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

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

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

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

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

Update: January 2012

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

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)

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

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’

Daily dose (mg): 12 year-old Formulation Brand Cost (30 day supply) Medication Daily dose (mg): 12 year-old Formulation Brand Cost (30 day supply) Phenobarbital 60 Tablets Generic £1.70 Phenytoin 100 £32 Carbamazepine 600 Tablets SR Tegretol SR £10.40 Ethosuximide 1000 Capsules £48.20 Sodium valproate 800 Epilim £4.80 £9.20 Lamotrigine 200 Lamictal £4.30 Topiramate Topamax £2.95 Levetiracetam 1500 Keppra £4.24 £84.02 Zonisamide Zonegran £62.72 Lacosamide Vimpat £96.50 Perampanel 8 Fycompa £140

And some evidence ….

Lamotrigine (Carbamazepine) The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial Marson A G, Al-Kharusi A M, Alwaidh M, Appleton R, Baker G A, Chadwick D W, Cramp C, Cockerell O C, Cooper P N, Doughty J, Eaton B, Gamble C, Goulding P J, Howell S J, Hughes A, Jackson M, Jacoby A, Kellett M, Lawson G R, Leach J P, Nicolaides P, Roberts R, Shackley P, other members of the SANAD study group Lancet 2007; 369: 1000–1015 Lamotrigine (Carbamazepine) Carbamazepine: more effective Lamotrigine: almost as effective but better tolerated so ‘won’

The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial Marson A G, Al-Kharusi A M, Alwaidh M, Appleton R, Baker G A, Chadwick D W, Cramp C, Cockerell O C, Cooper P N, Doughty J, Eaton B, Gamble C, Goulding P J, Howell S J, Hughes A, Jackson M, Jacoby A, Kellett M, Lawson G R, Leach J P, Nicolaides P, Roberts R, Shackley P, other members of the SANAD study group Lancet 2007; 369: 1016–1026 Sodium valproate

KOMET: an unblinded, randomised, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with 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 tolerated Generalised seizures: sodium valproate slightly more effective than levetiracetam

Standard And New Antiepileptic Drugs (SANADII) 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

Generalised or unclassified epilepsy Untreated epilepsy (2 or more unprovoked seizures) Age ≥ 5 years Blood or saliva sample for DNA bank Focal epilepsy Generalised or unclassified epilepsy Arm A Randomise lamotrigine levetiracetam zonisamide Arm B valproate 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

September: <16 years: 84

September: <16 years: 232

“And now for something completely different…”

Stiripentol (orphan drug status in the European Union for the treatment of Dravet syndrome) (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

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)

‘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’

Epidiolex (cannabidiol [CBD]) Over 100 CBD molecules 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

“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

Airway High-flow oxygen Don't ever forget glucose APLS > 2010 Guideline Airway High-flow oxygen Don't ever forget glucose YES vascular access? NO DM+CN 1995 Lancet 2005 lorazepam diazepam / midazolam 10 minutes lorazepam YES 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

‘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)

Questions / comments

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