seizure control following palliative resective surgery for intractable epilepsy—a pilot study

Accepted Manuscript

“Seizure control following palliative resective surgery for intractable epilepsy – a pilotstudy”

Mohammed Ilyas , M.D, Resident in Pediatric Neurology Lalitha Sivaswamy , M.D,Associate Professor in Pediatrics and Neurology Eishi Asano , M.D, PhD., AssociateProfessor of Pediatrics and Neurology Sandeep Sood , M.D., Associate Professorof Pediatrics and Neurosurgery Marwan Zidan , Ph.D., Assistant Professor ofBiostatistics Harry Chugani , M.D., Professor of Pediatrics and Neurology

PII: S0887-8994(14)00281-1

DOI: 10.1016/j.pediatrneurol.2014.05.005

Reference: PNU 8359

To appear in: Pediatric Neurology

Received Date: 24 February 2014

Revised Date: 19 April 2014

Accepted Date: 4 May 2014

Please cite this article as: Ilyas M, Sivaswamy L, Asano E, Sood S, Zidan M, Chugani H, “Seizurecontrol following palliative resective surgery for intractable epilepsy – a pilot study”, Pediatric Neurology(2014), doi: 10.1016/j.pediatrneurol.2014.05.005.

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http://dx.doi.org/10.1016/j.pediatrneurol.2014.05.005

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Title Page

Title “Seizure control following palliative resective surgery for intractable epilepsy – a pilot study”

Manuscript Type: original research – resident track

Word count: 2550

Corresponding Author: Dr. Mohammed Ilyas, M.D

Resident in Pediatric Neurology

Wayne State University School of Medicine

Children’s Hospital of Michigan

3901 Beaubien Street

Detroit, MI - 48201

Phone- (312) 532 0223 / (313) 745-5788

Fax- (313) 745-0955

Email: [email protected]

Co –authors: 1. Lalitha Sivaswamy, M.D

Associate Professor in Pediatrics and Neurology

Carmen and Ann Adams Department of Pediatrics


3901 Beaubien Street, Detroit, MI - 48201



2. Eishi Asano, M.D, PhD.

Associate Professor of Pediatrics and Neurology

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3. Sandeep Sood, M.D

Associate Professor of Pediatrics and Neurosurgery






4. Marwan Zidan, Ph.D.

Assistant Professor of Biostatistics


Children’s Research Center of Michigan




5. Harry Chugani, M.D

Professor of Pediatrics and Neurology

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Declaration of Conflicting Interests

The authors declare no potential conflicts of interest with respect to the authorship and/or publication

of this article.

Financial disclosure

The authors received no financial support for the research and/or authorship of this article.

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Background: Patients with intractable epilepsy who have bilateral epileptic foci may not qualify

for curative epilepsy surgery. In some cases palliative resection may be undertaken with a goal

to decrease seizure frequency and improve quality of life. Here, we present data on the

outcome of palliative epilepsy surgery in children. Methods: We reviewed medical charts of

children who underwent palliative resection for intractable epilepsy during the years 1999-2013

at Children’s Hospital of Michigan. The palliative intent of resection was declared preoperatively.

Outcome was assessed in terms of seizure reduction. Results: There were 18 patients (11 males,

median age of surgery was 3.5 (range 0 – 16 years). The median duration of follow up after

surgery was 12.5 (range 6 – 60 months). Hemispherectomy was the most commonly performed

palliative resection (9 patients), followed by lobectomy (6 patients), multilobar resection (1

patient), and tuberectomy (2 patients). Reduction in seizure frequency was seen in 11 patients,

with 8 patients achieving seizure freedom on antiepileptic drugs, and 3 with more than 50%

reduction in seizure frequency. Transient improvement in seizure frequency occurred in 2

patients, whereas there was no benefit observed in 5 patients. Conclusions: We believe that

beneficial effects of epilepsy surgery may be realized in carefully selected situations wherein the

most epileptogenic focus is resected to reduce seizure burden and improve quality of life.

Key Words: Palliative resection, epilepsy surgery, intractable epilepsy, quality of life.

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Seizure control following palliative resective surgery for intractable epilepsy – a pilot study

Introduction:

Medically refractory epilepsy in children imposes a significant burden on children and their caregivers,

with their quality of life (QOL) negatively impacted in a multitude of ways. Current studies indicate that

reduction in the severity of seizures can have a positive effect on medical and social outcomes in this

patient population1. Curative epilepsy surgery

2, defined as surgery being performed with the intention

of complete resection of the presumed epileptogenic zone, is a viable option in many children with

intractable epilepsy resulting in overall seizure freedom between 60-80% of cases3, 4

. However, except

for certain notable exceptions such as tuberous sclerosis5, the majority of children with bilateral

epileptic foci are not perceived as appropriate candidates for resective surgery as the perceived risks of

surgery outweigh potential benefits. Palliative surgical options are often considered in such children

with the goal of minimizing the seizure burden. Common palliative procedures encompass multiple

subpial transections, corpus callosotomy and vagus nerve stimulation6, 7

, whereas ‘palliative resective

surgery’ has only recently been recognized as a promising approach. Palliative resective surgery, in

which the major epileptogenic focus is removed, is performed to achieve dual treatment goals of a

reduction in seizure frequency/severity and improve QOL. The extent of cortical resection is determined

case by case after extensive discussion regarding the pros and cons of surgical resection of such areas.

Previous studies by Ciliberto et al8 and Boshuisen et al

9 have described positive outcomes in small series

of children who underwent palliative hemispherectomy for intractable epilepsy. Yet, we still have

limited experience on seizure control following palliative resective surgery in the pediatric age group. In

the present study, we report the seizure outcomes in children who underwent palliative resective

surgery at a level 4 epilepsy specialty center10

.

Materials & Methods:

Identification of Patients and Data Collection

We performed a retrospective cohort study of all children who underwent resective surgery for

intractable epilepsy between June 1993 and June 2013 at the comprehensive epilepsy center of

Children's Hospital of Michigan in Detroit. We then selected those children who were considered

preoperatively to be palliative surgical candidates in view of seizure semiology, bilateral ictal EEG

abnormalities, and imaging findings. Collection of data was approved by the Wayne State University

Institutional Review Board.

The inclusion criteria were: children between the ages of 0 and 18 years who i) had intractable

epilepsy defined as failure to respond to adequate trials of multiple well-tolerated, appropriately chosen

antiepileptic drugs (AEDs) to achieve seizure freedom11

, ii) were shown to have bilateral epileptic foci on

ictal scalp video-electroencephalography (video-EEG), iii) underwent a palliative cortical resection for

epilepsy management including hemispherectomy, multilobar resection, lobectomy, and/or

tuberectomy, and iv) had a minimum follow up period of 6 months after the surgical procedure. The

exclusion criteria were: children who underwent corpus callosotomy or multiple subpial transections

alone.

Case Note Review

Demographic and clinical data of interest included: age, gender, race, age at the time of seizure onset,

and age at the time of surgery. Number of AEDs, underlying etiology, seizure semiology, seizure

frequency, types of palliative resection, post-operative complications, and pre- and postoperative

neurological examinations were noted as well.

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Electroencephalographic measures of interest included: interictal and ictal abnormalities on long-term

scalp video-EEG recording. Review of the standard pre-surgical evaluation was performed in all

patients12

. Seizure semiology was noted as "generalized tonic-clonic seizures", "epileptic spasms", "focal

seizures", and "status epilepticus".

Neuroimaging measures of interest included: magnetic resonance imaging (MRI) and positron

emission tomography (PET) of glucose metabolism. MRI was performed on 1.5-Tesla or 3.0-Tesla unit

magnets with T1-weighted sagittal SPGR (spoiled gradient-recalled echo), axial FLAIR (fluid attenuated

inversion recovery images), coronal FLAIR, DWI (diffusion weighted images), T2-weighted axial and

coronal sequences in all patients13

. Interictal glucose metabolism PET scans were obtained in all

patients, using the GE Discovery STE positron tomograph following IV administration of 18-fluoro-2-

deoxyglucose14

.

Assessment of Surgical Outcome

Surgical outcomes were assessed with respect to the following variables: 1) change in seizure

frequency as defined by number of seizures per day, and 2) number of AEDs that were utilized after the

surgical procedure in a follow up period ranging between 6 months and 60 months. Surgical outcome

was classified as “favorable” or “unfavorable” in the present study. A favorable outcome was defined as

(i) complete seizure freedom on AEDs or (ii) more than 50% reduction in seizure frequency. An

unfavorable outcome was defined as (i) less than 50% reduction of seizure frequency. We are fully

aware that the large variance in the follow-up period is certainly a limitation of the present study; thus,

we intended that the results be interpreted as preliminary data.

Statistical Analysis

Descriptive statistics were calculated to describe the study group. Means and standard deviations (SD)

for normally distributed continuous variables, median and range for skewed continuous variables,

frequencies and percentages for categorical variables, are presented. The study group was then divided

into subgroups based on different independent variables. Fisher’s exact test was used to compare

categorical variables between the subgroups and is valid for all sample sizes15

. Wilcoxon signed ranks

test was used to compare the total AEDs and the number of seizures before and after the surgery.

Surgical outcomes were correlated with demographics, etiology, surgery type and side of resection.

Statistical Package for Social Sciences 21 (SPSS Inc., Chicago, IL, USA) was used to conduct the statistical

analysis. P-value of ≤ 0.05 indicates a significant result.

Results:

A total of 462 patient charts were reviewed spanning the time period from 1993-2013. Palliative

surgery had been performed in 18 patients (3.9 %). [Please see Table 1 for demographic data]. The

median and the range for follow up period for this small cohort were 12.5 and (6 – 60) months. There

was no significant association between demographic variables and seizure outcome following palliative

resection.

Post-operative seizure control

Reduction in seizure frequency was observed in 11/18 (61.1%) patients, with 8/18 (44%) children

achieving seizure freedom for the period of follow up (ILAE Class 116; patients #2, #4, #6, #8, #10, #13,

#16, and #18 in (Table 2), and 3 experiencing more than 50% reduction in seizure frequency (ILAE class

4; patients #12, 14 and 17). Transient improvement in seizure frequency occurred in 2 patients (patients

#1 & #3), as they were seizure-free for a period of 6 months but experienced seizure recurrence later.

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These patients did have a <50% decrease in their baseline seizure frequency, when the seizures

recurred. Taken together, patients #2, #4, #6, #8, #10, #12, #13, #14, #16, #17 and #18 were classified as

having ‘favorable outcome’, while the remaining patients were classified as ‘unfavorable outcome’.

No benefit was observed in 5 patients (patients #1, #3, #9, #11 and #15), one of whom (#15) had

worsening of seizures (ILAE class 6). Long-term follow up of these five children revealed that one of

them (#9) underwent implantation of vagus nerve stimulator 4 years after surgery and that two patients

(#11 and #15) were placed on ketogenic diet 1 year after surgery. The median number of AEDs used pre-

operatively was 4 (2-7), and declined to 2.5 (1-4) post-operatively (p=0.007).

Nature of surgery and relationship to post-operative seizure control

Hemispherectomy was the most commonly performed palliative surgical procedure (9/18, 50%),

followed by single lobe resection (6/18, 33.3%), multilobar resection (1/18, 5.5%), and tuber resection

(2/18, 11%). Multiple subpial transections were performed in addition to cortical resection in patients

#3, #6, and #8 while corpus callosotomy was added in patients #6 and #7 (Table 2). Of the 9 patients

who underwent hemispherectomy, 5 (55.6%) had a favorable outcome. Seven patients underwent

lobectomy, and 5 (71.4%) had favorable outcome. Fisher’s exact p-value obtained was 0.633.

Seizure Semiology and relationship to post-operative seizure control

In 10 patients who experienced multiple seizure types, 6 (60%) had a favorable outcome. In 4 children

with seizure semiology defined as infantile spasms, 3 (75%) had favorable outcomes which is not

statistically significant. One child who presented with status epilepticus and underwent urgent resective

surgery had a favorable outcome.

Etiology of epilepsy and relationship to post-operative seizure outcomes

Based on the MRI assessment, the underlying etiology in the study population included non-lesional

epilepsy (38.9%), cortical dysplasia (16.6%), tuberous sclerosis (16.6%), bilateral hippocampal sclerosis

(5.5%), traumatic brain injury (5.5%), hemorrhagic stroke (5.5%), viral encephalitis (5.5%) and a large

arachnoid cyst (5.5%).

Of the 11 patients with lesions, 9 (81.8%) had a favorable outcome, while out of 7 non-lesional cases, 2

(28.6%) had a favorable outcome. A p-value of 0.049 was obtained using Fisher’s exact test.

The pathology in 7 patients with non-lesional epilepsy (as defined by imaging) showed cortical

dysplasia in 3. In 6 patients identified as having cortical dysplasia by imaging or pathology, 4 had

favorable outcome. All other identifiable etiologies including bilateral hippocampal sclerosis, traumatic

brain injury, large arachnoid cyst, viral encephalitis and hemorrhagic stroke had favorable outcome.

[Please see Figure 1 for MRI brain, PET scan, EEG and histological findings of patient #17]

Side of surgery and relationship to post-operative seizure outcomes

Of the 18 patients, an equal number of children underwent surgery on the right and left hemispheres.

Favorable outcome was noted in 7/9 (77.7%) right hemispheric and in 4/9 (44.4%) left hemispheric cases

but the difference failed to reach statistical significance (p=0.34 on the Fisher exact test).

Time of surgery from seizure onset and relationship to post-operative seizure outcomes

Six patients (30%) had surgery within 1 year of seizure onset and 5 children (83%) had a favorable

outcome. On further analysis, nine patients (50%) had surgery within 2 years of seizure onset and 7

children (77.7%) had a favorable outcome. Therefore, it appears that patients who had epilepsy surgery

performed earlier in their disease process (within one or two years of seizure onset) had relatively

better outcomes with seizure reduction, but the difference failed to reach statistical significance.

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Discussion:

Palliative surgery can be undertaken in children with the goal of decreasing seizure frequency and

thereby improving QOL when medical treatment fails to adequately control their seizures. In our study,

patients with multifocal ictal onset with seizures arising from bilateral cortical foci at different

frequencies were selected. Surgery was performed to remove the most epileptogenic focus with the

hope of reducing seizure burden and improving QOL. From our preliminary study, with a small series of

patients, we noted that that palliative surgery appears to reduce the number of seizure despite the

absence of pre-operative factors that traditionally would predict seizure freedom, e.g. epileptic

discharges confined to one hemisphere or focal hemispheric epileptogenic brain lesions on imaging.

The overall seizure freedom rate of 44% in the present study is comparable to the average seizure

freedom noted in meta-analyses of various epilepsy surgeries performed at different centers reported

by Tellez-Zenteno et al2. They noted that patients who underwent temporal, extratemporal resections

and hemispherectomy for “curative” surgery had seizure free rates of 66%, 42% and 61%, respectively.

In our study, the outcome in terms of seizure freedom was less robust than in a carefully selected cohort

of children with strictly localized hemispheric pathology wherein, hemispherectomy resulted in seizure-

free rates of 70–80%17, 18

. It was somewhat surprising that 44% of our patients became seizure free after

what was considered to be a palliative resection. A reasonable explanation is that we had targeted the

major epileptic focus which was refractory to AEDs, while a contralateral ‘minor’ focus might have been

suppressed by AEDs and only uncovered during preoperative video-EEG monitoring when AEDs are

discontinued in order to capture seizures. The other possible reason for this apparent “success” might

be the fact that we did not have long term follow up which might have resulted in a relapse of epilepsy

at a later date19, 20

. As the burden of epilepsy is reduced, patients require fewer antiepileptic

medications and therefore experience reduced undesirable side effects. Halting developmental

regression because of persistent seizures should influence earlier intervention in children and better

seizure control, whenever possible21

.

In this study, the underlying etiology of the epilepsy predicted the surgical outcome. Those who had

no evidence of cortical dysplasia on pathological examination of the resected tissue were more likely to

have poor seizure outcome. Patients found to have either cortical dysplasia or tuberous sclerosis tended

to have a better long term seizure outcome. Out of the 11 patients who had a favorable outcome, 9 had

an identifiable abnormality on MRI and 2 had nonlesional etiology but their pathology showed cortical

dysplasia. This is in keeping with the findings of Tellez-Zenteno et al22

who found the odds of being

seizure free after surgery was 2.5 times higher in patients with lesions on MRI or histopathology

compared to nonlesional cases. A possible explanation is that a cortical lesion may be substantially

contained within the epileptogenic cortex, serving as a marker of the area to be resected, and allowing

for a more effective resection. Also, patients with MRI lesions may be considered for surgery earlier. A

shorter time period between onset of epilepsy and time of surgery may entail a better outcome. Fauser

et al., in a study of 67 patients, found that the postsurgical seizure outcome ranged from 43-67 % (Engel

class Ia) depending on the type of focal cortical dysplasia23, 24

. Our study showed a similar result with 4

out of 6 patients (66.6%) who showed cortical dysplasia having a favorable outcome. The variable result

in focal cortical dysplasia could be due to inadequate removal of the entire epileptogenic zone which

may extend beyond the boundaries of the MRI lesion25, 26, 27.

Favorable outcome was noted in 7 out of 9 patients who had surgery within two years of seizure

onset, which is consistent with previous studies where early relief from catastrophic epilepsy may allow

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resumption of developmental progression during critical stages of brain maturation. Delaying surgery,

on the other hand, may be associated with psychosocial, behavioral, and educational difficulties28, 29, 30

.

Better QOL generally paralleled good seizure outcomes in several previous studies31, 32, 33, 34

where QOL

was significantly better in children with seizure free outcomes than in children who were not seizure

free. Persistence of impairment in QOL after epilepsy surgery can be attributed to preexisting abnormal

neural substrates or to poor control of seizures after surgery35

.

Seven patients had unfavorable outcomes with little improvement in seizure frequency. Four of these

patients had nonlesional etiology and their pathology showed only gliosis. Nonlesional epilepsy surgery

cases even with a single EEG ictal focus are considered to be a difficult group in most centers, and it is

therefore not surprising that improvement was not achieved in these 4 patients. In contrast, Fischer

exact test indicated that the presence of lesion on MRI was associated with “favorable outcome”;

several other factors assessed were not statistically significant. Clearly, further studies are warranted to

determine if these factors can predict a better surgical outcome in such patients.

Limitations of our study include its retrospective design, small sample size and short duration of

follow-up. Larger prospective studies with multicenter collaboration could reveal clinically relevant

associations and correlate presurgical variables with outcomes.

The success of a decision to offer palliative surgery to some patients will depend on appropriate

selection of candidates with clear preoperative objectives for better outcome. We believe that beneficial

effects of epilepsy surgery may be realized in carefully selected situations wherein the most

epileptogenic focus is resected to reduce seizure burden and improve quality of life36

.

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Table 1: Table 1 depicts the demographic data of subjects.

Abbreviations used in Table 1:

% = percentage, n = number

Table 2: Table 2 summarizes the profile of 18 subjects who underwent palliative resective

surgery.

Abbreviations used in Table 2:

S.No = Serial number; M = male; F = female; Sx = surgery; R = right; L = left; n = number; yr =

year; AEDs = antiepileptic drugs; Pre-op = pre-operative; Gen = generalized; BG = background;

SW = spike and wave; b/l = bilateral; m/f = multifocal; Fr = frontal; T = temporal; T-O =

temporo-occipital; C = central; P = parietal; O = occipital; TBI = traumatic brain injury; CD =

cortical dysplasia; TS = tuberous sclerosis; N/L = Non Lesional; Ch. = chronic; * subpial

transections; ^ corpus callosotomy. Ψ ILAE class [8] 1) Completely seizure free; no auras, 2)

Only auras; no other seizures, 3) 1-3 seizure days per years; +/- auras, 4) 4 seizure days per year

to 50% reduction of baseline seizure days; +/- auras, 5) <50% reduction of baseline seizure days

to 100% increase of baseline days +/- auras, 6) >100% increase of baseline seizure days; +/-

auras.

Figure 1: highlights characteristics of patient #17.

Abbreviations used in Figure 1:

A. Axial T2 weighted magnetic resonance image shows no detectable abnormality.

B. The ictal FDG-PET scan shows increased activity in the right parietal and temporal lobes with

very active uptake of FDG.

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C. EEG is showing fast wave activity in the right occipital region followed by rhythmic theta wave

activity in the right parietal occipital temporal involving T6, PZ, and OZ (arrow).

D. EEG is demonstrating fast wave activity in the left occipital region involving O1 (arrow)

followed by diffuse background attenuation and rhythmic theta activity in the left temporal

region involving T3 and T5 (arrow).

E. Neurofilament protein (NFP, 40X) highlights normal laminar pattern of cortex.

F. NFP stain (40X) demonstrates irregular staining of dysplastic architecture of cortex with

obscured lamination.

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Table 1

Summary of patient demographics

Female gender, n (%)

7 (38.8%)

Ethnicity

Caucasians, n (%)

African Americans/Others, n (%)

12 (66.6%)

6 (33.3%)

Age of seizure onset, years

Median (Range)

0.5 (0.2-15)

Age of surgery in years

Median (Range)

3.5 (0.5-16)

Duration between seizure

onset and surgery in years,

Median (Range)

2 (0.1-14)

Follow up in months

Median (Range)

12.5 (6-60)

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

Table 2

S.No Gender,

Surgery

age (yr)

Nature of surgical

procedure

Seizure type Number of

AEDs

Seizure/day

(n)

Seizure

class (Ψ)

Pre -op

EEG

Imaging Pathology

Prior

to sx

1 yr

of sx

Pre Post

1 F, 3 L Hemispherectomy Focal, Gen,

Spasms.

7 2 10 5 5 b/l C-P-T SW CD CD

2 M, 13 R Fr Lobectomy Focal, Gen 2 2 0.5 0 1 b/l Fr-C SW N/L CD

3 M, 1 R Hemispherectomy* Spasms 5 4 5 3 5 b/l T SW N/L CD

4 M, 2 R Hemispherectomy Spasms 6 1 2 0 1 m/f SW CD CD

5 M, 16 R Fr Lobectomy Focal 5 4 0.5 0.5 5 b/l Fr SW N/L Gliosis

6 F, 16 L Fr Lobectomy *^ Focal, Gen 6 1 5 0 1 b/l Fr SW TBI Gliosis

7 F, 9 L Tuberectomy ^ Focal, Gen 2 2 10 5 5 Slow BG TS Tuber

8 M, 8 R Fr Tuberectomy Spasms 6 3 10 0 1 b/l Fr-T SW

TS Tuber

9 F, 4 L Hemispherectomy Focal 4 3 5 5 5 m/f SW N/L Gliosis

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

10 F, 2 R Hemispherectomy Spasms 4 1 5 0 1 b/l O SW Hemorrhagic

stroke

Porencephaly,

Gliosis

11 M, 3 L Hemispherectomy Focal, Gen 3 2 2 1 5 Gen SW N/L Gliosis

12 M, 6 L T-O Lobectomy S.E 5 4 -- 0.1 4 b/l T-C SW Viral

encephalitis

Ch. Inflammation,

Gliosis

13 M, 9 R Hemispherectomy Focal 3 2 1 0 1 b/l T-O SW TS Tubers

14 F, 0.5 R T Lobectomy Focal ,

Spasms

4 2 5 0.1 4 m/f SW Arachnoid

cyst

Hippocampal

Gliosis

15 M, 2 L T Lobectomy Focal, Gen 3 4 2 5 6 Slow BG. b/l

SW

N/L Gliosis

16 M, 2 L T Lobectomy Focal, Gen 4 3 10 0 1 b/l Fr-T

slowing

Bi-temporal

sclerosis

Gliosis

17 M, 0.5 R Hemispherectomy Focal 4 4 20 1 4 m/f SW N/L CD

18 F, 5 L Hemispherectomy* Focal ,

Spasms

7 2 20 0 1 b/l C-P-T SW CD CD

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

seizure control following palliative resective surgery for intractable epilepsy—a pilot study

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