Vagus Nerve Stimulation For Epilepsy Research Articles

Vagus nerve stimulation in epilepsy – literature review

Vagus nerve stimulation in epilepsy – literature review

Vagus Nerve Stimulation for Epilepsy During Pregnancy (P7-1.012)

Vagus Nerve Stimulation for Epilepsy During Pregnancy (P7-1.012)

ASCEND: A randomized controlled trial of titration strategies for vagus nerve stimulation in drug-resistant epilepsy

Vagus Nerve Stimulation (VNS) therapy is widely understood to provide clinically meaningful improvements in seizure control to patients with drug-resistant epilepsy, and has been a staple in the clinical armamentaria available to epileptologists for over 25 years. Despite the long history of evidence-based reviews by neurology professional societies, there is still evidence of a practice gap in VNS titration and dosing that aims to maximize clinical benefit. Recent retrospective analyses have strongly argued for a more consistent application of a population-wide target dose of VNS, and further argued the importance of quickly achieving this target dose to hasten the onset of clinical benefits; however, these analyses failed to provide evidence for practical implementation. Herein, we describe a randomized controlled trial assessing the impact of titrating VNS according to three different protocols to achieve the target dose of 1.5 mA at 500µsec, for a 20-Hz signal frequency. The study was registered as NCT02385526 on March 11, 2015. Sixty-two patients were randomized into treatment groups that followed different titration protocols. One protocol (Group A) was designed to align with currently accepted professional guidance for VNS titration and the manufacturer’s labeling for VNS in epilepsy (Heck et al., 2002), while the other two protocols were derived from VNS applications in other therapeutic areas. Group A participants were most likely to achieve the target dose parameters in 12 weeks or less (81.8%), with a median time-until-achievement of the target dose of 8.1 weeks, while less than 60% of patients in other groups were able to achieve the same endpoint. Participants in all groups experienced low levels of transient tolerability concerns and adverse events, suggesting titration to the target dose in 12 weeks or less following the Group A protocol is generally acceptable to most patients. These findings indicate that patients receiving VNS for epilepsy can achieve the manufacturer-recommended dose range in 12 weeks or less. A wider implementation of the approach will likely improve the clinical impact of VNS on seizure control and prevent undertreatment.

Clinical Benefit of Vagus Nerve Stimulation for Epilepsy: Assessment of Randomized Controlled Trials and Prospective Non-Randomized Studies.

We examined the efficacy of vagal nerve stimulation (VNS) for patients suffering from medically intractable epilepsy. Four randomized controlled trials (RCTs - 3 adult RCTs and 1 pediatric RCT) were identified in our comprehensive literature search. Across the 4 studies, high frequency VNS stimulation (frequency >20Hz) consistently achieved a greater seizure frequency reduction (23.4-33.1%) relative to low frequency VNS stimulation (1Hz, .6-15.2%). We identified 2 RCTs examining whether the parameters of stimulation influenced seizure control. These studies reported that VNS achieved seizure control comparable to those reported by the first 4 RCTs (22-43% seizure frequency reduction), irrespective of the parameters utilized for VNS stimulation. In terms of VNS associated morbidity, these morbidities were consistently higher in adults who underwent high frequency VNS stimulation (eg dysphonia 37-66%, dyspnea 6-25.3%). However, no such differences were observed in the pediatric population. Moreover, <2% of patients withdrew from the RCTs/prospective studies due to intolerable symptoms. To provide an assessment of how the risks and benefits of VNS impact the patient experience, 1 study assessed the well-being of enrolled patients (as a secondary end point) and found VNS was associated with an overall improvement in well-being. Consistent with this observation, we identified a prospective, non-randomized study that demonstrated improved quality of life for epilepsy patients managed with VNS and best medical practice relative to best medical practice alone. In aggregate, these RCT studies support the efficacy and benefit of VNS as a neuro-modulatory platform in the management of a subset of medically refractory epilepsy patients.

Closed-loop vagus nerve stimulation. Patient-tailored therapy or undirected treatment?

BackgroundIn multi-drug-resistant epilepsy vagus nerve stimulation (VNS) is an efficacious additional treatment to reduce seizure frequency and severity. A recently developed cardiac-based seizure detection (CBSD) algorithm triggers automate stimulation (AutoStim) upon heart rate increases of at least 20%. Yet, long term sensitivity and specificity of the CBSD-algorithm remain unclear. We present a case series of 15 adult patients with epilepsy with AutoStim VNS therapy. MethodsWe reviewed CBSD-settings, operating hours and battery status of the devices. Percentage of AutoStim was assessed in comparison to continuous but intermittent stimulation. If seizure diaries were available, we verified whether a high rate of AutoStim was present during the documented seizures. ResultsWe reviewed 15 patients with a mean age of 34 years (±11y). Mean duration since implantation was 47 months (±12 m). Of 1296 (±686) continuous intermittent stimulations per week, 4.8 (±3.9)% were AutoStim. Proportion of AutoStim varied substantially. While 9 patients had a mean of 1.5% (±1.4%), 6 patients had a significantly higher proportion of AutoStim 9.0% (±1.6%). Seizure-frequency was higher in patients with higher AutoStim frequency. Adverse events occurred in none of the patients. ConclusionWe provide long-term results for sensitivity and specificity of the CBSD algorithm. While sensitivity seems to be high, we presume specificity to be poor. An extremely high number of AutoStim is supposedly false-positive. Yet, treatment was well tolerated by the patients without any adverse events, despite the high number of AutoStim. CBSD is a promising development, yet the algorithm should be revised to provide a better specificity.

Vagus nerve stimulation in epilepsy: Efficiency and safety of outpatient practice

IntroductionOver the past 20 years, Vagus Nerve Stimulation (VNS) has become one of the tools for surgical treatment of patients with refractory cryptogenic epilepsy. The objective of this study was to determine the feasibility of implanting a Vagus Nerve Stimulation in ambulatory patients with chronic epilepsy. Patients and methodsVNS procedure was consecutively performed in outpatient surgery between November 2016 and November 2018 in patients with refractory epilepsy. The main endpoints were complications, prolonged hospitalization and readmission during the first postoperative month. This information was collected by retrospective analysis of clinical files. ResultsOf the 22 patients included, the majority were autonomous (77%) with only 5 institutionalized patients. Retrospective analysis revealed a single complication of temporary dysphonia (4.5%) and an unplanned hospitalisation for immediate post-operative vomiting (4.5%). No readmissions were observed during the postoperative month but an emergency room visit for generalized seizure disorder was reported for one patient. ConclusionThe outpatient implantation of VNS in patients with epilepsy is a valid strategy for 95% of patients.

Single-center long-term results of vagus nerve stimulation for epilepsy: A 10–17 year follow-up study

PurposeThe paper presents a long-term follow-up study of VNS patients, analyzing seizure outcome, medication changes, and surgical problems. Method74 adults with VNS for 10 to 17 years were evaluated yearly as: non-responder – NR (seizure frequency reduction <50%), responder – R (reduction ≥ 50% and <90%), and 90% responder – 90R (reduction ≥ 90%). Delayed R or 90R (≥ 4 years after surgery), patients with antiepileptic medication changes and battery or complete system replacement were identified. Statistical analysis of potential outcome predictors (age, seizure duration, MRI, seizure type) was performed. ResultsThe rates of R and 90R related to the patients with outcome data available for the study years 1, 2, 10, and 17 were for R 38.4%, 51.4%, 63.6%, and 77.8%, and for 90R 1.4%, 5.6%, 15.1%, and 11.1%. The absolute numbers of R and 90R increased until years 2 and 6. Antiepileptic therapy was changed in 62 patients (87.9%). There were 11 delayed R and four delayed 90R, with medication changes in the majority. At least one battery replacement was performed in 51 patients (68.9%), 49 of whom R or 90R. VNS system was completely replaced in 7 patients (9.5%) and explanted in 7 NR (9.5%). No significant predictor of VNS outcome was found. ConclusionsAfter an initial increase, the rate of R and 90R remains stable in long-term follow-up. The changes of antiepileptic treatment in most patients potentially influence the outcome. Battery replacements or malfunctioning system exchange reflect the patient’s satisfaction and correlate with good outcomes.

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

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. 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. 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. 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.

Laryngeal motility alteration: A missing link between sleep apnea and vagus nerve stimulation for epilepsy.

This study aimed to evaluate the prevalence and the relationship of sleep breathing disorders (SBDs) and laryngeal motility alterations in patients with drug-resistant epilepsy after vagus nerve stimulator (VNS) implantation. Twenty-three consecutive patients with medically refractory epilepsy underwent out-of-center sleep testing before and after VNS implantation. Eighteen eligible subjects underwent endoscopic laryngeal examination post-VNS implantation. Statistical analysis was carried out to assess an association between laryngeal motility alterations and the onset/worsening of SBDs. After VNS implantation, 11 patients showed a new-onset mild/moderate SBD. Half of the patients already affected by obstructive sleep apnea (OSA) showed worsening of SBD. All of the patients with a new-onset OSA had a laryngeal pattern with left vocal cord adduction (LVCA) during VNS stimulation. The association between VNS-induced LVCA and SBD was statistically significant. This study suggests an association between VNS and SBD, hinting to a pivotal role of laryngeal motility alterations. The relationship between SBD and VNS-induced LVCA supports the need to routinely investigate sleep respiratory and laryngeal motility patterns before and after VNS implantation.

Mortality and SUDEP in epilepsy patients treated with vagus nerve stimulation.

The risk of premature death is increased in patients with intractable epilepsy. The effect of vagus nerve stimulation (VNS) on mortality remains unclear. In a previous study by Annegers et al., mortality was raised, comparable to similar intractable cohorts. Our aim was to calculate standardized mortality ratios (SMRs), identify epilepsy-related deaths, and estimate sudden unexpected death in epilepsy (SUDEP) rates in patients treated with VNS for epilepsy. All United Kingdom patients undergoing VNS between January 1, 1995 and December 31, 2010 at King's College Hospital, London were flagged through the national Medical Research Information Service. Analysis was performed in relation to all deaths occurring by December 31, 2010. Deceased patients were identified from the national death register, and additional information on cause and circumstances of death sought where appropriate to allow for classification of deaths. The cohort consisted of 466 patients, with 2993.83 person-years of follow-up and a median observation period of 5.9 years. Twenty-nine deaths occurred, 27 with the device active. SMR was 7.1 (95% confidence interval [CI] 4.8-10.3) for the active device; 12 deaths were considered epilepsy related, including 10 definite or probable SUDEP and one fatal near SUDEP. Definite/probable and fatal near SUDEP occurred at a rate of 3.7/1,000 person-years. SMRs decreased from 10.5 (5.6-19.5) in the first 2 years after implantation to 5.9 (3.7-9.5) thereafter, although CIs overlapped. SUDEP rates did not alter over time. SMRs and SUDEP rate in this study are comparable to other cohorts with intractable epilepsy, with SUDEP an important cause of death. VNS does not appear to lower the risk of premature death overall. There was a clear trend with lower SMR after 2 years of implantation, although CIs overlapped. SUDEP rates, however, did not change.

Lead revision surgery for vagus nerve stimulation in epilepsy: Outcomes and efficacy

We present, to our knowledge, the first published analysis of vagus nerve stimulation (VNS) lead revisions to incorporate quality of life, clinical response, and antiepileptic drug (AED) burden in postrevision clinical outcomes. Ten patients were followed and had no postoperative complications. Seven patients had improvement in quality of life, and three experienced no change. Eight patients noted a restoration of clinical response comparable with initial VNS implantation. Seven patients reported 30–60% improvement in seizure reduction, two experienced >60%, and one noted <30%. Six patients had no change in AED burden. Vagus nerve stimulation lead revision should be considered a safe option for patients with VNS lead failure and medically intractable epilepsy.

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

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. 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. 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. 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.

Vagus nerve stimulation: from epilepsy to the cholinergic anti‐inflammatory pathway

The brain and the gut communicate bidirectionally through the autonomic nervous system (ANS). The vagus nerve (VN), a major component of the ANS, plays a key role in the neuro-endocrine-immune axis to maintain homeostasia through its afferents (through the activation of the hypothalamic pituitary adrenal axis and the central ANS) and through its efferents (i.e. the cholinergic anti-inflammatory pathway; CAP). The CAP has an anti-TNF effect both through the release of acetylcholine at the distal VN acting on macrophages and through the connection of the VN with the spleen through the splenic sympathetic nerve. Vagus nerve stimulation (VNS) of vagal afferents at high frequency (20-30 Hz) is used for the treatment of drug-resistant epilepsy and depression. Low-frequency (5 Hz) VNS of vagal efferents activates the CAP for an anti-inflammatory effect that is as an anti-TNF therapy in inflammatory diseases were TNF is a key cytokine as represented by experimental sepsis, postoperative ileus, burn-induced intestinal barrier injury, colitis. However, both vagal afferents and efferents are activated by VNS. The objective of this review was to explore the following: (i) the supporting evidence for the importance of VNS in epilepsy (and depression) and its mechanisms of action, (ii) the anti-inflammatory characteristics of the VN, (iii) the experimental evidence that VNS impact on inflammatory disorders focusing on the digestive tract, and (iv) how VNS could potentially be harnessed therapeutically in human inflammatory disorders such as inflammatory bowel diseases, irritable bowel syndrome, postoperative ileus, rheumatoid arthritis as an anti-inflammatory therapy.

Comprehensive long-term outcome of best drug treatment with or without add-on vagus nerve stimulation for epilepsy: A retrospective matched pairs case–control study

PurposeIn the treatment of epilepsy, the recommendation to add vagus nerve stimulation (VNS) to the best available drug therapy (BDT) mostly relies on uncontrolled studies which provide limited information about VNS-specific benefits. We report findings from a retrospective matched pairs case–control study comparing the long-term (>2 years) outcomes of BDT with or without VNS. MethodsIncluded were adult patients with therapy-refractory epilepsy who had undergone the pre-surgical work-up (baseline) and subsequently received BDT with VNS (BDT+VNS) or BDT alone (BDT group). Patients were matched in pairs for age, gender and follow-up. Health outcomes were assessed at least 24 months after the baseline by comprehensive postal surveys and included established psychometric scales. ResultsWe obtained data from 20 matched pairs of case and control patients. In both groups, seizures, health-related quality of life and mood improved over time. More BDT patients experienced a complete cessation of “major” seizures (12/20 vs. 4/20) whereas, in non-seizure free patients, BDT+VNS patients showed better seizure frequency reduction (>50% reduction: 12/19 vs. 7/16). BDT+VNS patients experienced equal drug related and additional VNS related side effects. No clinically relevant effect of VNS treatment was found on any psychological/psychosocial outcome measure. ConclusionThis retrospective study provided no positive evidence for therapeutic benefits of adding VNS to BDT. The follow-up health status of BDT+VNS patients was slightly worse than in patients receiving BDT alone. Despite minor group differences at baseline the two patient groups who had failed presurgical evaluation were comparable. Therapeutic improvements during long-term BDT alone are often underestimated resulting in a misattribution of positive changes to VNS in uncontrolled studies and reviews. Currently, there is no incontrovertible evidence for the clinical effectiveness of adding VNS to BDT.

Vagus nerve stimulation for epilepsy: A review of central mechanisms

In a previous paper, the anatomy and physiology of the vagus nerve was discussed in an attempt to explain which vagus nerve fibers and branches are affected by clinically relevant electrical stimulation. This companion paper presents some of vagus nerve stimulation's putative central nervous system mechanisms of action by summarizing known anatomical projections of vagal afferents and their effects on brain biogenic amine pathways and seizure expression.

Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response

Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response

Vagus nerve stimulation for epilepsy: A review of the peripheral mechanisms.

Vagus nerve stimulation (VNS) is a unique epilepsy treatment in that a peripheral intervention is used to treat a disease that is entirely related to pathological events occurring within the brain. To understand how stimulation of the vagus nerve can be used to stop seizures, an understanding of the peripheral anatomy and physiology of the vagus nerve is essential. The peripheral aspects of the vagus nerve are discussed in this review, with an explanation of which fibers and branches are involved in producing these antiepileptic effects, along with speculation about the potential for improving the therapy.

Canadian Experience with Vagus Nerve Stimulation for Epilepsy in Adults

An abstract is not available for this content so a preview has been provided. As you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Safety and Efficacy of Vagus Nerve Stimulation in Fibromyalgia: A Phase I/II Proof of Concept Trial

We performed an open-label Phase I/II trial to evaluate the safety and tolerability of vagus nerve stimulation (VNS) in patients with treatment-resistant fibromyalgia (FM) as well as to determine preliminary measures of efficacy in these patients. Of 14 patients implanted with the VNS stimulator, 12 patients completed the initial 3-month study of VNS; 11 patients returned for follow-up visits 5, 8, and 11 months after start of stimulation. Therapeutic efficacy was assessed with a composite measure requiring improvement in pain, overall wellness, and physical function. Loss of both pain and tenderness criteria for the diagnosis of FM was added as a secondary outcome measure because of results found at the end of 3 months of stimulation. Side effects were similar to those reported in patients treated with VNS for epilepsy or depression and, in addition, dry mouth and fatigue were reported. Two patients did not tolerate stimulation. At 3 months, five patients had attained efficacy criteria; of these, two patients no longer met widespread pain or tenderness criteria for the diagnosis of FM. The therapeutic effect seemed to increase over time in that additional participants attained both criteria at 11 months. Side effects and tolerability were similar to those found in disorders currently treated with VNS. Preliminary outcome measures suggested that VNS may be a useful adjunct treatment for FM patients resistant to conventional therapeutic management, but further research is required to better understand its actual role in the treatment of FM.

Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response

Vagus nerve stimulation (VNS) was approved by the US FDA in 1997 as an adjunctive treatment for medically refractory epilepsy. It is considered for use in patients who are poor candidates for resection or those in whom resection has failed. However, disagreement regarding the utility of VNS in epilepsy continues because of the variability in benefit reported across clinical studies. Moreover, although VNS was approved only for adults and adolescents with partial epilepsy, its efficacy in children and in patients with generalized epilepsy remains unclear. The authors performed the first meta-analysis of VNS efficacy in epilepsy, identifying 74 clinical studies with 3321 patients suffering from intractable epilepsy. These studies included 3 blinded, randomized controlled trials (Class I evidence); 2 nonblinded, randomized controlled trials (Class II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies. After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3-12 months after surgery and a 51% reduction after > 1 year of therapy. At the last follow-up, seizures were reduced by 50% or more in approximately 50% of the patients, and VNS predicted a ≥ 50% reduction in seizures with a main effects OR of 1.83 (95% CI 1.80-1.86). Patients with generalized epilepsy and children benefited significantly from VNS despite their exclusion from initial approval of the device. Furthermore, posttraumatic epilepsy and tuberous sclerosis were positive predictors of a favorable outcome. In conclusion, VNS is an effective and relatively safe adjunctive therapy in patients with medically refractory epilepsy not amenable to resection. However, it is important to recognize that complete seizure freedom is rarely achieved using VNS and that a quarter of patients do not receive any benefit from therapy.