Vagal Nerve Stimulation: A Bibliometric Analysis of Current Research Trends.

BACKGROUND: Vagal nerve stimulation (VNS) has become established as an effective tool for the management of various neurologic disorders. Consequently, a growing number of VNS studies have been published over the past four decades. This study presents a bibliometric analysis investigating the current trends in VNS literature. MATERIALS AND METHODS: Using the Web of Science collection data base, a search was performed to identify literature that discussed applications of VNS from 2000 to 2021. Analysis and visualization of the included literature were completed with VOSviewer. RESULTS: A total of 2895 publications were identified. The number of articles published in this area has increased over the past two decades, with the most citations (7098) occurring in 2021 and the most publications (270) in 2020. The h-index, i-10, and i-100 were 97, 994, and 91, respectively, with 17.0 citations per publication on average. The highest-producing country and institution of VNS literature were the United States and the University of Texas, respectively. The most productive journal was Epilepsia. Epilepsy was the predominant focus of VNS research, with the keyword "epilepsy" having the greatest total link strength (749) in the keyword analysis. The keyword analysis also revealed two major avenues of VNS research: 1) the mechanisms by which VNS modulates neural circuitry, and 2) therapeutic applications of VNS in a variety of diseases beyond neurology. It also showed a significant prevalence of noninvasive VNS research. Although epilepsy research appears more linked to implanted VNS, headache and depression specialists were more closely associated with noninvasive VNS. CONCLUSION: VNS may serve as a promising intervention for rehabilitation beyond neurologic applications, with an expanding base of literature over the past two decades. Although epilepsy researchers have produced most current literature, other fields have begun to explore VNS as a potential treatment, likely owing to the rise of noninvasive forms of VNS.

Early Implantation as a Main Predictor of Response to Vagus Nerve Stimulation in Childhood-Onset Refractory Epilepsy.

OBJECTIVE: We describe a multicenter experience with vagus nerve stimulator implantation in pediatric patients with drug-resistant epilepsy. Our goal was to assess vagus nerve stimulation efficacy and identify potential predictors of favorable outcome. METHODS: This is a retrospective study. Inclusion criteria: ≤18 years at time of vagus nerve stimulator implantation, at least 1 year of follow-up. All patients were previously found to be unsuitable for an excisional procedure. Favorable clinical outcome and effective vagus nerve stimulation therapy were defined as seizure reduction >50%. Outcome data were reviewed at 1, 2, 3, and 5 years after vagus nerve stimulator implantation. Fisher exact test and multiple logistic regression analysis were employed. RESULTS: Eighty-nine patients met inclusion criteria. Responder rate (seizure frequency reduction >50%) at 1-year follow-up was 25.8% (4.5% seizure-free). At last follow-up, 31.5% had a favorable outcome and 5.2% were seizure free. The only factor significantly predicting favorable outcome was time to vagus nerve stimulator implantation, with the best outcome achieved when vagus nerve stimulator implantation was performed within 3 years of seizure onset. Implantation between 3 and 5 years after epilepsy onset correlated with better long-term seizure freedom (13.3% at T5). Overall, 65.2% of patients evidenced improved quality of life at last follow-up. However, 12.4% had adverse events, but most were mild and disappeared after 3-4 months. CONCLUSIONS: Early vagus nerve stimulator implantation within 5 years of seizure onset was the only predictor of favorable clinical outcome in pediatric patients. Improved quality of life and a low incidence of significant adverse events were observed.

Adjunctive Vagus Nerve Stimulation for Treatment-Resistant Depression: a Quantitative Analysis.

Vagus nerve stimulation (VNS) has been increasingly studied in treating treatment-resistant depression (TRD), but the findings have been mixed. This updated meta-analysis was conducted to examine the efficacy and safety of adjunctive VNS for TRD. Controlled studies reporting on the efficacy and safety of adjunctive VNS for TRD were screened, identified and analyzed. Standardized mean difference (SMD), risk ratio (RR) and their 95% confidence intervals (CIs) were analyzed using RevMan version 5.3. Three controlled studies with a total of 1048 patients with TRD compared VNS (n = 622) with control (n = 426) groups. Only one study was rated as 'high quality' using the Jadad scale. Adjunctive VNS was significantly superior to the control group regarding study-defined response [SMD:1.96 (95%CI:1.60, 2.40), P < 0.00001, I2 = 0%]. Patient-reported voice alteration occurred more frequently with adjunctive VNS for patients with TRD. No significant group differences were found regarding discontinuation due to any reason [RR:0.50 (95%CI:0.12, 2.09), P = 0.34, I2 = 85%]. Adjunctive VNS appeared to be effective and relatively safe treatment for TRD. Further randomized controlled trials are needed to confirm the efficacy and safety of VNS for TRD.

Recent patterns of vagal nerve stimulator use in the United States: Is there a racial disparity?

OBJECTIVE: Patients with refractory epilepsy are at a high risk of complications but may not receive the same level of care across racial groups. We aimed to ascertain racial inequalities and trends in the use of a vagal nerve stimulator (VNS) among adult patients with refractory epilepsy. METHODS: A total of 24 159 adults (18 years and older) with refractory epilepsy from the National Inpatient Sample between the years 2006 and 2014 were included in this analysis. We used a multivariate logistic regression analysis to evaluate independent predictors of VNS use among patients with refractory epilepsy. Covariates included gender, age, insurance type, and household income. In addition, we evaluated for trends in VNS use over the 9-year period of data collection. RESULTS: A total of 1.56% of patients with refractory epilepsy had used a VNS between 2006 and 2014. Overall, there was a trend of decreased use of a VNS between 2006-2008 (2.1%) and 2012-2014 (0.9%). In the adjusted multivariate logistic regression analysis, blacks (odds ratio [OR] = 0.52, 95% confidence interval [CI] = 0.35-0.77) were significantly less likely to have used a VNS relative to non-Hispanic whites. Additional factors independently associated with a decreased likelihood of VNS use were age > 65 years (OR = 0.51, 95% CI = 0.28-0.95) and years 2012-2014 (OR = 0.44, 95% CI = 0.28-0.67). SIGNIFICANCE: There was a trend toward a decrease in the use of a VNS among adult patients with refractory epilepsy. Our results also suggest that black patients with refractory epilepsy were less likely to receive a VNS independently of other variables. Increased work toward effectively reducing racial disparities in access to quality epilepsy care is crucial.

Quality-of-life metrics with vagus nerve stimulation for epilepsy from provider survey data.

OBJECTIVE: Drug-resistant epilepsy is a devastating disorder associated with diminished quality of life (QOL). Surgical resection leads to seizure freedom and improved QOL in many epilepsy patients, but not all individuals are candidates for resection. In these cases, neuromodulation-based therapies such as vagus nerve stimulation (VNS) are often used, but most VNS studies focus exclusively on reduction of seizure frequency. QOL changes and predictors with VNS remain poorly understood. METHOD: Using the VNS Therapy Patient Outcome Registry, we examined 7 metrics related to QOL after VNS for epilepsy in over 5000 patients (including over 3000 with ≥12months follow-up), as subjectively assessed by treating physicians. Trends and predictors of QOL changes were examined and related to post-operative seizure outcome and likelihood of VNS generator replacement. RESULTS: After VNS therapy, physicians reported patient improvement in alertness (58-63%, range over follow-up period), post-ictal state (55-62%), cluster seizures (48-56%), mood change (43-49%), verbal communication (38-45%), school/professional achievements (29-39%), and memory (29-38%). Predictors of net QOL improvement included shorter time to implant (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.1-1.6), generalized seizure type (OR, 1.2; 95% CI, 1.0-1.4), female gender (OR, 1.2; 95% CI, 1.0-1.4), and Caucasian ethnicity (OR, 1.3; 95% CI, 1.0-1.5). No significant trends were observed over time. Patients with net QOL improvement were more likely to have favorable seizure outcomes (chi square [χ2]=148.1, p<0.001) and more likely to undergo VNS generator replacement (χ2=68.9, p<0.001) than those with worsened/unchanged QOL. SIGNIFICANCE: VNS for drug-resistant epilepsy is associated with improvement on various QOL metrics subjectively rated by physicians. QOL improvement is associated with favorable seizure outcome and a higher likelihood of generator replacement, suggesting satisfaction with therapy. It is important to consider QOL metrics in neuromodulation for epilepsy, given the deleterious effects of seizures on patient QOL.

Socioeconomic evaluation of vagus stimulation: A controlled national study.

PURPOSE: We aimed to determine the health costs and social outcomes in terms of education, employment and income level after insertion of a vagus nerve stimulator (VNS) in patients with epilepsy. METHODS: This is a case-control study using Danish health care and socioeconomic register data. The analysis of the effect involved a comparison of the health care costs, occupation and income status of VNS-treated epilepsy patients with those of a control group of epilepsy patients who had a VNS implanted during the 12 months before the index date (pre-period) and during the two years after the index date (post-period). RESULTS: 101 patients who had undergone VNS implantation and 390 control patients were included. VNS implantation was associated with fewer inpatient admissions and emergency room visits and less frequent use of prescription medication compared with epilepsy patients without VNS implantation. VNS implantation was not associated with changes in occupational status (including employment and income). In fact, the number of people on disability pension increased during the period. CONCLUSIONS: VNS implantation in people with epilepsy is associated with reduced health care use, but not with occupational or social status.

Decision analysis of intracranial monitoring in non-lesional epilepsy.

PURPOSE: Up to one third of epilepsy patients develop pharmacoresistant seizures and many benefit from resective surgery. However, patients with non-lesional focal epilepsy often require intracranial monitoring to localize the seizure focus. Intracranial monitoring carries operative morbidity risk and does not always succeed in localizing the seizures, making the benefit of this approach less certain. We performed a decision analysis comparing three strategies for patients with non-lesional focal epilepsy: (1) intracranial monitoring, (2) vagal nerve stimulator (VNS) implantation and (3) medical management to determine which strategy maximizes the expected quality-adjusted life years (QALYs) for our base cases. METHOD: We constructed two base cases using parameters reported in the medical literature: (1) a young, otherwise healthy patient and (2) an elderly, otherwise healthy patient. We constructed a decision tree comprising strategies for the treatment of non-lesional epilepsy and two clinical outcomes: seizure freedom and no seizure freedom. Sensitivity analyses of probabilities at each branch were guided by data from the medical literature to define decision thresholds across plausible parameter ranges. RESULTS: Intracranial monitoring maximizes the expected QALYs for both base cases. The sensitivity analyses provide estimates of the values of key variables, such as the surgical risk or the chance of localizing the focus, at which intracranial monitoring is no longer favored. CONCLUSION: Intracranial monitoring is favored over VNS and medical management in young and elderly patients over a wide, clinically-relevant range of pertinent model variables such as the chance of localizing the seizure focus and the surgical morbidity rate.

Revision surgeries following vagus nerve stimulator implantation.

The vagus nerve stimulator (VNS) has been shown to provide a safe, albeit costly, treatment for intractable epilepsy. We aimed to analyze the incidence, timing, and clinical/demographic associations of revision surgery post-VNS implantation in epilepsy patients. The Thomson Reuters MarketScan database, containing data from 23-50million individuals, was used. Epilepsy patients receiving VNS implantations from 2003 to 2009 were identified by Current Procedural Terminology and International Classification Of Diseases Ninth Revision codes. Incidence and timing of subsequent implant-related surgeries were recorded. Events were described using time-to-event methodology, with Kaplan-Meier failure estimation/Cox proportional hazard models adjusted for clinical/demographic factors. In 1234 patients, average incidence of revision surgeries over 6years of follow-up were <1%, <3%, 4-10%, and <1% for VNS electrode revision, battery revision/removal, battery replacement/implantation, and infection washout, respectively. For electrode revision and battery revision/replacement, the incidence was higher in the first year and for battery replacement in later years. Age, sex, insurance type, or geographic region did not significantly impact event occurrence. Implant-related revision surgeries are rare. Some events occur more often in certain follow-up years than others; none are significantly impacted by age, sex, insurance type, or geographic region. The most common reason for revision was battery replacement several years after VNS placement.

Rehospitalization and emergency department use rates before and after vagus nerve stimulation for epilepsy: use of state databases to provide longitudinal data across multiple clinical settings.

OBJECTIVES: Data regarding rehospitalization and emergency department (ED) visits following vagus nerve stimulation (VNS) present data analysis challenges. We present a method that uses California's multiple databases to more completely assay VNS efficacy. MATERIALS AND METHODS: The Healthcare Cost and Utilization Project's California Inpatient and Ambulatory Surgery databases were assayed for all VNS surgeries from 2005 to 2009. Patients were selected by epilepsy diagnosis codes and VNS procedure codes. Patients (total N = 629) were tracked across multiple databases using unique identifiers. Thirty-day and one-year post-implantation rates of VNS complication and healthcare visits were abstracted, along with one-year preoperative hospital and ED use. Statistics included correction for multiple comparisons. RESULTS: The one-year reoperation rate for adult patients (N = 536) was 3.9%; during the second year, an additional 3.2% of patients had reoperations. Within the first 30 days, <2% of patients experienced a complication. Four percent of patients were readmitted to a hospital, and 11.6% of patients visited an ED. The most common reason for rehospitalization or ED visit was seizure. In the first year after VNS, total seizure-related visits (hospitalization and ED) were 17% lower (2.12 visits per year to 1.71; p = 0.03). In the second year following VNS, seizure-related visits were 42% lower (2.21 visits per year to 1.27, p = 0.01). Pediatric patients (N = 93) had comparable results. CONCLUSIONS: VNS surgery has low rates of complications and reoperations and is associated with reduced incidence of seizure-related ED visits and hospital admissions in the first and second postoperative years.

High-resolution measurement of electrically-evoked vagus nerve activity in the anesthetized dog.

OBJECTIVE: Not fully understanding the type of axons activated during vagus nerve stimulation (VNS) is one of several factors that limit the clinical efficacy of VNS therapies. The main goal of this study was to characterize the electrical recruitment of both myelinated and unmyelinated fibers within the cervical vagus nerve. APPROACH: In anesthetized dogs, recording nerve cuff electrodes were implanted on the vagus nerve following surgical excision of the epineurium. Both the vagal electroneurogram (ENG) and laryngeal muscle activity were recorded in response to stimulation of the right vagus nerve. MAIN RESULTS: Desheathing the nerve significantly increased the signal-to-noise ratio of the ENG by 1.2 to 9.9 dB, depending on the nerve fiber type. Repeated VNS following nerve transection or neuromuscular block (1) enabled the characterization of A-fibers, two sub-types of B-fibers, and unmyelinated C-fibers, (2) confirmed the absence of stimulation-evoked reflex compound nerve action potentials in both the ipsilateral and contralateral vagus nerves, and (3) provided evidence of stimulus spillover into muscle tissue surrounding the stimulating electrode. SIGNIFICANCE: Given the anatomical similarities between the canine and human vagus nerves, the results of this study provide a template for better understanding the nerve fiber recruitment patterns associated with VNS therapies.

[Frequency of the use of vagus nerve stimulation for the treatment of intractable epilepsy during the first year of public health insurance coverage with in Kyushu Rosai Hospital and other areas in Japan].

Vagus nerve stimulation (VNS) is a palliative treatment for medically intractable epilepsy and has been covered by public health insurance in Japan since July 1, 2010. The frequency of the use of VNS during the first year of insurance coverage was determined by assessing the number of cases for which VNS was performed in Kyushu Rosai Hospital, the number of registered cases, and the questionnaire survey filled by 68 surgeons who are board certified as both epileptologists and neurosurgeons. VNS devices were placed in 98 patients from July 2010 to June 2011. These devices were placed in an average of 4.4 patients per month from July 2010 to November 2010 and in an average of 10.9 patients from December 2010 to June 2011. However, we did not observe an increasing trend. Almost all of the surgeries were performed in the Kanto (56 patients in 8 institutes) and Tokai (24 patients in 2 institutes) areas. VNS was not performed in many institutes primarily because VNS was not indicated for any of the patients. The questionnaire survey indicated that the use of VNS was likely to increase with an increase in the number of neurologists who decide on performing VNS preoperatively and regulate the conditions of the vagus nerve stimulator postoperatively. In conclusion, VNS is currently being applied in a limited number of institutes in the Kanto and Tokai areas, and a close association between the epileptologists and neurologists during preoperative and postoperative periods will increase the use of VNS.

Loss of the nerve monitoring signal during bilateral thyroid surgery.

BACKGROUND: This study aimed to assess current use of recurrent laryngeal nerve monitoring (RLNM) for bilateral thyroid surgery in Germany. It explored the willingness of surgeons to change strategy after loss of signal (LOS) on the first side of resection. METHODS: Surgical departments in Germany equipped with nerve monitors were asked to complete a structured questionnaire, specifying the number of thyroidectomies done in 2010, and the frequencies of RLNM, vagal stimulation, and electromyographic (EMG) recording before and after thyroidectomy. They were also asked about the surgical plan for bilateral goitre after LOS on the first side of resection. RESULTS: Based on manufacturers' sales data, 1119 (89·1 per cent) of 1256 surgical departments in Germany were equipped with nerve monitors in 2010. A total of 595 departments (53·2 per cent), accounting for approximately 75 per cent of all thyroidectomies in Germany during that year, returned a completed questionnaire. RLNM was used in 91·7-93·5 per cent of thyroidectomies, with the addition of routine vagal stimulation in 49·3 per cent before, and 73·8 per cent after resection. EMG responses to vagal stimulation were recorded in 54·8 per cent before, and 72·5 per cent after resection. Some 93·5 per cent of surgeons changed the resection plan for the other side in bilateral thyroid surgery after LOS had occurred on the first side. CONCLUSION: RLNM is now the standard of care during thyroidectomy in Germany. After LOS on the first side of resection in bilateral goitre, more than 90 per cent of respondents declared their willingness to change the resection plan for the contralateral side to avoid the risk of bilateral recurrent laryngeal nerve palsy.

[Treatment of pharmacoresistant epilepsy: stimulated refractoriness]. / Traitement des epilepsies réfractaires: rôle de la stimulation electrique.

Antiepileptic drugs allow controlling seizures in 70% of patients. For the others, a presurgical work-up should be undertaken, especially if a focal seizure origin is suspected; however, only a fraction of pharmacoresistant patients will be offered resective (curative) surgery. In the last 15 years, several palliative therapies using extra- or intracranial electrical stimulations have been developed. This article presents the vagal nerve stimulation, the deep brain stimulation (targeting the mesiotemporal region or the thalamus), and the cortical stimulation "on demand". All show an overall long-term responder rate between 30-50%, but less than 5% of patients becoming seizure free. It is to hope that a better understanding of epileptogenic mechanisms and of the implicated neuronal networks will lead to an improvement of these proportions.

[Treatment resistant depression: therapy and novel neuromodulatory treatments]. / Dépression résistant au traitement: enjeux, thérapie et place des nouvelles approches de neurostimulation.

Unipolar depression is among the leading cause of invalidity and disability-adjusted life-years. Many depressed patients do not respond to several antidepressant treatments. Several treatments have been investigated in resistant depression using electrical or magnetic stimulation of the brain. In this field, electroconvulsivotherapy remains to date the only treatment validated for efficacy and security. Novel neuromodulatory treatments used in neurological conditions are currently under investigation. Vagus nerve stimulation and deep brain stimulation may offer long-term efficacy and therefore justify expensive and highly specialized treatment programs.

Brain blood-flow change with acute vagus nerve stimulation in treatment-refractory major depressive disorder.

BACKGROUND: Existing neuroimaging studies of vagus nerve stimulation (VNS) in treatment resistant major depression (TRMD) suggest that many brain regions (eg, prefrontal cortex, thalamus, cingulate cortex, insular cortex) associated with mood disorders undergo alterations in blood flow/metabolism. OBJECTIVE/HYPOTHESIS: Positron emission tomography (PET oxygen-15 labeled water or PET [(15)O] H(2)O) was used to identify changes in regional cerebral blood flow (rCBF) in response to immediate VNS in 13 subjects with TRMD. We hypothesized rCBF changes along the afferent pathway of the vagus and in regions associated with depression (eg, orbitofrontal cortex, amygdala, insular cortex). METHODS: Six 90-second PET [(15)O] H(2)O scans were performed on 13 subjects in a VNS off-on sequence. After normalization for global uptake and realignment to standard atlas space, statistical t images (P < .005) were used to evaluate rCBF change. RESULTS: VNS induced significant rCBF decreases in the left and right lateral orbitofrontal cortex and left inferior temporal lobe. Significant increases were found in the right dorsal anterior cingulate, left posterior limb of the internal capsule/medial putamen, the right superior temporal gyrus, and the left cerebellar body. Post hoc analysis found small-to-moderate correlations between baseline acute change in rCBF and antidepressant response after 12 months of VNS. CONCLUSIONS: Regions undergoing rCBF change in response to acute VNS are consistent with the known afferent pathway of the vagus nerve and models of brain network in depression. Larger studies assessing the correlation between acute stimulation patterns and antidepressant outcomes with VNS are needed.

Efficacy of vagus nerve stimulation for epilepsy by patient age, epilepsy duration, and seizure type.

Medically refractory epilepsy is a morbid condition, and many patients are poor candidates for surgical resection because of multifocal seizure origin or eloquence near epileptic foci. Vagus nerve stimulation (VNS) was approved in 1997 by the US Food and Drug Administration as an adjunctive treatment of intractable epilepsy for individuals aged 12 years and more with partial epilepsy. Controversy persists regarding the efficacy of VNS for epilepsy and about which patient populations respond best to therapy. In this article, the authors retrospectively studied a patient outcome registry and report the largest, to their knowledge, analysis of VNS outcomes in epilepsy.

Vagus nerve stimulation: a proven therapy for treatment of epilepsy strives to improve efficacy and expand applications.

Vagus nerve stimulation (VNS) is an approved therapy for the treatment of adult patients and adolescents aged 12 years and older who have partial onset seizures refractory to antiepileptic medications. More than 50,000 patients worldwide have been implanted with the VNS system. Work continues to understand the mechanism of action of VNS with the goal of improving the treatment, particularly to identify patients who will be helped by VNS, to develop a closed-loop seizure detection system, and to improve the selection of stimulation parameters. VNS has also been approved for treatment-resistant depression, and it may have utility in the treatment of a variety of other medical disorders.

Vagus nerve stimulation in the treatment of pharmacoresistant depression.

Treatment-resistant depression is one of the major challenges in clinical psychiatry, considering that its current treatments are far from optimal. Although known for decades, in the last few years vagus nerve stimulation (VNS) has become increasingly popular as a novel method of treatment of pharmacoresistant depression. In spite of an emerging body of literature concerning the effectiveness and potential mechanisms of action of VNS, some crucial questions regarding those issues remain to be answered. We review the pre-clinical and clinical literature relating to VNS, with the impact of studies of efficacy and safety in treatment of pharmacoresistant depression and also in other clinical applications in the field of psychiatric disorders. We conclude that in light of emerging reports, VNS warrants more controlled studies for the treatment of other forms of depression, including depression in a younger population, and also of other psychiatric disorders. Because of its safety, VNS could potentially become a treatment of choice in fields in which treatment procedures traditionally require the least aggressive methods.