Overview Lifestyle Issues with Epilepsy Antiepileptic Drugs (Aeds)

AED Therapy in Children with Epilepsy Treatment of Epilepsy - Overview

• counselling patient and family • non-drug treatment issues e.g. factual information, EFV, emergency Mx of seizures • treatment of underlying cause e.g. hypoglycaemia, cerebral tumour • factors influencing choice of AEDs • avoid precipitating factors e.g. sleep deprivation, flashing lights • lifestyle constraints • general principles of AED therapy in children e.g. bathing, swimming, heights, alcohol, driving, vocational • management of comorbidities e.g. educational, psychological, psychiatric, behavioural • specific AEDs • antiepileptic drug therapy if indicated nb. which drug, how long, side effects, goals of Rx • special treatments for refractory epilepsies e.g. surgery, ketogenic diet, VNS

Lifestyle Issues with Epilepsy Antiepileptic Drugs (AEDs)

acetazolamide midazolam • safety at home (bathing, hot water, heights etc) ACTH oxcarbazepine • sports and hobbies (swimming, surfing, boating, climbing) brivaracetam paraldehyde carbamazepine phenobarbitone • school camps chlorazepate phenytoin •driving clonazepam prednisolone clobazam pregabalin • alcohol and recreational drugs diazepam primidone • sleep and sleep deprivation ethosuximide remacemide felbamate rufinamide • diet, exercise, smoking gabapentin stiripentol • AED compliance ganaxolone sulthiame • school/university, study and exams immunoglobulins tiagabine lacosamide topiramate • vocational choices and disclosure lamotrigine valproate • relationships, contraception and pregnancy levetiracetam vigabatrin lorazepam zonisamide

AED Therapy in Children with Epilepsy Factors Influencing AED Choices

• epileptic seizure & syndrome type - efficacy • non-drug treatment issues (seizures: GTCS, absence/myoclonic, partial/SGS, spasms, tonic) (syndrome: idiopathic vs symptomatic, some specific syndrome issues) • relative/specific efficacy and tolerability of AEDs • factors influencing choice of AEDs (tolerability >> efficacy in most ambulant settings) • patient age, gender, ethnicity and comorbidities (infant, adolescent girl, developmental disabilities, obesity, metabolic, • general principles of AED therapy in children Asians and AED hypersensitivity) • concomitant medication (adverse and beneficial PK and PD interactions) • specific AEDs • seizure frequency (quick fix vs. time to wait)

1 AED Efficacy by Seizure Type Relative Efficacy of AEDs (meta-analysis)

9.1 gabapentin 8.9 lamotrigine 6.7 tiagabine 6.3 zonisamide 4.4 oxcarbazepine 3.9 levetiracetam 3.8 vigabatrin 3.3 topiramate

0 3 6 9 12 15 18 21 mean number needed to treat to obtain one extra responder over placebo for RCTs of add-on for partial seizures in adults Brodie MJ & French JA Epileptic Disorders 2003; 5 S65-71 van Rijckevorsel. Seizure 2001;10:235-236

AED Efficacy by Epileptic Syndrome Which Drug Next? My Approach

Syndrome 1st line 2nd line (add or swap) Avoid febrile convulsions nil VPA,? prn BZP CBZ, OXC, GBP, VGB • for CBZ failure in symptomatic partial epilepsy infantile spasms (West) steroids VGB (TS), TPM, VPA PB - try high dose CBZ symptomatic partial epilepsy in infants PB CBZ, OXC, PHT, ?VGB VPA - swap to OXC if some benefit from CBZ benign myoclonic epilepsy of infancy VPA CZP, LTG CBZ, OXC, GBP, VGB, PB, PHT - add LEV or TPM depending on patient factors and urgency severe myoclonic epilepsy of infancy (Dravet) VPA+ CLB, TPM, LEV LTG, CBZ, OXC, GBP,VGB myoclonic astatic epilepsy (Doose) VPA+ESM LTG, CLB, PNL CBZ, OXC, GBP, VGB, PB, PHT • for CBZ failure in idiopathic partial epilepsy childhood epileptic encephalopathy (Lennox Gastaut) VPA+ LTG, TPM, CLB/CZP CBZ, OXC, GBP, VGB - change to VPA childhood absence epilepsy VPA ESM, LTG CBZ, OXC, GBP, VGB, PB, PHT - add CLB if still problematic benign occipital epilepsy (Panayatopoulos) Nil / ↓CBZ VPA, LTG ↑CBZ, OXC, GBP, VGB benign rolandic epilepsy Nil / ↓CBZ VPA, LTG ↑CBZ, OXC, GBP, VGB • for VPA failure in idiopathic generalised epilepsy acquired epileptic aphasia syndrome (Landau Kleffner) VPA+CLB VPA, ESM, PNL, ?LTG CBZ, OXC, GBP, VGB, PB, PHT - add LTG, then ESM (if absences) atypical BFEC (pseudo Lennox) VPA+CLB CLB, ESM, PNL, ?LTG CBZ, OXC, GBP, PB, PHT - add LTG, then CLB (if tonic clonic seizures) juvenile absence epilepsy VPA LTG, ESM CBZ, OXC, GBP, VGB, PB, PHT - if overweight, change VPA to LTG or TPM or LEV juvenile myoclonic epilepsy (Janz) VPA LTG, CLB, TPM, LEV CBZ, OXC, GBP, VGB IGE with TCS VPA LTG, PHT, TPM, LEV CBZ, OXC, GBP, VGB • for VPA failure in symptomatic generalised epilepsy photosensitive epilepsy – generalised or occipital VPA LTG, CLB CBZ, OXC, GBP, VGB - add LTG, TPM, CLB, PHT symptomatic partial epilepsies (TLE, FLE, etc.) CBZ OXC, LEV, TPM, PHT ?TGB

Factors Influencing AED Choices Side-effects: CNS

• epileptic seizure & syndrome type - efficacy (seizures: GTCS, absence/myoclonic, partial/SGS, spasms, tonic) • CNS side-effects common to all drugs, (syndrome: idiopathic vs symptomatic, some specific syndrome issues) especially during introduction and toxicity • relative/specific tolerability eg. drowsiness, ataxia, tremor, diplopia, vomiting, headache • patient age, gender, ethnicity and comorbidities esp. Na+ channel blockers (PHT, CBZ, VPA, TPM, LTG) (infant, adolescent girl, developmental disabilities, obesity, metabolic, Asians and AED hypersensitivity) • adverse behavioural effects relatively specific eg. hyperactivity, aggression, irritability, mood disturbance • concomitant medication esp. GABAergic drugs (VGB, PB, CZP, CLB) (adverse and beneficial PK and PD interactions) • seizure frequency • cognitive effects of AEDs in children are difficult to (quick fix vs. time to wait) disentangle from effects of seizures, epileptic EEG abnormalities, underlying brain abnormality

2 Side-effects: CNS Side-effects: CNS

• CNS side-effects common to all drugs, • CNS side-effects common to all drugs, especially during introduction and toxicity especially during introduction and toxicity eg. drowsiness, ataxia, tremor, diplopia, vomiting, headache eg. drowsiness, ataxia, tremor, diplopia, vomiting, headache esp. Na+ channel blockers (PHT, CBZ, VPA, TPM, LTG) esp. Na+ channel blockers (PHT, CBZ, VPA, TPM, LTG) • adverse behavioural effects relatively specific • adverse behavioural effects relatively specific eg. hyperactivity, aggression, irritability, mood disturbance eg. hyperactivity, aggression, irritability, mood disturbance esp. GABAergic drugs (PB, BZP, VGB, VPA), LEV esp. GABAergic drugs (PB, BZP, VGB, VPA), LEV • cognitive effects of AEDs in children are difficult to • cognitive effects of AEDs in children are difficult to disentangle from effects of seizures, epileptic EEG disentangle from effects of seizures, epileptic EEG abnormalities, underlying brain abnormality abnormalities and the underlying brain abnormality

Side-effects: Specific / Idiosyncratic Relative Tolerability of AEDs (meta-analysis)

carbamazepine rash, leukopenia, hyponatraemia 1.2 lamotrigine valproate weight gain, hair loss, pancreatitis, 1.3 levetiracetam hepatic failure 1.4 gabapentin phenobarbitone rash 1.7 zonisamide clonazepam increased secretions 1.8 tiagabine 2.2 phenytoin rash, serum sickness, hirsuitism, oxcarbazepine gum hypertrophy, osteoporosis 2. 6 topiramate 2.6 lamotrigine rash, SJS, severe hypersensitivity vigabatrin vigabatrin weight gain, retinopathy, psychosis 110 topiramate nephrolithiasis, weight loss, acidosis, Odds ratio (log10) for withdrawal from trial due to adverse events glaucoma (AED vs placebo) in RCTs of add-on in partial epilepsy in adults. oxcarbazepine hyponatraemia Marson et al. Epilepsia 1997;38(8):859-880; Castillo et al. Cochrane Database Syst Rev 2000;(3):CD 002028; Chaisewikul et al. Cochrane Database Syst Rev 2001;(1):CD001901; Chadwick et al. Cochrane Database Syst Rev 2002;(2): CD 001416

AEDs and Weight Changes AEDs, Fractures and Bone Mineral Density

• epilepsy and AED therapy are associated with increased • major issue with medication for many patients fracture risk and reduced bone mineral density (up to 40% of patients gain > 5 kg) • weight gain is common cause of non-compliance • fracture risk greater than attributable to reduced BMD, presumably related to trauma eg. TCS, falls, MVA • significant effects on psychological well-being • AEDs implicated in rickets, osteomalacia & osteoporosis • implications of obesity for diabetes, HT, IHD etc – increased vitamin D catabolism by liver induction – decreased absorption of calcium – increased catabolism of sex steroids – direct AED effect eg. PHT • epilepsy patients may have co-morbid medical, nutritional, drug and lifestyle reasonsVestergaard for low et al. Meta-analysis.BMD Acta Neurol Scand 2005. Van Staa et al. Bone 2002;31:508-514.

3 AEDs: Teratogenesis Factors Influencing AED Choices

• increased risk of most types of birth defects with all AEDs • epileptic seizure & syndrome type - efficacy (greatest risk with VPA ~10% and polytherapy) (seizures: GTCS, absence/myoclonic, partial/SGS, spasms, tonic) • small risk increase with epilepsy and no AEDs (1%) (syndrome: idiopathic vs symptomatic, some specific syndrome issues) • VPA risk reduced to other AEDs if <900mg/day • relative/specific tolerability • specific associations reported: • patient age, gender, ethnicity and comorbidities – neural tube defects and hypospadius (VPA, CBZ) (infant, adolescent girl, developmental disabilities, obesity, metabolic, – congenital heart defects (PHT, VPA, PB) Asians and AED hypersensitivity) – craniofacial abnormalities (PHT, VPA, PB, PRM) • concomitant medication – genitourinary defects (PHT, VPA, PB) (adverse and beneficial PK and PD interactions) – skeletal defects (VPA) • seizure frequency • effects of AEDs (esp. VPA) in pregnancy on cognition in (quick fix vs. time to wait) later childhood ? effects of AEDs on apoptosis and neuroreceptor expression in developing brain (Vinten J, Neurology 2005; Meador KJ, NEJM 2009)

obesity avoid VPA, CBZ, LTG, VGB, GBP, PGB (consider TPM) disabilities avoid CBZ, TPM, PHT, BZP, PB (consider LTG) Factors Influencing AED Choices OCP don’t use CBZ, OXC, PHT, PB (use LEV, GBP, TPM) (potential) pregnancy limit dose or use of VPA • epileptic seizure & syndrome type - efficacy migraine consider VPA, TPM (seizures: GTCS, absence/myoclonic, partial/SGS, spasms, tonic) mood disturbance ? caution all AEDs!! (consider VPA, LTG) (syndrome: idiopathic vs symptomatic, some specific syndrome issues) behavioural problems watch out LEV, BZP, PB, VPA, ?TPM • relative/specific tolerability sleep problems avoid LTG, LEV (consider CLB) saliva control avoid CZP, CLB • patient age, gender, ethnicity and comorbidities renal failure caution with GBP, LEV, VGB, TPM (infant, adolescent girl, developmental disabilities, obesity, metabolic, liver failure caution with CBZ, OXC, PHT, PB, VPA, LTG, BZP Asians and AED hypersensitivity) nephrolithiasis avoid TPM • concomitant medication metabolic disease may avoid VPA, TPM (adverse and beneficial PK and PD interactions) hyponatraemia caution CBZ and OXC glaucoma avoid TPM • seizure frequency osteoporosis may avoid VPA, PHT, TPM (quick fix vs. time to wait) visual impairment avoid / consider VGB hypersensitivity (Asian) caution CBZ, PHT, LTG, OXC psychosis caution LEV, VGB

AED Pharmacokinetics Effect of the concomitant administration of AEDs on the half-life of lamotrigine

1.6 CT lamotrigine with sodium valproate CE Dose ______ActivityActivity & 1.4 lamotrigine & 1.2 lamotrigine with carbamazepine or phenytoin CB + CU Toxicity Toxicity 1.0 CME 0.8

0.6 T 59 h Metabolism 1/2 0.4

C concentration (µg/ml) Plasma MT T 29 h Elimination ______0.2 1/2 T1/2 15 h C + C 0 MB MU 0 10203040506070 Time (h)

4 AED Metabolism Co-medication and AEDs Drug Metabolism Active metabolite VPA avoid CBZ, PHT; consider LTG, ESM CBZ hepatic oxidation CBZ-10,11-epoxide CLB hepatic demethylation N-desmethylclobazam CBZ/OXC avoid PHT, PB, VPA, OXC/CBZ, LTG DZP hepatic demethylation N-desmethyldiazepam BZP avoid PB, other BZP ESM hepatic oxidation PB avoid BZP, PHT, CBZ, TPM PHT hepatic oxidation PHT avoid VPA, CBZ, TPM, LTG, BZP, PB PB hepatic oxidation & renal excretion VPA hepatic oxidation & glucuronidation TPM avoid other AEDs if possible, PHT NZP hepatic reduction LEV OK PRM hepatic oxidation & renal excretion phenobarbitone GBP OK LTG hepatic glucuronidation GBP renal excretion VGB renal excretion stimulants ? OK TPM renal excretion, some hepatic metabolism SSRIs ? OK TGB hepatic metabolism antibiotics caution macrolides OXC hepatic metabolism MHD purgatives separate dosing LEV renal excretion

Factors Influencing AED Choices AED Titration Rates

• epileptic seizure & syndrome type - efficacy Rapid titration Slow titration (seizures: GTCS, absence/myoclonic, partial/SGS, spasms, tonic) (syndrome: idiopathic vs symptomatic, some specific syndrome issues) • benzodiazepines (load) • carbamazepine (weeks) • relative/specific tolerability • phenytoin (load) • oxcarbazepine (weeks) • patient age, gender, ethnicity and comorbidities • phenobarbitone (load) • lamotrigine (months) (infant, adolescent girl, developmental disabilities, obesity, metabolic, Asians and AED hypersensitivity) • gabapentin (days) • topiramate (months) • concomitant medication • levetiracetam (days) (adverse and beneficial PK and PD interactions) • valproate (weeks) • seizure frequency (quick fix vs. time to wait)

Factors Influencing AED Choices AED Mechanisms of Action

block Na+ enhance increase diminish decrease block carbonic novel • epileptic seizure & syndrome type - efficacy channels GABA GABA glutamate glutamate Ca++ anhydrase action (seizures: GTCS, absence/myoclonic, partial/SGS, spasms, tonic) effect levels effect release channels inhibition CBZ + (syndrome: idiopathic vs symptomatic, some specific syndrome issues) PHT + • relative/specific tolerability PB + + • patient age, gender, ethnicity and comorbidities BZP + (infant, adolescent girl, developmental disabilities, obesity, metabolic, VPA + ? ? Asians and AED hypersensitivity) ESM + LTG + + ? • concomitant medication GBP ? ? (adverse and beneficial PK and PD interactions) VGB + • seizure frequency TGB + (quick fix vs. time to wait) OXC + • AED drug mechanisms TPM + + ? + ? + ? LEV ? + (epileptogenesis and pharmacodynamics, rational polytherapy) PGB ?

5 Other Factors Influencing AED Choices Relative Efficacy and Tolerability of AEDs

• rich knowledge of RCTs (add-on, monotherapy, vigabatrin comparative) tiagabine

• own comfort or reluctance zonisamide

• parent wishes, beliefs, internet research

• relative cost to community (GBP, LEV) or patient (CLB)

• hassle (PBS authority, SPX)

• inducements (pens, dinners, travel)

Marson AG et al, BMJ 1996;313:1169-1174 Panayiotopoulos CP, Epileptic Syndromes and their Treatment, 2007

AED Therapy in Children with Epilepsy Goals of AED Therapy

• no seizures, or at least no “major” seizures • non-drug treatment issues • no AED side effects • no exacerbation (possibly improvement) in comorbidities • factors influencing choice of AEDs • reduce mortality and morbidity • improved quality of life (patient/family, home/school) • general principles of AED therapy in children • maximise normal development (cognitive, physical, social) • reduced health costs • specific AEDs • better QOL for doctor (fewer calls, visits, scripts, forms)

General Principles of AED Therapy General Principles of AED Therapy

• “treat the patient’s seizures, not their EEG” • “treat the patient’s seizures, not their EEG” • “start low and go slow” esp. LTG, TPM, CBZ, VPA, BZP • “start low and go slow” esp. LTG, TPM, CBZ, VPA, BZP • aim for monotherapy initially • aim for monotherapy initially • push AEDs to clinical effect, toxicity or high level • push AEDs to clinical effect, toxicity or high level • monitoring AED levels • monitoring AED levels - important in PHT, PB - important in PHT, PB - useful in CBZ - useful in CBZ - rarely useful in VPA, LTG - rarely useful in VPA, LTG - no value in BZP and new AEDs - no value in BZP and new AEDs • combination therapy where appropriate • combination therapy where appropriate - combine AEDs with different actions eg. VPA & LTG/TPM - combine AEDs with different actions eg. VPA & LTG/TPM - avoid combinations of drugs with similar actions eg. CBZ+PHT, BZP+PB - avoid combinations of drugs with similar actions eg. CBZ+PHT, BZP+PB - avoid AEDs with competing pharmacokinetics eg. VPA & CBZ/PHT - avoid AEDs with competing pharmacokinetics eg. VPA & CBZ/PHT • discontinue AEDs slowly esp. BZP and PB • discontinue AEDs slowly esp. BZP and PB

6 General Principles of AED Therapy General Principles of AED Therapy

General Principles of AED Therapy AED Level Monitoring

• reasons for doing AED levels • “treat the patient’s seizures, not their EEG” → check compliance → explain inefficacy or side-effects • “start low and go slow” esp. LTG, TPM, CBZ, VPA, BZP • may be useful if complicated PK • aim for monotherapy initially - non-linear kinetics • push AEDs to clinical effect, toxicity or high level - self-induction, dose-limited absorption - interactions • monitoring AED levels - important in PHT, PB • problems with AED level monitoring - useful in CBZ - drug-level-response relationship is poor for most drugs - rarely useful in VPA, LTG - reliable therapeutic ranges not available for most drugs - no value in BZP and new AEDs - wide variability in effects of different levels • combination therapy where appropriate - issue of unmeasured (neuroactive) free compound - combine AEDs with different actions eg. VPA & LTG/TPM • No evidence to support routine AED levels with the aim of - avoid combinations of drugs with similar actions eg. CBZ+PHT, BZP+PB optimisation of treatment of patients with newly-diagnosed - avoid AEDs with competing pharmacokinetics eg. VPA & CBZ/PHT epilepsy with AED monotherapy (Cochrane database 2007) • discontinue AEDs slowly esp. BZP and PB

Monitoring of AED levels AED Level Monitoring

carbamazepine when at high dose and ? go higher • reasons for doing AED levels valproate rarely → check compliance → explain inefficacy or side-effects barbiturates often, especially in infants/elderly * • may be useful if complicated PK phenytoin often, especially in infants/elderly * - non-linear kinetics benzodiazepines never - self-induction, dose-limited absorption lamotrigine never - interactions gabapentin never • problems with AED level monitoring - drug-level-response relationship is poor for most drugs vigabatrin never - reliable therapeutic ranges not available for most drugs oxcarbazepine never - wide variability in effects of different levels topiramate never - issue of unmeasured (neuroactive) free compound levetiracetam never • clinical or other laboratory evaluation may be more useful - history: sedation, insomnia, cognition, paraesthesia - exam: tremor, nystagmus, ataxia * side effects missed, changing weight and pharmacokinetics - bloods: WCC, Na+, LFTs, acid-base

7 General Principles of AED Therapy Monotherapy vs Polytherapy

• “treat the patient’s seizures, not their EEG” • improved compliance and lower costs with monoRx • “start low and go slow” esp. LTG, TPM, CBZ, VPA, BZP • fewer side effects with monoRx • aim for monotherapy initially • no drug interaction problems with monoRx • push AEDs to clinical effect, toxicity or high level • potential adverse PD effects with some AED combos • monitoring AED levels eg. PHT/CBZ/PB, PB/BZP/VGB, LTG/LEV, LTG/CBZ - important in PHT, PB - useful in CBZ • potential adverse PK effects with some AED combos - rarely useful in VPA, LTG eg. VPA and PHT/CBZ/PB - no value in BZP and new AEDs • combination therapy where appropriate - combine AEDs with different actions eg. VPA & LTG/TPM - avoid combinations of drugs with similar actions eg. CBZ+PHT, BZP+PB - avoid AEDs with competing pharmacokinetics eg. VPA & CBZ/PHT • discontinue AEDs slowly esp. BZP and PB

Monotherapy vs Polytherapy General Principles of AED Therapy

• improved compliance and lower costs with monoRx • “treat the patient’s seizures, not their EEG” • fewer side effects with monoRx • “start low and go slow” esp. LTG, TPM, CBZ, VPA, BZP • no drug interaction problems with monoRx • aim for monotherapy initially • potential adverse PD effects with some AED combos • push AEDs to clinical effect, toxicity or high level eg. PHT/CBZ/PB, PB/BZP/VGB, LTG/LEV, LTG/CBZ • monitoring AED levels - important in PHT, PB • potential adverse PK effects with some AED combos - useful in CBZ eg. VPA and PHT/CBZ/PB - rarely useful in VPA, LTG - no value in BZP and new AEDs • all drugs have multiple actions (known and unknown, • combination therapy where appropriate beneficial and adverse) ie. monoRx = polypharmacology - combine AEDs with different actions eg. VPA & LTG/TPM - avoid combinations of drugs with similar actions eg. CBZ+PHT, BZP+PB • potential synergistic PK/PD effects with some AED - avoid AEDs with competing pharmacokinetics eg. VPA & CBZ/PHT combos eg. VPA + LTG/ESM/CLB better than ↑↑ VPA • discontinue AEDs slowly esp. BZP and PB

Predictors of Seizure Recurrence AED Withdrawal Recommendations

• recognise favourable syndromes (BRE, BOE, CAE) and • seizure onset in second decade unfavourable syndromes (TLE, FLE) for withdrawal • symptomatic aetiology, intellectual disability, • consider after 2 yrs of seizure free therapy in unspecified abnormal neurological examination epilepsy syndromes • best if patient / parent initiated decision • myoclonus, especially JME • easier decision if AED side effects are present • strong family history of epilepsy • everyone understands and accept the risks • abnormal EEG before or during withdrawal • modify lifestyle (esp. driving), continue precautions, and ensure school/work environment is safe • recurrence after previous attempt to withdraw • withdraw one drug at a time slowly, very slowly for phenobarbitone and benzodiazepines • look out for mood and behaviour disturbances

8 AED Therapy in Children with Epilepsy Antiepileptic Drugs (AEDs)

acetazolamide midazolam ACTH oxcarbazepine • non-drug treatment issues brivaracetam paraldehyde carbamazepine phenobarbitone chlorazepate phenytoin • factors influencing choice of AEDs clonazepam prednisolone clobazam pregabalin diazepam primidone ethosuximide remacemide • general principles of AED therapy in children felbamate rufinamide gabapentin stiripentol ganaxolone sulthiame • specific AEDs immunoglobulins tiagabine lacosamide topiramate lamotrigine valproate levetiracetam vigabatrin lorazepam zonisamide

Carbamazepine (CBZ) Na Valproate (VPA)

Actions: blocks voltage-gated Na+ channels Actions: blocks Na+ channels +/- GABAergic action Indications: partial epilepsy and generalised TCS Indications: partial & generalised epilepsy, inc. absence Efficacy: partial seizures, 1o and 2o generalised TCS Efficacy: GTCS, absence, myoclonic, tonic + partial Sz Dosing: start 5 mg/kg/day drug of choice for idiopathic epilepsies incr. wkly over 2-3 wks to 15-20 mg/kg/day Dosing: start 10 mg/kg/day give b.d (CR) or t.i.d. (esp. syrup) +/- levels incr. wkly over 2-3 wks to 20-30 mg/kg/day Interactions: liver enzyme induction and lowers AED levels give b.d, no need for levels, take with food pharmacodynamic interaction with other Na Interactions: blocks liver enzymes and raises AED levels channel blockers (PHT, PB) competes for protein bindings Adverse: rash 3-5% Adverse: CNS side effects + tremor in toxicity CNS side effects + low Na+ & WCC in toxicity weight gain, hair loss, GIT disturbance exacerbates absence Sz and myoclonus in IGE risk of liver failure (infant, multiple AEDs, MR)

Benzodiazepines (BZP) Phenobarbitone (PB)

Actions: enhance GABA action at synapse Actions: blocks Na+ channels, enhances GABA Indications: partial & generalised epilepsy Indications: partial seizures, GTCS, neonatal seizures, Efficacy: partial, GTCS, myoclonic, tonic +/- absence status epilepticus Dosing: depends on drug eg. clonazepam, diazepam, Efficacy: partial and GTC seizures clobazam, nitrazepam, lorazepam Dosing: load 15-20 mg/kg (higher in SE) generally start very low and go very slow maintenance 5mg/kg/day (monitor levels) Interactions: minimal pharmacokinetic interactions Interactions: VPA, BZP Adverse: drowsiness, sedation (esp with PB, other BZPs) Adverse: behaviour and cognitive disturbance, rash increased secretions eg. drooling, respiratory behavioural change, mood disturbance tolerance and tachyphalaxis

9 Lamotrigine (LTG) Oxcarbazepine (OXC)

Actions: blocks Na+ channels + ? other actions Actions: converted to MHD, blocks Na+ channels Indications: partial and generalised seizures Indications: partial epilepsy and generalised TCS Efficacy: partial, absence, myoclonic, TCS, tonic Efficacy: partial seizures, 1o and 2o generalised TCS Dosing: start <0.5, max 5-15 mg/kg/day without VPA Dosing: start 5 mg/kg/day start <0.2, max 1-5 mg/kg/day with VPA increase over 2-3 wks to 15-25 mg/kg/day very slow titration Interactions: liver enzyme induction Interactions: VPA increases levels +++ Adverse: low Na+ beneficial PD effect when used with VPA exacerbates absence Sz and myoclonus in IGE potentiates CBZ side effects Adverse: rash 3-5%; severe hypersensitivity 0.3-1% CNS side effects including tremor in toxicity exacerbates seizures in SMEI

Levetiracetam (LEV) Topiramate (TPM)

Actions: novel – binds to synaptic vesicle protein Actions: blocks Na+ channels, blocks kainate/AMPA, Indications: partial seizures enhances GABA, carbonic anhydrase inhibition Efficacy: partial and generalised seizures Indications: partial and generalised seizures, LGS Dosing: start 10 mg/kg/day, target 25-50 mg/kg/day Efficacy: partial, GTCS, tonic, ?spasms, ?absence Interactions: nil significant Dosing: start 1, max 5-10 mg/kg/day slow titration Adverse: behaviour disorder, psychosis sleep disturbance Interactions: nil significant Adverse: cognitive, speech nephrolithiasis, weight loss

Vigabatrin (VGB) UKISS Study

Actions: non-competitive inhibition of • 107 infants with spasms were randomised to hormonal GABA transaminase treatment (synacthin or high dose prednisolone) or VGB. Control of spasms at Day 14 was achieved in 75% with Indications: partial seizures, infantile spasms hormonal treatment and 54% with VGB (p=0.04). More EEG improvement occurred with hormonal treatment. Efficacy: partial and tonic seizures esp. lesional, TS Dosing: 50-150 mg/kg/day, 0.5-4 g/day • Combined with results from an Italian trial comparing ACTH and VGB, hormonal treatments are superior to VGB in rapid titration possible stopping spasms - difference 22% (95%CI 7-38%). Interactions: nil significant • The cryptogenic subgroup showed a clinically and statistically Adverse: behaviour disorder, psychosis, weight gain significant difference in development: retinopathy - > 30% adults, ??? children - at age 14 months (mean VABS: hormonal 88 vs VGB 79) exacerbate myoclonic seizures - at age 4 yrs (median VABS: hormonal 96 vs VGB 63) • ICISS will compare hormonal treatment +/- VGB.

Lux AL et al. Lancet 2004;364:1773-1778. & Lancet Neurol 2005;4:712-717.

10 RCH Protocol for Infantile Spasms Some Tips

• start VPA for IGE/IPE and CBZ for SPE/IPE Prednisolone is 1st line treatment, except in TS or treatable IEM: • get comfortable with LTG, OXC and LEV • 10mg QID for 2 wks then wean by one 10mg dose every 5 days • avoid high doses of VPA, TPM, CLB/CZP • increase to 20mg tds if spasms continue after 1 week • use CBZ, LEV, GBP in high dose if working • twice-weekly monitoring of electrolytes, glucose and BP • tds dosing if using CBZ/OXC liquid (use CBZ-CR tablets) • plan out path of likely AED changes and additions Vigabatrin is 1st line treatment in TS and 2nd line treatment after 2-4 weeks of no response to prednisolone in non-TS settings: • consider low dose VPA+LTG+CLB combination • 50 mg/kg/day increasing to 150 mg/kg/day (max) over 1 week if • more side effects with big doses of one AED than small doses of spasms do not cease after each dosage step combinations (+ one drug = polypharmacology) • treat for 3 months, increasing the dose with increases in weight • remember old AEDs eg. ESM (absence, myoclonic, atypical BRE) • wean over 1 month PHT (older teenager), PB (infants briefly) • ACTH, other AEDs, ketogenic diet or surgery for refractory cases • levels only in PHT and PB (sometimes VPA, CBZ) • be wary of CBZ/OXC exacerbation of IGEs and BRE/BOE