Klinkenberg 2012.

Study characteristics
Methods	Randomised, double‐blinded add‐on, active‐control study in children with refractory focal seizures Pre‐randomisation baseline period: 12 weeks Duration of treatment phase: 20 weeks
Participants	A multicentre trial (the Netherlands) 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%); generalised 10% (Idiopathic 0, symptomatic 10%) Low‐output 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%); generalised 20% (Idiopathic 10%, symptomatic 10%) A small sample (6 participants) 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 focal 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 participants had an identical implantation of the vagus nerve stimulation device (NeuroCybernetic Prosthesis, Cyberonics).
Outcomes	Primary outcomes: Seizure frequency (50% reduction of seizures) Secondary outcomes: Treatment withdrawal Adverse events Intelligence quotient (IQ) assessment described in the methods section of the study
Notes	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 were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Investigators were blinded. Identical implants used
Incomplete outcome data (attrition bias) All outcomes	Low risk	3 participants withdrew, but the reasons for exclusion were 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 a priori outcomes.
Other bias	Unclear risk	All studies were sponsored by Cyberonics, the manufacturer of the device.