Klinkenberg 2012.

Methods	Randomised, double‐blinded add‐on, active‐control study in children with refractory partial seizures. Pre‐randomisation baseline period: 12 weeks. Duration of treatment phase: 20 weeks.
Participants	A multi‐centre trial (Holland). 41 people randomised. High‐output stimulation group: 21 participants; mean age at onset 2:10 (y:mo); median age at onset 1:2 (y:mo); mean age at implantation 10:11 (y:mo); 11/10 male/female; median seizures/day 2.1; Localisation related 90% (symptomatic 71%, cryptogenic (19%); Generalized 10% (Idiopathic 0, symptomatic 10%). Low‐ouput stimulation group: 20 participants; mean age at onset 1:8 (y:mo); median age at onset 1:2 (y:mo); mean age at implantation 11:6 (y:mo);12/8 male/female; median seizures/day 0.9; Localisation related 80% (symptomatic 50%, cryptogenic (30%); Generalized 20% (Idiopathic 10%, symptomatic 10%). A small sample (6 patients) had generalised epilepsy (2 idiopathic and 2 symptomatic).
Interventions	Comparison of high (output current 0.25 mA, duty‐cycle on/off 30 s/5 min, frequency 30 Hz, pulse width 0.5 ms) and low (output current 0.25 mA, duty‐cycle on/off 14 s/60 min, frequency 1 Hz, pulse width 0.1 ms) stimulation frequency in treatment of refractory partial seizures. In the treatment group the current was increased stepwise at 2 week intervals to the maximally tolerated output current (maximum 1.75 mA). All patients had an identical implantation of the vagus nerve stimulation device (NeuroCybernetic Prosthesis, Cyberonics).
Outcomes	Primary outcomes: Seizure frequency (50% reduction of seizures). Secondary outcomes: a) Dropouts. b) Adverse events. c) Intelligence quotient (IQ), assessment described in the methods section of the study.
Notes	AALBERS 2012 NeuroImmunoModulation is linked to this study. Supported by Cyberonics, Inc., Webster, TX.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated randomisation method used.
Allocation concealment (selection bias)	Low risk	Participants were allocated to a treatment condition by one trial nurse using a computer program.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Neurologist, participants and parents are blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Investigators are blinded. Identical implants used.
Incomplete outcome data (attrition bias) All outcomes	Low risk	3 patient withdrawals, but the reasons for exclusion are reported.
Selective reporting (reporting bias)	High risk	The secondary outcome of IQ described in the methods was not reported in the results. There was no protocol available to check to priori outcomes.
Other bias	Unclear risk	All studies are sponsored by Cyberonics, the manufacturer of the device