drug resistant epilepsy: diagnostic and treatment options mark a. granner, md medical director,...

Drug Resistant Epilepsy:Diagnostic and Treatment Options

Mark A. Granner, MD

Medical Director, Epilepsy Monitoring UnitCo-Director, Iowa Comprehensive Epilepsy Program

Professor and Vice Chair for Clinical ProgramsDepartment of Neurology

University of Iowa

Overview

• Definitions and statistics• Treatment options for drug resistant epilepsy

– AEDs, diet, VNS• Introduction to epilepsy surgery• The multidisciplinary approach to epilepsy

care• The Iowa Comprehensive Epilepsy Program

Iowa Comprehensive Epilepsy Program

Definitions

• Seizure– An episode of altered behavior or awareness– Associated with too much excitation of a population of

nerve cells (neurons)

• Epilepsy– The tendency to have recurrent, unprovoked seizures

(brain makes seizures happen)

• Acute symptomatic (provoked) seizure– A seizure occurring in the setting of some systemic

provoking factor (normal brain, body makes seizures happen)


Definitions

• Acute repetitive seizures (“cluster”)– A period of increased severity or frequency of seizures in an

epilepsy patient• Status epilepticus

– A single prolonged seizure (> 5-10 min)– Repeated seizures without recovery to baseline

• SUDEP– Sudden unexpected death in epilepsy patients

• 1-6 per 1000 patients per year• Probably under recognized, under reported• Needs further study


Definitions

• Drug resistant epilepsy– Failure of at least TWO seizure medications to

completely control seizures• Appropriately chosen for seizure type• Taken as prescribed• Well tolerated (not failed due to side effects)


Drug Resistant Epilepsy

• 470 patients with previously untreated epilepsy– Seizure-free to 1st medication 47%– Seizure-free to 2nd medication 13%– Seizure-free to 3rd medication or beyond 4%

• 36% of epilepsy patients are drug resistant!• The new generation of medications are generally safer

(fewer side effects), but are not significantly more effective.

Kwan P, Brodie M. NEJM 2000; 342(5)


Epidemiology of Seizures & Epilepsy

• In the U.S.– 10% lifetime risk of a seizure– 4% lifetime risk of recurrent seizures– 3% lifetime risk of epilepsy– 0.6% prevalence of epilepsy

• 2,000,000 Americans• $15,500,000,000 U.S. annual cost

• Higher in developing countries


Epidemiology of Epilepsy

0-1

5-9

15-1

9

25-2

9

35-3

9

45-4

9

55-5

9

65-6

9

75-7

985

+0

50

100

150

200

250

300

Incidence of epilepsy per year by age in Rochester, MN

1935-19841975-1984

Age

Nu

mb

er

pe

r 1

00

,00

0


Epidemiology of Epilepsy

2,000,000 with epilepsy

600,000 with DRE

1500 surgeries a year


120,000 surgery candidates

Options in Drug Resistant Epilepsy

• Medication– New, study drugs

• Diet– Ketogenic, Atkins

• Vagus Nerve Stimulator• Epilepsy Surgery

• Gamma knife• Brain stimulation


U.S. Epilepsy Drug Development

1857 1912 1937 1954 1960 1974 1975 1978 1993 1995 1997 2000 2005 2008 2009

Bromide salts

Clonazepam

Ethosuximide

Primidone

Phenytoin

Phenobarbital Lamotrigine

FelbamateGabapentin

Valproate

Carbamazepine

OxcarbazepineZonisamide

Levetiracetam

TopiramateTiagabine

Rufinamide

Pregabalin

1999

Lacosamide

2012

Ezogabine


Diets in Adults With Epilepsy

• Ketogenic diet– Effective (40% seizure reduction)– Compliance challenging (about 50% don’t follow

or stop)– Minimal short term side effects– Long term consequences not known

• Modified Atkin’s diet may be as effective and better tolerated

Vagus Nerve Stimulator• Effectiveness

– Average seizure reduction (24.5%)– 50% responder rate (31%)– Seizure free (0%)

• Side Effects– Hoarseness/voice change (37.2%)

• All patients should undergo video-EEG prior to VNS– Rule-out non-epileptic events– Screen for surgery

VNS Study Group. Neurology 1995Arain, et al. Epilepsy & Behavior 2011


UIHC VNS Experience

• > 100 patients currently followed• 21 implant surgeries in 2012• Seizure-free about 5-10%• Seizure reduction about 50%• Patient satisfaction high


Indications for Epilepsy Surgery

• Drug resistant epilepsy• Localized seizures• Which can safely and effectively be resected• Informed and willing patient• Referral to surgical epilepsy center

– Epilepsy duration before referral 18 (2-58) years– 61% sent by neurologist– 39% self-referred, never advised of surgery– 14% advised by neurologist not to have surgery– 83% seizure free

Iowa Comprehensive Epilepsy Program Benbadis et al. Seizure 2003.

Epilepsy Surgery Evaluation

Drug Resistant Epilepsy

Phase 1(Non-invasive)

Phase 2(Invasive)

Concordant

Discordant

Not acandidate

Phase 3 - Wada test - Surgery

Case Conference

Case Conference


Epilepsy Surgery Evaluation

Phase 1 (Non-invasive)• MRI (3T, sz protocol)• Ictal video-EEG• Neuropsychology• PET, SPECT• MEG

Phase 2 (Invasive)• Intracranial video-EEG• Indications:

– Phase 1 data not agreeing– Phase 1 data not localizing– Concern of left vs. right

side– Concern of middle vs.

surface temporal lobe– Onset outside temporal

lobe


Types of Surgery

• Lobectomy (removal of all or most of lobe)– Temporal >> frontal

• Corticectomy (removal of area of cortex)• Hemispherectomy (removal/disconnection of

hemisphere)• Corpus callosotomy (disconnection)• Multiple subpial transection


Outcome Measures

• Seizure freedom– Anterior temporal lobectomy

• 60-80%

– Extratemporal resection• 25-50%

– Better if lesion on MRI– Worse if widespread or multifocal seizure onset

• Complications– Major < 2% (stroke, hemorrhage)– Infection– Vision loss (temporal lobectomy)– Memory or mood change


Seizure Outcome After Anterior Temporal Lobectomy

Iowa Comprehensive Epilepsy ProgramWiebe, et al. NEJM 2001

Other Outcomes

Mean SeizureSeverity Score

Mean GlobalQuality of Life

Employed orAttending School

Iowa Comprehensive Epilepsy ProgramWiebe, et al. NEJM 2001

Seizure Outcome at UIHC: Anterior Temporal Lobectomy

Engel Score

Perc

en

t

2007 Surgical Outcome SurveyIowa Comprehensive Epilepsy Program

Grade 1 – Seizure freeGrade 2 – Rare seizuresGrade 3 – Significant reductionGrade 4 – No improvement

n=88


Sudden, unexpected death in epilepsy(SUDEP)

• Leading cause of premature death in epilepsy patients• Sudden death 20 times greater than in general population• Risks

– Generalized tonic clonic (“grand mal”) seizures– Male gender– Long duration of epilepsy– Seizure medicine polytherapy

• Possible mechanisms– Respiratory depression– Cardiac arrhythmia– Autonomic dysfunction

Iowa Comprehensive Epilepsy ProgramShorvon, Tomsen. Lancet, 2011.

Incidence of SUDEP

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

Research at the Iowa Comprehensive Epilepsy Program

• Human brain physiology– Auditory physiology– Microdialysis

• Respiratory mechanisms– SUDEP, SIDS– Study of respiratory monitoring on EMU

• Human-computer interface


Services Offered: Iowa Comprehensive Epilepsy Program

• Consultation– Episodes of unknown nature– New onset seizures– Drug resistant epilepsy– Special populations (pregnancy, elderly)

• Epilepsy monitoring unit– 9 beds adult / 5 beds pediatric– Specialty nursing staff– Epilepsy fellowship trained physicians– Safety protocols– 24-hour monitor observation

• Diagnostic tests– Electroencephalography (routine, prolonged outpatient, inpatient)– Imaging (MRI, fMRI, PET, SPECT)– Neuropsychology

• Multidisciplinary team– Neurosurgery– Psychiatry– Neuropsychology– Pharmacy– Social services– Physical, occupational therapy Iowa Comprehensive Epilepsy Program

Multidisciplinary Epilepsy Clinic

• Joint effort of Neurology, Neurosurgery, Psychiatry

• Launching later in 2013• New clinic space on Pomerantz Lower Level• Coordinated visits with more than one care

provider in same day• Coordinated tests (EEG, MRI, Neuropsychology)• Drug resistant or surgical epilepsy

– Maybe expand to other patient populations

EmergencyDepartment Primary Care Neurologist Epilepsy

Center

First seizure

Epilepsy Management


Seizures controlled

Seizures not controlled/diagnosis in

question

Initial consultation

Seizures not controlled/diagnosis in

question

Medication withdrawal

0

0-1

12

3

36+

Month

Seizures controlled

Modified from:National Association of Epilepsy Centers, 2010

drug resistant epilepsy: diagnostic and treatment options mark a. granner, md medical director,...

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