REVIEW ARTICLE


Identification
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
and Treatment of

VIDEO CONTENT
Drug-Resistant Epilepsy
A VA I L A B L E O N L I N E By Ji Yeoun Yoo, MD; Fedor Panov, MD

ABSTRACT
PURPOSE OF REVIEW: Drug-resistant epilepsy is a potentially life-threatening
condition affecting one-third of people living with epilepsy. Despite
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existing evidence of improved outcomes in patients who received surgical

treatment compared to continued medical treatment, epilepsy surgery
remains underused in patients with drug-resistant epilepsy. This article
discusses the gap between evidence and practice and common
misconceptions about epilepsy surgery and reviews the current diagnostic
and therapeutic surgical options.

CITE AS: RECENT FINDINGS: Three randomized controlled trials comparing the medical
CONTINUUM (MINNEAP MINN)
versus surgical treatment for patients with drug-resistant epilepsy have
2019;25(2, EPILEPSY):362–380.
shown the superiority of surgery in controlling seizures and improving
Address correspondence to patients’ quality of life. In addition to resective surgery, neuromodulation
Dr Ji Yeoun Yoo, Mount Sinai through devices such as responsive neurostimulation and vagal nerve
Hospital, 1468 Madison Ave,
Annenberg Bldg 210, New York,
stimulation have also shown efficacy in seizure control that increases over
NY 10029, jiyeoun.yoo@mssm.edu. time. Diagnostic and therapeutic surgical tools are tailored to the needs of
each patient.
RELATIONSHIP DISCLOSURE:
Dr Yoo has received publishing
royalties from Elsevier for the SUMMARY: Appropriate patients with drug-resistant epilepsy benefit more
book Rowan's Primer of EEG and from epilepsy surgery than from continuing medical treatment. These
has received personal
compensation as a lecturer for patients should be referred to comprehensive epilepsy centers where a
the Korean Epilepsy Society thorough presurgical workup and surgical options can be provided. The
and for serving on the advisory
board of Zimmer Biomet. Dr Yoo
gap between evidence and practice can be bridged by education,
has received research/grant community outreach, and providers’ earnest efforts to improve the quality
support from the NeuroNEXT of life of patients with epilepsy.
Program of the National
Institutes of Health/National
Institute of Neurological
Disorders and Stroke. Dr Panov INTRODUCTION
has received personal

D
compensation as a consultant for rug-resistant epilepsy is defined as the “failure of adequate trials of
NeuroPace, Inc and Zimmer two tolerated, appropriately chosen and used antiepileptic drug
Biomet.
(AED) schedules (whether as monotherapies or in combination) to
UNLABELED USE OF achieve sustained seizure freedom,” which could be either 3 times
PRODUCTS/INVESTIGATIONAL the prior interseizure interval or 1 year, whichever is longer.1
USE DISCLOSURE:
Drs Yoo and Panov report no
Drug-resistant epilepsy affects about one-third of people living with epilepsy.2
disclosures. Patients with epilepsy have worse quality of life, family function, and social
support compared to other patients who are chronically ill.3 Furthermore,
© 2019 American Academy patients with drug-resistant epilepsy face an increased risk of sudden unexpected
of Neurology. death in epilepsy (SUDEP) (TABLE 4-1).4

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 Since the development of modern surgical approaches to epilepsy in the 1950s,
resection of a seizure focus has become an important treatment tool for
drug-resistant epilepsy. Introduction of modern nonresective techniques, such as
laser interstitial thermal therapy, gamma knife radiosurgery, and devices such
as vagal nerve stimulation (VNS) and responsive neurostimulation, has recently
expanded the surgical options.
The effectiveness of epilepsy surgery has been demonstrated in randomized
controlled trials, case series, and observational studies. Epilepsy surgery can
potentially convert drug-resistant epilepsy to drug-responsive epilepsy. It may
also decrease the burden of antiepileptic medication side effects, thus improving

Overview of Drug-Resistant Epilepsya TABLE 4-1

Characteristic Comments

Epidemiology Focal epilepsy and focal onset seizures, with prevalence of 50% each among those with
epilepsy, are the most common syndromes and seizure types.5

Natural history and intractability The course of epilepsy can be predicted with reasonable accuracy within the first
2 years of therapy, but early remission does not necessarily predict a favorable
long-term outcome.6

Predictors of drug resistance Predictors of drug resistance include high initial seizure frequency, underlying etiology,
and failure to respond to antiepileptic drugs early on.7

Surgical utilization and referrals Epilepsy surgery is underutilized worldwide.8,9

Cost of epilepsy Successful epilepsy surgery is more cost-effective than medical therapy, and greater
savings accrue with earlier surgery.10,11

Indications for surgery The most common criteria used to define surgical candidacy are seizure frequency
(>1 per month) and failure of ≥2 antiepileptic drugs.12 In cases of lesional epilepsy,
surgery can be considered even earlier.

Seizure outcome after surgery Approximately 60–65% of patients are seizure free after temporal lobe resection,
compared with 40% of patients after extratemporal resection.13

Use of antiepileptic drugs after There is uncertainty about the proportion of patients who discontinue antiepileptic
surgery drugs after surgery.

Neuropsychological outcomes Epilepsy surgery is associated with specific cognitive decline (most often involving
after surgery verbal memory and naming after dominant lobe resections), but cognition may also
improve in some patients.14

Psychiatric outcomes after surgery There is either improvement or no change in psychiatric outcomes after surgery.15

Quality of life after surgery Quality of life improves after surgery and is strongly influenced by seizure freedom.16

Social outcome after surgery After surgery, improvement is seen in patients’ employment, driving, and relationships.17

Complications after surgery Surgical complications are usually minor or transient; major and minor neurologic
complications were reported in 4.7% and 10.9% of patients, respectively, with
resective surgery, with the most common being minor visual field deficits (affecting one
quadrant or less).18

Mortality after surgery Mortality appears to be lower if patients are rendered seizure free after epilepsy
surgery.19

a
Modified with permission from Jette N, et al, Neurology.12 © 2012 American Academy of Neurology.

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DRUG-RESISTANT EPILEPSY

quality of life. However, epilepsy surgery currently remains grossly underused.8

This article addresses why this occurs and what clinicians can do for people living
with drug-resistant epilepsy.

SURGICAL VERSUS MEDICAL TREATMENT FOR DRUG-RESISTANT EPILEPSY

Numerous case studies and observational studies about the efficacy of epilepsy
surgery have been conducted. Because of the difficulty of study design and
ethical implications in delaying surgical therapy, randomized controlled trials
comparing medical versus surgical treatment for refractory epilepsy were lacking
until 2001. Currently, three randomized controlled trials have shown the
superiority of surgery compared to continued medical treatment in patients with
drug-resistant epilepsy, not only for seizure control but also for quality of life.20
The first randomized controlled trial for adults with refractory temporal lobe
epilepsy, comparing patients who underwent immediate epilepsy surgery to
those randomly assigned to a 1-year waiting period of continued medical
treatment (this arm was usual care at that center), demonstrated the superiority
of surgical outcome. At 1 year, 58% of the surgery group were free of disabling
seizures compared to 8% in the medical group (P<.001). Improved quality of life
as well as a strong trend toward better social functioning (higher rates of
employment and school attendance) were present in the surgical versus the
medical arm.20 This pivotal study was followed by a multicenter randomized
controlled trial that compared early surgery to continued medical therapy in
patients with temporal lobe epilepsy.21 Although this study was terminated early
because of slow accrual, 11 of 15 patients in the surgery group were seizure free at
2 years, while none of the 23 patients in the medical group achieved seizure
freedom (odds ratio = ∞; 95% confidence interval, 11.8 to ∞; P<.001). Recently,
the superiority of surgery was also demonstrated in children with refractory
epilepsy (including, but not limited to temporal lobe epilepsy) in a single-center
randomized controlled trial showing 77% (44 of 57 patients) of participants in
the surgery group free of seizures at 1 year, versus 7% (4 of 59 patients) of
participants in the medical group (P<.001), as well as improved behavior and
quality of life in the surgical group.22
Beyond seizure frequency and quality of life, a significant decrease in
mortality was demonstrated in a large clinical cohort study (n = 1110, total
follow-up of 8126.62 person-years from 1986 to 2013) and was most pronounced
in patients who became free of generalized tonic-clonic seizures after surgery.23
Epilepsy surgery is also cost-effective when compared to costs of direct medical
care and long-term disability.10,11

A GAP BETWEEN EVIDENCE AND PRACTICE

Based on the Class I study in favor of epilepsy surgery20 and other literature, a
formal practice guideline in epilepsy surgery was published in 2003 jointly by the
American Academy of Neurology (AAN), American Epilepsy Society, and
American Association of Neurological Surgeons.24 It recommended that patients
for whom appropriate trials of first-line AEDs have failed should be considered
for referral to an epilepsy surgery center. Despite this practice parameter, referral
patterns for patients with drug-resistant epilepsy have not changed significantly
in the following years.8 According to one estimate, only 1% of patients with
drug-resistant epilepsy are referred to epilepsy centers,25 and this usually occurs
after an average of more than 20 years after the onset of their epilepsy.26

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 The reasons for the delays or lack of referral for surgery range from patients’ KEY POINTS
or families’ fears, health care providers’ lack of knowledge about epilepsy
● Drug-resistant epilepsy is
surgery, society or community health care access issues, or social and cultural defined as the “failure of
issues (eg, stigma).27 adequate trials of two
tolerated, appropriately
POSSIBLE BARRIERS TOWARD TIMELY REFERRAL FOR PATIENTS WITH chosen and used
antiepileptic drug schedules
DRUG-RESISTANT EPILEPSY
(whether as monotherapies
Several common misconceptions about epilepsy surgery continue to be held by or in combination) to
health care providers.25 This section discusses issues of importance in removing achieve sustained seizure
some barriers to timely referral of patients. freedom.”

● Drug-resistant epilepsy
Safety Profile of Epilepsy Surgery affects about one-third of
Epilepsy surgery is often considered dangerous and thus is thought of as a last people living with epilepsy.
resort for patients with drug-resistant epilepsy. In fact, epilepsy surgery is
generally safe; most complications associated with epilepsy surgery are minor ● Currently, three
randomized controlled
(defined as resolving completely within 3 months of surgery, whereas major trials have shown superiority
complications persist beyond that time frame).18 According to a systematic of surgery compared
review, major and minor medical complications were reported in 1.5% and 5.1% to continued medical
of patients, respectively, following resective surgery, the most common being treatment in patients with
drug-resistant epilepsy, not
CSF leak. Major and minor neurologic complications were reported in 4.7% and
only for seizure control but
10.9% of patients, respectively, with resective surgery, with the most common also for quality of life.
being minor visual field deficits (affecting one quadrant or less). Perioperative
mortality was rare (0.4% in temporal lobe cases and 1.2% in extratemporal ● A formal practice
cases); these numbers are skewed upward by large pediatric resections in guideline by the American
Academy of Neurology,
multilobar cases and are lower for the adult population.18 American Epilepsy Society,
Cognition and memory deficits are not contraindications to surgery. Epilepsy and American Association of
surgery is associated with specific cognitive changes, most notably verbal Neurological Surgeons
memory decline (44% decline in left-sided surgery and 20% decline in right) and recommends that the
patients for whom
naming (34% decline in left-sided surgery) in anterior temporal lobectomy.14 appropriate trials of first-line
Decline in visuospatial memory was also reported in about 20% of patients antiepileptic drugs have
irrespective of the side of the surgery.14 However, paradoxical gains in verbal failed should be considered
memory (gains in 7% to 14% of patients) and visuospatial memory (gains in 10% for referral to an epilepsy
surgery center.
to 15% of patients) and an increase in verbal fluency in left-sided surgery
(increase in 27% of patients) were also reported.14 The ability of the healthy ● A gap between evidence
circuits to recover and even improve in function after the seizure focus has been and practice exists in regard
removed is postulated as the reason for the postoperative gains mentioned to treatment for patients
with drug-resistant epilepsy.
above. Neuromodulation and selective laser ablation have been shown to avoid
Although evidence clearly
some of the above cognitive problems by minimizing the effect of surgery on the dictates referral of patients
surrounding brain tissue.28,29 It is important to note that the risk of cognitive with drug-resistant epilepsy
and memory decline is less when an abnormality is seen on imaging such as to a comprehensive epilepsy
mesial temporal sclerosis, or with earlier age of seizure onset, or with preexisting center, such referrals are
still not completed due to a
memory and language deficits. Preoperative neuropsychological assessment is variety of reasons.
useful for creating a risk-benefit profile, and presurgical counseling as well as
postsurgical rehabilitation referrals could diminish such deficits that may occur.30 ● Epilepsy surgery is
generally safe; most
complications are minor
Futility of Future Sequential Antiepileptic Drug Trials After Initial Drug and transient.
Resistance Is Clearly Established
The definition of drug-resistant epilepsy was driven in part from a prospective
study that showed that only 11% of patients with epilepsy became seizure free
after failure of the first AED and only 3% of patients with epilepsy became

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DRUG-RESISTANT EPILEPSY

seizure free after failure of the second AED.2 Despite the development of newer
AEDs, the rate of drug-resistant epilepsy does not seem to have significantly
changed.31 In a prospective observational study, the likelihood of seizure
freedom declined with successive drug regimens, most markedly from the first
to the third.32 Given the high likelihood of seizures remaining uncontrolled after
failure of two AEDs (ie, having recurrent seizure[s] after adequate trials) and
multiple disadvantages from living with epilepsy, any patient for whom two or
more AEDs have failed should be referred to a comprehensive epilepsy center
for multidisciplinary evaluation and surgical consideration, as consistent with
current guidelines.33

Patients With Drug-Resistant Epilepsy and Nonlesional Brain Magnetic

Resonance Imaging May Still Be Candidates for Surgery
Patients who have epilepsy due to a structural abnormality seen on brain MRI
have better surgical outcomes than those without an MRI abnormality. However,
not all radiographically “normal” MRIs are indeed normal. The most common
culprit is focal cortical dysplasia.34 In one study, 60% of patients with histologically
confirmed focal cortical dysplasia had “normal” MRIs when performed and
reported outside a major epilepsy center, but only 37% of these were still
“normal” when reviewed at the epilepsy center.35 Detailed EEG analysis by
epileptologists in combination with MRI interpretation by experienced
neuroradiologists with attention to the patient’s seizure symptomatology can
help identify subtle findings. Milder forms of dysplasia may still be invisible in
high-resolution MRIs and, in these cases, other imaging studies such as positron
emission tomography (PET) or ictal single-photon emission computed
tomography (SPECT) can be helpful.

Localization of the Epileptogenic Zone Requires Multimodality Evaluation

The theoretical concept of an epileptogenic zone is defined as “the minimum
amount of cortex that must be resected (inactivated or completely disconnected)
to produce seizure freedom.”36 There is not one ideal tool for epileptogenic zone
delineation; it is rather an approximation through multiple modalities, including
MRI, EEG, and neuropsychological tests. A focal lesion seen on a patient’s MRI
may or may not be responsible for the person’s epilepsy, and careful review
through multiple modalities are still necessary.

Eloquent Cortical Epileptogenic Foci May Still Be Amenable to

Epilepsy Surgery
Careful mapping of brain function is performed before resective surgery,
especially when the epileptogenic zone is in or near eloquent cortex. The regions
with essential function can be delineated and protected during resection.
Involvement of eloquent cortex is not a contraindication to epilepsy surgery.
When the resection of the epileptogenic zone is not possible because of a likely
functional deficit, neuromodulation such as responsive neurostimulation (RNS)
or VNS can be an effective treatment option. In a recent open-label observational
study of patients with medically intractable seizures arising from eloquent and
other neocortical areas who were implanted with RNS, median seizure reduction
was 70% in patients with frontal and parietal seizure onsets, 58% in patients
with temporal neocortical onset, and 51% in those with multilobar onsets, without
significant acute or chronic neurologic deficits.37

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Patients With Drug-Resistant Epilepsy With Multifocal Brain Lesions or KEY POINTS
Generalized Interictal Spiking May Still Be Candidates for Epilepsy Surgery
● Cognition and memory
A treatment-viable seizure onset zone can still be identified even if multiple or deficits are not
diffuse lesions are seen on MRI or if multifocal spikes are seen on EEG. The contraindications to
patient’s habitual seizure symptomatology along with EEG and imaging findings epilepsy surgery.
can successfully delineate the epileptogenic zones that may involve only a part
● The risk of cognitive and
of a lesion, leading to successful resection, laser ablation, or neuromodulation.
memory decline is less when
Bilateral spikes can be misleading, especially when the epileptiform activity an abnormality is seen in
comes from a frontal or occipital region because of rapid synchronization. It can imaging such as mesial
be especially tricky when encephalomalacia is present in the epileptogenic zone, temporal sclerosis, or with
as the epileptiform discharges can be falsely lateralizing. Careful review of the earlier age of seizure onset,
or with preexisting memory
imaging along with the patient’s habitual seizure symptomatology and EEG and language deficits.
analysis (eg, phase reversal, lateralizing higher amplitude) can help identify a
unilateral onset. What seems to be generalized epilepsy or bilateral spikes on EEG ● After failure (having
may still have a unilateral seizure onset zone. In cases of drug-resistant truly recurrent seizures despite
adequate trials) of two
generalized epilepsy, VNS can be considered, which has a 60% reported antiepileptic drugs, the
responder rate (>50% seizure reduction).38 chance of a third antiepileptic
drug effectively controlling
Patients With Drug-Resistant Epilepsy and Psychiatric Comorbidity May a patient’s seizures is
very low.
Still Be Candidates for Epilepsy Surgery
Psychiatric comorbidity is not a contraindication to surgery. In a systematic ● “Normal” brain MRIs are
review of literature regarding psychiatric outcomes after epilepsy surgery, not always normal. A careful
generally no changes or some improvements in psychiatric condition were review by dedicated
seen.15 De novo psychiatric issues postsurgery were relatively rare, ranging from neuroradiologists, with
attention to the patient’s
milder syndromes such as adjustment disorder (18%) to more severe conditions seizure symptomatology,
such as psychosis (1%). In a recent prospective case-control study, the patients and correlation with EEG
who received epilepsy surgery experienced a significant decrease in findings, can help identity
psychopathologic alterations, distress perception, anxiety, and depression when subtle findings.
compared to those who continued with medical treatment.39 Current evidence ● A focal lesion is not
also supports that cognition and mood remain stable with all neurostimulation always the culprit for the
therapies, with some evidence that there may be improvement.40 It should be patient’s seizures, and
understood that, in the setting of psychiatric illness, seizures will worsen a careful review through
multiple modalities is
patient’s quality of life and increase his or her day-to-day medical risk.
still necessary.

Epilepsy Center Referral Facilitates Comprehensive Epilepsy Care ● Involvement of

A referral to a comprehensive epilepsy center is not only for possible epilepsy eloquent cortex is not a
surgery but is also to identify a “pseudoresistance” and to adjust treatments contraindication to
epilepsy surgery. When
accordingly. This “pseudoresistance” results from medication noncompliance the resection of the
(which could be due to sensitivity to side effects), seizures that are nonepileptic epileptogenic zone is not
(including psychogenic attacks), failure to identify a treatable cause, wrong possible, a device can be an
drug for the patient’s type of epilepsy or wrong dosage or time of medication, effective treatment option.
and lifestyle issues such as substance abuse or sleep deprivation.25 In a ● A treatment-viable
comprehensive epilepsy center, these issues can be elucidated and treated by seizure onset zone can still
a multidisciplinary team approach with an improved outcome and without be identified even if multiple
surgical intervention. As an example, the often-overlooked dietary adjustment to or diffuse lesions are seen
on MRI or if multifocal
a ketogenic diet or modified Atkins diet can be very effective in seizure control.41
spikes are seen on EEG.

PRESURGICAL WORKUP
Workup with the goal of achieving seizure freedom by surgical means begins in
earnest with a referral to a comprehensive epilepsy center (FIGURE 4-1). A cohesive

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DRUG-RESISTANT EPILEPSY

FIGURE 4-1
Decision tree for patients with epilepsy.
AED = antiepileptic drug; EEG = electroencephalography; MRI = magnetic resonance imaging;
PET = positron emission tomography; SPECT = single-photon emission computed tomography.

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team crossing medical specialty boundaries is required to design an KEY POINTS
appropriate pathway for each patient. Such teams usually include
● What seems to be
epileptologists, neuropsychologists, neurosurgeons, and neuroradiologists. Yet, generalized epilepsy or
it is the invaluable support team that may include administrators, schedulers, bilateral spikes on EEG may
nurses, and advanced practice professionals that really allows for the complex still have a unilateral seizure
process to move forward smoothly, maintaining constant communication with onset zone, and in cases of
truly generalized epilepsy,
the patient and his or her family. Such teamwork builds confidence and reduces
a device can be an
anxiety for the patient. effective option.
The basic tests required include admission for video-EEG monitoring and
brain imaging, as well as a neuropsychology evaluation. Additional tests may ● A referral to an epilepsy
include magnetoencephalography (MEG), SPECT, functional MRI (fMRI), center is not only for
possible epilepsy surgery
Wada test (intracranial sodium amobarbital procedure that establishes language but is also to identify
and memory representation of each hemisphere), PET scans, and repetition of a “pseudoresistance” and
any tests deemed outdated from previous workups. Setting appropriate to adjust treatments
expectations for patients and learning the goals of them and their families are accordingly.
critical. At times, seizure freedom may not be achievable, but significant ● Invasive diagnostic tools
medication reduction or decrease in the severity of the episodes may be a realistic are used for delineating the
target. When noninvasive data are insufficient to delineate the epileptogenic intracranial seizure onset
zone, invasive monitoring using intracranial electrodes is indicated to zone and for functional brain
mapping. The diagnostic
anatomically define the epileptogenic zone as well as the nearby functional areas.
tools include grids, strips,
The surgical treatment of most patients is divided into the diagnostic phase depth electrodes, or stereo-
and the therapeutic phase; albeit, some patients will only go as far as the EEG, and these tools can be
diagnostic phase, while, in a select group, a single therapeutic stage may used as dictated by the
needs of the specific
be appropriate.
patient.

DIAGNOSTIC EPILEPSY SURGERY

Invasive diagnostic tools are used for delineating the intracranial seizure onset
zone and for functional brain mapping. The diagnostic tools include grids, strips,
depth electrodes, or stereo-EEGs, and these tools can be used as dictated by the
needs of the specific patient.

Grids and Strips

The classic surgical workup preferred for decades includes a craniotomy for
placement of subdural grids and strips over the suspicious areas of the brain to
elucidate the seizure focus during an inpatient monitoring phase that follows
(FIGURE 4-2). Grids and strip studies offer great coverage of the cortical surface
and allow the spatial contiguity in detecting the ictal onset and its immediate
spread.42 It is an efficacious option, especially when the hypothetical
epileptogenic zone is anatomically restricted to superficial cortical areas and is
in close relation with eloquent cortex.43 When necessary, it can be combined
with one or more depth electrodes to sample a deep focus (foci).

Stereo-Electroencephalography
Stereo-EEG uses three-dimensional analysis of many contacts placed into the
brain with stereotactic guidance with the aim of delineating the seizure
foci and the network of seizure propagation (FIGURE 4-3). Stereo-EEG stresses
the investigation of connectivity and spread with the goal of finding a node
where surgical intervention may be the most beneficial. It allows sampling of
deep cortical areas inaccessible with grids or strips. However, it lacks the spatial
continuity because the density of the electrodes cannot be as high as with grids. It

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DRUG-RESISTANT EPILEPSY

KEY POINT also relies heavily on the

implantation strategy with a
● Different surgical options
are available, including
preimplantation hypothesis.42,43
resection, laser ablation,
and neuromodulatory Trends
devices, with therapeutic
surgery tailored to the The grids and strips approach is
specific patient. favored when the epilepsy has
been lateralized and a high
likelihood of eloquent cortex
involvement exists.
The stereo-EEG approach is
favored when both hemispheres
need to be investigated; when the
likelihood of the patient needing
or agreeing to a craniotomy is low;
and when a deep structure such
as the mesial temporal lobe,
periventricular nodular
heterotopia, insula, or the
cingulate gyrus is hypothesized
as the culprit (TABLE 4-2).
A combination workup, while
technically demanding, is possible
with the placement of the
stereo-EEG electrodes first and
then proceeding to placement of
FIGURE 4-2
strips and/or grids. A combination
Grids and strips. A, Photograph of a craniotomy of the grid/strips and depth
and grid. B, X-ray of grid and strips. electrodes can also be used.

FIGURE 4-3
Stereo-EEG. A, Photograph of stereo-EEG electrode placement. B, X-ray of stereo-EEG
electrodes.

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THERAPEUTIC EPILEPSY SURGERY
Different surgical options are available, including resection, laser ablation, and
neuromodulatory devices (RNS, VNS, deep brain stimulation), with therapeutic
surgery tailored to the specific patient.
This section reviews case examples of each of the three surgical strategies, in
turn highlighting the advantages of each.

Resection
Resective surgery remains the gold standard against which all other procedures
are judged, as the majority of the randomized controlled trials were based on
this surgical method (CASE 4-1). The 2001 pivotal article by Wiebe and
colleagues20 outlined the benefits of surgical treatment and set up the number
needed to treat at two (only two patients need to undergo the procedure to make
a drastic difference in the life of one). This number compares favorably to many
other surgical procedures (eg, the number needed to treat for carotid
endarterectomy varies from 6 to 19.)44 Variations on the theme of resection
include callosotomy, hemispherectomy, and functional hemispherotomy, as
well as numerous disconnections designed specifically for the pathology
encountered. While beyond the scope of this article, the unifying theme of
these operations is localization of the seizure focus and its anatomic
(resection) or functional (disconnection, callosotomy) removal from the rest
of the functioning brain.

Thermal Ablation
If the seizure focus is deemed resectable without a significant decrease in
neuropsychological function or damage to another eloquent area such as
speech or motor areas, yet is difficult to get to with an open surgery, an
ablation may be performed. Such a procedure retains the minimally invasive
nature of the treatment while achieving comparable results to open resection
in well-selected patients.45 Data support improved neuropsychological function
after laser treatment compared to the open resection.29 Transcranial focused

Comparison of Stereo-Electroencephalography Versus Grids and Strips TABLE 4-2

Monitoring in the Evaluation of Patients with Epilepsy

Stereo-Electroencephalography in Preference to Grids or Strips

◆ Sulcal cortical areas including focal cortical dysplasia
◆ Deeply located cortical areas (eg, insulo-opercular complex, limbic system)
◆ Deep-seated or periventricular lesions such as hypothalamic hamartoma and
periventricular heterotopia
◆ Bilateral exploration
◆ MRI-negative patients
Grids or Strips in Preference to Stereo-Electroencephalography
◆ An extensive unilateral epileptogenic zone related to a lesion, requiring surface as well as
selected deep sampling
◆ Mapping the speech area when the epileptogenic zone is located within

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DRUG-RESISTANT EPILEPSY

ultrasound, an ultrasound-induced thermal ablation, may potentially be used

for treatment of epilepsy as well.46 While the success rate long-term may be
slightly lower than open resection, the option of trying this method first and
turning to more invasive surgery later is attractive to both patients and
practitioners. Such an approach may go a long way in breaking down the
barriers to the surgical treatment of epilepsy (CASE 4-2).

Neuromodulation
Patients with drug-resistant epilepsy with an epileptogenic focus located in
eloquent cortex are the most difficult to treat. As resection or ablation are not
valid options because of the potential damage to the patients’ function, these
patients have previously been relegated to continuing futile medical
management or placement of a vagal nerve stimulator with moderate efficacy in
seizure reduction (CASE 4-3).

CASE 4-1 A 58-year-old woman presented with a history of childhood-onset,

frequent, highly stereotyped, and brief nocturnal events characterized
by sudden awakening from sleep with a feeling of being in a trance and
having involuntary movements such as body rocking and grimacing,
typically lasting 10 to 15 seconds and clustering over 1 to 2 hours nightly.
Her seizures were highly medically refractory to trials of 10 different
antiepileptic drugs.
Brain MRI showed an area of focal left cingulate cortical thickening
with gray-white junctional blurring suspicious for focal cortical
dysplasia (FIGURE 4-4). Routine EEG was normal, and scalp-recorded
ictal video-EEG monitoring was nonlocalizing. Ictal single-photon
emission computed tomography (SPECT) demonstrated anterior
superior bifrontal hyperperfusion consistent with a possible focal
epileptogenic zone.
Stereo-EEG was implanted to cover the hypothesized areas of focal
seizure onset from the left hemisphere as determined by neuroimaging,
with contacts sampling predominantly from the left cingulate, frontal,
and insular regions. Several of her characteristic focal seizures with
altered awareness were captured (VIDEO 4-1, links.lww.com/CONT/
A274), which demonstrated highly stereotyped clinical behavior of
facial grimacing and oral and axial body rocking and writhing
automatisms. Ictal onset was consistently localized at the left
cingulate cortex, with nearly instantaneous spread to the left insular
region. Stereo-EEG demonstrated rhythmic sharp waves and fast
activity in contacts LN1-LN8, LY1-LY3, LZ21-LZ23, and LT4-LT6,
confirming ictal onset in the left cingulate region. A left cingulate focal
cortical resection demonstrated cortical type 2b dysplasia and has
rendered the patient seizure free at 2-year follow-up.

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 In 2013, the US Food and Drug Administration (FDA) approved a closed loop
responsive neurostimulation device for detection and treatment of drug-resistant
epilepsy. The latest 7-year data show a 72% mean reduction in seizure frequency.37
VNS remains an important tool for patients with generalized epilepsy or for
those who are not candidates for the previously described approaches. A recent
promising feature of VNS allows for the detection of cardiac rhythm and
stimulation based on this marker of possible seizure activity. The efficacy of VNS
does improve over time, with 60% of patients experiencing a significant
response (>50% seizure reduction), but the goal of seizure freedom is unlikely to
be attained with this therapy (8% seizure freedom after 2 years).38
Deep brain stimulation has been recently approved by the FDA for the
treatment of epilepsy. SANTE (Stimulation of the Anterior Nuclei of Thalamus
for Epilepsy), a multicenter, double-blind, randomized trial for patients with
drug-resistant focal epilepsy (n = 110), showed significant long-term seizure

FIGURE 4-4
Brain MRI of the patient in CASE 4-1 with drug-resistant focal cingulate epilepsy. Axial (A),
sagittal (B), and coronal (C) double inversion recovery sequences demonstrate subtle focal
thickening and blurring of the gray/white matter junction (arrows).
Courtesy of David B. Burkholder, MD; Jeffrey W. Britton, MD, FAAN; Elson L. So, MD, FAAN; Cheolsu Shin,
MD; Sotiris Mitropanopoulos, MD; Lily Wong-Kisiel, MD; Gregory A. Worrell, MD; Jamie Van Gompel, MD;
and Erik K. St. Louis, MD, MS, FAAN.

This case illustrates the utility of stereo-EEG in clarifying the epileptogenic COMMENT
zone, establishing that the brain MRI lesion was directly associated with
ictal onset of this patient’s habitual clinical seizures, and enabling the
surgical epilepsy team to pinpoint the boundaries of the surgical epileptic
focus necessary for producing an excellent outcome. Previously, patients
with similar presentations may have required widespread implantation of
subdural strip and grid electrodes, which pose risks of greater
perioperative morbidity. The advent of stereo-EEG has improved access
for offering surgical resections to patients with drug-resistant epilepsy
that can increase patients’ chances of becoming seizure free.
Case courtesy of David B. Burkholder, MD; Jeffrey W. Britton, MD, FAAN; Elson L. So, MD, FAAN;
Cheolsu Shin, MD; Sotiris Mitropanopoulos, MD; Lily Wong-Kisiel, MD; Gregory A. Worrell, MD;
Jamie Van Gompel, MD; and Erik K. St. Louis, MD, MS, FAAN.

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DRUG-RESISTANT EPILEPSY

CASE 4-2 A 27-year-old right-handed woman was referred for an evaluation at an

epilepsy center. She had a history of focal epilepsy since age 24, and her
seizures were described as feeling “cold, chilly, and scary” followed by
staring with unresponsiveness and lip smacking. Despite being on three
antiepileptic drugs, she continued to have one to three focal seizures with
impaired awareness per month. She reported having a depressed mood.
Three years prior, she had undergone video-EEG monitoring, which
showed occasional left temporal slowing and frequent left temporal sharp
waves as well as occasional left temporal rhythmic delta activity. A
previous brain MRI had been unremarkable; however, the MRI was not
done with a “seizure protocol.”
Given the EEG findings, a repeat brain MRI with thin cuts through the
temporal lobe was done at her current presentation, which revealed a left
temporal heterotopia involving the left temporal parahippocampal and
fusiform gyri (FIGURE 4-5A). A positron emission tomography (PET) scan
showed decreased metabolism in the lateral aspect of the left temporal
lobe. Repeat video-EEG monitoring was performed to characterize her
seizures, and two typical seizures were captured with left temporal onset.
Neuropsychological testing found deficits in attention and confrontation
naming, suggesting frontal or frontotemporal dysfunction, but did not
strongly lateralize. Wada testing confirmed left-sided language and
demonstrated poor left memory function (1/12 recall) and good right
memory function (10/12 recall).
She subsequently underwent left-sided stereo-EEG implantation with
electrodes in the hippocampus; amygdala; and orbitofrontal, posterior
temporal (following the course of the heterotopia), insular, and parietal
lobes. Three typical seizures were captured with left hippocampal onset,
and the contacts within the heterotopia were involved within 2 seconds of
the seizure onset (FIGURE 4-5B). She subsequently underwent laser ablation
of the left hippocampus and heterotopia (along the inferior aspect of the
temporal horn of the left lateral ventricle) (FIGURE 4-5C).
She was seizure free at her 1-year postoperative follow-up. She was
able to get a job, and her depressive mood improved significantly. At her
1-year follow-up neuropsychological testing, she showed improvements in
both learning and memory (eg, verbal immediate recall improved from
fourth to 13th percentile, and delayed memory improved from fourth to
42nd percentile). Gains in attention and concentration were also seen.

COMMENT In this patient, the seizure symptomatology and EEG findings raised
suspicion for a medial temporal–onset epilepsy, which prompted
additional imaging with attention to the medial temporal lobe, revealing a
left temporal heterotopia. To investigate the seizure onset zone, stereo-
EEG monitoring was planned, with a hypothesis that the seizure onset was
likely from the left medial temporal lobe within or along the heterotopia.
After confirming the patient’s seizure onset zone, laser ablation was
performed to access the deep location of the heterotopia and mesial
temporal lobe, rendering this patient seizure free.

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FIGURE 4-5
Imaging and EEG of the patient in CASE 4-2. A, Preablation coronal T1-weighted MRI
shows left temporal heterotopia involving the left temporal parahippocampal and
fusiform gyri (white arrows). B, Postablation coronal T2-weighted MRI after laser ablation
of the left hippocampus and left temporal heterotopia (white arrows). C, Stereo-EEG
showing seizure onset starting with left hippocampal fast rhythm followed by
hippocampal spike and low-voltage fast activity. Within 2 seconds, rhythmic beta
activity is seen in the heterotopia, lasting about 2 seconds (each location of the
contact is depicted). Seizures continue to evolve in the medial temporal region
(hippocampus and amygdala).
L HCP = left hippocampus.

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DRUG-RESISTANT EPILEPSY

CASE 4-3 A 37-year-old right-handed man

with a history of drug-resistant
epilepsy since the age of 2 was
referred to an epilepsy center.
His seizures started without
an aura, and witnesses had
described that he repeated
phrases like “go, go, go,”
became confused, and
sometimes walked into a
corner of the room. Despite
being on two antiepileptic
drugs, he had one bilateral
tonic-clonic seizure per month.
He was depressed.
His video-EEG showed
occasional left temporal sharp
waves, and two of his typical
seizures were captured with
left temporal onset. Brain
MRI with seizure protocol
was unremarkable. His
neuropsychological testing
showed frontotemporal
dysfunction, left worse than
the right. His Wada test
revealed left-sided language
and poor memory on both
sides, although memory on the
left (4/12) was better than the
right side (1.5/12). Given this
contradictory Wada test finding
and no obvious lesions seen on
FIGURE 4-6
MRI, he underwent bilateral Imaging and EEG of the patient in CASE 4-3.
stereo-EEG monitoring, Stereo-EEG electrode placements are shown (A).
including depth electrodes to Responsive neurostimulation device is placed with
both hippocampi and amygdala two leads into the bilateral hippocampi (B). Left
hippocampal–onset seizure (C, upper two lanes) is
(FIGURE 4-6A). Stereo-EEG detected, which triggered stimulation therapy with
showed frequent bilateral successful abolition of further seizure propagation.
hippocampal/amygdala Examples of left hippocampal–onset seizure (D)
epileptiform discharges, more and right hippocampal onset seizure (E) are shown.

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 frequent in the left than right, and two habitual seizures were captured
with the left hippocampal onset. A responsive neurostimulation device
was implanted to the bilateral hippocampi both as a long-term diagnostic
tool and as therapy (FIGURE 4-6B).
At his 1-year follow-up, his seizures had decreased from one
bilateral tonic-clonic seizure per month to three bilateral tonic-clonic
seizures in 1 year (FIGURE 4-6C); a left hippocampal onset seizure
was detected, which triggered stimulation therapy with successful
abolition of further seizure propagation. For 1 year, responsive
neurostimulation captured a total of 37 seizures, 26 from the left onset,
and two from the right (nine seizure onsets were not captured)
(FIGURE 4-6D and 4-6E). His responsive stimulation was recently revised to
stimulate one depth electrode in the left hippocampus and one strip in
the left lateral posterior temporal lobe.

This patient’s seizure symptomatology, EEG findings, and COMMENT

neuropsychological testing results indicated a left medial temporal lobe
epilepsy; however, brain MRI was nonlesional, and Wada testing showed
worse memory on the right side. Given the discordant data and long
duration of epilepsy, intracranial EEG monitoring was considered
necessary, and a responsive neurostimulation device was placed as both a
long-term diagnostic and therapeutic tool.

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DRUG-RESISTANT EPILEPSY

KEY POINT
● The efficacy of vagal
nerve stimulation improves
over time, with 60% of
patients experiencing a
significant response (>50%
seizure reduction), but the
goal of seizure freedom is
unlikely to be attained with
this therapy (8% seizure
freedom after 2 years).
reduction; by 2 years of bilateral stimulation, seizures were reduced by a median
56%, a 50% responder rate improvement occurred in 54% of patients, seizures
were less severe, and quality of life was improved.47
CONCLUSION
Drug-resistant epilepsy comprises one-third of all patients with epilepsy.
Drug-resistant epilepsy represents a life-threatening disorder. Epilepsy surgery is
an important and effective tool in patients with drug-resistant epilepsy, and any
patient who has recurrent seizures after adequate trials of two appropriately
chosen AEDs should be considered. Early identification of these patients and
timely referral to a comprehensive epilepsy center are critical. A thorough
presurgical evaluation by a multidisciplinary team and modern surgical
diagnostic and therapeutic approaches, including minimally invasive techniques,
can decrease the existing gap between evidence and practice, thus improving
the care of patients with epilepsy.

VIDEO LEGEND
VIDEO 4-1
Stereo-EEG of a 58-year-old woman with
drug-resistant focal cingulate epilepsy. Video
demonstrates rhythmic sharp waves and fast activity
in contacts LN1-LN8, LY1-LY3, LZ21-LZ23, and LT4-LT6,
confirming ictal onset in the left cingulate region.
links.lww.com/CONT/A274
© 2019 American Academy of Neurology

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