CQ 10-1

Should vagus nerve stimulation therapy be added to drug therapies for drug-resistant temporal lobe epilepsy?

Recommendation

We suggest to add vagus nerve stimulation to drug therapies (GRADE 2D) (weak recommendation, very low level of evidence).

• Supplementary note: In principle, vagus nerve stimulation is considered for patients with no indication for curative surgery. Implantation of the vagus nerve stimulation device involves surgery under general anesthesia in an experienced hospital. After implantation, the patients need to be followed in the hospital where operation was performed or other facilities, by experts with experience in stimulator control.

1. Background, priority of the problem

In patients with drug-resistant epilepsy in whom seizures are not controlled even after trials of two appropriate antiepileptic drugs, further addition of drugs has only limited effect. Vagus nerve stimulation added to antiepileptic drug therapy is expected to provide additive effect of seizure frequency reduction. Because vagus nerve stimulation is less invasive and has lower seizure control effect compared to brain surgery with craniotomy, it may be selected as a treatment option in patients with no indication for curative neurosurgery.

2. Comment

Evidence summary

Only one randomized controlled trial (RCT) examined the effectiveness of vagus nerve stimulation for drug-resistant epilepsy¹⁾. We therefore considered to use observational studies together. However, because outcomes of those studies, such as reduced seizure frequency and mood change, are susceptible to placebo effect, we determined to use a single RCT.

Regarding efficacy, the relative risk for 50% seizure frequency reduction was 1.34 (95% confidence interval 0.59‒3.04), and NNT (number needed to treat: indicating the number of persons needed to treat to achieve the outcome for one person) was 25. As for mood changes, there were no significant differences between the intervention group and control group in the scores for several scales: QOLIE-89 (89-item Quality of Life in Epilepsy Inventory), CES-D (Center for Epidemiologic studies Depression scale), and NDDI-E (Neurological Disorders Depression Inventory in Epilepsy scale). Regarding mood changes, the only scale showing a statistically significant difference was the 7-point evaluation scale CGI-I (Clinical Global Impression of Impression Important Scale), but the difference was only 0.5 (95% confidence interval 0.99‒0.01), showing a small effect. For serious adverse events, vocal cord paralysis and brief respiratory arrest occurred only in the intervention group, but were transient with no sequelae. There was no significant difference in the adverse event of dysphonia between the intervention group and the control group.

It should be noted that the selected RCT was prematurely terminated by the sponsor due to a low recruitment rate, because many study candidates did not accept randomization of the treatment. Therefore, the study may be underpowered for detection of the outcome.

3. Panel meeting

3-1. What is the overall quality of evidence across outcomes?

In the study reviewed, the risk of bias was high overall, which was judged as serious for all the outcomes, and was downgraded by one rank. The inconsistency of results was not downgraded because of only one study used. The indirectness was judged as not serious and without any problems. As for imprecision, the confidence intervals in many analyses crossed the clinical decision threshold, and it was hence downgraded by one or two ranks. As for publishing bias, there was only one study, and therefore was not downgraded. Consequently, the level of evidence for the outcomes was as follows: “very low” for seizure frequency ≤ 50%, serious adverse events, and dysphonia; and “low” for the other outcomes. The overall level of evidence was “very low”.

3-2. What is the balance between benefits and harms?

Since there was only one RCT, the certainty of the effect estimate was low, and it was difficult to consider the balance between benefits and harms.

3-3. What about patients’ values and preferences?

The importance of outcomes has great inter-individual differences, and it should be diverse, It should be noted that some patients place importance on the reduction of seizure frequency, while others regard the risk of adverse effects to be more important.

3-4. What is the balance between net benefit and cost or resources?

The electrode implantation for VNS surgery is conducted under general anesthesia. Vagus nerve stimulation is covered by health insurance, and the health insurance fee scale for implantation is 24,350 points, and that for exchange is 4,800 points (as of January 11, 2018). The reoperation should be done once every few years for replacement of the power generator because of degradation of the condenser. Considering the effectiveness for refractory epilepsy and the above-mentioned factors, the cost was judged to be moderate.

3-5. Recommendation grading

During the discussions at the panel meeting, considering the moderate burden and cost, and the few alternative treatment options available, the panelists concluded that it was reasonable to use this treatment method despite a certain amount of harm, burden and cost. The unanimous decision was “to propose implementing vagus nerve stimulation for drug-resistant epilepsy”. As an additional consideration, the patients’ families at the panel meeting expressed the following opinion: “We desire to overcome social constraints. If there is any method at all, please include it as one of the options.”

4. Descriptions in other related guidelines

In Japan, the “Practice guideline of vagus nerve stimulation therapy for epilepsy”²⁾ was published by the Japan Epilepsy Society in 2012, which states that “VNS has accommodative effect on drug-resistant epileptic seizures [recommendation grade A]”. Also, the American Academy of Neurology released a guideline update entitled “Vagus nerve stimulation for the treatment of epilepsy” in 2013. This guideline update describes the possibilities of the effectiveness of vagus nerve stimulation appearing several years after VNS operation, the effectiveness in children [rate of > 50% seizure reduction: 55% (95% confidence interval 50‒59%)], and an increased risk of infection in children compared to adults [odds ratio 3.4 (95% confidence interval 1.0‒11.2)].

According to the guidelines in Japan and overseas and the recommendation from the ILEA, the indication for vagus nerve stimulation is in principle patients who have no indication for curative neurosurgery^2-4).

5. Treatment monitoring and evaluation

Vagus nerve stimulation treatment requires adjustment of the stimulation conditions, management of complications, and solving equipment troubles. Epilepsy specialists or doctors trained by the specialists should perform monitoring and evaluation after the operation based on specialist knowledge.

6. Possibility of future research

The RCT reviewed for this CQ had high risk of bias. Therefore, it is desirable to have more RCTS with better quality. In addition, research focusing on how to identify good responders and the effects on status epilepticus is needed in the future.

7. RCT report reviewed for this CQ

Ryvlin 2014¹⁾

8. List of appendices (to be shown later)

Appendix CQ10-1-01. Flow diagram and literature search formula

Appendix CQ10-1-02. Risk of bias summary

Appendix CQ10-1-03. Risk of bias graph

Appendix CQ10-1-04. Forest plot

Appendix CQ10-1-05. Summary of Findings (SoF) table

Appendix CQ10-1-06. Evidence-to-Decision table

▪ References

1) Ryvlin P, Gilliam FG, Nguyen DK, et al. The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. Epilepsia. 2014; 55(6): 893-900.

2) Kawai K, Sugai K, Akamatsu N, et al. Guideline on implementation of vagus nerve stimulation therapy for epilepsy. Tenkan Kenkyu. 2012; 30(1): 68-72 (in Japanese).

3) Morris GL 3rd, Gloss D, Buchhalter J, et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013; 81(16): 1453-1459.

4) Cross JH, Jayakar P, Nordli D, et al. Proposed criteria for referral and evaluation of children for epilepsy surgery: recommendations of the Subcommission for Pediatric Epilepsy Surgery. Epilepsia. 2006; 47(6): 952-959.