Prescribing and Monitoring Anti-Epileptic Drugs
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1 Prescribing and Monitoring Anti-Epileptic Drugs Mark Granner, MD Clinical Professor and Vice Chair for Clinical Programs Director, Iowa Comprehensive Epilepsy Program Department of Neurology University of Iowa Hospitals and Clinics
2 Disclosure I have no actual or potential conflicts of interest in relation to the content of this lecture. Iowa Comprehensive Epilepsy Program
3 Basic Premise Epilepsy is an ideal condition to manage in an integrated care delivery model Emergency care Primary care Secondary care (Community Neurology) Tertiary care (Epilepsy Center) Iowa Comprehensive Epilepsy Program
4 Definitions Seizure A paroxysmal alteration in behavior associated with hyperexcitability of a population of neurons Provoked seizure A seizure occurring in the setting of some systemic provoking factor Epilepsy At least 2 unprovoked seizures at least 24 hours apart One unprovoked seizure and a probability of further seizures equal to above (60%) First degree family history Abnormal EEG Abnormal MRI Iowa Comprehensive Epilepsy Program
5 Epidemiology of Epilepsy United States Number Epilepsy total 3,000,000 New cases per year 150,000 Refractory epilepsy 1,000,000 Potential surgical candidates 200,000 Surgery per year 1,500 Iowa Number Epilepsy total 30,000 New cases per year 1,500 Refractory epilepsy 10,000 Potential surgical candidates Surgeries per year 25 2,000
6 Fountain NB, et al. Neurology 2015
7 Diagnosis of Epilepsy: History History Events Duration, responsiveness, movements Risk factors Febrile seizures TBI, CNS infection, stroke, neoplasm Family history Autoimmune disease Provoked by Alcohol, sleep deprivation, stress, lights Iowa Comprehensive Epilepsy Program
8 Diagnosis of Epilepsy: Tests MRI EEG In the ED consider CBC, electrolyte panel Urine drug screen CT Lumbar puncture Iowa Comprehensive Epilepsy Program
9 Previous Classification of Seizure Types Partial Simple Complex Secondary Generalized Generalized Tonic Clonic Tonic-clonic Atonic Myoclonic Absence Unclassified
10 ILAE 2017 Classification of Seizure Types Basic Version Focal Onset Aware Impaired Awareness Motor Non-Motor Focal to bilateral tonic-clonic Generalized Onset Motor Tonic-clonic Other motor Non-Motor (Absence) Unknown Onset Motor Tonic-clonic Other motor Non-Motor Unclassified Fisher RS, et al. Instruction Manual for the ILAE 2017 Operational Classification of Seizure Types. Epilepsia 2017.
11 First Generation Second Generation
12 First vs Second Generation AEDs No significant difference in efficacy Significant difference in toxicity Generally wider therapeutic windows Fewer (or no) drug interactions, hepatic enzyme induction Less adverse effect on bine density More broad spectrum options Allow for more individually tailored therapy
13 Pharmacotherapy of Epilepsy First Generation ( ) Generic Name Brand Name Phenobarbital Phenytoin Dilantin Primidone Mysoline Ethosuximide Zarontin Carbamazepine Tegretol Valproic acid Depakote Second Generation ( ) Generic Name Brand Name Gabapentin Neurontin Lamotrigine Lamictal Topiramate Topamax Oxcarbazepine Trileptal Levetiracetam Keppra Zonisamide Zonegran Pregabalin Lyrica Rufinamide Banzel Lacosamide Vimpat Iowa Comprehensive Epilepsy Program
14 Pharmacotherapy of Epilepsy: Effective For Partial Seizures Teratogenicity < 3% Minimal/No Averse Effect on Bone Density Generic Formulation Available Extended-Release Formulation Available (or long half-life) First Generation ( ) Second Generation ( ) Generic Name Brand Name Generic Name Brand Name Lamotrigine Lamictal Oxcarbazepine Levetiracetam Zonisamide Trileptal Keppra Zonegran Iowa Comprehensive Epilepsy Program
15
16 New Onset Focal Impaired Awareness (Complex Partial)
17 Generalized Tonic Clonic
18 Absence
19 Focal Seizure, Woman of Reproductive Age
20 Focal Seizures, Healthy Elderly
21 Focal Seizures, Ill Elderly
22 New Onset, Emergency Department
23 Epilepsy Medication in Primary Care Medication (Brand) Use Disadvantages Ethosuximide (Zarontin) Levetiracetam (Keppra) Absence epilepsy. Any seizure type. IV form for emergency use. Will not treat GTC, focal seizures. No significant. Lorazepam (Ativan) Phenytoin (Dilantin) Iowa Comprehensive Epilepsy Program Acute repetitive seizures, status epilepticus. Status epilepticus. Partial sz or GTC. Short half-life. Tolerance to chronic use. Side effects, drug interactions. (e.g. osteoporosis)
24 Monitoring Considerations Medication (Brand) Lamotrigine (Lamictal) Levetiracetam (Keppra) Considerations Metabolism increased with CYP 450 inducers phenytoin, carbamazepine, phenobarbital Metabolism decreased by valproic acid Levels fall (up to 50%) through pregnancy Measure plasma concentrations at least twice per trimester Adjust dose as needed Return to previous dose after delivery Initial titration must be slow (add 25 mg per week) SJS, TEN, other rashes Not liver metabolized Renal excretion Adjust dosing in chronic or acute kidney disease Levels fall through pregnancy Measure plasma concentrations at least twice per trimester Adjust dose as needed Return to previous dose after delivery
25 When To Check Blood Levels Doing well baseline Pregnancy Adherence Drug interactions Breakthrough seizure NOT annually or per routine
26 Emergencies in Epilepsy: Status Epilepticus Diagnosis Recurrent seizures without recovery to baseline Single prolonged seizure (5-10 min) Incidence patients / 100,000 55, ,000 SE cases / year in U.S. Mortality = 19-22% 11,000-25,000 deaths per year in U.S. Would rank #14 on CDC s mortality list 12% of new onset epilepsy present with SE Iowa Comprehensive Epilepsy Program 1 Hesdorffer, et al DeLorenzo, et al. 1995
27 Treatment of Convulsive Status Epilepticus Benzodiazpine IV lorazepam 0.1 mg/kg IV diazepam 0.15 mg/kg IV midazolam 0.2 mg/kg Long-acting AED IV phenytoin/fosphenytoin 20 mg/kg IV lacosamide 200 mg IV valproate 30 mg/kg IV levetiracetam mg Refractory pentobarbital 12 mg/kg; mg/kg/hr propofol 3-5 mg/kg; 1 mg/kg/hr midazolam 0.2 mg/kg; mg/kg/hour Iowa Comprehensive Epilepsy Program
28 Drug Resistant Epilepsy: Definition Failure to completely control seizures despite trials of 2 anti-epileptic drugs (AEDs) Appropriately chosen for seizure type Patient adherent Efficacy rather than tolerability failure 1/3 of epilepsy patients Only 4-6% will later achieve 1 year of seizure freedom $15,500,000,000 a year in U.S. (all epilepsy) 76% ($11,780,000,000) by DRE patients Iowa Comprehensive Epilepsy Program
29 Sudden, unexpected death in epilepsy (SUDEP) Leading cause of premature death in epilepsy patients Sudden death risk 20 times greater than in general population Risks Severity of epilepsy Frequent generalized tonic clonic seizures Polytherapy Male gender Non-adherence (low drug levels) Young age of onset and long duration of epilepsy Possible mechanisms Respiratory + arousal depression Cardiac arrhythmia Autonomic dysfunction Iowa Comprehensive Epilepsy Program Shorvon, Tomsen. Lancet, 2011.
30 Incidence of SUDEP Iowa Comprehensive Epilepsy Program Shorvon, Tomsen. Lancet, 2011.
31 Reducing the Risk of SUDEP Now Optimize seizure control, especially GTCs Referral to epilepsy center Educate patients and families Good adherence to therapy Alerting systems Not yet FDA-approved Future? Predicting risk The search for a biomarker UI Center for SUDEP Research Detection/alerting/response systems Pharmacotherapy? Iowa Comprehensive Epilepsy Program
32 Drug Resistant Epilepsy: Treatment Options Primary Surgery Resection Disconnection Minimally invasive Gamma knife Laser ablation Device therapy Vagus nerve stimulator (VNS) Responsive Neurostimulating System (RNS) Adjunctive Investigational drug trials Cannabidiol (CBD) Diet Ketogenic Modified Atkins Iowa Comprehensive Epilepsy Program
33 Integrated Epilepsy Management Month 0 First seizure 1 Initial consultation Seizures controlled Seizures controlled Seizures not controlled/diagnosis in question Medication withdrawal Seizures not controlled/diagnosis in question Emergency Department Primary Care Community Neurologist Epilepsy Center Iowa Comprehensive Epilepsy Program Modified from: National Association of Epilepsy Centers, 2010
34 Resources Epilepsy Foundation SUDEP resources csr.case.edu University of Iowa resources udep-research-program
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