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

Disclosure

• I have no actual or potential conflicts of interest in relation to the content of this lecture.

Iowa Comprehensive Epilepsy Program

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

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

Epidemiology of EpilepsyUnited 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

2,000

Surgeries per year 25

Fountain NB, et al. Neurology 2015

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

Diagnosis of Epilepsy: Tests

• MRI

• EEG

• In the ED consider• CBC, electrolyte panel• Urine drug screen• CT• Lumbar puncture

Iowa Comprehensive Epilepsy Program

Tonic

Clonic

Tonic-clonic

Atonic

Myoclonic

Absence

Secondary Generalized

GeneralizedPartial

Previous Classification of Seizure Types

Unclassified

Simple Complex

MotorTonic-clonic

Other motor

Non-Motor (Absence)

Unknown Onset

Motor

Non-Motor

Focal to bilateral tonic-clonic

Generalized OnsetFocal Onset

Motor

Tonic-clonic

Other motor

Non-Motor

ILAE 2017 Classification of Seizure Types Basic Version

Unclassified

Aware Impaired

Awareness

Fisher RS, et al. Instruction Manual for the ILAE 2017 Operational Classification of Seizure Types. Epilepsia 2017.

First Generation Second Generation

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

Pharmacotherapy of Epilepsy

First Generation (1900-1978)

Generic Name Brand Name

Phenobarbital

Phenytoin Dilantin

Primidone Mysoline

Ethosuximide Zarontin

Carbamazepine Tegretol

Valproic acid Depakote

Second Generation (1993-2009)

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

Pharmacotherapy of Epilepsy:Effective For Partial SeizuresTeratogenicity < 3%Minimal/No Averse Effect on Bone DensityGeneric Formulation AvailableExtended-Release Formulation Available (or long half-life)

First Generation (1900-1978)

Generic Name Brand Name

Second Generation (1993-2009)

Generic Name Brand Name

Lamotrigine Lamictal

Oxcarbazepine Trileptal

Levetiracetam Keppra

Zonisamide Zonegran

Iowa Comprehensive Epilepsy Program

New Onset Focal Impaired Awareness (Complex Partial)

Generalized Tonic Clonic

Absence

Focal Seizure, Woman of Reproductive Age

Focal Seizures, Healthy Elderly

Focal Seizures, Ill Elderly

New Onset, Emergency Department

Epilepsy Medication in Primary CareMedication (Brand) Use Disadvantages

Ethosuximide (Zarontin)

Absence epilepsy. Will not treat GTC, focal seizures.

Levetiracetam(Keppra)

Any seizure type. IV form for emergency use.

No significant.

Lorazepam (Ativan)

Acute repetitive seizures, status epilepticus.

Short half-life. Tolerance to chronicuse.

Phenytoin (Dilantin)

Status epilepticus.Partial sz or GTC.

Side effects, drug interactions.(e.g. osteoporosis)

Iowa Comprehensive Epilepsy Program

Monitoring Considerations

Medication(Brand)

Considerations

Lamotrigine(Lamictal)

Metabolism increased with CYP450 inducersphenytoin, carbamazepine, phenobarbital

Metabolism decreased by valproic acidLevels fall (up to 50%) through pregnancy

Measure plasma concentrations at least twice per trimesterAdjust dose as neededReturn to previous dose after delivery

Initial titration must be slow (add 25 mg per week)SJS, TEN, other rashes

Levetiracetam(Keppra)

Not liver metabolizedRenal excretion

Adjust dosing in chronic or acute kidney disease

Levels fall through pregnancyMeasure plasma concentrations at least twice per trimesterAdjust dose as neededReturn to previous dose after delivery

When To Check Blood Levels

• Doing well baseline

• Pregnancy

• Adherence

• Drug interactions

• Breakthrough seizure

• NOT annually or per routine

Emergencies in Epilepsy: Status Epilepticus• Diagnosis

• Recurrent seizures without recovery to baseline• Single prolonged seizure (5-10 min)

• Incidence• 18.31-412 patients / 100,000• 55,000 - 125,000 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. 19982 DeLorenzo, et al. 1995

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 2000-6000 mg

• Refractory• pentobarbital 12 mg/kg; 0.2-0.4 mg/kg/hr• propofol 3-5 mg/kg; 1 mg/kg/hr• midazolam 0.2 mg/kg; 0.1-0.25 mg/kg/hour

Iowa Comprehensive Epilepsy Program

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

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.

Incidence of SUDEP

Shorvon, Tomsen. Lancet, 2011.Iowa Comprehensive Epilepsy Program

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

Drug Resistant Epilepsy: Treatment OptionsPrimary

• 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

EmergencyDepartment

Primary CareCommunityNeurologist

Epilepsy Center

First seizure

Integrated Epilepsy Management

Iowa Comprehensive Epilepsy Program

Seizures controlled Seizures not controlled/diagnosis in question

Initial consultation

Seizures not controlled/diagnosis

in question

Medication withdrawal

0

1

12

3

36+

Month

Seizures controlled

Modified from:

National Association of Epilepsy Centers, 2010

Resources• Epilepsy Foundation

• http://www.epilepsy.com/• www.epilepsyiowa.org• www.epilepsy.com/accelerating-new-therapies/new-

therapies-pipeline

• SUDEP resources• www.sudepaware.org• csr.case.edu

• University of Iowa resources• https://www.uihealthcare.org/epilepsy/• https://www.medicine.uiowa.edu/neurology/research/s

udep-research-program