Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial

Abstract

AED Antiepileptic drug VNS Vagus nerve stimulationAIM The aim of this study was to evaluate the effects of vagus nerve stimulation (VNS) in children with intractable epilepsy on seizure frequency and severity and in terms of tolerability and safety.METHOD In this study, the first randomized active controlled trial of its kind in children, 41 children (23 males; 18 females; mean age at implantation 11y 2mo, SD 4y 2mo, range 3y 10mo-17y 8mo) were included. Thirty-five participants had localization-related epilepsy (25 symptomatic; 10 cryptogenic), while six participants had generalized epilepsy (four symptomatic; two idiopathic). During a baseline period of 12 weeks, seizure frequency and severity were recorded using seizure diaries and the adapted Chalfont Seizure Severity Scale (NHS3), after which the participants entered a blinded active controlled phase of 20 weeks. During this phase, half of the participants received high-output VNS (maximally 1.75mA) and the other half received low-output stimulation (0.25mA). Finally, all participants received high-output stimulation for 19 weeks. For both phases, seizure frequency and severity were assessed as during the baseline period. Overall satisfaction and adverse events were assessed by semi-structured interviews.RESULTS At the end of the randomized controlled blinded phase, seizure frequency reduction of 50% or more occurred in 16% of the high-output stimulation group and in 21% of the low-output stimulation group (p=1.00). There was no significant difference in the decrease in seizure severity between participants in the stimulation groups. Overall, VNS reduced seizure frequency by 50% or more in 26% of participants at the end of the add-on phase The overall seizure severity also improved (p<0.001).INTERPRETATION VNS is a safe and well-tolerated adjunctive treatment of epilepsy in children.Our results suggest that the effect of VNS on seizure frequency in children is limited. However, the possible reduction in seizure severity and improvement in well-being makes this treatment worth considering in individual children with intractable epilepsy.Vagus nerve stimulation (VNS) is a neuromodulatory treatment that is used as an adjunctive therapy for individuals with medically refractory epilepsy who are not eligible for epilepsy surgery or in whom surgery has failed, and in whom non-epileptic events are excluded. VNS consists of chronic intermittent electrical stimulation of the vagus nerve, delivered by a programmable pulse generator (neurocybernetic prosthesis [NCP]; Cyberonics Inc, Webster, TX, USA).Randomized active controlled trials, which have predominantly included adults, have demonstrated the safety and efficacy of VNS: 1,2 seizure frequency decreased by more than 50% in 23 to 31% of individuals in the treatment groups compared with 13 to 15% in the placebo group. These trials led to the U.S. Food and Drug Administration approval in 1997 of the use of VNS as adjunctive therapy in individuals older than 12 years with partial epilepsy refractory to treatment with...

Not all that glitters is gold: A guide to surgical trials in epilepsy

“…All were carried out in patients with drug‐resistant epilepsy, although the extent of epilepsy characterization was variable across studies: two studies evaluated patients with drug‐resistant mesial TLE,12, 34 five specified “partial” or “focal” epilepsy in their study criteria,11, 14, 18, 32, 33 one targeted adults with malformations of cortical development,13 and the rest required only “medically refractory seizures,” including two that explicitly included patients with generalized epilepsy 6, 17. Several RCTs (5/12) evaluated VNS (whether implanted9, 14, 17, 31, 32 or transcutaneous6). Two evaluated HS (implanted34 or transcranial12), and the rest individually evaluated CS,35 TNS,11 rTMS,13 thalamic stimulation,33 and RNS 10, 16, 18.…”

“…Since then, open‐label extensions of these trials and multiple observational studies have reported further reductions in seizure frequency fueling support for the use of this device 7, 8, 36. However, the one available pediatric RCT17 did not show a seizure control benefit to VNS (responder rate of 16% in high‐ vs. 21% in low‐output stimulation), and the one prospective RCT comparing VNS to medical therapy, rather than comparing high to low settings of stimulation as done previously, did not show any difference in seizure frequency or responder rates between the treatment and control arms 32. Complications of VNS placement included hoarseness (30%), dyspnea (13%), and infection (12%) 14, 31.…”

“…The lack of comparative effectiveness data, particularly among studies that used heterogeneous populations (including some generalized epilepsy6, 17 or no description of epilepsy phenotype9), limits the ability to define the ideal device for a given patient.…”

“…Resective epilepsy surgery, in appropriately selected patients, is the accepted treatment of choice for DRE as supported by two randomized clinical trials,3, 4 multiple retrospective cohort series, and a practice parameter issued by the American Academy of Neurology recommending a surgical evaluation for any patient with uncontrolled disabling complex partial seizures 5. Similarly, a plethora of nonresective yet surgical DRE treatments have flourished recently, including various neuromodulation procedures6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and thermal‐based19 and radiation‐based neurosurgeries 20. A position statement by the Practice Management Committee Health Care Reform Workgroup of the American Epilepsy Society called for access and insurance coverage for all patients with epilepsy for more aggressive therapeutic strategies, including neurosurgery and implanted electronic devices, when medications fail to yield optimal seizure control 21.…”

A Review of Neuromodulation in the Neurorehabilitation

“…Management of patients who have recurrent seizures and did not respond to medication or surgery is challenging. A number of double-blind randomized controlled trials have confirmed the therapeutic effects of Vagus Nerve Stimulation [VNS] for epilepsy [66][67][68][69]. A recent European long-term study [n=347] showed a 50% reduction in seizure frequency for up to 43.8% of patients [66].…”