Biomarkers of seizure response to vagus nerve stimulation: A scoping review.

Although vagus nerve stimulation (VNS) is a common procedure, seizure outcomes are heterogeneous, with few available means to preoperatively identify the ideal surgical candidate. Here, we perform a scoping review of the literature to identify biomarkers of VNS response in patients with drug-resistant epilepsy. Several databases (Ovid MEDLINE, Ovid Embase, BIOSIS Previews, and Web of Science) were searched for all relevant articles that reported at least one biomarker of VNS response following implantation for intractable epilepsy. Patient demographics, seizure data, and details related to biomarkers were abstracted from all studies. From the 288 records screened, 28 articles reporting on 16 putative biomarkers were identified. These were grouped into four categories: network/connectomic-based biomarkers, electrophysiological signatures, structural findings on neuroimaging, and systemic assays. Differences in brain network organization, connectivity, and electrophysiological synchronicity demonstrated the most robust ability to identify VNS responders. Structural findings on neuroimaging yielded inconsistent associations with VNS responsiveness. With regard to systemic biomarkers, heart rate variability was shown to be an independent marker of VNS response, whereas inflammatory markers were not useful. There is an unmet need to preoperatively identify candidates who are likely to benefit from VNS. Several biomarkers demonstrate promise in predicting seizure responsiveness to VNS, particularly measures of brain network connectivity. Further efforts are required to validate existing biomarkers to inform clinical decision-making.

Seizure freedom as an outcome in epilepsy treatment clinical trials.

Seizure freedom is recognized as the goal of epilepsy treatment by patients, families, and in treatment guidelines and is associated with notably improved quality of life. However, many studies of epilepsy treatments (including antiseizure medications/antiepileptic drugs, neurostimulation, and dietary therapies) fail to report data on seizure freedom. Even among studies that include this outcome, methods for defining and analyzing seizure freedom vary considerably. Thus, the available data are often difficult to interpret and comparisons between studies are particularly challenging. Although these issues had been identified over a decade ago, there remains a lack of clarity and standardized methods used in analyzing and reporting seizure freedom outcomes in studies of epilepsy treatments. In addition, it remains unclear whether short-term seizure freedom outcomes from pivotal clinical trials are predictive of longer-term seizure freedom outcomes for patients with treatment-refractory epilepsy. Ultimately, the limitations of the available data lead to the potential for misinterpretation and misunderstanding of seizure freedom outcomes associated with the spectrum of available treatments when examining treatment options for patients. Clearly defined outcome analyses of seizure freedom attainment and duration are essential in future clinical studies of treatment for seizures to guide treatment selection and modification for patients.

Long-term effects of vagus nerve stimulation in refractory pediatric epilepsy: A single-center experience.

INTRODUCTION: Vagus nerve stimulation (VNS) has been used as an adjunctive therapy for both children and adults with refractory epilepsy, over the last two decades. In this study, we aimed to evaluate the long-term effects and tolerability of VNS in the pediatric drug-resistant epilepsy (DRE) and to identify the predictive factors for responsiveness to VNS. METHODS: We retrospectively reviewed the medical records of pediatric patients who underwent VNS implantation between 1997 and 2018. Patients with ≥50% reduction of seizure frequency compared with the baseline were defined as "responders". The clinical characteristics of responders and nonresponders were compared. RESULTS: A total of 58 children (male/female: 40/18) with a mean follow-up duration of 5.7 years (3 months to 20 years) were included. The mean age at implantation was 12.4 years (4.5 to 18.5 years). Approximately half (45%) of our patients were responders, including 3 patients (5.8%) who achieved seizure freedom during follow-up. The age of seizure-onset, duration of epilepsy, age at implantation, and etiologies of epilepsy showed no significant difference between responders and nonresponders. Responders were more likely to have focal or multifocal epileptiform discharges (63%) on interictal electroencephalogram (EEG), when compared to nonresponders (36%) (p = .07). Vocal disturbances and paresthesias were the most common side effects, and in two patients, VNS was removed because of local reaction. CONCLUSION: Our series had a diverse etiological profile and patients with transition to adult care. Long-term follow-up showed that VNS is an effective and well-tolerated treatment modality for refractory childhood onset epilepsy. Age at implantation, duration of epilepsy and underlying etiology are not found to be predictors of responsiveness to VNS. Higher response rates were observed for a subset of patients with focal epileptiform discharges.

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.

Vagus nerve stimulation for patients with refractory epilepsy: Demographic features and neuropsychological outcomes of the VNS Taiwan child neurology society database.

OBJECTIVES: Vagus nerve stimulation (VNS) is an established adjunctive therapy for medically refractory epilepsy, which is commonly associated with cognitive impairment, especially in children in whom seizures may disrupt development that is essential to their intellectual and social maturation. The Taiwan Child Neurology Society intends to expand the use of VNS by reporting the experience in a nationwide population, displaying the demographic features and neuropsychological outcomes of VNS. METHODS: The enrollment included 105 patients of all ages and seizure types who underwent VNS implantation for refractory epilepsy. Basic data included etiology, past history, seizure phenotypes, and epileptiform syndromes. For efficacy analysis, seizure frequencies were recorded at the baseline and at 3, 12, 24, and 36 months after VNS implantation. For psychological assessment, intelligence quotients (IQ) and Parental Stress Index (PSI) scores were evaluated before and after the VNS. RESULTS: During the study period, 95 patients with VNS had followed seizure frequency, IQ and PSI recording. After implantation, there was a decreased frequency at 3 (P < .001), 12 (P < .001), 24 (P = .010), and 36 (P < .01) months. After implantation, the reduction rate (0-50%) of seizure frequency ranged around 26.1-36.1% from 3 to 36 months. For PSI scores, the VNS significantly improved the PSI- total score (P = .001) and PSI-parent domain (P = .001) but not the PSI-children domain (P = .052). No significant improvement in the IQ test performance was observed. CONCLUSIONS: This prospective nationwide database of VNS in Taiwan indicates long-term efficacy of VNS therapy, which has achieved a trend of seizure frequency reduction over a period of up to 36 months. It also shows the trend of decreased parental stress after VNS implantation.

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.

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.

Differential efficacy of non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A meta-analysis.

BACKGROUND: Two randomized, double-blind, sham-controlled trials (ACT1, ACT2) evaluated non-invasive vagus nerve stimulation (nVNS) as acute treatment for cluster headache. We analyzed pooled ACT1/ACT2 data to increase statistical power and gain insight into the differential efficacy of nVNS in episodic and chronic cluster headache. METHODS: Data extracted from ACT1 and ACT2 were pooled using a fixed-effects model. Main outcome measures were the primary endpoints of each study. This was the proportion of participants whose first treated attack improved from moderate (2), severe (3), or very severe (4) pain intensity to mild (1) or nil (0) for ACT1 and the proportion of treated attacks whose pain intensity improved from 2-4 to 0 for ACT2. RESULTS: The pooled population included 225 participants (episodic: n = 112; chronic: n = 113) from ACT1 (n = 133) and ACT2 (n = 92) in the nVNS (n = 108) and sham (n = 117) groups. Interaction was shown between treatment group and cluster headache subtype (p < 0.05). nVNS was superior to sham in episodic but not chronic cluster headache (both endpoints p < 0.01). Only four patients discontinued the studies due to adverse events. CONCLUSIONS: nVNS is a well-tolerated and effective acute treatment for episodic cluster headache. TRIAL REGISTRATION: The studies were registered at clinicaltrials.gov (ACT1: NCT01792817; ACT2: NCT01958125).

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.

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".

Existing and emerging applications for the neuromodulation of nerve activity through targeted delivery of electric stimuli.

The effective treatment of many diseases requires the use of multiple treatment strategies among which neuromodulation is playing an increasingly important role. Neuromodulation devices that act to normalize or modulate nerve activity through the targeted delivery of electrical stimuli will be the focus of this review. These devices encompass deep brain stimulators, vagus nerve stimulators, spinal cord simulators and sacral nerve stimulators. Already neuromodulation has proven successful in the treatment of a broad range of conditions from Parkinson's disease to chronic pain and urinary incontinence. Many of these approaches seek to exploit the activities of the autonomic nervous system, which influences organ function through the release of neurotransmitters and associated signalling cascades. This review will outline existing and emerging applications for each of these neuromodulation devices, proposed mechanisms of action and clinical studies evaluating both their safety and therapeutic efficacy.

The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue and Immune Responses in Patients With Primary Sjögren's Syndrome.

OBJECTIVES: Primary Sjögren's syndrome (pSS) sufferers have rated chronic fatigue as the most important symptom needing improvement. Emerging data suggest that stimulation of the vagus nerve can modulate immunological responses. The gammaCore device (electroCore), developed to stimulate the cervical vagus nerve noninvasively, was used to assess the effects of vagus nerve activation on immune responses and clinical symptoms of pSS. MATERIALS AND METHODS: Fifteen female pSS subjects used the nVNS device twice daily a 26-day period. At baseline, blood was drawn before and after application of the gammaCore device for 90 sec over each carotid artery. The following fatigue-related outcome measures were collected at baseline, day 7 and day 28: EULAR patient reported outcome index, profile of fatigue (Pro-F), visual analogue scale of abnormal fatigue, and Epworth sleepiness scale (ESS). Whole blood samples were stimulated with 2 ng/mL lipopolysaccharide (LPS) and the supernatant levels of IFNγ, IL12-p70, TNFα, MIP-1α, IFNα, IL-10, IL-1ß, IL-6, and IP-10 were measured at 24 hours. In addition, clinical hematology and flow cytometric profiles of whole blood immune cells were analyzed. RESULTS: Pro-F and ESS scores were significantly reduced across all three visits. LPS-stimulated production of IL-6, IL-1ß, IP-10, MIP-1α, and TNFα were significantly reduced over the study period. Patterns of NK- and T-cell subsets also altered significantly over the study period. Interestingly, lymphocyte counts at baseline visit correlated to the reduction in fatigue score. CONCLUSION: The vagus nerve may play a role in the regulation of fatigue and immune responses in pSS and nVNS may reduce clinical symptoms of fatigue and sleepiness. However, a sham-controlled follow-up study with a larger sample size is required to confirm the findings.

Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy.

OBJECTIVE: Limited data are available regarding the evolution over time of the rate of sudden unexpected death in epilepsy patients (SUDEP) in drug-resistant epilepsy. The objective is to analyze a database of 40 443 patients with epilepsy implanted with vagus nerve stimulation (VNS) therapy in the United States (from 1988 to 2012) and assess whether SUDEP rates decrease during the postimplantation follow-up period. METHODS: Patient vital status was ascertained using the Centers for Disease Control and Prevention's National Death Index (NDI). An expert panel adjudicated classification of cause of deaths as SUDEP based on NDI data and available narrative descriptions of deaths. We tested the hypothesis that SUDEP rates decrease with time using the Mann-Kendall nonparametric trend test and by comparing SUDEP rates of the first 2 years of follow-up (years 1-2) to longer follow-up (years 3-10). RESULTS: Our cohort included 277 661 person-years of follow-up and 3689 deaths, including 632 SUDEP. Primary analysis demonstrated a significant decrease in age-adjusted SUDEP rate during follow-up (S = -27 P = .008), with rates of 2.47/1000 for years 1-2 and 1.68/1000 for years 3-10 (rate ratio 0.68; 95% confidence interval [CI] 0.53-0.87; P = .002). Sensitivity analyses confirm these findings. SIGNIFICANCE: Our data suggest that SUDEP risk significantly decreases during long-term follow-up of patients with refractory epilepsy receiving VNS Therapy. This finding might reflect several factors, including the natural long-term dynamic of SUDEP rate, attrition, and the impact of VNS Therapy. The role of each of these factors cannot be confirmed due to the limitations of the study.

Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A randomized, double-blind, sham-controlled ACT2 study.

Background Clinical observations and results from recent studies support the use of non-invasive vagus nerve stimulation (nVNS) for treating cluster headache (CH) attacks. This study compared nVNS with a sham device for acute treatment in patients with episodic or chronic CH (eCH, cCH). Methods After completing a 1-week run-in period, subjects were randomly assigned (1:1) to receive nVNS or sham therapy during a 2-week double-blind period. The primary efficacy endpoint was the proportion of all treated attacks that achieved pain-free status within 15 minutes after treatment initiation, without rescue treatment. Results The Full Analysis Set comprised 48 nVNS-treated (14 eCH, 34 cCH) and 44 sham-treated (13 eCH, 31 cCH) subjects. For the primary endpoint, nVNS (14%) and sham (12%) treatments were not significantly different for the total cohort. In the eCH subgroup, nVNS (48%) was superior to sham (6%; p < 0.01). No significant differences between nVNS (5%) and sham (13%) were seen in the cCH subgroup. Conclusions Combing both eCH and cCH patients, nVNS was no different to sham. For the treatment of CH attacks, nVNS was superior to sham therapy in eCH but not in cCH. These results confirm and extend previous findings regarding the efficacy, safety, and tolerability of nVNS for the acute treatment of eCH.

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.

Chronic vagus nerve stimulation reverses heart rhythm complexity in patients with drug-resistant epilepsy: An assessment with multiscale entropy analysis.

OBJECTIVE: Vagus nerve stimulation (VNS) is an adjunctive treatment in drug-resistant epilepsy. The alterations in heart rate dynamics through VNS are not well understood. This study aimed to determine changes in heart rhythm complexity in association with VNS and to relate the findings to the outcome of VNS treatment in patients with drug-resistant epilepsy. METHODS: We prospectively analyzed 32 patients with drug-resistant epilepsy, who underwent VNS implantation, and 32 age- and sex-matched healthy control subjects. The interictal heartbeat intervals were analyzed using the heart rhythm complexity with multiscale entropy (MSE) and traditional heart rate variability (HRV) analyses based on ambulatory 24-hour electrocardiograms (ECGs). RESULTS: Patients had significantly decreased complexity indices (Slope 5, Area 1-5, Area 6-15, Area 6-20) on MSE analysis and decreased HRV measurements (standard deviation of the heartbeat interval (SDNN), square root of the mean of sum of squares of the differences between adjacent RR intervals (RMSSD), pNN50, very low frequency (VLF), low frequency (LF), high frequency (HF), total power (TP)) in time and frequency domain analyses. After one year of VNS treatment in patients with drug-resistant epilepsy, there was a trend in an elevated MSE profile with significant higher values between the scales 1 and 9. Vagus nerve stimulation induces a more significant increase of MSE in VNS responders than those in the nonresponders. The conventional HRV measurements did not change. CONCLUSION: Our results suggest that heart rhythm complexity is impaired in patients with drug-resistant epilepsy, and this is at least partially reversed by VNS treatment. Furthermore, VNS-induced effects on heart rate complexity may be associated with the therapeutic response to VNS in patients with drug-resistant epilepsy.

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."

Vagal nerve stimulation for medically refractory epilepsy in Angelman syndrome: a series of three cases.

BACKGROUND: We describe three children with Angelman syndrome and medically refractory epilepsy. METHODS: Case series of three pediatric patients with Angelman syndrome and medically refractory epilepsy. All three patients failed medical treatment and were recommended for vagal nerve stimulator (VNS) implantation. RESULTS: Following VNS implantation, all three patients experienced reduction in seizure frequency greater than that afforded by medication alone. CONCLUSION: We present vagal nerve stimulator implantation as a viable treatment option for medically refractory epilepsy associated with Angelman syndrome.

Cluster headache: present and future therapy.

Cluster headache is characterized by severe, unilateral headache attacks of orbital, supraorbital or temporal pain lasting 15-180 min accompanied by ipsilateral lacrimation, rhinorrhea and other cranial autonomic manifestations. Cluster headache attacks need fast-acting abortive agents because the pain peaks very quickly; sumatriptan injection is the gold standard acute treatment. First-line preventative drugs include verapamil and carbolithium. Other drugs demonstrated effective in open trials include topiramate, valproic acid, gabapentin and others. Steroids are very effective; local injection in the occipital area is also effective but its prolonged use needs caution. Monoclonal antibodies against calcitonin gene-related peptide are under investigation as prophylactic agents in both episodic and chronic cluster headache. A number of neurostimulation procedures including occipital nerve stimulation, vagus nerve stimulation, sphenopalatine ganglion stimulation and the more invasive hypothalamic stimulation are employed in chronic intractable cluster headache.