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Epilepsy surgery: an under-utilized
treatment modalityDipika Aggarwal, MD
Clinical Neurophysiology Fellow
Background
• Epilepsy is among the most serious primary disorders of the
brain, accounting for 1% of the global burden of disease
• Second most common cause of mental health disability,
particularly among young adults
• World wide burden of illness similar to breast cancer in
women and lung cancer in men
• Prevalence : 5 to 10 per 1,000 population in the US
• Pharmacotherapy is unsuccessful in controlling seizures in 20-
40% of patients
• Medically intractable epilepsy patients account for 80% of the
cost of epilepsy in the US
Background
• Temporal lobe epilepsy (TLE) is the most common cause of pharmaco-resistant seizures
• Most easily and effectively treated with surgery, 60-80% of patients become free of disabling seizures
• More than 100,000 patients, while fewer than 2000 received surgical treatment (Engel and Shewmon, 1993)
• Average duration of 22 years between onset of epilepsy and referral (Berg et al., 2003)
• Reason - Absence of a randomized control trial (RCT) to demonstrate the superiority of surgical intervention over continued pharmacotherapy
Objective
• Who is a surgical candidate?
• Types of surgical treatments
• Pre surgical evaluation in adults: non invasive
and invasive
• Risks and outcome
Objective
• Who is a surgical candidate?
• Types of surgical treatments
• Pre surgical evaluation in adults: non invasive
and invasive
• Risks and outcome
Failure of adequate trials of two well tolerated and appropriately chosen
and used AEDs to achieve sustained seizure freedom for a sufficiently long
period of time.
A sufficiently long period of time is defined for an individual patient as
three times the longest inter seizure interval for that patient, or 1 year,
whichever is longer.
www.epilepsycases.com
www.epilepsycases.com
When to refer children for
comprehensive epilepsy evaluation
• All children
– Persistent generalized or partial seizures after failure of 2 or 3 AEDs, or
unacceptable side effects
– Urgent if more than one seizure per day
• Children under age 2 years
– Urgent referral to prevent developmental delay and epileptic
encephalopathy esp. if daily seizures
• Special circumstances
– TLE, cortical dysplasia, hemi-megalencephaly, Rasmussen’s
encephalitis, tumors, prior ischemic brain injury, tuberous sclerosis,
hypothalamic hamartomas
Common misconceptions and pitfalls
• Lesions in the dominant hemisphere, bilateral interictal
epileptiform discharges, a normal MRI brain, or memory
deficits are contraindications for surgery
• Patients who may not seem to meet surgical criteria at a non
specialized center may be deemed surgical candidates after
expert assessment
• Patients with psychiatric conditions, cognitive disabilities, and
the elderly can often benefit from surgical procedures
Objective
• Who is a surgical candidate?
• Types of surgical treatments
• Pre surgical evaluation in adults: non invasive
and invasive
• Risks and outcome
Types of surgical treatments
Standardized resections
• Anterior temporal resections
• Amygdalohippocampectomy
• Hemispherectomy
Tailored resections
• Localized cortical resections
• Lesionectomies
• Multilobar resections
Disconnections
• Corpus callosotomy
• Multiple subpial resections
Other
• Gamma knife
• Deep brain stimulation
• Response stimulation
• Early Randomization Surgical Epilepsy Trial (ERSET), 2012
• Multicenter, 16 US epilepsy surgery centers
• 38 participants – MTLE and disabling seizures for no more than 2
years following adequate trials of 2 appropriately chosen AEDs
• 23 continued AED, 15 standardized AMTR plus AED
• Primary outcome: seizure freedom during 2 year follow up period
• Secondary outcome: measure of quality of life (QOLIE-89), cognitive
function and social adaptation
• Results: • 0/23 in the medical group and 11/15 patients in the surgical group
were seizure free during 2 years
• QOLIE-89 score was higher in surgical group
Objective
• Who is a surgical candidate?
• Types of surgical treatments
• Pre surgical evaluation in adults: non invasive
and invasive
• Risks and outcome
Pre surgical evaluation
• Goal of epilepsy surgery:
– Complete removal of epileptic tissue
– No neurological or neuropsychological deficits
• These goals can be achieved only by a thorough pre surgical
evaluation during which the epileptic tissue and essential
brain regions are localized as accurately as possible
Cortical zones• Irritative zone: brain region where inter ictal spikes can be recorded
• Seizure-onset zone: brain region where seizures originate (where ictal
epileptiform discharges begin)
• Ictal symptomatogenic zone: brain region responsible for the generation of the
first clinical symptoms during a seizure
• Functional deficit zone: brain region which is affected by non epileptic
functional disturbances (NP, EEG, SPECT, PET and WADA)
• Epileptogenic lesion: structural lesion causative for the patient’s seizure
• Epileptogenic zone: brain region whose removal is necessary and sufficient to
achieve a seizure free outcome
Pre-surgical evaluation
• Phase 1: Non-invasive tests
– Video EEG monitoring
– MRI
– Neuropsychological testing
– SPECT, PET, functional MRI, MR Spectroscopy, magneto-
encephalography, Wada test
• Phase 2: Invasive tests
Video-EEG Monitoring
• Cornerstone of non invasive evaluation
• Continuous EEG and video for at least 5 days
• Goals
– Documentation of seizure semiology
– Sampling of inter ictal EEG
– Documentation of ictal changes and their correlation with
clinical seizure semiology
Intensive Video-EEG Monitoring
• So why is clinical seizure semiology so important??
– Epileptic versus non-epileptic and their frequencies
– Single or multiple different seizure types indicating
multiple seizure onset zones
– Lateralization and localization of seizure onset zone
Lateralizing signs
• Ipsilateral signs
– unilateral hand
automatism
– non versive (early) head
turning
– postictal nose wiping
– peri-ictal headache
– unilateral eye blinking
– lateral tongue biting
• Contralateral signs
– unilateral dystonic/ tonic
posturing
– unilateral mouth deviation
– unilateral clonic
movements
– figure of 4 sign
– ictal hemiparesis
– postictal hemiparesis
Lateralizing signs
• Dominant Hemisphere
– postictal aphasia
– ictal vocalization
• Non-dominant Hemisphere
– preserved ictal language
– automatism with preserved
responsiveness
– ictal retching/vomiting
– ictal spitting
– peri-ictal urinary urge
– peri-ictal water drinking
Sensitivity of scalp EEG
• First EEG is abnormal in only 30-50% of seizure patients
• Serial EEG (by the 3rd) raise the sensitivity to 80-90%
• Sensitivity can be increased by:
– Slow-wave sleep activates IED (inter ictal epileptiform
discharges)
– IED are activated after seizure
– Anterior temporal electrodes, sphenoidal electrodes or closely
placed electrodes
– Longer duration of scalp EEG
Magnetic resonance imaging
• Major breakthrough in pre surgical evaluation
• Post op seizure control is significantly increased if an
epileptogenic lesion can be identified on pre-op scans
• With improvement in MRI hardware (3T), acquisition, and
post processing methods, relevant structural abnormalities
can now be identified in 10-30% of patients with previously
unremarkable scans
Neuropsychological (NP) testing
• Mandatory for localization of epileptogenic zone and
functional deficit zone and to assess the NP risks for surgery
• TLE – memory and language
• Dominant TLE – verbal memory deficits
• Non dominant TLE – visuospatial memory deficits
• Memory decline – most common deficit after TLE surgery
• Patients with average or above average memory and language
function are at higher risk for developing postoperative
deficits
SPECT• 99mTc-HMPAO (hexamethyl-propyleneamine) and 99mTc-ECD
(ethyl cysteinate dimer)
• Regional blood flow (rCBF) markers
• Marked increase in rCBF can be seen within the seizure onset zone during ictal SPECT
• In TLE, inter ictal SPECT shows regional temporal hypo-perfusion in 40-50% of patients ipsilateral to epileptogenic zone
• Sensitivity of ictal SPECT can be significantly increased by the co-registration of ictal SPECT with inter ictal SPECT and MRI –subtraction ictal SPECT co-registered to MRI (SISCOM)
PET
• [18F]FDG (fluorodeoxyglucose)
• Inter ictal glucose hypometabolism
• In TLE sensitivity is 65-90%, less in patients with normal
MRI
• PET is generally utilized in evaluation of cryptogenic cases
and for identifying seizure spread patterns
Other ancillary tests
Functional MRI (fMRI)
• Assessment of functional deficit
zone
• Language lateralization
• Concordance: 90-100 % in left
dominant, 67-100% in right
dominant and 50-75% bilateral
dominant patients
Magnetoencephalography
• Measures brain’s weak magnetic
field
• MEG is more sensitive than EEG
in neocortical epilepsy
• Can be useful in non lesional
cases
• Can localize the eloquent cortex-
sensorimotor cortex, language
mapping
Wada test
• Intracarotid amobarbital procedure
• Language and memory lateralization
• Atypical language lateralization is more likely in epilepsy patients
• Rationale – anesthetize mesial temporal structures to simulate
potential effects of the proposed surgery
• Patients with impaired memory ipsilateral to the epileptogenic
focus and intact memory contralaterally are at lowest risk for
postoperative memory decline
• Despite of high accuracy, it is associated with false negatives and
false positives
Invasive Phase 2 evaluation
• Scalp EEGs are unable to lateralize in up to one-third of patients
with TLE
• Up to 10% of lateralizing non invasive tests could be falsely
localizing
• Indications
– Discordance amongst non invasive test results
– Multifocal / bitemporal epilepsy
– MRI negative TLE
– MRI with questionable / widely extended lesion
– Epileptogenic lesion is close to, or overlaps with eloquent areas
– Extra temporal lobe epilepsy syndromes
Invasive Phase 2 evaluation
• Intra cerebral “depth” electrodes, subdural strips, subdural
grid recordings
• Each technique has specific advantages and limitations
• Intracerebral “depth” electrodes:
– Penetrate brain tissue directly
– Recording from deep structures such as
amygdala, hippocampus, insula or sulcal cortex
– Target lesions in deep cerebral locations such as
heterotopic gray matter abnormalities,
hypothalamic hamartomas etc
Invasive Phase 2 evaluation
• Subdural electrodes:
– overlie the surface of the brain
– localization of epileptogenic regions on
the cortical surface
– Inter hemispheric locations
– inaccurate for defining EEG patterns
arising from deep generators
• Subdural grids:
– ideal for functional mapping of cortex
• Often used together
Risks associated with surgery for TLE
• Motor deficits: – Contralateral hemiplegia
– 2% of the cases, majority patients improve over months to a year
• Cranial nerve deficits:– Oculomotor nerve (CNIII) and trochlear nerve (CNIV)
– 1.5-3%, transient, traction injury
• Visual field deficits:– Superior quadrantanopsia
– Damage to lateral aspect of Meyer’s loops (optic radiations)
– ~ 55% of patients
– Most cases patients are unaware, diagnosed on formal visual field testing
Risks associated with surgery for TLE
• Language deficits:
– Dominant TLE surgery
– Most common - transient anomia
• Memory deficits:
– Patients may still suffer significant memory deficits following TLE
surgery despite of favorable WADA testing and results
– High ipsilateral memory function - greater degree of post operative
memory decline
Risks associated with surgery for TLE
• Psychiatric risks:
– TLE associated with depression ~ 50%
– Preoperative history of depression
– Suicide rates greater than 5 times general population
– Rare – psychotic type illness , schizophrenia
– Low threshold for psychiatric assessment
66% seizure
freedom at 5 yrs
7.6 years seizure
freedom
62% - adults
50% - children
Seizure freedom (%): no.
of yrs
75% : 2 years
67% : 5 years
51%: 10 years
When to withdraw AEDs?
• AED withdrawal uncovers the natural history of epilepsy, or
the success of a surgical procedure, without influencing the
long-term seizure outcomes
• No RCT in post surgical patients
• Previous studies: in medically treated patients, the risk of
seizure recurrence is high until 2 years after AED withdrawal
• It has been recommended to continue AEDs for at least 2
years after surgery in seizure free patients, largely based on
AED withdrawal policies in nonsurgical cohorts
KU Case
• 49 year old right handed female with medically intractable epilepsy with complex partial seizures at least 1-2 per day since age 30
• She has been on several name brand AEDs with no improvement
• EEG: epileptogenic tissue in the right temporal and left frontal lobes
• VEEG: typical seizures captured, lateralizing to the left hemisphere
• MRI: normal hippocampi bilaterally
• fMRI: right hemispheric dominance
• PET: moderate to marked decreased activity in the left mesial and anterior temporal lobe
Case (contd.)
• Neuropsych testing: dominant (probably left) hemisphere involvement
• WADA test: right hemispheric language dominance and adequate memory function from right hemisphere
• Phase II evaluation localized seizures to left anterolateral temporal lobe and left hippocampus
• Left anterior temporal lobectomy (4cm) and hippocampectomy in May 2014
• Seizure free since then and counting days when she would be able to drive
How are we doing?
• Since 2013, 9 patients with medically intractable epilepsy
were evaluated for surgery
• 6 underwent surgery and are seizure free and doing well thus
far
• 1 ATL resection earlier this week
• More cases to go!!
Questions