Management of vagus nerve stimulation–related complications in drug resistant epilepsy: a system-based review

Cervical vagus nerve stimulation (VNS) is a clinically available treatment for refractory epilepsy and depression. Animal studies show that electrical activation of the noradrenergic brain region, locus coeruleus (LC), is essential for the therapeutic effects of cervical VNS for the treatment of these conditions. Cervical VNS often causes side effects such as coughing, headache, and apnea-hypopnea. Such side effects can be mitigated by reducing stimulation intensity; however, evidence suggests this reduces efficacy of treatment. Abdominal VNS, targeting the vagus nerve below the nerve branches that cause these side effects, is an alternative strategy to deliver VNS. This study aimed to assess whether abdominal VNS increases spike activity in the LC without causing any off-target effects. Cervical and abdominal vagi of anesthetized male Sprague-Dawley rats were implanted with cuff electrode arrays, and a tungsten electrode was used to record neural activity in the LC. Changes in the firing rate of LC neurons and changes to the heart and breathing rate were recorded during cervical and abdominal VNS. Cervical VNS significantly reduced heart and/or breathing rate (two-way repeated measures analysis of variance, p < 0.05; n = 6) when stimulation was 0.82 ± 0.09 mA or higher. This stimulation level was termed the "off-target effect threshold." Abdominal VNS did not produce any changes in heart and breathing rate at any stimulus level tested. Cervical and abdominal VNS, delivered at 2 mA (maximum tested) significantly increased spike activity predominantly in the anteromedial LC, compared with prestimulation baseline (paired t-test, p < 0.001, n = 6). However, when "safe levels," that is, below the off-target effect threshold, of VNS were applied, only abdominal VNS increased spike activity in the LC. Abdominal VNS activated the LC without causing changes to vitals and could be used as an alternative approach to providing VNS therapy for brain disorders such as drug-resistant epilepsy and depression.

HighlightsWhat are the main findings?In a pediatric cohort with drug-resistant epilepsy, 76.9% of patients achieved ≥50% seizure reduction following vagus nerve stimulation (VNS).Optimal clinical response was observed at an output current of ~1.5 mA and a duty cycle of 10%, beyond which additional increases did not improve outcomes.What is the implication of the main finding?Children may respond to lower-intensity VNS settings than adults, suggesting a need for age-specific programming protocols.Early stabilization at effective thresholds may reduce unnecessary stimulation and improve treatment tolerability in pediatric epilepsy care.Objectives: Drug-resistant epilepsy (DRE) remains a major challenge in pediatric neurology, as many children fail to achieve seizure control despite appropriate medications. Vagus nerve stimulation (VNS) offers an effective adjunctive treatment; however, optimal stimulation parameters for children are not well defined and are often extrapolated from adult protocols. This retrospective two-center cohort study aimed to evaluate the clinical effectiveness of VNS in pediatric DRE and to determine stimulation thresholds—particularly output current and duty cycle—most strongly associated with seizure reduction. Methods: Fifty-two pediatric patients (aged 0–18 years) with DRE who underwent VNS implantation and were followed for at least 12 months were retrospectively analyzed. Stimulation frequency and pulse width were fixed at 30 Hz and 250 µs, while output current and duty cycle were titrated based on clinical response. Seizure outcomes were derived from caregiver-maintained seizure diaries and confirmed during structured follow-up visits. Treatment response was defined as a ≥50% reduction in seizure frequency compared to baseline. Results: At 12 months post-implantation, 76.9% of patients achieved ≥ 50% seizure reduction, 32.7% experienced ≥ 90% reduction, and 11.5% attained complete seizure freedom. Optimal outcomes were associated with output currents of approximately 1.5 mA and duty cycles of 10%. Conclusions: VNS is a highly effective and well-tolerated treatment for pediatric DRE. Stabilization at an output current of 1.5 mA and a 10% duty cycle may serve as a clinically useful programming target. These findings support the use of individualized, age-specific stimulation strategies to optimize outcomes in pediatric VNS therapy.

Cervical vagus nerve stimulation (VNS) is an effective neuromodulation therapy for patients with drug-resistant epilepsy (DRE). The previous studies reported that VNS may reduce seizures by regulating the functional connectivity (FC) between cortical and subcortical regions. However, no studies on brainstem have been done in responders who achieved≥50% seizure reduction following VNS. Eight healthy controls and eight patients who became responders after 3months of operation were enrolled in this study. Resting-state functional MRI (rs-fMRI) was performed, and two sample and paired sample t test were, respectively, used to detect altered FC between brainstem and cortical/subcortical regions between controls and patients, between preoperative and postoperative patients. In the control group, regions with highest FC to brainstem included bilateral anterior cingulate gyri, left basal ganglia, left insula, left cuneus, right precuneus, and bilateral cerebellum. In preoperative patients, right frontal middle gyrus, bilateral basal ganglia, and right cerebellum were showed highest FC to brainstem. Compared with the controls, preoperative patients exhibited increased FC in bilateral inferior frontal gyri, right temporal cortex, while decreased FC in left insula, left postcentral gyrus, right posterior cingulate gyrus, right precuneus, and left superior parietal gyrus. In postoperative patients, regions with increased FC to brainstem were left insula, left precuneus and left cuneus, and those with decreased FC were right inferior occipital gyrus and right cerebellum. Recurrent seizures caused disturbances in brainstem-cortical/subcortical FC, especially in motor executive function related regions and default mode network. VNS could reorganize the altered FC between brainstem and insula, precuneus, and cerebellum in responders.

Vagus nerve stimulation (VNS) is a safe and effective treatment option for patients with drug-resistant epilepsy (DRE) and for those with treatment-resistant depression. VNS can lead to the amelioration of depressive symptoms in patients with DRE, independent of its impact on seizure control. However, the relationship between depressive symptoms and seizure outcomes in patients receiving VNS therapy remains uncertain. This study aimed to assess whether the presence or absence of depressive symptoms influences seizure outcomes in patients with DRE treated with VNS. This follow-up study included 51 consecutive adult DRE patients treated with VNS at the Neurology Outpatient Clinic at Tampere University Hospital. All patients underwent a psychiatric evaluation before VNS at baseline (pre-implantation). The severity of depressive symptoms was assessed using the Beck Depression Inventory-1A (BDI) at baseline and repeatedly throughout the follow-up period. We categorized patients into two groups based on the presence or absence of depressive symptoms, as determined by their BDI scores at baseline and during the follow-up after VNS implantation: i) patients with depressive symptoms (PWE+DS), with a BDI score>12 at least once either at baseline or during the follow-up, and ii) patients without depressive symptoms (PWE - DS), with all BDI scores≤12. The primary seizure outcome measure was the number of patients with>50% seizure reduction (responders) for their predominant seizure type. At baseline, psychiatric comorbidities were diagnosed in 29.4% of patients, and the average baseline BDI score was 7.0 (median 5.0, range 0-41). PWE+DS comprised 41.2% and PWE - DS 58.8% of the study population. The median duration of follow-up was 39months (range 6-102months). The overall responder rate was 52.1% for the predominant seizure type, with significantly more responders in the PWE+DS group than in the PWE - DS group (73.7% vs. 37.9%, p=0.027). Among the 11 patients whose predominant seizure type was focal to bilateral tonic-clonic seizures (FBTCS), 81.8% were responders, and 72.8% achieved seizure freedom for this seizure type. Our study indicates that DRE patients with depressive symptoms respond better to VNS therapy for their predominant seizure type than those without depressive symptoms. This unexpected finding may be explained by the shared neurobiological background of seizures and depressive symptoms, potentially influenced by VNS treatment. Patients with FBTCS as their predominant seizure type achieved the most favourable outcomes. Further investigations in a larger cohort of DRE patients with depressive symptoms are warranted to validate our results.

Vagus nerve stimulation (VNS) has garnered widespread application in patients with drug-resistant epilepsy (DRE), while the efficacy and prognostic factors of VNS in DRE remain elusive. Moreover, clinical determinants associated with rapid response to VNS have never been uncovered. This study aimed to elucidate factors influencing efficacy and rapid response to VNS. A consecutive series of patients with DRE undergoing VNS surgery from January 2014 to December 2023 was collected to describe VNS efficacy. Both univariate and multivariate analyses were performed to identify statistically significant prognostic factors, and a predictive model was developed. Furthermore, we examined clinical determinants of rapid/slow response to VNS and VNS current changes. A total of 65 patients underwent VNS implantation. Seizure frequency significantly decreased post-VNS, with mean seizure reduction rates of 35.7, 49.0, 48.5, 52.8, 63.2, and 66.8% at 6 (n = 65), 12 (n = 65), 24 (n = 50), 36 (n = 40), 60 (n = 31), and 84 (n = 19) months, respectively. At final follow-up, 61.5% (40/65) were responders (50-100% seizure reduction), and 10.8% (7/65) achieved seizure freedom for ≥1 year. Univariate analysis identified age at seizure onset ≥6 years (p = 0.003), baseline seizure frequency ≤30/month (p = 0.001), focal seizures (p = 0.002), developmental and epileptic encephalopathies (p = 0.037), and surgical history (p < 0.001) as significant prognostic factors. Multivariate analysis confirmed age at seizure onset ≥6 years (OR: 5.726, p = 0.039), baseline seizure frequency ≤30/month (OR: 4.697, p = 0.048), and focal seizures (OR: 4.791, p = 0.025) as independent predictors, enabling the development of a predictive model for VNS efficacy. Additionally, among responders, the median response duration was 6 months (range: 1-60 months), with baseline seizure frequency ≤30/month significantly associated with rapid response of VNS in DRE (<6 months, p = 0.033). Vagus nerve stimulation is effective for treating DRE, with efficacy increasing with follow-up duration. Age at seizure onset ≥6 years, baseline seizure frequency ≤30/month, and focal seizure were predictive of VNS success, underscoring the need for careful preoperative assessment of patients with DRE before VNS surgery.

Comparison of traditional and closed loop vagus nerve stimulation for treatment of pediatric drug-resistant epilepsy: A propensity-matched retrospective cohort study

Cervical vagus nerve stimulation (VNS) prevents manipulation-induced intestinal inflammation and improves intestinal transit in a mouse model of postoperative ileus (POI). Cervical VNS, however, is accompanied by cardiovascular and respiratory side effects. In view of potential clinical application, we therefore evaluated the safety and feasibility of abdominal VNS via laparoscopic approach in a porcine model. Six pigs were used in a non-survival study for both cervical and abdominal VNS. Two cardiac pacing electrodes were positioned around the right cervical and posterior abdominal vagus nerve and connected to an external stimulator. VNS was performed using four different settings (5 and 20 Hz, 0.5 and 1 ms pulse width) during 2 min with ECG recording. Laparoscopic VNS was timed and videotaped, and technical difficulties were noted. A validated National Aeronautics and Space Administration Task Load Index (NASA-TLX) questionnaire was used to evaluate the task and workload. The procedure was completed in all pigs with 4-port laparoscopic technique. Cervical and abdominal VNS were performed after correct identification and isolation of the nerve, and positioning of the electrodes around the nerve. Median laparoscopic operating time was 16 min (range 8-33 min), and median NASA-TLX was 31 (range 11-74). No major complications were encountered. Reduction of heart rate was between 5.5 and 14% for cervical VNS and undetectable for abdominal VNS. In a porcine model, laparoscopic VNS is feasible and safe with cardiac pacing electrodes and may lead to a similar novel approach in humans in the near future.

Long-Term Vagus Nerve Stimulation for Severe Refractory Depression: A Case Study With a Six-Year Follow-Up

Neuromodulation is a viable option for patients with drug-resistant epilepsies. We reviewed the management of patients with two deep brain neurostimulators. In addition, patients implanted with a device targeting the centromedian-parafascicular (CM-Pf) nuclear complex supplements this report to provide an illustrative case to implantation and programming a patient with three active devices. A narrative review using PubMed and Embase identified patients with drug-resistant epilepsy implanted with more than one neurostimulator was performed. Combinations of vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) were identified. We provide a background of a newly reported case of an adult with a triple implant eventually responding to CM-Pf DBS as the third implant following suboptimal benefit from VNS and RNS. In review of the literature, dual-device therapy is increasing in reports of use with combinations of VNS, RNS, and DBS to treat patients with drug-resistant epilepsy. We review dual-device implants with thalamic DBS device combinations, functional neural networks, and programming patients with dual devices. CM-Pf is a new target for DBS and has shown a variable response in focal epilepsy. We report the unique case of 28-year-old male with drug-resistant focal epilepsy who experienced a 75% seizure reduction with CM-Pf DBS as his third device after suboptimal responses to VNS and RNS. After 9 months, he also experienced seizure freedom from recurrent focal to bilateral tonic-clonic seizures. No medical or surgical complications or safety issues were encountered. We demonstrate safety and feasibility in an adult combining active VNS, RNS, and CM-Pf DBS. Patients with dual-device therapy who experience a suboptimal response to initial device use at optimized settings should not be considered a neuromodulation "failure." Strategies to combine devices require a working knowledge of brain networks.

Over the past two decades, the number of somatic treatments for psychiatric disorders has expanded, leading to new insights into the complex relationship between chemical and electric transmission of signals in the brain. In this article, the authors discuss the different device-based treatments currently available in psychiatry. They review clinical indications; putative mechanism of action; efficacy and adverse effects; the results and limitations of salient clinical trials; and active areas of research into the neurobiology of device-based stimuli.

V AGUS NERVE stimulation (VNS) is a new treatment available for patients with refractory epilepsy. The first implant was performed in 1988, and since then more than 900 patients have received this therapy. There has been skepticism among epileptologists concerning VNS. Many have questioned the efficacy of this treatment, referring frequently to the disappointing results of early cerebellar and thalamus stimulation attempts. Vagus nerve stimulation has erroneously been compared with epilepsy resective surgery, and many have the opinion that VNS proponents promote using VNS rather than traditional surgery when it is indicated. Some neurosurgeons have insinuated that clinicians who use VNS are depriving their patients of the possibility of resective surgery and have not even bothered to evaluate them properly. Because of these misconceptions and heated debates, I want to make clear the distinction between resective surgery, which is a successful and superior method of treating selected patients who are deemed appropriate candidates, and VNS, which is best compared with the efficacy and adverse effects of the new antiepileptic drugs (AEDs). All patients entering into VNS protocols are usually extensively evaluated for epilepsy surgery and are not implanted with the VNS device haphazardly. Unfortunately, the majority of patients with refractory cases are not epilepsy surgery candidates, so the development of other techniques, such as new drugs and VNS, are, of course, necessary. The VNS generator (NeuroCybernetic Prosthesis System, Cyberonics Inc, Webster, Tex) is implanted in the upper left area of the chest, with the stimulating lead attached to the left vagus nerve in the neck. The generator is then programmed externally with a programming wand attached to a personal computer. Frequency, output current, pulse width, signal-on time, signal-off time, and magnet parameters are adjusted by the physician using the programming system. The most commonly studied stimulation paradigm has been a 20to 30-Hz, 1.0to 2.0-mA, 500-microsecond pulse width, with 3 seconds–on time and 5 minutes off, 24 hours a day regardless of seizure activity. There is a magnet provided that can restart the VNS generator at its own parameters for a brief time to try to abort an emerging seizure. Magnet parameters may be programmed to their own settings by the same method as for the continual intermittent stimulation parameter settings. Vagus nerve stimulation is approved in Europe and other countries; therefore, this procedure is now used in regular clinical practice. Two double-blind studies comparing high stimulation (30 seconds on and 5 minutes off) with low stimulation (30 seconds on and 90 minutes off) have been completed. The first study (EO-3) was conducted in the United States, Germany, the Netherlands, and Sweden. The most recent study (EO-5) was conducted in the United States (Cyberonics Inc, unpublished data, August 1997). All patients in these trials had at least 6 partial seizures monthly despite the use of multiple AEDs at entry. Some were considered epilepsy surgery failures or not appropriate candidates for resective surgery. Other study protocols that have included 500 patients have been open-label trials. Efficacy results of the doubleblind trials at the end of 3 months of VNS treatment were remarkably similar, with a median of 24% (EO-3) and 27% (EO-5) reduction of seizure frequency, and 30% and 23%, respectively, with greater than 50% reduction in seizures for the patients receiving high stimulation. After 2 years of VNS therapy, 71 of 87 evaluable patients from the EO-3 study were still receiving VNS and 43% had experienced a greater than 50% reduction in seizures (Cyberonics Inc, unpublished data, June 1997). Besides delivering continual intermittent stimulation, the VNS generator allows patients the option of using a magnet to activate the device (“therapy on demand”) when experiencing an aura or a simple partial seizure. In many cases, this effectively prevents spreading of seizure activity and can give the patient a method to exert some type of control over his or her seizures. The safety profile of VNS is very favorable and the adverse effects are completely different from those seen with the use of AEDs. Cognitive and sedative adverse effects are not generally reported. In fact, many actually report an increase in awareness. Adverse effects of VNS have been restricted to local irritation, hoarseness, coughing, and, in a few cases, swallowing difficulties when the stimulator was on. All were immediately reversible with reduction of the stimulation parameters or when the generator was turned off. Vagus nerve stimulation does not interfere negatively with concomitant AED use or with any other drug given for other disorders. Surgery morbidity is very low, with infections causing the most problems (2%). SECTION EDITOR: VLADIMIR HACHINSKI, MD, FRCPC, DSCMED

Retention rate of vagus nerve stimulation for the treatment of drug-resistant epilepsy: A single-centre, retrospective study.

Dysregulation of the autonomic nervous system in heart failure (HF) has received considerable attention during the past 3 decades, largely because of the well-recognized association between increased sympathetic activity and the elaboration of biologically active molecules, collectively referred to as neurohormones, that help to maintain cardiovascular homeostasis through increased volume expansion, peripheral arterial vasoconstriction, and increased myocardial contractility. However, high and sustained levels of these biologically active molecules (eg, norepinephrine, angiotensin II, aldosterone) are overtly toxic to the heart and circulation.1 These and other insights have led to the clinical use of neurohormonal antagonists, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists, and β-blockers to treat patients with HF with a reduced left ventricular ejection fraction (LVEF).1 The effectiveness of these pharmacological agents is predominantly because of their ability to directly antagonize the deleterious effects of excessive sympathetic and renin–angiotensin activation. However, the current guideline-directed medical therapy (GDMT) in patients with HF fails to completely restore normal autonomic balance disrupted as a part of HF pathophysiology. During the last decade, a novel approach has generated widespread interest: modulation of the autonomic nervous system as a result of either a one-time intervention (eg, denervation) or of ongoing active therapy (eg, electric stimulation) as a means of further diminishing the sympathovagal imbalance that develops in HF.2,3 Of note, therapeutic neuromodulation with device-based therapies, either with spinal cord stimulation (SCS) or vagal stimulation (VS), has been used safely in patients with chronic pain, epilepsy, and depression, since the 1980s. As noted above, HF with a reduced LVEF is associated with sustained activation of the sympathetic nervous system that is accompanied by a withdrawal of parasympathetic tone. Impaired arterial baroreflexes have been proposed as an important mechanism that contributes to the sympathovagal imbalance present in HF4 …

We read with great interest the article entitled ‘Subthreshold vagal stimulation suppresses ventricular arrhythmia and inflamamatory response in a canine model of acute cardiac ischaemia and reperfusion’ by Zhang et al. (2016). Given that vagal nerve stimulation has been shown by others (Katare et al. 2009; Chen et al. 2016) and by us (Shinlapawittayatorn et al., 2013, 2014) to exert an anti-infarct effect against cardiac ischaemia and reperfusion injury, the lack of a decrease in the infarct size in the study by Zhang et al. (2016) needs to be discussed. The authors reported that subthreshold vagal stimulation (SVS) without heart rate reduction significantly suppressed ischaemia- and reperfusion-induced ventricular arrhythmias and decreased serum concentrations of C-reactive protein, interleukin-6, tumour necrosis factor-α, high-mobility group box 1 and noradrenaline during both the ischaemic and the reperfusion periods. It has also been well established in a number of preclinical studies of ischaemia and reperfusion injury that SVS has a significant infarct-limiting effect (Katare et al. 2009; Shinlapawittayatorn et al., 2013, 2014; Chen et al. 2016). In the study by Zhang et al. (2016), the left anterior descending coronary artery was occluded for 1 h, followed by a reperfusion period of 3 h. Vagal stimulation was applied 15 min before the ischaemic period until the end of reperfusion (Zhang et al. 2016). We have previously shown that SVS applied either before or during ischaemia effectively reduced cytochrome c release, increased the amount of phosphorylated connexin 43 and attenuated cardiac mitochondrial dysfunction, which could be responsible for the anti-infarct and anti-ventricular arrhythmia effects in a swine model (Shinlapawittayatorn et al., 2013, 2014). A possible explanation for the discrepancy between the results of Zhang et al. (2016) and others (Katare et al. 2009; Shinlapawittayatorn et al., 2013, 2014; Chen et al. 2016) could be the different vagal nerve stimulation protocols (unilateral versus bilateral cervical vagal stimulation). Specifically, bilateral cervical vagal trunks were stimulated in the study by Zhang et al. (2016) at a voltage 50% lower than the threshold chosen as the voltage for SVS. In contrast, unilateral cervical vagal stimulation was used in our studies (Shinlapawittayatorn et al., 2013, 2014) and others (Katare et al. 2009; Chen et al. 2016), raising the question of whether unilateral vagal stimulation might be more effective than bilateral vagal stimulation. Furthermore, a recent study using a similar electrode to that reported by Zhang et al. (2016) with lower strength stimulus could still reduce infarct size by 53% (Chen et al. 2016). Unfortunately, Zhang et al. (2016) did not discuss the possible contributions of this discrepancy regarding the anti-infarct effect of SVS in their article. At this time, it remains unclear whether SVS, which exerts both anti-inflammatory and anti-sympathetic effects, can improve myocardial function after ischaemia and reperfusion injury, and the study by Zhang et al. (2016) did not provide this important piece of information. None declared.

Responsiveness to vagus nerve stimulation (VNS) in children with drug-resistant epilepsy (DRE) is often defined based on reduction in seizure frequency, typically at the 50% threshold, with limited consideration to the effects of therapy on seizure severity and health-related quality of life (HRQoL). In the current report, we sought to better characterize the effects of VNS beyond seizure frequency in children with DRE. Sixty-seven children from the Connectomic profilingand Vagus nerve stimulation Outcomes Study (CONNECTiVOS) database, a multicenter study including children aged 0-18 who underwent VNS at eight North American centers, were included. Data were collected prospectively at baseline and 6, 12, and 24 months after VNS. Seizure outcomes were assessed using the 50% threshold, percentage change in seizure count and change on a frequency timescale, a categorical measure of seizure occurrence (e.g., daily to weekly seizures). The Seizure Severity Questionnaire and the Quality of Life in Childhood Epilepsy were also collected. Linear mixed models were constructed to study longitudinal changes in seizure severity and HRQoL. Among 67 children, 55.2% experienced >50% reduction in seizures, whereas only 37.3% demonstrated reductions in seizure timescales. Notably, 17.9% experienced no reduction in timescales despite meeting the 50% threshold. Furthermore, 31.9% of children experienced a meaningful improvement in seizure severity without any reduction in seizure timescales. HRQoL improvements were driven by the reduction in timescales (mean yearly increase of 3.65; 95% confidence interval [CI]: 0.71-6.52, p = 0.023), rather than responsiveness based on the 50% threshold or percentage change in seizure counts (p > 0.05). Reduced overall seizure severity was also independently associated with higher HRQoL after VNS (p = 0.035). The conventional 50% responder threshold failed to capture meaningful gains in HRQoL, which aligned more closely with seizure timescales. Furthermore, nearly one-third of children realized improvements in seizure severity without any reduction in timescales. Improvements in both seizure frequency timescales and seizure severity drive postoperative HRQoL gains.