive model was evaluated by receiver operating characteristic curve (ROC), calibration curves, and decision curve analyses (DCA). A total of 45 DRE children were included in this study, and the frequency of seizures was significantly reduced after VNS treatment, with 25 responders (55.6%), of whom 6 (13.3%) achieved seizure freedom. There was a significant improvement in the Quality of Life in Childhood Epilepsy Questionnaire (15.5%) and Seizure Severity Score (46.2%). 16 potential factors affecting the efficacy of VNS were included, and three statistically significant positive predictors were ultimately screened: shorter seizure duration, focal seizure, and absence of intellectual disability. We developed a nomogram for predicting the efficacy of VNS in the treatment of DRE children. The ROC curve confirmed that the predictive model has good diagnostic performance (AUC = 0.864, P < 0.05), and the nomogram can be further validated by bootstrapping for 1,000 repetitions, with a C-index of 0.837. Besides, this model showed good fitting and calibration and positive net benefits in decision curve analysis. VNS is a safe and effective treatment for DRE children. We developed a predictive nomogram for the efficacy of VNS, which provides a basis for more accurate selection of VNS patients.

Norwegian population-based study of effectiveness of vagus nerve stimulation in patients with developmental and epileptic encephalopathies.

Evaluate the long-term efficacy of vagus nerve stimulation (VNS) in patients with developmental and epileptic encephalopathies (DEE) compared with epilepsy patients without intellectual disability (ID). Long-term outcomes from a Norwegian VNS quality registry are reported in 105 patients with DEEs (Lennox-Gastaut syndrome [LGS] n = 62; Dravet n = 16; Rett n = 9; other syndromes n = 18) were compared with 212 epilepsy patients without ID, with median follow-up of 88 and 72 months, respectively. Total seizure reduction was evaluated at 6, 12, 24, 36, and 60 months. Effect on different seizure types was evaluated at baseline and last observation carried forward (LOCF). Median monthly seizure frequency at LOCF was reduced by 42.2% (p < 0.001) in patients with DEE and by 55.8% (p < 0.001) in patients without ID. In DEE patients, ≥50% seizure reduction at 6 and 24 months were 17.1% and 37.1%, respectively, and 33.5% and 48.6% for patients without ID. Seizure reduction ≥75% at 60 months occurred in 14.3% of DEE patients and 23.1% of patients without ID. Highest median reduction was for atonic seizures, most notably 64.6% for LGS patients. A better effect was seen at 2 years among DEE patients with unchanged medication compared with those with changed medication (54.5% vs. 35.6% responders, p = 0.078). More DEE patients were reported to have greater improvement in ictal or postictal severity (43.8% vs. 28.3%, p = 0.006) and alertness (62.9% vs. 31.6%, p < 0.001) than patients without ID. For both groups, use of the magnet reduced seizure severity. Hoarseness was the most common adverse effect in both groups. In addition, DEE patients were frequently reported to have sleep disturbance, general discomfort, or abdominal problems. Our data indicate that VNS is very effective for atonic seizures. Patients without ID had best overall seizure reduction, however, patients with DEE had higher retention rates probably due to other positive effects. DEE refers to a group of patients with severe epilepsy and intellectual disability. Many of these patients have restricted lifestyles with frequent seizures. VNS is a treatment option for patients who do not respond well to medicines, either because of insufficient effect or serious adverse effects. Our study shows that VNS is well tolerated in this patient group and leads to a reduction in all seizure types, most notably for seizures leading to fall. Many patients experience other positive effects like shorter and milder seizures, as well as improvement in alertness.

The efficacy and safety of transcutaneous auricular vagus nerve stimulation for patients with minimally conscious state: a sham-controlled randomized double-blind clinical trial.

Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a potentially effective neuromodulation technique for addressing neurological disorders, including disorders of consciousness. Expanding upon our prior clinical study, which demonstrated the superior effectiveness of a 4-week taVNS treatment in patients with minimally conscious state (MCS) compared to those in a vegetative state/unresponsive wakefulness state, the aim of this investigation was to evaluate the safety and therapeutic efficacy of taVNS in individuals with MCS through a sham-controlled randomized double-blind clinical trial. A cohort of 50 adult patients (male = 33, female = 17) diagnosed with a MCS were randomly assigned to either the active taVNS (N = 25) or sham taVNS (N = 25) groups. The treatment period lasted for 4 weeks, followed by an 8-week follow-up period. The Coma Recovery Scale-Revised (CRS-R) and Glasgow Coma Scale (GCS) were administered at baseline and weekly during the initial 4 weeks. Additionally, the Disability Rating Scale (DRS) was used to assess the patients' functional abilities via telephone at week 12. Furthermore, various neurophysiological measures, including electroencephalogram (EEG), upper-limb somatosensory evoked potentials (USEP), brainstem auditory evoked potentials (BAEP), and P300 event-related potentials (P300), were employed to monitor changes in brain activity and neural conduction pathways. The scores for the active taVNS group in the CRS-R and GCS showed greater improvement over time compared to the sham taVNS group (CRS-R: 1-week, Z = -1.248, p = 0.212; 2-week, Z = -1.090, p = 0.276; 3-week, Z = -2.017, p = 0.044; 4-week, Z = -2.267, p = 0.023. GCS: 1-week, Z = -1.325, p = 0.185; 2-week, Z = -1.245, p = 0.213; 3-week, Z = -1.848, p = 0.065; 4-week, Z = -1.990, p = 0.047). Additionally, the EEG, USEP, BAEP, and P300 also demonstrated significant improvement in the active taVNS group compared to the sham taVNS group at week 4 (EEG, Z = -2.086, p = 0.037; USEP, Z = -2.014, p = 0.044; BAEP, Z = -2.298, p = 0.022; P300 amplitude, Z = -1.974, p = 0.049; P300 latency, t = 2.275, p = 0.027). Subgroup analysis revealed that patients with MCS derived greater benefits from receiving taVNS treatment earlier (CRS-R, Disease duration ≤ 1-month, mean difference = 8.50, 95% CI = [2.22, 14.78], p = 0.027; GCS, Disease duration ≤ 1-month, mean difference = 3.58, 95% CI = [0.14, 7.03], p = 0.044). By week 12, the active taVNS group exhibited lower Disability Rating Scale (DRS) scores compared to the sham taVNS group (Z = -2.105, p = 0.035), indicating a more favorable prognosis for MCS patients who underwent taVNS. Furthermore, no significant adverse events related to taVNS were observed during treatment. The findings of this study suggest that taVNS may serve as a potentially effective and safe intervention for facilitating the restoration of consciousness in individuals diagnosed with MCS. This therapeutic approach appears to enhance cerebral functioning and optimize neural conduction pathways. http://www.chictr.org.cn, Identifier ChiCTR2200066629.

Effects of vagus nerve stimulation on the quality of sleep and sleep apnea in patients with drug-resistant epilepsy: A systematic review.

The objective was to systematically evaluate the current evidence surrounding the effect of vagus nerve stimulation (VNS) on quality of sleep and obstructive sleep apnea (OSA) among patients with epilepsy. A literature search was conducted using the Embase and MEDLINE databases. Studies were included if they involved patients with drug-resistant epilepsy treated with VNS and used validated tools to report on quality of sleep or sleep apnea. The literature search yielded 112 citations related to VNS and sleep quality, and 82 citations related to sleep apnea. Twelve articles were included in the review, of which five measured quality of sleep among patients who underwent VNS, six studies measured sleep apnea, and one study measured both outcomes. Studies measuring quality of sleep used different methods, including sleep quality questionnaires and the percentage of sleep in each cycle. Studies also varied in patient populations, the use of control groups, and whether multiple measurements were taken for each patient. Some studies found improved sleep quality after VNS, whereas others found reductions in deep sleep stages. Additionally, mixed results in sleep quality were found when comparing patients with epilepsy who received VNS treatment versus patients with epilepsy who did not receive VNS treatment. Variables such as VNS intensity and age could potentially confound quality of sleep. Studies measuring sleep apnea consistently found increased proportions of patients diagnosed with OSA or increased sleep index scores after VNS implantation. Overall, the effect of VNS on quality of sleep remains unclear, as studies were very heterogeneous, although the effect on sleep apnea has consistently shown an increase in sleep apnea severity indices after VNS implantation. Future studies with consistent measures and discussions of confounding are required to determine the effect of VNS on quality of sleep, and the effect of VNS parameters should be further explored among patients who develop sleep apnea.

Optimizing Noninvasive Vagus Nerve Stimulation for Systemic Lupus Erythematosus: Protocol for a Multicenter Randomized Controlled Trial.

Systemic lupus erythematosus is a chronic, multisystem, inflammatory disease of autoimmune etiology occurring predominantly in women. A major hurdle to the diagnosis, treatment, and therapeutic advancement of this disease is its heterogeneous nature, which presents as a wide range of symptoms such as fatigue, fever, musculoskeletal involvement, neuropsychiatric disorders, and cardiovascular involvement with varying severity. The current therapeutic approach to this disease includes the administration of immunomodulatory drugs that may produce unfavorable secondary effects. This study explores the known relationship between the autonomic nervous system and inflammatory pathways to improve patient outcomes by treating autonomic nervous system dysregulation in patients via noninvasive vagus nerve stimulation. In this study, data including biomarkers, physiological signals, patient outcomes, and patient quality of life are being collected and analyzed. After completion of the clinical trial, a computer model will be developed to identify the biomarkers and physiological signals related to lupus activity in order to understand how they change with different noninvasive vagus nerve stimulation frequency parameters. Finally, we propose building a decision support system with integrated noninvasive wearable technologies for continuous cardiovascular and peripheral physiological sensing for adaptive, patient-specific optimization of the noninvasive vagus nerve stimulation frequency parameters in real time. The protocol was designed to evaluate the efficacy and safety of transauricular vagus nerve stimulation in patients with systemic lupus erythematosus. This multicenter, national, randomized, double-blind, parallel-group, placebo-controlled study will recruit a minimum of 18 patients diagnosed with this disease. Evaluation and treatment of patients will be conducted in an outpatient clinic and will include 12 visits. Visit 1 consists of a screening session. Subsequent visits up to visit 6 involve mixing treatment and evaluation sessions. Finally, the remaining visits correspond with early and late posttreatment follow-ups. On November 2022, data collection was initiated. Of the 10 participants scheduled for their initial appointment, 8 met the inclusion criteria, and 6 successfully completed the entire protocol. Patient enrollment and data collection are currently underway and are expected to be completed in December 2023. The results of this study will advance patient-tailored vagus nerve stimulation therapies, providing an adjunctive treatment solution for systemic lupus erythematosus that will foster adoption of technology and, thus, expand the population with systemic lupus erythematosus who can benefit from improved autonomic dysregulation, translating into reduced costs and better quality of life. ClinicalTrials.gov NCT05704153; https://clinicaltrials.gov/study/NCT05704153. DERR1-10.2196/48387.

Neuroimmune Modulation Through Vagus Nerve Stimulation Reduces Inflammatory Activity in Crohn's Disease Patients: A Prospective Open-label Study.

Crohn's disease [CD] is a debilitating, inflammatory condition affecting the gastrointestinal tract. There is no cure and sustained clinical and endoscopic remission is achieved by fewer than half of patients with current therapies. The immunoregulatory function of the vagus nerve, the 'inflammatory reflex', has been established in patients with rheumatoid arthritis and biologic-naive CD. The aim of this study was to explore the safety and efficacy of vagus nerve stimulation in patients with treatment-refractory CD, in a 16-week, open-label, multicentre, clinical trial. A vagus nerve stimulator was implanted in 17 biologic drug-refractory patients with moderately to severely active CD. One patient exited the study pre-treatment, and 16 patients were treated with vagus nerve stimulation [4/16 receiving concomitant biologics] during 16 weeks of induction and 24 months of maintenance treatment. Endpoints included clinical improvement, patient-reported outcomes, objective measures of inflammation [endoscopic/molecular], and safety. There was a statistically significant and clinically meaningful decrease in CD Activity Index at Week 16 [mean ± SD: -86.2 ± 92.8, p = 0.003], a significant decrease in faecal calprotectin [-2923 ± 4104, p = 0.015], a decrease in mucosal inflammation in 11/15 patients with paired endoscopies [-2.1 ± 1.7, p = 0.23], and a decrease in serum tumour necrosis factor and interferon-γ [46-52%]. Two quality-of-life indices improved in 7/11 patients treated without biologics. There was one study-related severe adverse event: a postoperative infection requiring device explantation. Neuroimmune modulation via vagus nerve stimulation was generally safe and well tolerated, with a clinically meaningful reduction in clinical disease activity associated with endoscopic improvement, reduced levels of faecal calprotectin and serum cytokines, and improved quality of life.

Brain functional connectivity and network characteristics changes after vagus nerve stimulation in patients with refractory epilepsy.

This study aims to investigate the impact of vagus nerve stimulation (VNS) on the connectivity and small-world metrics of brain functional networks during seizure periods. Ten refractory epilepsy patients underwent video encephalographic monitoring before and after VNS treatment. The 2-min electroencephalogram segment containing the ictal was selected for each participant, resulting in a total of 20 min of seizure data. The weighted phase lag index (wPLI) and small-world metrics were calculated for the whole frequency band and different frequency bands (delta, theta, alpha, beta, and gamma). Finally, the relevant metrics were statistically analyzed, and the false discovery rate was used to correct for differences after multiple comparisons. In the whole band, the wPLI was notably enhanced, and the network metrics, including degree (D), clustering coefficient (CC), and global efficiency (GE), increased, while characteristic path length (CPL) decreased (P < 0.01). In different frequency bands, the wPLI between the parieto-occipital and frontal regions was significantly strengthened in the delta and beta bands, while the wPLI within the frontal region and between the frontal and parieto-occipital regions were significantly reduced in the beta and gamma bands (P < 0.01). In the low-frequency band (<13 Hz), the small-world metrics demonstrated significantly increased CC, D, and GE, with a significantly decreased CPL, indicating a more efficient network organization. In contrast, in the gamma band, the GE decreased, and the CPL increased, suggesting a shift toward less efficient network organization. VNS treatment can significantly change the wPLI and small-world metrics. These findings contribute to a deeper understanding of the impact of VNS therapy on brain networks and provide objective indicators for evaluating the efficacy of VNS.

Randomized controlled study to evaluate the safety and clinical impact of percutaneous auricular vagus nerve stimulation in patients with severe COVID-19.

Introduction: A severe course of COVID-19 is characterized by a hyperinflammatory state resulting in acute respiratory distress syndrome or even multi-organ failure along a derailed sympatho-vagal balance. Methods: In this prospective, randomized study, we evaluate the hypothesis that percutaneous minimally invasive auricular vagus nerve stimulation (aVNS) is a safe procedure and might reduce the rate of clinical complications in patients with severe course of COVID-19. In our study, patients with SARS-CoV-2 infection admitted to the intensive care unit with moderate-to-severe acute respiratory distress syndrome, however without invasive ventilation yet, were included and following randomization assigned to a group receiving aVNS four times per 24h for 3h and a group receiving standard of care (SOC). Results: A total of 12 patients were included (six in the aVNS and six in the SOC group). No side effects in aVNS were reported, especially no significant pain at device placement or during stimulation at the stimulation site or significant headache or bleeding after or during device placement or lasting skin irritation. There was no significant difference in the aVNS and SOC groups between the length of stay in the intensive care unit and at the hospital, bradycardia, delirium, or 90-day mortality. In the SOC group, five of six patients required invasive mechanical ventilation during their stay at hospital and 60% of them venovenous extracorporeal membrane oxygenation, compared to three of six patients and 0% in the aVNS group (p = 0.545 and p = 0.061). Discussion: Vagus nerve stimulation in patients with severe COVID-19 is a safe and feasible method. Our data showed a trend to a reduction of progression to the need of invasive ventilation and venovenous extracorporeal membrane oxygenation which encourages further research with larger patient samples.

Predictive factors for successful vagus nerve stimulation in patients with refractory epilepsy: real-life insights from a multicenter study.

Vagus nerve stimulation (VNS) therapy is an established treatment for patients with drug-resistant epilepsy that reduces seizure frequency by at least 50% in approximately half of patients; however, the characteristics of the patients with the best response have not yet been identified. Thus, it is important to identify the profile of patients who would have the best response to guide early indications and better patient selection. This retrospective study evaluated vagus nerve stimulation (VNS) as an adjuvant therapy for patients with drug-resistant epilepsy from six epilepsy centers in Brazil. Data from 192 patients aged 2-66 years were analyzed, and all patients received at least 6 months of therapy to be included. Included patients were aged 2-66 years (25.6 ± 14.3), 105 (54.7%) males and 87 (45.8%) females. Median follow-up interval was 5 years (range, 2005-2018). Overall, the response rate (≥50% seizure reduction) after VNS implantation was 65.6% (126/192 patients). Most patients had 50-90% seizure reduction (60.9%) and nine patients became seizure-free. There were no serious complications associated with VNS implantation. The rate of a ≥ 50% seizure reduction response was significantly higher in patients with no history of neurosurgery. The presence of focal without generalized seizures and focal discharges on interictal EEG was associated with better response. Overall, etiological predictors of a better VNS response profile were tumors while a worse response to VNS was related to the presence of vascular malformations and Lennox-Gastaut Syndrome. We observed an association between a better response to VNS therapy no history of neurosurgery, focal interictal epileptiform activity, and focal seizure pattern. Additionally, it is important to highlight that age was not a determinant factor of the response, as children and adults had similar response rates. Thus, VNS therapy should be considered in both adults and children with DRE.

Chronic vagus nerve stimulation in patients with heart failure: challenge or failed translation?

Autonomic imbalance between the sympathetic and parasympathetic nervous systems contributes to the progression of chronic heart failure (HF). Preclinical studies have demonstrated that various neuromodulation strategies may exert beneficial cardioprotective effects in preclinical models of HF. Based on these encouraging experimental data, vagus nerve stimulation (VNS) has been assessed in patients with HF with a reduced ejection fraction. Nevertheless, the main trials conducted thus far have yielded conflicting findings, questioning the clinical efficacy of VNS in this context. This review will therefore focus on the role of the autonomic nervous system in HF pathophysiology and VNS therapy, highlighting the potential reasons behind the discrepancy between preclinical and clinical studies.

Single-center long-term results of vagus nerve stimulation for pediatric epilepsy: a 10-17-year follow-up study.

A retrospective study, based on a prospectively built database, presents the results of long-term follow-up care of pediatric vagus nerve stimulation (VNS) patients in terms of seizure outcome, surgical aspects, the potential impact of maturation, and medication changes. From a prospectively built database, 16 VNS patients (median age 12.0years, range 6.0 to 16.0years; median seizure duration 6.5years, range 2.0 to 15.5years) followed for at least 10years were graded as non-responder - NR (seizure frequency reduction < 50%), responder - R (reduction ≥ 50% and < 80%), and 80% responder - 80R (reduction ≥ 80%). Data about surgical aspects (battery replacement, system complications), seizure dynamics, and medication changes were taken from the database. The early percentages of good results (80R + R) were 43.8% (year 1), 50.0% (year 2), and 43.8% (year 3). These percentages remained stable between years 10 and 12 (50% year 10; 46.7% year 11; 50% year 12) and increased in years 16 (60%) and 17 (75%). Depleted batteries were replaced in ten patients, six of whom were either R or 80R. In the four NR, the indication for replacement was improved quality of life. Three patients had VNS explanted or switched off-one had repeated asystolia and two were NR. The effect of hormonal changes in menarche on seizure was not proven. During the study, antiseizure medication was changed in all patients. The study proved the efficacy and safety of VNS in pediatric patients over an exceptionally long follow-up period. The demand for battery replacements indicates a positive treatment effect.

Outcomes of Surgical Resection and VNS in Patients with Medically Refractory Epilepsy and GAD65 Antibody Positivity (S40.004)

<h3>Objective:</h3> To determine effectiveness of vagus nerve stimulator (VNS) and surgical resection in patients with drug-resistant epilepsy associated with glutamic acid decarboxylase 65 (GAD65) antibodies. <h3>Background:</h3> Epilepsy associated with high-titer GAD65 antibodies is often refractory to immunotherapies and antiseizure medications (ASMs), underscoring the need for alternate treatment strategies. <h3>Design/Methods:</h3> We retrospectively identified Mayo Clinic Rochester patients (January 2003 – April 2022) with drug-resistant epilepsy and high serum GAD65-antibody titers (&gt;20 nnmol/L) who underwent surgical resection and/or VNS implantation. A “favorable” surgical outcome was defined as Engel I-II, and a responder to VNS was defined as a &gt;50% reduction in seizure frequency from baseline. <h3>Results:</h3> We identified 15 patients (13 females, 86.7%) who underwent surgical resection (n=7), VNS implantation (n=6), and both (n=2). Patients had failed a median of 5.5 anti-seizure medications. Twelve patients had GAD65 tested in the CSF, all were positive (median titer 3.8). Of the nine patients who underwent surgical intervention (all involving the temporal region), three (33.3%) had a favorable outcome, which was sustained for at least 3.5 years in one, 10 years in another, and the third was lost to follow-up after 1 year. Pathology was available in four patients, only one had evidence of inflammation. Of the 8 patients who underwent VNS implantation, 3 (37.5%) were initially considered a responder, but this was not sustained in two of the three. No clinical factors were statistically associated with favorable surgical or VNS outcomes. <h3>Conclusions:</h3> Temporal surgical resection and VNS are not highly effective in drug-resistant autoimmune-associated epilepsy related to high-titer GAD65 antibodies. Additional therapies are greatly needed for this challenging clinical scenario. <b>Disclosure:</b> Dr. Zhao-Fleming has nothing to disclose. Dr. Britton has received personal compensation in the range of $0-$499 for serving as a Online course with American Clinical Neurophysiology Society. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. The institution of Dr. Dubey has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Astellas. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argenx. Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for AGRIMS. Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Advances in Neurology . Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Moffit Cancer Center . Dr. Dubey has received research support from Department of Defense . Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Smith has received research support from CURE Epilepsy.

Optimizing the modulation paradigm of transcutaneous auricular vagus nerve stimulation in patients with disorders of consciousness: A prospective exploratory pilot study protocol.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique. Several studies have reported the effectiveness of taVNS in patients with disorders of consciousness (DOC); however, differences in the modulation paradigm have led to inconsistent treatment outcomes. This prospective exploratory trial will include 15 patients with a minimally conscious state (MCS) recruited according to the coma recovery scale-revised (CRS-R). Each patient will receive 5 different frequencies of taVNS (1, 10, 25, 50, and 100 Hz); sham stimulation will be used as a blank control. The order of stimulation will be randomized, and the patients' CRS-R scores and resting electroencephalography (EEG) before and after stimulation will be recorded. The overall study of taVNS used in treating patients with DOC is still in the preliminary stage of exploration. Through this experiment, we aim to explore the optimal stimulation frequency parameters of taVNS for the treatment of DOC patients. Furthermore, we expect to achieve a stable improvement of consciousness in DOC patients by continuously optimizing the neuromodulation paradigm of taVNS for the treatment of DOC patients. https://www.chictr.org.cn/index.aspx, identifier ChiCTR 2200063828.

Transauricular vagus nerve stimulation for patients with disorders of consciousness: A randomized controlled clinical trial.

Disorders of consciousness (DoCs) are a frequent complication of brain injury disease, and effective treatments are currently lacking. Transauricular vagus nerve stimulation (tVNS) has been proposed as a promising therapeutic method for neurological disorders such as epilepsy and depression. In our previous study, we demonstrated that vagus nerve stimulation promoted recovery in rats with DoCs caused by traumatic brain injury. However, the clinical effect of vagus nerve stimulation on consciousness disorders is unclear. We aimed to investigate the therapeutic efficacy and safety of tVNS in patients with DoCs. We conducted a randomized, double-blinded, sham-controlled trial. Patients (N = 60) with DoCs, including minimally conscious state (MCS) and vegetative state/unresponsive wakefulness syndrome, were enrolled and randomized to groups receiving either active or sham tVNS. A frequency of 20 Hz and pulse wave of 200 us was used in the active-tVNS protocol, which was performed in the auricular branch of the vagus nerve in the left outer ear. The sham-tVNS protocol was the same as the active-tVNS protocol although without current input. Both groups of patients also received conventional treatments. Consciousness was evaluated according to the Coma Recovery Scale-Revised before and after the 4-week intervention. We also recorded the type and number of behavioral responses. Safety was primarily assessed according to the incidence of treatment-emergent adverse events. Each patient's heart rate and blood pressure were monitored during all treatment sessions. Ultimately, 57 patients completed the study: 28 patients underwent active tVNS and 29 patients underwent sham tVNS. No significant differences were observed in Coma Recovery Scale-Revised scores between the active- and sham-tVNS groups before the tVNS sessions. Compared with patients in the sham-tVNS group (9.28 ± 4.38), patients with DoCs treated with active tVNS showed improved consciousness (10.93 ± 4.99), although not statistically significant. Further analysis revealed obvious differences between patients with MCS receiving active and sham tVNS, but no significant difference in patients with vegetative state/unresponsive wakefulness syndrome in both groups. All side effects were considered common medical conditions with no obvious correlation to tVNS. These preliminary data provide early evidence that tVNS may be an effective and safe approach for promoting the recovery of consciousness, especially in patients with MCS. https://www.chictr.org.cn/edit.aspx?pid=175938&htm=4, identifier: ChiCTR2200066629.

Investigation of the effectiveness of vagus nerve stimulation for pediatric drug-resistant epilepsies secondary to nonaccidental trauma.

Epilepsy following non-accidental trauma (NAT) occurs in 18% of pediatric patients. About 33% of patients with epilepsy develop drug-resistant epilepsy. For these patients, vagus nerve stimulation (VNS) is a palliative treatment option. We aimed to investigate the effectiveness of VNS among pediatric NAT-related epilepsy patients compared to those with non-NAT-related epilepsy. We performed an 11-year retrospective analysis of VNS implantations for drug-resistant epilepsy at UPMC Children's Hospital of Pittsburgh. Patients were split into two groups: NAT vs. non-NAT. The primary outcome was the attainment of ≥ 50% seizure frequency reduction at 1-year post-VNS implantation. Fisher's exact tests and Wilcoxon rank-sum tests were used to compare groups. Significance was assessed at the alpha = 0.05 level. This analysis included data from 370 pediatric VNS patients, of whom 9 had NAT-related epilepsy. NAT patients had a significantly younger age of epilepsy onset than non-NAT patients (0.3years vs. 3.3years). Otherwise, there were no statistically significant baseline differences between groups, including patient sex and quantity of antiseizure medications pre-VNS. Overall, 71% of NAT patients experienced ≥ 50% seizure frequency reduction compared to 48% of non-NAT patients (p = 0.269). VNS may allow a higher proportion of pediatric patients with NAT-related epilepsy to achieve ≥ 50% seizure frequency reduction compared to other epilepsy etiologies. While the results of this study were not statistically significant, the effect size was large. Our results underscore the need for larger, multi-center studies to validate the effectiveness of VNS for this patient population.

Benefits of Vagus Nerve Stimulation in Patients with Traumatic Brain Injury and Reduced Cognitive Status: a systematic literature review

Benefits of Vagus Nerve Stimulation in Patients with Traumatic Brain Injury and Reduced Cognitive Status: a systematic literature review

Noninvasive Vagus Nerve Stimulation in the Treatment of Methamphetamine Use Disorder: A Review Article

Context: Methamphetamine (MA) use and the mortality it causes are increasing worldwide. The neurobiological mechanisms underlying the destructive effects of MA use are complex; however, there is much evidence that MA induces the dysfunction of monoaminergic transmission and causes oxidative stress, neuroinflammation, gliosis, and apoptosis. These toxic effects are associated with cardiotoxicity and neurotoxicity and with an imbalance in the autonomic nervous system, which altogether manifest themselves in clinical symptoms, such as neuropsychiatric disorders and cardiovascular diseases. Evidence Acquisition: There is no approved treatment for methamphetamine use disorder (MUD) despite all efforts made to date. The behavioral and pharmacological approaches currently used for the treatment of MUD are not completely effective. In this study, it is hypothesized that the stimulation of the vagus nerve and biological pathways underlying the processes of this stimulation might be effective as adjunctive therapy. Results: Despite the potential effects of vagus nerve stimulation (VNS) to improve MUD, no study has yet examined the clinical potential effects of VNS in patients with the disorder. Conclusions: Therefore, further studies, including experimental and clinical trials, are needed to examine the effects of VNS on MUD.