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Different features of histopathological subtypes of pediatric focal cortical dysplasia.

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Different Features of Histopathological
Subtypes of Pediatric Focal Cortical
Dysplasia
Pavel Krsek, MD, PhD,1 Bruno Maton, MD,2 Brandon Korman, PsyD,3 Esperanza Pacheco-Jacome, MD,4
Prasanna Jayakar, MD, PhD,2 Catalina Dunoyer, MD,2 Gustavo Rey, PhD,3 Glenn Morrison, MD,5,6
John Ragheb, MD,5,6 Harry V. Vinters, MD, PhD,7 Trevor Resnick, MD,2,8 and Michael Duchowny, MD2,8
Objective: Focal cortical dysplasia (FCD) is the most frequent pathological finding in pediatric epilepsy surgery patients. Several
histopathological types of FCD are distinguished. The aim of the study was to define distinctive features of FCD subtypes.
Methods: We retrospectively reviewed clinical, electroencephalographic, magnetic resonance imaging, neuropsychological, and
surgical variables, and seizure outcome data in 200 children. Cortical malformations were histopathologically confirmed in all
patients, including mild malformation of cortical development type II (mMCD) in 36, FCD type Ia in 55, FCD type Ib in 39,
FCD type IIa in 35, and FCD type IIb in 35 subjects.
Results: Perinatal risk factors were more frequent in mMCD/FCD type I than FCD type II. Children with FCD type IIb had
more localized ictal electroencephalographic patterns and magnetic resonance imaging changes. Increased cortical thickness,
abnormal gyral/sulcal patterns, gray/white matter junction blurring, and gray matter signal abnormality in fluid-attenuated
inversion recovery and T2-weighted sequences occurred more often in FCD type II, were infrequent in FCD type I, and rare
in mMCD. Lobar hypoplasia/atrophy was common in FCD type I. Hippocampal sclerosis was most frequent in FCD type I.
Neuropsychological testing demonstrated no significant differences between the groups. There was a trend toward better surgical
outcomes in FCD type II compared with FCD type I patients.
Interpretation: Different histopathological types of mMCD/FCD have distinct clinical and imaging characteristics. The ability
to predict the subtype before surgery could influence surgical planning. Invasive electroencephalographic study should be considered when mMCD/FCD type I is expected based on noninvasive tests.
Ann Neurol 2008;63:758 –769
Focal cortical dysplasia (FCD) is the single most important cause of focal intractable epilepsy in childhood.
It is histopathologically proved in at least 20% of patients in adult epilepsy surgery series1–3 and in almost
50% of children undergoing surgical therapy for epilepsy.4 – 8 The true prevalence of FCD in patients with
epilepsy is unknown; recent epidemiological studies
identified malformations of cortical development in up
to 25% of all children with symptomatic epilepsy.1,9,10
Taylor and colleagues11 were among the first to describe distinctive abnormalities of cortical structure that
we now recognize as severe (type IIb) FCD. FCD was
originally viewed as a histologically uniform entity. It
was subsequently classified into two subtypes according
to the presence or absence of balloon cells (“Taylor”
and “Non-Taylor” types).12,13 There is, however,
growing evidence to suggest that histopathological abnormalities in FCD are more diverse and constitute a
continuum of specific gross architectural and cytoarchitectural features.
Several classification schemes of cortical malformations have been proposed based on imaging characteristics, genetics, and neuropathology.13–18 Palmini and
Lüders19 proposed the most frequently used histological classification, and it was recommended by an expert
panel.20 It divides FCD into three major subtypes:
mild malformation of cortical development (mMCD),
FCD type I, and FCD type II. Two further subcategories are recognized within each of the types: mMCD
type I, mMCD type II, FCD type Ia, FCD type Ib,
FCD type IIa, and FCD type IIb. Several studies reported different electroclinical and imaging characteris-
From the 1Department of Pediatric Neurology, Charles University,
Second Medical School, Motol University Hospital, Prague, Czech
Republic; 2Neurology and Comprehensive Epilepsy Program, Brain
Institute; 3Neuropsychology Section, Brain Institute and Behavioral
Medicine; Departments of 4Radiology and 5Neurological Surgery,
Brain Institute, Miami Children’s Hospital; 6Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL;
7
Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, Los Angeles, CA;and 8Department of Neurol-
ogy, University of Miami Miller School of Medicine, Miami, FL.
758
Received Oct 6, 2007, and in revised form Feb 10, 2008. Accepted
for publication Feb 19, 2008.
Address correspondence to Dr Krsek, Department of Pediatric Neurology, Charles University, Second Medical School, Motol University Hospital, V Uvalu 84, CZ 15006 Prague 5, Czech Republic.
E-mail: pavel.krsek@post.cz
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
tics, as well as seizure outcomes, in individual histopathological groups of FCD. However, selection bias
and the methodology of previous studies render these
categories controversial. Several studies included not
only FCD, but also other cortical malformations including polymicrogyria, nodular neuronal heterotopia,
and tuberous sclerosis.15,21 Other studies focused only
on FCD type II.22–26 Nevertheless, studies analyzing
the entire spectrum of FCD patients have reached controversial results, especially regarding seizure outcome.6,18,27–32 There have been no studies to date that
have analyzed mMCD outside the temporal lobes.
This study aims to analyze clinical, electroencephalographic (EEG), magnetic resonance imaging (MRI),
neuropsychological, surgical, and seizure outcome data
in a large cohort of children with histologically proven
mMCD/FCD. Our goal was to identify distinctive
characteristics of individual subtypes to achieve earlier
diagnosis and enhance surgical management.
Subjects and Methods
Inclusion Criteria
All patients who underwent resective epilepsy surgery at the
Miami Children’s Hospital from March 1986 to June 2006
were retrospectively analyzed. We included only subjects
with a confirmed histopathological diagnosis of mMCD/
FCD in the study. Children with tuberous sclerosis complex,
benign developmentally based brain tumors such as ganglioglioma and dysembryoplastic neuroepithelial tumor, polymicrogyria, nodular heterotopia, Sturge–Weber syndrome, and
hemimegalencephaly were excluded. Hippocampal sclerosis
(HS) may have been present in a given case. Patients with an
inadequate surgical specimen preventing reliable histopathological review and/or classification of a cortical malformation
(n ⫽ 6) were also excluded.
Neuropathological Analysis and Classification
Brain tissue analysis was performed at the Department of
Pathology, Miami Children’s Hospital (Miami, FL; 1986 –
2003) and at the Department of Pathology and Laboratory
Medicine (Neuropathology), David Geffen School of Medicine at University of California Los Angeles (Los Angeles,
CA; 2003–2006). The same neuropathological methodology
was used at both institutions and has been reported in detail
previously.14,26
All neuropathological findings were reclassified according to
the current classification scheme19,20 (Fig 1). mMCD was
characterized by normal cortical architecture and abundant ectopically placed neurons in or adjacent to layer 1 (mMCD
type I) or in the white matter (mMCD type II). There were
no patients with ectopic neurons located only in or adjacent to
layer 1 in our series; all of our mMCD cases were therefore
classified as mMCD type II. Ectopically placed neurons in the
white matter were immunohistochemically identified by
NeuN, and their number was semiquantitatively estimated.
The presence of a small number of ectopic neurons in the
temporal lobe was not regarded as a significant pathological
finding. Architectural cortical abnormality was present in all
Fig 1. Histopathological findings in different types of mild
malformation of cortical development/focal cortical dysplasia
(mMCD/FCD). Hematoxylin and eosin staining is used in all
panels. (A) mMCD type II characterized by abundant heterotopic white matter neurons (arrows). (B) FCD type Ia defined
by abnormal neuronal polarity and clustering of neurons, especially at right of the image. (C) FCD type Ib. Micrograph
shows neuronal disorganization and scattered enlarged neurons
(arrow). (D) FCD type IIa defined by neuronal disorganization, abnormal clustering of neurons with abnormal polarity,
and moderately dysmorphic neurons. (E) FCD type IIb. Micrograph shows severe neuronal disorganization and smaller
dysmorphic neurons scattered among typical balloon cells (arrows). (F) FCD type IIb at high magnification. Arrows highlight very dysmorphic neurons.
subjects with FCD. FCD type Ia was defined as architectural
disturbance with microcolumnar arrangement of cortical neurons, usually together with an increased number of ectopic
white matter neurons. In FCD type Ib, minor cellular abnormalities (giant or immature but not dysmorphic neurons) were
present together with the cortical dyslamination. FCD type II
included more pronounced architectural and cytoarchitectural
disturbances such as dysmorphic neurons (FCD type IIa) and
additional balloon cells (FCD type IIb).
Clinical Data
Demographic and clinical variables were obtained at the time
of admission for epilepsy surgery. Patients underwent a comprehensive preoperative evaluation that always included 32channel scalp video-EEG and MRI scan. A majority of cases
had thorough neuropsychological testing. Selected children
also underwent additional diagnostic tests including positron
emission tomography, single-photon emission computed tomography, functional MRI, and intracarotid sodium amytal
testing; evaluation of these results was not included in this
study.
Electroencephalographic Evaluation
Scalp EEG data were reviewed from epilepsy monitoring
unit evaluation reports. Standard 10-20 system of electrode
placement was used in all patients; additional electrodes were
Krsek et al: Pediatric Cortical Dysplasia
759
applied whenever more precise localization was required. Invasive EEG data were not analyzed in this study.
Magnetic Resonance Imaging Evaluation
MRI scanners and protocols varied during the period of this
study as new techniques became available. Children operated
on before June 1992 were examined using 0.3T magnetic
resonance (MR) imager. From June 1992, an MR scanner
with a 1.5T strength field was used for the acquisition of all
MRI, and fluid-attenuated inversion recovery (FLAIR) sequences were obtained routinely in all epilepsy patients.
Only subjects with a good-quality presurgical MRI scan performed on a 1.5-T MR imager (n ⫽ 154) were included in
the MRI study. The remaining 46 children were either examined using a 0.3T scanner or had no available presurgical
MRI. MRI data were reevaluated independently by three experienced investigators (P.K., B.M., E.P.-J.) who were aware
of the pathological diagnosis but were not informed about
the subtype. Discrepancies between the reviewers led to a
case being re-reviewed together until a consensus was
reached. If disagreement remained, the MRI feature in question was omitted from the analysis.
Neuropsychological Evaluation
Intellectual test results and/or overall adaptive functioning
questionnaires of the patients were reevaluated and rated by
two independent experts in the psychological assessment of
children with neurocognitive disorders (B.K., G.R.). A total
of 133 of 200 children had available presurgical psychometric data (ie, intellectual, cognitive, or adaptive functioning).
Cases without available quantitative data were excluded from
this ranking process. In 122 cases, neuropsychological testing
was performed at our neuropsychological department. The
remaining 11 children underwent comprehensive neuropsychological evaluation at another institution. Global functional ranking was determined for purposes of this study. We
used this unified global parameter because heterogeneous
neuropsychological batteries had been utilized over the years
in the assessment of cases and also because some of the subjects could not be examined with common psychometric instruments because of pervasive intellectual or developmental
impairments. The categories for rankings were based on
Standard Scores on the instruments surveyed as follows:
Ranking 1: moderate-to-severe impairment, intelligence quotient [IQ] ⱕ 59; Ranking 2: mild impairment, IQ 60 to 69;
Ranking 3: borderline intelligence, IQ 70 to 79; Ranking 4:
low average intelligence and above, IQ ⱖ 80.
Surgery
All patients underwent at least one excisional procedure at the
Department of Neurological Surgery, Miami Children’s Hospital. Five subjects underwent previous surgery at other institutions. Decisions regarding surgery and the type of procedure
were made at interdisciplinary case conferences based on seizure semiology, neurological status, interictal and ictal EEG,
and neuroimaging findings. In patients with negative MRI results, surgery was offered only when there were sufficient data
to assume that only one hemisphere was epileptogenic. All patients with negative MRI results underwent invasive EEG recording using subdurally placed electrodes.
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Postoperative Follow-up and Outcome
Postoperative seizure status 2 years after the final surgery was
analyzed. Seizure outcome was assessed during outpatient visits and telephone contact. Patients lost for follow-up or those
with a follow-up period shorter than 2 years (n ⫽ 51) were
excluded from the outcome analysis; we therefore evaluated
seizure outcome in 149 of 200 subjects. Surgical outcome
was classified according to Engel’s classification scheme: I ⫽
completely seizure free, auras only or only atypical early postoperative seizures; II ⫽ ⱖ90% seizure reduction or nocturnal seizures only; III ⫽ ⱖ50% seizure reduction; and IV ⫽
more than 50% seizure reduction.
Statistical Analysis
The primary statistical procedure used to evaluate the relation between pathological subtype (ie, mMCD, FCD type
Ia, FCD type Ib, FCD type IIa, and FCD type IIb) and a
variety of profile variables (eg, clinical, EEG, and MRI features) was contingency table analysis. Overall independence
between the rows and columns of a particular table was evaluated with an overall ␹2 statistic. When appropriate (ie, ordered categories), the Cochran–Armitage test for trends was
also applied. If the outcome was binomial, and the overall ␹2
statistic indicated a lack of independence, follow-up procedures were based on normal approximation (ie, least significant difference). If the outcome was multinomial, examination of the residual pattern and/or the collapsing/omission of
categories was used to determine the likely categories of the
contingency table that were creating the lack of independence. Although none of the tables was extremely sparse (ie,
expected values ⬍ 1.0), some did have expected values less
than 5. In addition, all p values were determined using exact
statistical methods (StatExact-5; Cytel Software Corporation,
Cambridge, MA). ␹2 results are given in the following form:
␹2 (value of the ␹2 statistic), p value.
Results
From an epilepsy surgery database of 567 patients
(1986 –2006), 200 subjects (82 female and 118 male
subjects) met the earlier-mentioned criteria. The population included 192 children and adolescents (younger
than 20 years) and 8 young adults (aged 20 –25 years).
There were 36 subjects with a pathological classification of mMCD type II, 55 had FCD type Ia, 39 had
FCD type Ib, 35 had FCD type IIa, and 35 had FCD
type IIb. A total of 60 clinical, neuropsychological,
EEG, MRI, surgical, and seizure outcome variables
were compared between the groups.
Clinical and Demographic Data
Data concerning history, neurological findings, and seizure characteristics are shown in Table 1. Prenatal and
perinatal risk factors (such as severe prematurity, asphyxia, bleeding, hydrocephalus) were significantly
more common in mMCD/FCD type I than in FCD
type II (mMCD 17%, FCD type Ia 24%, FCD type
Ib 13%, FCD type IIa 0%, FCD type IIb 6%; ␹2 ⫽
Table 1. Clinical Data and Neurological Findings in Patients
Characteristics
mMCD
(n ⴝ 36)
FCD Type Ia
(n ⴝ 55)
FCD Type Ib
(n ⴝ 39)
FCD Type IIa
(n ⴝ 35)
FCD Type IIb
(n ⴝ 35)
Risk factors for epilepsy, n
(%)
Family history of epilepsy
4 (11)
9 (16)
2 (5)
2 (6)
3 (9)
Perinatal adverse events
6 (17)
13 (24)
5 (13)
0 (0)
2 (6)a
Febrile seizures
2 (6)
4 (7)
1 (3)
0 (0)
1 (3)
Head trauma
3 (8)
2 (4)
0 (0)
0 (0)
0 (0)
CNS infection
3 (8)
2 (4)
2 (5)
0 (0)
1 (3)
11 (31)
20 (36)
15 (38)
13 (37)
8 (23)
Neurological status, n (%)
Abnormal neurological
finding
Hemiparesis
4 (11)
14 (25)
7 (18)
11 (31)
7 (20)
Other neurological
deficitsb
8 (19)
10 (18)
10 (26)
5 (14)
5 (14)
3.2 (0.1–12)
2.4 (0.1–9)
Mean age at seizure onset,
yr
3.7 (0.1–13)
2.9 (0.1–10)
2.2(0.1–14)
Incidence of individual
seizure types, n (%)
Infantile spasms
1 (3)
8 (15)
7 (18)
9 (26)
5 (14)
First seizure with fever
3 (8)
9 (16)
2 (5)
1 (3)
2 (6)
Simple partial
5 (14)
5 (9)
3 (8)
4 (11)
2 (6)
Complex partial
31 (86)
48 (87)
32 (82)
31 (89)
31 (89)
SGTCS
15 (42)
19 (35)
15 (38)
12 (34)
5 (14)
6 (17)
15 (27)
13 (33)
9 (26)
7 (20)
25 (69)
38 (69)
28 (72)
29 (83)
31 (89)
Status epilepticus
Seizure frequency, n (%)
Patients with daily
seizures
Mean age at (first) surgery,
yr
11.9 (1.6–23.5)
11.9 (1.6–24.5)
9.5 (0.2–24.5)
9.4 (0.2–20.1)
7.1 (0.1–20.8)
Mean duration of epilepsy,
yr
8.3 (1.4–23.3)
8.8 (1.3–24.1)
7.0 (0.2–19.5)
6.9 (0.2–20.1)
4.7 (0.1–15.8)
If p ⬍ 0.05.
Such as hypotonia, ataxia, microcephaly, and quadriparesis.
mMCD ⫽ mild malformation of cortical development; FCD ⫽ focal cortical dysplasia; CNS ⫽ central nervous system; SGTCS ⫽
secondarily generalized tonic-clonic seizures.
a
b
12.80; p ⫽ 0.0115). There were no other differences in
clinical parameters among histopathological groups.
63%; ␹2 ⫽ 12.41; p ⫽ 0.0140). There were no group
differences in the incidence of other EEG variables.
Electroencephalography
Scalp EEG results are shown in Table 2. Only six patients in the series had a normal interictal EEG. We
found one statistically significant group difference: Ictal
patterns were more frequently regional (precisely localized) in mMCD and FCD type IIb patients compared
with other groups (mMCD 58%, FCD type Ia 40%,
FCD type Ib 33%, FCD type IIa 31%, FCD type IIb
Magnetic Resonance Imaging
Results of the reevaluation of MRI findings in 154
subjects with good-quality presurgical scans are given
in Table 3 (Fig 2). Thirty-eight patients (25%) had
normal MRI scans. Normal MRI findings were significantly more frequent in the mMCD group than in
FCD type Ia and Ib or FCD type IIa and IIb groups
(␹2 ⫽ 15.89; p ⫽ 0.0029). A total of 34 children
Krsek et al: Pediatric Cortical Dysplasia
761
Table 2. Scalp Electroencephalographic Findings in Patients
Characteristics
mMCD
(n ⴝ 36)
Normal interictal EEG, n (%)
FCD Type Ia
(n ⴝ 55)
FCD Type Ib
(n ⴝ 39)
FCD Type IIa
(n ⴝ 35)
FCD Type IIb
(n ⴝ 35)
0 (0)
4 (7)
1 (3)
0 (0)
1 (3)
Slow background activity, n
(%)
15 (42)
21 (38)
19 (49)
16 (46)
14 (40)
Focal intermittent slowing, n
(%)
18 (50)
24 (44)
22 (56)
17 (49)
24 (69)
Focal continuous slowing, n
(%)
9 (25)
11 (20)
7 (18)
10 (29)
5 (14)
EEG status epilepticus, n (%)
2 (6)
5 (9)
2 (5)
8 (23)
1 (3)
Secondary bilateral synchrony,
n (%)
1 (3)
11 (20)
7 (18)
4 (11)
3 (9)
Regional interictal epileptiform
activity, n (%)
13 (36)
21 (38)
12 (31)
9 (26)
18 (51)
Regional ictal patterns, n (%)
21 (58)
22 (40)
13 (33)
11 (31)
22 (63)a
4 (11)
12 (22)
8 (21)
4 (11)
3 (9)
Nonlocalizing scalp EEG, n
(%)
a
If p ⬍ 0.05.
mMCD ⫽ mild malformation of cortical development; FCD ⫽ focal cortical dysplasia; EEG ⫽ electroencephalography.
(22%) had other MRI abnormalities such as encephalomalacia and porencephaly (n ⫽ 12), periventricular
leukomalacia (n ⫽ 10), shunted hydrocephalus (n ⫽
5), diffuse brain atrophy (n ⫽ 5), ventricular dilatation
(n ⫽ 3), and nonspecific gliosis (n ⫽ 3).
MRI abnormalities typical for cortical malformations
were identified in 101 subjects (66%). Blurring of the
gray/white matter junction was the most frequent feature, occurring in 90 patients (58%). The least frequent characteristic was the transmantle sign, which
was found in only eight patients (5%). White matter
signal abnormality in FLAIR was the most frequently
encountered signal intensity change (76 subjects,
49%), whereas gray matter signal change in T2 weighting was the least sensitive signal intensity parameter occurring in 17 patients (11%).
Important distinguishing imaging features of the histopathological groups were documented. Several MRI
features were significantly more typical for both FCD
type II groups. The transmantle sign was encountered
exclusively in FCD type II patients. Increased cortical
thickness and abnormal gyral/sulcal patterns were also
highly specific for FCD types IIa and IIb (␹2 ⫽ 65.59,
p ⬍ 0.0001; and ␹2 ⫽ 46.16, p ⬍ 0.0001, respectively). Gray/white matter junction blurring, as well as
gray matter signal abnormality in FLAIR and T2
weighting, were significantly more common in FCD
type IIa and IIb groups, less frequent in FCD type Ia
and Ib groups, and least common in the mMCD
group (␹2 ⫽ 16.02, p ⫽ 0.0026; ␹2 ⫽ 47.76, p ⬍
0.0001; and ␹2 ⫽ 23.59, p ⫽ 0.0001, respectively).
No subject from the mMCD group evidenced gray
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matter signal intensity change. The incidence of white
matter signal abnormalities was not significantly different between FCD type I and II groups; however, they
were less frequently encountered in mMCD (␹2 ⫽
9.78; p ⫽ 0.0441).
Lobar hypoplasia/atrophy was more typical of FCD
type I than FCD type II patients (␹2 ⫽ 11.79; p ⫽
0.0179). The incidence of this feature in mMCD patients lay between FCD types I and II.
Regarding hippocampal MRI abnormalities, we
found atrophy in 40 (26%) and signal intensity
changes in 29 (19%) patients. These changes were seen
most frequently in FCD type Ia and Ib patients, less
frequently in mMCD patients, and were rarely found
in FCD type IIa and IIb patients (see Table 3 for details; ⌾2 ⫽ 19.44, p ⫽ 0.0005; and ⌾2 ⫽ 23.29, p ⫽
0.0001, respectively).
We combined MRI and histopathological criteria to
evaluate the presence of HS. HS was determined in each
patient by evaluating histopathological findings or
through MRI evidence of hippocampal atrophy and signal intensity change, when there was insufficient tissue
for pathological analysis. Based on these criteria, we confirmed the presence of HS in 35 subjects: 6 mMCD
(25%), 19 FCD type Ia (39%), 9 FCD type Ib (30%),
1 FCD type IIa (4%), and no FCD type IIb case.
Eleven patients evidenced only MRI confirmation of HS
(one mMCD, eight FCD type Ia, two FCD type Ib).
Differences in the incidence of HS among groups were
statistically significant (␹2 ⫽ 20.82; p ⫽ 0.0003).
When the extent of MRI abnormalities typical for
cortical malformations was compared between the
Table 3. Magnetic Resonance Imaging Findings in 154 Patients with Reevaluated Magnetic Resonance Imaging
Scans
Characteristics
mMCD FCD Type Ia FCD Type Ib
(n ⴝ 24)
(n ⴝ 49)
(n ⴝ 30)
FCD Type IIa
(n ⴝ 23)
FCD Type IIb
(n ⴝ 28)
No MRI proof of mMCD/FCD, n (%)
14 (58)
20 (41)
11 (37)
5 (22)
3 (11)a
Entirely normal MRI, n (%)
12 (50)
14 (29)
6 (20)
5 (22)
1 (4)a
Other MRI abnormalities, n (%)
5 (21)
14 (29)
4 (13)
1 (4)
4 (14)
0 (0)
1 (2)
3 (10)
12 (52)
19 (68)a
0 (0)
0 (0)
0 (0)
2 (23)
6 (21)b
G/W matter junction blurring
7 (29)
26 (53)
18 (60)
17 (74)
22 (79)a
Abnormal gyral/sulcal patterns
1 (4)
1 (2)
5 (17)
12 (52)
17 (61)a
Lobar hypoplasia/atrophy
7 (29)
12 (45)
13 (43)
4 (17)
4 (14)a
FLAIR G matter signal change
0 (0)
9 (18)
5 (17)
11 (48)
20 (71)a
T2-weighted G matter signal change
0 (0)
6 (12)
3 (10)
7 (30)
13 (46)a
FLAIR W matter signal change
6 (25)
27 (55)
17 (59)
12 (52)
19 (68)a
T2-weighted W matter signal change
6 (25)
25 (51)
17 (57)
11 (48)
17 (61)a
T1-weighted W matter signal change
3 (12)
17 (35)
13 (43)
11 (48)
13 (46)a
Hippocampal atrophy
4 (17)
21 (43)
11 (37)
3 (13)
1 (4)a
Hippocampal signal change
4 (17)
18 (37)
7 (24)
0 (0)
0 (0)a
25
39
30
4
0a
No MRI proof of mMCD/FCD
14 (58)
20 (41)
11 (37)
5 (22)
3 (11)a
Unilobar
6 (25)
14 (29)
7 (23)
10 (43)
18 (64)a
Multilobar
1 (4)
7 (14)
6 (20)
2 (9)
3 (11)
Hemispheric
3 (13)
8 (16)
6 (20)
6 (26)
4 (14)
Individual MRI features of mMCD/
FCD, n (%)
Increased cortical thickness
“Transmantle sign”
Hippocampal abnormalities, n (%)
All cases with HSc
Extent of MRI abnormalities typical for
cortical malformations, n (%)
If p ⬍ 0.05.
b
Statistics not done because of small numbers of subjects in individual groups
c
See text for diagnostic criteria.
mMCD ⫽ mild malformation of cortical development; FCD ⫽ focal cortical dysplasia; MRI ⫽ magnetic resonance imaging; G ⫽
gray; W ⫽ white; FLAIR ⫽ fluid-attenuated inversion recovery; HS ⫽ hippocampal sclerosis.
a
groups (eg, nonspecific changes such as periventricular
leukomalacia were not considered in this evaluation),
we found that MRI abnormalities in patients with
FCD type IIb were significantly more likely to be confined to one lobe compared with other histopathological subtypes (␹2 ⫽ 24.61; p ⫽ 0.0168).
Neuropsychology
Results of neuropsychological ranking are provided in
Figure 3. We found no significant differences in proportions of individual IQ categories between the histopathological groups in 133 patients with neuropsychological test scores.
Surgery
Surgical variables in our patients are presented in Table
4. Numbers of subjects who underwent an invasive
study using subdural electrodes was greater in histopathologically “milder” forms of cortical malformation. Hippocampal resections were more frequent in
mMCD and FCD type I than FCD type II patients.
We found no other differences between groups in surgical variables.
Outcome
Data concerning seizure outcome are provided in Figure 4. Mean follow-up was 6.56 years (range, 0.5–18
Krsek et al: Pediatric Cortical Dysplasia
763
Fig 2. Magnetic resonance imaging (MRI) characteristics of different histopathological types of mild malformation of cortical development/focal cortical dysplasia (mMCD/FCD). (A, C, E, G, I) Coronal T2-weighted images. (B, D, F, H, J) Axial fluid-attenuated
inversion recovery (FLAIR) images. Abnormalities are depicted by arrows. (A) Hemispheric mMCD in a 2-year-old boy with the encephalomalacic lesion in the left middle cerebral artery distribution. Blurring of the gray/white matter junction and white matter signal
changes in the left temporal lobe are apparent. (B) Right frontal mMCD characterized by a mild gray/white matter junction blurring
and white matter signal changes. (C) Hemispheric FCD type Ia with the gray/white matter junction blurring and white matter signal
changes most prominent in the left temporal lobe; the atrophy of the whole left hemisphere is present. (D) Right temporal FCD type Ia
associated with the hippocampal sclerosis. Minor blurring of the gray/white matter junction and white matter signal changes are apparent. (E) Left anterior temporal FCD type Ib with the blurred gray/white matter junction and white matter signal changes more pronounced in the mesial aspect of the temporal pole. (F) Right frontal FCD type Ib characterized by a widespread gray/white matter
junction blurring and white matter signal changes. (G) Right temporoparietooccipital FCD type IIa in a 2-month-old boy with marked
gray/white matter junction blurring, abnormal gyral/sulcal pattern, and signal changes of both the gray and white matter. (H) Left
frontal FCD type IIa with an increased cortical thickness, “transmantle sign,” abnormal gyral/sulcal pattern, prominent blurring of the
gray/white matter junction, and signal changes of both the gray and white matter. (I) Right temporal FCD type IIb with a “tuber-like”
appearance characterized by the increased cortical thickness, blurring of the gray/white matter junction, and dramatic signal changes of
both the gray and white matter. (J) Right opercular/insular FCD type IIb with increased cortical thickness, abnormal gyration, and a
pronounced signal change of the gray matter.
years). Two years after surgery, there were no statistically significant differences in seizure frequency among
histopathological groups (n ⫽ 149). Seizure freedom
was achieved in the following proportions of patients
in individual FCD subgroups: mMCD 52%, FCD
type Ia 49%, FCD type Ib 45%, FCD type IIa 61%,
and FCD type IIb 75%.
Discussion
The size of this data set, all collected at one institution,
greatly facilitates the ability to distinguish clinically important differences between histopathological subtypes
of mMCD and FCD. Significant differences that may
assist in the surgical management of these patients were
found.
Prenatal and perinatal risk factors including prematurity, asphyxia, bleeding, and hydrocephalus occurred
in 13% of children in our series. Several studies have
reported an even greater incidence of prenatal and perinatal adverse events in patients with different types of
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Fig 3. Results of the neuropsychological ranking in a group of
133 patients with available neuropsychological tests. Proportions of Standard Score categories in individual histopathological groups are given in percentages. mMCD ⫽ mild malformation of cortical development; FCD ⫽ focal cortical
dysplasia.
Table 4. Surgical Variables in Patients
Characteristics
mMCD
(n ⴝ 36)
FCD Type Ia
(n ⴝ 55)
FCD Type Ib
(n ⴝ 39)
FCD Type IIa
(n ⴝ 35)
FCD Type IIb
(n ⴝ 35)
Side of surgery (L/R)
18/18
32/23
22/17
17/18
19/16
Invasive monitoring, n (%)
29 (81)
38 (69)
23 (59)
18 (51)
19 (54)
Reoperated patients, n (%)
3 (8)
6 (11)
6 (15)
5 (14)
7 (20)
Lobar
21 (58)
33 (60)
22 (56)
17 (49)
23 (66)
Multilobar
13 (36)
12 (22)
12 (31)
11 (31)
9 (26)
2 (6)
10 (18)
5 (13)
7 (20)
3 (8)
Frontal
23 (64)
29 (53)
20 (51)
22 (63)
24 (69)
Temporal
21 (58)
37 (67)
26 (67)
21 (60)
11 (31)
Parietal
7 (19)
17 (31)
15 (38)
14 (40)
15 (43)
Occipital
7 (19)
15 (27)
13 (33)
12 (34)
7 (20)
Frontal
14
12
10
10
13
Temporal
8
19
11
6
3
Parietal
0
2
1
1
4
Extent of resections (including
reoperations), n (%)
Hemispherectomy
Localization of resections (all
types of surgeries, including
reoperations), n (%)
Localization of unilobar
resections, n (%)
0
0
0
1
1
Hippocampal resections, n (%)
Occipital
11 (31)
19 (33)
15 (38)
5 (14)
1 (3)
Multiple subpial transections, n
(%)
2 (6)
2 (4)
2 (5)
1 (3)
1 (3)
mMCD ⫽ mild malformation of cortical development; FCD ⫽ focal cortical dysplasia.
cortical malformation15,31,33; however, little is knownabout their role in the pathogenesis of FCD. A causative role for prenatal insults such as ischemia in the
pathogenesis of cortical dysplasia has been proposed
based on experimental models34 and observations in
children with perinatally acquired encephalopathies.35
Intrauterine insults could produce cytoarchitectural alterations of the developing neocortex that eventually
cause the neuropathological findings compatible with
“acquired” FCD.
Prenatal and perinatal adverse events were significantly associated with histopathologically “milder” forms
of cortical malformation (mMCD and FCD type I)
than FCD type II. Widdess-Walsh and colleagues31 note
equal proportions of perinatal risks between FCD types;
however, we recently noted similar disproportions in another pediatric epilepsy surgery series (17% in FCD type
I group, and no case in FCD type II group).32 Our observations lend support to the belief that intrauterine
factors operating during the late second or early third
trimester of pregnancy could account for “severe” FCD
(eg, type II), whereas events occurring closer to birth
would explain “milder” forms of cortical malformation
(eg, mMCD and FCD type I).8
The frequent association of cortical malformations
with other brain lesions acquired in the prenatal and
perinatal periods appears to be a distinctive feature of
mMCD/FCD type I. It has been suggested that “mild”
cortical malformations could play an important role in
the pathogenesis of epilepsy and neurological deficits in
children with acquired neonatal encephalopathies, and
constitute an independent prognostic factor in this population.35 MRI proof of mMCD/FCD type I is often
lacking (see later), especially in cases with associated
brain pathology. We speculate that the MRI features of
cortical malformations could easily be overlooked or
misinterpreted in these patients, and the true incidence
of mMCD/FCD in children with acquired neonatal encephalopathies might be underestimated. Presurgical detection of associated cortical malformations in patients
with perinatally acquired brain lesions could have important practical consequences for surgical planning, be-
Krsek et al: Pediatric Cortical Dysplasia
765
Fig 4. Seizure outcome in 149 patients with at least 2 years
of surgical follow-up. Definitions of Engel categories are explained in the text. Proportions of patients in individual histopathological groups are given in percentages.
cause the malformed cortex is likely to be at least a part
of the epileptogenic zone and its resection critical for
obtaining a seizure-free outcome.
Patients in the histopathological subgroups did not
differ in mean age at seizure onset, seizure type, seizure
frequency, or incidence of status epilepticus. These observations provide reasonable evidence that all of the
histopathological subtypes of mMCD/FCD possess a
comparable degree of epileptogenicity. Our results contradict previous observations that patients with FCD
type II have an earlier age of seizure onset and earlier
age of surgical resection,36 and that FCD containing
balloon cells has higher intrinsic epileptogenicity.37 We
supported a recent finding that FCD subtype does not
influence the degree of epileptogenesis; that is, even
mildly dysplastic features (such as mMCD) are highly
epileptogenic.38
Several studies have described EEG features typical
for FCD such as fast-frequency patterns39,40 and
rhythmic or continuous epileptiform discharges on
scalp EEG.41 Little is known about distinctive EEG
characteristics of histopathological groups. We were
not able to identify EEG features that were specific to
individual histopathological subtypes of mMCD/FCD.
Continuous epileptiform activity (EEG status epilepticus) was apparent in only 9% of patients, with similar
proportions in individual pathological types. This incidence is apparently lower than what Gambardella and
coworkers41 reported; however, Raymond and coauthors15 found a comparable number of subjects in a
population of patients with different malformations of
cortical development.
Localizing features in the scalp EEG of individuals
in dysplasia subgroups were analyzed. Ictal EEG patterns were significantly more precisely localized in
mMCD and FCD type IIb than in other FCD types; a
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similar trend was found regarding interictal EEG activity in FCD type IIb. We suspect that ictal localization
in patients with FCD type IIb is likely related to the
more restricted MRI abnormalities in this pathologically defined subgroup (see later). However, a similar
result in patients with mMCD is rather surprising and
difficult to interpret because there are no comparable
data from previous studies. We note that two recent
studies addressing the issue of localizing value of EEG
in individual FCD subtypes found no differences between patients with FCD type I and FCD type II.31,32
MRI characteristics of FCD have been reviewed
thoroughly.6,18,26,28,31,42– 46 However, only a minority
of studies have focused on FCD type I,6,18,28,31,44 and
there are no reports of imaging findings in mMCD.
Detailed analysis of MRI features of individual histopathological subtypes of mMCD/FCD has not yet
been performed. By the thorough reevaluation of findings in the cohort of 154 subjects with good-quality
presurgical MRI, we suggest the following distinctive
imaging characteristics of the pathological subtypes of
cortical dysplasia:
1. Increased cortical thickness, abnormal gyral/sulcal
patterns, and transmantle sign are features almost
exclusively encountered in FCD type II. The
former two occurred in FCD type I rarely and
were never observed in patients with mMCD.
2. Lobar hypoplasia and atrophy are typical of FCD
type I and assist in distinguishing it from FCD
type II. However, lobar hypoplasia also occurs in
a significant proportion of patients with mMCD
(29% in our series), complicating the use of this
feature as an identifier of FCD type I.
3. Blurring of the gray-white matter junction is the
most sensitive marker of FCD and is found in
proportion to the severity of histopathological
changes.
4. Gray matter signal abnormalities (in FLAIR and
T2 weighted) are far more common in FCD
type II than in FCD type I and do not occur in
mMCD; they therefore represent another important clue to the differentiation of the pathologies.
5. White matter signal abnormalities (in FLAIR,
T2 weighted, and T1 weighted) are not useful to
differentiate FCD type I from FCD type II because they occur equally in both groups; they are
less frequent in mMCD.
6. We found no MRI features that distinguish
FCD type Ia from type Ib or FCD type IIa from
type IIb.
7. Both FCD (mainly type I) and mMCD are not
infrequently associated with other brain abnormalities (such as encephalomalacic lesions and
periventricular leukomalacia).
In individual patient groups, our findings show that
FCD type II is usually characterized by focal cortical
thickening, abnormal gyral and sulcal patterns, transmantle sign, prominent blurring of the gray-white matter junction, and signal changes in both gray and white
matter (see Figs 2F–I); FCD type I is associated with
less prominent gray/white matter junction blurring and
signal changes predominantly in white matter and
prominent lobar hypoplasia (see Figs 2B–E); MRI abnormalities in mMCD are least frequent and usually
consist of less pronounced abnormalities described in
FCD type I (see Figs 2A, B). The MRI changes found
in mMCD contradict the belief that this pathological
subtype cannot be detected by MRI.20
Our findings lend support to previous investigations
that demonstrate that MRI findings in FCD can be
correlated with histopathological features. High signal
intensity in the gray matter has been shown to correspond to dyslamination and morphological abnormalities of cortical neurons that are more prominent in
FCD type II.47 Alternatively, high signal intensity in
the white matter and blurring of the gray/white matter
junction could also be caused by dysmyelination, with
reduction in the number of myelinated fibers and ectopic clustering of neurons and proliferated glial cells,
with or without cellular dysmorphism, that is, changes
present in both FCD types I and II.42,44 mMCD (type
II) is characterized by a normal cortical structure with
cellular abnormalities (ectopic neurons) only in the
white matter.20 Not surprisingly, MRI changes were
confined to the white matter in this pathological subtype.
Normal or nonspecific MRI findings were noted in
34% of patients. They were more commonly observed
in mild histopathological types (especially mMCD) but
could not be excluded in “severe” FCD such as type
IIb. The observation that mMCD and FCD type I are
more difficult to identify and demarcate using current
brain imaging techniques has important implications
for surgical planning. Surgery that is based only on
MRI and scalp EEG findings in these patients may result in incomplete resection and less favorable surgical
outcome. We suggest implanting subdural electrodes
for cases with likely mild histopathological findings.
Regarding the extent of MRI abnormalities, FCD
type IIb was more frequently precisely localized than
other histopathological types. The finding is in accord
with the observation of better-localized epileptiform
EEG abnormalities in this subgroup.
There were no significant differences in the prevalence of individual mMCD/FCD types in temporal
lobes. However, FCD type I was far more likely to be
associated with HS than FCD type II; that is, FCD
type I in the temporal location was frequently associated with HS, whereas FCD type II was not. The occurrence of cortical malformations in the ipsilateral
temporal lobe in patients with mesial temporal lobe epilepsy (MTLE) associated with HS (“dual pathology”)
has been described repeatedly.48 –50 Fauser and colleagues2,30 also report a greater prevalence of histopathologically “milder” types of cortical malformations in their MTLE series. Temporal pole mMCD/
FCD type I in these patients is likely part of more
widespread temporal lobe pathology, in agreement with
a hypothesis that Falconer and coauthors51 originally
postulated. Nevertheless, the total incidence of “dual
pathology” in our population (17.5%) was lower than
in previous FCD series.18,45,49 We therefore believe
that our pediatric mMCD/FCD type I cases are clinically different from the reported cases of adults with
MTLE. We also note that febrile seizures occurred far
less frequently in our series (4% of cases) than in
MTLE populations.2,45,49
Surprisingly little is known about neuropsychological
characteristics of children with FCD. Previous studies
usually report only subjects with mental retardation,
and most series were too small to draw any particular
profile of these patients.26,27,52 To our knowledge,
only four reports compared neuropsychological findings with histopathological types including FCD type I
patients. Klein and coworkers53 report that histological
type of cortical dysplasia (classified as mild, moderate,
or severe) was not significantly associated with intellectual outcome. Tassi and others18 found the greatest
number of mentally retarded children in FCD type Ib,
lowest in FCD type Ia, and intermediate in FCD type
II. However, the numbers of patients in individual
groups were low (eg, six subjects in FCD type Ib
group). Widdess-Walsh and colleagues31 describe that
patients with below-average full-scale IQ were more
frequently encountered in both FCD type II groups
(67% and 68%, respectively) than in FCD type Ia and
Ib groups (38% and 57%, respectively). We recently
reported prominent differences between children with
FCD type I and FCD type II with significantly lower
intelligence scores in FCD type I (eg, severe mental
retardation with IQ less than 35 was encountered in
27% of FCD type II compared with 55% of FCD type
I children; 33% of FCD type II but only 4% of FCD
type I subjects had low/average intelligence).32 In this
series, no statistical differences in cognitive functioning
among patient groups were demonstrated.
The review of previous studies of cognitive function
in pediatric FCD cases shows extreme variability of
their neuropsychological profiles. The variability is
likely to represent several factors such as the age at seizure onset, the extent of the pathology (which can be
underestimated on MRI), the severity of the epilepsy,
and the side effects of medical treatment.54 Further
studies analyzing influences of different variables on
neuropsychological profiles of children with FCD are
needed.
Krsek et al: Pediatric Cortical Dysplasia
767
There were no significant differences in the types of
resections in individual patient’s groups except for the
need to perform invasive monitoring that was closely
related to the ability of MRI to detect and localize the
epileptogenic zone according to mMCD/FCD type.
However, the extent of surgery was similar in all subtypes.
No statistically significant differences in seizure outcome were observed among the groups. However, the
greatest number of seizure-free patients (75%) and
lowest number of subjects with less than 50% reduction of postoperative seizure frequency (8%) occurred
in FCD type IIb. On the contrary, patients with FCD
type Ib had the poorest surgical outcomes, with only
45% becoming seizure free and 35% showing no
change in seizure frequency. Children with mMCD exhibited intermediate surgical success with 52% achieving postoperative seizure freedom and 24% not showing improvement.
The seizure outcome results of this study are comparable with the outcomes by Tassi and others18 and
Widdess-Walsh and colleagues,31 who reported slightly
better results in FCD type II than in FCD type I. In
contrast, Fauser and colleagues30 found greater proportions of seizure-free patients in histopathologically
“milder” forms of cortical malformations, but these results probably reflect selection bias because a high proportion of MTLE cases associated with HS were included in their mMCD/FCD type I groups. Krsek and
coauthors32 recently reported even more striking differences in seizure outcome between FCD type I (21% of
seizure-free children) and FCD type II (75% of seizure
freedom), which were likely attributed to a greater proportion of multilobar cases (88%) in the FCD type I
group from Vogtareuth, Germany.32 The better outcomes in FCD type IIb patients might be related to
significantly more localized MRI abnormalities and
EEG epileptiform activity in these subjects. However,
seizure outcomes could be influenced by several other
variables (age at seizure onset, age at surgery, extent
and localization of resections, concomitant pathologies
such as HS, among other variables). Predictors of outcome in mMCD/FCD patients will be analyzed in a
separate study.
In conclusion, we found important distinctive features of patients with different histopathological subtypes of mMCD/FCD. They were clinical (incidence
of prenatal/perinatal risk factors), electrophysiological
(localization of ictal patterns on scalp EEG), as well as
imaging features (ability of MRI to show cortical malformations, coincidence with HS, extent of MRI abnormalities, and several specific characteristics as discussed earlier). Our study appears to confirm a
practical value for the histopathological classification of
cortical malformations into mMCD, FCD type I, and
FCD type II categories. On the other hand, we found
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no single feature distinguishing FCD type Ia from
FCD type Ib and only minor differences between FCD
types IIa and IIb (such as more frequently regional ictal
EEG patterns and more circumscribed MRI changes in
FCD type IIb). Based on our results, the clinical and
prognostic importance of this detailed classification of
mMCD/FCD patients into subcategories is questionable. Further studies are necessary to draw more detailed information about differences in neuropsychological findings and postsurgical seizure outcome in the
different patient groups.
This work was supported by Grants of the Czech Ministry of
Health (IGA NR/8843-4 and FNM 00000064203 [P. K.]).
We acknowledge Dr D. Ludwig for his contribution.
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features, dysplasia, cortical, focal, different, histopathological, pediatrics, subtypes
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