A/B1 Paediatric epilepsy Richard Appleton, Alder Hey Children’s Hospital

1. A/B1Paediatric epilepsyRichard Appleton, Alder Hey Children’s Hospital

2. ‘Old, new or newest: which anti-epileptic drug to use first in the treatment of the paediatric epilepsies…..? To treat or not to treat; that is not the question; to treat with what – now that is the question!’

3. Rufinamide, Lacosamide, Retigabine, Perampanel, Brivaracetam …. others History and dates of introduction of antiepileptic drugs

4. How to choose the AED • What is the most effective AED for the child’s epilepsy syndrome / seizure type(s): if multiple seizure types, is it broad-spectrum • What is its side-effect profile • What is its dosing regime • What preparations are available • What is its cost • What is its licensed status • Have I discussed the options with the family

5. Wisdom … the quality or state of being wise; knowledge of what is true  or right coupled with just judgement as to action; discernment; insight; application of knowledge

6. Update: January 2012

7. Current NICE recommendations: initial drug options (newly-diagnosed epilepsies) • Focal seizures and syndromes: .carbamazepine or lamotrigine • Generalised seizures and syndromes: .sodium valproate or lamotrigine .ethosuximide / sodium valproate (absences) • Epileptic (infantile) spasms: .vigabatrin (VGB) or corticosteroids (VGB for TSC) • Unclassified: .sodium valproate > lamotrigine

8. New anti-epileptic drugs (AEDs) (1) • >95% of new AEDs: initial licence for adults with drug-resistant focal (partial) seizures (£/$); (rufinamide for ‘drop attacks’ in children + adults with Lennox-Gastaut syndrome) • use of AEDs in children with focal seizures: .extrapolation downwards from adult data (reasonable practice in children aged > 4 years) .anecdotal reports / case series .drug trials in children (usually Phase IV and V)

9. New anti-epileptic drugs (AEDs) (2) • subsequent expanded open use in patients with other types of intractable seizures (e.g.):.lamotrigine in tonic-clonic and absence seizures .vigabatrin in epileptic (infantile) spasms .levetiracetam in tonic-clonic and myoclonic seizures .rufinamide in focal seizures • subsequent longer term use identifies adverse side-effects: (e.g.): .lamotrigine and myoclonus .vigabatrin and visual fields .topiramate and cognitive slowing / psychoses .felbamate and fatal aplastic anaemia / liver failure .perampanel and psychoses

10. New anti-epileptic drugs(2) • are they as effective as the ‘older’ drugs: .seizure reduction .seizure freedom • are they safer (better-tolerated) than the ‘older’ drugs:.serious adverse effects .mild adverse effects • what are their interactions with other drugs:.other AEDs .other commonly-prescribed drugs • are they available in infant and child-friendly formulations • are their dosing regimes acceptable (once or twice daily) • are they cost-effective; does the gain in seizure control and ‘quality of life’ justify their cost (Quality-Adjusted Life Year [QALY]) • when should they be used: early monotherapy or ‘add-on’

12. And some evidence ….

13. Lamotrigine (Carbamazepine) Carbamazepine: more effective Lamotrigine: almost as effective but better tolerated so ‘won’

14. Sodium valproate

15. KOMET: an unblinded, randomised, two parallel-group, stratified trial comparing the effectiveness of levetiracetamwith controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy (JNNP 2012)1688 patients aged >16 years‘LEV monotherapy was not superior to standard AEDs for the global outcome, namely time to treatment withdrawal, in patients with newly diagnosed focal or generalised seizures’Focal seizures: carbamazepine slightly more effective than levetiracetam; carbamazepine better toleratedGeneralised seizures: sodium valproate slightly more effective than levetiracetam

16. A clinical trial comparing the effectiveness and cost-effectiveness of levetiracetam and zonisamide versus standard treatments for epilepsy: a comparison of Standard And New Antiepileptic Drugs (SANADII) Recruitment started December 2012

17. Untreated epilepsy (2 or more unprovoked seizures) Age ≥ 5 years Generalised or unclassified epilepsy Focal epilepsy Blood or saliva sample for DNA bank Arm A Randomise lamotrigine levetiracetam zonisamide Arm B Randomise valproate levetiracetam • Clinical follow-up: 3, 6, 12 months and annually until close of trial • Data-collection: seizures, AR, drug treatment and treatment failure • QoL questionnaires: baseline, 3, 6, 12 months and annually

18. September: <16 years: 84

19. September: <16 years: 232

20. “And now for something completely different…”

21. Stiripentol(orphan drug status in the European Union for the treatment of Dravetsyndrome) (Biocodex) • Multiple mechanisms of action: enhances inhibitory effect of GABA • Effective in the treatment of multiple seizure types in Dravet syndrome • Synergism with valproate + clobazam • (May be synergistic with carbamazepine in focal seizures / epilepsy syndromes) • Significant interactions: other AEDs • Significant side-effects (lethargy; reduced appetite; insomnia) • Expensive

22. Everolimus(a derivative of rapamycin [sirolimus]): an mTOR(mammalian target of rapamycin) inhibitor (Novartis) • Observational secondary outcome data from ‘EXIST 1’ Study suggested reduced seizure frequency (EXIST 1: everolimus and SEGAs [117 pts]) • ‘EXIST 3’ Study: international study; placebo-controlled; aged >3 years; 340 patients; results in early 2016 • Oro-mucosal side-effects common • Significant drug interactions • If effective → potentially life-long treatment • Expensive (Individual Funding Request with NHS England)

23. ‘Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy’. Epilepsy and Behaviour 2013 (‘Facebook’ survey: 19 patients; 13 Dravet syndrome) FDA:‘Expanded access: allows treatment to be used in children where there is felt to be an urgent need’

24. Epidiolex(cannabidiol [CBD]) • GW Pharmaceutical product (from cultured plant) • Explosive ‘open’ use in the USA (>600 individuals); ‘Charlotte’s Web’ provides Hemp oil • FDA-approved ‘orphan drug development’ in Dravet Synd • Unknown mechanism of action • First international Phase II + III studies (US and Europe) in 2014/15 – in children! • Significant interactions with other AEDs (clobazam; stiripentol) • Divided opinion in use between epileptologists and families Over 100 CBD molecules

25. “Charlotte’s Web is named for Charlotte Figi – who experienced a drastic reduction in her epileptic seizures after her first dose of medical marijuana at five years of age” UK CBD™ does not manufacture, distribute or sell any product that contradicts the 'Misuse of Drugs Act 1971'. The company does Grow, sell and distribute EU Approved Hemp based products that have been grown legally, under licence. Cannabidiol is not mentioned on the 'Misuse of Drugs Regulations 2001’ On sale from July 2015

26. APLS > 2010 Guideline AirwayHigh-flow oxygenDon't ever forget glucose vascular access? YES NO Lancet 2005 DM+CN 1995 lorazepam diazepam / midazolam 10 minutes YES lorazepam vascular access? 10 minutes NO EcLiPSE Rectal paraldehyde (optional use) phenytoin (i.v.) 20mg/kg + call anaesthetist seizure continues 20 minutes after PHY RSI with thiopentone

27. ‘Old, new or newest: which anti-epileptic drug to use first in the treatment of the paediatric epilepsies…..? In the ideal world, every child with epilepsy – newly-diagnosed or chronic and drug-resistant – should be entered into an open, pragmatic, randomised, controlled and ‘head-to-head’ trial ..... (with parental [and child] consent)

28. Questions / comments

29. A/B1Paediatric epilepsyRichard Appleton, Alder Hey Children’s Hospital