Responsive neurostimulation in pediatric patients with drug-resistant epilepsy

Nicole FallsDepartment of Neurosurgery, Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix; and
University of Arizona College of Medicine, Phoenix, Arizona

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Jorge I. ArangoDepartment of Neurosurgery, Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix; and

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P. David AdelsonDepartment of Neurosurgery, Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix; and

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OBJECTIVE

Medically refractory epilepsy remains a therapeutic challenge when resective surgery is not a practical option and indirect neurostimulation efficacy may be limited. In these instances responsive neurostimulation (RNS) has been used in adults, with good outcomes in most patients. However, the utility of RNS in children and young adults has not been systematically explored. In this study, the authors present a single institution’s experience with RNS in pediatric patients.

METHODS

A single-center retrospective chart review of patients who underwent RNS implantation at Phoenix Children’s Hospital during the 4-year period between January 2018 and December 2021 was performed.

RESULTS

Following evaluation for epilepsy surgery, 22 patients underwent RNS implantation using different anatomical targets depending on the predetermined epileptic focus/network. In the cohort, 59% of patients were male, the mean age at implantation was 16.4 years (range 6–22 years), and the mean follow-up time was 2.7 years (range 1.0–4.3 years). All patients had a preoperative noninvasive evaluation that included MRI, video-electroencephalography, and resting-state functional MRI. Additionally, 13 patients underwent invasive monitoring with stereo-electroencephalography to help determine RNS targets. All patients had variable positive responses with reduction of seizure frequency and/or intensity. Overall, seizure frequency reduction of > 50% was seen in the majority (86%) of patients. There were two complications: one patient experienced transitory weakness and one generator failed, requiring replacement. A patient died of sudden unexpected death in epilepsy 3 years after implantation despite being seizure free during the previous year.

CONCLUSIONS

RNS used in children with medically refractory epilepsy improved seizure control after implantation, with decreases in seizure frequency > 50% from preoperative baseline in the majority of patients. Preliminary findings indicate that functional MRI and stereo-electroencephalography were helpful for RNS targeting and that RNS can be used safely even in young children.

ABBREVIATIONS

AED = antiepileptic drug; DRE = drug-resistant epilepsy; EEG = electroencephalography; fMRI = functional MRI; MEG = magnetoencephalography; RNS = responsive neurostimulation; rs-fMRI = resting-state fMRI; SEEG = stereo-EEG; SOZ = seizure onset zone; VEEG = video-EEG; VNS = vagus nerve stimulation.

OBJECTIVE

Medically refractory epilepsy remains a therapeutic challenge when resective surgery is not a practical option and indirect neurostimulation efficacy may be limited. In these instances responsive neurostimulation (RNS) has been used in adults, with good outcomes in most patients. However, the utility of RNS in children and young adults has not been systematically explored. In this study, the authors present a single institution’s experience with RNS in pediatric patients.

METHODS

A single-center retrospective chart review of patients who underwent RNS implantation at Phoenix Children’s Hospital during the 4-year period between January 2018 and December 2021 was performed.

RESULTS

Following evaluation for epilepsy surgery, 22 patients underwent RNS implantation using different anatomical targets depending on the predetermined epileptic focus/network. In the cohort, 59% of patients were male, the mean age at implantation was 16.4 years (range 6–22 years), and the mean follow-up time was 2.7 years (range 1.0–4.3 years). All patients had a preoperative noninvasive evaluation that included MRI, video-electroencephalography, and resting-state functional MRI. Additionally, 13 patients underwent invasive monitoring with stereo-electroencephalography to help determine RNS targets. All patients had variable positive responses with reduction of seizure frequency and/or intensity. Overall, seizure frequency reduction of > 50% was seen in the majority (86%) of patients. There were two complications: one patient experienced transitory weakness and one generator failed, requiring replacement. A patient died of sudden unexpected death in epilepsy 3 years after implantation despite being seizure free during the previous year.

CONCLUSIONS

RNS used in children with medically refractory epilepsy improved seizure control after implantation, with decreases in seizure frequency > 50% from preoperative baseline in the majority of patients. Preliminary findings indicate that functional MRI and stereo-electroencephalography were helpful for RNS targeting and that RNS can be used safely even in young children.

Epilepsy is one of the most common neurological conditions experienced by children and adults worldwide. There are an estimated 3 million people living in the United States with epilepsy, and the incidence has been reported as ranging between 50.4 to 81.7 cases per 100,000 people per year.1 There is an especially high disease burden in children, with an annual incidence ranging from 33.3 to 82 cases per 100,000 individuals per year and a prevalence of approximately 2%.2 Whereas more than half of children are able to be maintained seizure free using 1 or 2 medications, upwards of one-third of patients will develop drug-resistant epilepsy (DRE),2 which is defined as failure of two or more adequate trials of antiepileptic drugs (AEDs) to control their seizures.3

In an early study done by Kwan and Brodie,4 the percentage of patients successfully managed with their first AED was 47%, but adding a second or third AED increased seizure control by 13% and 4%, respectively. As a result, seizures in more than one-third of patients become medically intractable. Children in general are an underserved population, but DRE in children is particularly impactful due to the combination of uncontrolled seizures and the impact of medication on the child’s neurological and psychosocial development. Individuals with DRE are often referred for alternative treatments including cannabidiol (Epidiolex5), ketogenic dietary therapy, and/or surgical interventions—resective surgery and/or neuromodulation.

Neuromodulation is most often recommended when resective surgery is not practical because of diffuse, bilateral, or eloquent seizure network localization. The technologies available for neuromodulation include vagus nerve stimulation (VNS), deep brain stimulation, or responsive neurostimulation (RNS).6 RNS is a closed-loop system that is designed to detect abnormal electrical signals from the suspected seizure onset zone (SOZ) by using digital signal analysis of electroencephalography (EEG) through a predefined seizure detection algorithm, and delivering a stimulus to arrest the seizure.7,8 RNS is an FDA-approved system for the management of DRE in adults8,9 but has only been used off label in children when no other treatment options are available.7,911 A retrospective analysis of 5 different pediatric centers identified 35 patients who underwent RNS implantation, 17 of whom were younger than 18 years old. The researchers found that there were no statistically significant differences in the rates of seizure reduction or complications between children and young adults in this cohort or between the cohort as a whole and the adult literature on RNS.12

The limited evidence in the pediatric population highlights the need for further assessment of RNS as a treatment modality for children with DRE. In this study we sought to assess the potential role of RNS for the treatment of children with DRE in whom other more conventional treatments have failed, and to determine the potential diagnostic criteria for optimal patient selection and system configuration.

Methods

Following institutional review board approval, we performed a retrospective chart review that included all patients treated with RNS at Phoenix Children’s Hospital during the period between January 2018 and December 2021.

Clinically, all patients with new-onset seizures or epilepsy are treated with medical therapy. Patients in whom 2 or more medications had been tried with suboptimal results are identified in a quality dashboard and considered for further diagnostic evaluation and multidisciplinary assessment within the Comprehensive Epilepsy Program of the Barrow Neurological Institute at Phoenix Children’s Hospital. The individuals whose cases are presented here were identified by querying this dashboard. The information disclosed for study purposes included the different elements assessed to determine surgical candidacy (demographic characteristics, medical and seizure history, seizure semiology, previous and concomitant treatments for seizure management, video-EEG [VEEG] results, anatomical and functional MRI (fMRI) results, PET and magnetoencephalography [MEG]), RNS placement details, and post-RNS implantation outcomes, including seizure reduction and Engel classification at least 1 year from implantation.

As previously reported by our team, we use resting-state fMRI (rs-fMRI) to assess normal functional networks of motor and language as well as abnormal functional networks that might represent seizure sources in pediatric epilepsy,1315 and PET to assess focal areas of abnormality in patients with partial seizures. Each case is discussed in a multidisciplinary epilepsy conference to determine suitability for surgical intervention or whether further diagnostic testing is necessary, including stereo-EEG (SEEG). Depending on the diagnostic findings, a consensus is developed as to the next step for treatment—whether there is the possibility of resection or whether a neuromodulatory strategy is necessary due to the following factors: 1) nonlocalizability of the seizure focus/network; 2) multiple seizure foci or bilateral involvement (i.e., bilateral temporal lobe seizure origins); or 3) location of the seizure focus within eloquent areas of cortex or tissue.

If the consensus leans toward neuromodulatory management, VNS is usually the first line of treatment, but if VNS fails to provide seizure control after 1 year or if the seizure focus could be fairly well localized, RNS implantation is considered.

For study purposes, SOZ localization obtained through the different diagnostic modalities was compared to the actual electrode placement during the RNS procedure. Three different configurations were identified for electrode placement: 1) 2 electrodes placed at surface; 2) 1 electrode placed at surface and 1 at depth; and 3) 2 electrodes placed at depth. Electrode targeting during RNS system implantation involved either frame-based stereotaxy using a Leksell frame, or frameless stereotaxy with image guidance using the Medtronic Stealth system with either a Vertek arm or Stealth Autoguide neurosurgical robot. Sixteen patients underwent targeting using the Stealth Autoguide and 6 patients underwent targeting with the Leksell frame, which was used exclusively for deep thalamic targeting (Table 1). In terms of electrode placement, 5 of the 6 deep electrodes were within 2 mm of the planned target.

TABLE 1.

Summary of electrode placement and localization for 22 patients who underwent RNS implantation

CharacteristicValue
Laterality
 GeneratorLt 55%, rt 45%
 ElectrodesLt 69%, rt 31%
Electrode placement
 Surface:surface7 (32%)
 Surface:depth9 (41%)
 Depth:depth6 (27%)
Electrode locations
 Cortical/thalamus38/6; 22 pts, 44 total electrodes
 Temporal17
 Frontal12
 Parietal2
 Frontoparietal2
 Insula4
 Occipital1
 Centromedian nucleus6
Targeting
 Vertek/Stealth Autoguide16 (73%)
 Leksell frame6 (27%)

Pts = patients.

Data analysis was performed using IBM SPSS Statistics software (IBM Corp.). Descriptive elements were calculated for all fields, with absolute numbers and percentages calculated for categorical variables and mean, median, maximum, and minimum for continuous variables. Percentage of agreement was calculated by dividing the number of times in which each diagnostic category matched electrode location, by the total number of times the diagnostic procedure was used, and then converting that number to a percentage. Ordinal logistic regression was used to test the predictive value of demographic and disease characteristics in treatment outcomes (Engel classification).

Results

Twenty-two patients underwent RNS implantation between June 2018 and September 2021. Thirteen of the patients were male (59%), 73% of patients identified as Caucasian, and 27% as Hispanic/Latino. The mean age at onset of seizures was 7.1 years (minimum 0.5 years, maximum 16 years). The seizure types were identified as complex partial seizures in 15 patients (68%), syndromic seizures (i.e., Lennox-Gastaut) in 4 patients (18%), and generalized tonic-clonic seizures in 3 patients (14%). All patients were classified as having medically intractable epilepsy—2 or more AEDs having failed individually or in combination (mean 3 AEDs, SD 2, minimum 2, maximum 8). Five patients (23%) were taking cannabidiol and 5 patients (23%) were on ketogenic diet therapy. VNS was the preferred method of neuromodulation as first-line "surgical" treatment in half of the patients (Table 2). The mean age at time of RNS implantation was 16.4 years (median 17.4, minimum 6, maximum 22 years). Of those who first had VNS treatment and then required further treatment with RNS, the mean number of years between VNS and RNS procedures was 3.8 years (minimum 1.3, maximum 7.3 years).

TABLE 2.

Case summary

Case No.Sz TypeNo. of AEDsOther TherapiesWorkupSz ReductionEngel Class
1Complex partial2MRI, VEEG, rs-fMRI50–74%II
2Complex partial1MRI, VEEG, rs-fMRI, PET, SEEG, MEG1–24%III
3Complex partial3CT, MRI, VEEG, rs-fMRI, PET, SEEG90–99%I
4Complex partial2VNSMRI, VEEG, rs-fMRI, PET25–49%III
5Complex partial3VNSMRI, VEEG, rs-fMRI, PETSz freeI
6Syndromic4MRI, VEEG, rs-fMRI, PET, SEEG90–99%I
7Complex partial2Keto diet, cannabidiolMRI, VEEG, rs-fMRI, PET, SEEGNo changeV
8Complex partial4VNSMRI, VEEG, rs-fMRI, PET, SEEG50–74%II
9Syndromic1VNSMRI, VEEG, rs-fMRI, PET, MEG75–90%II
10Complex partial1VNSMRI, VEEG, rs-fMRI, SEEG, MEG90–99%I
11Tonic-clonic3Keto diet, cannabidiol, VNSMRI, VEEG, rs-fMRI, PET, SEEGNo changeIV
12Complex partial3CannabidiolMRI, VEEG, rs-fMRI, PET90–99%I
13Complex partial4MRI, VEEG, rs-fMRI, PET, MEG90–99%I
14Complex partial2MRI, VEEG, rs-fMRI, PET, SEEG, MEG25–49%III
15Complex partial2MRI, VEEG, rs-fMRI, PETSz freeI
16Syndromic8Keto diet, cannabidiol, VNSMRI, VEEG, rs-fMRI, PET75–89%I
17Tonic-clonic6Keto diet, cannabidiol, VNSMRI, VEEG, rs-fMRI, PET, SEEG25–49%I
18Syndromic5Keto diet, VNSMRI, VEEG, rs-fMRI, SEEG75–89%I
19Complex partial1MRI, VEEG, rs-fMRI, PET, MEG50–74%II
20Tonic-clonic3VNSMRI, VEEG, rs-fMRI, PET, SEEGSz freeI
21Complex partial3VNSMRI, VEEG, rs-fMRI, SEEG25–50%III
22Complex partial2MRI, VEEG, rs-fMRI, PET, SEEGNo changeIV

Sz = seizure.

All patients underwent MRI as part of their anatomical imaging evaluation, and they all underwent VEEG monitoring and rs-fMRI prior to their RNS implantation, whereas PET was performed in 18 patients (82%), and MEG in 6 patients (27%). MRI findings demonstrated that 59% of the cases of epilepsy were lesional including cortical dysplasia, encephalomalacia, and other lesions. Thirteen patients (59%) underwent phase II surface and/or SEEG invasive monitoring to define the SOZ and potential targets for RNS electrode placement.

The level of agreement between electrode placement location and SOZ identified with the different diagnostic modalities is presented in Table 3. Kappa values are not presented because electrode placement location was used as the reference field, and therefore all values were constant. Age, sex, race, seizure type, prior VNS placement, and electrode localization were tested as independent outcome predictors, but none attained statistical significance.

TABLE 3.

Percentage of agreement between localization modalities and RNS electrode placement

Localization Technique% of Agreement
SEEG54%
VEEG41%
MRI45%
Functional imaging (rs-fMRI/PET/MEG)41%

There were two surgical complications of note; one case of mild lower-extremity motor weakness following placement of a surface electrode over the motor strip, which resolved within 1 week of the operation and did not result in prolonged hospitalization or require rehabilitation. The second was a generator failure that occurred while the child was still an inpatient and required a return to the operating room for replacement within 6 hours. There were no infections in this cohort.

The mean follow-up time with Engel classification was 2.7 years (minimum 1.0, maximum 4.3 years). More than two-thirds of patients had a significant improvement in their seizure frequency (Table 4), with another 18% having some level of response. Two of the patients died during the study period, although none of the deaths were related to the operative RNS placement. One patient died following an automobile versus pedestrian event, although this individual was seizure free for more than 1 year after device implantation. The other patient died of sudden unexpected death in epilepsy after being seizure free for 3.2 years following RNS, and was still taking AEDs at the time of death.

TABLE 4.

Outcomes after RNS procedure

ClassificationNo. of Pts% Outcome
Engel I1150%
Engel II418%
Engel III418%
Engel IV314%

Illustrative Cases

Case 1

This 11-year-old right-handed girl had seizure onset at 7 years, with complex partial seizures that had different semiologies and were unresponsive to AEDs, ketogenic diet, and VNS; she was still having 3–6 seizures per month. Her VEEG-confirmed seizures revealed independent left and right onsets biparietally. MRI showed an isolated dysplasia/encephalomalacia of the right parietal lobe and her functional imaging including CT/PET also localized to the right parietal lobe. Her rs-fMRI indicated 5 overlapping abnormal signal sources over the right lateral prefrontal cortex but did not include the right parietal lobe. Her MEG showed 3 bilateral independent sources.

An RNS device was implanted with one surface electrode and one depth electrode targeting the more significant MEG clusters. Over the next 2.5 years her seizures continued to decrease in intensity and frequency, and ultimately her outcome was classified as Engel class I (seizure free) despite seeing continued frequent abnormal electrical activity on the RNS monitoring (Fig. 1). She is presently weaning medicines down to 1 AED. This case highlights an excellent outcome despite what appears to be an increased number of activations by the pulse generator and the utility of continued EEG monitoring during the weaning of the AEDs.

FIG. 1.
FIG. 1.

RNS activations over time showing the differences observed between the illustrative cases.

Case 2

This 15-year-old right-handed girl had seizure onset at 10 years of age secondary to autoimmune encephalitis and status epilepticus. She was unresponsive to more than 8 AEDs, cannabidiol, ketogenic diet, and VNS, and was still experiencing 7–10 seizures per month. Her anatomical and functional imaging were nonfocal, although her rs-fMRI showed her SOZ to be bilateral frontoparietal and adjacent prefrontal cortex and diencephalon. Because of the lack of concordance of data, she underwent SEEG bilaterally, which showed bilateral independent foci without a clear dominant SOZ. However, two sets of electrodes had high-frequency oscillations before or during the seizure onset in the right amygdala and diffusely in the left hemisphere. It was decided that her RNS electrode configuration should include a surface electrode subtemporal in the area of the right amygdala and a depth electrode in the centromedian nucleus of the left thalamus. In follow-up visits over the next 1.5 years, although she had some seizure improvement, her outcome was classified as poor (Engel class IV), with a seizure reduction of only approximately 25%. Interestingly, her seizure detections were originally upward of 1985 events per day but decreased significantly over the 12-month follow-up period (Fig. 1). This case highlights the fact that targeting the RNS electrodes based on the SEEG and high-frequency oscillations can improve the underlying electrophysiological abnormality, but in contrast to case 1, it does not necessarily improve the seizure syndrome. For this child it is possible that additional electrodes stimulating other abnormal areas might be helpful, but it remains to be studied.

Discussion

Epilepsy is a potentially fatal disease and there is a constant need for improved and updated treatment modalities, both medical and surgical, to improve the quality of life of these patients. DRE remains a challenge for both adult and pediatric patients when there are no further medical or alternative therapies available. These patients represent a particular challenge when the seizure network cannot be identified, it is too diffuse or bilateral, or it is localized within eloquent areas of the cortex. Neuromodulation through RNS is an evolving treatment modality to aid in improving outcomes in these patients with DRE. The benefit of RNS is that it can detect subclinical and clinical seizures at their onset and attenuate their effects. Although not curative, it does potentially provide palliative measures, improve quality of life, and is effective in reducing seizure burden in adults.

Outcome

Even with only a mean follow-up time of 2.7 years, two-thirds of our patients were markedly improved, with half reaching 90% or more reduction in seizure frequency and an additional 18% reaching between 50% and 79% reduction. A meta-analysis of 8 studies defined a seizure reduction of ≥ 50% as a response to treatment.16 Therefore, 68% of the patients in our study responded to treatment and not a single patient worsened after implantation. In a retrospective analysis of 5 different pediatric centers where 17 patients underwent RNS implantation, no statistically significant differences were reported in seizure reduction or complication rates between children and young adults within the cohort or in comparison to the adult literature on RNS.17 Such findings represent a remarkable improvement over the addition of new medications and provide a potential opportunity in pediatric care.

The Engel classification is a measure of outcome based on seizure frequency changes that may be influenced by the reporting accuracy from the patient and/or family; the time at which the seizures take place (nocturnal vs daytime); the clinical or subclinical character of the seizures; and the proximity of time between seizures and clinic visits, unless specifically recorded in seizure diaries and/or direct measures. It is also important to recognize that RNS treatment outcomes may be influenced by other less measurable effects like long-term neuromodulation, and the impact this may have in brain connectivity, neurological development, and cognitive development. Additionally, given that RNS activity is recorded by the device, the benefits of being able to assess seizure burden; changes in EEG patterns; and effects of neuromodulation, medication, and/or other alternative treatments long term may be useful.

Optimal Location of Electrodes

Part of the potential impact on outcome may be due to the ability of the electrodes to optimally read the electrical signal and respond to that signal as part of the closed-loop system. Inadequate localization of the SOZ and/or insufficient information to determine the location and type of electrodes (i.e., surface or depth electrode), can negatively impact outcomes. The decision regarding localization depends on concordance of the data during the presurgical evaluation. The optimal noninvasive diagnostic test or decision-making algorithm to best target for the SOZ and/or seizure network, and to then target an area for neurostimulation, has not been defined. In instances in which targeting is unclear, SEEG attempts to synthesize the concordance of the presurgical data and translate that to a targeting of the hypothesized SOZ, with a later plan to translate this to RNS electrode placement. Whereas others have reported that 90% of patients who underwent RNS implantation had prior invasive EEG monitoring done to determine seizure foci,12 we used invasive monitoring with SEEG in only 59% of our patients because we frequently depended on the noninvasive diagnostic studies for final RNS electrode placement. Given our reasonably good outcomes, it is unclear whether SEEG will be necessary as other noninvasive technologies emerge for improved source localization. As was highlighted, achieving good localization—noted by lessening activations—did not necessarily translate into a good outcome. The question still requires further study as to the best localization methods and/or combination of diagnostic tools to provide the most sensitive algorithm for electrode placement.

Additionally, in this study thalamic targets were used in a limited number of patients based on previous reports1820 indicating the utility of the centromedian nucleus, particularly in patients with multifocal or generalized epilepsy. The potential efficacy of deep brain stimulation in pediatric generalized epilepsy has been reported in a systematic review18 that for the most part used an open-loop neuromodulatory system. More recent studies have shown the potential benefit of a closed-loop system such as RNS whereby seizure burden and feedback can be obtained long term to show success of treatment.19,20 Although its sample size was limited, the present study similarly showed the early potential utility of the RNS for thalamic targets in this patient population.

Complications

In this study RNS was found to be safe, with only two complications—one patient with postoperative lower-extremity weakness with a surface electrode placed over a motor area that resolved quickly, and another patient who required an immediate return to surgery due to a generator failure. A single-institution retrospective review of 27 patients documented infection as the main complication.17 We had no postoperative infection in our cohort, but the risk is probably similar to that of other types of implants. We used a meticulous implant protocol that included minimizing room traffic, minimizing handling of the implants, prophylactic intravenous antibiotics and surface antibiotic irrigation, and last, powdered vancomycin on all the implants prior to closure to try to minimize the risk of this complication.

As noted by many, although RNS reduces seizure burden, it is not curative, with continued chronic seizures observed on EEG studies. Having had 1 case of sudden unexpected death in epilepsy occur despite RNS and continued AED treatment makes us aware that RNS is a palliative procedure and does not prevent this possible devastating outcome.

Limitations

Although the retrospective character and a small sample size are limitations to the strength of the evidence, RNS has been offered under a standard protocol at our institution, with relevant data prospectively collected. The use of the seizure onset localization modalities has been standardized, although it can vary between patients and did limit our capacity to provide a more accurate comparison between localization mechanisms, electrode placement, and treatment response. The size of the cohort and the relatively variable seizure syndromes, preoperative evaluation, surgical targeting, and follow-up periods created additional limitations to our capacity to assess the significance of our results and the effectiveness of the intervention. Although further study is necessary, these patients do provide early additional data to the literature to build our better understanding regarding how this technology may be efficacious for younger patients and how we may optimize the targeting for potential improved outcomes.

As seen in the literature, there is significant variability in the methodologies and processes that are used to arrive at the decision to undergo RNS implantation. Further prospective evaluation is important for guiding clinical decision-making and can aid in deciding whether or not to operate in cases of DRE. SEEG was the closest in agreement to final placement of electrodes and potentiates the need for further evaluation of this diagnostic tool in an RNS placement protocol, but may not be necessary with improved evaluative measures. With tighter evaluation guidelines, there is the potential for quicker decision-making regarding treatment for those experiencing DRE.

Conclusions

This study adds to the evidence supporting the potential use of RNS in younger patients. Although there is still much to explore in relation to RNS in children, reducing seizure frequency in this complex group has the potential to improve quality of life. It is still unclear why some pediatric and adult patients respond better to RNS than others, but further study of improved diagnostics, patient selection, and evaluation of the long-term EEG studies obtained through the RNS may help optimize the efficacy of this treatment. Technically, RNS placement in children was no different than in adults but with improved targeting and perioperative protocols, complications can possibly be minimized. Further prospective study and clinical trials will be necessary to determine the potential use of this technology for younger patients in the future.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Adelson, Arango. Acquisition of data: Falls. Analysis and interpretation of data: Adelson, Arango. Drafting the article: Falls. Critically revising the article: Adelson, Arango. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Adelson. Statistical analysis: Arango. Administrative/technical/material support: all authors. Study supervision: Adelson, Arango.

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    FIG. 1.

    RNS activations over time showing the differences observed between the illustrative cases.

  • 1

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