A systematic review of deep brain stimulation for the treatment of drug-resistant epilepsy in childhood

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OBJECTIVE

Drug-resistant epilepsy (DRE) presents a therapeutic challenge in children, necessitating the consideration of multiple treatment options. Although deep brain stimulation (DBS) has been studied in adults with DRE, little evidence is available to guide clinicians regarding the application of this potentially valuable tool in children. Here, the authors present the first systematic review aimed at understanding the safety and efficacy of DBS for DRE in pediatric populations, emphasizing patient selection, device placement and programming, and seizure outcomes.

METHODS

The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and recommendations. Relevant articles were identified from 3 electronic databases (MEDLINE, Embase, and Cochrane CENTRAL) from their inception to November 17, 2017. Inclusion criteria of individual studies were 1) diagnosis of DRE; 2) treatment with DBS; 3) inclusion of at least 1 pediatric patient (age ≤ 18 years); and 4) patient-specific data. Exclusion criteria for the systematic review included 1) missing data for age, DBS target, or seizure freedom; 2) nonhuman subjects; and 3) editorials, abstracts, review articles, and dissertations.

RESULTS

This review identified 21 studies and 40 unique pediatric patients (ages 4–18 years) who received DBS treatment for epilepsy. There were 18 patients with electrodes placed in the bilateral or unilateral centromedian nucleus of the thalamus (CM) electrodes, 8 patients with bilateral anterior thalamic nucleus (ATN) electrodes, 5 patients with bilateral and unilateral hippocampal electrodes, 3 patients with bilateral subthalamic nucleus (STN) and 1 patient with unilateral STN electrodes, 2 patients with bilateral posteromedial hypothalamus electrodes, 2 patients with unilateral mammillothalamic tract electrodes, and 1 patient with caudal zona incerta electrode placement. Overall, 5 of the 40 (12.5%) patients had an International League Against Epilepsy class I (i.e., seizure-free) outcome, and 34 of the 40 (85%) patients had seizure reduction with DBS stimulation.

CONCLUSIONS

DBS is an alternative or adjuvant treatment for children with DRE. Prospective registries and future clinical trials are needed to identify the optimal DBS target, although favorable outcomes are reported with both CM and ATN in children.

ABBREVIATIONS ATN = anterior thalamic nucleus; CM = centromedian nucleus of the thalamus; DBS = deep brain stimulation; DRE = drug-resistant epilepsy; RNS = responsive neurostimulation; STN = subthalamic nucleus; VNS = vagus nerve stimulation.

OBJECTIVE

Drug-resistant epilepsy (DRE) presents a therapeutic challenge in children, necessitating the consideration of multiple treatment options. Although deep brain stimulation (DBS) has been studied in adults with DRE, little evidence is available to guide clinicians regarding the application of this potentially valuable tool in children. Here, the authors present the first systematic review aimed at understanding the safety and efficacy of DBS for DRE in pediatric populations, emphasizing patient selection, device placement and programming, and seizure outcomes.

METHODS

The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and recommendations. Relevant articles were identified from 3 electronic databases (MEDLINE, Embase, and Cochrane CENTRAL) from their inception to November 17, 2017. Inclusion criteria of individual studies were 1) diagnosis of DRE; 2) treatment with DBS; 3) inclusion of at least 1 pediatric patient (age ≤ 18 years); and 4) patient-specific data. Exclusion criteria for the systematic review included 1) missing data for age, DBS target, or seizure freedom; 2) nonhuman subjects; and 3) editorials, abstracts, review articles, and dissertations.

RESULTS

This review identified 21 studies and 40 unique pediatric patients (ages 4–18 years) who received DBS treatment for epilepsy. There were 18 patients with electrodes placed in the bilateral or unilateral centromedian nucleus of the thalamus (CM) electrodes, 8 patients with bilateral anterior thalamic nucleus (ATN) electrodes, 5 patients with bilateral and unilateral hippocampal electrodes, 3 patients with bilateral subthalamic nucleus (STN) and 1 patient with unilateral STN electrodes, 2 patients with bilateral posteromedial hypothalamus electrodes, 2 patients with unilateral mammillothalamic tract electrodes, and 1 patient with caudal zona incerta electrode placement. Overall, 5 of the 40 (12.5%) patients had an International League Against Epilepsy class I (i.e., seizure-free) outcome, and 34 of the 40 (85%) patients had seizure reduction with DBS stimulation.

CONCLUSIONS

DBS is an alternative or adjuvant treatment for children with DRE. Prospective registries and future clinical trials are needed to identify the optimal DBS target, although favorable outcomes are reported with both CM and ATN in children.

ABBREVIATIONS ATN = anterior thalamic nucleus; CM = centromedian nucleus of the thalamus; DBS = deep brain stimulation; DRE = drug-resistant epilepsy; RNS = responsive neurostimulation; STN = subthalamic nucleus; VNS = vagus nerve stimulation.

In Brief

The authors performed a systematic review of the current literature of deep brain stimulation in the treatment of drug-resistant epilepsy in children. The safety and efficacy of this novel method have yet to be elucidated.

Drug-resistant epilepsy is a complex condition that may be treated surgically using a wide range of procedures in the appropriately selected patient. These include resections and ablative surgery, functional disconnections, and neuromodulation. In children, surgical treatments are increasingly emphasized given the medical and psychosocial burden of drug-resistant epilepsy (DRE)22 and the detrimental effects of seizures and medications on the developing brain.16 The Early Randomized Surgical Epilepsy Trial provided class I evidence for the benefit of early resection11 compared with medical management in adolescents with temporal lobe epilepsy. Furthermore, a single-center randomized controlled trial of children younger than 18 years with DRE demonstrated a 77% seizure freedom for surgical treatment compared with 7% for medical treatment.10 In patients without localization-related epilepsy or unacceptable iatrogenic risk to eloquent cortex, neuromodulation may decrease the seizure burden and improve quality of life.31 Vagus nerve stimulation (VNS) is a viable outcome with long-term seizure reduction,31 although complications such as hardware failure, deep infection, hoarseness, dysphasia, and torticollis have been described in children.36 The responsive neurostimulation (RNS) system was approved by the FDA in 2003 for use in patients 18 years or older with DRE. Studies have demonstrated that adults can benefit from moderate seizure reduction,14,17 but this new therapy has not yet been thoroughly studied in children.

Deep brain stimulation (DBS) is a therapeutic option that delivers electrical stimulation in order to modulate cortical excitability, thereby reducing the frequency and severity of seizures in an adjustable and reversible manner. The SANTE (Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy) trial demonstrated statistically significant reductions in seizure frequency in a multicenter prospective randomized cohort of 110 adults with DRE who underwent anterior nucleus DBS.12 Several DBS targets have been studied,8 including the anterior thalamic nucleus (ATN) for patients with frontotemporal epilepsy,21,27,32 the centromedian nucleus of the thalamus (CM) for patients with generalized epilepsy,40,43,45 and the hippocampus for patients with temporal lobe epilepsy.4,6

DBS for children is often only considered when patients have reached a treatment-refractory stage of their disease, often with few options remaining.30 Most commonly used to treat intractable primary generalized childhood dystonia, the potential for DBS in pediatric populations offers new hope to improve a child’s quality of life. Despite its potential value, there remain important unanswered questions regarding DBS for epilepsy in children. Current evidence is limited to case reports and small case series; long-term data regarding its safety and efficacy are lacking. Much of the evidence is translated from adult studies; the procedure and its associated risks as well as device programming and follow-up are modified, thereby posing a challenge to clinicians given the biological differences in children. Although DBS could provide significant seizure freedom for children with DRE, it is not offered routinely, as it is still fairly novel in pediatric populations. The current report is the first to present a synthesis of the available evidence for DBS in children with DRE to assess the efficacy and safety of DBS in pediatric patients with DRE. This systematic review aims to analyze the current literature to understand the effects of DBS for epilepsy in a pediatric population, focusing on safety and efficacy and highlighting patient selection, DBS placement and settings, and seizure freedom.

Methods

Search Strategy

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)28 guidelines and recommendations. The strategy was developed a priori but not published. A literature search was performed using MEDLINE, Embase, and Cochrane CENTRAL on November 17, 2017, by a librarian (M.A.). The database searches used keywords (individually and/or in combination), specifically “electrical stimulation,” “deep brain stimulation” or “DBS,” and “seizure(s),” or “epilepsy” with the appropriate subject headings. The reference lists of retrieved review articles were reviewed to identify additional relevant articles.

Study Selection and Data Extraction

Retrieved studies were systematically assessed using inclusion and exclusion criteria by 2 reviewers (H.Y. and E.T.). Inclusion criteria were 1) diagnosis of DRE, as defined by the individual studies; 2) treatment with DBS; 3) inclusion of at least 1 pediatric patient; and 4) patient-specific data. Exclusion criteria for the systematic review included 1) missing data for age, DBS target, or seizure freedom; 2) nonhuman subjects; and 3) editorials, abstracts, review articles, and dissertations. When duplicate studies were found, only the most recent and complete reports were included for quantitative assessment.

All data were extracted from article texts, tables, and figures. Each retrieved article was reviewed by 2 investigators independently (H.Y. and E.T.). Any discrepancies were reviewed in conference.

Results

Literature Search

The search strategy identified a total of 6352 studies (Fig. 1). After removal of 1490 duplicate studies, inclusion and exclusion criteria were applied to the titles of the 4862 articles. This yielded 26 studies that underwent full-text analysis, of which 5 studies did not meet the inclusion criteria (Fig. 1). When patients originated from the same hospital, the demographic information of the patients was analyzed. Six patients were included in multiple papers,27,33,40,42,44 and only the most recent publication was included in this analysis. Thus, 21 studies were included.

Fig. 1.
Fig. 1.

PRISMA flowchart. Figure is available in color online only.

Cohort Description

A total of 40 patients were included in this systematic review of pediatric epilepsy patients treated with DBS (Table 1). The ages ranged from 440 to 18 years. Sex was not reported for 10 patients.40,44 Of the remaining 30 patients, there were 19 males and 11 females. The shortest follow-up duration was 0.5 months,44 and this was in the context of a protocol to follow DBS of the hippocampus with a subsequent temporal lobectomy. The majority of patients (n = 24) had at least 18 months of follow-up when seizure freedom was measured, although 2 patients only had reported follow-up of 2 weeks.

TABLE 1.

Demographic information

Authors & YearCountryPt No.SexAge (yrs)Notes
Anderson et al., 2017South Africa1M9North Sea progressive myoclonus epilepsy w/ GOSR2 mutation
Benabid et al., 2002France2F5Cortical dysplasia
3M16Tuberous sclerosis
Benedetti-Isaac et al., 2015Colombia4M16Autism
5M9Focal cortical dysplasia; infection & temporary unilat battery removal
Chabardès et al., 2002France6M17
Cukiert et al., 20177Brazil7F14Lt mesial temp sclerosis, recurrent status epilepticus
Ding et al., 2016China8M10Febrile convulsive seizures
Fisher et al., 1992US9M16
10M16Rt hypothalamic hamartoma
Khan et al., 2009UK11F13Lt hypothalamic hamartoma
Kim et al., 2017South Korea12F16
Kokoszka et al., 2018US13M14Type 1 focal cortical dysplasia
Lee et al., 2017Taiwan14F174 wks of status epilepticus prior to DBS
15M14Removal due to infection
Lee et al., 2006South Korea16F14
17F14
Lee et al., 2012South Korea18M14
19M18  
Lim et al., 2007Taiwan20M18ATN & STN insertion, removal of STN
Valentín et al., 2013UK/Spain21F18
22M14
Valentín et al., 2017UK23M9
24F8
25F17
Velasco et al., 1987Mexico26M15Previous status epilepticus
27M16Previous status epilepticus
28F11Medial temp sclerosis
Velasco et al., 200041Mexico29M11
Velasco et al., 200044Mexico3015
318
327Explanted due to skin erosion
339Explanted due to skin erosion
3413
Velasco et al., 2006Mexico3511Rupture of electrode lead, replacement
3610
374Tuberous sclerosis
3813
3913Cerebral infarct
Velasco et al., 200742Mexico40M14
Pt = patient; temp = temporal; UK = United Kingdom.

Seizure Characteristics

All patients included were offered DBS treatment because their epilepsy was refractory to medical treatment. These patients had a wide range of etiologies ranging from focal epilepsy secondary to focal cortical dysplasia to multifocal epilepsy resulting from genetic or syndromic conditions. Two patients were previously diagnosed with tuberous sclerosis,3,40 2 patients had mesial temporal sclerosis,7,41 2 had hypothalamic hamartomas,18 and 3 had cortical dysplasia.2,5,20

One patient included in the analysis was one of 3 individuals from a family with North Sea progressive myoclonus epilepsy and confirmed GOSR2 mutation.1 All 3 members of this family presented with ataxia, tremor, early gait difficulties, and myoclonic and generalized tonic-clonic epilepsy, and each received benefit from DBS treatment; only 1 of these patients was a child. Kokoszka et al.20 presented a patient with West syndrome who, historically as an infant, had classic findings of infantile spasms with the electroencephalogram having shown hypsarrhythmia. Another child had been diagnosed with autosomal-dominant nocturnal frontal lobe epilepsy that did not respond to DBS treatment.5 Nine patients from the same study all had Lennox-Gastaut syndrome,40 a childhood epilepsy pathology characterized by drug-resistant generalized seizures and cognitive deterioration. These seizures were associated with slow spike-wave complexes and bursts of rapid rhythms during slow sleep on electroencephalography.

Seizure type was described in a heterogeneous manner by the different studies. The majority of patients (n = 27) had generalized or secondarily generalized seizures (Table 2). Four patients had previous episodes of status epilepticus,7,24,45 including 1 patient who was in a continuous 4-week episode of intractable status epilepticus, which only improved after DBS treatment.24

TABLE 2.

Epilepsy characteristics

Authors & YearPt No.Duration of Epilepsy (mos)Sz Frequency (no./mo)LocalizationSyndromeAntiepileptic AgentsOther Treatment
Anderson et al., 20171366GeneralizedNorth Sea progressive myoclonus epilepsyCarbamazepine, sodium valproate
Benabid et al., 2002236210Lt parietalNAPhenytoin, carbamazepine, stiripentol, γ-vinyl-GABA, clobazam; pre-Sx phenobarbital, valproic acid, clonazepamPrevious lt parietal biopsy
31881200GeneralizedNACarbamazepine, clonazepam
Benedetti-Isaac et al., 2015413212GeneralizedNAPhenytoin, clonazepam, lorazepam
5103245Rt centralNAValproate, lamotrigineRt precentral frontal resection
Chabardès et al., 20026132600Lt insulofrontalADNFLEPhenytoin, clonazepam, levetiracetam, piracetam 
Cukiert et al., 20177713210Lt tempNANA
Ding et al., 20168126NAGeneralizedNANAPrevious lt anterior temp lobectomy
Fisher et al., 1992916830GeneralizedNAPhenytoin, clorazepate
109612GeneralizedNAMultipleRefused resective surgery
Khan et al., 200911141120Gelastic, generalizedNANA
Kim et al., 201712180NABilat frontal parietalNANA
Kokoszka et al., 201813162NALt tempWest syndromeNAConcurrent RNS; previous rt frontal lobectomy, complete corpus callosotomy, VNS, lt temp lobectomy, & posterior quandrantectomy
Lee et al., 2017146077GeneralizedNALorazepam, levetiracetam, valproic acid, topiramate, perampanel, midazolamKetogenic diet, midazolam infusion
15NA42GeneralizedGlobal cognitive delayTopiramate, lamotrigine, valproate, vigabatrin
Lee et al., 200616NA450Rt motorNANA
17361200GeneralizedNANA
186095Bilat frontalNANA
Lee et al., 2012198430Bilat centroparietalNANA
Lim et al., 20072017426GeneralizedNACarbamazepine, topiramate, clonazepam
Valentín et al., 2013211683006GeneralizedNALevetiracetam, lamotrigine, acetazolamide, clonazepamPrevious VNS
22NA10Focal motorNANA
Valentín et al., 201723NA>1000GeneralizedNANA
24NA900GeneralizedGenetic syndrome NYDNA
2510–37GeneralizedNAPhenytoin, carbamazepine, valproateAED overdose
Velasco et al., 1987267–150GeneralizedNAPhenytoin, carbamazepine, clonazepamAED overdose
2726–60GeneralizedNAPrimidone, carbamazepine, clonazepam
28724FocalNAOxcarbazepinePost-DBS temp lobectomy
Velasco et al., 200041294812GeneralizedNACarbamazepine, valproatePost-DBS temp lobectomy
Velasco et al., 20004430NA119GeneralizedNANA
31123119GeneralizedLennox-GastautNA
32124300GeneralizedLennox-GastautNA
33243780GeneralizedLennox-GastautNA
34963030GeneralizedLennox-GastautNA
Velasco et al., 2006351081200GeneralizedLennox-GastautNA
3611550GeneralizedLennox-GastautNA
3746150AtypicalLennox-GastautNA
3810835GeneralizedLennox-GastautNA
397250AtypicalLennox-GastautNA
Velasco et al., 200742403625GeneralizedCarbamazepine, phenytoin
ADNFLE = autosomal-dominant nocturnal frontal lobe epilepsy; AED = antiepileptic drug; NA = not available; NYD = not yet diagnosed; Sx = symptom(s); Sz = seizure.

Five patients had previous surgery in an attempt to treat their epilepsy.2,5,9,20,37 The operations included a biopsy to identify a possible epileptogenic lesion,2 a right precentral frontal lobe resection5 and a left anterior temporal lobectomy9 to attempt seizure reduction, and VNS;37 1 patient had already undergone right fontal lobectomy, complete corpus callosotomy, VNS, left temporal lobectomy, and posterior quandrantectomy.20 These procedures did not achieve the desired seizure reduction, and DBS was offered as an alternative treatment. Two patients had subacute electrical stimulation of the hippocampal formation or gyrus for 2–3 weeks to identify and suppress temporal lobe epileptogenesis prior to temporal lobectomy.41 In the 16 days of monitoring, DBS treatment eliminated seizures for one of these patients. Given the complex and dissimilar histories of these patients, it is difficult to correlate specific risk factors that would predict the effectiveness of surgery or DBS.

Since all patients included in this study were diagnosed with DRE, these children were receiving at a minimum 2 seizure medications, and 1 child had been on 6 seizure medications simultaneously prior to DBS surgery.24 Although most of the studies did not report post-DBS medication changes, all studies that reported these data in tables or text demonstrated a decrease in antiepileptic medication.3,29,40,45

DBS Location and Seizure Freedom

The DBS target was determined largely by the institution and the experience of the surgeon treating adult populations (Table 3). Seizure reduction was heterogeneously reported, mostly by self-report at follow-up appointments; only 1 study7 clarified the use of a seizure diary. Ultimately, 5 of the 40 patients (12.5%) had an International League Against Epilepsy class I (i.e., seizure-free) outcome. Among the 40 patients, 34 (85%) patients had seizure reduction with DBS stimulation, and 6 (15%) patients had no seizure reduction.

TABLE 3.

DBS and seizure outcomes

Authors & YearPt No.DBS LocationAnesthesiaFrequency (Hz)Pulse Width (μsec)Volt/CurrentSz ReductionFU (mos)Notes
Anderson et al., 20171Bilat cZINR1304502.1 mA100% of GTC84
Benabid et al., 20022Lt STNGA130905.2 V80.7%30
3Bilat pHypGA185902.7 V100%48Improved aggression
Benedetti-Isaac et al., 20154Bilat pHypGA185902.8 V89.6%2Aggression improved for only 2 mos
5Bilat STNGA130903.8 V67.8%15
Chabardès et al., 20026Bilat STNGA130603.0 V0%6
Cukiert et al., 201777Lt hippocampusGA1303002.0 V0%>6
Ding et al., 20168Rt hippocampusGA1303002.2 V80%18
Fisher et al., 19929Bilat CMNR65900.5–10 V∼30%>350% reduction stimulator off, 15% reduction w/ stimulator on
10Rt MMTGA140903 V100%21
Khan et al., 200911Lt MMTGA140903.5 V86%13Returned to school after 2 yrs
Kim et al., 201712Bilat CMGA130901.5–2.0 V92.9%18
Kokoszka et al., 201813Bilat ATNNR100; 200160; 1600.5 mA80–90%19Responsive neurostimulation also used
Lee et al., 201714Bilat ATNNR1451208 V90%1.5
15Bilat STNLocal13090NA71.4%1
Lee et al., 200616Bilat ATNLocal13090NA50%2
17Bilat ATNLocal100–18590–1501.5–3.1 V80.8%59
Lee et al., 201218Bilat ATNLocal100–18590–1501.5–3.1 V0%24
19Bilat ATNLocal100–18590–1501.5–3.1 V0%28
Lim et al., 200720Bilat ATNLocal180906 V37%48
Valentín et al., 201321Bilat CMGA60905 V50% for complex partial; 95% for simple partial36
22Bilat ATNGANANANA>60%12
Valentín et al., 201723Bilat CMGANANANA>60%48
24Bilat CMGANANANA0%18
25Bilat CMNR60–1001002.0 mA85% for tonic-clonic; 100% for complex partial3Reduced AED dosages & side effects
Velasco et al., 198726Bilat CMNR60–1001002.0 mA100% for tonic-clonic, complex partial3Reduced AED dosages & side effects
27Bilat CMNR60–1001002.0 mA95% for tonic-clonic; 100% for complex partial3
28Bilat hippocampusNR1304502–4 mA0%0.5
Velasco et al., 20004129Bilat hippocampusNR1304502–4 mA100%0.5
Velasco et al., 20004430Bilat CMGA60NA4–6 V80.60%>12
31Lt CMGA1304506–8 V100%18
32Bilat CMGA1304506–8 V100%18
33Rt CMGA1304506–8 V95%18
34Bilat CMGA1304506–8 V95%18
Velasco et al., 200635Bilat CMGA1304506–8 V95%18
36Bilat CMGA1304506–8 V70%18
37Rt CMGA1304506–8 V58%18
38Rt CMGA1304506–8 V53%18
39Lt CMGA1304506–8 V30%18
Velasco et al., 20074240Lt hippocampusNR1304503.0 mA64%18
cZI = caudal zona incerta; FU = follow-up; GA = general anesthesia; GTC = generalized tonic-clonic; MMT = mammillothalamic tract; NR = not reported; pHyp = posteromedial hypothalamus; Volt = voltage.

There were 18 patients from 7 different studies who had DBS electrodes placed in the CM bilaterally or unilaterally.13,19,37,38,40,44,45 There was seizure reduction in 17 of these patients, ranging from 30% to 100%. There were 9 patients with Lennox-Gastaut syndrome who were treated with unilateral or bilateral CM DBS.40 This study included the 5 patients with unilateral CM electrode placement and stimulation, due to inaccurate placement of one of 2 bilateral CM electrodes.

Eight patients from 6 different studies had DBS electrodes placed in the anterior thalamic nucleus (ATN) bilaterally.20,24–26,29,38 There was seizure reduction in 6 of the 8 patients, with seizure reduction ranging from 37% to 90%. The 2 patients with no improvement in seizure outcome had seizures localized to the bilateral frontal lobe and bilateral centroparietal lobe.26 The most recent study20 uniquely attempted the use of a right temporal cortical strip for RNS and a left thalamic depth electrode simultaneously inserted during the same operation, using an off-label application of the RNS for children. A corticothalamic stimulation trial showed improved 50% reduction in seizure frequency with DBS and cortical detection compared with unilateral cortical stimulation from RNS alone.

Five patients had DBS electrodes placed in the hippocampus.7,9,41,42 Two of these patients with intractable temporal lobe seizures had bilateral depth and subdural electrodes implanted to determine the location and extent of the epileptic focus before a temporal lobectomy.41 These electrodes only provided stimulation for 16 days, with seizure freedom in one patient and no change in the other. Three of the 5 patients were treated with DBS electrode placement in the hippocampus unilaterally. Two patients had left hippocampal DBS placement: one patient had left mesial temporal sclerosis with 0% seizure rate reduction,7 and the other patient was enrolled in a double-blind study where the stimulation was on or off for 1 month following implantation and demonstrated 64% seizure reduction when the stimulation was on.42 The patient with right hippocampal DBS placement had previously undergone left anterior temporal lobectomy, with 80% seizure reduction.

Three patients had bilateral subthalamic nucleus (STN) DBS placement, in an attempt to inhibit the substantia nigra from spreading paroxysmal discharges to disrupt seizure pathways.5,25 One of these 3 patients had successful seizure reduction (71.4%) after 1 month, but the case was complicated by infection of the implantable pulse generator and the entire system had to be explanted.25 Similarly, another patient with focal cortical dysplasia had bilateral STN placement after a failed precentral frontal resection also had an implantable pulse generator infection with a temporary explantation; during this period, the seizure frequency increased.5 A third patient who was diagnosed with autosomal-dominant nocturnal frontal lobe epilepsy was treated with bilateral STN DBS placement and had no change in seizure frequency.5 One child in whom a previous left parietal biopsy had led to the diagnosis of cortical dysplasia underwent left-sided STN placement, with an 80.7% seizure reduction.2 One patient initially underwent insertion of ATN and STN electrodes, but the STN electrode was explanted after the ATN electrode proved to provide better seizure relief.29

Two patients underwent bilateral posteromedial hypothalamus DBS in an attempt to treat both epilepsy and aggression.3 Both patients had improved seizure control, with 89.6% and 100% seizure frequency reduction. The aggression for both patients also improved, although the improvement in 1 patient was only temporary for 2 months.

Two patients with hypothalamic hamartomas were treated with unilateral mammillothalamic tract DBS; both patients had favorable results with seizure reduction of 86% and 100%.18

Finally, 1 patient with North Sea progressive myoclonus epilepsy underwent bilateral caudal zona incerta DBS placement and showed 100% reduction in seizures at 84 months.1 This treatment was also effective for 2 adult relatives with the same pathology due to genetic mutation of GOSR2.

Complications

The majority of studies noted very few or no complications, and there were no deaths. There were 4 complications, all due to infection. One patient required an explant of the DBS due to infection of the anterior chest battery with Staphylococcus aureus.25 There were also 2 occurrences of skin erosion of batteries in children 7 and 9 years old, leading to explantation.40 The second child retained the seizure freedom after DBS explantation. Finally, 1 patient had electrode lead breakage after 31 months, and the battery and electrodes were replaced, with the same favorable seizure outcome.40

Discussion

In this systematic review of pediatric cases of epilepsy treated with DBS, 40 patients with DRE from 21 papers were analyzed. There were 18 patients with bilateral or unilateral CM electrodes,13,19,37,38,40,44,45 8 patients with bilateral ATN electrodes,20,24–26,29,38 3 patients with unilateral hippocampal electrodes,7,9,42 2 patients with bilateral hippocampal electrodes,41 3 patients with bilateral5,25 and 1 patient with unilateral STN electrodes,2 2 patients with bilateral posteromedial hypothalamus electrodes,3 2 patients with unilateral mammillothalamic tract electrodes,18 and 1 patient with caudal zona incerta electrode placement.1 In summary, 34 of the 40 (85%) patients had reduction in seizure frequency with DBS stimulation.

Only 6 patients demonstrated no reduction in seizure frequency.5,7,26,38,41 Two of these patients had bilateral ATN placement for seizures identified in the bilateral frontal hemispheres and bilateral centroparietal lobes.26 A patient with autosomal-dominant nocturnal frontal lobe epilepsy who showed seizures originating from the left insulofrontal cortex did not have any seizure improvement with bilateral STN DBS.5 Another nonresponder was an 8-year-old girl with a genetic syndrome of unknown etiology.38 Her bilateral CM DBS treatment was unsuccessful at 12 months with a slight worsening of seizure frequency, and thus the DBS electrodes were removed at 18 months. The patient with bilateral hippocampal DBS placement prior to temporal lobectomy who demonstrated no response was the only participant without a positive response to treatment in the study.41 This may have been because this patient had stimulation contacts located in the white matter adjacent to the hippocampus instead of the hippocampus proper. The last nonresponder was the only nonresponder in a prospective, controlled, randomized, double-blind study looking at hippocampal DBS in refractory temporal lobe epilepsy.7 This 14-year-old girl with left mesial temporal sclerosis demonstrated no change in her simple partial seizures and an increase in her complex partial seizures after left hippocampal DBS.

In this cohort, 16 patients40–42,44,45 were from Mexico, 13 of whom had DBS placement in the CM. The earliest study was from 198745 and drew on the hypothesis that the red nucleus, and the CM situated above it, can induce cortical desynchronization and block epileptic synchronous discharges. Since the SANTE trial demonstrated 38% seizure reduction compared with 14.5% in a multicenter, randomized, double-blinded parallel-group study, the ATN has become the most effective and acceptable therapy for refractory epilepsy.13,35 Although DRE is heterogeneous in clinical presentation, certain brain networks may be more important for cortical synchronization and seizure propagation, thus making nodes of these networks more important neuromodulation targets in epilepsy. For example, the cortico-striato-thalamic network and the limbic circuit of Papez have been postulated as targets for stimulation.23,34 One hypothesis for the mechanism of ATN DBS is the modulation of ipsilateral Papez structures such as the entorhinal cortex, hippocampus, parahippocampal gyrus, mammillothalamic tract, cingulate, and inferior temporal gyrus.15,23,39

Even in children, DBS is now used in conjunction with other treatments. Kokoszka et al.20 used RNS as an adjunct to DBS, providing a reversible and modulatory treatment option that provides a capacity for chronic recording of brain activity to better localize seizure foci. Their treatment in a nonambulatory, nonverbal 14-year-old boy not only decreased seizure frequency and severity, but also improved his behavior, attentiveness, and level of engagement at school. This boy’s seizures did not respond to antiepileptic medications, right frontal lobectomy, complete corpus callosotomy, VNS, left temporal lobectomy, or posterior quandrantectomy. At 19 months’ follow-up, cortical stimulation resulted in sustained reduction in both seizure frequency and severity and subsequent DBS reduced seizure frequency by another 50%. This paper is not a direct comparison between DBS and RNS, as the patient in whom both modalities were used had a complex resection history and possibly unique neural circuitry. Velasco et al.41 also utilized hippocampal DBS as an adjunct to temporal lobectomy. Taking patients completely off antiepileptics, in correctly placed hippocampal DBS electrodes, continuous high-frequency and low-intensity stimulation of the anterior pes hippocampi and parahippocampal gyrus close to the amygdaloid nucleus and entorhinal cortex increases seizure threshold and decreases clinical seizures. They also conducted a histopathological study following the temporal lobectomy, showing no difference between the stimulated or nonstimulated hippocampus, suggesting that the DBS mechanisms affect physiology independent of tissue pathology.

The specific indications for DBS for the treatment of childhood epilepsy have yet to be defined. It is often trialed after failed ablative surgery if there is too much risk for resective surgery or the target for resective surgery is unclear. There are no studies that have compared DBS to other neuromodulatory systems, such as RNS or VNS.

Given that the majority of studies included both adult and pediatric patients, the complications specific to children were not thoroughly analyzed and synthesized in this paper. In this series, there were 4 patients who required permanent or temporary explantation due to infection or skin erosion.5,25,40 One patient required DBS electrode replacement after a lead was broken.40 The youngest patient in this cohort was 4 years old, and it is currently unreported if younger children would benefit from DBS for DRE. The long-term complications of DBS in children is not yet understood, although one may hypothesize of unknown migration challenges with placing a DBS electrode in a growing brain.

Limitations of this study include the inclusion of only 1 randomized control trial,7 5 blinded studies,13,29,37,42,44 and 8 prospective trials,9,13,19,26,29,37,40–42,44 with the remaining 12 studies being retrospective case reports and case series. Furthermore, it is difficult to analyze and compare the effectiveness of DBS between studies, as different metrics and outcomes are reported. The majority of studies determined seizure frequency by patient or caregiver report at clinical follow-up instead of specifying the use of a seizure diary or electroencephalography. The characterization of clinical presentation and etiology of seizures are reported in a heterogeneous manner. The rate of seizure frequency was usually measured at the last follow-up, but this ranged anywhere from 16 days to 84 months. Furthermore, there was an inconsistent presentation of antiepileptic medication at the time of treatment and whether there was a reduction or freedom from seizure medication after DBS treatment.

Conclusions

This is the first systematic review that analyzes the effectiveness of DBS on epilepsy in children and youth. Overall, the outcomes analyzed suggest promise for bilateral DBS stimulation of the ATN or CM to achieve a reduction in seizure frequency. Given the initial nascent results seen in a few patients with DBS placement in the hippocampus, STN, posteromedial hypothalamus, mammillothalamic tract, or caudal zona incerta, further understanding of the pathways may better direct the use of these anatomical targets for specifically indicated epilepsy patients. Future studies directed at blinded randomized control trials of stimulation-on/-off states of DBS after placement, with a consistent framework for the reporting of outcomes and complications, will lead to a better understanding of the best clinical scenarios to utilize DBS in children with epilepsy. This would provide an adjunct treatment option for children with DRE who are not candidates for resective surgery.

Disclosures

Dr. Kalia: speaker’s honorarium from Medtronic.

Author Contributions

Conception and design: Ibrahim. Acquisition of data: Yan, Toyota, Anderson. Analysis and interpretation of data: Yan. Drafting the article: Yan, Toyota. Critically revising the article: all authors. Reviewed submitted version of manuscript: Yan, Anderson, Abel, Donner, Kalia, Drake, Rutka, Ibrahim. Approved the final version of the manuscript on behalf of all authors: Yan. Study supervision: Ibrahim.

References

  • 1

    Anderson DGNémeth AHFawcett KASims DMiller JKrause A: Deep brain stimulation in three related cases of North Sea progressive myoclonic epilepsy from South Africa. Mov Disord Clin Pract 4:2492532017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Benabid ALMinotti LKoudsié Ade Saint Martin AHirsch E: Antiepileptic effect of high-frequency stimulation of the subthalamic nucleus (corpus luysi) in a case of medically intractable epilepsy caused by focal dysplasia: a 30-month follow-up: technical case report. Neurosurgery 50:138513922002

    • Search Google Scholar
    • Export Citation
  • 3

    Benedetti-Isaac JCTorres-Zambrano MVargas-Toscano APerea-Castro EAlcalá-Cerra GFurlanetti LL: Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior. Epilepsia 56:115211612015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Boon PVonck KVan Roost DClayes PDe Herdt VAchten E: Amygdalohippocampal deep brain stimulation (AH-DBS) for refractory temporal lobe epilepsy. Rev Neurol (Paris) 161 (Suppl 1):1S191S212005

    • Search Google Scholar
    • Export Citation
  • 5

    Chabardès SKahane PMinotti LKoudsie AHirsch EBenabid AL: Deep brain stimulation in epilepsy with particular reference to the subthalamic nucleus. Epileptic Disord 4 (Suppl 3):S83S932002

    • Search Google Scholar
    • Export Citation
  • 6

    Cukiert ACukiert CMBurattini JALima AM: Seizure outcome after hippocampal deep brain stimulation in a prospective cohort of patients with refractory temporal lobe epilepsy. Seizure 23:692014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Cukiert ACukiert CMBurattini JAMariani PPBezerra DF: Seizure outcome after hippocampal deep brain stimulation in patients with refractory temporal lobe epilepsy: a prospective, controlled, randomized, double-blind study. Epilepsia 58:172817332017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Cukiert ALehtimäki K: Deep brain stimulation targeting in refractory epilepsy. Epilepsia 58 (Suppl 1):80842017

  • 9

    Ding PZhang SZhang JHu XYu XLiang S: Contralateral hippocampal stimulation for failed unilateral anterior temporal lobectomy in patients with bilateral temporal lobe epilepsy. Stereotact Funct Neurosurg 94:3273352016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Dwivedi RRamanujam BChandra PSSapra SGulati SKalaivani M: Surgery for drug-resistant epilepsy in children. N Engl J Med 377:163916472017

  • 11

    Engel J JrMcDermott MPWiebe SLangfitt JTStern JMDewar S: Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA 307:9229302012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Fisher RSalanova VWitt TWorth RHenry TGross R: Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 51:8999082010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Fisher RSUematsu SKrauss GLCysyk BJMcPherson RLesser RP: Placebo-controlled pilot study of centromedian thalamic stimulation in treatment of intractable seizures. Epilepsia 33:8418511992

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Geller EBSkarpaas TLGross REGoodman RRBarkley GLBazil CW: Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy. Epilepsia 58:99410042017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Gibson WSRoss EKHan SRVan Gompel JJMin HKLee KH: Anterior thalamic deep brain stimulation: functional activation patterns in a large animal model. Brain Stimul 9:7707732016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Ibrahim GMRutka JTSnead OC III: Epilepsy surgery in childhood: no longer the treatment of last resort. CMAJ 186:9739742014

  • 17

    Jobst BCKapur RBarkley GLBazil CWBerg MJBergey GK: Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas. Epilepsia 58:100510142017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Khan SWright IJaved SSharples PJardine PCarter M: High frequency stimulation of the mamillothalamic tract for the treatment of resistant seizures associated with hypothalamic hamartoma. Epilepsia 50:160816112009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Kim SHLim SCYang DWCho JHSon BCKim J: Thalamo-cortical network underlying deep brain stimulation of centromedian thalamic nuclei in intractable epilepsy: a multimodal imaging analysis. Neuropsychiatr Dis Treat 13:260726192017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Kokoszka MAPanov FLa Vega-Talbott MMcGoldrick PEWolf SMGhatan S: Treatment of medically refractory seizures with responsive neurostimulation: 2 pediatric cases. J Neurosurg Pediatr 21:4214272018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Krishna VKing NKKSammartino FStrauss IAndrade DMWennberg RA: Anterior nucleus deep brain stimulation for refractory epilepsy: insights into patterns of seizure control and efficacious target. Neurosurgery 78:8028112016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Kwan PArzimanoglou ABerg ATBrodie MJAllen Hauser WMathern G: Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51:106910772010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Laxpati NGKasoff WSGross RE: Deep brain stimulation for the treatment of epilepsy: circuits, targets, and trials. Neurotherapeutics 11:5085262014

  • 24

    Lee CYLim SNWu TLee ST: Successful treatment of refractory status epilepticus using anterior thalamic nuclei deep brain stimulation. World Neurosurg 99:14182017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Lee KJJang KSShon YM: Chronic deep brain stimulation of subthalamic and anterior thalamic nuclei for controlling refractory partial epilepsy. Acta Neurochir Suppl 99:87912006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Lee KJShon YMCho CB: Long-term outcome of anterior thalamic nucleus stimulation for intractable epilepsy. Stereotact Funct Neurosurg 90:3793852012

  • 27

    Lee WGShon YMSeo DW: Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy: a longitudinal data analysis. Epilepsia 57 (Suppl 2):392016 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 28

    Liberati AAltman DGTetzlaff JMulrow CGøtzsche PCIoannidis JPA: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6:e10001002009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Lim SNLee STTsai YTChen IATu PHChen JL: Electrical stimulation of the anterior nucleus of the thalamus for intractable epilepsy: a long-term follow-up study. Epilepsia 48:3423472007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Lipsman NEllis MLozano AM: Current and future indications for deep brain stimulation in pediatric populations. Neurosurg Focus 29(2):E22010

  • 31

    Morris GL IIIMueller WM: Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05. Neurology 53:173117351999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    Möttönen TKatisko JHaapasalo JTähtinen TKiekara TKähärä V: Defining the anterior nucleus of the thalamus (ANT) as a deep brain stimulation target in refractory epilepsy: Delineation using 3 T MRI and intraoperative microelectrode recording. Neuroimage Clin 7:8238292015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Oh YSKim HJLee KJKim YILim SCShon YM: Cognitive improvement after long-term electrical stimulation of bilateral anterior thalamic nucleus in refractory epilepsy patients. Seizure 21:1831872012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Oikawa HSasaki MTamakawa YKamei A: The circuit of Papez in mesial temporal sclerosis: MRI. Neuroradiology 43:2052102001

  • 35

    Salanova VFisher R: Long term efficacy of the SANTE trial (Stimulation of the Anterior Nucleus of Thalamus for Epilepsy). Epilepsy Curr 13 (Suppl 1):1231242013 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 36

    Smyth MDTubbs RSBebin EMGrabb PABlount JP: Complications of chronic vagus nerve stimulation for epilepsy in children. J Neurosurg 99:5005032003

  • 37

    Valentín AGarcía Navarrete EChelvarajah RTorres CNavas MVico L: Deep brain stimulation of the centromedian thalamic nucleus for the treatment of generalized and frontal epilepsies. Epilepsia 54:182318332013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Valentín ASelway RPAmarouche MMundil NUghratdar IAyoubian L: Intracranial stimulation for children with epilepsy. Eur J Paediatr Neurol 21:2232312017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    van Rijckevorsel KAbu Serieh Bde Tourtchaninoff MRaftopoulos Cl: Deep EEG recordings of the mammillary body in epilepsy patients. Epilepsia 46:7817852005

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    Velasco ALVelasco FJiménez FVelasco MCastro GCarrillo-Ruiz JD: Neuromodulation of the centromedian thalamic nuclei in the treatment of generalized seizures and the improvement of the quality of life in patients with Lennox-Gastaut syndrome. Epilepsia 47:120312122006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Velasco ALVelasco MVelasco FMenes DGordon FRocha L: Subacute and chronic electrical stimulation of the hippocampus on intractable temporal lobe seizures: preliminary report. Arch Med Res 31:3163282000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Velasco ALVelasco FVelasco MTrejo DCastro GCarrillo-Ruiz JD: Electrical stimulation of the hippocampal epileptic foci for seizure control: a double-blind, long-term follow-up study. Epilepsia 48:189519032007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Velasco FVelasco ALVelasco MJiménez FCarrillo-Ruiz JDCastro G: Deep brain stimulation for treatment of the epilepsies: the centromedian thalamic target. Acta Neurochir Suppl 97 (Pt 2):3373422007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Velasco FVelasco MJiménez FVelasco ALBrito FRise M: Predictors in the treatment of difficult-to-control seizures by electrical stimulation of the centromedian thalamic nucleus. Neurosurgery 47:2953052000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Velasco FVelasco MOgarrio CFanghanel G: Electrical stimulation of the centromedian thalamic nucleus in the treatment of convulsive seizures: a preliminary report. Epilepsia 28:4214301987

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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Article Information

Contributor Notes

Correspondence Han Yan: The Hospital for Sick Children, Toronto, ON, Canada. hhan.yan@mail.utoronto.ca.INCLUDE WHEN CITING Published online November 30, 2018; DOI: 10.3171/2018.9.PEDS18417.Disclosures Dr. Kalia: speaker’s honorarium from Medtronic.
Headings
Figures
References
  • 1

    Anderson DGNémeth AHFawcett KASims DMiller JKrause A: Deep brain stimulation in three related cases of North Sea progressive myoclonic epilepsy from South Africa. Mov Disord Clin Pract 4:2492532017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Benabid ALMinotti LKoudsié Ade Saint Martin AHirsch E: Antiepileptic effect of high-frequency stimulation of the subthalamic nucleus (corpus luysi) in a case of medically intractable epilepsy caused by focal dysplasia: a 30-month follow-up: technical case report. Neurosurgery 50:138513922002

    • Search Google Scholar
    • Export Citation
  • 3

    Benedetti-Isaac JCTorres-Zambrano MVargas-Toscano APerea-Castro EAlcalá-Cerra GFurlanetti LL: Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior. Epilepsia 56:115211612015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Boon PVonck KVan Roost DClayes PDe Herdt VAchten E: Amygdalohippocampal deep brain stimulation (AH-DBS) for refractory temporal lobe epilepsy. Rev Neurol (Paris) 161 (Suppl 1):1S191S212005

    • Search Google Scholar
    • Export Citation
  • 5

    Chabardès SKahane PMinotti LKoudsie AHirsch EBenabid AL: Deep brain stimulation in epilepsy with particular reference to the subthalamic nucleus. Epileptic Disord 4 (Suppl 3):S83S932002

    • Search Google Scholar
    • Export Citation
  • 6

    Cukiert ACukiert CMBurattini JALima AM: Seizure outcome after hippocampal deep brain stimulation in a prospective cohort of patients with refractory temporal lobe epilepsy. Seizure 23:692014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Cukiert ACukiert CMBurattini JAMariani PPBezerra DF: Seizure outcome after hippocampal deep brain stimulation in patients with refractory temporal lobe epilepsy: a prospective, controlled, randomized, double-blind study. Epilepsia 58:172817332017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Cukiert ALehtimäki K: Deep brain stimulation targeting in refractory epilepsy. Epilepsia 58 (Suppl 1):80842017

  • 9

    Ding PZhang SZhang JHu XYu XLiang S: Contralateral hippocampal stimulation for failed unilateral anterior temporal lobectomy in patients with bilateral temporal lobe epilepsy. Stereotact Funct Neurosurg 94:3273352016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Dwivedi RRamanujam BChandra PSSapra SGulati SKalaivani M: Surgery for drug-resistant epilepsy in children. N Engl J Med 377:163916472017

  • 11

    Engel J JrMcDermott MPWiebe SLangfitt JTStern JMDewar S: Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA 307:9229302012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Fisher RSalanova VWitt TWorth RHenry TGross R: Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 51:8999082010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Fisher RSUematsu SKrauss GLCysyk BJMcPherson RLesser RP: Placebo-controlled pilot study of centromedian thalamic stimulation in treatment of intractable seizures. Epilepsia 33:8418511992

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Geller EBSkarpaas TLGross REGoodman RRBarkley GLBazil CW: Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy. Epilepsia 58:99410042017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Gibson WSRoss EKHan SRVan Gompel JJMin HKLee KH: Anterior thalamic deep brain stimulation: functional activation patterns in a large animal model. Brain Stimul 9:7707732016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Ibrahim GMRutka JTSnead OC III: Epilepsy surgery in childhood: no longer the treatment of last resort. CMAJ 186:9739742014

  • 17

    Jobst BCKapur RBarkley GLBazil CWBerg MJBergey GK: Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas. Epilepsia 58:100510142017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Khan SWright IJaved SSharples PJardine PCarter M: High frequency stimulation of the mamillothalamic tract for the treatment of resistant seizures associated with hypothalamic hamartoma. Epilepsia 50:160816112009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Kim SHLim SCYang DWCho JHSon BCKim J: Thalamo-cortical network underlying deep brain stimulation of centromedian thalamic nuclei in intractable epilepsy: a multimodal imaging analysis. Neuropsychiatr Dis Treat 13:260726192017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Kokoszka MAPanov FLa Vega-Talbott MMcGoldrick PEWolf SMGhatan S: Treatment of medically refractory seizures with responsive neurostimulation: 2 pediatric cases. J Neurosurg Pediatr 21:4214272018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Krishna VKing NKKSammartino FStrauss IAndrade DMWennberg RA: Anterior nucleus deep brain stimulation for refractory epilepsy: insights into patterns of seizure control and efficacious target. Neurosurgery 78:8028112016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Kwan PArzimanoglou ABerg ATBrodie MJAllen Hauser WMathern G: Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51:106910772010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Laxpati NGKasoff WSGross RE: Deep brain stimulation for the treatment of epilepsy: circuits, targets, and trials. Neurotherapeutics 11:5085262014

  • 24

    Lee CYLim SNWu TLee ST: Successful treatment of refractory status epilepticus using anterior thalamic nuclei deep brain stimulation. World Neurosurg 99:14182017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Lee KJJang KSShon YM: Chronic deep brain stimulation of subthalamic and anterior thalamic nuclei for controlling refractory partial epilepsy. Acta Neurochir Suppl 99:87912006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Lee KJShon YMCho CB: Long-term outcome of anterior thalamic nucleus stimulation for intractable epilepsy. Stereotact Funct Neurosurg 90:3793852012

  • 27

    Lee WGShon YMSeo DW: Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy: a longitudinal data analysis. Epilepsia 57 (Suppl 2):392016 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 28

    Liberati AAltman DGTetzlaff JMulrow CGøtzsche PCIoannidis JPA: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6:e10001002009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Lim SNLee STTsai YTChen IATu PHChen JL: Electrical stimulation of the anterior nucleus of the thalamus for intractable epilepsy: a long-term follow-up study. Epilepsia 48:3423472007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Lipsman NEllis MLozano AM: Current and future indications for deep brain stimulation in pediatric populations. Neurosurg Focus 29(2):E22010

  • 31

    Morris GL IIIMueller WM: Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05. Neurology 53:173117351999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    Möttönen TKatisko JHaapasalo JTähtinen TKiekara TKähärä V: Defining the anterior nucleus of the thalamus (ANT) as a deep brain stimulation target in refractory epilepsy: Delineation using 3 T MRI and intraoperative microelectrode recording. Neuroimage Clin 7:8238292015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Oh YSKim HJLee KJKim YILim SCShon YM: Cognitive improvement after long-term electrical stimulation of bilateral anterior thalamic nucleus in refractory epilepsy patients. Seizure 21:1831872012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Oikawa HSasaki MTamakawa YKamei A: The circuit of Papez in mesial temporal sclerosis: MRI. Neuroradiology 43:2052102001

  • 35

    Salanova VFisher R: Long term efficacy of the SANTE trial (Stimulation of the Anterior Nucleus of Thalamus for Epilepsy). Epilepsy Curr 13 (Suppl 1):1231242013 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 36

    Smyth MDTubbs RSBebin EMGrabb PABlount JP: Complications of chronic vagus nerve stimulation for epilepsy in children. J Neurosurg 99:5005032003

  • 37

    Valentín AGarcía Navarrete EChelvarajah RTorres CNavas MVico L: Deep brain stimulation of the centromedian thalamic nucleus for the treatment of generalized and frontal epilepsies. Epilepsia 54:182318332013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Valentín ASelway RPAmarouche MMundil NUghratdar IAyoubian L: Intracranial stimulation for children with epilepsy. Eur J Paediatr Neurol 21:2232312017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    van Rijckevorsel KAbu Serieh Bde Tourtchaninoff MRaftopoulos Cl: Deep EEG recordings of the mammillary body in epilepsy patients. Epilepsia 46:7817852005

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    Velasco ALVelasco FJiménez FVelasco MCastro GCarrillo-Ruiz JD: Neuromodulation of the centromedian thalamic nuclei in the treatment of generalized seizures and the improvement of the quality of life in patients with Lennox-Gastaut syndrome. Epilepsia 47:120312122006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Velasco ALVelasco MVelasco FMenes DGordon FRocha L: Subacute and chronic electrical stimulation of the hippocampus on intractable temporal lobe seizures: preliminary report. Arch Med Res 31:3163282000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Velasco ALVelasco FVelasco MTrejo DCastro GCarrillo-Ruiz JD: Electrical stimulation of the hippocampal epileptic foci for seizure control: a double-blind, long-term follow-up study. Epilepsia 48:189519032007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Velasco FVelasco ALVelasco MJiménez FCarrillo-Ruiz JDCastro G: Deep brain stimulation for treatment of the epilepsies: the centromedian thalamic target. Acta Neurochir Suppl 97 (Pt 2):3373422007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Velasco FVelasco MJiménez FVelasco ALBrito FRise M: Predictors in the treatment of difficult-to-control seizures by electrical stimulation of the centromedian thalamic nucleus. Neurosurgery 47:2953052000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Velasco FVelasco MOgarrio CFanghanel G: Electrical stimulation of the centromedian thalamic nucleus in the treatment of convulsive seizures: a preliminary report. Epilepsia 28:4214301987

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
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