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Treatment of Epileptic Encephalopathies: Current State of the Art

This article provides an overview of the current treatment options for epileptic encephalopathies, with a focus on infantile spasms. It discusses the definition of a responder, the use of high-dose ACTH and vigabatrin, and the cognitive outcomes associated with early treatment. The article also addresses concerns about retinal toxicity with vigabatrin.

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Treatment of Epileptic Encephalopathies: Current State of the Art

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  1. Treatment of Epileptic Encephalopathies: Current State of the Art Shlomo Shinnar, MD, PhD Professor of Neurology and Pediatrics Hyman Climenko Professor of Neuroscience Research Director, Comprehensive Epilepsy Management Center Montefiore Medical Center Albert Einstein College of Medicine Bronx, New York

  2. Shinnar Disclosures • Funded by NIH/NINDS grants 2R37NS043209, 2U01NS045911, U10NS077308 and 1U01NS088034 • Consulting: Epalex, Neurelis, Upsher Smith, Xeris • Scientific Advisory Boards: Acorda, AstraZenica, Questcor, Upsher-Smith • DSMB: UCB Pharma

  3. Treatment of Epileptic Encephalopahties- Overview • Generally medically refractory from onset • Treatment often not with conventional AEDs • Hormonal therapy plays a prominent role • Goal is not just to control seizures but to prevent or reverse neurological loss of function • One of few settings where treating the EEG may be important

  4. Infantile Spasms: Definition of Responder • In the American Academy of Neurology (AAN) and Child Neurology Society (CNS) practice parameter, a responder is characterized by • Complete cessation of spasms, as confirmed by video electroencephalogram (EEG) • Abolition of hypsarrhythmia on prolonged EEG Mackay et al. Neurology 2004;62:1668-1681.

  5. Infantile Spasms: Definition of Responder • The AAN/CNS practice parameter definition of response as an “all or none” phenomenon is very different from the usual definition of 50% reduction in seizures • It reflects our understanding of the pathophysiology of the disease • Unless one abolishes the hypsarrhythmia, there is progression and cognitive decline Mackay et al. Neurology. 2004;62:1668-1681

  6. ACTH: High-dose ACTH vs Prednisone (1996) Baram et al. Pediatrics. 1996;97:375-379.

  7. Oral Corticosteroids • Likely have efficacy but data are unclear. • In the RCTs high dose ACTH is superior • UKISS did not utilize video EEG and used very low dose ACTH • The recent study by Hussain et al did show improved response rate using the UKISS regimen confirmed by videoEEG. Even in that trial some of the failures responded to ACTH. Arya et al J Child Neurol2012; 27:1284-1288 Mackay et al. Neurology. 2004;62:1668-1681 Hussain et al Epilepsia 2014; 55:103-107 Lux et al Lancet 2004;364(9447)1773-1778

  8. How Does ACTH Work? Release of natural corticosteroids from adrenals; low dose sufficient Direct action on the CNS; high dose needed as poor penetration across Blood Brain Barrier Hippocampus CRH CRH Amygdala Hypothalamus CRH 2 Pituitary ACTH CORTISOL Adrenal 1 Brunson et al. Ann Neurol. 2001; 49:304-12

  9. ACTH: Relapse Rates and Time to Treatment • Singer et al, 1980 • 55 patients treated with ACTH (80 U QOD) • Response rate • Treatment with ACTH within the first month of onset of spasms produced a higher incidence of spasm-free state and a shorter duration of spasms compared with a similar regimen of ACTH begun after seizures had persisted for more than a month • Relapse rates • 3.7% for infants treated within 1 month of spasm onset • 21.4% for infants treated after 1 month of infantile spasms diagnosis • Sher et al, 1993 • 26 patients treated with ACTH (40-129 U/m2/d) • Response rate: 65% of patients (17 out of 26) • Relapse rates • 1 relapse of spasms during the initial withdrawal of medication; 1 infant experienced a “recurrence” of infantile spasms many months later • Early treatment with high response rates and low relapse rates Singer et al. J Pediatr. 1980;96:485-489 Sher and Sheikh. Pediatr Neurol. 1993;9:451-456.

  10. ACTH: Cognitive Outcomes • Favorable cognitive outcomes • In cryptogenic cases treated early, there is a high rate of long-term normal outcome • Normal is defined as normal intelligence and no seizure disorder, on no medications • This is really NORMAL Kivity et al. Epilepsia. 2004;45:255-262 Lombroso. Epilepsia. 1983;24:135-158 Riikonen. Brain Dev. 2001;23:683-687 Cohen-Sadan et al Eur J Neurol 2009;16:482-487.

  11. Vigabatrin • AAN/CNS practice parameter • VGB is possibly effective for short-term treatment of infantile spasms • Tuberous sclerosis • Serious concerns about retinal toxicity • Review of 14 studies • 1 placebo-controlled randomized • 2 randomized controlled • 6 prospective open-label • 5 retrospective case series Mackay et al. Neurology. 2004;62:1668-1681.

  12. Vigabatrin + Resolution of Spasms Resolution of Spasms and Hypsarrhythmia Patients (%) VGB* (n=20) Placebo* (n=20) *Etiology of infantile spasms in each group: 70% symptomatic, 30% cryptogenic/idiopathic. Appleton et al. Epilepsia. 1999;40:1627-1633.

  13. Vigabatrin • In other randomized controlled studies • Symptomatic responders: 21% to 44%1-3 • Tuberous sclerosis (5 prospective studies)1,3,4-6 • Overall cessation of spasms: ~91% • 100% response rate reported • Cryptogenic responders: 27% to 57%1-3 • Relapse rate: 8% to 20%1-3 1. Vigevano and Cilio. Epilepsia. 1997;38:1270-1274. 2. Appleton et al. Epilepsia. 1999;40:1627-1633. 3. Elterman et al. Neurology. 2001;57:1416-1421. 4. Covanis et al. J Epilepsy. 1998;11:265-269. 5. Vles et al. Neuropediatrics. 1993;24:230-231. 6. Granstrom et al. Epilepsia. 1999;40:950-957.

  14. Hormonal Therapy vs Vigabatrin • UK Infantile Spasms study comparing vigabatrin with hormonal therapy with vigabatrin • Primary outcome was clinical cessation of spasms • Minimum doses • Tetracosactide (ACTH analogue) 40 IU qod IM (n=25) • Prednisone 40 mg per day (n=30) • Vigabatrin 100 mg per day (n=52) • Efficacy • Hormonal therapy 73% (40/55) • Vigabatrin 54% (28/52) p=0.04 • Cognitive outcomes in cryptogenic cases at 12-14 months • Vineland scales • Hormonal therapy mean =88 • Vigabatrin therapy mean = 79 p=0.025 1. Lux et al Lancet 2004;364(9447)1773-1778. 2. Lux et al. Lancet Neurology 2005;4:712-717.

  15. Dietary Therapies: Ketogenic Diet KD (n=13) vs ACTH (n=20) as initial therapy Retrospective, nonrandomized After 1 month of therapy Spasm freedom KD, 62% (8/13) vs ACTH, 90% (18/20; P=0.06) Normal EEG ACTH, 53% (9/17) > KD, 9% (1/11; P=0.02) No difference in relapse Adverse events (6 months) KD, 31% (4/13) < ACTH, 80% (16/20; P=0.006) 15 Kossoff et al. Epilepsia. 2008;49(9):1504-1509.

  16. Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics • Infantile spasms – NOT Tuberous Sclerosis • ACTH – level B • Alternative options (expert opinion – consider for infants with static severe neuro-insults and no regression) • Oral steroids • Vigabatrin • Valproate • Infantile spasms – Tuberous Sclerosis • Vigabatrin – level C Wilmshurst et al Epilepsia 2015 56:1185-1197

  17. Surgical Treatment of Infantile Spasms 60 50 40 Patients (%) 30 20 24-60 Months 12-24 Months 10 6-12 Months 0-6 Months 0 1 2 3 4 5 Class: SeizureFree <1/Month 1-4/Month 5-30/Month >30/Month Outcome 17 Shields. Int Rev Neurobiol. 2002;49:253.

  18. Surgical Treatment of Infantile Spasms Surgical Procedure TSC (n=2) Tumor (n=2) 4% 4% Other (n=4) 8% Hemispherectomy(n=21) LobarResection(n=6) 41% 12% 31% MultilobarResection(n=16) 18 Shields. Int Rev Neurobiol. 2002;49:253.

  19. Future Research • Further studies are required to determine the optimal treatment of children with infantile spasms • Further studies of new agents and antiepileptic drugs are required to assess their efficacies • Development of animal models can help identify novel targets for therapeutic development • Long-term measures should include cognitive outcomes using standardized psychometric assessments • Standardized dosage and duration of treatment are essential to allow comparison of short- and long-term outcomes Mackay et al. Neurology. 2004;62:1668-1681.

  20. International League Against Epilepsy (ILAE) Treatment Guidelines “There is an especially alarming lack of well-designed, properly conducted RCTs for patients with generalized seizures/epilepsies and for children in general.” Courtesy DrWheless.

  21. 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. PediatrNeurol, 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. Courtesy DrWheless

  22. Lennox Gastaut • Hormonal/Immune Therapy • Steroids • ACTH • IVIG • No RCTs. Small cases series reporting some benefit in each case. Vigevano et al Epilepsia 2013; 54 (Suppl 8): 45-50 Mikati et al Epilepsy Behav 2010; 17:90-94

  23. Lennox-Gastaut Syndrome: Treatment 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. PediatrNeurol, 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. Courtesy DrWheless

  24. 1st AED Monotherapy 2nd AED Monotherapy Polytherapy Trials OR Re-evaluate Medications Consider Other Treatments Vagus Nerve Stimulation Ketogenic Diet Epilepsy Surgery Lennox – Gastaut Syndrome Treatment Sequence Courtesy DrWheless

  25. Lennox Gastaut • We do not have good treatments for full seizure freedom except in rare lesional cases • Our treatments are not very good at preventing slow cognitive decline • Cognitive and behavioral outcomes have not been outcome variables in the drug trials • No good comparative effectiveness trials among the available therapies.

  26. Treatment of ESES • Pooled analysis of 575 patients (950 treatments) • Cognitive domain • EEG improvement (>25% reduction in spike wave index) Van den Munckhof et al - epilepsy stockholm 2014

  27. Treatment of ESES Improvement Treatment N Cognitive EEG AED 310 32% 33% Benzodiazepines 107 45% 46% Steroids 100 70% 68% Surgery 30 83% 74% Other 38 71% 26% Total 585 44% 43% Van den Munckhof et al - epilepsy stockholm 2014

  28. RESCUE ESES - Randomized European trial of steroids versus Clobazam Usage for Encephalopathy with ESES • 130 children age 2-12 years with ESES syndrome - within 6 months of diagnosis • Steroids – methylprednisolone pulse-therapy IV or oral prednisolone • Clobazam • Outcomes (after 6 and 18 months) • Primary – cognition • Secondary – EEG (SWI during non-REM sleep), seizures, safety and tolerability • Currently recruiting Van den Munckhof et al - epilepsy stockholm 2014

  29. Autoimmune Encephalopathies • In common with the epileptic encephalopathies which may well overlap • You are treating more than just the seizures. • EEG is often encephalopathic • There is an associated decline in neurological function

  30. Autoimmune Encephalopathies • No evidence based consensus guidelines • Seizures treated with appropriate AEDs • Mainstay of treatment are immune therapies

  31. Autoimmune Encephalopathies • First Line Treatment • Corticosteroids • Intravenous Gammaglobulins • Plasmaphoresis • Second Line Treatments • Cyclophosphamide • Rituximab Lim et al PediatrClin North Am 2015; 62:667-685

  32. Autoimmune Encephalopathies • We are in need of RCTs to determine optimal therapy • We are hindered by • Relative rarity of cases • Not clear that class is homogenous • Diagnosis often made late in the course

  33. Summary • While epileptic encephalopathies are a small proportion of all epilepsy, they account for a disproportionate amount of intractable epilepsy with adverse effects on cognition, QOL, higher rate of SUDEP and increased economic burden on families.

  34. Summary • We need better evidence based guidelines for the treatment of these disorders. • Novel therapies are very much needed • Treatments are needed not just for the seizures but to improve overall neurological outcomes, especially cognition and behavior • You will be hearing about some potential novel treatments in the remainder of this session.

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