Drug Resistant Epilepsy: Diagnostic and Treatment Options

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Drug Resistant EpilepsyDiagnostic 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

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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

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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)

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Definitions

• Acute repetitive seizures (cluster)
• A period of increased severity or frequency of
  seizures in an epilepsy patient
• Status epilepticus
• A single prolonged seizure (gt 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

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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)

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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)
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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

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Epidemiology of Epilepsy
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Epidemiology of Epilepsy
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Options in Drug Resistant Epilepsy

• Medication
• New, study drugs
• Diet
• Ketogenic, Atkins
• Vagus Nerve Stimulator
• Epilepsy Surgery
• Gamma knife
• Brain stimulation

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U.S. Epilepsy Drug Development
Bromide salts
Ethosuximide
Felbamate Gabapentin
Oxcarbazepine Zonisamide
Clonazepam
Phenytoin
Topiramate Tiagabine
Rufinamide
Ezogabine
1857
1912
1937
1954
1960
1974
1975
1978
1993
1995
1997
2000
2005
2008
2009
1999
2012
Primidone
Valproate
Levetiracetam
Lacosamide
Phenobarbital
Lamotrigine
Carbamazepine
Pregabalin
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Diets in Adults With Epilepsy

• Ketogenic diet
• Effective (40 seizure reduction)
• Compliance challenging (about 50 dont follow or
  stop)
• Minimal short term side effects
• Long term consequences not known
• Modified Atkins diet may be as effective and
  better tolerated

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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 1995 Arain, et al.
Epilepsy Behavior 2011
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UIHC VNS Experience

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

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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

Benbadis et al. Seizure 2003.
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Epilepsy Surgery Evaluation
Drug Resistant Epilepsy
Phase 1 (Non-invasive)
Concordant
Case Conference
Discordant
Phase 2 (Invasive)
Phase 3 - Wada test - Surgery
Not a candidate
Case Conference
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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

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Types of Surgery

• Lobectomy (removal of all or most of lobe)
• Temporal gtgt frontal
• Corticectomy (removal of area of cortex)
• Hemispherectomy (removal/disconnection of
  hemisphere)
• Corpus callosotomy (disconnection)
• Multiple subpial transection

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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 lt 2 (stroke, hemorrhage)
• Infection
• Vision loss (temporal lobectomy)
• Memory or mood change

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Seizure Outcome After Anterior Temporal Lobectomy
Wiebe, et al. NEJM 2001
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Other Outcomes
Mean Seizure Severity Score
Mean Global Quality of Life
Employed or Attending School
Wiebe, et al. NEJM 2001
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Seizure Outcome at UIHC Anterior Temporal
Lobectomy
Grade 1 Seizure free Grade 2 Rare
seizures Grade 3 Significant reduction Grade 4
No improvement
n88
Percent
Engel Score
2007 Surgical Outcome Survey Iowa Comprehensive
Epilepsy Program
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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

Shorvon, Tomsen. Lancet, 2011.
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Incidence of SUDEP
Shorvon, Tomsen. Lancet, 2011.
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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

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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

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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

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Epilepsy Management
Month
First seizure
0
Initial consultation
0-1
Seizures controlled
Seizures not controlled/diagnosis in question
3
Seizures not controlled/diagnosis in question
Seizures controlled
12
Medication withdrawal
36
Emergency Department
Primary Care
Neurologist
Epilepsy Center
Modified from National Association of Epilepsy
Centers, 2010