Intracranial neuromodulation with deep brain stimulation and responsive neurostimulation in children with drug-resistant epilepsy: a systematic review

Mehdi Khan BSc1,3, Jaber Paktiawal MD2,3, Rory J. Piper MBChB, MRCS3,4, Aswin Chari MA, BMBCh, MRCS3,4, and Martin M. Tisdall MD, FRCS(SN)3,4
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  • 1 University College London Medical School, London, United Kingdom;
  • | 2 Medical University Pleven, Pleven, Bulgaria;
  • | 3 Department of Neurosurgery, Great Ormond Street Hospital, London, United Kingdom; and
  • | 4 Developmental Neuroscience, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
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OBJECTIVE

In children with drug-resistant epilepsy (DRE), resective, ablative, and disconnective surgery may not be feasible or may fail. Neuromodulation in the form of deep brain stimulation (DBS) and responsive neurostimulation (RNS) may be viable treatment options, however evidence for their efficacies in children is currently limited. This systematic review aimed to summarize the literature on DBS and RNS for the treatment of DRE in the pediatric population. Specifically, the authors focused on currently available data for reported indications, neuromodulation targets, clinical efficacy, and safety outcomes.

METHODS

PRISMA guidelines were followed throughout this systematic review (PROSPERO no. CRD42020180669). Electronic databases, including PubMed, Embase, Cochrane Library, OpenGrey, and CINAHL Plus, were searched from their inception to February 19, 2021. Inclusion criteria were 1) studies with at least 1 pediatric patient (age < 19 years) who underwent DBS and/or RNS for DRE; and 2) retrospective, prospective, randomized, or nonrandomized controlled studies, case series, and case reports. Exclusion criteria were 1) letters, commentaries, conference abstracts, and reviews; and 2) studies without full text available. Risk of bias of the included studies was assessed using the Cochrane ROBINS-I (Risk of Bias in Non-randomised Studies - of Interventions) tool.

RESULTS

A total of 35 studies were selected that identified 72 and 46 patients who underwent DBS and RNS, respectively (age range 4–18 years). Various epilepsy etiologies and seizure types were described in both cohorts. Overall, 75% of patients had seizure reduction > 50% after DBS (among whom 6 were seizure free) at a median (range) follow-up of 14 (1–100) months. In an exploratory univariate analysis of factors associated with favorable response, the follow-up duration was shorter in those patients with a favorable response (18 vs 33 months, p < 0.05). In the RNS cohort, 73.2% of patients had seizure reduction > 50% after RNS at a median (range) follow-up of 22 (5–39) months. On closer inspection, 83.3% of patients who had > 50% reduction in seizures actually had > 75% reduction, with 4 patients being seizure free.

CONCLUSIONS

Overall, both DBS and RNS showed favorable response rates, indicating that both techniques should be considered for pediatric patients with DRE. However, serious risks of overall bias were found in all included studies. Many research needs in this area would be addressed by conducting high-quality clinical trials and establishing an international registry of patients who have undergone pediatric neuromodulation, thereby ensuring robust prospective collection of predictive variables and outcomes.

ABBREVIATIONS

ANT = anterior nucleus of the thalamus; CMN = centromedian nucleus of the thalamus; DBS = deep brain stimulation; DRE = drug-resistant epilepsy; FIRES = febrile infection–related epilepsy syndrome; GTC = generalized tonic-clonic; LGS = Lennox-Gastaut syndrome; RNS = responsive neurostimulation; VNS = vagus nerve stimulation.

Supplementary Materials

    • Supplemental Tables and Figures (PDF 5,733 KB)

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  • 1

    Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011;365(10):919926.

  • 2

    Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5):314319.

  • 3

    Keezer MR, Sisodiya SM, Sander JW. Comorbidities of epilepsy: current concepts and future perspectives. Lancet Neurol. 2016;15(1):106115.

    • Search Google Scholar
    • Export Citation
  • 4

    Barba C, Cross JH, Braun K, Cossu M, Klotz KA, De Masi S, et al. Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: country-, center-, and age-specific variation. Epilepsia. 2020;61(2):216227.

    • Search Google Scholar
    • Export Citation
  • 5

    Lamberink HJ, Boshuisen K, van Rijen PC, Gosselaar PH, Braun KPJ. Changing profiles of pediatric epilepsy surgery candidates over time: a nationwide single-center experience from 1990 to 2011. Epilepsia. 2015;56(5):717725.

    • Search Google Scholar
    • Export Citation
  • 6

    Lozano AM, Lipsman N, Bergman H, Brown P, Chabardes S, Chang JW, et al. Deep brain stimulation: current challenges and future directions. Nat Rev Neurol. 2019;15(3):148160.

    • Search Google Scholar
    • Export Citation
  • 7

    Kang JY, Wu C, Tracy J, Lorenzo M, Evans J, Nei M, et al. Laser interstitial thermal therapy for medically intractable mesial temporal lobe epilepsy. Epilepsia. 2016;57(2):325334.

    • Search Google Scholar
    • Export Citation
  • 8

    Panebianco M, Rigby A, Weston J, Marson AG. Vagus nerve stimulation for partial seizures. Cochrane Database Syst Rev. 2015;(4):CD002896

  • 9

    Sourbron J, Klinkenberg S, Kessels A, Schelhaas HJ, Lagae L, Majoie M. Vagus nerve stimulation in children: a focus on intellectual disability. Eur J Paediatr Neurol. 2017;21(3):427440.

    • Search Google Scholar
    • Export Citation
  • 10

    Nagel SJ, Najm IM. Deep brain stimulation for epilepsy. Neuromodulation. 2009;12(4):270280.

  • 11

    Hodaie M, Wennberg RA, Dostrovsky JO, Lozano AM. Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia. 2002;43(6):603608.

    • Search Google Scholar
    • Export Citation
  • 12

    Velasco AL, Velasco F, Jiménez F, Velasco M, Castro G, Carrillo-Ruiz JD, et al. 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. 2006;47(7):12031212.

    • Search Google Scholar
    • Export Citation
  • 13

    Shon YM, Lee KJ, Kim HJ, Chung YA, Ahn KJ, Kim YI, et al. Effect of chronic deep brain stimulation of the subthalamic nucleus for frontal lobe epilepsy: subtraction SPECT analysis. Stereotact Funct Neurosurg. 2005;83(2-3):8490.

    • Search Google Scholar
    • Export Citation
  • 14

    Capecci M, Ricciuti RA, Ortenzi A, Paggi A, Durazzi V, Rychlicki F, et al. Chronic bilateral subthalamic stimulation after anterior callosotomy in drug-resistant epilepsy: long-term clinical and functional outcome of two cases. Epilepsy Res. 2012;98(2-3):135139.

    • Search Google Scholar
    • Export Citation
  • 15

    Valentín A, Selway RP, Amarouche M, Mundil N, Ughratdar I, Ayoubian L, et al. Intracranial stimulation for children with epilepsy. Eur J Paediatr Neurol. 2017;21(1):223231.

    • Search Google Scholar
    • Export Citation
  • 16

    Velasco F, Velasco M, Jiménez F, Velasco AL, Brito F, Rise M, Carrillo-Ruiz JD. Predictors in the treatment of difficult-to-control seizures by electrical stimulation of the centromedian thalamic nucleus. Neurosurgery. 2000;47(2):295305.

    • Search Google Scholar
    • Export Citation
  • 17

    Salanova V, Witt T, Worth R, Henry TR, Gross RE, Nazzaro JM, et al. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology. 2015;84(10):10171025.

    • Search Google Scholar
    • Export Citation
  • 18

    Kim SH, Lim SC, Yang DW, Cho JH, Son BC, Kim J, et al. Thalamo-cortical network underlying deep brain stimulation of centromedian thalamic nuclei in intractable epilepsy: a multimodal imaging analysis. Neuropsychiatr Dis Treat. 2017;13:26072619.

    • Search Google Scholar
    • Export Citation
  • 19

    Fisher RS, Uematsu S, Krauss GL, Cysyk BJ, McPherson R, Lesser RP, et al. Placebo-controlled pilot study of centromedian thalamic stimulation in treatment of intractable seizures. Epilepsia. 1992;33(5):841851.

    • Search Google Scholar
    • Export Citation
  • 20

    Valentín A, García Navarrete E, Chelvarajah R, Torres C, Navas M, et al. Deep brain stimulation of the centromedian thalamic nucleus for the treatment of generalized and frontal epilepsies. Epilepsia. 2013;54(10):18231833.

    • Search Google Scholar
    • Export Citation
  • 21

    Bergey GK, Morrell MJ, Mizrahi EM, Goldman A, King-Stephens D, Nair D, et al. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures. Neurology. 2015;84(8):810817.

    • Search Google Scholar
    • Export Citation
  • 22

    Heck CN, King-Stephens D, Massey AD, Nair DR, Jobst BC, Barkley GL, et al. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial. Epilepsia. 2014;55(3):432441.

    • Search Google Scholar
    • Export Citation
  • 23

    Morrell MJ. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology. 2011;77(13):12951304.

    • Search Google Scholar
    • Export Citation
  • 24

    National Institute for Health Research. PROSPERO. National Institute for Health Research, Centre for Reviews and Dissemination, University of York. Accessed September 11, 2021. https://www.crd.york.ac.uk/prospero/

    • Search Google Scholar
    • Export Citation
  • 25

    Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10(1):89.

    • Search Google Scholar
    • Export Citation
  • 26

    Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512521.

    • Search Google Scholar
    • Export Citation
  • 27

    Sterne JAC, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919.

    • Search Google Scholar
    • Export Citation
  • 28

    McGuinness LA, Higgins JPT. Risk-of-bias VISualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods. 2021;12(1):5561.

    • Search Google Scholar
    • Export Citation
  • 29

    Lee CY, Lim SN, Wu T, Lee ST. Successful treatment of refractory status epilepticus using anterior thalamic nuclei deep brain stimulation. World Neurosurg. 2017;99:1418.

    • Search Google Scholar
    • Export Citation
  • 30

    Khan S, Wright I, Javed S, Sharples P, Jardine P, Carter M, Gill SS. High frequency stimulation of the mamillothalamic tract for the treatment of resistant seizures associated with hypothalamic hamartoma. Epilepsia. 2009;50(6):16081611.

    • Search Google Scholar
    • Export Citation
  • 31

    Sa M, Singh R, Pujar S, D’Arco F, Desai N, Eltze C, et al. Centromedian thalamic nuclei deep brain stimulation and Anakinra treatment for FIRES - Two different outcomes. Eur J Paediatr Neurol. 2019;23(5):749754.

    • Search Google Scholar
    • Export Citation
  • 32

    Alcala-Zermeno JL, Gregg NM, Wirrell EC, Stead M, Worrell GA, Van Gompel JJ, Lundstrom BN. Centromedian thalamic nucleus with or without anterior thalamic nucleus deep brain stimulation for epilepsy in children and adults: a retrospective case series. Seizure. 2021;84:101107.

    • Search Google Scholar
    • Export Citation
  • 33

    Kwon CS, Schupper AJ, Fields MC, Marcuse LV, La Vega-Talbott M, Panov F, Ghatan S. Centromedian thalamic responsive neurostimulation for Lennox-Gastaut epilepsy and autism. Ann Clin Transl Neurol. 2020;7(10):20352040.

    • Search Google Scholar
    • Export Citation
  • 34

    Kokoszka MA, Panov F, La Vega-Talbott M, McGoldrick PE, Wolf SM, Ghatan S. Treatment of medically refractory seizures with responsive neurostimulation: 2 pediatric cases. J Neurosurg Pediatr. 2018;21(4):421427.

    • Search Google Scholar
    • Export Citation
  • 35

    Yan H, Toyota E, Anderson M, Abel TJ, Donner E, Kalia SK, et al. A systematic review of deep brain stimulation for the treatment of drug-resistant epilepsy in childhood. J Neurosurg Pediatr. 2018;23(3):274284.

    • Search Google Scholar
    • Export Citation
  • 36

    Warren AEL, Dalic LJ, Thevathasan W, Roten A, Bulluss KJ, Archer J. Targeting the centromedian thalamic nucleus for deep brain stimulation. J Neurol Neurosurg Psychiatry. 2020;91(4):339349.

    • Search Google Scholar
    • Export Citation
  • 37

    Nair DR, Laxer KD, Weber PB, Murro AM, Park YD, Barkley GL, et al. Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy. Neurology. 2020;95(9):e1244e1256.

    • Search Google Scholar
    • Export Citation
  • 38

    Theroux L, Shah Y, Cukier Y, Rodgers S, Karkare S, Bonda D, Kothare S. Improved seizure burden and cognitive performance in a child treated with responsive neurostimulation (RNS) following febrile infection related epilepsy syndrome (FIRES). Epileptic Disord. 2020;22(6):811816.

    • Search Google Scholar
    • Export Citation
  • 39

    Bercu MM, Friedman D, Silverberg A, Drees C, Geller EB, Dugan PC, et al. Responsive neurostimulation for refractory epilepsy in the pediatric population: a single-center experience. Epilepsy Behav. 2020;112:107389.

    • Search Google Scholar
    • Export Citation
  • 40

    Skirrow C, Cross JH, Owens R, Weiss-Croft L, Martin-Sanfilippo P, Banks T, et al. Determinants of IQ outcome after focal epilepsy surgery in childhood: a longitudinal case-control neuroimaging study. Epilepsia. 2019;60(5):872884.

    • Search Google Scholar
    • Export Citation
  • 41

    Panov F, Ganaha S, Haskell J, Fields M, La Vega-Talbott M, Wolf S, et al. Safety of responsive neurostimulation in pediatric patients with medically refractory epilepsy. J Neurosurg Pediatr. 2020;26(5):525532.

    • Search Google Scholar
    • Export Citation
  • 42

    Herlopian A, Cash SS, Eskandar EM, Jennings T, Cole AJ. Responsive neurostimulation targeting anterior thalamic nucleus in generalized epilepsy. Ann Clin Transl Neurol. 2019;6(10):21042109.

    • Search Google Scholar
    • Export Citation
  • 43

    Kokkinos V, Urban A, Sisterson ND, Li N, Corson D, Richardson RM. Responsive neurostimulation of the thalamus improves seizure control in idiopathic generalized epilepsy: a case report. Neurosurgery. 2020;87(5):E578E583.

    • Search Google Scholar
    • Export Citation
  • 44

    Arzimanoglou A, French J, Blume WT, Cross JH, Ernst JP, Feucht M, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 2009;8(1):8293.

    • Search Google Scholar
    • Export Citation
  • 45

    Muthiah N, Zhang J, Remick M, Welch W, Sogawa Y, Jeong JH, Abel TJ. Efficacy of vagus nerve stimulation for drug-resistant epilepsy in children age six and younger. Epilepsy Behav. 2020;112:107373.

    • Search Google Scholar
    • Export Citation
  • 46

    Orosz I, McCormick D, Zamponi N, Varadkar S, Feucht M, Parain D, et al. Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347 children. Epilepsia. 2014;55(10):15761584.

    • Search Google Scholar
    • Export Citation
  • 47

    Elliott RE, Rodgers SD, Bassani L, Morsi A, Geller EB, Carlson C, et al. Vagus nerve stimulation for children with treatment-resistant epilepsy: a consecutive series of 141 cases. J Neurosurg Pediatr. 2011;7(5):491500.

    • Search Google Scholar
    • Export Citation
  • 48

    McCulloch P, Altman DG, Campbell WB, Flum DR, Glasziou P, Marshall JC, et al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet. 2009;374(9695):11051112.

    • Search Google Scholar
    • Export Citation
  • 49

    Blachut B, Hoppe C, Surges R, Stahl J, Elger CE, Helmstaedter C. Counting seizures: the primary outcome measure in epileptology from the patients’ perspective. Seizure. 2015;29:97103.

    • Search Google Scholar
    • Export Citation
  • 50

    Lim SN, Lee ST, Tsai YT, Chen IA, Tu PH, Chen JL, et al. Electrical stimulation of the anterior nucleus of the thalamus for intractable epilepsy: a long-term follow-up study. Epilepsia. 2007;48(2):342347.

    • Search Google Scholar
    • Export Citation

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