What defines response to vagus nerve stimulation in children with drug-resistant epilepsy? A prospective cohort study from the CONNECTiVOS collaboration

Abstract

Objectives: Responsiveness to vagus nerve stimulation (VNS) in children with drug-resistant epilepsy (DRE) is often defined based on reduction in seizure frequency, typically at the 50% threshold, with limited consideration to the effects of therapy on seizure severity and health-related quality of life (HRQoL). In the current report, we sought to better characterize the effects of VNS beyond seizure frequency in children with DRE.

Methods: Sixty-seven children from the Connectomic profiling and Vagus nerve stimulation Outcomes Study (CONNECTiVOS) database, a multicenter study including children aged 0-18 who underwent VNS at eight North American centers, were included. Data were collected prospectively at baseline and 6, 12, and 24 months after VNS. Seizure outcomes were assessed using the 50% threshold, percentage change in seizure count and change on a frequency timescale, a categorical measure of seizure occurrence (e.g., daily to weekly seizures). The Seizure Severity Questionnaire and the Quality of Life in Childhood Epilepsy were also collected. Linear mixed models were constructed to study longitudinal changes in seizure severity and HRQoL.

Results: Among 67 children, 55.2% experienced >50% reduction in seizures, whereas only 37.3% demonstrated reductions in seizure timescales. Notably, 17.9% experienced no reduction in timescales despite meeting the 50% threshold. Furthermore, 31.9% of children experienced a meaningful improvement in seizure severity without any reduction in seizure timescales. HRQoL improvements were driven by the reduction in timescales (mean yearly increase of 3.65; 95% confidence interval [CI]: 0.71-6.52, p = 0.023), rather than responsiveness based on the 50% threshold or percentage change in seizure counts (p > 0.05). Reduced overall seizure severity was also independently associated with higher HRQoL after VNS (p = 0.035).

Significance: The conventional 50% responder threshold failed to capture meaningful gains in HRQoL, which aligned more closely with seizure timescales. Furthermore, nearly one-third of children realized improvements in seizure severity without any reduction in timescales. Improvements in both seizure frequency timescales and seizure severity drive postoperative HRQoL gains.

Keywords: drug‐resistant; epilepsy; epilepsy surgery; pediatric epilepsy; quality of life; vagus nerve stimulation.

FIGURE 1

Long‐term changes in seizure frequency after VNS. (A) Overall response to VNS based on >50% reduction in seizure frequency. Percentage reduction in seizures at 6, 12, and 24 months post‐VNS. (B) Seizure frequency timescales at baseline and final follow‐up at either the 12‐month or the 24‐month follow‐up. Overall response to VNS at 6, 12, and 24 months based on reduction in sliding seizure timescales. Dissociation between the 50% reduction threshold and reduction in seizure timescales. Benefit at 12‐ or 24‐month follow‐up based on early reduction in sliding timescales at 6 months. VNS, vagus nerve stimulation.

FIGURE 2

Long‐term changes in seizure severity after VNS. (A) Significant and clinically meaningful reduction in the total score and all subscales of the SSQ at the 12‐ and 24‐month follow‐ups. (B) Change in the total SSQ score and the overall seizure severity and bothersomeness of all seizures based on reduction in seizure timescales at the final follow‐up. (C) Dissociation between reduction in seizure severity and change in seizure frequency based on the >50% reduction in seizure frequency or reduction in sliding timescales. VNS, vagus nerve stimulation.

FIGURE 3

Long‐term changes in HRQoL after VNS. (A) Overall QOLCE score over time. The proportion of children who experienced a clinically significant improvement in HRQoL at the 6‐, 12‐, and 24‐month follow‐ups. (B) Mean overall QOLCE at each timepoint based on the 50% reduction threshold in seizure frequency and a reduction in seizure timescales at the final follow‐up. Postoperative HRQoL change at each timepoint based on meaningful reduction in the overall severity and bothersomeness of all seizures. VNS, vagus nerve stimulation.