Neuromodulation for Drug-Resistant Epilepsy in Children

Hyoung Won Choi

doi:10.26815/acn.2026.01515

Ann Child Neurol > Volume 34(3); 2026 > Article

Choi: Neuromodulation for Drug-Resistant Epilepsy in Children

Review article

Annals of Child Neurology 2026;34(3):181-191.

Published online: July 1, 2026

DOI: https://doi.org/10.26815/acn.2026.01515

Neuromodulation for Drug-Resistant Epilepsy in Children

Hyoung Won Choi, MD

Division of Neurology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA

Corresponding author: Hyoung Won Choi, MD Division of Neurology, Department of Pediatrics, Emory University School of Medicine, 1400 Tullie Rd NE Suite 420, Atlanta, GA, USA
Tel: +1-404-785-5437 Fax: +1-404-785-4750 E-mail: hwchoi6@emory.edu

Received March 28, 2026 Revised April 23, 2026 Accepted April 25, 2026

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Neuromodulation has emerged as a promising therapeutic strategy for drug-resistant epilepsy. For several modalities, long-term follow-up data are now available in adults; however, high-level evidence supporting their use in children remains limited. Vagus nerve stimulation has long been used to treat drug-resistant epilepsy in both adults and children. In contrast, responsive neurostimulation and deep brain stimulation are not formally approved for pediatric use worldwide, although they are offered off-label in select healthcare systems. This narrative review summarizes the current literature on neuromodulation for pediatric epilepsy, focusing on mechanisms of action, efficacy, patient selection, and safety.

Keywords: Epilepsy; Vagus nerve stimulation; Deep brain stimulation

Introduction

Drug-resistant epilepsy (DRE) presents a substantial therapeutic challenge in children and often requires multiple treatment modalities. Neuromodulation therapy has emerged as an option for patients with DRE, especially when they are not candidates for resective surgery due to multifocal or diffuse seizure foci, seizure foci overlapping eloquent cortex, or a preference for less invasive approaches [1-3]. Neuromodulation refers to the electrical modification of neural signal transmission through dynamic, ongoing modulation of specific neural networks using adjustable stimulation parameters [4]. Unlike ablative or resective epilepsy surgery, neuromodulation is non-ablative, reversible, and adjustable.

Several neuromodulation techniques are available, depending on the region of the nervous system targeted and the method by which stimulation is delivered (Table 1). Vagus nerve stimulation (VNS) has long been used as adjunctive therapy for pediatric epilepsy. In contrast, responsive neurostimulation (RNS) and deep brain stimulation (DBS) are not formally approved for pediatric use worldwide due to limited data, although both are offered off-label in select healthcare systems. This review provides a comprehensive overview of the major neuromodulation modalities used to treat DRE, focusing on their mechanisms of action, efficacy, and safety based on the most current evidence.

Vagus Nerve Stimulation

The concept of stimulating the vagus nerve to treat seizures originated with Dr. James Corning, an American neurologist who, in the 1880s, proposed that epilepsy arose from cerebral hyperemia and attempted to reduce cerebral blood flow through carotid artery compression and transcutaneous VNS [5]. With continued advances in stimulation techniques, VNS has become the most widely available form of neuromodulation worldwide for both children and adults. VNS systems consist of an implantable pulse generator and a lead wire. The device is implanted subcutaneously in the left upper chest, and the lead wire is attached to the generator and wound around the left vagus nerve in the neck (Fig. 1).

1. Mechanism of action

VNS systems function by activating fast afferent myelinated A and B fibers of the vagus nerve [6,7] through an appropriate volume of electrical impulses determined by output current and pulse width. The vagus nerve transmits signals to the nucleus tractus solitarius in the brainstem, from which vagal afferent information is relayed through second-order neurons to key brainstem structures, including the noradrenergic locus coeruleus, serotonergic raphe nuclei, cerebellum, periaqueductal gray, and parabrachial nuclei [8,9]. The ascending vago-solitario-parabrachial pathways provide dense innervation to the limbic system and other cortical areas [10-12]. Consistent with this neuroanatomical framework, VNS has been reported to modulate gamma-aminobutyric acid, glycine, other amino acid pools, and receptor densities [13-16]. Anti-inflammatory effects have also been postulated as a potential mechanism of VNS in studies that evaluated VNS-induced changes in proinflammatory cytokines and tryptophan metabolites in peripheral blood [17-19]. The long-term antiseizure effects of VNS are thought to be associated with chronic stimulation-related modification of neural circuitry across large-scale brain regions, including brainstem nuclei, subcortical nuclei, and cortical structures [20-23].

In summary, modulation of the vagal afferent network by an implanted VNS device appears to trigger a cascade of neurochemical and electrophysiological events that originate in the brainstem and extend to the limbic system and, ultimately, the cortex [7]. This cascade may disrupt abnormal functional connectivity in epileptogenic networks and thereby contribute to long-term antiseizure effects.

2. Efficacy

Although numerous studies have evaluated VNS as a treatment for DRE, prospective controlled trials focused on pediatric DRE remain limited. The first randomized controlled trial comparing low-output (0.25 mA) and high-output (maximum of 1.75 mA) VNS in 41 children with DRE reported responder rates (RRs; defined as ≥50% reduction in seizure frequency) of 16% in the high-output group and 21% in the low-output group at the end of the 20-week blinded phase [19]. After an additional 19 weeks of VNS treatment, during which all participants received high-output stimulation, the RR reached 26%. A recent meta-analysis of 99 studies comprising 3,474 pediatric patients (≤18 years of age) reported pooled prevalence estimates of 56.4% for RR (95% confidence interval [CI], 52.4% to 60.4%) and 11.6% for seizure freedom (95% CI, 9.6% to 13.9%) [24]. This higher RR may be partly attributable to longer follow-up (mean, 2.54 years) and advances in device technology; however, most studies included in this meta-analysis were retrospective and observational, and modification of antiseizure medication was allowed.

The Comprehensive Outcomes Registry in Subjects with Epilepsy Treated with VNS (CORE-VNS) is a global prospective registry designed to examine the safety and effectiveness of VNS therapy in real-world settings [25]. The study was officially launched and began enrolling patients in May 2018, and two recently published subgroup analyses have important implications for the treatment of pediatric DRE. The 24-month interim analysis of patients with generalized tonic-clonic seizures (GTCS) at baseline (n=115; age range, 2.6 to 67.9 years) showed a median GTCS reduction of 73.9%, with 37% of participants reporting freedom from GTCS during the 3 months before the 12-month follow-up [26]. Another CORE-VNS subgroup analysis, which focused on patients with Lennox-Gastaut syndrome (LGS) (n=60; age range, 2.2 to 47.6 years), reported RRs of 66.7% and 47.4% for focal and generalized seizures, respectively, at the 24-month follow-up [27].

In one study comparing seizure outcomes and quality of life between early (≤5 years of age) and late (>5 years of age) VNS implantation in children, age had no effect on post-implantation seizure frequency; however, the younger group had better cognitive and quality-of-life outcomes [28]. Similarly, many VNS clinical trials have reported benefits across various quality-of-life measures during VNS treatment, including improvements in alertness, verbal communication, memory, and mood [29,30]. Another single-center retrospective study associated early VNS implantation, defined as implantation less than 2 years after epilepsy onset, with better seizure outcomes [31]. These findings are consistent with the hypothesis that a shorter duration of uncontrolled epilepsy before VNS implantation may allow less time for abnormal circuitry to become established, highlighting the importance of considering VNS earlier in the treatment course for DRE [32].

3. Patient selection

VNS patient selection centers on identifying individuals with DRE who are not suitable candidates for resective surgery or in whom surgery has failed [33]. Three pivotal clinical trials of VNS for DRE in adolescents and adults demonstrated efficacy in focal epilepsy [34-36], and successful VNS use has also been reported in many children with generalized epilepsy [37-39]. No specific seizure etiology has been shown to predict a favorable VNS response. Unlike RNS and DBS, VNS is an extracranial procedure and therefore avoids the risks associated with intracranial surgery. For patients seeking the least invasive epilepsy surgery option, VNS may be considered before resective surgery, RNS, or DBS [33].

4. Programming

VNS therapy ‘dosing’ is defined by five interrelated stimulation parameters: output current, signal frequency, pulse width, signal-on time, and signal-off time [40]. Modern VNS systems use three stimulation modes. In normal mode, cyclic stimulation is delivered automatically at programmed intervals [41,42]. In patient-triggered manual mode, a magnet is swiped over the pulse generator to deliver an additional stimulation dose intended to stop a seizure or shorten a seizure cluster. In auto-stimulation mode, heart rate variability is used as a marker of potential ictal onset, and an additional stimulation dose is delivered when the preset tachycardia threshold is met. Auto-stimulation mode has been available since the introduction of the AspireSR® Model 106 (Cyberonics Inc., Houston, TX, USA) in 2015 and, subsequently, the Sentiva® Model 1000 (LivaNova USA Inc., Houston, TX, USA) in 2017 [43].

High-level evidence supporting an optimal dose–response relationship for VNS therapy is lacking. Standard parameter settings, as determined in clinical trials and outlined by Heck et al. [42], include a frequency of 20–30 Hz, pulse width of 250–500 µs, output current of 1.50–2.5 mA, signal-on time of 30 seconds, and signal-off time of 5 minutes. Recently published consensus-based guidelines emphasize proactive use of available stimulation options through the fastest safe titration schedules [33,44]. In this context, rapid duty cycling (RDC) and ultra-rapid duty cycling (URDC) have gained attention as methods for improving seizure control in medically refractory epilepsy by reducing stimulation-off times.

In one retrospective pediatric study, switching from a normal duty cycle to RDC (off time, 1.1 minutes; duty cycle <50%) increased the RR from 45.5% to 77.3% [45]. The same group also compared URDC (on time, 7 seconds; off time, 0.2 minutes) with less frequent stimulation delivered using RDC (off time, <1.1 minutes) and normal duty cycling (off time, 1.1 minutes) in 36 pediatric patients with medically refractory absence seizures [46]. After a mean follow-up of 32.6 months, the RR reached 80% with URDC, 78.57% with RDC, and 66.67% with normal duty cycling. Six of 10 patients (60%) receiving URDC achieved complete seizure freedom.

5. Safety

The side effects of VNS are primarily stimulation-related and reversible [15], with coughing, shortness of breath, and voice changes reported most frequently. These side effects are typically mild and tend to improve over time or with adjustment of stimulation settings [33]. Other potential VNS-related adverse effects include stimulation-related paresthesia, headache, pharyngitis, pain, obstructive sleep apnea, surgical complications (vascular injury, nerve injury, and surgical-site wound infection), and bradyarrhythmia [39,47-49]. Despite the extensive vagal network distributed across multiple organ systems, major clinical trials of VNS have not reported significant cardiac or gastrointestinal complications.

Responsive Neurostimulation

The RNS^® System (NeuroPace Inc., Mountain View, CA, USA) is a closed-loop neuromodulation technology that delivers electrical stimulation only in response to detected patterns of brain activity that precede seizures in an individual patient [50]. The stimulating device is implanted within the skull and delivers stimulation through electrodes placed at the estimated seizure foci (Fig. 2) [51].

1. Mechanism of action

The RNS System is based on the concept that electrical stimulation of the brain in response to epileptiform activity can reduce seizure frequency and severity, an idea originally posited by Penfield and Jasper [52]. Later, Lesser et al. [53] used afterdischarges (ADs) as a model of epileptiform activity and observed that brief bursts of pulse stimulation decreased AD duration, supporting the concept that electrical stimulation applied at seizure onset can abort seizures. The exact mechanism of action of the RNS System is not fully understood; however, clinical experience, advanced neuroimaging, and analyses of device-recorded data have helped clarify how the device may produce long-term antiseizure effects [54]. Although the RNS System was initially intended to stop seizures immediately, studies have shown that it also produces slower, long-term changes in brain dynamics that better predict clinical outcomes [55,56]. An analysis of stimulation effects on electrographic seizure patterns in electrocorticography showed that immediate inhibition of these patterns was not associated with clinical outcomes, whereas indirect effects—defined as changes occurring before seizure onset or after a latency of more than 10 seconds following stimulation—were associated with outcomes [57]. The slow and progressive time course of seizure reduction with RNS System therapy provides additional evidence for an indirect neuromodulatory effect of the RNS System on seizure-generating brain networks [58].

2. Efficacy

The RNS System was approved by the U.S. Food and Drug Administration in 2013 for adults with medically intractable focal epilepsy. Previously, a multicenter randomized controlled trial (n=191) had demonstrated a 38% reduction in seizures in treated individuals (n=97) versus 17% in the sham group (n=94; P=0.012) during the 3-month blinded phase [59]. Longer follow-up studies showed subsequent seizure reductions of 53% after 2 years and 75% after 9 years of open-label stimulation [60,61]. RNS System therapy has not yet been thoroughly studied in children; however, the available data are promising. A multicenter combined prospective and retrospective study of patients aged ≤18 years who underwent RNS System implantation (n=51) reported a 65% RR (33/51), including seizure freedom in 10% of patients (5/51), at a mean follow-up of 11.7 months [62]. The Nautilus study is a randomized controlled trial of the RNS System evaluating whether the therapy produces a statistically significant reduction in GTCS in patients aged 12 years or older with drug-resistant idiopathic generalized epilepsy. Preliminary 18-month data presented at the 2025 American Epilepsy Society meeting showed a 77% median reduction in GTCS.

3. Programming

RNS System programming is a patient-specific, closed-loop process in which detection and stimulation parameters are iteratively adjusted based on recorded electrocorticography. Programming typically begins approximately 1 month after implantation and initially prioritizes optimization of detection algorithms to reliably capture electrographic seizures within seconds of onset before stimulation is enabled. Initial settings are conservative; commonly used parameters include high-frequency stimulation (approximately 100 to 200 Hz), 160-µs pulse width, 100-ms burst duration, and low current amplitudes of approximately 1 mA, consistent with pivotal trial configurations [60,62,63].

Subsequent optimization is guided by longitudinal electrocorticography review, with gradual titration of stimulation that often involves increasing current in 0.5-mA increments every few months as tolerated. Target charge density is typically tailored to anatomical location, with lower limits for mesial temporal structures (approximately 2 µC/cm²) and higher thresholds for neocortical targets (up to approximately 6 µC/cm²) [64,65]. Burst duration and frequency may be adjusted in refractory cases to improve seizure control [66]. This data-driven approach highlights both the major strength and a limitation of the RNS System in children: it enables highly individualized therapy and continuous biomarker-informed optimization, but it also requires sustained expertise, frequent follow-up, and reliable long-term access to specialized epilepsy care teams, which may limit broader applicability in pediatric practice.

4. Patient selection

Patient selection is critical for successful RNS System therapy. The RNS System is designed to deliver electrical stimulation to seizure foci or key nodes in the epileptogenic network. In clinical practice, the RNS System is most frequently indicated when medically refractory focal seizures originate in or propagate through highly eloquent cortex, such as motor, language, or sensory areas, where surgical resection poses an unacceptable risk of functional deficit. Ideal candidates for RNS System therapy were initially thought to have well-defined seizure foci identified by imaging, scalp electroencephalography, and intracranial monitoring. However, patients with poorly demarcated and spatially extensive regional neocortical seizure foci may also respond well to the RNS System, even though the electrical stimulation fields near the intracranial electrodes are smaller than the seizure-focus area [67]. Emerging evidence suggests that RNS may also be feasible for patients with diffuse or multifocal epilepsy, including approaches that use thalamic targeting [68,69].

5. Safety

The RNS System demonstrates a favorable safety profile in both adult and pediatric populations with DRE. Long-term adult follow-up studies of up to 9 years reported no serious adverse effects related to stimulation, and the rate of sudden unexplained death in epilepsy was significantly lower than predefined comparators (P<0.05, one-tailed χ²) [61]. Complications reported in pediatric RNS studies include malpositioned leads and transient weakness, occurring in 5.3% of patients [62].

Deep Brain Stimulation

DBS differs from RNS in that it is an open-loop system that delivers scheduled electrical current to the brain parenchyma independent of local or distant physiological feedback [58]. DBS was widely used to treat movement disorders before gaining momentum in epilepsy therapy. The procedure involves implanting stimulating electrodes into deep brain structures; the electrodes are connected through a subcutaneous wire to a pulse generator on the chest wall. Clinicians use a tablet device to communicate with the implanted pulse generator (IPG) and adjust programming parameters to maximize seizure control while minimizing side effects.

1. Mechanism of action

The precise mechanism of action of DBS in epilepsy is not fully understood. Notably, studies have shown that simply inserting DBS electrodes into the target structure can reduce seizure activity even before stimulation is initiated [70,71]. This phenomenon, also observed in RNS trials, is referred to as the ‘insertional effect’ or ‘microthalamotomy’ and suggests that electrode insertion itself may contribute to the therapeutic effect of DBS. Several preclinical studies have shown that electrode insertion leads to a series of inflammatory responses resulting from interactions between the biomaterial and surrounding neural tissue after microtrauma to the brain parenchyma [72-74]. These responses may ultimately contribute to the functional reorganization of the epileptogenic network.

In contrast to RNS, DBS has benefited from well-established rodent models that provide direct access for evaluating underlying neurophysiological and molecular mechanisms. At the molecular level, many in vitro and animal studies have demonstrated roles for adenosine [75,76], differential microRNA regulation [77], and inflammatory pathway modulation [78,79] in the mechanism of action of DBS. At the network level, DBS appears to act not only at the stimulation site but also by altering the dynamics of interconnected brain regions [80,81].

Selecting a DBS target requires an understanding of the overall epileptogenic network and the anatomical hubs that play key roles in seizure propagation [71,82]. Several brain regions have been identified as potential DBS targets for epilepsy. The anterior nucleus of the thalamus (ANT) is typically targeted for limbic seizures because of its involvement in the Papez circuit [83]. The centromedian nucleus of the thalamus (CMT) is considered a promising target for generalized epilepsy because of its diffuse connections with the brainstem, including the reticular formation, nucleus solitarius, and nucleus ambiguus, as well as the basal ganglia, insula, and cortical regions [84-86]. In addition, the CMT is a presumed propagation point in the epileptic network in LGS, which has been suggested to involve a cortically driven network that subsequently engages the thalamus and brainstem [87,88]. DBS targeting the pulvinar nucleus of the thalamus is an emerging treatment that appears safe and effective, particularly for posterior quadrant focal epilepsy [85].

2. Efficacy

DBS has established efficacy in adult DRE, supported by level I evidence from the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial. In this multicenter randomized controlled study of 110 adults with focal epilepsy, DBS produced a greater reduction in seizure frequency than control treatment during the blinded phase (40% vs. 15% median reduction at 3 months), with durable long-term benefit demonstrated at 5 to 7 years (median reduction up to 79%) [83,89,90]. The Electrical Stimulation of Thalamus for Epilepsy of Lennox-Gastaut Phenotype (ESTEL) trial extended these findings to LGS, showing that centromedian thalamic DBS yielded a 59% electrographic RR during the blinded phase, although functional and cognitive outcomes did not improve significantly [91].

In contrast, pediatric evidence remains limited to observational data, with no randomized controlled trials available to guide clinical decision-making. Reported pediatric experience suggests meaningful seizure reduction in most patients (approximately 85%), but complete seizure freedom is uncommon (approximately 12%), and the data are derived from small, heterogeneous cohorts [92,93].

Clinically, these findings indicate that although DBS is an evidence-based option in adults and is increasingly used in selected pediatric cases, its application in children remains extrapolative. Treatment decisions require careful consideration of developmental neurobiology, limited long-term safety data, and the possibility that pediatric outcomes may differ from adult outcomes despite similar seizure network targets.

3. Patient selection

The antiseizure effects of DBS vary significantly among individuals in existing studies. Factors associated with outcomes include electrode positioning, stimulation parameters, epilepsy type, and stimulation duration [94]. According to the pivotal SANTE trial of DBS-ANT, only the subgroup with temporal lobe seizures had a sufficient sample size to demonstrate a significant treatment effect [83]. In long-term follow-up beyond 2 years, patients with frontal lobe seizures also showed significant improvement; however, the efficacy of ANT stimulation for parietal, occipital, and multifocal seizures remains unclear [89,90]. DBS targeting the CMT is a promising treatment for pediatric generalized and/or multifocal epilepsies, although it is not yet approved for this indication in any major jurisdiction [91,95-98].

4. Programming

Individualized optimization of DBS programming for epilepsy remains challenging because the clinical benefits may have a delayed onset. Programming protocols established in pivotal trials are generally followed and then combined with trial-and-error adjustments. Recently commercialized IPGs include sensing features that allow chronic bioelectric recordings, which may provide useful objective information regarding patients’ clinical status (Percept by Medtronic, Dublin, Ireland). Neuronal signals recorded through the IPG are interpreted as local field potentials (LFPs), which reflect summed synchronized electrical activity [99]. Several proof-of-principle pilot studies have demonstrated the feasibility of LFP-based DBS programming [99,100], although the clinical benefits of brain sensing in DBS have not been fully established.

5. Safety

In the SANTE trial, the most frequent serious adverse events reported at any time after implantation were infection (10.0%) and leads not within the target (8.2%); all other events occurred in 1.8% or fewer of participants [90]. Depressive events were reported in 37.3% of patients at some point after implantation; three events in three participants were considered device-related. The ESTEL trial reported a similar adverse-event profile, including infection-related device removal (1/20), postoperative drowsiness (12/20), and paresthesia [87].

Conclusion

Neuromodulation is a promising, safe, and effective therapy for pediatric DRE. Successful neuromodulation has been documented in several pediatric epilepsy syndromes that are typically refractory to currently available medical therapies, including tuberous sclerosis [101-103], Dravet syndrome [104,105], hypothalamic hamartoma [106], and progressive myoclonic epilepsy [107]. Choosing among VNS, RNS, and DBS for children with DRE requires integration of epilepsy localization, epilepsy syndrome, age-related anatomical considerations, and evidence of efficacy. The extent to which seizure foci can be anatomically localized is the principal factor guiding device selection. VNS is generally favored in children with generalized, multifocal, or poorly localized epilepsy because it does not require precise localization of the seizure-onset zone and exerts broad neuromodulatory effects through afferent projections to thalamocortical and limbic networks. This broad applicability has made VNS the most widely used neuromodulation strategy in children. In contrast, RNS is best suited for patients with one or two well-defined epileptogenic foci, particularly when those foci overlap functionally eloquent cortex or are bilateral. DBS, especially centromedian thalamic DBS, has shown promise in generalized epilepsies such as LGS, with small pediatric studies reporting meaningful seizure reduction. However, DBS remains less established than VNS in this population and is typically reserved for patients in whom VNS has failed or for cases in which network-level thalamic modulation is specifically desired. Age and body habitus are important considerations in pediatric neuromodulation. VNS is the least invasive modality and has been safely implanted even in infants and very young children, making it an attractive first-line neuromodulatory option in younger patients. Because the generator is implanted in the chest and the lead is extracranial, VNS avoids the challenges of cranial implantation in small children. RNS and DBS require intracranial implantation, which introduces additional considerations related to skull thickness, cranial size, and device fit. These factors may limit use in smaller children, although successful implantation has been reported in children younger than 10 years.

The evidence supporting neuromodulation in children consists primarily of open-label studies. In the absence of pediatric randomized controlled trials, efficacy data for RNS and DBS are largely extrapolated from adult studies; however, such extrapolation warrants caution because developmental neurobiology, age-dependent network organization, anatomical constraints, and long-term safety considerations may differentially influence outcomes in children. Several important gaps also remain in the application of neuromodulation for pediatric DRE, including the absence of head-to-head comparative studies of VNS, RNS, and DBS; limited understanding of optimal patient selection and intervention timing; uncertainty regarding the most effective stimulation targets and parameters for specific epilepsy syndromes; and limited knowledge of the long-term neurodevelopmental, cognitive, and psychosocial effects of chronic neurostimulation in the developing brain. Collaborative efforts, such as the Child & Youth Comprehensive Longitudinal Database for Deep Brain Stimulation project led by the University of Toronto and the Pediatric Epilepsy Research Consortium in the United States, aim to standardize data collection from children undergoing epilepsy surgery, including neuromodulation [92]. These initiatives will be instrumental in addressing existing knowledge gaps and informing future guidelines for the safe and effective use of neuromodulation in children.

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Author contribution

Conceptualization: HWC. Data curation: HWC. Formal analysis: HWC. Writing-original draft: HWC. Writing-review & editing: HWC.

Fig. 1.

Vagus nerve stimulation (VNS) system. (A) Implantation of a VNS pulse generator, most commonly in the upper chest wall, and insertion of a helical coil electrode wrapped around the vagus nerve within the carotid sheath for stimulation. (B) The programmer and wand connect wirelessly. The clinician can interrogate the generator to adjust therapy parameters, assess generator and lead function, view device histories, and export session reports. (C) The magnet allows patients and caregivers to manually deliver an extra dose of therapy, which can stop a seizure once it starts (Courtesy of LivaNova Inc.).

Fig. 2.

Responsive neurostimulation (RNS^®) system. (A) Implantable RNS® System, consisting of a neurostimulator and cortical strip lead and/or depth lead. (B) The patient uses the remote monitor and wand to gather information from the implanted neurostimulator and upload it to the Patient Data Management System (Courtesy of NeuroPace Inc.).

Table 1.

Key differences between neuromodulation therapies

	VNS	DBS	RNS^® system
Target site	Vagus nerve	Thalamus	Seizure focus
Device location	Chest	Chest	Cranium
Mechanism	Open-loop	Open-loop	Closed-loop
Indication	Generalized, multifocal, or poorly localized epilepsy	Multifocal or network-based epilepsy without single resectable foci	Focal epilepsy with 1–2 well-localized, unresectable seizure foci
Key advantages	Least invasive; broad applicability; extensive pediatric experience and safety data	Provides chronic intracranial EEG data; personalized closed-loop therapy	Effective in generalized and multifocal epilepsy
Main limitations	Delayed response	Programming complexity; limited pediatric long-term data	Requires precise localization; limited pediatric experience

VNS, vagus nerve stimulation; DBS, deep brain stimulation; RNS, responsive neurostimulation; EEG, electroencephalography.

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