Ernie Somerville Prince of Wales Hospital EPILEPSY

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1 Ernie Somerville Prince of Wales Hospital EPILEPSY

2 Overview Classification New and old anti-epileptic drugs (AEDs) Neuropsychiatric side-effects Limbic encephalitis Non-drug therapies Therapeutic wishlist

3 Classification of Seizures Simple partial Partial/ Focal Complex partial 2 0 generalised Absence 1 0 generalised Tonic-clonic Tonic Myoclonic

4 2010 changes Simple partial Aura Partial/ Focal Complex partial 2 0 generalised Focal dyscognitive Evolving to bilateral convulsive 1 0 generalised Absence Tonic-clonic Tonic Myoclonic

5 Epilepsy Syndromes The same seizure type can occur in different syndromes Syndrome depends on seizure type precipitating factors age of onset associated CNS symptoms and signs EEG Genetics

6 Syndromes/epilepsies Focal Idiopathic Symptomatic Cryptogenic Structural- Genetic Metabolic- Unknown Immune- Infectious Generalised Idiopathic generalised Symptomatic generalised

7 The need for better AEDs 30-40% unresponsive Side-effects common Teratogenicity

8 Number of drugs approved Antiepileptic Drug (AED) Development (2014) Newer Older Bromide Phenobarbital Phenytoin Calendar year Topiramate Tiagabine Felbamate Gabapentin Zonisamide Lamotrigine Vigabatrin Sodium Valproate Carbamazepine Ethosuximide Benzodiazepines Primidone Oxcarbazepine Pregabalin Levetiracetam More (Perampanel) (Eslicarbazepine) (Retigabine) (Stiripentol) (Rufinamide) Lacosamide Modified from Wong P

9 AED mechanisms Blockade of Na channels Blockade of Ca channels Opening of K channels Inhibition of GABA breakdown Inhibition of GABA reuptake Alteration in GABA synthesis and turnover Interaction with receptors Interaction with synaptic vesicle proteins Others + +

10 Which drug?

11 AEDs available in Australia O L D * Carbamazepine (CBZ) * Valproate (VPA) * Phenytoin (PHT) Ethosuximide Clobazam Phenobarbital Primidone Clonazepam N E W Lamotrigine Topiramate Levetiracetam Oxcarbazepine Gabapentin Tiagabine Lacosamide Pregabalin Zonisamide Vigabatrin

12 Which drug? It s not how good is a drug but how appropriate. How much do these factors matter for this patient? Efficacy in syndrome Certainty of syndromic Dx Cost Weight Cognitive Pregnancy Pharmacokinetics Time to achieve therapeutic dose Medication history Co-morbidity Ease of use Compliance Blood monitoring Gender Cosmetic Pregnancy Age Interactions Formulations IV, paediatric, scored Race/HLA type?

13 Sz type/syndrome & choice of drug Focal Carbamazepine The rest 1º Generalised (idiopathic generalised ep) Valproate Lamotrigine Topiramate Levetiracetam Ethosuximide if only absence sz

14 Benefits of New AEDs Efficacy no better in trials than CBZ in focal or VPA in generalised BUT may be better in individuals May have less side-effects Drug levels not necessary Not enzyme inducers May be safer in pregnancy

15 Problems of New AEDs Side effects can be serious Some require v. slow introduction Some require tid dosing Few IV formulations Interactions with other AEDs Encourage polytherapy May inappropriately delay surgical Rx Cost!

16 Neuropsychiatric effects of AEDs Sedation and cognitive slowing ALL can do esp barbiturates, benzodiazepines (except clobazam) ALL will do if dose is high enough Topiramate may cause expressive dysphasia Dizziness, diplopia Dose related esp carbamazepine, phenytoin, lamotrigine Insomnia Lamotrigine, levetiracetam

17 Neuropsychiatric effects of AEDs Aggression Levetiracetam Depression Levetiracetam Psychosis Vigabatrin, topiramate, levetiracetam Suicidality Any? Behavioural effects in kids and intellectually disabled Any but cause-effect unclear

18 Neuropsychiatric effects of AEDs Side-effects more likely if Multiple drugs Rapid introduction Elderly Perceived side-effects are often unrelated! Withdrawal symptoms Clonazepam (not clobazam), barbiturates

19 Limbic encephalitis Not all are paraneoplastic Treatable with immunotherapy May present with neuropsychiatric symptoms NMDA receptor antibodies Voltage-gated potassium channel (VGKC) antibodies

20 Case PM 64 yo woman Seizures? 12 mth history of sudden contraction L side of mouth and L upper limb movement. Rarely affects L leg. Last only a few secs. Worsening, up to 8/h 2 x GTCS starting with L side, lasting few mins. Poor AED response (CBZ, LEV, Clobazam, VPA) Memory impairment 1y duration mainly short term memory

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22 Coronal FLAIR Axial FLAIR

23 Case PM Bloods: Low Na (119) Anti VGKC 1030 pm (< 100 pm) Antineuronal: negative Tumour markers: negative

24 Annals of Neurology Volume 69, Issue 5, pages , May 2011

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26 NMDA-R limbic encephalitis Mostly children-young adults Ovarian teratoma in females >18yrs Psychosis, memory deficits, and language disintegration mutism Seizures Catatonia Abnormal movements Autonomic and breathing instability

27 Non-drug therapies Surgery Removal of area where seizures start Corpus callosotomy Neurostimulation Vagus nerve stimulation Deep brain stimulation Responsive cortical stimulation Dietary Ketogenic diet Modified Atkins diet

28 Temporal lobectomy

29 Lesionectomy

30 Non-drug therapies Surgery Removal of area where seizures start Corpus callosotomy Neurostimulation Vagus nerve stimulation Deep brain stimulation Responsive cortical stimulation Dietary Ketogenic diet Modified Atkins diet

31 What we need Drugs with much better efficacy Drugs that work as well in generalised epilepsies as VPA but without its weight and pregnancy issues Predictors of efficacy and side effects Imaging of MRI-negative lesions Anti-epilepsy rather than anti-seizure therapies