Using Medications to Treat Epilepsy

John F. Kerrigan, M.D. Associate Professor of Child Health and Neurology

University of Arizona College of Medicine – Phoenix

Director, Pediatric Epilepsy Program and Clinical Neurophysiology Laboratory

Phoenix Children’s Hospital

Epilepsy Foundation of Arizona

Patient Education Conference

April 12, 2014

What is a Seizure?

An abnormal electrical discharge of neurons

in the brain

resulting in diverse symptoms

Too Much

Excitation

Too Little

Inhibition

Excessive Net Excitation

Basic Concept #1

Synchrony

Basic Concept #2

What is Epilepsy?

An enduring tendency

to experience seizures

Epilepsy = Seizure Disorder

Anderson, Hauser, 1986

Incidence

Per

100,000

0

50

100

200

150

Age Years

0 20 60 80 40

Epilepsy in Children Prevalence

Type I Diabetes 0.2%

Epilepsy 0.6%

Febrile Seizures 5%

Asthma 12%

Seizure Classification

Single Event

Clinical Features and EEG

Focal or Partial

Simple

Complex

Secondarily Generalized

Generalized

Absence

Tonic

Atonic

Tonic-Clonic

Others

Epilepsy Syndrome Classification

Single Patient Includes All Clinical Information

Multiple Factors Age of Onset

Seizure Type or Types

EEG Pattern

Natural History

Associated Features

Others…

1-2

Years

2-6

Years

6-12

Years

>12

Years

3-12

Months

0-3

Months

Benign Neonatal

Seizures

Infantile

Spasms

Lennox-Gastaut

Syndrome

Benign Rolandic

Epilepsy

Juvenile Myoclonic

Epilepsy

Early Myoclonic

Encephalopathy

Childhood Absence

Epilepsy

Anti-Epilepsy Drugs (AEDs) 2014

phenytoin Dilantin

carbamazepine Tegretol

ethosuximide Zarontin

sodium valproate Depakote

felbamate Felbatol

gabapentin Neurontin

topiramate Topamax

lamotrigine Lamictal

zonisamide Zonegran levetiracetam

Keppra

oxcarbazepine Trileptal

Anti-Epilepsy Drugs (AEDs) 2014

pregabalin Lyrica

rufinamide Banzel

lacosamide Vimpat

vigabatrin Sabril ezogabine

Potiga

clobazam Onfi

Anti-Epilepsy Drugs (AEDs) 2014

But Wait, There’s More!

eslicarbazepine Aptiom

perampanel Fycompa

stiripentol Diacomit

GENERALIZED ONSET

Absence

Tonic-clonic

Myoclonic

Atonic

Tonic

PARTIAL ONSET

Simple

Complex

Secondary

Ethosuximide

Valproate

Carbamazepine

Phenytoin

Phenobarbital

Primidone

Benzodiazepines

1993

Use of Anti-Epilepsy Drugs (AEDs) 2014

Partial Onset

Generalized Onset

Simple

Complex

Secondary GTC

Absence

Tonic-Clonic

Myoclonic

Atonic/Tonic

Ethosuximide

Benzodiazepines

Levetiracetam

Valproic Acid

Felbamate

Lamotrigine

Topiramate

Zonisamide

Rufinamide

Vigabatrin

Clobazam

Stiripentol

Phenobarbital

Phenytoin

Carbamazepine

Gabapentin

Tiagabine

Oxcarbazepine

Pregabalin

Lacosamide

Ezogabine

Eslicarbazepine

Perampanel

Classification of Epilepsy Medications

Older Generation Medications

• More Side Effects

• More complex Drug-drug Interactions

Newer Generation Medications

• Less Side Effects

• Simpler Drug-Drug Interactions

• A Lot More Expensive!

Difference in anti-seizure effect is hard to measure.

Dose

Response

Blood Level

Response

Time One Day

Blood

Level

“Standard” Formulation Three Times A Day

“Peak”

Possible Dose-Related

Side Effects

“Trough”

Possible Increase

In Seizures

Time

Blood

Level

“Slow Release” Formulation Twice A Day

Neonate Infant Child Adult Elderly

Renal Function

Albumin

Hepatic Metabolism

CYPs

UGTs a orb

Anderson & Rho, in Wyllie, Treatment of Epilepsy, 4th Ed.

Dose

% Effectiveness

Side Effects

Dose-Related Side Effects

All Seizure Medications Can Cause … – Sleepiness

– Difficulty Concentrating

– Nausea, Vomiting

– Coordination Problems

– Double Vision

– Learning Issues

• Trouble Concentrating or Inattention

• Slowed Responses

• Difficulty Multitasking

…If the Dose Is Too High

Specific Side Effects - I

Serious Allergic Rash

Uncommon: Lamictal, Dilantin, Tegretol, Trileptal, Phenobarbital

Very Uncommon: Topamax, Zarontin, Zonegran

Almost Never: Keppra, Depakote, Benzodiazepines

Specific Side Effects - II

Serious Liver Problems

Uncommon: Depakote (Age <2 and Polytherapy)

Very Uncommon: Tegretol, Dilantin

Hematologic Problems

Depakote: decreased platelets

Tegretol > Trileptal: decreased white blood counts

Electrolyte Problems (Low Sodium)

Trileptal > Tegretol

Specific Side Effects - III

Weight Gain

Depakote, Neurontin, Lyrica

Weight Loss

Topamax, Zonegran, Felbatol

Anger/Behavior Problems

Keppra

Hyperactivity

Phenobarbital

Insomnia

Felbatol, Lamictal

Long-Term Side Effects

Liver Damage

No

Kidney Damage

No

Cancer

No

Decreased Bone Health

Yes!! For Some Medications

Loscher and Schmidt, Nat Rev Neurol 2012

Kwan and Brodie, NEJM, 2000

Kwan et al, Epilepsia, 2010

47%

13%

5%

“Two-Drug Rule”

When to Consider Epilepsy Surgery?

Not

Controlling

Seizures

Too

Many

Side Effects

Or

When are You a Good Candidate

For Epilepsy Surgery?

Seizures Always

Start in the

Same Place

or Area

That Place

or Area is

Safe

To Remove

And

Wiebe S, NEJM, 2001

2012 Annual Report, Cyberonics, Inc

Vagal Nerve Stimulation

FDA Approved 1997

Model 105 Introduced 2011

For Epilepsy Treatment

93,000 Systems Implanted

In 67,000 Patients

Revenue FY 2012

$219M

Epilepsy Treatment Algorithm

Yes No

Resective

Surgery

First Drug

Second Drug

Third Drug/Combination

Candidate for Surgical Resection?

Investigational

Medication VNS Ketogenic

Diet

47%

13%

5%

40-

80%

<5%

Drug Treatment for Epilepsy…

2014 and Beyond?

Brivaracetam

ICA-105665

2-Deoxy-Glucose Ganaxolone

Imepitoin NAX 810-2

Tonabersat VX-765 YKP3089

EILAT Conference 2012

Who Has Epilepsy?