- Top of page
- What this paper adds
- Online Material/Supporting Information
- Supporting Information
Aim 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 available antiepileptic drugs (AEDs).
The effectiveness of VNS might be more variable in children than in adults. Numerous prospective and retrospective studies at various centres worldwide describing more than 650 children, aged 0 to 19 years, have reported a reduction in seizure frequency of more than 50% in 0 to 90%.3–28 However, these studies were uncontrolled, and there was a large variation in study groups, for example regarding age, epilepsy syndromes, and follow-up duration, which varied from 3 months to 10 years.
No randomized active controlled paediatric trial that unequivocally demonstrates the efficacy of VNS in children has yet been conducted. This study was carried out with the aim of evaluating the tolerability and effectiveness of VNS in children with intractable epilepsy. Moreover, we sought to identify responder characteristics that may improve future participant selection.
- Top of page
- What this paper adds
- Online Material/Supporting Information
- Supporting Information
This study is the first randomized active controlled study on the effectiveness of VNS in children. We observed no statistically significant difference in seizure frequency reduction and seizure severity when comparing high- and low-stimulation groups. However, both seizure frequency and seizure severity at the end of the add-on phase were significantly decreased compared with baseline. A reduction in seizure frequency of 50% or more was reached in nine out of 34 of the participants at the end of the add-on phase. There was a trend towards a significant correlation between age at onset and a favourable response to VNS. Strikingly, the completion rate and overall satisfaction were very high, as stimulation was discontinued in only one out of 41 participants, because of the lack of effect, and more than three-quarters of parents and guardians reported some kind of improvement.
Our results confirm previous reports demonstrating that VNS in children is safe when performed by experienced neurosurgeons: no major adverse events occurred and side effects of VNS were mild, mostly transient, and related to stimulation. Infection occurred in only two participants and was completely resolved with short-term antibiotics.
We were not able to demonstrate a favourable effect of high stimulation versus low stimulation, as has been observed in adult randomized trials.1,2 Several factors may account for this. First of all, the size of our population might have been too small. Owing to the lack of other randomized studies in children, the power analysis was based on open-label studies, which suggested a larger effect than in adults. According to the current results, future studies should include a larger study population. Second, there are differences in vagus nerve electrophysiology between adults and children: threshold currents are higher and conduction velocities are lower in younger children than in older children and adults, indicating that maturation of the vagus nerve is not yet complete in young children.33 Moreover, the developing brain may respond differently to VNS. De Herdt et al.34 additionally observed a lower efficacy of VNS in children than in adults.
Our results particularly contrast with the findings of Murphy,5 who reported a median seizure frequency reduction of 23% after 3 months of stimulation. This difference may be explained by differences in experimental design: Murphy5 included 41 participants from the Compassionate Protocol as well. As this protocol is uncontrolled, VNS effectiveness may have been overestimated. Indeed, several other studies observed no seizure frequency reduction in some of their study population7,8,11,12,22,24 or in the entire study population.26,27
In our study, seizure frequency reduction in the lower output group was higher than expected. A decrease in seizure frequency may have resulted from the natural fluctuation of the disease, which is probably higher in children than in adults.7(addendum) Indeed, children were twice as likely as adults to respond with a greater than 50% seizure frequency reduction during placebo treatment.35 Although active controlled treatment is not equivalent to placebo treatment, it is unlikely that low stimulation may yield a true effect, as previous studies have demonstrated that the chosen combination of current intensity and pulse width does not evoke an action potential.33,36
Overall, VNS reduced seizure frequency by 50% or more in nine out of 34 participants. It has been proposed that the effectiveness of VNS is influenced by several factors. First, it has been suggested that learning disability may be a negative predictor.20,26,37,38 As all but three of our participants had learning disabilities, this may have contributed to the modest effect of VNS in our study. The chosen stimulation parameters may also have affected VNS efficacy. In our study, the output current was no higher than 1.75mA during the blinded phase and 2.25mA during the add-on phase in order to prevent demyelination of the nerve, which can occur even at normal output currents (1.5mA, 250μs, 20Hz).39 It is unlikely that a further increase in output current would have resulted in a larger effect of VNS, as our results demonstrated that a higher output current was not correlated with a more favourable response. Furthermore, even a low output current (<1mA) can reduce seizure frequency in a substantial portion of participants.40 Moreover, we did not adjust the duty cycle to rapid cycling, that is, a mode of stimulation with a faster intermittent pulse stimulation. We presume that this did not influence seizure reduction significantly because several studies have shown that rapid cycling does not provide any additional persistent seizure control over normal cycling.10,41,42 We cannot exclude the possibility that a longer follow-up would have yielded different results. Some studies have suggested that a larger percentage of participants respond at longer follow-up,23,43,44 while others do not demonstrate an effect of longer stimulation.12,26 However, in our study the number of responders at the end of the add-on phase was not significantly different from that in the blinded period.
An increase in seizure severity in response to VNS was observed as well, just as described in the adult trials2,45 and in one retrospective and two prospective paediatric trials.4,7,10 This might be explained by the natural course of the disease, which is variable over time: in both of the participants described by Parker et al. (addendum)7 who experienced an initial increase in seizure frequency, seizure frequency returned to baseline level when follow-up duration was prolonged. In one out of the six participants described by Helmers et al.10 who experienced a more than 50% increase in seizure frequency after 3 months, the increased seizure frequency persisted after 6 months.
Several other studies have tried to identify a profile of responders. In line with the results of Patwardhan et al.,8 we found a trend towards a correlation between age at onset and response to VNS. According to Janzsky et al.,46 the absence of bilateral interictal epileptic discharges and the presence of malformation of cortical development were factors predicting a favourable outcome. In our responding group, seven out of nine participants in whom 50% or more seizure frequency reduction was achieved had bilateral interictal epileptic dischargers compared with 18 out of 25 non-responders. Only one of the participants with malformation of cortical development (n=8) had a 50% or more seizure frequency reduction. Callosotomy before VNS treatment was reported to be associated with a positive response,10,46 but this was not the case in our participant who had undergone a callosotomy.
Finally, it is important to realize that a moderate effect on seizure frequency does not signify low utility of VNS. After all, this population of participants is highly refractory. For comparison, only 3% of children with refractory epilepsy become seizure-free after the addition of a third AED.47 Furthermore, in contrast to the effect of AEDs, when children respond positively to VNS, this response is long-lasting.5,10,25,48 The benefits therefore might be of great value for the individual child with therapy-resistant epilepsy. This is especially true when the safety of the implantation procedure and favourable side-effect profile of VNS are taken into account. Moreover, irrespective of the (lack of) effect on seizure frequency, the possible reduction in seizure severity and improvement in well-being make this treatment worth considering.49,50