Treatment of Refractory Ep ... Treatment of Refractory Epilepsy Pre-surgical Evaluation, Surgical Options,

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  • Treatment of Refractory Epilepsy Pre-surgical Evaluation, Surgical Options, and Neurostimulation

    Michael C. Smith, MD Director, Rush Epilepsy Center

    Professor and Senior Attending Neurologist Rush University Medical Center

    Chicago, Illinois

  • Surgical Treatment of Epilepsy

    • Patient selection

    • Diagnostic evaluation for surgical treatment

    • Types of surgical treatment

    • Outcomes of therapy: risk/benefit • Seizure freedom/cognitive function

  • Partial Epilepsy Goals of Therapy

    • Render patient seizure-free

    • Avoid neurological morbidity

    • Improve quality of life

    • Participating and productive member of society

  • Focal Epilepsy Treatment

    • “Old” drugs (CBZ, PB, PHT, VPA)


    • Electrical stimulation (VNS, RNS, DBS)

    • Diet (Ketogenic, Atkins, Low-Glycemic Index)

    • Epilepsy surgery (ablative/resective/ disconnection)

  • Response to AED Therapy 5-Year Follow-Up

    • 525 newly diagnosed patients

    • 470 AED-naïve

    • 55 AED-experienced

    • 63% seizure-free for 1 year

    • AED-naïve: 64% • 60% after first or second

    monotherapy trial

    • AED-experienced: 56%

    • Most withdrawals or change of treatment were due to intolerable side effects

    Kwan P, et al. N Engl J Med. 2000.



    1% 3% 0






    First Second Third 2 drugs

    AED-Naïve Patients

    Monotherapy Trial

    R e

    sp o

    n se

    t o

    A ED

    ( %

    p at

    ie n

    ts )

  • Epilepsy Efficacy of Treatment

    • 63% were seizure-free the last year

    • Only 11% who failed the first AED became seizure- free

    • About 30%–40% will have a difficult-to-control seizure disorder

    • 0% seizure-free on ≥3 AEDs

    Brodie MJ, et al. Neurology. 2012.

  • Definition of Intractable Epilepsy

    Some variability in published definitions, but there are three main components:

    1. Absence of response to 2 AEDs tolerated at reasonable doses

    2. Minimal frequency (1 seizure/m) or lack of seizure remission of 6–12 months

    3. Duration of epilepsy of 1–10 years of uncontrolled seizures

    Berg AT, et al. Epilepsia. 2006; Berg AT. Neurol Clin. 2009; Kwan P, et al. Epilepsia. 2009.

  • Medically Intractable Surgical Evaluation My Criteria

    • Failed two or more drugs to maximally tolerated dose (VPA, DPH, CBZ, LTG, LEV, TOP, ZNG). Different MOA

    • Failure due to lack of efficacy, not intolerance

    • Add adjunctive AED or combination (LEV-LTG, VPA- LTG) with synergistic MOAs

    • Unable to achieve complete seizure control within 2 years

  • Evaluation of the Medically Intractable Patient Questions

    • Does the patient have epilepsy?

    • Need to record with EEG the events in question? • Nonepileptic event

    • Psychiatric or medical etiology

    • Are the AEDs that have been used appropriate for the seizure type?

    • Have adequate blood levels been tolerated and documented to prove that seizures are medically intractable due to lack of efficacy, not tolerability?

  • Surgical Decision Making

    • Focal resections • First choice in appropriate candidates? Ablation?

    • Importance of early intervention

    • Palliative surgery (successful outcome does not always mean “cure”) • Vagus nerve stimulation (VNS)

    • Corpus callosum division (CCD)

    • Multiple subpial transection (MST)

  • Epilepsy Surgery Comparative Study

    • N Engl J Med, August 2, 2001

    • Randomized controlled study

    • 80 patients with TLE

    • London, Ontario, Canada

    • Surgery effective (P

  • NEJM Editorial

    • Few accepted therapeutic interventions are as underutilized as surgical treatment of epilepsy

    • Two million patients suffer with epilepsy in the United States

    • 400,000 to 600,000 not controlled with AEDs

    • 1990 survey: 1500 therapeutic surgical interventions

    • Seizure-free rate: 70%–90% with surgical therapy

    • Quality of life for patients with epilepsy treated surgically is related to the reoccurrence of seizures

    • QOL—higher employment/school attendance in surgical group

    Engel J. N Engl J Med. 2001.

  • Practice Parameters TLE Surgery

    • Epilepsy: chronic neurologic disorder affects 0.5%–1% of world’s population

    • In the United States and other industrial nations with many AEDs available, 30%–40% of patients not adequately controlled

    • WHO survey: disability from epilepsy accounts for ~1% of global burden of disease as measured by disability- adjusted life years (DALYs)

    • This ranks third behind affective disorder and alcohol dependence among neurologic disorders. Comparable to worldwide burden due to lung and breast cancer

    Engel J, et al. Epilepsia. 2003.

  • Practice Parameters TLE Surgery

    • Surgical procedures for treatment of epilepsy • 1985: ~500 year

    • 1990: ~1500 year

    • 2003: ~3000 year

    • Estimated that there are 100,000–200,000 potential surgical candidates in the United States

    • Early intervention may prevent or reverse the psychosocial sequelae of continued seizures in children

    Engel J, et al. Epilepsia. 2003.

  • Practice Parameters TLE Surgery

    • Surgical efficacy compared to results from randomized clinical trials of AEDs

    • Same patients with intractable partial epilepsy

    • Responder rate (50% reduction of seizure frequency) of 50% is a good response

    • Few patients rendered seizure-free

    • Best results • VGB 6000 mg/d: 54% RR

    • Most AEDs lower RR

    • Vagal nerve stimulator: 30%–50% RR at 1 year

    Engel J, et al. Epilepsia. 2003.

  • Temporal Lobectomy Presurgical Evaluation

    • Routine EEG

    • MRI-head

    • Seizure protocol/volumetrics

    • Long-term EEG monitoring to record seizures

    • Neuropsychological testing

    • Sodium amobarbital study—functional MRI

    • Other: MEG, fMRI, SISCOM, PET, intracranial EEG recording/stimulation

  • Wyllie E. The Treatment of Epilepsy: Principles and Practice. 4th ed. 2005.

  • Wyllie E. The Treatment of Epilepsy: Principles and Practice. 4th ed. 2005.

  • Imaging in Epilepsy Surgically Remediable Syndromes

    • Lesional epilepsy: tumor, vascular anomaly, malformation of cortical development • Structural MRI

    • Medial temporal lobe epilepsy: mesial temporal sclerosis • Structural MRI, PET

  • Wieshmann UC. J Neurol Neurosurg Psychiatry. 2003.

    CT vs MRI


    • Neonate

  • von Oertzen J, et al. J Neurol Neurosurg Psychiatry. 2002.

    Standard MRI vs Epilepsy Protocol Surgical Patients (N=90)

    Specificity %

    Sensitivity %

    Non-expert reader 22 —

    Expert reader, standard MRI 40 —

    Epilepsy protocol 89 >90

  • Multiple Normal 1.5T MRIs Prior to High-resolution 3T MRI

    • Cortical malformation

    • Left • 3T MRI high-resolution 3D

    structural scan

    • Right • 3T MRI high-resolution

    Cubic FLAIR

  • Long-term Intracranial Monitoring Subdural Grid Implantation

  • Functional Brain Monitoring

  • Surgery

    • Mesial temporal lobe epilepsy

    • Frontal lobe epilepsy

    • Lesional focal epilepsy • Focal encephalomalacia

    • Tumor

    • Vascular malformation

    • Congenital developmental anomaly

    • Neocortical cryptogenic epilepsy

    Engel J, et al. Epilepsia. 2003; Wiebe S, et al. New Engl J Med. 2001; Zimmerman R, et al. Mayo Clin Proc. 2003; Treiman DM. Neuropsych Dis and Treat. 2010; Asadi-Pooya AA, et al. Epilepsy Behav. 2008.

    Epilepsies That May Benefit Available Interventions

    • Resection of the seizure focus

    • Multiple subpial transection when seizure focus is in eloquent cortex

    • Destruction of seizure focus by gamma knife/RF/laser*

    • Corpus callosotomy

    *Gamma knife, RF, and laser ablation are not FDA approved.

  • Randomized, Controlled Trial of Surgery for TLE

    • 80 patients randomly assigned for either surgery (40 patients) or AED therapy (40 patients) for 1 year

    • Out of 40 patients, 4 refused surgery; of the remaining 36 patients, 6 required invasive pre- surgical investigation

    • Results: percentage of patients free of seizures that impair awareness • 58% randomized to surgery

    • 8% randomized to AED therapy

    • 64% actually had surgery

    • P

  • Temporal Lobectomy Efficacy

    • Long-term operative outcome (5 years)

    • 62 of 89 patients (70%) seizure-free

    • 18 of 89 patients (20%) significantly improved

    Sperling MR, et al. JAMA. 1996.