Long-term outcome of vagus nerve stimulation therapy in patients with refractory epilepsy.

We retrospectively assessed the long-term efficacy of vagus nerve stimulation (VNS) therapy in 31 patients with refractory partial and generalized seizures who were not candidates for resective epilepsy surgery. Following implantation of VNS there was significant improvement in seizure frequency at 6 months. Sixteen patients continued to have sustained response to VNS therapy 4 years later. Adverse effects of VNS therapy were transient and tolerable. The majority of the patients did not gain body weight and some of them had significant weight loss. Therefore VNS is safe and effective therapy and has a long-term sustained effect in refractory epilepsy.     

Long-term results of vagus nerve stimulation in refractory epilepsy.

Vagus nerve stimulation (VNS) is an adjunctive antiepileptic treatment for patients with refractory epilepsy. Limited information on long-term treatment with VNS is available. The purpose of this paper is to present our experience with VNS with a follow-up of up to 4 years. Twenty-five patients (13 females and 12 males) with refractory partial epilepsy were treated with VNS. The first 15 patients with a mean age of 30 years and a mean duration of epilepsy of 17.5 years have sufficient follow-up for analysis. Mean post-implantation follow-up was 29 months and mean stimulation output 2.25 mA. There was a mean seizure frequency reduction from 14 complex partial seizures (CPS) per month before implantation to 8 CPS per month after implantation (P = 0.0016; Wilcoxon signed-rank rest (WSRT)). The mean maximum CPS-free interval changed from 9 to 312 days (P = 0.0007; WSRT). Six patients were free of CPS for at least one year. In one patient, one antiepileptic drug (AED) was tapered; in 10 patients, AEDs remained unchanged; in four, one adjunctive AED was administered. Side effects occurred in six patients, three of whom required a temporary reduction of output current. Nine patients reported no side effects at all. Treatment with VNS remains effective in the long-term. In this series 4 / 15 (27%) patients with highly refractory epilepsy experienced entirely seizure-free intervals of 12 months or more.     

Cost-benefit of vagus nerve stimulation for refractory epilepsy

PURPOSE: Vagus nerve stimulation (VNS) is an established treatment for patients with medically refractory epilepsy who are unsuitable candidates for conventional epilepsy surgery. VNS requires an initial financial investment but apart from our own previous study there are no reports on cost-benefit published to date. The purpose of this paper is to assess prospectively the cost-benefit ratio of VNS in a series of patients with long term follow-up. METHODS: Our experience with VNS comprises 25 patients of whom 20 with sufficient follow-up will be further discussed. These 20 patients have a mean post-implantation follow-up of 26 months (range: 6-50 months). Mean age was 30 years (range: 12-45 years); mean duration of epilepsy 17 years (range: 5-35 years). We prospectively assessed seizure frequency, prescribed AEDs, number of hospital admission days and side effects and calculated the epilepsy related direct medical cost and compared this with pre-implantation data. RESULTS: Mean seizure frequency decreased from 14 seizures/month (range: 2-40) to 9 seizures/month (range: 0-30) (p = 0.0003). The mean yearly epilepsy related direct medical costs per patient dropped from 6,682 USD (range: 829-21,888 USD) to 3,635 USD (range: 684-12,486 USD) (p = 0.0046). The mean number of hospital admission days was reduced from 16 days/year (range: 0-60) to 4 days/year (range: 0-30) (p = 0.0029). CONCLUSION: VNS is an efficacious and cost-beneficial treatment for refractory partial seizures.     

Programmed and magnet-induced vagus nerve stimulation for refractory epilepsy.

Vagus nerve stimulation (VNS) is an effective alternative treatment for patients with refractory epilepsy. The generator produces intermittent stimulation trains and does not require patient intervention. Using currently available technology, continuous stimulation is incompatible with a reasonable battery life. Because earlier studies have demonstrated the persistence of a stimulation effect after discontinuation of the stimulation train, we intended to evaluate the clinical efficacy of VNS in both the programmed intermittent stimulation mode and the magnet stimulation mode. Patients, companions, and caregivers were instructed on how to administer additional stimulation trains when an aura or a seizure onset occurred. We assumed that patients or caregivers could recognize habitual seizures and were able to evaluate sudden interruption of these seizures. During a mean follow-up of 35 months, 46% of patients became responders, with a reduction in seizure frequency of more than 50%. Twenty-nine percent of patients stopped having convulsive seizures. In two thirds of patients who were able to self-administer or receive additional magnet stimulation, seizures could be interrupted consistently or occasionally. More than half of the patients who reported a positive effect of magnet stimulation became responders. Only three patients were able to use the magnet themselves. In most cases, support from caregivers was necessary. This study is the first to document the efficacy of magnet-induced VNS in a larger patient population during long-term follow-up. The magnet is a useful tool that provides patients who are treated with VNS and mainly caregivers of such patients with an additional means of controlling seizures. To further confirm the self-reported results from our patients, additional studies comparing programmed stimulation and magnet-induced stimulation during monitoring conditions are needed.     

迷走神经刺激术在难治性癫痫领域的临床进展

迷走神经刺激术(vagus nerve stimulation,VNS)是通过躯体性刺激治疗神经-精神疾病的一种方法.自1883年以来,许多学者对VNS的抗癫痫作用进行了研究,最终认为VNS是治疗难治性癫痫的新途径[1-3].1997年7月VNS首次通过美国食品药物管理局(FDA)认证,用于成人和年龄大于12岁青少年癫痫的辅助治疗.目前为止全球已经有超过100 000的患者接受了VNS治疗[4].     

Long-term follow-up of 37 patients with refractory partial seizures treated with vagus nerve stimulation

Stimulation of the vagus nerve for the treatment of refractory seizures of partial onset has been studied in two pilot studies and one randomized, blinded, parallel study. Results from the controlled study have been promising, but more information is required regarding the long-term safety and efficacy of vagus nerve stimulation. A cohort of the first 37 patients to finish the controlled study was examined on a long-term basis. The response of patients at 1 year and 18 months of stimulation revealed that efficacy does not decrease over time. The system is well-tolerated, and no major adverse events occurred with long-term exposure to the stimulation. Normal device end of service occurred in a majority of the patients, with most choosing to have their generators replaced. This analysis demonstrates that stimulation of the vagus nerve for the treatment of refractory epilepsy manifested by seizures of partial onset continues to be safe and effective over extended periods of time.     

Right-sided vagus nerve stimulation as a treatment for refractory epilepsy in humans

PURPOSE: We present three children who underwent right-sided vagus nerve stimulation (R-VNS). This treatment option for people with refractory epilepsy has not been described in children. METHODS: We reviewed our database of >350 patients implanted with vagus nerve stimulators and now describe our experience in three patients with R-VNS for the treatment of intractable seizures. All three patients improved dramatically with left-sided vagus nerve stimulation (L-VNS), but the devices had to be removed because of infection. The patients were thought to be at high risk for nerve injury if they were reapproached for L-VNSs; therefore R-VNSs were implanted. RESULTS: All three patients with an R-VNS had a reduction in seizures. Our first patient has had an R-VNS for 5 years; he has been seizure free for >2 years on R-VNS monotherapy. The second patient had an R-VNS for 8 months. His seizure control improved slightly, but not as dramatically as with L-VNS. The third child has had an R-VNS for >7 months and has cessation of his most disabling seizure type (generalized tonic-clonic seizures). None of the patients had cardiac side effects from therapeutic R-VNS. However, two of the three patients had respiratory events with R-VNS. CONCLUSIONS: VNS is known to be an effective treatment in pharmacoresistant epilepsy. R-VNS should be considered if a patient has significant benefit from L-VNS but is unable to continue with L-VNS. R-VNS appears also to have antiepilepsy effects. Additionally, our case report suggests that in some patients, a differential response is found regarding seizure control with R-VNS or L-VNS, raising the question whether L-VNS failures should pursue a trial of R-VNS. Patients should be cautioned and monitored for reactive airway disease if they undergo R-VNS. More research is needed to compare the effects of right- and left-sided VNS on cardiac and pulmonary function in humans and to determine which has the best antiseizure effect.     

Long-term seizure and psychosocial outcomes of vagus nerve stimulation for intractable epilepsy

Vagus nerve stimulation (VNS) is a widely used adjunctive treatment option for intractable epilepsy. Most studies have demonstrated short-term seizure outcomes, usually for up to 5 years, and thus far, none have reported psychosocial outcomes in adults. We aimed to assess long-term seizure and psychosocial outcomes in patients with intractable epilepsy on VNS therapy for more than 15 years. We identified patients who had VNS implantation for treatment of intractable epilepsy from 1997 to 2013 at our Comprehensive Epilepsy Program and gathered demographics including age at epilepsy onset and VNS implantation, epilepsy type, number of antiepilepsy drugs (AEDs) and seizure frequency before VNS implantation and at the last clinic visit, and the most recent stimulation parameters from electronic medical records (EMR). Phone surveys were conducted by research assistants from May to November 2014 to determine patients' current seizure frequency and psychosocial metrics, including driving, employment status, and use of antidepressants. Seizure outcomes were based on modified Engel classification (I: seizure-free/rare simple partial seizures; II: > 90% seizure reduction (SR), III: 50–90% SR, IV: < 50% SR; classes I to III (> 50% SR) = favorable outcome). A total of 207 patients underwent VNS implantation, 15 of whom were deceased at the time of the phone survey, and 40 had incomplete data for medical abstraction. Of the remaining 152, 90 (59%) were contacted and completed the survey. Of these, 51% were male, with the mean age at epilepsy onset of 9.4 years (range: birth to 60 years). There were 35 (39%) patients with extratemporal epilepsy, 19 (21%) with temporal, 18 (20%) with symptomatic generalized, 5 (6%) with idiopathic generalized, and 13 (14%) with multiple types. Final VNS settings showed 16 (18%) patients with an output current > 2 mA and 14 (16%) with rapid cycling. Of the 80 patients with seizure frequency information, 16 (20%) had a modified Engel class I outcome, 14 (18%) had class II, 24 (30%) had class III, and 26 (33%) had class IV. Eighty percent said having VNS was worthwhile. Among the 90 patients, 43 patients were ≥ 18 years old without developmental delay in whom psychosocial outcomes were further analyzed. There was a decrease in the number of patients driving (31% vs 14%, p = 0.052) and working (44% vs 35%, p = 0.285) and an increase in the number of patients using antidepressant medication (14% vs 28%, p = 0.057) at the time of survey compared to before VNS. In this subset, patients with > 50% SR (60%) were taking significantly fewer AEDs at the time of survey compared to patients with unfavorable outcomes (median: 3 vs 4, p = 0.045). The associations of > 50% SR with the psychosocial outcomes of driving, employment, and antidepressant use were not significant, although 77% of this subset said VNS was worthwhile.This is the first study that assesses both seizure and psychosocial outcomes, and demonstrates favorable seizure outcomes of > 50% SR in 68% of patients and seizure freedom in 20% of patients. A large majority of patients (80%) considered VNS therapy worthwhile regardless of epilepsy type and psychosocial outcomes.     

Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to 5 years

We assessed the long-term efficacy of vagus nerve stimulation (VNS) in 64 refractory epilepsy patients. After implantation, intermittent stimulation was delivered and seizure frequency and severity were counted. Average treatment time was 20 months. Nineteen of 47 patients with partial seizures, five of nine patients with idiopathic generalized seizures, and five of eight patients with Lennox-Gastaut syndrome had >50% seizure reduction. Side effects were mild. VNS is a safe and effective treatment for refractory epilepsy.     

Animal models for vagus nerve stimulation in epilepsy

Vagus nerve stimulation (VNS) is a moderately effective adjunctive treatment for patients suffering from medically refractory epilepsy and is explored as a treatment option for several other disorders. The present review provides a critical appraisal of the studies on VNS in animal models of seizures and epilepsy. So far, these studies mostly applied short-term VNS in seizure models, demonstrating that VNS can suppress and prevent seizures and affect epileptogenesis. However, the mechanism of action is still largely unknown. Moreover, studies with a clinically more relevant setup where VNS is chronically applied in epilepsy models are scarce. Future directions for research and the application of this technology in animal models of epilepsy are discussed.     

Long-term results with vagus nerve stimulation in children with pharmacoresistant epilepsy.

PURPOSE: To retrospectively review our experience with VNS in pediatric patients with pharmacoresistant epilepsy and examine the seizure-frequency outcome and rates of discontinuation in two age groups: adolescent and pre-adolescent children. RESULTS: Complete pre- and post-VNS data were available for 46/49 patients. Median age at implantation was 12.1 (range 2.3-17.9) and median duration of epilepsy 8.0 (1.9-16.9) years. Twenty-one patients (45.6%) were under 12 years at the time of surgery. Median follow-up was 2 years; follow-up exceeded 4 years in 9/46 patients. As compared to baseline, median seizure-frequency reduction in the setting of declining numbers was 56% at 3 months, 50% at 6, 63% at 12, 83% at 24 and 74% at 36 months. When a last observation carried forward analysis was employed median seizure-frequency reduction in the range of 60% was observed at 1, 2 and 3 years post-VNS. Twenty patients (43.5%) had >75% seizure-frequency reduction. No response (increase or <50% reduction) was observed in 19/46 (41.3%). Five patients (10.1%) were seizure-free for more than 6 months by their last follow-up. There was no difference in the number of AEDs used before and after VNS. The long-term discontinuation rate was 21.7% and reflected a lack of clinical response or infection. CONCLUSIONS: In this series VNS was well-tolerated and effective as add-on therapy for refractory seizures in children of all ages. Response was even more favorable in the younger group (<12 years at implantation). Infection and lack of efficacy were the most common reasons for discontinuation of long-term VNS therapy in this group.     

Long-term results of vagus nerve stimulation in children and adolescents with drug-resistant epilepsy

Purpose  

The purpose of this study was to evaluate long-term seizure reduction and on-demand magnet use in children and adolescents with drug-resistant epilepsy who were treated with vagus nerve stimulation therapy.     

Acute blood flow changes and efficacy of vagus nerve stimulation in partial epilepsy

OBJECTIVE: To determine possible sites of therapeutic action of vagus nerve stimulation (VNS), by correlating acute VNS-induced regional cerebral blood flow (rCBF) alterations and chronic therapeutic responses. BACKGROUND: We previously found that VNS acutely induces rCBF alterations at sites that receive vagal afferents and higher-order projections, including dorsal medulla, somatosensory cortex (contralateral to stimulation), thalamus and cerebellum bilaterally, and several limbic structures (including hippocampus and amygdala bilaterally). METHODS: VNS-induced rCBF changes were measured by subtracting resting rCBF from rCBF during VNS, using [O-15]water and PET, immediately before ongoing VNS began, in 11 partial epilepsy patients. T-statistical mapping established relative rCBF increases and decreases for each patient. Percent changes in frequency of complex partial seizures (with or without secondary generalization) during three months of VNS compared with pre-VNS baseline, and T-thresholded rCBF changes (for each of the 25 regions of previously observed significant CBF change), were rank ordered across patients. Spearman rank correlation coefficients assessed associations of seizure-frequency change and t-thresholded rCBF change. RESULTS: Seizure-frequency changes ranged from 71% decrease to 12% increase during VNS. Only the right and left thalami showed significant associations of rCBF change with seizure-frequency change. Increased right and left thalamic CBF correlated with decreased seizures (p < 0.001). CONCLUSIONS: Increased thalamic synaptic activities probably mediate some antiseizure effects of VNS. Future studies should examine neurotransmitter-receptor alterations in reticular and specific thalamic nuclei during VNS.     

Vagus nerve stimulation for refractory epilepsy.

Vagus nerve stimulation (VNS) is a neurophysiological treatment for patients with medically or surgically refractory epilepsy. Since the first human implant in 1989, more than 10 000 patients have been treated with VNS. Two randomized controlled studies have shown a statistically significant decrease in seizure frequency during a 12-week treatment period versus a baseline period when 'high stimulation' mode was compared with 'low stimulation' mode. The efficacy appears to increase over time. In general, one third of the patients show a >50% reduction of seizure frequency; one third show a 30-50% seizure reduction, and one third of patients show no response. Few patients become seizure-free. Side effects during stimulation are mainly voice alteration, coughing, throat paraesthesia and discomfort. When studied on a long-term basis, VNS is an efficacious, safe and cost-effective treatment not only in adults but also in children and the elderly. The precise mechanism of action remains to be elucidated. In recent years much progress has been made through neurophysiological, neuroanatomical, neurochemical and cerebral blood flow studies in animals and patients treated with VNS. Further elucidation of the mechanism of action of VNS may increase its clinical efficacy and our general understanding of some physiopathological aspects of epilepsy. Finally, VNS may become an alternative treatment for other conditions such as depression and pain.     

迷走神经刺激术早期不同程控方案在儿童难治性癫痫中的应用效果

目的通过比较迷走神经刺激术(VNS)早期不同程控方案在儿童难治性癫痫中的应用效果和安全性,寻找最佳早期程控方案。方法回顾性分析首都儿科研究所附属儿童医院神经外科2016年8月至2018年12月行VNS治疗的54例难治性癫痫患儿的临床资料。根据术后程控方案的刺激电流幅度,分为低参数组(≤1 mA,28例)和高参数组(>1 mA,26例)。术后6个月行临床随访,对比两组的治疗有效率和治疗相关并发症的发生率。结果VNS治疗6个月,54例患儿的无发作率为13.0%(7/54),总体有效率为66.7%(36/54)。其中低参数组的有效率(82.1%,23/28)高于高参数组(50.0%,13/26)(χ^2=6.268,P=0.012)。54例患者术后总体并发症的发生率为7.4%(4/54)。低参数组治疗相关并发症的发生率(0%)与高参数组(15.4%,4/26)之间的差异无统计学意义(χ^2=4.652,P=0.102)。结论VNS是治疗儿童难治性癫痫的有效手段,相对于高参数程控方案,患儿可能从低参数程控方案获益更多。     

Acute single photon emission computed tomographic study of vagus nerve stimulation in refractory epilepsy

PURPOSE: Left-sided vagus nerve stimulation (VNS) is an efficacious treatment for patients with refractory epilepsy. The precise mechanism of action remains to be elucidated. Only limited data on VNS-induced changes in regional cerebral blood flow (rCBF) are available. The aim of this study was to investigate rCBF changes during initial VNS with single-photon emission computed tomography (SPECT). METHODS: In 12 patients (8 women, 4 men) with mean age of 32 years and mean duration of epilepsy of 19 years, VNS-induced rCBF changes were studied by means of a 99mTc-ethyl cysteinate dimer activation study with a single-day split-dose protocol before and immediately after initial stimulation. Images were acquired on a triple-head camera with fan-beam collimators and were reconstructed with scatter and attenuation correction. After coregistration to a standardized template, both a semiquantitative analysis using predefined volumes-of-interest (VOIs) as well as voxel-by-voxel analysis of the intrasubject activation were performed. During follow-up, efficacy of VNS in terms of seizure-frequency reduction was studied. RESULTS: The semiquantitative analysis, with reference to the total counts in all VOIs, revealed a significant decrease of activity in the left thalamus immediately after the initial stimulation train. These results agreed with voxel-by-voxel analysis. In our study ipsilateral thalamic hypoperfusion was the most significant finding. Mean frequency of complex partial seizures was reduced from 30 per month before implantation to six per month after implantation. CONCLUSIONS: VNS induces rCBF changes immediately after initial stimulation that can be studied with SPECT. VNS-induced changes in the thalamus may play an important role in suppression of seizures. However, no significant relation between the level of hypoperfusion and subsequent clinical efficacy was found.     

The mechanism of action of vagus nerve stimulation for refractory epilepsy: the current status.

Vagus nerve stimulation (VNS) is a neurophysiologic treatment for patients with medically or surgically refractory epilepsy. Since the first human implant in 1989, more than 10,000 patients have been treated with VNS. The precise mechanism of action remains to be elucidated. Animal experiments with VNS were initially performed to demonstrate efficacy and safety preceding the clinical trials in human patients. Mechanism of action research involving animal experiments can provide essential clues. Animal experiments are often labor-intensive even in the hands of experienced researchers, however, and the results remain only a reflection of the complicated pathophysiologic systems of the human brain. Mechanism of action research in human patients treated with VNS is particularly challenging because of safety concerns, the large number of patients required, and the heterogeneous nature of various small patient series. This study provides an overview of the progress that has been made in the past 10 years through neurophysiologic, neuroanatomic, neurochemical, and cerebral blood flow studies in animals and patients treated with VNS. Further elucidation of the mechanism of action of VNS may increase its clinical efficacy. It may also provide inspiration for the development of new therapeutic modalities for refractory epilepsy.