Clinical and economic impact of vagus nerve stimulation therapy in patients with drug-resistant epilepsy

We evaluated long-term medical and economic benefits of vagus nerve stimulation (VNS) therapy in drug-resistant epilepsy. A pre-post analysis was conducted using multistate Medicaid data (January 1997-June 2009). One thousand six hundred fifty-five patients with one or more neurologist visits with epilepsy diagnoses (ICD-9 345.xx, 780.3, or 780.39), one or more procedures for vagus nerve stimulator implantation, one or more antiepileptic drugs (AEDs), and 6 or more months of continuous Medicaid enrollment pre- and post-VNS were selected. The pre-VNS period was 6 months. The post-VNS period extended from implantation to device removal, death, Medicaid disenrollment, or study end (up to 3 years). Incidence rate ratios (IRRs) and cost differences ($2009) were estimated. Mean age was 29.4 years. Hospitalizations decreased post-VNS compared with pre-VNS (adjusted IRR=0.59, P<0.001). Grand mal status events decreased post-VNS compared with pre-VNS (adjusted IRR=0.79, P<0.001). Average total health care costs were lower post-VNS than pre-VNS ($18,550 vs $19,945 quarterly, P<0.001). VNS is associated with decreased resource utilization and epilepsy-related clinical events and net cost savings after 1.5 years.     

Outcome measurement after vagal nerve stimulation therapy: proposal of a new classification

PURPOSE: Vagal nerve stimulation (VNS) is an adjunctive palliative therapy for refractory epilepsy. Effects of treatment are varied and some, such as the use of an external magnet for seizure termination, are unique to VNS. No accepted standard exists for outcome measurement after VNS treatment. We present a novel classification for outcome, which includes assessment of both seizure frequency and severity in VNS-treated patients. METHODS: We devised a classification system modeled on the Engel classification for surgically treated patients, but tailored for use in VNS therapy, which incorporates five classes of outcome. We retrospectively reviewed VNS-treated patients in our centre, and used the data to illustrate our system and compare it with the Engel model. RESULTS: With this system, 48 patients (mean age, 30 years) were followed up over a median of 18 months. Seventy-eight percent had partial epilepsy. Sixteen and a half percent experienced class I outcome (>80% seizure-frequency reduction). Twenty percent had class II improvement (50-79% seizure-frequency reduction). One-third had no improvement (class V). The remaining patients comprised class III (seizure-frequency reduction <50%) or class IV (magnet benefit alone) outcomes. Class I-III outcomes were further subdivided according to effects on ictal or postictal severity. CONCLUSIONS: We propose a new classification, which can be used for all epilepsies and which reflects outcome measures beyond seizure-frequency reduction alone. Use of this system would allow greater comparison between future studies of VNS therapy.     

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.     

Long-term outcome of vagus nerve stimulation for refractory partial epilepsy

We assessed 1- and 2-year outcomes of specific seizure types, quality of life, depression, and anxiety among patients treated with vagus nerve stimulation (VNS) for refractory partial epilepsy. Patients completed a seizure questionnaire, the Quality of Life in Epilepsy-89 (QOLIE-89) questionnaire, the Beck Anxiety Inventory (BAI), and the Beck Depression Inventory (BDI) at baseline and 1 year, and 2 years after activation of VNS. VNS was associated with >or=50% reduction in total seizure frequency in 54% of patients at 1 year and 61% of patients 2 years post-VNS activation compared with baseline. No statistically significant changes from baseline to 12 or 24 months were found in mean quality of life, depression, or anxiety measures in the overall study population. Patients with at least 50% reduction in seizures had significant improvement in anxiety at 12 and 24 months compared with patients who did not have the same degree of seizure reduction.     

Vagus nerve stimulation for treatment of epilepsy in Rett syndrome

This case series presents the outcomes of seven females with Rett syndrome and medically refractory epilepsy who were treated with adjunctive vagus nerve stimulation (VNS) therapy for a minimum of 12 months. Patients ranged in age from 1 to 14 years (median age 9 y) at the time of implantation, had experienced seizures for a median period of approximately 6 years, and had failed at least two trials of antiepileptic drugs before receiving VNS. The median number of seizures per month was 150 (range 12-3600). At 12 months, six females had >or=50% reduction in seizure frequency. VNS was safe and well tolerated, with no surgical complications and no patients requiring explantation of the device. Quality of life outcomes of note among these patients included reports at 12 months of increased alertness among all seven patients. No change in mood or communication abilities was noted.     

Outcomes of vagal nerve stimulation in a pediatric population: A single center experience

ObjectiveTo evaluate the efficacy of vagus nerve stimulation (VNS) in pediatric patients with medically refractory epilepsy.MethodWe reviewed the medical records of 252 consecutive patients who underwent VNS implantation at a single center over a 5-year period. Patients with complete 6- and 12-month follow-up data were included. Analysis was also done across various subgroups including gender, age at implantation, seizure type, abnormal MRI findings pre-implantation, number of medications at baseline, history of SE, and duration of epilepsy.ResultsComplete follow-up data were available for 69 patients. Median seizure reduction for these patients was 50% (Q1: 0%; Q3: 73%) at 6 months and 40% (Q1: −25%; Q3: 75%) at 12 months. When stratified by baseline seizure frequency, there was a significant reduction from baseline of 61% at 6 months and 69% at 12 months for patients in the high-baseline frequency group. There were no significant reductions at month 6 or 12 months for the lower-baseline frequency group. Adverse events were reported in 40.6% (28 out of 69 patients). Six patients had the VNS removed for reasons including lack of efficacy and side effects and were excluded from the study group.ConclusionVNS provides significant seizure reduction, in particular in pediatric patients with a higher baseline seizure frequency.     

Vagus nerve stimulation for medication-resistant generalized epilepsy. E04 VNS Study Group

We treated 24 generalized epilepsy patients with vagus nerve stimulation (VNS), comparing seizure rates during a 1-month baseline with 3 months of VNS. Median seizure rate reduction was -46%. Sixteen of the 24 patients had better than a -30% reduction and 11 of the 24 patients had better than a -50% reduction in seizure rate. A mild cough during stimulation occurred in six patients. Patients with higher baseline seizure rates and later ages at epilepsy onset had the best responses to VNS. Our findings suggest VNS is an effective treatment for medication-resistant generalized epilepsy even in patients as young as 4 years.     

Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05

OBJECTIVE: To perform an open-label, long-term efficacy and safety/tolerability study of vagus nerve stimulation (VNS) of 454 patients with refractory epilepsy. METHODS: Subjects were enrolled from five clinical trials of VNS between 1988 and 1995 after undergoing an implantation of a pulse generator in the chest and a left cervical vagus nerve-stimulating lead coil. Patients were assessed at 6-month intervals until device approval. Seizure frequencies, medication treatment, and adverse events (AEs) were recorded and entered into a database. RESULTS: A total of 454 patients were implanted, and 440 patients yielded assessable data. A > or =50% seizure reduction postimplantation occurred in 36.8% of patients at 1 year, in 43.2% at 2 years, and in 42.7% at 3 years. Median seizure reductions compared with baseline were 35% at 1 year, 44.3% at 2 years, and 44.1% at 3 years. Most common AEs postimplantation at 1 year were hoarseness (28%) and paraesthesias (12%), at 2 years were hoarseness (19.8%) and headache (4.5%), and at 3 years was shortness of breath (3.2%). Continuation rates were 96.7% at 1 year, 84.7% at 2 years, and 72.1% at 3 years. CONCLUSION: Long-term, open-label vagus nerve stimulation (VNS) provided seizure reduction similar to or greater than acute studies, for median reductions and for those reaching a > or =50% seizure reduction. VNS remained safe and well tolerated, with nearly three-quarters of the patients choosing to continue therapy.     

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.     

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.     

Long-term vagus nerve stimulation in the treatment of Lennox–Gastaut syndrome

The long-term effects of vagus nerve stimulation (VNS) on seizure frequency were studied in 30 patients with Lennox–Gastaut syndrome. Median observation time was 52 months (17–123). The effect parameters investigated were total number of seizures and different seizure types. The median reduction in number of seizures was 60.6%. The effects of VNS varied considerably between seizure types. Best effects were observed with atonic seizures (80.8% median reduction, number of responders: 8/12), followed closely by tonic seizures (73.3% median reduction, number of responders: 8/13). Least effects were with generalized tonic–clonic seizures (median reduction 57.4%, number of responders: 11/20). Additional positive effects included milder or shorter ictal or postictal phase in 16 patients. Improved alertness was reported in 76.7%. Adverse effects, of which drooling and voice alteration were most frequent, were reported in 20 patients. There was a statistically significant reduction in the median number of antiepileptic drugs used. The discontinuation rate was 16.7%.     

Outcome of vagus nerve stimulation for drug‐resistant epilepsy: the first three years of a prospective Japanese registry

Aims. Vagus nerve stimulation (VNS) is an established option of adjunctive treatment for patients with drug‐resistant epilepsy, however, evidence for long‐term efficacy is still limited. Studies on clinical outcomes of VNS in Asia are also limited. We report the overall outcome of a national, prospective registry that included all patients implanted in Japan. Methods. The registry included patients of all ages with all seizure types who underwent VNS implantation for drug‐resistant epilepsy in the first three years after approval of VNS in 2010. The registry excluded patients who were expected to benefit from resective surgery. Efficacy analysis was assessed based on the change in frequency of all seizure types and the rate of responders. Changes in cognitive, behavioural and social status, quality of life (QOL), antiepileptic drug (AED) use, and overall AED burden were analysed as other efficacy indices. Results. A total of 385 patients were initially registered. Efficacy analyses included data from 362 patients. Age range at the time of VNS implantation was 12 months to 72 years; 21.5% of patients were under 12 years of age and 49.7% had prior epilepsy surgery. Follow‐up rate was >90%, even at 36 months. Seizure control improved over time with median seizure reduction of 25.0%, 40.9%, 53.3%, 60.0%, and 66.2%, and responder rates of 38.9%, 46.8%, 55.8%, 57.7%, and 58.8% at three, six, 12, 24, and 36 months of VNS therapy, respectively. There were no substantial changes in other indices throughout the three years of the study, except for self/family‐accessed QOL which improved over time. No new safety issues were identified. Conclusions. Although this was not a controlled comparative study, this prospective national registry of Japanese patients with drug‐resistant epilepsy, with >90% follow‐up rate, indicates long‐term efficacy of VNS therapy which increased over time, over a period of up to three years. The limits of such trials, in terms of AED modifications and during follow‐up and difficulties in seizure counting are also discussed.     

Successful outcome of episodes of status epilepticus after vagus nerve stimulation: a multicenter study

Background and purpose: Vagus nerve stimulation (VNS) has been reported to be a safe and effective treatment for drug-resistant epilepsy. The aim of this study is to describe the effect of VNS in patients with a history of repeated episodes of status epilepticus (SE) before implantation. Methods: From a total of 83 adult patients with drug-resistant epilepsy who had VNS implanted in four tertiary centers in Spain between 2000 and 2010, eight had a previous history of repeated episodes of SE. We performed a retrospective observational study analyzing the outcome of seizures and episodes of SE after implantation. Stimulation was started at the usual settings, and intensity increased according to clinical response and tolerability. Results: Regarding the eight patients with a history of SE, the mean age at time of VNS implantation was 25.1 [14-40] years. Duration of epilepsy until the implantation was 21.7 [7-39.5] years, and they had been treated with a mean of 12 antiepileptic drugs [10-16]. Mean follow-up since implantation was 4.15 [2-7.5] years. Average seizure frequency decreased from 46 to 8.2 per month. Interestingly, four of the eight patients remained free of new episodes of SE after implantation, and in two additional patients, the frequency decreased by >75%. Adverse effects were mild or moderate in intensity and included mainly coughing and dysphonia. Conclusion: In those patients with refractory epilepsy and history of SE who are not surgical candidates, VNS is a safe and effective method to reduce seizure frequency and episodes of SE.     

Vagal nerve stimulation for refractory epilepsy in children: indications and experience at The Hospital for Sick Children

Objectives The management of intractable epilepsy in children is a challenging problem. For those patients who do not respond to antiepileptic drugs and are not candidates for epilepsy surgery, vagal nerve stimulation (VNS), can be a viable alternative for reducing seizure frequency. We have reviewed the historical and clinical background of VNS treatment. We also include our experience at The Hospital for Sick Children in children who underwent VNS implantation.Methods Forty-one children underwent VNS implantation for epilepsy over 6 years. After a mean follow-up of 31 months, 15 (38%) patients had a seizure frequency reduction of more than 90%. Fifteen (38%) children failed to respond to the VNS treatment. The device was removed in five children: in one, due to late infection; the other four could not tolerate the side effects of chronic VNS therapy. Two patients required reimplantation due to electrode failure. The most common side effects in our series were cough and vocal disturbances.Conclusions Our results show that VNS implantation can be a safe and effective alternative therapy for children with drug-resistant epilepsy who are not candidates for epilepsy surgery.     

迷走神经刺激对癫痫患者生活质量影响的临床研究

目的评估迷走神经刺激对癫痫患者生活质量的影响。方法 14例药物难治性全身性癫痫患者进行迷走神经刺激术治疗,比较其术前及术后癫痫患者生活质量量表-31(QOLIE-31)评分的变化。结果平均随访12月,患者发作频率平均减少61.0%,其中5例发作频率减少<50%,6例发作频率减少≥50%,3例发作停止。癫痫患者生活质量量表总分从术前的50.5上升至术后的57.1,平均增加6.6(P=0.0276)。各个分量表中得分均有一定程度增加,其中认知功能、情绪两项改善有统计学意义。癫痫患者生活质量量表总分及7个分量表得分改善与发作减少均无相关性。结论迷走神经刺激是一种治疗药物难治性癫痫安全、有效的方法。其作用不仅体现在癫痫发作的减少,对生活质量也有一定的改善作用。而且这两者之间无相关性,提示生活质量改善是迷走神经刺激独立的临床疗效评价指标之一。     

Vagus nerve stimulation in children with refractory epilepsy: unusual complications and relationship to sleep-disordered breathing

Background Vagus nerve stimulation (VNS) is approved for use in patients with refractory epilepsy over the age of 12 years. While this procedure is widely used, there is little data on adverse events in young children. Materials and methods A retrospective chart review was conducted on 26 children who had VNS implantation for refractory epilepsy from 1998 to 2004. Results Ages ranged from 3 to 17 years (16 boys and 10 girls). Seventy-seven percent had moderate to severe mental retardation. Sixty-five percent had more than 30 seizures per month. Symptomatic-generalized epilepsy was the predominant epilepsy syndrome seen in 77% of children. The duration of VNS treatment ranged from 1 month to 8 years (mean = 3.5 years). Twenty of 26 patients (77%) were on rapid-cycling mode. More than 50% reduction in seizure frequency was noted in 54% with two patients achieving seizure freedom. Twenty-three percent had less than 50% seizure reduction. Four patients were able to terminate seizures with use of the magnet. VNS was removed from one patient because of intractable cough persisting in spite of stimulation being turned off for 1 month. Another patient had it removed twice for infection. Obstructive sleep apnea (OSA) was observed in four patients (15%) after placement of VNS. Conclusion VNS appears to be an effective treatment for children with refractory epilepsy. Development of intractable cough in one patient in spite of device being turned off and recurrent infection-related removal in another are unusual complications. Polysomnography before implantation of VNS should be considered to identify patients with pre-existing OSA. This work was presented as an abstract at the American Epilepsy Society Meetings in Washington, DC, 2–6 December 2005. S. Neff, deceased during publication of this article.     

Effect of vagus nerve stimulation on adults with pharmacoresistant generalized epilepsy syndromes.

INTRODUCTION: Although vagus nerve stimulation (VNS) therapy is approved for the treatment of partial onset seizures, its efficacy for generalized seizures has not been fully evaluated. This Investigational Device Exemption assessed the outcome of VNS therapy among patients with generalized epilepsy syndromes. METHODS: Sixteen patients with pharmacoresistant generalized epilepsy syndromes and stable antiepileptic drug (AED) regimens were implanted with the VNS therapy device and were evaluated for changes in seizure frequency and type between baseline and follow-up of 12-21 months. RESULTS: The patients experienced a statistically significant overall median seizure frequency reduction of 43.3% (P = 0.002, Wilcoxon signed rank test) after 12-21 months of VNS therapy. Types of seizures that may involve a fall or collapse decreased with reductions in the frequency of myoclonic (60% reduction, n = 9; P = 0.016, Wilcoxon signed rank test), tonic (75% reduction, n = 8, NS), atonic (98.6%, n = 3, NS), and clonic seizures (86.7%, n = 1, NS). Conclusion: The benefits of reduced seizure frequency and reduced risk of injury merit consideration of VNS therapy for patients with pharmacoresistant generalized seizure syndromes.     

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.     

Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures

PURPOSE: To determine the long-term efficacy of vagus nerve stimulation (VNS) for refractory seizures. VNS is a new treatment for refractory epilepsy. Two short-term double-blind trials have demonstrated its safety and efficacy, and one long-term study in 114 patients has demonstrated a cumulative improvement in efficacy at 1 year. We report the largest prospective long-term study of VNS to date. METHODS: Patients with six or more complex partial or generalized tonic-clonic seizures enrolled in the pivotal EO5 study were prospectively evaluated for 12 months. The primary outcome variable was the percentage reduction in total seizure frequency at 3 and 12 months after completion of the acute EO5 trial, compared with the preimplantation baseline. Subjects originally randomized to low stimulation (active-control group) were crossed over to therapeutic stimulation settings for the first time. Subjects initially randomized to high settings were maintained on high settings throughout the 12-month study. RESULTS: The median reduction at 12 months after completion of the initial double-blind study was 45%. At 12 months, 35% of 195 subjects had a >50% reduction in seizures, and 20% of 195 had a >75% reduction in seizures. CONCLUSIONS: The efficacy of VNS improves during 12 months, and many subjects sustain >75% reductions in seizures.