1. Anti-Epileptic Drugs (AED’s) A Quick Review Mark M. Stecker, M.D. Ph.D Professor of Neuroscience Joan C. Edwards Marshall University School of Medicine

2. Lecture Outline Classification of Seizure Medication – Old AED’s – New AED’s – Choice of AED Based Upon Seizure Type Side Effects Pharmacokinetics Some Specific Medications – Diastat – Vimpat – Banzel VNS

3. Classification of AED’s-I “Old vs New vs Recent” Old – Phenobarbital – Dilantin (Phenytoin) – Mysoline (Primidone) – Tegretol (Carbamazepine, Epitol) – Depakote (Depakene, Valproic Acid, Divalproex Sodium) – Zarontin (ethosuccimide) – Benzodiazepines (Ativan, Valium, Clonazepin)

4. Classification of AED’s-II New – Lamictal (Lamotrigine) – Keppra (Levetiracetam) – Topamax (Topiramate) – Zonegran (Zonisamide) – Trileptal (Oxcarbazepine) Recent – Banzel (Rufinamide) – Sabril (Vigabatrin) – Lacosamide (Vimpat)

5. Classification of AED’s-III General Rule – Old AED’s More Side Effects More complex Drug-drug Interactions – New AED’s Less Side Effects Simpler Drug-Drug Interactions – Difference in anti-seizure effect is hard to measure. Drugs are individually chosen based upon seizure type and side effect profile.

6. Typical AED Uses Primary Generalized Epilepsy (Childhood Absence Epilepsy, Juvenile Myoclonic Epilepsy- genetic) – Depakote – Lamictal – Zarontin (staring only) – Benzodiazepines (Ativan, Clonopin)—slight help especially with staring and myoclonus

7. Typical AED Uses-II Partial Epilepsy (Structural Injury) – Tegretol – Dilantin – Depakote – Trileptal General Purpose – Keppra – Zonegran

8. Side Effects of AED’s

9. Non-Specific Side Effects All AED’s can cause – Sleepiness – Difficulty Concentrating – Nausea, Vomiting – Coordination Problems – Double Vision (Trouble Reading) – School Specific Issues Trouble Concentrating/Day Dreaming Slowed Responses Difficulty Multitasking

10. Specific AED Side Effects-I Severe Rash (Stevens-Johnson Syndrome) – Dilantin – Tegretol – Trileptal – Lamictal – Less Likely (Phenobaribital, Topamax, Zarontin, Zonisamide) – Very Unlikely/Never Keppra Depakote Benzodiazepine

11. Specific Side Effects-II Depression (maybe all to some extent) – Phenobarbital – Primidone Anger/Behavior Problems – Keppra Hyperactivity (children) – Phenobarbital Lack of Sleep – Lamictal

12. Specific Side Effects-III Serious Liver Problems – Depakote (Age<2 and Polytherapy) – Rare Tegretol, Dilantin Hematologic Problems – Depakote (platelets) – Tegretol>>Trileptal (Low White Count) Low Sodium – Trileptal>>Tegretol

13. Pharmacology

14. Time Blood Level 8am 4pm (A) (B) (C) Regular Release Pills Twice a Day Regular Release Pills 4x a Day Extended Release Pills Twice a Day Therapeutic Level

15. How Does This Affect a Child In School? 2 Pills Twice a Day (A) – Toxic at 8am and 4pm (side effects) – Low Levels at Noon (Seizures) 4 Pills a Day (B) – Lower Peak Levels so Less Toxicity – Higher Trough Levels so Less Chance of Seizures in School – Has to Take Pill During School Extended Release Twice a Day – Has the maximum advantage and minimum side effects

16. Although a Treatment May Work It Has to Be Practical

17. Newer Medications

18. Geier-The Symbolism of Epilepsy

19. Diastat Rectal Valium Gel – Well absorbed – Useful with longer than usual seizures before EMS arrives or there is no IV access—to reduce the duration of the seizures. – Very few side effects – Very simple to use

20. Rufinamide Mechanism: Stabilization of the sodium channel inactive state Prevents conduction of certain nerve impulses Approved as adjunctive treatment of seizures in patients with Lennox-Gastaut syndrome older than the age of 4. 45% of patients had more than 50% reduction in seizure frequency in trials (Kluger et. al. Acta neurol Scand 2010). This drops to 27% at 18 months after starting the medication (Kluger et. al. Epilepsy Behav 2010) – 32% reduction in seizure frequency – 53% of Banzel patients showed improvement in seizure severity vs 31% with placebo Side Effects: – Dizziness, headache, fatigue, nausea

21. Vimpat (Lacosamide) Enhances slow inactivation of sodium channels. Impairs conduction of certain nerve impulses Adjunctive treatment of partial seizures. Responder rate (40.5%-Lacosamide) vs (25.8%-Placebo). 36% seizure reduction rate vs 20.5% for placebo REMEMBER many patients were already taking multiple anticonvulsants in the study thus these numbers are falsely low. Side effects – Dizziness – Headache, ataxia, tremor, vomiting, diplopia

22. Vigabatrin (Sabril) Inhibits GABA transaminase and increases GABA levels. GABA is an inhibitory neurotransmitter FDA approval monotherapy children 1month-2years of age with infantile spasms – Other countries: adjunctive treatment for complex partial seizures, secondary generalized seizures. Side effects – May lower dilantin and tegretol levels. – Sleepiness, headache, fatigue – Atrophy of the retinal nerve fibre layer—may have visual problems and visual evoked potentials become abnormal in half of patients.

23. Retigabine Opens KCNQ/Kv7 potassium channels—but only affects neuronal and not cardiac potassium channels and so should have limited cardiac side effects. Hyperpolarizes nerve membranes and prevents transmission of certain nerve impulses. Completed clinical trials – Seizure Frequency Reduced 35% compared to 13% for placebo – 33% responded to the drug and 16% to placebo – Peak dose 1.5 hours after taking – Half-Life 8 hours Still Awaiting approval by FDA

24. Brivaracetam Chemically related to keppra (levetiracetam) Works by binding to synaptic vesicle protein 2A--- thus impairs the release of neurotransmitters: – Prevents transmission of signals from cell to cell Not yet released 36% responder rate in early studies 40-50% seizure reduction rate Phase III clinical trials not in agreement regarding effectiveness. Release pending additional studies/analysis.

25. New Surgical Treatments for Epilepsy

26. Vagal Nerve Stimulator-I 1997, the US Food and Drug Administration (FDA) approved the use of VNS. – Adjunctive treatment for refractory partial-onset seizures in adults and adolescents older than 12 years. To date, probably more than 8,000 people have been treated with VNS. Epilepsia. 2001 Aug;42(8):1017-20. Vagus nerve stimulation: analysis of device parameters in 154 patients during the long- term XE5 study.DeGiorgio CM, et. al.DeGiorgio CM Epilepsia. 1994 May-Jun;35(3):616-26. Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. First International Vagus Nerve Stimulation Study Group. Ben-Menachem E, et. al.Ben-Menachem E

28. Bromfield EB-an introduction to Epilepsy www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi...

29. Vagal Nerve Stimulator-II – 29-50% responder rate (50% seizure reduction) – 21-51% seizure reduction rate – 11% had >75% reduction in seizures – With longer periods of stimulation the seizure reduction rate may go up to 52% after 12 years. Neurology. 2004 Sep 28;63(6):1124-6. Effectiveness of vagus nerve stimulation in epilepsy patients: a 12-year observation. Uthman BM, et. al. – This means that frequent evaluation of the settings and appropriate adjustments are critical to the function of the device.

30. Summary Anticonvulsants (AED’s) do help 75% of patients with epilepsy. Understanding the effects that these medications may have on school performance is important.