Vagus nerve stimulation in children with refractory seizures associated with Lennox-Gastaut syndrome

PURPOSE: Vagus nerve stimulation (VNS) is approved for use for refractory partial seizures. Nevertheless, information regarding VNS therapy for special populations, including Lennox-Gastaut syndrome (LGS) is limited. We discuss the effectiveness, tolerability, and safety of VNS therapy in patients with LGS. METHODS: A six-center, retrospective study evaluated the effectiveness of VNS therapy in patients with LGS at 3 and 6 months and compared preimplant and postimplant seizure frequency. Adverse effects and quality of life (QOL) were included as secondary measures. RESULTS: Fifty patients, median age 13 years, with medically refractory epilepsy, were implanted. Median age at onset of seizures was 1.4 years, and a median of nine anticonvulsants (AEDs) had been tried before implantation. Data-collection forms were designed for retrospectively gathering data on each patient's preimplant history, seizures, implants, device settings, QOL, and adverse events. Median reductions in total seizures were 42% at 1 month, 58.2% at 3 months, and 57.9% at 6 months. The most common adverse events reported were voice alteration and coughing during stimulation. Other uncommon adverse events included increased drooling and behavioral changes. Investigators noted that QOL had improved for some patients in the study. CONCLUSIONS: VNS is an effective treatment for medically refractory epilepsy in LGS. This treatment is well tolerated, safe, and may improve QOL.     

迷走神经刺激术治疗五例顽固性癫痫及其随访研究

寻求顽固性癫痫的有效治疗方法。方法用迷走神经刺激术治疗５例顽固性癫痫患者，并进行１年的随访。结果４例患者的癫痫发作频率较术前减少５０％以上；另１例为失张力伴强直－阵挛发作，失张力发作无明显改变，但１年中未见强直－阵挛发作。所有患者的发作强度均有所减轻，持续时间缩短。迷走神经刺激术后血浆抗癫痫药物浓度未见明显改变。５例中４例患者的脑电图所见较术前有明显改进，表现为原有的棘波、尖波消失，阵发性异常消失或时间缩短；另１例脑电图改变不明显。５例患者除在植于体内脉冲发生器刺激时感到喉部有轻微震动感和声音略有低哑外，未见有其他副作用。心电图均正常。结论迷走神经刺激术治疗顽固性癫痫安全并可有一定效果，但其确切疗效仍有待于进一步研究。     

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].     

迷走神经刺激治疗药物难治性癫痫的随访研究（附62例分析）

目的研究迷走神经刺激治疗药物难治性癫痫的疗效。方法回顾性分析62例接受迷走神经刺激（vNs）治疗的药物难治性癫痫患者的临床资料。通过患者来院或电话对患者的发作频率、持续时间和生活质量等进行随访。结果62例患者,失访5例,1例患者刺激时间小于2个月未纳入统计范围,对接受迷走神经刺激治疗3～40个月的56例患者进行统计分析,McHughⅠ级22例（39．3％）,Ⅱ级16例（28．6％）,Ⅲ级13例（23．2％）,Ⅳ级＋Ⅴ级5例（8．9％）。其中3例（5．4％）术后无发作,38例（67．9％）发作减少50％以上。结论迷走神经刺激是治疗药物难治性癫痫安全、有效的方法。VNS刺激时间和刺激参数可能是影响其对药物难治性癫痫疗效的重要因素,随刺激时间延长疗效增加。     

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.     

迷走神经刺激术治疗顽固性癫痫初步探讨

目的 探讨迷走神经刺激术治疗顽固性癫痫的治疗效果.方法 对21例顽固性癫痫患者进行迷走神经刺激手术治疗,术后2周开机,分次调试参数,脉冲发生器输出电流从0.25 mA逐渐增加,但不超过3.0 mA,刺激时间为30 s,间歇5 min,信号频率为20～30 Hz,脉宽为250～1000μs.对治疗效果进行随访,分析治疗效果.结果 经4-16个月刺激,McHugh Ⅰ级3例,Ⅱ级7例,Ⅲ级9例,Ⅴ级2例.其中10例患者癫痫发作减少50%以上.结论 迷走神经刺激术治疗顽固性癫痫是一种相对安全、有效的治疗方法 .     

Efficacy and long-term tuning parameters of vagus nerve stimulation in long-term treated depressive patients

Vagus nerve stimulation (VNS) is a promising neurostimulation tool for the treatment of treatment-resistant depression. Here, we report the effects of positive remission rates and tuning parameters in a group of 18 (6 female, 12 male, mean age 54) long-term treated patients.Treatment varied between 3 and 200 months (mean 104.9 months). Mean stimulation intensity was 1.46 mA, ranging from 0.5 to 2.0 mA and high-frequency stimulation of 20–25 Hz (mean 23.61 Hz).The remission rates in our study population clearly indicate ongoing positive effects of VNS and highlight stimulation tunings between 0.5 and 2.0 mA and 20–25 Hz as best dosage for achieving remittance in long-term treatment of VNS.     

迷走神经刺激术治疗药物难治性癫痫的初步研究

目的 探讨迷走神经刺激术治疗药物难治性癫痫的方法及效果. 方法 回顾性分析上海交通大学医学院附属仁济医院神经外科自2007年1月至2011年1月收治的14例药物难治性、全身性癫痫患者临床资料,其中脑炎后继发癫痫6例,外伤后继发癫痫3例,原因不明5例,所有患者均行左侧迷走神经刺激术治疗.术后3周内开机,初始刺激参数为:刺激电流0.25 mA,频率30 Hz,刺激时间30 s,间歇时间5 min,脉宽500 μs.刺激电流强度以0.25 mA为一调整单位逐渐递增,并综合其他参数调控以到达满意疗效. 结果 随访3月以上,14例患者术后发作频率平均减少63.6％,其中3例发作频率减少＜50％,11例发作频率减少≥50％,6例发作频率减少＞80％,2例发作停止.5例患者使用磁铁后发作控制得到改善. 结论 迷走神经刺激术是一种治疗药物难治性癫痫有效、安全的方法,对全身性癫痫发作患者同样有效.     

Cardiac autonomic control in patients with refractory epilepsy before and during vagus nerve stimulation treatment: a one-year follow-up study

PURPOSE: To elucidate possible effect of vagus nerve stimulation (VNS) therapy on interictal heart rate (HR) variability in patients with refractory epilepsy before and after 1-year VNS treatment. METHODS: A 24-hour electrocardiogram (ECG) was recorded at the baseline and after 12 months of VNS treatment in 14 patients with refractory epilepsy, and once in 28 healthy age- and sex-matched control subjects. Time and frequency domain measures, along with fractal and complexity measures of HR variability, were analyzed from the ECG recordings. RESULTS: The mean value of the RR interval (p=0.008), standard deviation of N-N intervals (SDNN) (p<0.001), very-low frequency (VLF) (p<0.001), low-frequency (LF) (p=0.001), and high-frequency (HF) (p=0.002) spectral components of HR variability, and the Poincaré components SD(1) (p=0.005) and SD(2) (p<0.001) of the patients with refractory epilepsy were significantly lower than those of the control subjects before VNS implantation. The nocturnal increase in HR variability usually seen in the normal population was absent in patients with refractory epilepsy. VNS had no significant effects on any of the HR-variability indexes despite a significant reduction in the frequency of seizures. CONCLUSIONS: HR variability was reduced, and the nocturnal increase in HR variability was not present in patients with refractory epilepsy. One-year treatment with VNS did not have a marked effect on HR variability, suggesting that impaired cardiovascular autonomic regulation is associated with the epileptic process itself rather than with recurrent seizures.     

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.     

迷走神经刺激术治疗药物难治性癫痫的价值

尽管目前癫痫的药物治疗已取得较大进展,但仍有20％～30％的患者对癫痫药物治疗反应差,部分癫痫发作难以有效控制,即所谓的药物难治性癫痫。癫痫病灶切除术是治疗药物难治性癫痫的有效方法,但并非所有患者均能找到确切病灶,而且部分患者手术后效果不佳。1988年,迷走神经刺激术(vagus nerve stimulation,VNS)开始应用于治疗药物难治性部分性癫痫,为药物难治性癫痫提供了一种新的治疗方法。     

Vagus nerve stimulation for the treatment of bilateral independent temporal lobe epilepsy

PURPOSE: We studied the effect of vagus nerve stimulation (VNS) on seizure reduction in patients with intractable epilepsy with bilateral independent temporal lobe foci. METHODS: Ten patients who met the criterion of the presence of two distinctive clinical and ictal EEG seizure patterns were identified and followed up for 1 year. RESULTS: Six patients had >50% reduction in their seizure frequency that persisted up to > or =1 year of follow-up, whereas four patients reported small or no reduction in their partial seizures. CONCLUSIONS: VNS is often effective and well tolerated in this select group of intractable epilepsy patients.     

A retrospective analysis of the effects of magnet-activated stimulation in conjunction with vagus nerve stimulation therapy

Vagus nerve stimulation (VNS) therapy offers two methods to help control seizures, automatic stimulation delivered at programmed intervals and on-demand stimulation initiated with a magnet. This study retrospectively analyzes magnet use during the E03 and E04 clinical trials of VNS therapy. Magnet activation that aborted, decreased, terminated, or diminished a seizure was classified as an improvement; for purposes of evaluation, the patient was considered to have received a benefit. When patients in the E03 trial used magnets to activate stimulation, patients with active magnets were more likely to report seizure improvement than patients with inactive magnets (P=0.0479, Fisher's test). In the E04 trial, 22% of patients using the magnet reported seizure termination and 31% reported seizure diminution. Unrelated to seizure reduction with programmed VNS therapy, approximately half of the patients who used the magnet in this study received some benefit. Additional studies can provide a better understanding of this unique mode of delivering antiseizure therapy.     

Clinically-derived vagus nerve stimulation enhances cerebrospinal fluid penetrance

IntroductionVagus nerve stimulation (VNS) is an FDA-approved neuromodulatory treatment used in the clinic today for epilepsy, depression, and cluster headaches. Moreover, evidence in the literature has led to a growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood. In parallel, the glymphatic and meningeal lymphatic systems have recently been described as methods by which the brain maintains a healthy homeostasis and removes waste without a traditionally defined lymphatic system. In particular, the glymphatic system relates to the interchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) whose net effect is to wash through the brain parenchyma removing metabolic waste products and misfolded proteins.Objective/HypothesisAs VNS has well-documented effects on many of the pathways recently linked to the clearance systems of the brain, we hypothesized that VNS could increase CSF penetrance in the brain.MethodsWe injected a low molecular weight lysine-fixable fluorescent tracer (TxRed-3kD) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following an application of a clinically-derived VNS paradigm (30 Hz, 10% duty cycle).ResultsWe found that the clinical VNS group showed a significant increase in CSF tracer penetrance as compared to the naïve control and sham groups.Conclusion(s): This study demonstrates that VNS therapeutic strategies already being applied in the clinic today may induce intended effects and/or unwanted side effects by altering CSF/ISF exchange in the brain. This may have broad ranging implications in the treatment of various CNS pathologies.     

Efficacy of vagus nerve stimulation as a treatment for medically intractable epilepsy in brain tumor patients. A case-controlled study using the VNS therapy Patient Outcome Registry

PurposeVagus nerve stimulation (VNS) therapy is a procedure to control seizure frequency in patients with medically intractable epilepsy. However, there is no data on efficacy in the subset of these patients with brain tumors. The purpose of this study is to evaluate the efficacy of VNS therapy in patients with brain tumor-associated medically intractable epilepsy.MethodsData from the VNS therapy Patient Outcome Registry, maintained by the manufacturer of the device, Cyberonics Inc. (Houston, TX, USA), was queried to characterize the response of patients in whom a brain tumor was listed as the etiology of epilepsy. A case–control analysis was implemented and patient outcome was measured by Engel classification, median seizure response and responder rate (≥50% seizure reduction) using t-tests and chi-squared tests.ResultsIn 107 patients with an epilepsy etiology related to a brain tumor, seizure reduction was 45% at 3 months and 79% at 24 months with a responder rate of 48% at 3 months and 79% at 24 months. There was no statistical difference in seizure reduction compared with 326 case–control patients from the registry without brain tumors. There was no significant difference in anti-epileptic drug (AED) usage from baseline to 24 months post implant in either group.ConclusionsVNS therapy is equally effective in patients who suffer seizures secondary to brain tumors as in patients without history of a brain tumor. VNS therapy is a viable treatment option for patients with brain tumor associated medically intractable epilepsy, assuming cytoreductive and other adjuvant therapies have been fully explored.     

迷走神经刺激对药物难治性癫痫大鼠脑内多药耐药蛋白过表达的抑制作用

目的 主要研究迷走神经刺激(VNS)对癫痫大鼠脑内多药耐药蛋白(P-gp)表达的调控作用.方法 采用氯化锂-匹鲁卡品制备颞叶癫痫大鼠,苯巴比妥钠(PB)诱导建立药物难治性癫痫(RE)大鼠模型.在此模型基础上,大鼠按随机数字表顺序分为四组:单纯VNS(A)组、VNS+ PB(B)组、假VNS+PB(C)组、生理盐水(D)组.VNS组行刺激电极植入术,通过改进的VNS参数(频率30 Hz,波宽500μs,电流0.75 mA,刺激时间30 s,间歇5min,12 h/d)进行电刺激,观察各组大鼠VNS前后发作次数,检测各组P-gp表达含量的变化.结果 (1)A、B组癫痫平均发作次数分别减少79.6％和85.9％,C、D组无明显改善;(2)B组P-gp过表达量与C组相比差异有统计学意义(P＜0.05),A组P-gp表达量较D组差异有统计学意义(P＜0.05).结论 VNS疗法可以有效降低RE的发作次数,对由药物引起的P-gp的过表达具有较强的抑制作用,与药物联合应用可以达到较好的治疗效果.     

Cerebral activation during vagus nerve stimulation: a functional MR study

PURPOSE: To study the short-term effects of vagus nerve stimulation (VNS) on brain activation and cerebral blood flow by using functional magnetic resonance imaging (fMRI). METHODS: Five patients (three women, two men; mean age, 35.4 years) who were treated for medically refractory epilepsy with VNS, underwent fMRI. All patients had a nonfocal brain MRI. The VNS was set at 30 Hz, 0.5-2.0 mA for intervals of activation of 30 s on and 30 s off, during which the fMRI was performed. Statistical parametric mapping (SPM) was used to determine significant areas of activation or inhibition during vagal nerve stimulation (p < 0.05). RESULTS: VNS-induced activation was detected in the thalami bilaterally (left more than right), insular cortices bilaterally, ipsilateral basal ganglia and postcentral gyri, right posterior superior temporal gyrus, and inferomedial occipital gyri (left more than right). The most robust activation was seen in the thalami (left more than right) and insular cortices. Conclusions: VNS-induced thalamic and insular cortical activation during fMRI suggests that these areas may play a role in modulating cerebral cortical activity, and the observed decrease in seizure frequency in patients who are given VNS may be a consequence of this increased activation.     

Effects of vagus nerve stimulation on progressive myoclonus epilepsy of Unverricht-Lundborg type

PURPOSE: A 34-year-old woman with progressive myoclonus epilepsy of Unverricht-Lundborg type was considered for vagus nerve stimulation (VNS) therapy. METHODS: After demonstration of intractability to multiple antiepileptic regimens and progressive deterioration in cerebellar function, the patient was implanted with a vagus nerve stimulator and followed for 1 year. Neurological status, seizure frequency, and parameter changes were analyzed. RESULTS: VNS therapy resulted in reduction of seizures (more than 90%) and a significant improvement in cerebellar function demonstrated on neurological examination. The patient reported improved quality of life based in part on her ability to perform activities of daily living. CONCLUSIONS: VNS therapy may be considered a treatment option for progressive myoclonus epilepsy. The effects of VNS on seizure control and cerebellar dysfunction may provide clues to the underlying mechanism(s) of action.     

Research progress of vagus nerve stimulation in the treatment of epilepsy

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