Autonomic Neuromodulation for Atrial Fibrillation Following Cardiac Surgery: JACC Review Topic of the Week.

Autonomic neuromodulation therapies (ANMTs) (ie, ganglionated plexus ablation, epicardial injections for temporary neurotoxicity, low-level vagus nerve stimulation [LL-VNS], stellate ganglion block, baroreceptor stimulation, spinal cord stimulation, and renal nerve denervation) constitute an emerging therapeutic approach for arrhythmias. Very little is known about ANMTs' preventive potential for postoperative atrial fibrillation (POAF) after cardiac surgery. The purpose of this review is to summarize and critically appraise the currently available evidence. Herein, the authors conducted a systematic review of 922 articles that yielded 7 randomized controlled trials. In the meta-analysis, ANMTs reduced POAF incidence (OR: 0.37; 95% CI: 0.25 to 0.55) and burden (mean difference [MD]: -3.51 hours; 95% CI: -6.64 to -0.38 hours), length of stay (MD: -0.82 days; 95% CI: -1.59 to -0.04 days), and interleukin-6 (MD: -79.92 pg/mL; 95% CI: -151.12 to -8.33 pg/mL), mainly attributed to LL-VNS and epicardial injections. Moving forward, these findings establish a base for future larger and comparative trials with ANMTs, to optimize and expand their use.

Epilepsy through the eyes of the media: A paradox of positive reporting and challenges of access to advanced neurotechnology.

OBJECTIVE: Media coverage of disorders and medical advancements can impact public perception regarding the riskiness, effectiveness, and accessibility of treatment options. We studied that coverage for epilepsy with a focus on surgical interventions and emerging neurotechnologies. METHODS: Epilepsy-related English language articles published through 2019 were retrieved from online International news media with a circulation of 80,000 or above. We used directed content analysis of news articles to code content into a priori categories both to identify salient themes and to characterize their valence. RESULTS: One hundred forty-six unique articles matched our search terms. Overall, there was a steady increase in epilepsy reporting over time, with a majority of articles published with a positive tone. Neuromodulation was the focus of over 50% of all the articles in the time points analyzed. Vagus nerve stimulation (VNS) and deep-brain stimulation (DBS) were discussed more prominently than other types of neurotechnological interventions; VNS was the neurotechnological focus in 39% of the pediatric articles; resective surgery was the focus in 34% of adult articles. Access, support, and epilepsy literacy were the central themes in the context of ethical, legal, and social issues. SIGNIFICANCE: News media can influence the trust that the public places in science and medicine, and by extension, influences health policy. As innovations in neurotechnology for epilepsy emerge, understanding of individual and societal values is essential to their beneficial evolution and translation to care.

A 12-month pilot study outcomes of vagus nerve stimulation in Crohn's disease.

BACKGROUND: The vagus nerve has anti-inflammatory properties. We aimed to investigate vagus nerve stimulation (VNS) as a new therapeutic strategy targeting an intrinsic anti-inflammatory pathway in a pilot study in Crohn's disease patients. The main objectives addressed the questions of long-term safety, tolerability, and anti-inflammatory effects of this therapy. This study is the continuation of previous reported findings at 6 months. METHODS: Nine patients with moderate active disease underwent VNS. An electrode wrapped around the left cervical vagus nerve was continuously stimulated over 1 year. Clinical, biological, endoscopic parameters, cytokines (plasma, gut), and mucosal metabolites were followed-up. KEY RESULTS: After 1 year of VNS, five patients were in clinical remission and six in endoscopic remission. C-reactive protein (CRP) and fecal calprotectin decreased in six and five patients, respectively. Seven patients restored their vagal tone and decreased their digestive pain score. The patients' cytokinergic profile evolved toward a more "healthy profile": Interleukins 6, 23, 12, tumor necrosis factor α, and transforming growth factorß1 were the most impacted cytokines. Correlations were observed between CRP and tumor necrosis factor α, and some gut mucosa metabolites as taurine, lactate, alanine, and beta-hydroxybutyrate. VNS was well tolerated. CONCLUSION & INFERENCES: Vagus nerve stimulation appears as an innovative and well-tolerated treatment in moderate Crohn's disease. After 12 months, VNS has restored a homeostatic vagal tone and reduced the inflammatory state of the patients. VNS has probably a global modulatory effect on the immune system along with gut metabolic regulations. This pilot study needs replication in a larger randomized double-blinded control study.

Epilepsy surgery reduced seizure frequency for patients with severe motor and intellectual disorders.

INTRODUCTION: Little is known about epilepsy surgery for patients with severe motor and intellectual disorders (SMIDs). We hypothesized that epilepsy surgery could reduce epileptic seizure frequency in these patients. The purpose of this study was to compare pre- and postoperative seizure frequency in patients with SMIDs. METHODS: A total of 288 surgeries were performed for pediatric patients, including those with SMIDs, from 2009 to 2018. Inclusion criteria were as follows: Oshima classification 1 (intelligence quotient <20 and bedridden), ≥2 years old, proven ictal events evaluated by long-term video electroencephalography, and ≥1-year follow-up. Seizure frequency and the number of antiseizure medications (ASMs) were compared between pre- and postepilepsy surgery. Patients' respiratory and feeding conditions were also examined to determine comorbidities. RESULTS: Nineteen patients (5 girls, 14 boys; age: 2 to 12 years) fulfilled the inclusion criteria. One patient underwent focus resection, 2 patients underwent total corpus callosotomy, and 16 patients underwent vagus nerve stimulation therapies. Of 19 patients, 16 (84.2%) had daily seizures, and 3 (15.8%) had weekly seizures before surgery. Epilepsy surgery significantly reduced seizure frequency (p = 0.029). Five patients (26.3%) had status epilepticus (SE) before surgery, which disappeared in all but one after surgery (p = 0.046). The number of ASMs did not change between before and after surgery (p = 0.728). CONCLUSION: Epilepsy surgery reduced the frequency of epileptic seizures and improved SE even among patients with compromised respiratory function and compromised food intake.

Vagus Nerve Stimulation versus Responsive Neurostimulator System in Patients with Temporal Lobe Epilepsy.

INTRODUCTION: Patients with medically refractory temporal lobe epilepsy (TLE) are candidates for neuromodulation procedures. While vagus nerve stimulation (VNS) was historically the procedure of choice for this condition, the responsive neurostimulation system (RNS) has come into favor for its more targeted approach. While both VNS and RNS have been reported as efficacious treatments for TLE, the outcomes of these 2 procedures have not been directly compared. This study aims to compare outcomes following VNS versus RNS for TLE. METHODS: We retrospectively reviewed the records of all patients with TLE who underwent VNS or RNS placement at our institution from 2003 to 2018. The primary outcome was change in seizure frequency. Other outcomes included Engel score, change in anti-epileptic medications, and complications. RESULTS: Twenty-three patients met inclusion criteria; 11 underwent VNS and 12 underwent RNS. At baseline, the 2 groups were statistically similar regarding age at surgery, epilepsy duration, and preoperative seizure frequency. At last follow-up, both groups displayed reduced seizure frequency (mean reduction of 46.3% for the VNS group and 58.1% for the RNS group, p = 0.49). Responder rate, Engel score, and change in medications were statistically similar between groups. Compared to 0.0% of the VNS group, 13.3% of the RNS group experienced infection requiring re-operation. CONCLUSION: Despite their different mechanisms, VNS and RNS resulted in similar response rates for patients with TLE. We suggest that VNS should not be excluded as a treatment for patients with medically refractory TLE who are not candidates for resective or ablative procedures.

Research progress of vagus nerve stimulation in the treatment of epilepsy.

The International League Against Epilepsy (ILAE) defined drug-resistant epilepsy (DRE) that epilepsy seizure symptoms cannot be controlled with two well-tolerated and appropriately chosen antiepileptic drugs, whether they are given as monotherapy or in combination. According to the WHO reports, there is about 30%-40% of epilepsy patients belong to DRE. These patients need some treatments other than drugs, such as epilepsy surgery, and neuromodulation treatment. Traditional surgical approaches may be limited by the patient's clinical status, pathological tissue location, or overall prognosis. Thus, neuromodulation is an alternative choice to control their symptoms. Vagus nerve stimulation (VNS) is one of the neuromodulation methods clinically, which have been approved by the Food and Drug Administration (FDA). In this review, we systematically describe the clinical application, clinical effects, possible antiepileptic mechanisms, and future research directions of VNS for epilepsy.

Long-term outcome in neurostimulation of epilepsy.

For patients with pharmacoresistant focal epilepsy, neurostimulation offers nonpharmacological strategies to improve seizure control. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior thalamic nuclei, and responsive neurostimulation (RNS) are approved therapies which have shown efficacy in randomized short-term trials. Controlled data from prospective studies are needed to confirm reports on stable or even increasing evidence from studies with longer follow-up and to confirm that neurostimulation may offer advantages also regarding cognitive tolerability and sudden unexpected death in epilepsy (SUDEP)-risk. Here, a review of long-term outcomes is given, highlighting both achievements in terms of efficacy and tolerability and limitations of conclusions thereon related to an uncontrolled data basis and decreasing cohort sizes. This article is part of the Special Issue? "Individualized Epilepsy Management: Medicines, Surgery and Beyond".

Do certain subpopulations of adults with drug-resistant epilepsy respond better to modified ketogenic diet treatments? Evaluation based on prior resective surgery, type of epilepsy, imaging abnormalities, and vagal nerve stimulation.

OBJECTIVE: Adults with drug-resistant epilepsy (DRE) are among the most challenging to treat. This study assessed whether specific subpopulations of adult patients with refractory epilepsy responded differently to modified ketogenic diet (MKD) therapy. METHODS: Changes in seizure frequency, severity, and quality of life (QOL) were retrospectively analyzed based on pre-MKD surgical history, type of epilepsy, imaging findings, and vagal nerve stimulation (VNS) history among adults, ≥17 years of age, with DRE, receiving MKD therapy for three months. Additionally, particular attention was made to medication and VNS adjustments. RESULTS: Responder rates in seizure frequency, severity, and QOL reported among those with prior surgery were 56%, 75%, and 94%, respectively. Among those with focal epilepsy: 57%, 76%, and 76% had improvements in seizure frequency, seizure severity, and QOL, respectively whereas 83% improvement was seen for all three measures in those with generalized epilepsy. Among those with abnormal imaging: just over 50% reported improvements on all measures. For those with VNS, 53%, 63%, and 95% had improvements in seizure frequency, seizure severity, and QOL, respectively. No statistical differences in seizure frequency, severity, or QOL were noted between groups based on prediet surgical history, seizure type, imaging abnormalities, or VNS history. Compared with expected improvement from medication adjustment alone, significant improvement was seen for all groups; notably, the Z-test for proportions for the surgery group, when compared with placebo responder rates at 20%, was 3.6, p < 0.001. CONCLUSIONS: Modified ketogenic diet therapies are effective in improving seizure frequency, severity, and QOL and may offer the best chance for improvement among those whose seizures have persisted despite surgical intervention and VNS therapy. All types of epilepsy respond to MKDs, and possibly those with generalized epilepsy may respond better.

Children with autism spectrum disorders and drug-resistant epilepsy can benefit from epilepsy surgery.

OBJECTIVE: The objective of this research was to evaluate a cohort of children with both autism spectrum disorder (ASD) and drug-resistant epilepsy (DRE) after epilepsy surgery to determine predictors of best outcome. METHODS: Retrospective chart review was done for 29 children ages 2 to 18 years with ASD and DRE who had neurosurgical intervention for seizure management over 15 years at one institution. All subjects had at least 1 year of follow-up. Data abstraction included demographic information, seizure diagnosis, treatment, investigations, surgical intervention, neuropsychological assessment, and outcome. Statistical analysis software (SAS) was used for statistical analysis. Engel classification was used to assess seizure outcome. RESULTS: Fifteen subjects had resective surgery. Fourteen had palliative surgery with vagal nerve stimulator (VNS) insertion (13) and corpus callosotomy (1). Of the 29 subjects, 35% had class I outcome (all in the resective group). When combining all subjects (resective and palliative), 66% of subjects benefited with class I-III outcomes. In the total cohort, age at time of surgery was significant, with class I outcome more frequently seen in the younger age group when compared with classes II-IV (p = 0.01). CONCLUSION: A subset of children with ASD can benefit from resective surgery, and for those who are not candidates, a VNS can offer significant improvements in seizure control.

Vagus nerve stimulation (VNS) therapy update.

Epilepsy affects millions of people worldwide. Approximately one-third have pharmacoresistant epilepsy, and of these, the majority are not candidates for epilepsy surgery. Vagus nerve stimulation (VNS) therapy has been an option to treat pharmacoresistant seizures for 30 years. In this update, we will review the clinical data that support the device's efficacy in children, adolescents, and adults. We will also review its side-effect profile, quality of life and cost benefits, and the impact the device has on sudden unexpected death in epilepsy (SUDEP). We will then discuss candidate selection and provide guidance on dosing and future models. Vagus nerve stimulation therapy is an effective treatment for many seizure types and epilepsy syndromes with a predictable and benign side-effect profile that supports its role as the most commonly prescribed device to treat pharmacoresistant epilepsy. "This article is part of the Supplement issue Neurostimulation for Epilepsy."

A novel flexible cuff-like microelectrode for dual purpose, acute and chronic electrical interfacing with the mouse cervical vagus nerve.

OBJECTIVE: Neural reflexes regulate immune responses and homeostasis. Advances in bioelectronic medicine indicate that electrical stimulation of the vagus nerve can be used to treat inflammatory disease, yet the understanding of neural signals that regulate inflammation is incomplete. Current interfaces with the vagus nerve do not permit effective chronic stimulation or recording in mouse models, which is vital to studying the molecular and neurophysiological mechanisms that control inflammation homeostasis in health and disease. We developed an implantable, dual purpose, multi-channel, flexible 'microelectrode' array, for recording and stimulation of the mouse vagus nerve. APPROACH: The array was microfabricated on an 8 µm layer of highly biocompatible parylene configured with 16 sites. The microelectrode was evaluated by studying the recording and stimulation performance. Mice were chronically implanted with devices for up to 12 weeks. MAIN RESULTS: Using the microelectrode in vivo, high fidelity signals were recorded during physiological challenges (e.g potassium chloride and interleukin-1ß), and electrical stimulation of the vagus nerve produced the expected significant reduction of blood levels of tumor necrosis factor (TNF) in endotoxemia. Inflammatory cell infiltration at the microelectrode 12 weeks of implantation was limited according to radial distribution analysis of inflammatory cells. SIGNIFICANCE: This novel device provides an important step towards a viable chronic interface for cervical vagus nerve stimulation and recording in mice.

Palliative epilepsy surgery in Dravet syndrome-case series and review of the literature.

PURPOSE: Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy (SMEI), is a rare genetic disorder that results in severe childhood-onset epilepsy. Children with DS initially present with seizures in the first year of life that are often associated with fevers. With age, multiple seizure types develop. There are few reports and no guidelines regarding palliative surgical treatment for DS. Therefore, we reviewed our surgical experience with DS. METHODS: We conducted a retrospective review of all patients with genetically confirmed DS who underwent either vagal nerve stimulator (VNS) implantation or corpus callosotomy (CC) from May 2001 to April 2014 at our institution. All inpatient and outpatient relevant documentation were reviewed. Demographic information, genetic mutation, operation performed, and preoperative and postoperative seizure frequency were recorded. Inclusion criteria required greater than one-year postoperative follow-up. RESULTS: Seven children with DS were assessed. Six patients were treated with VNS and one patient was treated with CC. In one child, VNS was followed by CC as a secondary procedure. Therefore, in total, eight surgeries were performed on seven patients during the study period. At least 1 year elapsed from presentation to our hospital and surgery for all patients. Average time after the first seizure to VNS was 4.1 years, and the average time after the first seizure to CC was 7.6 years. The mean age of patients undergoing VNS implantation was 4.3 years, and the mean age for patients undergoing CC was eight. Average follow-up for all seven patients was 6.6 years. Seizures were decreased in five of the six patients with VNS and decreased in the two patients after CC. Four of the six patients who had VNS implanted had a greater than 50 % reduction in seizure frequency, and one of the six patients who had VNS implanted had a less than 50 % reduction in seizure frequency. One patient did not respond effectively to the VNS and had very limited change in seizure frequency. Both patients who had a CC had a greater than 50 % reduction in seizure frequency. CONCLUSIONS: Both VNS and CC in patients with DS can be effective at reducing seizure frequency. Patients with DS may benefit from earlier and more aggressive surgical intervention. Studies using larger patient cohorts will help clarify the role that surgery may play in the multidisciplinary approach to controlling seizures in DS. Further studies will help determine the appropriate timing of and type of surgical intervention.

Complications and safety of vagus nerve stimulation: 25 years of experience at a single center.

OBJECTIVE The goal of this paper was to investigate surgical and hardware complications in a longitudinal retrospective study. METHODS The authors of this registry study analyzed the surgical and hardware complications in 247 patients who underwent the implantation of a vagus nerve stimulation (VNS) device between 1990 and 2014. The mean follow-up time was 12 years. RESULTS In total, 497 procedures were performed for 247 primary VNS implantations. Complications related to surgery occurred in 8.6% of all implantation procedures that were performed. The respective rate for hardware complications was 3.7%. Surgical complications included postoperative hematoma in 1.9%, infection in 2.6%, vocal cord palsy in 1.4%, lower facial weakness in 0.2%, pain and sensory-related complications in 1.4%, aseptic reaction in 0.2%, cable discomfort in 0.2%, surgical cable break in 0.2%, oversized stimulator pocket in 0.2%, and battery displacement in 0.2% of patients. Hardware-related complications included lead fracture/malfunction in 3.0%, spontaneous VNS turn-on in 0.2%, and lead disconnection in 0.2% of patients. CONCLUSIONS VNS implantation is a relatively safe procedure, but it still involves certain risks. The most common complications are postoperative hematoma, infection, and vocal cord palsy. Although their occurrence rates are rather low at about 2%, these complications may cause major suffering and even be life threatening. To reduce complications, it is important to have a long-term perspective. The 25 years of follow-up of this study is of great strength considering that VNS can be a life-long treatment for many patients. Thus, it is important to include repeated surgeries such as battery and lead replacements, given that complications also may occur with these surgeries.

Chronic vagus nerve stimulation in Crohn's disease: a 6-month follow-up pilot study.

The vagus nerve (VN) is a link between the brain and the gut. The VN is a mixed nerve with anti-inflammatory properties through the activation of the hypothalamic-pituitary-adrenal axis by its afferents and by activating the cholinergic anti-inflammatory pathway through its efferents. We have previously shown that VN stimulation (VNS) improves colitis in rats and that the vagal tone is blunted in Crohn's disease (CD) patients. We thus performed a pilot study of chronic VNS in patients with active CD. Seven patients under VNS were followed up for 6 months with a primary endpoint to induce clinical remission and a secondary endpoint to induce biological (CRP and/or fecal calprotectin) and endoscopic remission and to restore vagal tone (heart rate variability). Vagus nerve stimulation was feasible and well-tolerated in all patients. Among the seven patients, two were removed from the study at 3 months for clinical worsening and five evolved toward clinical, biological, and endoscopic remission with a restored vagal tone. These results provide the first evidence that VNS is feasible and appears as an effective tool in the treatment of active CD.

Evaluating innovation. Part 2: Development in neurosurgery.

OBJECT Patients, practitioners, payers, and regulators are advocating for reform in how medical advances are evaluated. Because surgery does not adhere to a standardized developmental pathway, how the medical community accepts a procedure remains unclear. The authors developed a new model, using publication data and patterns, that quantifies this process. Using this technique, the authors identified common archetypes and influences on neurosurgical progress from idea inception to acceptance. METHODS Seven neurosurgical procedures developed in the past 15-25 years were used as developmental case studies (endovascular coil, deep brain stimulation, vagus nerve stimulation, 1,3-bis(2-chloroethyl)-l-nitrosourea wafer, and 3 radiosurgery procedures), and the literature on each topic was evaluated. A new metric the authors termed "progressive scholarly acceptance" (PSA) was used as an end point for community acceptance. PSA was reached when the number of investigations that refine or improve a procedure eclipsed the total number of reports assessing initial efficacy. Report characteristics, including the number of patients studied, study design, and number of authoring groups from the first report to the point of PSA, were assessed. RESULTS Publication data implicated factors that had an outsized influence on acceptance. First, procedural accessibility to investigators was found to influence the number of reports, number of patients studied, and number of authoring groups contributing. Barriers to accessibility included target disease rarity, regulatory restrictions, and cost. Second, the ease or difficulty in applying a randomized controlled trial had an impact on study design. Based on these 2 factors, 3 developmental archetypes were characterized to generally describe the development of surgery. CONCLUSIONS Common surgical development archetypes can be described based on factors that impact investigative methods, data accumulation, and ultimate acceptance by society. The approach and proposed terminologies in this report could inform future procedural development as well as any attempts to regulate surgical innovation.

Long-term Expectations of Vagus Nerve Stimulation: A Look at Battery Replacement and Revision Surgery.

BACKGROUND: Vagus nerve stimulation (VNS) is an established surgical treatment for medically intractable epilepsy with more than 75 000 devices implanted worldwide. While there are many reports documenting efficacy, complications, and clinical use, there are very few reports concerning VNS battery replacement and revision surgeries. OBJECTIVE: To review our experience with VNS battery replacement and revision surgery. METHODS: We retrospectively reviewed 1144 consecutive VNS procedures performed by a single surgeon between 1998 and 2012. Six hundred forty-four of those procedures were the initial placement of the VNS device. These patients were then followed to determine when a battery change occurred and what type of revision or removal was necessary. RESULTS: In the study, 46% of patients required at least 1 or more type of battery replacement or revision surgery. The most common types of surgery were for generator battery depletion (27%), poor efficacy (9%), and lead malfunction (8%). Only 2% of patients were noted to have an infection. CONCLUSION: VNS battery replacement, revisions, and removals account for almost one-half of all VNS procedures. Our findings suggest important long-term expectations for VNS including expected complications, battery life, and other surgical issues. Review of the literature suggests that this is the first large review of VNS revisions by a single center. Our findings are important to better characterize long-term surgical expectations of VNS therapy. A significant portion of patients undergoing VNS therapy will eventually require revision.

Theoretical Basis of Vagus Nerve Stimulation.

Despite a myriad of medical and surgical treatments for epilepsy developed over the past few decades, a large subset of patients remains refractory to treatment. Over this time period, vagus nerve stimulation (VNS) has become an accepted and viable treatment modality for this population. Since the earliest report of VNS implantation in 1988, tens of thousands of patients worldwide have received VNS therapy, and >100,000 patient-years of experience have been accrued. The mechanisms underlying the response to VNS therapy continue to be elucidated. As understanding of the VNS mechanisms of action continues to grow, more pathologies will arise as potential treatment indications. Furthermore, current treatment populations with refractory epilepsy, depression, and inflammatory diseases may enjoy improved response to stimulation.

[Vagus nerve stimulation therapy for epilepsy].

Vagus nerve stimulation is a palliative treatment for medically intractable epilepsy. This treatment reduces the frequency and severity of seizures refractory to antiepileptic drugs. Implanted generator and helical electrodes electrically stimulate the left vagus nerve at the neck chronically and intermittently. This was the first electrostimulation therapy clinically introduced for epilepsy. This treatment approach is supported by randomized double-blind trials even though the anti-seizure effect of vagus nerve stimulation is palliative and not curative. In Western countries, particularly the United States, this therapy has become an important alternative treatment for a subpopulation of patients with drug-resistant seizures who are not good candidates for craniotomy. In Japan, vagus nerve stimulation therapy was finally approved in January 2010 and has been covered by public health insurance since July 2010. Here, the author reviews the history, efficacy, and safety of this treatment, surgical anatomy and physiology of the vagus nerve, and the putative mechanisms underlying inhibition of epileptic seizures and accompanying effect on the central nervous system. Further experimental and clinical studies regarding this treatment approach are required to elucidate the detailed mechanism of action, to clarify the predicting factors of favorable outcome, and to scientifically confirm the anti-seizure effect in children and in generalized seizures and the efficacy in improvement of cognitive function, development, and quality of life.