Vagus nerve stimulation for partial seizures

Epilepsy is a disorder where unexpected electrical discharges from the brain cause seizures. Most seizures can be controlled by a single antiepileptic drug but sometimes seizures do not respond to drugs. Some people require more than one antiepileptic medication to control their seizures, especially if these originate from one area of the brain (partial epilepsy), instead of involving the whole brain.

The vagus nerve stimulator (VNS) is a device that is useful as an additional treatment for epilepsy that does not respond well to drugs, and only affects one part of the brain. The device is connected to the vagus nerve in the neck, and sends mild electrical impulses to it. This is particularly important for treating people whose epilepsy does not respond well to drugs and who are not eligible for epilepsy surgery, or in whom surgery was not successful in reducing frequency of seizures. The aim of this systematic review was to look at the current evidence on how effective vagus nerve stimulation is in reducing frequency of epileptic seizures and any side effects associate with using the device.

Overall the five multi-centre randomised controlled trials (RCTs) recruited a total of 439 participants and between them compared different types of VNS therapy. Overall there were three randomised controlled trials which compared high frequency stimulation to low frequency stimulation in participants aged 12-60 years and another trial examined high frequency stimulation versus low frequency stimulation in children. Additionally, one trial examined three different stimulation frequencies.

The review of these trials found that vagus nerve stimulation is effective, when used with one or more antiepileptic drugs, to reduce the number of seizures for people whose epilepsy does not respond to drugs alone. Common side effects were voice alteration and hoarseness, pain, shortness of breath, cough, feeling sickly, tingling sensation, headache or infection at the site of the operation, with shortness of breath, voice alteration and hoarseness more common in people receiving high frequency stimulation compared to people receiving low level stimulation.

Out of the five included studies, two studies were rated individually as being of high quality and the other three studies were rated as being of unclear quality due to lack of reported information in the study paper about the methods of study design. The evidence for the effectiveness and side effects of VNS therapy was limited and imprecise from the small number of studies included in this review, so was rated as being of moderate to low quality. Further large, high quality studies are required to provide more information about the effectiveness and side effects of VNS therapy.

Authors' conclusions: 

VNS for partial seizures appears to be an effective and well tolerated treatment in 439 included participants from five trials. Results of the overall efficacy analysis show that VNS stimulation using the high stimulation paradigm was significantly better than low stimulation in reducing frequency of seizures. Results for the outcome "withdrawal of allocated treatment" suggest that VNS is well tolerated as withdrawals were rare. No significant difference was found in withdrawal rates between the high and low stimulation groups, however limited information was available from the evidence included in this review so important differences between high and low stimulation cannot be excluded . Adverse effects associated with implantation and stimulation were primarily hoarseness, cough, dyspnea, pain, paresthesia, nausea and headache, with hoarseness and dyspnea more likely to occur on high stimulation than low stimulation. However, the evidence on these outcomes is limited and of moderate to low quality. Further high quality research is needed to fully evaluate the efficacy and tolerability of VNS for drug resistant partial seizures.

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Background: 

Vagus nerve stimulation (VNS) is a neuromodulatory treatment that is used as an adjunctive therapy for treating people with medically refractory epilepsy. VNS consists of chronic intermittent electrical stimulation of the vagus nerve, delivered by a programmable pulse generator. The majority of people given a diagnosis of epilepsy have a good prognosis, and their seizures will be controlled by treatment with a single antiepileptic drug (AED), but up to 20%-30% of patients will develop drug-resistant epilepsy, often requiring treatment with combinations of AEDs. The aim of this systematic review was to overview the current evidence for the efficacy and tolerability of vagus nerve stimulation when used as an adjunctive treatment for people with drug-resistant partial epilepsy. This is an updated version of a Cochrane review published in Issue 7, 2010.

Objectives: 

To determine:

(1) The effects on seizures of VNS compared to controls e.g. high-level stimulation compared to low-level stimulation (presumed sub-therapeutic dose); and
(2) The adverse effect profile of VNS compared to controls e.g. high-level stimulation compared to low-level stimulation.

Search strategy: 

We searched the Cochrane Epilepsy Group's Specialised Register (23 February 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 23 February 2015), MEDLINE (1946 to 23 February 2015), SCOPUS (1823 to 23 February 2015), ClinicalTrials.gov (23 February 2015) and ICTRP (23 February 2015). No language restrictions were imposed.

Selection criteria: 

The following study designs were eligible for inclusion: randomised, double-blind, parallel or crossover studies, controlled trials of VNS as add-on treatment comparing high and low stimulation paradigms (including three different stimulation paradigms - duty cycle: rapid, mid and slow) and VNS stimulation versus no stimulation or a different intervention. Eligible participants were adults or children with drug-resistant partial seizures not eligible for surgery or who failed surgery.

Data collection and analysis: 

Two review authors independently selected trials for inclusion and extracted data. The following outcomes were assessed: (a) 50% or greater reduction in total seizure frequency; (b) treatment withdrawal (any reason); (c) adverse effects; (d) quality of life; (e) cognition; (f) mood. Primary analyses were intention-to-treat. Sensitivity best and worst case analyses were also undertaken to account for missing outcome data. Pooled Risk Ratios (RR) with 95% confidence intervals (95% Cl) were estimated for the primary outcomes of seizure frequency and treatment withdrawal. For adverse effects, pooled RRs and 99% CI's were calculated.

Main results: 

Five trials recruited a total of 439 participants and between them compared different types of VNS stimulation therapy. Baseline phase ranged from 4 to 12 weeks and double-blind treatment phases from 12 to 20 weeks in the five trials. Overall, two studies were rated as having a low risk of bias and three had an unclear risk of bias due to lack of reported information around study design. Effective blinding of studies of VNS is difficult due to the frequency of stimulation-related side effects such as voice alteration; this may limit the validity of the observed treatment effects. Four trials compared high frequency stimulation to low frequency stimulation and were included in quantitative syntheses (meta-analyses).The overall risk ratio (95% CI) for 50% or greater reduction in seizure frequency across all studies was 1.73 (1.13 to 2.64) showing that high frequency VNS was over one and a half times more effective than low frequency VNS. For this outcome, we rated the evidence as being moderate in quality due to incomplete outcome data in one included study; however results did not vary substantially and remained statistically significant for both the best and worst case scenarios. The risk ratio (RR) for treatment withdrawal was 2.56 (0.51 to 12.71), however evidence for this outcome was rated as low quality due to imprecision of the result and incomplete outcome data in one included study. The RR of adverse effects were as follows: (a) voice alteration and hoarseness 2.17 (99% CI 1.49 to 3.17); (b) cough 1.09 (99% CI 0.74 to 1.62); (c) dyspnea 2.45 (99% CI 1.07 to 5.60); (d) pain 1.01 (99% CI 0.60 to 1.68); (e) paresthesia 0.78 (99% CI 0.39 to 1.53); (f) nausea 0.89 (99% CI 0.42 to 1.90); (g) headache 0.90 (99% CI 0.48 to 1.69); evidence of adverse effects was rated as moderate to low quality due to imprecision of the result and/or incomplete outcome data in one included study. No important heterogeneity between studies was found for any of the outcomes.

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