Epilepsy Surgery Overview Anumeha Sharma Fellow, clinical neurophysiology - EEG University of Cincinnati Medical Center

Case - GT 36 year old RHM seen in clinic for a 7 year history of episodes of panic, nausea, déjà vu initially diagnosed as panic attacks. Subsequently additional behaviors of patting, slapping with right hand and confusion, asking strange questions – “When does school start again? What grade am I in?” Frequency – Clusters of upto 9 seizures every 2-3 months EEG – normal MRI – normal Medications tried - Topamax (aggression – NE), Lamictal - NE) Current medications – Keppra (depression), Zonisamide

What would be the next step in management? Start lacosamide Refer for presurgical evaluation Refer for VNS placement Refer to psychiatry

Prognosis of epilepsy Prevalence ~ 0.5% to 1.0% (Hauser, 1998) ~ 70 % (35- 82%) have complete control with medications Generalized - 74- 82% Focal onset - 35-58% (strokes and vascular malformations respond better than trauma, CD, MTS, tumors) ~ 20 – 40 % have drug resistant* disease ~ 4-16% chance of seizure freedom with additional drug trials

Prognosis of epilepsy over time Sillanpaa et al NEJM 1998

Diminishing returns of multiple AED trials Kwan NEJM 2000;342:314-9NEJM 2Kwan000;342:314-9.

Pharmacoresistance Introduction of newer AEDs ~ 25-50% responder rate (50% seizure reduction) 5% of previously refractory patients become seizure free (French et al 2004) ~ 5-10 % discontinue the medications due to adverse effects (Singhvi et al 2000) VNS has a very low chance of achieving seizure freedom in MRE Should not be considered before resective surgery Reserved for poor candidates (palliative)

Pharmacoresistence No agreement over the frequency and duration of epilepsy to constitute intractability Pharmacoresistance should be established within a few years of starting AED therapy (Berg et al, 2003; Devinsky, 1999) Absolute seizure freedom is the only outcome associated with improved quality of life

Medically Refractory Epilepsy ILAE definition - Failure of adequate trials of two tolerated and and appropriately used AED regimens as monotherapy or in combination to achieve seizure freedom Treatment failure due to lack of clinical efficacy Seizure freedom should be at least 1 year or 3 times the pretreatment seizure free interval

Predictors of therapy resistance Early age at seizure onset Tonic or myoclonic seizures Symptomatic etiologies History of status epilepticus (Chen et al, 2002; Ko and Holmes, 1999).

Risks of refractory Epilepsy Mortality SMR 5.1 compared to 1.6 - 2.3 in general epilepsy population Successful epilepsy surgery decreases mortality (Sperling et al, 1996) Sudden unexpected death in epilepsy (SUDEP) - 0.5% per year, cumulative over lifetime (Sillanpaa et al, 1998) Increased seizure frequency Increasing number of AEDs (ever used) Early onset of epilepsy Frequent changes of AEDs GTCs Nilsson et al. 1999; Langan et al 2005, Beran et al. 2004,

Risks of Refractory Epilepsy Cognitive - Slowly progressive cortical atrophy and Cognitive decline (Jokeit and Ebner, 1999) Psychiatric – Depression ~1.8x in patients with epilepsy vs. general population, 20-55% in MRE vs. 3-9 % in well controlled epilepsy patients High seizure frequency, focal onset seizures, female gender (JJ Barry et al 2008) Injury Quality of life, Driving, School and Employment

Candidates for surgery ~ 50 % of MRE patients are candidates for focal resective surgery Rest can be considered for a variety of palliative procedures i.e. VNS, RNS or diets Symptomatic focal onset related epilepsy - most likely to receive seizure freedom from surgery

Temporal lobectomy vs. medication Wiebe et al, NEJM, 2001

AAN Practice parameter 2003 One Class I RCT of surgery for MTLE 58% of patients randomized in the surgical arm (64% of those who received surgery) were free of disabling seizures, compared with 8% seizure freedom in the medical arm Improvement in quality of life and driving, employment, mortality, some neuropsychological parameters

AAN practice parameter 2003 “Patients with disabling complex partial seizures, with or without secondarily generalized seizures, who have failed appropriate trials*of first-line antiepileptic drugs should be considered for referral to an epilepsy surgery center”(Engel et al 2003)

Surgical outcome - summary Epilepsy Outcome (seizure free) Temporal lobe lesion ~ 80% Mesial temporal sclerosis ~ 70% “Normal” temporal lobe ~ 60% Lesional extratemporal Nonlesional extratemporal < 50%

Morbidity and mortality Infections, hemorrhage, and neurological deficits, ~ transient Principal post surgical complication – cognitive Some decline in verbal or non verbal memory or language Transiently worsened anxiety or depression in 20-40 % (Engel et al 2003) In general, overall risk of surgery is lower than risk of refractory epilepsy (Engel et al 2003) mortality in RCTS of AEDS ~ 0.78% per year

Who is not a surgical candidate? Clear evidence of more than one focus or bilateral onset Progressive disease (multiple sclerosis, cerebral vasculitis, HIV, meningitis, and high-grade malignant brain tumors) Diffuse neuropsychological deficits Significant psychiatric disease

Epilepsy Surgery Evaluation - Initial History and examination Video and (scalp) EEG monitoring Structural Imaging – MRI Functional Imaging – PET, Ictal and Interictal SPECT Tests for functional localization – Wada, Neuropsychometric testing, functional MRI

Structural Imaging - MRI Best available tool for identification of epileptogenic lesions Provides information about Presumptive pathology Anatomic location Coronal T1 and FLAIR with thin cuts – MTS, CD GRE – cavernoma Hamartomas, polymicrogyria, neuronal migration disorders, AVM, low grade tumors

MRI Lesion on MRI may or may not reflect the epileptogenic zone The success rates for epilepsy surgeries done on patients with “unremarkable” MRI is much lower Use of 3 Tesla magnets has lead to increased number of patients eligible for surgery (knake et al, 2005)

MRI – GT

Long term video EEG monitoring Both ictal and interictal EEG Essential to capture complete sample of typical seizures to clarify region(s) of seizure onset Ictal EEG gives valuable lateralizing and localizing information with regard to the seizure focus (Jobst et al, 2001) Temporal lobe seizures higher yield than extratemporal 76 – 83 vs 47 – 65%

Phase I scalp EEG - GT

Phase I scalp EEG - GT

Functional Imaging - PET scan Metabolic maps of the brain Especially useful in non lesional MRI 18F FDG provides measure of interictal regional glucose metabolism Decreased metabolism represents functional deficit zone (65 - 90% of TLE patients) Unilateral temporal lobe hypometabolism on 18F-FDG-PET strongly predicts seizure freedom with resection of that temporal lobe, independent of MRI findings (Theodore et al 1992)

PET Scan - GT Coronal and axial images

Functional localization Eloquent cortices essential for language, memory, motor, or sensory functions must often be delineated Resection can be tailored to avoid causing functional deficits. Neuropsychometric testing Functional MRI IAP (Wada) test Magnetoencephalography

Neuropsychometric testing Quantify, lateralize and localize cognitive deficits Predict cognitive decline after epilepsy surgery Obtained pre and post operatively to determine if new deficits have developed Correlated with seizure foci identified using other techniques

Wada test Functions as the transient mimic of the effects of the proposed surgery Amobarbital is injected into the ICA , temporarily disrupting function on that side, while language and memory tests are performed The best validated method of determining Language dominant hemisphere Assess risk of postoperative memory deterioration after temporal lobectomy

Predictors of higher risk of cognitive decline after temporal lobectomy Intact baseline cognitive ability Dominant temporal lobe resection Later age of epilepsy onset Normal MRI results Female gender Loss of memory function during injection of amobarbital into the carotid artery on the side of planned surgery

Summary of phase 1 evaluation - GT MRI – Non lesional PET – bilateral hypometabolism, non lateralizing Video EEG - 1 clear right and 4 likely left temporal seizures, no post ictal language delay Temporal lobe onset, unclear lateralization

Summary of phase 1 evaluation - GT Neuropsychometric testing Not well localized or lateralized anatomically Excellent cognitive abilities overall High risk for cognitive decline post operatively Wada test Left sided language dominance Slightly decreased memory on the left No major risk of post-operative amnesia with surgery on either side

Phase II (intracranial) evaluation Precisely delineate the extent of a epileptogenic zone and its relationship to areas of eloquent functional cortex. Determine if right or left onset 10-20% of temporal lobe, 40%-70% extratemporal cases ~75% of implanted patients go on to have resective surgery. Complications – minor, 1% to 2% of cases (Siegel, 2004)

Depth electrodes Multiple contact needles Provide direct access to deep structures Very detailed but focused sampling Lower complication rate, implanted through burr holes Can be left in place for days and weeks with low risk of infections permitting longer monitoring

Subdural Electrodes Used if seizure focus cannot be located with scalp EEG or other diagnostic tests Grids or strips Placed on brain surface, grids and strips are placed through craniotomy and burr holes respectively More precise recording especially for neocortical seizures Cortical mapping for functional areas can occur Higher complication rate especially for grids

Grid and Strip

Intracranial electrode placement- GT

Phase II intracranial EEG – GT

Phase II monitoring – GT 4 typical seizures arising from left depth electrode (left mesial temporal region) Risk vs. benefits of surgery were discussed Patient elected to undergo left anterior temporal lobectomy 3 month follow up – No seizures, mild anomia, resolved with steroids.

Epilepsy surgery Timing and trends in the US Time interval between onset of seizures and referral for pre-surgical evaluation – 18- 25 years Comparison of referral data for patients with TLE from 1995 to 1998 and 2005 to 2008 Determine whether AAN practice parameter resulted in a change in referral patterns for surgical evaluation No improvement in timing of referral for pre-surgical evaluation

sharm 112,026 hospitalizations for medically refractory focal epilepsy 6,653 (5.9%) resective surgeries from 1990 to 2008. A trend of increasing hospitalizations over time but overall trend of decreasing surgery rates

Thank You David Ficker, MD Mariano Fernandez Ulloa, MD