Drug Resistant Epilepsy:
Diagnostic and Treatment Options
Mark A. Granner, MD
Medical Director, Epilepsy Monitoring Unit
Co-Director, Iowa Comprehensive Epilepsy Program
Professor and Vice Chair for Clinical Programs
Department 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)
Iowa Comprehensive Epilepsy Program
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
Iowa Comprehensive Epilepsy Program
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)
Iowa Comprehensive Epilepsy Program
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)
Iowa Comprehensive Epilepsy Program
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
Iowa Comprehensive Epilepsy Program
Epidemiology of Epilepsy
Incidence of epilepsy per year by age in Rochester, MN
300
Number per 100,000
250
200
1935-1984
1975-1984
150
100
50
0
Age
Iowa Comprehensive Epilepsy Program
Epidemiology of Epilepsy
1500 surgeries a year
2,000,000 with
epilepsy
120,000 surgery candidates
600,000 with DRE
Iowa Comprehensive Epilepsy Program
Options in Drug Resistant Epilepsy
• Medication
– New, study drugs
• Diet
– Ketogenic, Atkins
• Vagus Nerve Stimulator
• Epilepsy Surgery
• Gamma knife
• Brain stimulation
Iowa Comprehensive Epilepsy Program
U.S. Epilepsy Drug Development
Bromide salts
Ethosuximide
Phenytoin
Felbamate
Gabapentin
Clonazepam
Oxcarbazepine
Zonisamide
Topiramate
Tiagabine
Rufinamide
Ezogabine
1857 1912 1937 1954 1960 1974 1975 1978 1993 1995 1997 1999 2000 2005 2008 2009 2012
Primidone
Valproate
Levetiracetam
Lacosamide
Phenobarbital
Carbamazepine
Lamotrigine
Iowa Comprehensive Epilepsy Program
Pregabalin
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
Iowa Comprehensive Epilepsy Program
VNS Study Group. Neurology 1995
Arain, 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
Iowa Comprehensive Epilepsy Program
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
Concordant
Phase 1
(Non-invasive)
Case Conference
Discordant
Phase 3
- Wada test
- Surgery
Phase 2
(Invasive)
Case Conference
Iowa Comprehensive Epilepsy Program
Not a
candidate
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
Iowa Comprehensive Epilepsy Program
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
Iowa Comprehensive Epilepsy Program
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
Iowa Comprehensive Epilepsy Program
Seizure Outcome After Anterior
Temporal Lobectomy
Iowa Comprehensive Epilepsy Program
Wiebe, et al. NEJM 2001
Other Outcomes
Mean Seizure
Severity Score
Mean Global
Quality of Life
Iowa Comprehensive Epilepsy Program
Employed or
Attending School
Wiebe, et al. NEJM 2001
Seizure Outcome at UIHC: Anterior
Temporal Lobectomy
70
50
Grade 1 – Seizure free
Grade 2 – Rare seizures
Grade 3 – Significant reduction
Grade 4 – No improvement
40
n=88
Percent
60
30
20
10
0
1
2
Engel Score
3
4
2007 Surgical Outcome Survey
Iowa Comprehensive Epilepsy Program
Iowa Comprehensive Epilepsy Program
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 Program
Shorvon, Tomsen. Lancet, 2011.
Incidence of SUDEP
Iowa Comprehensive Epilepsy Program
Shorvon, Tomsen. Lancet, 2011.
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
Iowa Comprehensive Epilepsy Program
Services Offered: Iowa Comprehensive
Epilepsy Program
•
Consultation
–
–
–
–
•
Epilepsy monitoring unit
–
–
–
–
–
•
9 beds adult / 5 beds pediatric
Specialty nursing staff
Epilepsy fellowship trained physicians
Safety protocols
24-hour monitor observation
Diagnostic tests
–
–
–
•
Episodes of unknown nature
New onset seizures
Drug resistant epilepsy
Special populations (pregnancy, elderly)
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
Epilepsy Management
Month
0
First seizure
0-1
Seizures
controlled
Seizures
controlled
3
12
Initial consultation
Seizures not
controlled/diagnosis in
questionSeizures not
controlled/diagnosis in
question
Medication
withdrawal
36+
Emergency
Department
Primary Care
Neurologist
Iowa Comprehensive Epilepsy Program
Epilepsy
Center
Modified from:
National Association of Epilepsy Centers, 2010