Table 2.

Advanced RCTs on new non-pharmacological treatments for epilepsy.

References	Type of RCT and treatment	Study population (n° of pts, type of epilepsy, mean age ± SD)	Previously tested vs. concomitant ASMs (range, mean)	Primary end point	Outcomes
Orosz et al. (31)	Retrospective, open-label, multicenter study VNS Therapy, Cyberonics	347 pts with DRE of any type M 2.7 ± 3.0 y	1–27, M 6.9 1–6, M 3.0	Change in the “predominant sz type” frequency at 12 months of FU	- 5.5% pts became sz free (i.e., no sz of the “predominant sz type”) - 32.1% pts achieved ≥50% sz reduction - 17.1% pts had a 25–49% sz reduction - The percentage of responders increasing over time: 32.5%, 37.6%, and 43.8% at 6, 12, and 24 months of FU
Boon et al. (32)	Prospective, observational, unblinded, multicenter study Model 106 VNS Therapy System	31 pts with focal-onset sz, iTC, and DRE M 39.6 ± 13.4 y	na na	≥80% sensitivity for iTC sz in at least one CBSDA, and investigate FP rate	- 37/66 (56%) sz were associated with a ≥20% heart rate increase - 11/66 (17%) sz were associated with iTC (55% or 35 bpm heart increase from baseline, minimum 100 bpm) - ≥80% sz detection sensitivity achieved in multiple CBSDA - FP rate ranged from 0.5 to 7.2/h
Bergey et al. (37)	Prospective, open-label, multicenter study RNS System, NeuroPace	230 pts with focal-onset sz, sGTC sz, and DRE (feasibility and pivotal studies already completed) M 34.0 ± 11.4 y	na 0–8, M 2.9	Long-term efficacy and safety of RNS	- 66% median reduction in sz at 6 y of FU with a RR of 56% - Improvements in QoL were maintained at 5 y of FU (p < 0.05) - Most common serious device-related AEs (5.4 y of FU) were implant site infection (9.0%) and neurostimulator explantation (4.7%)
DeGiorgio et al. (40)	Double-blind, parallel-group, phase 2, multicenter RCT External pulse generator for eTNS	50 pts with focal-onset sz, sGTC sz, and DRE M 33.7 y	na, M 3.35 na	Change in mean monthly SF, and RR (>50% sz reduction), time to the fourth sz	- 16.1% reduction in sz frequency for the treatment group vs. 10.5% reduction for the control group - 30.2% RR for the treatment group vs. 21.1% RR for the control group - Net increase 2.5 d (20%) to fourth sz in the treatment group vs. decrease 5 d (21.7%) in the control group (p = 0.73)

AEs, adverse events; ASMs, antiseizure medications; bpm, beats per minute; CBSDA, cardiac-based seizure detection algorithm; DRE, drug-resistant epilepsy; eTNS, external trigeminal nerve stimulation; FP, false positive; FU, follow-up; h, hours; iTC, ictal tachycardia; M, mean; n°, number; na, not assessed; Pts, patients; RCT, randomized clinical trial; Ref, reference; RNS, responsive neurostimulation; RR, retention rate; SF, seizure frequency; sGTC, secondarily generalized tonic-clonic; sz, seizures; VNS, vagal nerve stimulation; y, years.