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Lennox-Gastaut Syndrome (LGS)

Lennox-Gastaut Syndrome (LGS). Henri Gastaut 1915-1995. William G. Lennox 1884-1960. James W. Wheless, MD Professor and Chief of Pediatric Neurology Le Bonheur Chair in Pediatric Neurology University of Tennessee Health Science Center

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Lennox-Gastaut Syndrome (LGS)

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  1. Lennox-Gastaut Syndrome (LGS) Henri Gastaut 1915-1995 William G. Lennox 1884-1960 James W. Wheless, MD Professor and Chief of Pediatric Neurology Le Bonheur Chair in Pediatric Neurology University of Tennessee Health Science Center Director, Neuroscience Institute & Le Bonheur Comprehensive Epilepsy Program Le Bonheur Children’s Hospital Memphis, TN USA

  2. Lennox-Gastaut Syndrome (LGS) • History • Epidemiology • Diagnostic Criteria • Etiology • Evaluation • Pathophysiology • Prognosis • Treatment

  3. Lennox-Gastaut Syndrome: History Lennox & Davis describe multiple seizure types2 Gastaut describes 100 patients (Lennox Syn.)4 ILAE classifies LGS as epileptic encephalopathy 1969 1939 1965 Gibbs, Gibbs & Lennox describe slow spike & wave pattern (Petit Mal Variant)1 1950 1966 2001 Dravet 1st precise description published (epileptic encephalopathy) (Lennox Syn.)3 LGS 1st appears-suggested by Margaret Buchtal-Lennox5 1. Gibbs F. Arch Neurol & Psychiatr, 1939; 41: 1111.2. Lennox WG, Davis JP. Pediatrics, 1950; 5(4):626-644. 3.Dravet C. Encephalopathie Epileptique de l’Enfant avec Pointe-Onde Lente Diffuse (petit Mal Variant), Thesis, Marseille, 1965. 4.Gastaut H, et al. Epilepsia, 1966; 7: 139-179. 5.Niedermeyer E, Dtsch Z, Nervenheilkd, 1969;195(4):263-282.

  4. Lennox-Gastaut Syndrome: Epidemiology • LGS is typically diagnosed between the ages of 2 and 8 years, with peak onset between 3 and 5 years1 • Diagnosis in adolescents and adults is also possible2 • Estimated to account for 1%-10% of all childhood epilepsies3 • Affects patients throughout their lives1 • Mortality rate is estimated at 3%-7%4 • Male predominance 1van Rijckevorsel K. Neuropsychiatr Dis Treat. 2008; 4(6):1001-1019 2Arzimanoglou A, et al. Epileptic Disord. 2011; 139(suppl 1):S3-S13 3Hancock EC, et al. Cochrane Database Syst Rev. 2009(4):1-39 4Glauser TA. Epilepsia. 2004; 45(suppl 5):23-26

  5. LGS Diagnostic Criteria: Triad of Common Features1 Not all patients with LGS display the characteristic triad of features2,4 1Arzimanoglou A, et al. Epileptic Disord. 2011; 13 (suppl 1):S3-S13. 2Arzimanoglou A, et al. Lancet Neurol. 2009; 8(1):82-93. 3Ferrie CD, et al. Eur J Pediatr Neurol. 2009; 13(6):493-504. 4Kerr M, et al. Epileptic Disord. 2011; 13(suppl 1):S15-S26

  6. Multiple Seizure Types Are Associated with LGS1-3 • Tonic • Atypical absence • Atonic • Nonconvulsive status epilepticus • Myoclonic • Generalized tonic-clonic • Clonic • Partial (focal) • Markand ON. J ClinNeurophysiol. 2003; 20(6):426-441. 2. Ferrie CD, et al. Eur J Peadiatr Neurol. 2009; 13(6):493-504. 3. Arzimanoglou A, et al. Lancet Neurol. 2009; 8(1):82-93

  7. Cognitive Impairment in LGS Can Range From Mild to Severe1-4 • Most patients with LGS have cognitive impairment, which continues to worsen over time1,2 • Gastaut tested the IQ of 50 hospitalized children with LGS and found that 80% had an IQ <50, half of whom had severe intellectual disability3 • 10%-20% of patients with LGS are within a normal range for cognitive function, but often have difficulties with daily tasks, with IQ seldom exceeding 903,4 IQ Range 25 50 75 90 1. Oguni H, et al. Epilepsia. 1996; 37(suppl 3):44-47. 2. Goldsmith IL, et al. Epilepsia. 2000; 41(4):395-399.3. Gastaut H, et al. Epilepsia. 1966;7:139-179. 4. Arzimanoglou A, et al. Lancet Neurol. 2009; 8(1):82-93.

  8. Classic EEG Pattern Seen in LGS Slow Spike-Wave (1.5-2.5 Hz) Associated with Atypical Absence Seizures

  9. The Path to Lennox-Gastaut Syndrome (LGS) Infantile spasms (West Syndrome) LGS Wheless JW, Constantinou JE. J Child Neurol, 1997; 17 (3): 203 – 211. Crumrine PK. J Child Neurol, 2002; 17 (Suppl. 1): 570-575. Arzimanoglou A et al. Lancet Neurol, 2009; 8 (1): 82-93.

  10. The Path to Lennox-Gastaut Syndrome (LGS) Known etiology (70-75%) (Structural-Metabolic) Unknown etiology (25-30%) LGS Wheless JW, Constantinou JE. J Child Neurol, 1997; 17 (3): 203 – 211. Crumrine PK. J Child Neurol, 2002; 17 (Suppl. 1): 570-575. Arzimanoglou A et al. Lancet Neurol, 2009; 8 (1): 82-93.

  11. The Path to Lennox-Gastaut Syndrome (LGS) Infantile spasms (West Syndrome) Known etiology (70-75%) (Structural-Metabolic) Unknown etiology (25-30%) LGS Wheless JW, Constantinou JE. J Child Neurol, 1997; 17 (3): 203 – 211. Crumrine PK. J Child Neurol, 2002; 17 (Suppl. 1): 570-575. Arzimanoglou A et al. Lancet Neurol, 2009; 8 (1): 82-93.

  12. LGS Can Arise From Multiple Etiologies1-4 • Cryptogenic • In 30% of LGS cases, the underlying cause is unknown1,2 • Symptomatic • 70% of LGS cases have a known origin arising from cerebral dysfunction, caused by1-3 • Pre-or perinatal insult • Infection • Various brain malformations • Head Trauma • Genetic Factors Because LGS can arise from various etiologies, clinical presentation can vary4 1van Rijckevorsel K. Neurospychiatr Dis Treat. 2008; 4(6):1001-1019 2Markand ON. J Clin Neurophysiol. 2003:20(6):426-441. 3Arzimanoglou A, et al. Epileptic Disord. 2011;13(suppl 1):S3-S13. 4Bourgeois BFD, et al. Epilepsia. 2014; 55(suppl.4):4-9.

  13. Lennox-Gastaut Syndrome: Genetics • SCN1A1,2 (1 of 22 adults screened) • SCN1A2 (1/12 with epilepsy onset in the 1st 2 years of life) • Trisomy 213 (late onset, reflex seizures) • Tuberous Sclerosis Complex 5 • GPR56 mutation (16q12.2-21)(Bilateral Frontoparietal Polymicrogyria)4 • LIS15, DCX5,6 • 15q11.1 q13.3 duplication7 • FOXG1-related disorder (14q12)8 • Copy number variants9,10 1Selmer KK et al. Epilepsy Behav, 2009; 16(3):555-557. 2Harkin LA, et al. Brain 2007, 130:843-852 3Ferlazzo E et al. Epilepsia, 2009; 50(6):1587-1595.4Parrini E et al. Epilepsia, 2009; 50(6):1344-1353. 5Guerrini R, Filippi T. J. Child Neurol, 2005;20:287-299.6Lawrence KM et al. Epilepsia, 2010;51(9):1902-1905. 7Rocha J et al. Epileptic Disord, 2012; 14(2):159-162. 8Terrone G et al. Epilepsia, 2014; 55(11):e116-e119. 9Lund C et al. Epilepsia Research; 2013; 105:110-117. 10Lund C et al. Epilepsia Behav, 2014; 33:18-21.

  14. Lennox-Gastaut Syndrome of Unknown Cause:Clinical Characteristics (Epilepsy Phenome/ Genome Project) • N=135; 66% males; epilepsy range of onset 1-13 yrs. • 93% diagnosed with LGS within 1 yr. of onset. • 59% (N=80) had normal development prior to seizure onset • EEG: N=11 had normal posterior rhythm • All had generalized epileptiform discharges (median 2 Hz) • 11.8% (N=16) had prior West Syndrome • N=50 adults (≥ 18 yrs.): 42% completed secondary school Widdess-Walsh P et al. Epilepsia, 2013; 54(11): 1898-1904. http://www.epgp.org

  15. De novo Mutations in Epileptic Encephalopathies • Exome sequencing of patients with Infantile spasms (N=149), Lennox-Gastaut Syndrome (N=115) and their parents. • These mutations are enriched in specific gene sets, including genes regulated by the Fragile X protein. Epi4K Consortium & Epilepsy Phenome/Genome Project. Nature, 2013; 501 (7466): 217-221. www.epgp.org

  16. De novo Mutations in Epileptic Encephalopathies • Exome sequencing of patients with epileptic encephalopathies (N = 356). Primary protein-protein interaction network. EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, & Epi4K Consortium. Amer J Human Genetics, 2014; 95 (4): 360-370.

  17. Epileptic Encephalopathy in Childhood (N=110) Mercimek-Mahmutoglu S, et al. Epilepsia, 2015; 561(5):707-716

  18. Lennox-Gastaut Syndrome: Evaluation Clinical History/ Examination Brain MRI, EEG Routine Laboratory Studies Chromosome Microarray Targeted next-generation sequencing epileptic encephalopathy panels Whole Exome Sequencing Mercimek-Mahmutoglu S, et al. Epilepsia, 2015; 56(5): 707-716 (Toronto Sick Children’s Protocol). Epilepsy Phenome/Genome Project & Epi4K Consortium, Ann Neurol, 2015; 78 (2): 323-328.

  19. Lennox- Gastaut Syndrome: A Common Neuronal Network Significant activation of brainstem and thalamus (especially centromedian and anterior thalamus) EEG- fMRI Group Analysis (N=11)(p<0.001) Siniatchkin M et al. Epilepsia, 2011; 52(4): 776-774

  20. Lennox-Gastaut Syndrome: A Network Disorder • Thalamus acts as a synchronizer & amplifier • Pons appear involved in tonic seizures Subtraction SPECT Studies in Tonic Seizures Intusoma U et al. Epilepsia, 2013; 54 (12): 2151 – 2157. Archer JS et al. Front. Neurol, 2014; 5:225

  21. Lennox-Gastaut Syndrome: A Network Disorder • Common electroclinical phenotype, despite varying etiologies, suggests a common underlying mechanism • Functional neuroimaging confirms epileptiform discharges in LGS recruit widespread areas of association cortex (diffuse association network activity) (spares primary cortical regions). • Epileptiform discharges in LGS are characterized by a breakdown in normal brain network behavior (co-activation of attention and default-mode networks). • Epileptic process of LGS is initiated from the cortex. Blume WT. Epileptic Disorders, 2001;3 (4): 183 – 196. Pillay N et al. Neurology, 2013; 81 (7): 665 – 673. Archer JS et al. Front Neurol, 2014; 5:225. Archer JS et al. Epilepsia, 2014; 55 (8): 1245 – 1254.

  22. Lennox-Gastaut Syndrome Affects Patients Throughout Their Lives1 LGS features often change with age1 • Kerr M, et al. Epileptic Disord. 2011; 13(suppl 1):S15-S26. 2. van Rijckevorsel K. Neuropsychiatr Dis Treat. 2008;4(6):1001-1019

  23. The Triad of Features Changes From Childhood to Adulthood1 Consider a diagnosis of LGS when a adult patient presents with cognitive impairment and multiple seizure types1 1Kerr M et al. Epileptic Disord, 2011; 13 (Suppl 1):S15-S26. 2Arzimanoglou A etal. Lancet Neurol, 2009; 8(1): 82-93. 3Kim HJ et al, Epilepsy Research, 2015; 110:10-19.4Ferrie CD et al. Eur J Paediatr Neurol, 2009; 13(6):493-504.

  24. Lennox- Gastaut Syndrome: Change in Seizure Type Over Time Kim HJ, et al. Epilepsy Res, 2015; 110: 10-19

  25. Lennox-Gastaut Syndrome: Change in EEG over Time % Kim HJ, et al. Epilepsy Res, 2015; 110:10-19

  26. Common Misperceptions in LGS Diagnosis Core seizure types (tonic, atonic, atypical absence) are always present at onset2 LGS is strictly a pediatric epilepsy syndrome1 Drop attacks are caused only by atonic seizures3,4 • Kerr M, et al. Epileptic Disord. 2011;13(suppl 1):S15-S26. 2. Arzimanoglou A, et al. Lancet Neurol. 2009;8(1):82-93. 3. Tatum WO. Atypical absence seizures, myoclonic, tonic, and atonic seizures. In:Wyllie E, Cascino GD, Gidal BE, Goodkin HP, eds. Wyllie’s Treatment of Epilepsy: Principles and Practice. 5th ed. Philadelphia, PA: Lippencott Williams & Wilkins; 2011. • 4. Ikeno T, et al. Epilepsia. 1985;26(6):612-621.

  27. Common Misperceptions in LGS Diagnosis Core seizure types (tonic, atonic, atypical absence) are always present at onset2 LGS is strictly a pediatric epilepsy syndrome1 LGS typically has a childhood onset, but persists into adulthood Drop attacks are caused only by atonic seizures3,4 • Kerr M, et al. Epileptic Disord. 2011;13(suppl 1):S15-S26. 2. Arzimanoglou A, et al. Lancet Neurol. 2009;8(1):82-93. 3. Tatum WO. Atypical absence seizures, myoclonic, tonic, and atonic seizures. In:Wyllie E, Cascino GD, Gidal BE, Goodkin HP, eds. Wyllie’s Treatment of Epilepsy: Principles and Practice. 5th ed. Philadelphia, PA: Lippencott Williams & Wilkins; 2011. • 4. Ikeno T, et al. Epilepsia. 1985;26(6):612-621.

  28. Common Misperceptions in LGS Diagnosis Core seizure types (tonic, atonic, atypical absence) are always present at onset2 LGS changes as a patient ages; not all seizure types are present at onset, and seizure presentations change over disease course2 LGS is strictly a pediatric epilepsy syndrome1 LGS typically has a childhood onset, but persists into adulthood Drop attacks are caused only by atonic seizures3,4 • Kerr M, et al. Epileptic Disord. 2011;13(suppl 1):S15-S26. 2. Arzimanoglou A, et al. Lancet Neurol. 2009;8(1):82-93. 3. Tatum WO. Atypical absence seizures, myoclonic, tonic, and atonic seizures. In:Wyllie E, Cascino GD, Gidal BE, Goodkin HP, eds. Wyllie’s Treatment of Epilepsy: Principles and Practice. 5th ed. Philadelphia, PA: Lippencott Williams & Wilkins; 2011. • 4. Ikeno T, et al. Epilepsia. 1985;26(6):612-621.

  29. Common Misperceptions in LGS Diagnosis Core seizure types (tonic, atonic, atypical absence) are always present at onset2 LGS changes as a patient ages; not all seizure types are present at onset, and seizure presentations change over disease course2 LGS is strictly a pediatric epilepsy syndrome1 LGS typically has a childhood onset, but persists into adulthood Drop attacks are caused only by atonic seizures3,4 The majority of drops associated with LGS are due tonic seizures and are seldom a result of atonic seizures3,4 • Kerr M, et al. Epileptic Disord. 2011;13(suppl 1):S15-S26. 2. Arzimanoglou A, et al. Lancet Neurol. 2009;8(1):82-93. 3. Tatum WO. Atypical absence seizures, myoclonic, tonic, and atonic seizures. In:Wyllie E, Cascino GD, Gidal BE, Goodkin HP, eds. Wyllie’s Treatment of Epilepsy: Principles and Practice. 5th ed. Philadelphia, PA: Lippencott Williams & Wilkins; 2011. • 4. Ikeno T, et al. Epilepsia. 1985;26(6):612-621.

  30. LGS: Prognostic Factors Poor Outcome • History of Infantile Spasms, Status Epilepticus or cognitive impairment before LGS Diagnosis • Onset before age 3 years • Symptomatic LGS • Early appearance of dysphagia, predominance of atypical absence seizures • High seizure frequency and repeated bouts of Status Epilepticus • Persistence of diffuse background slowing and slow spike & wave complexes. Ogawa K et al. Seizure, 2001; 10: 197-202. Dulac o, N’Guyen T. Epilepsia, 1993; 34 (Suppl &): S7-S17. Markand ON. J Clin Neurophysiol, 2003; 20 (^): 426-441.

  31. Lennox-Gastaut Syndrome: Treatment Treatments to Avoid: • Prominent drug interactions (PB, PHT, CBZ). • Poor oral absorption in infants (PHT, CBZ). • Difficult pharmacokinetics (PHT, CBZ). • Long-term side-effects - Unhealthy serum lipid profile (PB, PHT, CBZ) - Negative effects on bone-health (PB, PHT, CBZ, VPA) • Possible seizure exacerbation: PB, PHT, CBZ, OXC, TGB, LTG, VGB, GBP Wheless JW. J Child Neurol, 2009; 24 (Suppl 8): S24 - S32. Brodie MJ et al. Epilepsia, 2013; 54 (1): 11 – 27.

  32. Lennox-Gastaut Syndrome: Treatment 1. Medical • Historical/Expert 1st Choice: Valproate1,2,4 • USA FDA Approved: clobazam, clonazepam, felbamate, lamotrigine, rufinamide, topiramate 1Montouris GD, Wheless JW, Glauser TA. Epilepsia, 2014; 55 (Suppl.4): 10-20. 2Wheless JW et al. Pediatr Neurol, 1997;17(3):203-211. 3Wheless JW et al. Epilepsia, 2004; 45(Suppl. 5): 17-22. 4Wheless JW et al. J Child Neurol, 2009; 24(Suppl. 8): S24-S32. 5Wheless JW et al. J Child Neurol, 2005; 20 (Suppl.1):S1-S60.

  33. Lennox-Gastaut Syndrome: Treatment 1. Medical • Historical/Expert 1st Choice: Valproate1,2,4 • USA FDA Approved: clobazam, clonazepam, felbamate, lamotrigine, rufinamide, topiramate 2. Dietary2,3: Ketogenic diet, Atkins diet, Low glycemic index diet 1Montouris GD, Wheless JW, Glauser TA. Epilepsia, 2014; 55 (Suppl.4): 10-20. 2Wheless JW et al. Pediatr Neurol, 1997;17(3):203-211. 3Wheless JW et al. Epilepsia, 2004; 45(Suppl. 5): 17-22. 4Wheless JW et al. J Child Neurol, 2009; 24(Suppl. 8): S24-S32. 5Wheless JW et al. J Child Neurol, 2005; 20 (Suppl.1):S1-S60.

  34. Lennox-Gastaut Syndrome: Treatment 1. Medical • Historical/Expert 1st Choice: Valproate1,2,4 • USA FDA Approved: clobazam, clonazepam, felbamate, lamotrigine, rufinamide, topiramate 2. Dietary2,3: Ketogenic diet, Atkins diet, Low glycemic index diet 3. Surgical2,3: Vagus nerve stimulation, complete corpus callosotomy, lesionectomy/lobectomy 1Montouris GD, Wheless JW, Glauser TA. Epilepsia, 2014; 55 (Suppl.4): 10-20. 2Wheless JW et al. Pediatr Neurol, 1997;17(3):203-211. 3Wheless JW et al. Epilepsia, 2004; 45(Suppl. 5): 17-22. 4Wheless JW et al. J Child Neurol, 2009; 24(Suppl. 8): S24-S32. 5Wheless JW et al. J Child Neurol, 2005; 20 (Suppl.1):S1-S60.

  35. Lennox-Gastaut Syndrome: Treatment 1. Medical • Historical/Expert 1st Choice: Valproate1,2,4 • USA FDA Approved: clobazam, clonazepam, felbamate, lamotrigine, rufinamide, topiramate 2. Dietary2,3: Ketogenic diet, Atkins diet, Low glycemic index diet 3. Surgical2,3: Vagus nerve stimulation, complete corpus callosotomy, lesionectomy/lobectomy 4. Other: Rehabilitation services (PT, OT, ST), Social services, Neuropsychology, Psychiatry, Helmet 5. Have a seizure emergency plan 1Montouris GD, Wheless JW, Glauser TA. Epilepsia, 2014; 55 (Suppl.4): 10-20. 2Wheless JW et al. Pediatr Neurol, 1997;17(3):203-211. 3Wheless JW et al. Epilepsia, 2004; 45(Suppl. 5): 17-22. 4Wheless JW et al. J Child Neurol, 2009; 24(Suppl. 8): S24-S32. 5Wheless JW et al. J Child Neurol, 2005; 20 (Suppl.1):S1-S60.

  36. LGS Foundation • Mission: Improve the lives of individuals affected by Lennox-Gastaut Syndrome through research, programs, and education. • International LGS Day: November 1st (2015-Nashville Zoo, TN, USA) • 4th International Family & Professional Conference on Lennox-Gastaut Syndrome; April 29-May 1, 2016, Denver, CO, USA • Rare Epilepsy Network (REN; www.ren.rti.org) • www.lgshope.com for Newsletter www.lgsfoundation.org

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