LennoxGastaut Syndrome LGS William G Lennox 1884 1960

Lennox-Gastaut Syndrome (LGS) William G. Lennox 1884 -1960 Henri Gastaut 1915 -1995 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

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

Lennox-Gastaut Syndrome: History 1939 Gibbs, Gibbs & Lennox describe slow spike & wave pattern (Petit Mal Variant)1 Lennox & Davis describe multiple seizure types 2 1950 1965 Dravet 1 st precise description published (epileptic encephalopathy) (Lennox Syn. )3 Gastaut describes 100 patients (Lennox Syn. )4 1966 ILAE classifies LGS as epileptic encephalopathy 1969 LGS 1 st appearssuggested by Margaret Buchtal. Lennox 5 2001 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.

Lennox-Gastaut Syndrome: Epidemiology • LGS is typically diagnosed between the ages of 2 and 8 years, with peak onset between 3 and 5 years 1 – Diagnosis in adolescents and adults is also possible 2 • Estimated to account for 1%-10% of all childhood epilepsies 3 • Affects patients throughout their lives 1 • Mortality rate is estimated at 3%-7%4 • Male predominance 1 van Rijckevorsel K. Neuropsychiatr Dis Treat. 2008; 4(6): 1001 -1019 2 Arzimanoglou A, et al. Epileptic Disord. 2011; 139(suppl 1): S 3 -S 13 3 Hancock EC, et al. Cochrane Database Syst Rev. 2009(4): 1 -39 4 Glauser TA. Epilepsia. 2004; 45(suppl 5): 23 -26

LGS Diagnostic Criteria: Triad of Common Features 1 1. Multiple Seizure Types 2 Mainly generalized 3. Abnormal EEG 3 Slow spike-wave discharges (<2. 5 Hz) 2. Cognitive Impairment 2 Developmental Delay Not all patients with LGS display the characteristic triad of features 2, 4 1 Arzimanoglou A, et al. Epileptic Disord. 2011; 13 (suppl 1): S 3 -S 13. 2 Arzimanoglou A, et al. Lancet Neurol. 2009; 8(1): 82 -93. 3 Ferrie CD, et al. Eur J Pediatr Neurol. 2009; 13(6): 493 -504. 4 Kerr M, et al. Epileptic Disord. 2011; 13(suppl 1): S 15 -S 26

Multiple Seizure Types Are Associated with LGS 1 -3 • • Tonic Atypical absence Atonic Nonconvulsive status epilepticus Myoclonic Generalized tonic-clonic Clonic Partial (focal) 1. Markand ON. J Clin Neurophysiol. 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

Cognitive Impairment in LGS Can Range From Mild to Severe 1 -4 • Most patients with LGS have cognitive impairment, which continues to worsen over time 1, 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 disability 3 • 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.

Classic EEG Pattern Seen in LGS Slow Spike-Wave (1. 5 -2. 5 Hz) Associated with Atypical Absence Seizures

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.

The Path to Lennox-Gastaut Syndrome (LGS) Known etiology (70 -75%) (Structural-Metabolic) LGS Unknown etiology (25 -30%) 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.

The Path to Lennox-Gastaut Syndrome (LGS) Infantile spasms (West Syndrome) Known etiology (70 -75%) (Structural-Metabolic) LGS Unknown etiology (25 -30%) 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.

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

Lennox-Gastaut Syndrome: Genetics • • • 1 Selmer SCN 1 A 1, 2 (1 of 22 adults screened) SCN 1 A 2 (1/12 with epilepsy onset in the 1 st 2 years of life) Trisomy 213 (late onset, reflex seizures) Tuberous Sclerosis Complex 5 GPR 56 mutation (16 q 12. 2 -21)(Bilateral Frontoparietal Polymicrogyria)4 LIS 15, DCX 5, 6 15 q 11. 1 q 13. 3 duplication 7 FOXG 1 -related disorder (14 q 12)8 Copy number variants 9, 10 KK et al. Epilepsy Behav, 2009; 16(3): 555 -557. 2 Harkin LA, et al. Brain 2007, 130: 843 -852 3 Ferlazzo E et al. Epilepsia, 2009; 50(6): 1587 -1595. 4 Parrini E et al. Epilepsia, 2009; 50(6): 13441353. 5 Guerrini R, Filippi T. J. Child Neurol, 2005; 20: 287 -299. 6 Lawrence KM et al. Epilepsia, 2010; 51(9): 1902 -1905. 7 Rocha J et al. Epileptic Disord, 2012; 14(2): 159 -162. 8 Terrone G et al. Epilepsia, 2014; 55(11): e 116 -e 119. 9 Lund C et al. Epilepsia Research; 2013; 105: 110 -117. 10 Lund C et al. Epilepsia Behav, 2014; 33: 18 -21.

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

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. Epi 4 K Consortium & Epilepsy Phenome/Genome Project. Nature, 2013; 501 (7466): 217 -221. www. epgp. org

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

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

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 & Epi 4 K Consortium, Ann Neurol, 2015; 78 (2): 323 -328.

Lennox- Gastaut Syndrome: A Common Neuronal Network EEG- f. MRI Group Analysis (N=11)(p<0. 001) Significant activation of brainstem and thalamus (especially centromedian and anterior thalamus) Siniatchkin M et al. Epilepsia, 2011; 52(4): 776 -774

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

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 (coactivation 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.

Lennox-Gastaut Syndrome Affects Patients Throughout Their Lives 1 LGS features often change with age 1 1. Kerr M, et al. Epileptic Disord. 2011; 13(suppl 1): S 15 -S 26. 2. van Rijckevorsel K. Neuropsychiatr Dis Treat. 2008; 4(6): 1001 -1019

The Triad of Features Changes From Childhood to Adulthood 1 Multiple Seizure Types 1 -3 The number and variety of seizure types usually decrease, although tonic seizures tend to persist, particularly during sleep Abnormal EEG 1, 3 -4 Slow spike-wave lost in about half of symptomatic cases and a third of LGS cases with no known cause. Cognitive Impairment 1, 2 Increases with age in the majority of cases Consider a diagnosis of LGS when a adult patient presents with cognitive impairment and multiple seizure types 1 1 Kerr M et al. Epileptic Disord, 2011; 13 (Suppl 1): S 15 -S 26. 2 Arzimanoglou A etal. Lancet Neurol, 2009; 8(1): 82 -93. 3 Kim HJ et al, Epilepsy Research, 2015; 110: 1019. 4 Ferrie CD et al. Eur J Paediatr Neurol, 2009; 13(6): 493 -504.

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

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

Common Misperceptions in LGS Diagnosis LGS is strictly a pediatric epilepsy syndrome 1 Core seizure types (tonic, atypical absence) are always present at onset 2 Drop attacks are caused only by atonic seizures 3, 4 1. Kerr M, et al. Epileptic Disord. 2011; 13(suppl 1): S 15 -S 26. 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. 5 th ed. Philadelphia, PA: Lippencott Williams & Wilkins; 2011. 2. 4. Ikeno T, et al. Epilepsia. 1985; 26(6): 612 -621.

Common Misperceptions in LGS Diagnosis LGS is strictly a pediatric epilepsy syndrome 1 Core seizure types (tonic, atypical absence) are always present at onset 2 Drop attacks are caused only by atonic seizures 3, 4 LGS typically has a childhood onset, but persists into adulthood 1. Kerr M, et al. Epileptic Disord. 2011; 13(suppl 1): S 15 -S 26. 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. 5 th ed. Philadelphia, PA: Lippencott Williams & Wilkins; 2011. 2. 4. Ikeno T, et al. Epilepsia. 1985; 26(6): 612 -621.

Common Misperceptions in LGS Diagnosis LGS is strictly a pediatric epilepsy syndrome 1 Core seizure types (tonic, atypical absence) are always present at onset 2 LGS typically has a childhood onset, but persists into adulthood LGS changes as a patient ages; not all seizure types are present at onset, and seizure presentations change over disease course 2 Drop attacks are caused only by atonic seizures 3, 4 1. Kerr M, et al. Epileptic Disord. 2011; 13(suppl 1): S 15 -S 26. 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. 5 th ed. Philadelphia, PA: Lippencott Williams & Wilkins; 2011. 2. 4. Ikeno T, et al. Epilepsia. 1985; 26(6): 612 -621.

Common Misperceptions in LGS Diagnosis LGS is strictly a pediatric epilepsy syndrome 1 Core seizure types (tonic, atypical absence) are always present at onset 2 Drop attacks are caused only by atonic seizures 3, 4 LGS typically has a childhood onset, but persists into adulthood LGS changes as a patient ages; not all seizure types are present at onset, and seizure presentations change over disease course 2 The majority of drops associated with LGS are due tonic seizures and are seldom a result of atonic seizures 3, 4 1. Kerr M, et al. Epileptic Disord. 2011; 13(suppl 1): S 15 -S 26. 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. 5 th ed. Philadelphia, PA: Lippencott Williams & Wilkins; 2011. 2. 4. Ikeno T, et al. Epilepsia. 1985; 26(6): 612 -621.

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 &): S 7 -S 17. Markand ON. J Clin Neurophysiol, 2003; 20 (^): 426 -441.

Lennox-Gastaut Syndrome: 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): S 24 - S 32. Brodie MJ et al. Epilepsia, 2013; 54 (1): 11 – 27.

Lennox-Gastaut Syndrome: Treatment 1. Medical • Historical/Expert 1 st Choice: Valproate 1, 2, 4 • USA FDA Approved: clobazam, clonazepam, felbamate, lamotrigine, rufinamide, topiramate 1 Montouris GD, Wheless JW, Glauser TA. Epilepsia, 2014; 55 (Suppl. 4): 10 -20. 2 Wheless JW et al. Pediatr Neurol, 1997; 17(3): 203 -211. 3 Wheless JW et al. Epilepsia, 2004; 45(Suppl. 5): 17 -22. 4 Wheless JW et al. J Child Neurol, 2009; 24(Suppl. 8): S 24 -S 32. 5 Wheless JW et al. J Child Neurol, 2005; 20 (Suppl. 1): S 1 -S 60.

Lennox-Gastaut Syndrome: Treatment 1. Medical • Historical/Expert 1 st Choice: Valproate 1, 2, 4 • USA FDA Approved: clobazam, clonazepam, felbamate, lamotrigine, rufinamide, topiramate 2. Dietary 2, 3: Ketogenic diet, Atkins diet, Low glycemic index diet 1 Montouris GD, Wheless JW, Glauser TA. Epilepsia, 2014; 55 (Suppl. 4): 10 -20. 2 Wheless JW et al. Pediatr Neurol, 1997; 17(3): 203 -211. 3 Wheless JW et al. Epilepsia, 2004; 45(Suppl. 5): 17 -22. 4 Wheless JW et al. J Child Neurol, 2009; 24(Suppl. 8): S 24 -S 32. 5 Wheless JW et al. J Child Neurol, 2005; 20 (Suppl. 1): S 1 -S 60.

Lennox-Gastaut Syndrome: Treatment 1. Medical • Historical/Expert 1 st Choice: Valproate 1, 2, 4 • USA FDA Approved: clobazam, clonazepam, felbamate, lamotrigine, rufinamide, topiramate 2. Dietary 2, 3: Ketogenic diet, Atkins diet, Low glycemic index diet 3. Surgical 2, 3: Vagus nerve stimulation, complete corpus callosotomy, lesionectomy/lobectomy 1 Montouris GD, Wheless JW, Glauser TA. Epilepsia, 2014; 55 (Suppl. 4): 10 -20. 2 Wheless JW et al. Pediatr Neurol, 1997; 17(3): 203 -211. 3 Wheless JW et al. Epilepsia, 2004; 45(Suppl. 5): 17 -22. 4 Wheless JW et al. J Child Neurol, 2009; 24(Suppl. 8): S 24 -S 32. 5 Wheless JW et al. J Child Neurol, 2005; 20 (Suppl. 1): S 1 -S 60.

Lennox-Gastaut Syndrome: Treatment 1. Medical • Historical/Expert 1 st Choice: Valproate 1, 2, 4 • USA FDA Approved: clobazam, clonazepam, felbamate, lamotrigine, rufinamide, topiramate 2. Dietary 2, 3: Ketogenic diet, Atkins diet, Low glycemic index diet 3. Surgical 2, 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 1 Montouris GD, Wheless JW, Glauser TA. Epilepsia, 2014; 55 (Suppl. 4): 10 -20. 2 Wheless JW et al. Pediatr Neurol, 1997; 17(3): 203 -211. 3 Wheless JW et al. Epilepsia, 2004; 45(Suppl. 5): 17 -22. 4 Wheless JW et al. J Child Neurol, 2009; 24(Suppl. 8): S 24 -S 32. 5 Wheless JW et al. J Child Neurol, 2005; 20 (Suppl. 1): S 1 -S 60.

LGS Foundation • Mission: Improve the lives of individuals affected by Lennox-Gastaut Syndrome through research, programs, and education. • International LGS Day: November 1 st (2015 -Nashville Zoo, TN, USA) • 4 th 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