Part II
Systematic Review Digest

CQ 9-2 Digest Edition
CQ 9-2

Should temporal lobe resection be added to drug therapy in
drug-resistant temporal lobe epilepsy?
Recommendation
We recommend temporal lobectomy in addition to drug therapies in patients with drug-resistant epilepsy (GRADE
2D) (weak recommendation, very low level of evidence).
• Supplementary note: In the GRADE system, when the evidence level is “very low”, in principle it is not possible
to grade “strong recommendation”. Since temporal lobe resection is highly effective with low incidence of adverse
effects, almost all the panelists supported “strong recommendation”, but due to the constraint of the GRADE
system, the final grading was “weak recommendation”.

1. Background, priority of the problem
For drug-resistant epilepsy, adding further new drugs has limited effect. The temporal lobe resection is expected to achieve
seizure-free condition despite its invasiveness.

2. Comment

Evidence summary
There were 2 randomized controlled trials (RCT) (total 118 patients) on the effectiveness of temporal lobe resection for
drug-resistant epilepsy1, 2). With regard seizure outcome, the relative risk was 20.57 (95% confidence interval 4.24‒99.85)
and the number needed to treat (NNT: indicating the number of persons needed to treat to achieve the outcome for one
person) was 4, showing superiority of temporal lobe resection. Neither of the two RCTs mentioned decrease of antiepileptic
drugs after surgery. Death rate did not differ between two groups.
The relative risk of surgical complications was 12.33 (95% confidence interval 1.67‒90.89), and was higher in the temporal
lobe resection group. Death, memory impairment, and psychiatric symptoms were not significantly different between thetwo groups. Quality of life (QOL) improvement was superior in the temporal lobe resection group.

3. Panel meeting

3-1. What is the overall quality of evidence across outcomes?
Since we were not able to mask the intervention, the risk of bias was high overall in the collected studies. Bias for death
was considered not serious, while that for the other outcomes was considered serious and was downgraded one rank.
Inconsistency and non-directness of the results were without question and considered not serious. For imprecision, confidence
intervals crossed the clinical decision threshold in many items, and was downgraded one or two ranks. Publication bias
could not be judged because of the small number of studies. Consequently, the level of evidence for the outcomes was asfollows: “low” for seizure freedom, death, surgical complications, and quality of life improvement; and “very low” for memory
impairment and psychiatric symptoms. The overall level of evidence was “D (very low)”.
* For surgical therapy, since blinding of the control group is difficult, the level of evidence is generally low.

3-2. How is the balance between benefits and harms?
Temporal lobe resection can be expected to control seizures. As a result, antiepileptic drugs are possibly reduced although
it is not shown in RCT. The incidence of serious adverse effects was low. Therefore, the risk of temporal lobe resection isconsidered to be smaller compared to its benefit.

148Part II

Systematic Review Digest

3-3. What about patients’ values and preference?
Some patients may feel resistant to receive invasive surgical therapy, but the beneficial effect of seizure-free produced by
the surgery outweighs the resistance to the invasive procedure. There is perhaps no significant uncertainty or variability invalue among the patients.

3-4. What is the balance between net benefit and cost or resources?
The health insurance fee scale for epilepsy surgery using a microscope (including temporal lobe resection) is 131,630
points (as of January 11, 2018). The surgery is conducted under general anesthesia and requires neurosurgeons.
However, through reducing antiepileptic drugs, decreasing hospitalization duration accompanying reduced seizures, andenabling more active social activities, epilepsy surgery is expected to lead to saving in the long term. For this reason, the cost
can be considered negligible.

3-5. Recommendation grading
During the discussions at the panel meeting, temporal lobe resection was expected to eliminate seizures, and overall thecost of the surgery could be considered negligible. Even taking the adverse effects into account, the surgery was supported
by panelists.
At the panel meeting, many panelists supported a recommendation grade of “strong recommendation”. However, in the
GRADE system, when the evidence level is “very low”, in general we are not able to grade “strong recommendation”. For thisreason, the final grading was “weak recommendation”.

4. Descriptions in other related guidelines
In Japan, the Japan Epilepsy Society published the “Guideline on indications for epilepsy surgery”3) in 2008, and“Guideline on diagnosis and surgical indications of mesial temporal lobe epilepsy”4) in 2010.
The “Guideline on indications for epilepsy surgery” recommends surgical treatment for mesial temporal lobe epilepsy at asuitable timing, stating that “since surgical results are superior in cases of mesial temporal lobe epilepsy with a localizedorganic lesion or with extensive lesions in unilateral hemisphere, consider surgical treatment from an early stage and do not
miss the timing of surgery”. The “Guideline on diagnosis and surgical indications of mesial temporal lobe epilepsy” also
follows the above recommendation, stating that “patients should be selected in accordance with the guideline on indications
for epilepsy surgery”.
In overseas countries, the Quality Standards Subcommittee of the American Academy of Neurology, the American
Epilepsy Society, and the American Association of Neurological Surgeons published a guideline5) in 2003. The guideline
states that “drug-resistant epilepsy should be considered for referral to an epilepsy surgery center” and that “patients whomeet established criteria for an anteromesial temporal lobe resection and who accept the risks and benefits of this procedure
should be offered surgical treatment”.

5. Treatment monitoring and evaluation
Monitoring and evaluation during the perioperative period of treatment are generally performed by a neurosurgeon. After
this period, although a neurosurgeon is not necessarily required to monitor and evaluate, follow-up and support should be
provided to the patients.

6. Possibility of future researchSome memory-preserving or minimally invasive surgery may be developed in the future. In addition, we would like toknow the surgical outcomes and adverse events over a longer follow-up period because the observation periods of the two
RCT were 1 year1) and 2 years2).

7. RCT reports reviewed for this CQ
Wiebe 20011), Engel 20122)

CQ 9-2

Digest Edition149

8. List of appendices (to be shown later)
Appendix CQ9-2-01. Flow diagram and literature search formula
Appendix CQ9-2-02. Risk of bias summary
Appendix CQ9-2-03. Risk of bias graphAppendix CQ9-2-04. Forest plot
Appendix CQ9-2-05. Summary of Findings (SoF) table
Appendix CQ9-2-06. Evidence-to-Decision table▪ References
1) Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001; 345(5): 311-318.
2) Engel J Jr, McDermott MP, Wiebe, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012; 307(9):922-930.
3) Mihara T, Fujiwara T, Ikeda A, et al. Guideline on indications for epilepsy surgery. Tenkan Kenkyu. 2008; 26(1): 114-118 (in Japanese).
4) Watanabe E, Fujiwara T, Ikeda A, et al. Guideline on diagnosis and surgical indications of mesial temporal lobe epilepsy. Tenkan Kenkyu. 2006;
27(3): 412-416 (in Japanese).
5) Engel J Jr, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality
Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Associationof Neurological Surgeons. Neurology. 2003; 60(4): 538-547.

150Part II

Systematic Review Digest

Appendix CQ 9-2-01.

Flow diagram and literature search formula

Literature search
PICO
P: Patients with drug-resistant epilepsy
I: Temporal lobe resection added to drug therapy
C: Compared with drug therapy alone
O: Are seizures eliminated or reduced?
Are antiepileptic drugs reduced or discontinued?
Is there increase in death related to surgery?
Are there increases in complications (medical/neurological) related to surgery?
Is memory (IQ, memory) lowered?
Is QOL (including psychiatric symptoms) improved?

▪ Search formula
PubMed search: September 28, 2016
#1 Search ((“drug resistant epilepsy” [mesh] OR ((epilepsy OR seizures OR convulsions) AND (intractable OR refractory OR resistant))#2 Search (“anterior temporal lobectomy” OR (temporal lobe AND surgery [sh]))#3 Search (randomized controlled trial[pt] OR meta-analysis[pt] OR randomized OR blind OR observation* OR cohort OR “follow-up” OR cross
OR case OR series OR prospective OR retrospective OR placebo OR trial)#4 (#1 AND #2 AND #3)
Cochrane CENTRAL search: September 28, 2016
(epilepsy OR seizures) AND “temporal lobe” AND surgery

CQ 9-2

Digest Edition151

CQ9-2. Flow diagram of literature search (modified PRISMA 2009)

152

Part II

Systematic Review Digest

Appendix CQ9-2-02 and -03.   Risk of bias summary
Risk of bias graphs

CQ 9-2

Digest Edition

153

154

Part II

Systematic Review Digest

CQ 9-2

Digest Edition

155

Appendix CQ9-2-04.   Forest plot

156

Part II

Systematic Review Digest

CQ 9-2

Digest Edition

157

Appendix CQ9-2-05.   Summary of Findings (SoF) table
Patients: Patients with drug resistant epilepsy
Intervention: Temporal lobe resection + drug therapy
Comparison: Drug therapy

OutcomeSeizure freedom

Expected absolute effect*(95% confidence interval)
Risk of vagus
Risk of drug
nerve stimulation
therapy+ drug therapy
16 (per 1,000)
327 (per 1,000)(67–1,000)0 (per 1,000)

Relative effect:risk ratio(RR)(95% confidence
interval)

No. ofpatients(No. ofstudies)

RR 20.57(4.24–9.85)

118(2 RCTs)0 (per 1,000)(0–0)
5 (per 1,000)(0–126)Not estimable(0 RCTs)⊕⊕⃝⃝
Lowa,b
‒

RR 0.33(0.01–7.95)

118(2 RCTs)

⊕⊕⃝⃝
Lowc

Quality ofevidence(GRADE)

Reduction/discontinuationof antiepileptic drugs
Death

16 (per 1,000)

Surgical complications

0 (per 1,000)0 (per 1,000)(0–0)

RR 12.33(1.67–90.89)

118(2 RCTs)⊕⊕⃝⃝
Lowa.bMemory impairment

0 (per 1,000)0 (per 1,000)(0–0)

RR 12.00(0.71–202.18)

26(1 RCT)⊕⃝⃝⃝
Very lowa,cPsychiatric symptoms

225 (per 1,000)

200 (per 1,000)(86–466)

RR 0.89(0.38–2.07)

80(1 RCT)⊕⃝⃝⃝
Very lowa,b

QOL improvement: change
in QOLIE-89 (89-item
Quality of Life in Epilepsy
Inventory) mental healthscore (range of QOLIE-89:
0‒100)

Mean QOL
improvement(change in
QILIE-89) was 0

QOL improvementby temporal lobe
resection + drug
therapy was 8.6
times higher (0.14‒
17.06 higher) thandrug therapy group‒38(1 RCT)⊕⊕⃝⃝
Lowa,dComment*Risk (and 95% confidence interval) in the intervention group was estimated based on the risk in the control group and the effect due tointervention (and 95% confidence intervals).
Grades of quality of evidence according to the GRADE Working Group:
High:
High certainty of the effect estimate. True effect is near the effect estimate.
Moderate: Moderate certainty of the effect estimate. The effect estimate is considered to be near the true effect, but further research
may change the effect estimate.
Low:
There is limitation in the certainty of the effect estimate. Although the effect estimate may be near the true effect, further
research is very likely to change the effect estimate.
Very low: Very low certainty of the effect estimate. The true effect is very likely to be different from the effect estimate.
: because masking was not done, which affected the outcomes: because although confidence interval of effect estimate does not cross the clinical decision threshold of appreciable benefit or that ofappreciable harm, it does not satisfy the criteria for optimal information size (OIS).
c: because confidence interval of effect estimate crosses the clinical decision thresholds of both appreciable benefit and appreciable harmd: because confidence interval of effect estimate crosses the clinical decision threshold of appreciable benefit, but not the clinical decisionthreshold of appreciable harm
a

b

158

Part II

Systematic Review Digest

Appendix CQ 9-2-06.   Evidence-to-Decision table
Evaluation table of recommendation decision criteria
Study population: Patients with drug-resistant temporal lobe epilepsy
Intervention: Temporal lobe resection (added to drug therapy)
CRITERIAJUDGEMENTS

PROBLEMDESIRABLEEFECTSUNDESIRABLE
EFFCETSIs there apriority problem?
More serious
problems andmore urgent
problems havehigher priority- No- Probably no- Probably yes- Yes- Varies- Don’t know

How substantial
are the desirable
anticipatedeffects?

- Trivial- Small- Moderate- Large- Varies- Don’t know

How substantial
are theundesirable
anticipatedeffects?

- Large- Moderate- Small- Trivial- Varies- Don’t know

CERTAINTY OF
THE EVIDENCE

What is theoverall certaintyof this evidence?

VALUESIs thereimportantuncertainty
about orvariability in
how much people
value the main
outcomes?

Does thebalance between
desirable andundesirable
effects favor theintervention or
the comparison?

- Very low- Low- Moderate- High- No included studies- Important
uncertainty orvariability- Probably important
uncertainty orvariability- Probably noimportant uncertainty
or variability- No important
uncertainty andvariability

BALANCE OF EFFECTS- Control is superior- Control is probably
superior- Control andintervention areequivalent- Intervention isprobably superior- Intervention issuperior- It depends- Don’t know

ADDITIONALCONSIDERATIONSRESEARCH EVIDENCE
For drug resistant epilepsy, the effect of further adding new drugs is limited.
Temporal lobe resection is a treatment that can be expected to achieve seizure
freedom.

The relative importance or values of the main outcomes of interest:
Relative
importance

Certainty of theevidence (GRADE)

Seizure freedom

CRITICAL⊕⊕⃝⃝
LOW

Reduction/discontinuationof antiepileptic drugs

CRITICALDeathCRITICAL⊕⊕⃝⃝
LOW

Surgical complications

CRITICAL⊕⊕⃝⃝
LOW

Memory impairment

CRITICAL⊕⃝⃝⃝
VERY LOW

Psychiatric symptoms

CRITICAL⊕⃝⃝⃝
VERY LOWQOL improvement

CRITICAL⊕⊕⃝⃝
LOW

Outcome

It depends on patient.
Memory impairment canbe predicted to someextent. One RCT (Wiebe
2001) reported transient
asymptomatic visual defectin 22 of 40 patients.
Surgery generally has
evidence with low
certainty due to difficulties
with blinding.

Summary of findings
OutcomeNo temporallobe
resection

Temporallobe
resection

Difference(95% CI)

Relative
effect (RR)
(95% CI)

Seizure freedom

1.6%

32.7%
(6.7 to100.0)

31.1% more
(5.1 more to156.9 more)

RR 20.57(4.24 to99.85)

Death

1.6%

0.5% (0.0
to 12.6)

1.1% fewer(1.6 fewer
to 11 more)

RR 0.33(0.01 to7.95)

Surgicalcomplications

0.0%

0.0% (0.0
to 0.0)0.0% fewer(0 fewer to
0 fewer)

RR 12.33(1.67 to90.89)

Memoryimpairment

0.0%

0.0% (0.0
to 0.0)0.0% fewer(0 fewer to
0 fewer)

RR 12.00(0.71 to202.18)

Psychiatric
symptoms

22.5%

20.0%
(8.6 to46.6)

2.5% fewer(14 fewer to24.1 more)

RR 0.89(0.38 to2.07)

QOL
improvement

Mean
QOL
improvement
was 0

-

MD 8.6higher (0.14higher to
17.06
higher)-Reduction/
discontinuationof antiepilepticdrugs

CQ 9-2

Digest Edition

159

Summary: With regard seizure outcome, relative risk was 20.57 (95%
confidence interval 4.24‒99.85) and NNT was 4. No study on the outcome ofantiepileptic drug reduction was found. There was no significant increase indeath due to surgery. Surgical complications was increased with relative risk of
12.33 (95% confidence interval 1.67‒90.89), and included stroke and infection.
Other than these, Wiebe et al, reported transient visual defect in approximately
one-half of patients in surgery group. Memory impairment tended to increase
when temporal lobe resection was added to drug therapy but there was no
significant difference. The main psychiatric symptom was depression, but there
was no significant difference between with and without temporal lobe resection.
Quality of life (QOL) was superior in the group with add-on temporal lobe
resection.
COST ANDRESOURCEACCEPTABILITYFEASIBILITY160

How large are
the required
resources (cost)?

- High cost
- Moderate cost
- Negligible- Moderate saving- Large saving- Varies- Don’t know

The health insurance fee scale for epilepsy surgery using a microscope (including
temporal lobe resection) is 131,630 points (as of January 11, 2018). The surgery
is conducted under general anesthesia and requires a neurosurgeon. However,through reducing antiepileptic drugs, hospitalization decreases accompanying
reduced seizures, and more active social activities are possible. these are expected
to lead to saving in the long term.

Is the option
acceptable to key
stakeholders?

- No- Probably no- Probably yes- Yes- Varies- Don’t know

Access to facility capable of surgery is required, but is possible.

Is the option
feasible toimplement?

- No- Probably no- Probably yes- Yes- Varies- Don’t know

Feasible in specialized facilities. To find hospitals capable of surgery, consult thefollowing websites:
1. The Japan Neurosurgical Society http://jns.umin.ac.jp/
2. Epilepsy Surgery Society of Japan http://plaza.umin.ac.jp/~jess/
3. The Japan Epilepsy Society http://square.umin.ac.jp/jes/Part II

Systematic Review Digest

Recommendation decision table
Type of recommendation
Judgment

Strongrecommendation
against theintervention

Conditional
recommendation
against theintervention

Conditional
recommendation for
either the intervention
or the comparison

Conditional
recommendation for
the intervention

Strongrecommendation
for the intervention

○

○

○

●

○

Recommendation

Addition of temporal lobe resection to drug therapy is recommended for drug-resistant temporal lobe epilepsy.
(GRADE 2D, strength of recommendation “weak recommendation” / certainty of evidence “very low”)

Justification

Question (CQ): Should temporal lobe resection be added to drug therapy for drug resistant temporal lobe epilepsy?
Patients (P): Patients with drug resistant epilepsy
Intervention (I): Temporal lobe resection (added to drug therapy)
Comparison (C): Continued drug therapy only
Outcome (O): Seizure freedom, death, surgical complications
Summary of evidence: Systematic review identified 2 RCTs (118 subjects). Relative risk of freedom from seizure due totemporal lobe resection was 20.57 (95% confidence interval 4.24‒99.85) and NNT was 4. No studies investigating theoutcome of antiepileptic drug reduction was found. There was no significant increase in death due to surgery.
Complications related to surgery were increased with relative risk of 12.33 (95% confidence interval 1.67‒90.89), andincluded stroke and infection. Other than these, Wiebe et al, reported transient visual defect in approximately one-halfof patients in surgery group. Memory impairment tended to increase when temporal lobe resection was added to drug
therapy, but there was no significant difference. The main psychiatric symptom was depression, but there was no
significant difference between with and without temporal lobe resection. Quality of life (QOL) was superior in the groupwith add-on temporal lobe resection.
Certainty of evidence: Since masking of the intervention was impossible, the risk of bias in the studies collected was highoverall. Bias for death was considered not serious, while that for other outcomes was considered serious and downgraded
one rank. Inconsistency and non-directness of the results were without question, and not serious. For imprecision,confidence intervals crossed the clinical decision threshold in many cases, and was downgraded one or two ranks.
Publication bias could not be judged because of the small number of studies. Consequently, the certainty of evidence forthe outcomes was as follows: “low” for seizure freedom, death, surgical complications, and QOL improvement; and “verylow” for memory impairment and psychiatric symptoms. The overall certainty of evidence was “D (very low)”.
Judgment of benefits and harms, burden, and cost:
Surgical invasiveness is high. However, the merit of freedom from seizure in patients with drug resistant epilepsy is great,
and the efficacy is also high.
Recommendation:
Addition of temporal lobe resection to drug therapy is proposed for drug resistant temporal lobe epilepsy.
(strength of recommendation “weak recommendation” / certainty of evidence “very low”)
Additional considerations:
According to GRADE, when the certainty of evidence is “very low”, in principle it is not possible to rank “strong
recommendation”. Since temporal lobe resection is expected to be highly effective with low incidence of adverse effects,
the opinion of almost all of the panelists was “strong recommendation” at the panel meeting, but due to the constraint of
the GRADE system, the final grade was “weak recommendation”.

Subgroup
No RCTs comparing surgical methods were identified.
considerations.
Consider how to set
criteria for patient
population or intervention,
which may change therecommendation statement
Implementation
Selection of the optimal surgical method depending on the cause is necessary.
considerations.
Follow-up and support after surgery are necessary.
In clinical practice,problems such as feasibility
and tolerability may arise.
Monitoring andevaluation.
What kind of monitoringis necessary during
implementation? Is
evaluation necessary
before or after publication?
Research possibilities.
What are the unclear
points in judgment that
require future research?

There is room for further research on the development of memory-preserving, minimally invasive surgery. In addition,
the observation periods of the two RCT were 1 year and 2 years, and there is accumulating interest on the data of surgicaloutcomes and adverse events over a longer period of follow-up.

CQ 9-2

Digest Edition

161

CQ 10-1 Digest Edition
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 levelof 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 patientswith 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, suchas 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 thescores 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 moodchanges, 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 asmall 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 theintervention 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 underpoweredfor detection of the outcome.

162

Part II

Systematic Review Digest

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 ofevidence 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 somepatients 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 coveredby 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 ofharm, 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: “Wedesire 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 thetreatment 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 neurosurgery2-4).

5. Treatment monitoring and evaluation
Vagus nerve stimulation treatment requires adjustment of the stimulation conditions, management of complications, andsolving equipment troubles. Epilepsy specialists or doctors trained by the specialists should perform monitoring andevaluation 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.

CQ 10-1

Digest Edition

163

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 graphAppendix 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.

164

Part II

Systematic Review Digest

Appendix CQ 10-1-01.    Flow diagram and literature search formula

CQ 10-1 Literature search
PICO
P: Patients with drug resistant epilepsy (children as subgroup)
I: Vagus nerve stimulation added to drug therapy
C: Compared with drug therapy alone
O: Are seizures controlled (25, 50, 75%)?
Is there a decrease in treatment continuation rate?
Is there an increase in dysphonia/hoarseness?
Is there an increase in coughing?
Is there an increase in pain?
Is mood improved (= mood change)?

▪ Search formula
PubMed search: September 28, 2016
#1 Search ((“drug resistant epilepsy” [mesh] OR ((epilepsy OR seizures OR convulsions) AND (intractable OR refractory))))#2 Search (“vagus nerve stimulation” [mesh] OR (“vagal nerve” AND stimulation) OR (“vagus nerve” AND “electric stimulation therapy”))#3 Search (randomized controlled trial [pt] OR meta-analysis [pt] OR randomized OR blind OR observation* OR cohort OR “follow-up” OR cross
OR case OR series OR prospective OR retrospective OR placebo OR trial)#4 (#1 AND #2 AND #3)
Cochrane CENTRAL search: September 28, 2016
(epilepsy OR seizures) AND vagus nerve stimulation

CQ 10-1

Digest Edition

165

CQ10-1. Flow diagram of literature search (modified PRISMA 2009)

166

Part II

Systematic Review Digest

Appendix CQ10-1-02 and -03.    Risk of bias summary
Risk of bias graphs

CQ 10-1

Digest Edition

167

168

Part II

Systematic Review Digest

CQ 10-1

Digest Edition

169

170

Part II

Systematic Review Digest

Appendix CQ10-1-04.   Forest plot

CQ 10-1

Digest Edition

171

172

Part II

Systematic Review Digest

Appendix CQ10-1-05.    Summary of Findings (SoF) table
Patients: Patients with drug-resistant epilepsy
Intervention: Vagus nerve stimulation (VNS) + drug therapy
Comparison: Drug therapy

Outcome12-month seizure
frequency ≤50%

Expected absolute effect*(95% confidence interval)
Risk of vagus nerve
Risk of drug
stimulation + drug
therapy
therapy
Study subject population
241 (per 1,000)
323 (per 1,000)(142–734)
Low risk population
120 (per 1,000)
161 (per 1,000)(71–365)
High risk population
480 (per 1,000)
643 (per 1,000)(283–1,000)
Mood change
Mean mood change(QOLIE-89): 0 (QOLIE-89) in vagus
nerve stimulation + drug
therapy group was 1.3
higher (1.56‒4.16) thandrug therapy group

Mood after 12 months:
change in QOLIE-89(89-item Quality of Lifein Epilepsy Inventory)
mental health score(range of QOLIE-89:
0‒100)
Mood after 12 months:
Mood changechange in CES-D (Centre (CES-D): 0
for Epidemiologic Studies
Depression scale) score(range of CED-D: 0‒60)

Mean mood change(CES-D score) in vagus
nerve stimulation + drug
therapy group was 2.7
lower (6.54‒1.14) thandrug therapy group
Mood after 12 months:
Mood change
Mean mood changechange in NDDI-E(NDDI-E): 0(NDDI-E score) in(Neurological Disorders
vagus nerve stimulation
Depression Inventory in+ drug therapy group
Epilepsy scale) score
was 0.8 lower(range of NDDI-E: 6‒24)(2.26‒0.66) than drug
therapy group
Mood after 12 months:
Mood change
Mean mood changechange in CGI-I (Clinical (CHI-I): 0(CHI-I score) in vagus
Global Impression of
nerve stimulation + drug
Improvement scale) score
therapy group was 0.5(range of CGI-I: 1‒7)
lower (0.99‒0.01) thandrug therapy group
Serious adverse events
Study subject population
52 (per 1,000)
93 (per 1,000)(23–369)
Low risk population
25 (per 1,000)
45 (per 1,000)(11–178)High risk population
100 (per 1,000)
179 (per 1,000)(45–713)Dysphonia
0 per 1,000
0 per 1,000(0 to 0)Relative effect:risk ratio (RR)
(95% confidence
interval)

No. ofpatients(No. ofstudies)

Quality ofevidence(GRADE)

RR 1.34(0.59–3.04)

60(1 RCT)⊕⃝⃝⃝
Very low a,b‒60(1 RCT)⊕⊕⃝⃝
Low a,c‒60(1 RCT)⊕⊕⃝⃝
Low a,d‒60(1 RCT)⊕⊕⃝⃝
Lowa,c‒60(1 RCT)⊕⊕⃝⃝
Low a,c

RR 1.79(0.45–7.13)

112(1 RCT)⊕⃝⃝⃝
Very low a,b

RR 4.69
0.23–93.70)

60(1 RCT)⊕⃝⃝⃝
Very low a,b

Comment*Risk (95% confidence interval) in the intervention group was estimated based on the risk in the control group and the effect due tointervention (and 95% confidence intervals).

CQ 10-1

Digest Edition

173

Grades of quality of evidence according to the GRADE Working Group:
High:
High certainty of the effect estimate. True effect is near the effect estimate.
Moderate: Moderate certainty of the effect estimate. The effect estimate is considered to be near the true effect, but further research
may change the effect estimate.
Low:
There is limitation in the certainty of the effect estimate. Although the effect estimate may be near the true effect, further
research is very likely to change the effect estimate.
Very low: Very low certainty of the effect estimate. The true effect is very likely to be different from the effect estimate.
: because masking was not done, which affected the outcome.
: because confidence interval of effect estimate crosses the clinical decision thresholds of both appreciable benefit and appreciable harm.
c: because although confidence interval of effect estimate does not cross the clinical decision threshold of appreciable benefit or that ofappreciable harm, it does not satisfy the criteria for optimal information size (OIS).
d: because confidence interval of effect estimate crosses the clinical decision threshold of appreciable benefit, but does not cross the clinicaldecision threshold of appreciable harm.
a

b

174

Part II

Systematic Review Digest

Appendix CQ 10-1-06.   Evidence-to-Decision table
Evaluation table of recommendation decision criteria
Study population: Patients with drug resistant temporal lobe epilepsy
Intervention: vagus nerve stimulation
CRITERIA

ADDITIONALCONSIDERATIONSPROBLEMJUDGEMENTSRESEARCH EVIDENCE

Is there a priority
problem?
More serious
problems andmore urgent
problems havehigher priority- No- Probably no- Probably yes- Yes- Varies- Don’t know

For drug-resistant epilepsy in which seizures cannot be controlled even with
two regimens of appropriate antiepileptic drugs, the effect of adding further
drugs is limited. By adding vagus nerve stimulation (VNS) to antiepileptic
drugs, the effect of lowering the seizure frequency is expected. Compared withbrain surgery by craniotomy, VNS is minimally invasive and may be selected as
one of the treatment options.

How substantial
are the desirable
anticipatedeffects?

- Trivial- Small- Moderate- Large- Varies- Don’t know

DESIRABLE EFECTS
UNDESIRABLE EFFCETS

How substantial
are theundesirable
anticipatedeffects?

CERTAINTY OF THE
EVIDENCE

What is theoverall certaintyof the evidenceof effects?

- Large- Moderate- Small- Trivial- Varies- Don’t know

- Very low- Low- Moderate- High- No included
studies

The relative importance or values of the main outcomes of interest:
Outcome Relative

Relative
importance

Certainty of theevidence (GRADE)

Seizure frequency ≤50%

CRITICAL⊕⃝⃝⃝
VERY LOW

Mood: change in QOLIE-89(89-item Quality of Life in
Epilepsy Inventory) mental
health score

CRITICAL⊕⊕⃝⃝
LOW

Mood: change in CES-D(Centre for Epidemiologic
Studies Depression scale)

CRITICAL⊕⊕⃝⃝
LOW

Mood: change in NDDI-E(Neurological Disorders
Depression Inventory in
Epilepsy scale)

CRITICAL⊕⊕⃝⃝
LOW

Mood: change in CGI-I(Clinical Global Impressionof Improvement scale)

CRITICAL⊕⊕⃝⃝
LOW

Serious adverse events

CRITICAL⊕⃝⃝⃝
VERY LOW

Dysphonia

CRITICAL⊕⃝⃝⃝
VERY LOW

Summary of findings

OutcomeDrugtherapy

Vagus nerve
stimulation(VNS) + drug
therapy

Seizure frequency≤ 50%

241 per
1,000

323 per 1,000(142 to 734)

82 more per
1,000 (from99 fewer to
492 more)

120 per
1,000

161 per 1,000(71 to 365)

41 more per
1,000 (from49 fewer to
245 more)

480 per
1,000

643 per 1,000(283 to 1,000)

163 more per
1,000 (from197 fewer to
979 more)

Mood: change in
QOLIE-89(89-item Qualityof Life in Epilepsy
Inventory) mental
health score

Relative
effect
(RR)(95% CI)

Difference(95% CI)

RR 1.34(0.59 to3.04)

MD 1.3higher (1.56
lower to 4.16
higher)Relative risk for seizure
frequency ≤ 50% byintervention was 1.34
(0.59‒3.04), and NNT
was 25. For mood change,
the effect was small for all
the scales.

In the intervention group(31 patients), serious
adverse events occurred in
5 patients, 2 (40%) ofwhom had vocal cordparalysis and 1 had brief
respiratory arrest, but all
recovered completely.
Therefore, from RCT, therelative risk of significant
undesirable effects occurringin clinical practice isestimated to be smaller
than 1.79 (0.45–7.13).

-

CQ 10-1

Digest Edition

175

VALUESIs thereimportantuncertainty
about orvariability in
how much people
value the main
outcomes?

Does the balance
betweendesirable andundesirable
effects favor theintervention or
the comparison?

BALANCE OF EFFECTS
COST ANDRESOURCEACCEPTABILITYFEASIBILITY

176- Important
uncertainty orvariability- Probably
importantuncertainty orvariability- Probably noimportantuncertainty orvariability- No important
uncertainty andvariability- Control is superior- Control is probably
superior- Control andintervention areequivalent- Intervention isprobably superior- Intervention issuperior- It depends- Don’t know

Mood: change in
CES-D (Centre
for Epidemiologic
Studies Depression
scale)

MD 2.7lower (6.54
lower to 1.14
higher)Mood: change in
NDDI-E(Neurological
DisordersDepression
Inventory in
Epilepsy scale)

MD 0.8lower (2.26
lower to 0.66
higher)Mood: change in
CGI-I (ClinicalGlobal Impressionof Improvement
scale)

MD 0.5lower (0.99
lower to 0.01
lower)

Serious adverse
event

Dysphonia

52 per
1,000

93 per 1,000(23 to 369)

41 more per
1,000 (from28 fewer to
317 more)

25 per1,000

45 per 1,000(11 to 178)

20 more per
1,000 (from14 fewer to
153 more)

100 per
1,000

179 per 1,000(45 to 713)

79 more per
1,000 (from55 fewer to
613 more)

0 per
1,000

0 per 1,000 (0to 0)

0 fewer per
1,000 (from0 fewer to 0
fewer)

Individuals differ in theway they attach importanceto outcomes. Some patientsplace importance on the
reduction of seizure
frequency, while others
regard the risk of adverse
effects to be more important.

RR 1.79(0.45 to7.13)

RR 4.69(0.23 to93.70)

Summary: Only one RCT was extracted from the literature search, and thisRCT was prematurely terminated by the sponsor due to a low enrollment rate,
which resulted primarily from the strong views expressed by candidates towardrandomization. Therefore, there is a possibility that the study was underpoweredfor detecting the outcome. The relative risk for reduction of seizure frequency to≤ 50% was 1.34 (0.59‒3.04).
The relative risk for mood change was 1.3 (−1.56‒4.16) for QOLIE-89, −2.7(−6.54‒1.14) for CES-D, −0.8 (−2.26‒0.66) for NDDI-E, and −0.5 (−0.99‒0.01)
for CGI-I.
The relative risk for serious adverse events was 1.79 (0.45‒7.13). Although there
was no significant difference, the result suggests a possibility of increase in risk.
However, vocal cord paralysis and brief respiratory arrest seen only in theintervention group were transient.

How large are
the resource
requirement(cost)?

- High cost
- Moderate cost
- Negligible- Moderate saving- Large saving- Varies- Don’t know

Is the option
acceptable to key
stakeholders?

- No- Probably no- Probably yes- Yes- Varies- Don’t know

Is the option
feasible toimplement?

- No- Probably no- Probably yes- Yes- Varies- Don’t know

Part II

The implantation 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 ofJanuary 11, 2018). Also, it is necessary to replace the generator once every few
years when the battery runs out, which requires reoperation. The cost of
exchange is approximately ¥2,000,000 (covered by health insurance).

In the past, there were several prefectures that did not have vagus nerve
stimulation device implantation facility or guidance/management facility, andaccess to treatment was poor in some regions. However, currently the criteria foradjusting doctor have been relaxed and access has improved. If the environmentof access to device implantation facility and guidance/management facility
continues to improve, adjustment of stimulation condition is feasible.

Systematic Review Digest

A list of facilities that can
provide this therapy isposted on the Society
website.

Recommendation decision table
Type of recommendation
Judgment

Strongrecommendation
against theintervention

Conditional
recommendation
against theintervention

Conditional
recommendation for
either the intervention
or the comparison

Conditional
recommendation for
the intervention

Strongrecommendation
for the intervention

◯

◯

◯

●

◯

Recommendation

Addition of vagus nerve stimulation on drug therapy is proposed for drug resistant epilepsy. (GRADE 2D, strength ofrecommendation “weak recommendation” / certainty of evidence “very low”)

Justification

Question (CQ): Should vagus nerve stimulation be used for drug resistant epilepsy?
Patient (P): Drug resistant epilepsy
Intervention (I): Vagus nerve stimulation (added to drug therapy)
Comparison (C): Drug therapy
Outcome: Seizure frequency ≤ 50%, mood improvement (QOLIE-8, CES-D, NDDI-E, CGI-I), serious adverse events,
dysphonia
Summary of evidence: Systematic review identified 1 RCT (96 subjects). When seizure frequency ≤ 50% is the outcome,relative risk due to intervention was 1.34 (95% confidence interval 0.59‒3.04). For mood change, the result differeddepending on the evaluation scale, but the effect was small.
Certainty of evidence: The study collected had a high overall bias risk which was judged as serious for all the outcomes,
and was downgraded by 1 rank. For inconsistency of results, there was only one study, and therefore was not downgraded.
There was no problem with indirectness and was judged not serious. As for imprecision, the confidence intervals in many
analyses crossed the clinical decision threshold; hence was downgraded by one or two ranks. As for publishing bias, there
was only one study, and therefore was not downgraded. Consequently, the certainty of evidence for the outcomes was asfollows: “very low” for seizure frequency ≤ 50%, serious adverse events, and dysphonia; and “low” for the other outcomes.
The overall certainty of evidence was “very low”.
Judgment of benefits and harms, burden and cost:
Since there was only 1 RCT, the certainty of effect estimate was low, and it was difficult to judge the balance between
benefits and harms. Among the serious adverse events, vocal cord paralysis and brief respiratory arrest that occurred onlyin the intervention group were transient with no sequelae. Burden and cost are moderate. Considering that there are notmany treatment options, it is appropriate to implement the therapy with expectation of the effectiveness even at theexpense of harms, burden and cost.
Recommendation:
Addition of vagus nerve stimulation on drug therapy is proposed for drug resistant epilepsy. (strength of recommendation“weak recommendation” / certainty of evidence “very low”.
Additional considerations:
At the panel meeting, the patient’s families expressed the following opinion: “There is desire to overcome social constraints.
If there is any method at all, please include it as one of the options.”

Subgroup
considerations.
Consider how to set
criteria for patient
population or intervention,
which may change therecommendation statement

In children, no RCT comparing with and without vagus nerve stimulation was found. In addition, the 2013 guidelines
update of the American Academy of Neurology [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 theAmerican Academy of Neurology. 2013; 81(16): 1453-1459.] analyzed 14 non-RCT studies (481 subjects). The rate of ≥50% seizure reduction was 55% (95% confidence interval 51‒59%) and the seizure-free rate was 7% (95% confidence
interval 5‒10%). However, the heterogeneity between studies was very large. The same guideline update suggests that therisk of infection is higher in children (odds ratio 3.4, 95% confidence interval 1.0‒11.2) than in adults.

Implementationconsiderations.
In clinical practice,problems such as feasibility
and tolerability may arise.

To initiate therapy, access to vagus nerve stimulation device implantation facility and guidance/management facility
becomes an issue. Patient should be given explanation that surgery is necessary before therapy can be initiated, and that
it is not possible to predict beforehand whether it will be effective for any patient. Indication judgment and stimulation
device implantation are performed by or under the guidance of a doctor specializing in epilepsy surgery, who is both aJapan Epilepsy Society board-certified specialist and a Japanese Neurosurgical Society board-certified specialist.
Adjustment of the stimulation conditions after therapy initiation as well as follow-up of therapeutic effect and adverse
events are conducted by or under the guidance of a Japan Epilepsy Society board-certified specialist, or a board-certified
specialist of the Japanese Society of Child Neurology, Japanese Society of Neurology, Japanese Society of Psychiatry, orJapanese Neurosurgical Society [Japan Epilepsy Society Criteria for VNS Qualification (enforced on January 8, 2010,
revised on July 1, 2014 and June 26, 2016)].

Monitoring andevaluation.
What monitoring isnecessary during
implementation? Is
evaluation of effectnecessary before or after
publication?

Implementation of vagus nerve stimulation requires a system that allows adjustment of the stimulation conditions,interventions for complications, and correction of equipment troubles. Monitoring and evaluation are conducted by
specialists or physicians who have received guidance from the specialists.

Research possibilities.
What are the unclear
points in judgment that
require future research?

RCT with better quality is desirable. In addition, research focusing on identifying good responders and the effects on
status epilepticus is needed in the future.

CQ 10-1

Digest Edition177

CQ 10-2

Digest Edition

CQ 10-2

When conducting vagus nerve stimulation for
drug resistant epilepsy, which intensity of stimulation(high or low) should we use?
Recommendation
When conducting vagus nerve stimulation for drug-resistant epilepsy, we suggest to use high intensity stimulation
rather than low intensity stimulation (GRADE 1C) (strong recommendation, low level of evidence).
• Supplementary note: Adjustment of stimulation conditions should be conducted in the hospital where theelectrode implantation was performed or in a hospital/institution where VNS specialist is present.

1. Background, priority of this issue
The efficacy of vagus nerve stimulation is known to depend on the stimulation conditions. The intensity of stimulation
should be adjusted while monitoring its therapeutic effect and adverse effects. Therefore, it is necessary to clarify whether
high intensity stimulation or low intensity stimulation is superior when conducting VNS.
In addition, as mentioned in CQ 10-1 “Should vagus nerve stimulation therapy be added to drug therapies for drugresistant temporal lobe epilepsy?”, we have difficulty in performing comparison between real VNS and sham VNS (with nostimulation). Therefore, there is an increase in randomized controlled trials (RCTs) using low intensity stimulation as shamstimulation (placebo stimulation or pseudo-stimulation) to compare with high intensity stimulation.
There is one Cochrane Review1) on a similar clinical question. This review shows that high intensity stimulation has
superior therapeutic effect, while treatment withdrawal is rare both when using high and low intensity stimulation.

2. Comment

Evidence summary
There were 4 RCTs that examined the efficacy of vagus nerve stimulation therapy for drug-resistant epilepsy2‒5).
For efficacy, the relative risk of seizure frequency ≤ 50% was 1.74 (95% confidence interval 1.14‒2.65) and NNT (number
needed to treat: indicating the number of persons needed to treat to achieve the outcome for one person) was 10. For adverse
events, low level stimulation was significantly superior in dysphonia and hoarseness (relative risk 2.06, 95% confidence
interval 1.34‒3.17) and dyspnea (relative risk 2.43, 95% confidence interval 1.29‒4.57). Treatment withdrawal, cough, andpain did not differ significantly between high level and low level stimulations.

3. Panel meeting

3-1. What is the quality of evidence about the overall outcomes?
In all the studies collected, the risk of bias was low overall, and the level was not downgraded for all the outcomes. For
inconsistency of the results, I2 was 32% for only dysphonia / hoarseness. Since the effect estimate differed between studies,
heterogeneity was considered high. Inconsistency was thus considered serious and was downgraded one rank. There was noproblem with indirectness, and was judged not serious. As for imprecision, the confidence intervals in many analyses crossed
the clinical decision thresholds, and hence was downgraded by one or two ranks. Regarding publication bias, there were only
four studies, and therefore was not downgraded. Consequently, the level of evidence for the outcomes was as follows:“moderate” for seizure frequency ≤ 50%, cough, and dyspnea; “low” for treatment withdrawal, dysphonia/ hoarseness, andpain. The overall level of evidence was “low”.

178

Part II

Systematic Review Digest

3-2. What is the balance between benefits and harms?
High level stimulation was superior to low level stimulation for the outcome of seizure frequency ≤ 50%. Among theadverse events, dysphonia/hoarseness and dyspnea showed lower rates in low level stimulation, but since there was no
significant difference in treatment withdrawal between two groups, there must be few adverse events serious enough to cause
treatment withdrawal. According to expert opinion, many adverse events are reversible and can be controlled by adjusting
the stimulation current intensity. Taken together, we decided that high level stimulation is probably superior in terms of thebalance between benefits and harms.

3-3. What about patients’ values and preferences?
We concluded that there is probably no significant uncertainty and variability in patient’s values and preferences because
high level stimulation is more effective than low level stimulation, and although adverse events are more prevalent in highlevel stimulation, they are reversible and can be controlled by adjusting the stimulation current.

3-4. What is the balance between net benefit and cost or resources?
Adjustment of stimulation intensity can be done by placing the programming wand over the subcutaneously implanted
generator; thus resources and costs are negligible. However, reoperation is needed to replace the generator every few years
when the battery runs out. Battery consumption is higher for high level stimulation than for low level stimulation. Based onthese, it was decided that high level stimulation costs moderately more as compared to low level stimulation.

3-5. Recommendation grading
In the discussions at the panel meeting, high level stimulation was considered superior in efficacy, and adverse effects were
acceptable because most of them were presumably at a level that would not cause treatment withdrawal. As for burden andcost, high level stimulation was expected to consume more battery power, requiring more frequent generator exchange.
Based on the above arguments, despite considerable adverse events that did not cause treatment withdrawal as well as theincreased burden and cost, we finally unanimously recommended using high level stimulation, considering the highly
anticipated seizure control effect.

4. Descriptions in other related guidelines
In Japan, the “Guideline on implementation of vagus nerve stimulation therapy for epilepsy”6) was published by the Japan
Epilepsy Society in 2012, which states that “In principle, initiate VNS two weeks after implantation. Start with low stimulation
intensity and then gradually increase the intensity while monitoring the adverse effects [recommendation grade C]”.
In 2013, the American Academy of Neurology released a guideline update entitled “Vagus nerve stimulation for thetreatment of epilepsy”. There is no recommendation for high level or low level stimulation in that guideline. However, it
states that whether stimulation at a higher frequency is more likely to reduce seizures than usual stimulation remains
unknown.

5. Treatment monitoring and evaluation
For adjusting stimulation intensity, we need a system which is capable of managing complications and coping withequipment troubles.

6. Future research issues
Further research on the optimal intensity of stimulation is needed. In addition, other than stimulus intensity, there is no
RCT on supplementary techniques such as magnet stimulation, which will be a future research subject. It is also desirable toelucidate the mechanisms underlying the subgroup with high response and develop evaluation methods to identify thesesubjects.

7. RCT reports reviewed for this CQ
Michael 19932), VNS study Group 19953), Handforth 19984), Klinkenberg 20125)

CQ 10-2

Digest Edition179

8. List of appendices (to be shown later)
Appendix CQ10-2-01. Flow diagram and search formula for references
Appendix CQ10-2-02. Risk of bias summary
Appendix CQ10-2-03. Risk of bias graphAppendix CQ10-2-04. Forest plot
Appendix CQ10-2-05. Summary of Findings (SoF) table
Appendix CQ10-2-06. Evidence-to-Decision table▪ References
1) Panebianco M, Rigby A, Weston J, et al. Vagus nerve stimulation for partial seizures. Cochrane Database Syst Rev. 2015; (4): CD002896.
2) Michael JE, Wegener K, Barnes. Vagus nerve stimulation for intractable seizures: one year follow-up. J Neurosci Nurs. 1993; 25(6): 362-366.
3) The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractableseizures. The Vagus Nerve Stimulation Study Group. Neurology. 1995; 45(2): 224-230.
4) Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.
Neurology. 1998; 51(1): 48-55.
5) Klinkenberg S, Aalbers MW, Vles JS, et al. Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial. Dev Med
Child Neurol. 2012; 54(9): 855-861.
6) 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).
7) 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.

180

Part II

Systematic Review Digest

Appendix CQ10-2-01.   Flow diagram and literature search formula

CQ 10-2

Literature search

PICO
P: Patients with drug-resistant epilepsy (children as subgroup)
I: Vagus nerve stimulation at high level stimulation
C: Compared with vagus nerve stimulation at low level stimulation
O: Are seizures controlled (25, 50, 75%)?
Is there a decrease in treatment continuation rate?
Is there an increase in dysphonia/hoarseness? / and cough?
Is there an increase in dyspnea?
Is there an increase in pain?

▪ Search formula
PubMed search: September 28, 2016
#1 Search ((“drug resistant epilepsy” [mesh] OR ((epilepsy OR seizures OR convulsions) AND (intractable OR refractory))))#2 Search (“vagus nerve stimulation” [mesh] OR (“vagal nerve” AND stimulation) OR (“vagus nerve” AND “electric stimulation therapy”))#3 Search (randomized controlled trial [pt] OR meta-analysis [pt] OR randomized OR blind OR observation* OR cohort OR “follow-up” OR cross
OR case OR series OR prospective OR retrospective OR placebo OR trial)#4 (#1 AND #2 AND #3)
Cochrane CENTRAL search: September 28, 2016
(epilepsy OR seizures) AND vagus nerve stimulation

CQ 10-2

Digest Edition

181

CQ10-2. Flow diagram of literature search (modified PRISMA 2009)

182

Part II

Systematic Review Digest

Appendix CQ10-2-02 and -03.   Risk of bias summary
Risk of bias graphs

CQ 10-2

Digest Edition

183

184

Part II

Systematic Review Digest

CQ 10-2

Digest Edition

185

Appendix CQ10-2-04.  Forest plot

186

Part II

Systematic Review Digest

CQ 10-2

Digest Edition

187

Appendix CQ10-2-05.    Summary of Findings (SoF) table
Patients: Patients with drug-resistant epilepsy
Intervention: High level stimulation
Comparison: Low level stimulation

OutcomeSeizure frequency ≤ 50%

Expected absolute effect*(95% confidence interval)
Risk of low level Risk of high levelstimulation
stimulation
144 (per 1,000)
251 (per 1,000)(165–382)

Relative effect:risk ratio (RR)
(95% confidence
interval)

No. ofpatients(No. ofstudies)

Quality ofevidence(GRADE)

RR 1.74(1.14–2.65)

373(4 RCTs)⊕⊕⊕⃝
Moderatea

Treatment withdrawal

10 (per 1,000)

26 (per 1,000)(5–129)RR 2.51(0.50–12.61)

375(4 RCTs)

⊕⊕⃝⃝
Lowb

Dysphonia/hoarseness251 (per 1,000)

518 (per 1,000)(337–797)

RR 2.06(1.34–3.17)

334(3 RCTs)⊕⊕⃝⃝
Lowc,dCough

291 (1,000)

315 (per 1,000)(233–425)

RR 1.08(0.80–1.46)

334(3 RCTs)⊕⊕⊕⃝
Moderated

Dyspnea74 (1,000)

179 (per 1,000)(95–336)

RR 1.08(0.80–1.46)

312(2 RCTs)⊕⊕⊕⃝
ModeratedPain

239 (1,000)

239 (per 1,000)(163–352)

RR 1.00(0.68–1.47)

312(2 RCTs)

⊕⊕⃝⃝
Lowb

Comment*Risk (95% confidence interval) in the intervention group was estimated based on the risk in the control group and the effect due tointervention (and 95% confidence intervals).
Grades of quality of evidence according to the GRADE Working Group:
High:
High certainty of the effect estimate. True effect is near the effect estimate.
Moderate: Moderate certainty of the effect estimate. The effect estimate is considered to be near the true effect, but further research
may change the effect estimate.
Low:
There is limitation in the certainty of the effect estimate. Although the effect estimate may be near the true effect, further
research is very likely to change the effect estimate.
Very low: Very low certainty of the effect estimate. The true effect is very likely to be different from the effect estimate.
: because confidence interval of effect estimate crosses the clinical decision threshold of appreciable benefit: because confidence interval of effect estimate crosses the clinical decision thresholds of both appreciable benefit and appreciable harm.
c: because I2 = 32%; effect estimates differ among studies, heterogeneity is probably highd
: because confidence interval of effect estimate crosses the clinical decision threshold of appreciable harm
a

b

188

Part II

Systematic Review Digest

Appendix CQ 10-2-06.  Evidence-to-Decision table
Evaluation table of recommendation decision criteria
Study population: Patients with drug-resistant temporal lobe epilepsy
Intervention: vagus nerve stimulation
CRITERIA

ADDITIONALCONSIDERATIONSPROBLEMDESIRABLEEFECTSJUDGEMENTSRESEARCH EVIDENCE

Is there a priority
problem?
More serious
problems andmore urgent
problems havehigher priority- No- Probably no- Probably yes- Yes- Varies- Don’t know

Vagus nerve stimulation is known to have different effects depending on thestimulation conditions. The intensity of stimulation should be adjusted while
monitoring the therapeutic effect and adverse effects.

How substantial
are the desirable
anticipated effects?

- Trivial- Small- Moderate- Large- Varies- Don’t know

How substantial
are the undesirable
anticipated effects?

- Large- Moderate- Small- Trivial- Varies- Don’t know

The relative importance or values of the main outcomes of interest:

UNDESIRABLE EFFCETS

OutcomeRelative
importance

Certainty of the evidence(GRADE)

Seizure frequency ≤ 50%

CRITICAL⊕⊕⊕⃝
MODERATE

Treatment withdrawal

CRITICAL⊕⊕⃝⃝
LOW

Dysphonia, hoarseness

CRITICAL

⊕⊕⃝⃝
LOW

Cough

CRITICAL⊕⊕⊕⃝
MODERATE

Dyspnea

CRITICAL⊕⊕⊕⃝
MODERATE

Pain

CRITICAL⊕⊕⃝⃝
LOW

Summary of findings

CERTAINTY OF
THE EVIDENCE

What is theoverall certaintyof the evidenceof effects?

VALUESIs there important
uncertainty aboutor variability in
how much people
value the main
outcomes?

- Very low- Low- Moderate- High- No included
studies- Important
uncertainty orvariability- Probably
importantuncertainty orvariability- Probably noimportantuncertainty orvariability- No important
uncertainty andvariability

Relative
effect (RR)
(95% CI)

Low levelstimulation

High levelstimulation

Difference(95% CI)

Seizurefrequency≤ 50%

144 per
1,000

251 per 1,000(165 to 382)

107 moreper 1,000(from 20
more to 238
more)

RR 1.74(1.14 to2.65)

Treatment
withdrawal

10 per1,000

26 per 1,000(5 to 129)

15 moreper 1,000(from 5 fewer
to 119 more)

RR 2.51(0.50 to12.61)

Dysphonia/
hoarseness251 per
1,000

518 per 1,000(337 to 797)

267 moreper 1,000(from 85
more to 46
more)

RR 2.06(1.34 to
3.17)

Cough

291 per
1,000

315 per 1,000(233 to 425)

23 moreper 1,000(from 58
ewer to 134
more)

RR 1.08(0.80 to1.46)

Dyspnea

74 per
1,000

179 per 1,000(95 to 336)

105 moreper 1,000(from 21
more to 263
more)

RR 2.43(1.29 to
4.57)

Pain

239 per
1,000

239 per 1,000(163 to 352)

0 fewer
per 1,000(from 77
fewer to 112
more)

RR 1.00(0.68 to
1.47)

OutcomeCQ 10-2Comparison between highand low level stimulation
was examined, because
research comparing with vs.
without vagus stimulation
is difficult to implement
due to issues in research
execution
The relative risk of seizure
frequency ≤50% for highlevel stimulation was 1.74
(1.14‒2.65), and wassignificantly superior to
low level.

Significant differences
between high level and low
level stimulation wereobserved for dysphonia/
hoarseness (relative risk
2.06, 1.34 to 3.17) anddyspnea (relative risk 2.43,
1.29 to 4.57). However, therelative risk of treatment
withdrawal was 2.51 (0.50
to 12.61), with no significant
difference between highlevel and low levelstimulation. It can beinferred that there are few
adverse events serious
enough to cause treatment
discontinuation. Adverse
effects are reversible andcan be controlled byadjusting electric current.

Digest Edition

189

BALANCE OF EFFECTS
COST ANDRESOURCEACCEPTABILITYFEASIBILITY

190

Does the balance
between desirable
and undesirable
effects favor theintervention or
the comparison?

- Control is superior- Control is probably
superior- Control andintervention areequivalent- Intervention isprobably superior- Intervention issuperior- It depends- Don’t know

Summary: High frequency stimulation is significantly superior for the outcomeof seizure frequency ≤ 50% (relative risk 1.74, 1.14‒2.65). For adverse events,
low level stimulation was significantly superior for dysphonia/hoarseness(relative risk 2.06, 1.34‒3.17) and dyspnea (relative risk 2.43, 1.29‒4.57).
Treatment withdrawal, cough, and pain did not differ significantly between two
groups.

How large are
the resource
requirement(cost)?

- High cost
- Moderate cost
- Negligible- Moderate saving- Large saving- Varies- Don’t know

Stimulation intensity can be adjusted by manipulating the programming wandlocated above the subcutaneously implanted generator, and resources and costs
are negligible. However, it is necessary to replace the generator once every few
years when the battery runs out, requiring exchange with a cost or about¥2,000,000 (covered by health insurance). Battery consumption is higher forhigh level stimulation than for low level stimulation.

Is the option
acceptable to key
stakeholders?

- No- Probably no- Probably yes- Yes- Varies- Don’t know

Is the option
feasible toimplement?

- No- Probably no- Probably yes- Yes- Varies- Don’t know

Part IIIn the past, there were several prefectures that did not have vagus nerve stimulation
device implantation facility or guidance/management facility, and access totreatment was poor in some regions. However, currently the criteria for adjusting
doctor have been relaxed and access has improved.
If the environment of access to device implantation facility and guidance/
management facility continues to improve, adjustment of stimulation condition
is feasible.

Systematic Review Digest

A list of facilities that can
provide this therapy isposted on the Society
website.

Recommendation decision table
Type of recommendation
Judgment

Strongrecommendation
against theintervention

Conditional
recommendation
against theintervention

Conditional
recommendation for
either the intervention
or the comparison

Conditional
recommendation for
the intervention

Strongrecommendation
for the intervention

◯

○

◯

◯

●

Recommendation

When conducting vagus nerve stimulation for drug resistant epilepsy, high level stimulation rather than low levelstimulation is recommended (GRADE 1C, strength of recommendation “strong recommendation”/certainty ofevidence “low”.

Justification

Question (CQ): When conducting vagus nerve stimulation for drug resistant epilepsy, should high-level stimulation or
low-level stimulation be used?
Patients (P): Patients with drug-resistant epilepsy who were implanted a vagal nerve stimulating device.
Intervention (I): High level stimulation
Comparison (C): Low level stimulation
Outcomes (O): Seizure frequency ≤50%, treatment withdrawal, dysphonia/hoarseness, cough, dyspnea, pain
Summary of evidence: Systematic review identified four RCTs (375 patients). For seizure frequency ≤50%, high levelstimulation was significantly superior (relative risk 1.74, 1.14‒2.65) [NNT 10]. Among adverse events, significant
differences were observed for dysphonia/ hoarseness (relative risk 2.06, 1.34‒3.17) and dyspnea (relative risk 2.43,
1.29‒4.57). The relative risk of treatment withdrawal was 2.51 (0.50‒12.61), with no significant difference between highlevel stimulation and low level stimulation groups.
Certainty of evidence: In all the studies collected, the risk of bias was low overall, and was not downgraded for all theoutcomes. For inconsistency of the results, I2 was 32% for only dysphonia and hoarseness. Since the effect estimate
differed between studies, heterogeneity was considered high. Inconsistency was thus considered serious and was
downgraded one rank. There was no problem with indirectness, which was not serious. As for imprecision, the confidence
intervals in many analyses crossed the clinical decision thresholds, and hence was downgraded by one or two ranks.
Regarding publication bias, there were only four studies, and therefore was not downgraded. Consequently, the certaintyof evidence for the outcomes was as follows: “moderate” for seizure frequency ≤50% cough, and dyspnea; and “low” fortreatment withdrawal, dysphonia/ hoarseness, and pain. The overall certainty of evidence was “low”.
Judgment of benefits and harms, burden and cost:
In 4 RCTs, high level stimulation was significantly superior for the outcome of seizure frequency ≤50% outcome. Amongthe adverse events, dysphonia/ hoarseness (relative risk 2.06, 1.34‒3.17) and dyspnea (relative risk 2.43, 1.29‒ 4.57) weresignificantly more frequent in high level stimulation, but both were transient. There was no significant difference intreatment withdrawal between two groups (relative risk 2.51, 0.50‒12.61). As for the burden and cost, it is expected thathigh level stimulation consumes more battery power and requires a higher frequency of generator exchange. Taking theabove into consideration, despite adverse events that do not lead to treatment withdrawal and the possibility of increases
in burden and cost, it is worth trying high level stimulation in anticipation of seizure control.
Recommendation:
When conducting vagus nerve stimulation for drug resistant epilepsy, high level stimulation rather than low levelstimulation is recommended (strength of recommendation “strong recommendation”/certainty of evidence “low”).
Additional considerations:Due to the problems with research execution, it is difficult to realize comparative study of vagus nerve stimulation versus
no stimulation. Therefore, there is an increase in RCT comparing high level stimulation versus low level stimulation.
Low level stimulation is generally treated as sham stimulation (placebo group). On the other hand, theoretically there
exists an argument: the fact that low level stimulation is harmful may account for the therapeutic effect observed whencompared with high level stimulation.

Subgroup considerations.
Consider how to set criteria
for patient population orintervention, which may
change therecommendation statement

There was one RCT in children (Klinkenberg 2012). The relative risk of 50% reduction of seizure frequency for high levelstimulation was 1.19 (0.94‒1.44), with no significant difference compared to low level stimulus. On the other hand, therelative risk of treatment withdrawal was 1.90 (1.75‒2.06) and was significantly higher. However, since the observation
period in this RCT was only 20 weeks, and therapeutic effect can be expected with prolonged treatment, this finding
alone cannot be used as evidence for withholding treatment.

Implementationconsiderations.
In clinical practice,problems such as feasibility
and tolerability may arise.

High level stimulation usually refers to the intensity of stimulation used in treatment. On the other hand, low levelstimulation refers to control stimulation (so-called sham stimulation) in which the stimulation frequency, pulse width,and stimulation frequency are set at low levels.
There may be a problem in the case of poor access to vagus nerve stimulation device implantation facility and guidance/
management facility due to changing residence and other reasons.

Monitoring andevaluation.
What monitoring isnecessary for
implementation? Is
evaluation of effectnecessary before or after
publication?

For adjustment of stimulation intensity, a system has to be in place to respond to complications and to cope withequipment troubles. The frequency of hospital visit is about once a month after implantation surgery, and once every 3months when the condition is stabilized.

Research possibilities.
What are the unclear
points in judgment that
require future research?

Further studies are needed to examine the optimal intensity of stimulation, elucidate the characteristics of subgroupdemonstrating high efficacy, and develop methods to identify the high responders. Also, apart from adjusting stimulation
intensity, there are no RCTs on other supplementary techniques such as magnet stimulation, which is a topic of future
research.

CQ 10-2

Digest Edition

191