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Neuropediatrics 2017; 48(03): 143-151
DOI: 10.1055/s-0037-1601324
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Lennox–Gastaut Syndrome: A State of the Art Review

Mario Mastrangelo
1   Division of Pediatric Neurology, Department of Pediatrics, Child Neurology and Psychiatry, Sapienza-University of Rome, Rome, Italy
› Institutsangaben
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Publikationsverlauf

17. Januar 2017

21. Februar 2017

Publikationsdatum:
27. März 2017 (online)

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Abstract

Lennox–Gastaut syndrome (LGS) is a severe age-dependent epileptic encephalopathy usually with onset between 1 and 8 years of age. Functional neuroimaging studies recently introduced the concept of Lennox–Gastaut as “secondary network epilepsy” resulting from dysfunctions of a complex system involving both cortical and subcortical structures (default-mode network, corticoreticular connections, and thalamus). These dysfunctions are produced by different disorders including hypoxic–ischemic encephalopathies, meningoencephalitis, cortical malformations, neurocutaneous disorders, or tumors. The list of etiologies was expanded to pathogenic copy number variants at whole-genome array comparative genomic hybridization associated with late-onset cases or pathogenic mutations involving genes, such as GABRB3, ALG13, SCN8A, STXBP1, DNM1, FOXG1, or CHD2. Various clinical trials demonstrated the usefulness of different drugs (including rufinamide, clobazam, lamotrigine, topiramate, or felbamate), ketogenic diet, resective surgery, corpus callosotomy, and vagus nerve stimulation in the treatment of epileptic manifestations. The outcome of LGS often remains disappointing regarding seizure control or cognitive functioning. The realization of animal models, which are still lacking, and the full comprehension of molecular mechanisms involved in epileptogenesis and cognitive impairment would give a relevant support to further improvements in therapeutic strategies for LGS patients.

Keywords

epileptic encephalopathies - intellectual disability - epilepsy
 

  • References

  • 1 Bourgeois BF, Douglass LM, Sankar R. Lennox-Gastaut syndrome: a consensus approach to differential diagnosis. Epilepsia 2014; 55 (Suppl. 04) 4-9
    PubMedSuche in Google Scholar
  • 2 Camfield PR. Definition and natural history of Lennox-Gastaut syndrome. Epilepsia 2011; 52 (Suppl. 05) 3-9
    CrossrefPubMedSuche in Google Scholar
  • 3 Trevathan E, Murphy CC, Yeargin-Allsopp M. Prevalence and descriptive epidemiology of Lennox-Gastaut syndrome among Atlanta children. Epilepsia 1997; 38 (12) 1283-1288
    CrossrefPubMedSuche in Google Scholar
  • 4 Pati S, Deep A, Troester MM, Kossoff EH, Ng YT. Lennox-Gastaut syndrome symptomatic to hypothalamic hamartoma: evolution and long-term outcome following surgery. Pediatr Neurol 2013; 49 (1) 25-30
    CrossrefPubMedSuche in Google Scholar
  • 5 Correia JA, Schweder PM, Mews PJ, Patel R, Law AJ. Lennox-Gastaut syndrome and idiopathic intracranial hypertension. J Clin Neurosci 2010; 17 (9) 1208-1209
    CrossrefPubMedSuche in Google Scholar
  • 6 Kumar A, Paliwal VK, Agarwal V, Neyaz Z, Lal H, Goel G. Relationship of Lennox-Gastaut syndrome with perinatal event: A cross-sectional study. J Pediatr Neurosci 2015; 10 (2) 98-102
    CrossrefPubMedSuche in Google Scholar
  • 7 Lund C, Brodtkorb E, Røsby O, Rødningen OK, Selmer KK. Copy number variants in adult patients with Lennox-Gastaut syndrome features. Epilepsy Res 2013; 105 (1-2): 110-117
    CrossrefPubMedSuche in Google Scholar
  • 8 Rocha J, Guerra C, Oliveira R, Dória S, Rego R, Rosas MJ. Late-onset Lennox-Gastaut syndrome as a phenotype of 15q11.1q13.3 duplication. Epileptic Disord 2012; 14 (2) 159-162
    PubMedSuche in Google Scholar
  • 9 Orrico A, Zollino M, Galli L, Buoni S, Marangi G, Sorrentino V. Late-onset Lennox-Gastaut syndrome in a patient with 15q11.2-q13.1 duplication. Am J Med Genet A 2009; 149A (5) 1033-1035
    CrossrefPubMedSuche in Google Scholar
  • 10 Parrini E, Ferrari AR, Dorn T, Walsh CA, Guerrini R. Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations. Epilepsia 2009; 50 (6) 1344-1353
    CrossrefPubMedSuche in Google Scholar
  • 11 Allen AS, Berkovic SF, Cossette P , et al; Epi4K Consortium; Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 2013; 501 (7466): 217-221
    CrossrefPubMedSuche in Google Scholar
  • 12 Terrone G, Bienvenu T, Germanaud D , et al. A case of Lennox-Gastaut syndrome in a patient with FOXG1-related disorder. Epilepsia 2014; 55 (11) e116-e119
    CrossrefPubMedSuche in Google Scholar
  • 13 Lund C, Brodtkorb E, Øye AM, Røsby O, Selmer KK. CHD2 mutations in Lennox-Gastaut syndrome. Epilepsy Behav 2014; 33: 18-21
    CrossrefPubMedSuche in Google Scholar
  • 14 Delmiro A, Rivera H, García-Silva MT , et al. Whole-exome sequencing identifies a variant of the mitochondrial MT-ND1 gene associated with epileptic encephalopathy: west syndrome evolving to Lennox-Gastaut syndrome. Hum Mutat 2013; 34 (12) 1623-1627
    CrossrefPubMedSuche in Google Scholar
  • 15 Selmer KK, Lund C, Brandal K, Undlien DE, Brodtkorb E. SCN1A mutation screening in adult patients with Lennox-Gastaut syndrome features. Epilepsy Behav 2009; 16 (3) 555-557
    CrossrefPubMedSuche in Google Scholar
  • 16 Blume WT. Pathogenesis of Lennox-Gastaut syndrome: considerations and hypotheses. Epileptic Disord 2001; 3 (4) 183-196
    PubMedSuche in Google Scholar
  • 17 Arzimanoglou A, French J, Blume WT , et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol 2009; 8 (1) 82-93
    CrossrefPubMedSuche in Google Scholar
  • 18 Auvin S, Cilio MR, Vezzani A. Current understanding and neurobiology of epileptic encephalopathies. Neurobiol Dis 2016; 92 (Pt A): 72-89
    CrossrefPubMedSuche in Google Scholar
  • 19 Markand ON. Lennox-Gastaut syndrome (childhood epileptic encephalopathy). J Clin Neurophysiol 2003; 20 (6) 426-441
    CrossrefPubMedSuche in Google Scholar
  • 20 Archer JS, Warren AE, Stagnitti MR, Masterton RA, Abbott DF, Jackson GD. Lennox-Gastaut syndrome and phenotype: secondary network epilepsies. Epilepsia 2014; 55 (8) 1245-1254
    CrossrefPubMedSuche in Google Scholar
  • 21 Archer JS, Warren AE, Jackson GD, Abbott DF. Conceptualizing Lennox-Gastaut syndrome as a secondary network epilepsy. Front Neurol 2014; 5: 225
    PubMedSuche in Google Scholar
  • 22 Pillay N, Archer JS, Badawy RA, Flanagan DF, Berkovic SF, Jackson G. Networks underlying paroxysmal fast activity and slow spike and wave in Lennox-Gastaut syndrome. Neurology 2013; 81 (7) 665-673
    CrossrefPubMedSuche in Google Scholar
  • 23 Intusoma U, Abbott DF, Masterton RA , et al. Tonic seizures of Lennox-Gastaut syndrome: periictal single-photon emission computed tomography suggests a corticopontine network. Epilepsia 2013; 54 (12) 2151-2157
    CrossrefPubMedSuche in Google Scholar
  • 24 Badawy RA, Macdonell RA, Vogrin SJ, Lai A, Cook MJ. Cortical excitability decreases in Lennox-Gastaut syndrome. Epilepsia 2012; 53 (9) 1546-1553
    CrossrefPubMedSuche in Google Scholar
  • 25 Warren AE, Abbott DF, Vaughan DN, Jackson GD, Archer JS. Abnormal cognitive network interactions in Lennox-Gastaut syndrome: A potential mechanism of epileptic encephalopathy. Epilepsia 2016; 57 (5) 812-822
    CrossrefPubMedSuche in Google Scholar
  • 26 Pedersen M, Curwood EK, Archer JS, Abbott DF, Jackson GD. Brain regions with abnormal network properties in severe epilepsy of Lennox-Gastaut phenotype: Multivariate analysis of task-free fMRI. Epilepsia 2015; 56 (11) 1767-1773
    CrossrefPubMedSuche in Google Scholar
  • 27 Berg AT, Berkovic SF, Brodie MJ , et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010; 51 (4) 676-685
    CrossrefPubMedSuche in Google Scholar
  • 28 Shyu HY, Lin JH, Chen C, Kwan SY, Yiu CH. An atypical case of Lennox-Gastaut syndrome not associated with mental retardation: a nosological issue. Seizure 2011; 20 (10) 820-823
    CrossrefPubMedSuche in Google Scholar
  • 29 Hoffmann-Riem M, Diener W, Benninger C , et al. Nonconvulsive status epilepticus--a possible cause of mental retardation in patients with Lennox-Gastaut syndrome. Neuropediatrics 2000; 31 (4) 169-174
    Thieme ConnectPubMedSuche in Google Scholar
  • 30 Ferlazzo E, Nikanorova M, Italiano D , et al. Lennox-Gastaut syndrome in adulthood: clinical and EEG features. Epilepsy Res 2010; 89 (2-3): 271-277
    CrossrefPubMedSuche in Google Scholar
  • 31 Al-Banji MH, Zahr DK, Jan MM. Lennox-Gastaut syndrome. Management update. Neurosciences (Riyadh) 2015; 20 (3) 207-212
    CrossrefPubMedSuche in Google Scholar
  • 32 Newham BJ, Curwood EK, Jackson GD, Archer JS. Pontine and cerebral atrophy in Lennox-Gastaut syndrome. Epilepsy Res 2016; 120: 98-103
    CrossrefPubMedSuche in Google Scholar
  • 33 Siniatchkin M, Capovilla G. Functional neuroimaging in epileptic encephalopathies. Epilepsia 2013; 54 (Suppl. 08) 27-33
    CrossrefPubMedSuche in Google Scholar
  • 34 Montouris GD, Wheless JW, Glauser TA. The efficacy and tolerability of pharmacologic treatment options for Lennox-Gastaut syndrome. Epilepsia 2014; 55 (Suppl. 04) 10-20
    CrossrefPubMedSuche in Google Scholar
  • 35 Hancock EC, Cross JH. Treatment of Lennox-Gastaut syndrome. Cochrane Database Syst Rev 2013; 2 (2) CD003277
    PubMedSuche in Google Scholar
  • 36 Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology 2008; 70 (21) 1950-1958
    CrossrefPubMedSuche in Google Scholar
  • 37 Kluger G, Glauser T, Krauss G, Seeruthun R, Perdomo C, Arroyo S. Adjunctive rufinamide in Lennox-Gastaut syndrome: a long-term, open-label extension study. Acta Neurol Scand 2010; 122 (3) 202-208
    CrossrefPubMedSuche in Google Scholar
  • 38 Ohtsuka Y, Yoshinaga H, Shirasaka Y, Takayama R, Takano H, Iyoda K. Rufinamide as an adjunctive therapy for Lennox-Gastaut syndrome: a randomized double-blind placebo-controlled trial in Japan. Epilepsy Res 2014; 108 (9) 1627-1636
    CrossrefPubMedSuche in Google Scholar
  • 39 Ohtsuka Y, Yoshinaga H, Shirasaka Y, Takayama R, Takano H, Iyoda K. Long-term safety and seizure outcome in Japanese patients with Lennox-Gastaut syndrome receiving adjunctive rufinamide therapy: An open-label study following a randomized clinical trial. Epilepsy Res 2016; 121: 1-7
    CrossrefPubMedSuche in Google Scholar
  • 40 Grosso S, Coppola G, Dontin SD , et al. Efficacy and safety of rufinamide in children under four years of age with drug-resistant epilepsies. Eur J Paediatr Neurol 2014; 18 (5) 641-645
    CrossrefPubMedSuche in Google Scholar
  • 41 Kessler SK, McCarthy A, Cnaan A, Dlugos DJ. Retention rates of rufinamide in pediatric epilepsy patients with and without Lennox-Gastaut Syndrome. Epilepsy Res 2015; 112: 18-26
    CrossrefPubMedSuche in Google Scholar
  • 42 Arzimanoglou A, Ferreira JA, Satlin A , et al. Safety and pharmacokinetic profile of rufinamide in pediatric patients aged less than 4 years with Lennox-Gastaut syndrome: An interim analysis from a multicenter, randomized, active-controlled, open-label study. Eur J Paediatr Neurol 2016; 20 (3) 393-402
    CrossrefPubMedSuche in Google Scholar
  • 43 McMurray R, Striano P. Treatment of adults with Lennox-Gastaut Syndrome: Further analysis of efficacy and safety/tolerability of rufinamide. Neurol Ther 2016; 5 (1) 35-43
    CrossrefPubMedSuche in Google Scholar
  • 44 Wisniewski CS. Rufinamide: a new antiepileptic medication for the treatment of seizures associated with Lennox-Gastaut syndrome. Ann Pharmacother 2010; 44 (4) 658-667
    CrossrefPubMedSuche in Google Scholar
  • 45 Purcarin G, Ng YT. Experience in the use of clobazam in the treatment of Lennox-Gastaut syndrome. Ther Adv Neurol Disorder 2014; 7 (3) 169-176
    PubMedSuche in Google Scholar
  • 46 Conry JA, Ng YT, Paolicchi JM , et al. Clobazam in the treatment of Lennox-Gastaut syndrome. Epilepsia 2009; 50 (5) 1158-1166
    CrossrefPubMedSuche in Google Scholar
  • 47 Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA ; OV-1012 Study Investigators. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology 2011; 77 (15) 1473-1481
    CrossrefPubMedSuche in Google Scholar
  • 48 Ng YT, Conry J, Paolicchi J , et al; OV-1004 study investigators. Long-term safety and efficacy of clobazam for Lennox-Gastaut syndrome: interim results of an open-label extension study. Epilepsy Behav 2012; 25 (4) 687-694
    CrossrefPubMedSuche in Google Scholar
  • 49 Ng YT, Conry J, Mitchell WG , et al. Clobazam is equally safe and efficacious for seizures associated with Lennox-Gastaut syndrome across different age groups: Post hoc analyses of short- and long-term clinical trial results. Epilepsy Behav 2015; 46: 221-226
    CrossrefPubMedSuche in Google Scholar
  • 50 Motte J, Trevathan E, Arvidsson JF, Barrera MN, Mullens EL, Manasco P ; Lamictal Lennox-Gastaut Study Group. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. N Engl J Med 1997; 337 (25) 1807-1812
    CrossrefPubMedSuche in Google Scholar
  • 51 Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger G ; Topiramate YL Study Group. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Neurology 1999; 52 (9) 1882-1887
    CrossrefPubMedSuche in Google Scholar
  • 52 Glauser TA, Levisohn PM, Ritter F, Sachdeo RC ; Topiramate YL Study Group. Topiramate in Lennox-Gastaut syndrome: open-label treatment of patients completing a randomized controlled trial. Epilepsia 2000; 41 (Suppl. 01) S86-S90
    CrossrefPubMedSuche in Google Scholar
  • 53 Shah YD, Singh K, Friedman D, Devinsky O, Kothare SV. Evaluating the safety and efficacy of felbamate in the context of a black box warning: A single center experience. Epilepsy Behav 2016; 56: 50-53
    CrossrefPubMedSuche in Google Scholar
  • 54 Miskin C, Khurana DS, Valencia I, Legido A, Hasbani DM, Carvalho KS. Efficacy and tolerability of lacosamide in the treatment of children with refractory generalized epilepsy. J Child Neurol 2016; 31 (7) 925-928
    CrossrefPubMedSuche in Google Scholar
  • 55 Andrade-Machado R, Luque-Navarro-de Los Reyes J, Benjumea-Cuartas V , et al. Efficacy and tolerability of add-on Lacosamide treatment in adults with Lennox-Gastaut syndrome: An observational study. Seizure 2015; 33: 81-87
    CrossrefPubMedSuche in Google Scholar
  • 56 Devinsky O, Marsh E, Friedman D , et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol 2016; 15 (3) 270-278
    CrossrefPubMedSuche in Google Scholar
  • 57 Hussain SA, Zhou R, Jacobson C , et al. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome. Epilepsy Behav 2015; 47: 138-141
    CrossrefPubMedSuche in Google Scholar
  • 58 Kossoff EH, Shields WD. Nonpharmacologic care for patients with Lennox-Gastaut syndrome: ketogenic diets and vagus nerve stimulation. Epilepsia 2014; 55 (Suppl. 04) 29-33
    CrossrefPubMedSuche in Google Scholar
  • 59 Lemmon ME, Terao NN, Ng YT, Reisig W, Rubenstein JE, Kossoff EH. Efficacy of the ketogenic diet in Lennox-Gastaut syndrome: a retrospective review of one institution's experience and summary of the literature. Dev Med Child Neurol 2012; 54 (5) 464-468
    CrossrefPubMedSuche in Google Scholar
  • 60 Caraballo RH, Fortini S, Fresler S , et al. Ketogenic diet in patients with Lennox-Gastaut syndrome. Seizure 2014; 23 (9) 751-755
    CrossrefPubMedSuche in Google Scholar
  • 61 Douglass LM, Salpekar J. Surgical options for patients with Lennox-Gastaut syndrome. Epilepsia 2014; 55 (Suppl. 04) 21-28
    PubMedSuche in Google Scholar
  • 62 Kim JY, Kang HC, Kim K, Kim HD, Im CH. Localization of epileptogenic zones in Lennox-Gastaut syndrome (LGS) using graph theoretical analysis of ictal intracranial EEG: a preliminary investigation. Brain Dev 2015; 37 (1) 29-36
    CrossrefPubMedSuche in Google Scholar
  • 63 Kim JY, Kang HC, Cho JH, Lee JH, Kim HD, Im CH. Combined use of multiple computational intracranial EEG analysis techniques for the localization of epileptogenic zones in Lennox-Gastaut syndrome. Clin EEG Neurosci 2014; 45 (3) 169-178
    CrossrefPubMedSuche in Google Scholar
  • 64 Cho JH, Kang HC, Jung YJ , et al. Localization of epileptogenic zones in Lennox-Gastaut syndrome using frequency domain source imaging of intracranial electroencephalography: a preliminary investigation. Physiol Meas 2013; 34 (2) 247-263
    CrossrefPubMedSuche in Google Scholar
  • 65 Jung YJ, Kang HC, Choi KO , et al. Localization of ictal onset zones in Lennox-Gastaut syndrome using directional connectivity analysis of intracranial electroencephalography. Seizure 2011; 20 (6) 449-457
    CrossrefPubMedSuche in Google Scholar
  • 66 Lancman G, Virk M, Shao H , et al. Vagus nerve stimulation vs. corpus callosotomy in the treatment of Lennox-Gastaut syndrome: a meta-analysis. Seizure 2013; 22 (1) 3-8
    CrossrefPubMedSuche in Google Scholar
  • 67 Karceski S. Vagus nerve stimulation and Lennox-Gastaut syndrome: a review of the literature and data from the VNS patient registry. CNS Spectr 2001; 6 (9) 766-770
    CrossrefPubMedSuche in Google Scholar
  • 68 Camfield PR, Bahi-Buisson N, Trinka E. Transition issues for children with diffuse cortical malformations, multifocal postnatal lesions, (infectious and traumatic) and Lennox-Gastaut and similar syndromes. Epilepsia 2014; 55 (Suppl. 03) 24-28
    CrossrefPubMedSuche in Google Scholar
  • 69 Kim HJ, Kim HD, Lee JS, Heo K, Kim DS, Kang HC. Long-term prognosis of patients with Lennox--Gastaut syndrome in recent decades. Epilepsy Res 2015; 110: 10-19
    CrossrefPubMedSuche in Google Scholar
  • 70 Ng YT, Pati S, Fesler JR. Lennox-Gastaut syndrome may be a curable, reversible epileptic encephalopathy. Epilepsia 2015; 56 (3) 499-500
    CrossrefPubMedSuche in Google Scholar
  • 71 Autry AR, Trevathan E, Van Naarden Braun K, Yeargin-Allsopp M. Increased risk of death among children with Lennox-Gastaut syndrome and infantile spasms. J Child Neurol 2010; 25 (4) 441-447
    CrossrefPubMedSuche in Google Scholar