doi:10.1093/brain/awn224
Brain (2008), 131, 3246 ^3255
Small focal cortical dysplasia lesions are located
at the bottom of a deep sulcus
Pierre Besson, Frederick Andermann, Francois Dubeau and Andrea Bernasconi
Department of Neurology and Neurosurgery and Brain Imaging Center, McGill University, Montreal Neurological Institute
and Hospital, Montreal, Quebec, Canada
Correspondence to: Andrea Bernasconi, MD, Montreal Neurological Hospital and Institute, 3801 University Street, Montreal,
Quebec, Canada H3A 2B4
E-mail: andrea@bic.mni.mcgill.ca
Keywords: epilepsy; focal cortical dysplasia; sulcal morphology; MRI; image analysis
Received May 9, 2008. Revised August 11, 2008. Accepted August 18, 2008. Advance Access publication September 23, 2008
Introduction
Taylor-type focal cortical dysplasia (FCD) (Taylor et al.,
1971), a malformation due to abnormal neuroglial proliferation and organization (Barkovich et al., 2005), is an important cause of focal and often pharmacologically intractable
epilepsy (Frater et al., 2000; Sisodiya, 2000, 2004). The term
FCD designates a spectrum of histological abnormalities
of the laminar structure of the cortex variably associated
with cytopathological features, such as giant (or cytomegalic)
neurons, dysmorphic neurons and balloon cells (Prayson
et al., 2002; Palmini et al., 2004).
Improvements of MRI techniques have allowed the in vivo
recognition of FCD in an increasing number of patients
(Barkovich and Raybaud, 2004a; Bernasconi, 2004). The most
frequently described imaging features are cortical thickening,
blurring of the grey–white matter (GM–WM) junction, and
a hyperintense signal within the dysplastic lesion and its
underlying white matter (Barkovich and Kuzniecky, 1996;
Bronen et al., 1997; Colliot et al., 2006a). In patients with
obvious malformations of cortical development gross sulco–
gyral abnormalities may be noted and are characterized by
a spectrum of changes ranging from clefts of various depth
(Bronen et al., 2000) to broad gyri, shallow or deep sulci, or
gyral simplification (Raymond et al., 1995; Yagishita et al.,
1997). In many patients, however, FCD lesions go unrecognized by standard radiological analysis due to their subtlety.
In their original observation, Taylor et al. (1971) noted
that in all patients the cortical surface of the fixed tissue
appeared normal to the naked eye and that histologically, in
most cases, grotesque glial cells were present in the depths
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Focal cortical dysplasia (FCD) is often characterized by minor structural changes that may go unrecognized
by standard radiological analysis.Visual assessment of morphological characteristics of FCD and sulci harbouring them is difficult due to the complexity of brain convolutions. Our purpose was to elucidate and quantify
the spatial relationship between FCD lesions and brain sulci using automated sulcal extraction and morphometry. We studied 43 consecutive FCD patients using high-resolution MRI. Lesions were classified into
small and large using qualitative (detection on initial clinical assessment of conventional MRI) and quantitative
(volume) criteria. Sulci were identified and labelled automatically using an algorithm based on a congregation
of neural networks. Segmented FCD lesions and sulci were then simultaneously visualized in 3D. We measured mean and maximum depth of sulci related to each FCD and of the corresponding sulci in 21 healthy
controls. In addition, we calculated sulcal depth within the FCD neighbourhood. Twenty-one (21/43 = 49%)
patients had small FCD lesions (volume range: 128^3093 mm3). Among them, 17 (81%) had been overlooked
during initial radiological evaluation and were subsequently identified using image processing. Eighteen
(18/21 = 86%) small FCD lesions were located at the bottom of a sulcus. Two others were related to the walls
of two sulci and one was located at the crown of a gyrus. Mean and maximum depth of sulci related to the
FCD was higher than that of the corresponding sulci in controls (P _ 0.008). Sulcal depth within lesional neighbourhood had larger mean depth than that of the entire sulcus (P _ 0.0002). Evidence that small FCD lesions
are preferentially located at the bottom of an abnormally deep sulcus may be used to direct the search for developmental abnormalities, particularly in patients in whom large-scale MRI features are only mildly abnormal
or absent.
Bottom of a sulcus cortical dysplasia
Methods
Subjects
We studied 43 consecutive patients with FCD (21 males, mean
age SD = 24 10 years) who had been investigated at the
Montreal Neurological Institute and Hospital for refractory focal
epilepsy. All patients had routine EEG recordings and prolonged
video-EEG monitoring. The EEG background was abnormal in 34
patients (79%). Maximum interictal spike activity was concordant
with the location of FCD lesions in 31 patients (72%). Ictal
discharges recorded on surface EEG had localizing value in 24
patients (56%). Invasive monitoring using stereotactic implanted
depth electrodes (SEEG) was performed in nine patients because
EEG data and imaging did not sufficiently converge to plan the
resection. In all of them SEEG demonstrated a very active, at times
continuous interictal epileptic activity and focal electrographic
changes at seizure onset in the electrodes close to or in the lesion.
Patients were compared to 21 age-matched healthy individuals
(7 males, mean age 23 9 years). The Ethics Board of the Montreal Neurological Institute and Hospital approved the study and
written informed consent was obtained from all participants.
Twenty-nine patients (29/43 = 67%) underwent resective surgery and the FCD was confirmed by histopathology in all. Mean
post-operative follow-up was 6.4 years (median = 7.0 years).
Twenty-one patients (21/29 = 72%) became free of disabling
seizures (Engel’s class I) (Engel et al., 1993), four had rare
disabling seizures (class II), three a worthwhile improvement
(class III) and one no worthwhile improvement (class IV).
Histological features of the resected tissue were graded as proposed by Palmini et al. (2004). In this scheme, type I dysplasias are characterized by isolated architectural abnormalities (Ia)
3247
or by an association of cortical dyslamination and giant or
immature neurons (Ib). Type II dysplasias consist of architectural
abnormalities with dysmorphic neurons, but without balloon
cells (IIa) or with dysmorphic neurons and balloon cells (IIb).
According to this classification, 20 of our patients had FCD IIb,
six FCD IIa and three had FCD Ib. Three patients await
operation. Three patients refused surgery and one with normal
neurological examination was not operated because the lesion
encroached on the dominant sensorimotor hand area. Two more
patients were operated in a centre abroad and were lost for followup. In five others, seizures were controlled with antiepileptic
medication.
The FCD lesions were located in the frontal lobe in 20/43 (47%)
patients, the central area in 10/43 (23%), the parietal lobe in 8/43
(19%), the Sylvian region in 2/43 (5%), the occipital lobe in 1/43
(2%), in the posterior temporal lobe in 1/43 (2%) and in the
insular cortex in 1/43 (2%).
MRI acquisition and image pre-processing
MR images were acquired on a 1.5 T Gyroscan (Philips Medical
Systems, Eindhoven, Netherlands) using a 3D T1-fast field echo
sequence (TR = 18; TE = 10; NEX = 1; flip angle = 30; matrix
size = 256 256; FOV = 256; slice thickness = 1 mm), providing
an isotropic voxel size of 1 1 1 mm3. Each image underwent
automated correction for intensity non-uniformity and intensity
standardization (Sled et al., 1998). Images were then linearly
registered into a standardized stereotaxic space based on the
Talairach atlas (Talairach and Tournoux, 1988; Collins et al.,
1994). We chose the ICBM 152 T1-weighted target as template
for linear registration and subsequent tricubic resampling
(Mazziotta et al., 1995).
As part of our clinical protocol, coronal and axial protondensity (PD) and T2-weighted images (thickness 3.0–5.0 mm, gap
0.3 mm, TR 2100 ms, TE 20, 78 ms) were obtained in all patients
and showed an increase in signal within the lesion in 26 of them.
Coronal fluid attenuation inversion recovery images (FLAIR, slice
thickness 3.0 mm, inter-slice gap 0.3 mm, TR 6000 ms, TE 150 ms,
TI 1900 ms, FOV 230 mm) were available for analysis in 37
patients and showed increased signal in 17 of them. A linear or
funnel-shaped abnormal signal intensity extending from the
cortical-white matter junction to the margin of the lateral
ventricular surface, i.e. transmantle dysplasia (Barkovich et al.,
1997), was seen in five patients.
A lesion was defined as ‘overlooked’ if it had not been identified
during the initial routine clinical assessment of conventional MRI.
Overlooked lesions were subsequently identified with the help of
our image processing tools, including curvilinear reformatting
(Bastos et al., 1999), texture analysis based on FCD computational models (Bernasconi et al., 2001), voxel-based morphometry
(Colliot et al., 2005), and co-registration of multispectral images
(Mahvash et al., 2006). We previously demonstrated that these
techniques yield a significantly increased sensitivity in detecting
FCD lesions relative to conventional MRI by maintaining high
specificity.
Automatic sulcal extraction and labelling
Figure 1 illustrates the main steps involved in the automated sulcal
extraction and labelling as described below.
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of the affected cortex and subjacent white matter. In two
patients in whom no macroscopic abnormality was found,
the authors indicated that: ‘the crown of the affected gyrus
was spared, the anomalous neurons being concentrated
around the base of the sulcus’. More recent MRI-based
clinical observations also suggest that FCD may be located
in the depth of a sulcus (Bastos et al., 1999; Urbach et al.,
2002; Barkovich and Raybaud, 2004b). To date, however,
no study has evaluated systematically the exact relationship
between FCD lesions and brain sulci.
The visual identification of morphologic sulcal characteristics is difficult on orthogonal planes obtained in conventional MRI. This disadvantage is bypassed when using
precise and robust computer-based identification algorithms that allow automatic labelling on the brain surface
(Mangin et al., 1995; Riviere et al., 2002) and spatial relationship between lesions and brain sulci. Moreover, they
allow quantified comparison of inter-subject sulcal morphometry. Using these techniques, we were able to quantify
sulcal patterns of the basal temporal lobe and demonstrated
that a single-branched, unbroken collateral sulcus is the
predominant folding pattern found in patients with
temporal lobe epilepsy (Kim et al., 2008).
In the present study, we sought to elucidate and quantify
the spatial relationship between FCD lesions and brain sulci
using automated sulcal extraction and morphometry.
Brain (2008), 131, 3246 ^3255
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Brain (2008), 131, 3246 ^3255
Generation of brain surfaces and sulcal models
For sulcal extraction, images were processed using BrainVISA.
This image analysis software allows to reconstruct the surfaces
corresponding to GM–WM and GM–CSF interfaces and to extract
the brain sulci (Riviere et al., 2002). To compute accurate cortical
surfaces and brain sulcal folds, image processing includes the
following steps: (i) brain segmentation; (ii) classification of
WM, GM and CSF generating separate maps in each hemisphere;
(iii) reconstruction of the surfaces corresponding to the GM–WM
and GM–CSF interfaces using the above classification maps and
(iv) extraction of the sulcal folds by segmenting the skeletonized
GM–CSF interface into simple surfaces.
Sulcal labelling
To place the threshold, we used entropy, a measure of
homogeneity. This enabled us to maximize the ‘information
gain’, which is the gain in homogeneity after thresholding.
The entropy of our dataset S is defined by:
EntropyðSÞ ¼ p log2 p ð1 p Þlog2 ð1 p Þ
where p = number of lesions seen on MRI divided by total
number of lesions.
By setting a threshold T, our dataset was divided into two sets,
S1 and S2. S1 grouped lesions of volume smaller than T and S2
grouped larger lesions. The information gain is given by:
GainðS,T Þ ¼ Entropy ðSÞ Entropy ðS1 Þ þ Entropy ðS2 Þ
The threshold for which the gain is maximized ensures that the
sum of entropies of S1 and S2 is minimized. In other words, the
probabilities of the events ‘lesion is overlooked if smaller than T ’
and ‘lesion is seen if larger than T ’ are maximized simultaneously.
Criteria to categorize FCD position with
respect to sulci
Spatial correspondence between an FCD lesion and sulci related to
it was assessed by synchronized visual inspection of 2D MR
images and 3D surface rendering of that image. An FCD lesion
was considered to be located at the bottom of a given sulcus (from
now on identified as the FCD sulcus) if centred at the highest
curvature of its sulcal pial surface and spreading along its walls.
Criteria to separate small from large FCD lesions
First, an expert observer manually segmented all FCD lesions as
previously described (Colliot et al., 2006b). In 18 patients, two
observes had segmented the same lesions to assess accuracy.
Details about similarity indices, which showed good agreement
between raters, are published elsewhere (Colliot et al., 2006b). We
then separated small and large FCD lesions by placing a threshold
along the volume continuum based on quantitative and qualitative
criteria. The small lesion group was defined to include lesions with
a volume below the threshold (as defined below) and to have high
rate of overlooked lesions.
Measure of sulcal depth
To calculate the depth of a given sulcus, we first obtained the sulcal
bottom (‘fundus’) line, which is defined by the inner edge of the
sulcus (Cachier et al., 2001) as shown in Fig. 2. The depth of each
point along this line was determined by calculating the shortest
distance computed using the Chamfer’s distance transform
(Borgefors, 1996) from the outer cortical surface (Smith, 2002).
For controls and patients, we evaluated mean and maximum
sulcal depth (Fig. 2B). Mean depth was calculated by averaging
the depth of all points along the sulcal bottom (i.e. fundus) line,
Fig. 1 Automated sulcal identification and labelling (see methods for details). (A) Grey matter (GM) and white matter extraction
overlaid on the T1-weighted MRI; (B) skeletonization of the GM^ CSF union; (C) automatically colour-labelled sulci are shown on the
3D MRI surface rendering of a healthy control subject. The right central sulcus (red) is extracted for better visualization.
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After extraction, sulci are automatically labelled using a congregation of neural networks trained on a database of manually
identified sulci by maximizing similarity of sulci features and sulci
relations (Rivière et al., 2000).
In each healthy control, we identified the sulcus that matched
the one related to the FCD in each patient. Moreover, by
simultaneously inspecting individuals’ sulcal morphology and
labelling, we ensured the best possible sulcal equivalence between
subjects. The sulcal nomenclature provided by Brain-VISA in the
labelling step was verified on the atlas of Ono et al. (1990).
P. Besson et al.
Bottom of a sulcus cortical dysplasia
Brain (2008), 131, 3246 ^3255
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which is defined by the inner edge of a given sulcus. The deepest
point of the sulcal bottom line determined the sulcal maximum
depth.
Our purpose was to generate parameters for global and local
morphology providing complementary information about sulcal
depth. Indeed, for a given sulcus, depending on its shape, high
value of maximum depth does not necessarily imply high mean
sulcal depth value, and conversely. Thus, these two measurements
are not directly comparable to each other. We also calculated the
average depth of the portion of the sulcal bottom line located
in the neighbourhood of the lesion, as determined by a 4-mm
dilation of the FCD label (Fig. 2C).
Statistical analysis
We compared mean depth in patients to mean depths in controls
using a one-tailed Wilcoxon signed-rank test. Similarly, maximum
sulcal depth in patients was compared to maximum sulcal depth
in controls. In addition, the sulcal portion within neighbourhood
of the lesion was compared to the mean depth of the whole
sulcus. EEG data of patients with small and large FCD lesions were
compared using two-tailed Fisher exact test.
Results
The FCD volumes ranged from 128 mm3 to 94620 mm3
(mean SD: 7731 14891 mm3). Based on the entropy
measurement described above, small lesions were defined as
those having a volume smaller than T = 3093 mm3 (Fig. 3).
Using this threshold, 21/43 (49%) FCD lesions
were considered to be small (range: 128–3093 mm3; mean:
1282 852 mm3). Separating groups according to the size
of FCD lesions was an efficient method, as demonstrated by
the maximization of the information gain that allowed us
to form two uniform groups: 17/21 (81%) of small lesions
had been overlooked versus 0% of large lesions.
Details about sulcal depth values in controls and patients
are presented in Table 1. 18/21 (86%) small FCD lesions
were located at the bottom of a sulcus. Among them, one
lesion was at the bottom of two neighbouring sulci, giving
a total of 19 FCD sulci.
Fig. 3 Plot showing information gain as function of threshold (T)
location. Small lesions were defined as those having a volume
below T = 3093 mm3 (red line).
To identify potential outliers in healthy controls, we used
a leave-one-out procedure and compared the mean and
maximum depths of all sulci corresponding to those
harbouring the FCD in patients using a two-tailed
Wilcoxon signed-rank test. This procedure revealed that
sulci were deeper only in one healthy control (P = 0.02) and
shallower in another (P = 0.02).
Mean and maximum depth values of the FCD sulci were
higher than those of the corresponding sulci in healthy
controls (P50.008). Moreover, the sulcal portion within
the neighbourhood of the lesion had larger mean depth
than that of the whole sulcus (P50.0002).
Figure 4 shows three representative examples of small,
histologically proven FCD lesions located at the bottom of
deep sulci.
Although the proportion of patients with interictal EEG
spikes concordant with the FCD location was lower in
patients with small than large lesions, the difference was not
significant (57% versus 86%, P = 0.5). Similarly, we found
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Fig. 2 Sulcal depth measurements. (A) Three-dimensional surface rendering of the MRI of a patient with right frontal focal cortical dysplasia. The intermediate right frontal sulcus (turquoise) and the lesion (red) are shown in semi-transparent. (B) The sulcal bottom line
(yellow) was used to calculate mean and maximum depth (see methods for details). (C) We calculated the average depth of the portion of
the sulcal bottom line located in the lesional neighbourhood (purple), as determined by a 4 mm dilation of the FCD lesion label (red wireframe in B and C).
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P. Besson et al.
Table 1 Mean and maximum depth (in millimetres), and z-scores (in parenthesis) of FCD sulci presented by lobes and regions
Patients
Frontal lobe
Inferior frontal, L
Inferior pre-central, L
Intermediate frontal, L
Pre-central L
Intermediate frontal, RA
Pre-central, R
Superior frontal, R
Central, RC
Parietal lobe
Intraparietal, L
Intraparietal, R
Sylvian region
Sylvian fissure, L
Insular region
Insular, R
Mean
Max
Neighbourhood
Mean SD
Max SD
8.6 (0.6)
9.9 (0.5)
11.7 (2.0)
6.0 (1.1)
12.1 (1.8)
18.1 (3.2)
11.2 (0.5)
12.6 (0.7)
11.5 (0.2)
10.5 (0.2)
11.8 (0.4)
16.9 (0.6)
20.7 (0.6)
17.6 (1.1)
11.8 (2.1)
20.3 (2.6)
22.2 (2.1)
19.7 (1.2)
20.1 (1.0)
19.9 (0.9)
17.9 (0.2)
20.3 (1.1)
13.6 (2.6)
18.9 (2.6)
10.4 (1.0)
7.7 (2.1)
18.1 (5.4)
20.2 (4.0)
14.2 (1.7)
18.3 (3.0)
13.9 (1.2)
11.1 (0.1)
15.0 (1.6)
9.5 1.6
11.3 2.9
9.1 1.3
4.3 1.6
9.0 1.7
9.9 2.6
18.9 3.1
18.1 4.3
15.6 1.8
7.1 2.2
14.9 2.1
16.2 2.9
10.9 2.5
17.5 2.6
11.5 (1.2)
12.2 (0.7)
14.0 (0.6)
13.6 (0.2)
21.1 (0.6)
21.6 (0.3)
24.0 (1.4)
23.3 (0.9)
11.8 (1.0)
18.2 (3.6)
18.6 (5.2)
15.7 (2.3)
13.2 1.4
22.1 1.6
13.4 1.0
22.1 1.4
18.6 (3.4)
13.3 (1.1)
32.1 (3.6)
21.7 (1.8)
27.3 (5.7)
20.3 (6.9)
6.1 3.7
12.0 1.2
10.4 6.0
25.2 2.0
11.7 (0.4)
20.8 (0.7)
16.3 (1.4)
9.9 4.5
16.4 6.7
15.6 (0.6)
32.1 (1.5)
12.3 (0.1)
12.7 5.2
20.1 7.8
Note that the FCD lesion in one patient was related to the bottom of two sulci (intraparietal and Sylvian). Average depth of the portion of
the sulcal bottom line in the neighbourhood of the FCD lesion (see Methods section for details) is also shown. Mean and maximum ( SD)
depths for the same sulcus in controls are also shown. Letters in superscript (A^ C) correspond to the three examples shown in Fig 4.
Fig. 4 Histologically proven focal cortical dysplasia at the bottom of a sulcus in three patients (A^C). Top row. Three-dimensional
surface rendering of the MRI. The FCD sulcus (turquoise) and the lesion (red) are shown in semi-transparent. Sulci related to the FCD
are magnified. Bottom rows: T1-weighted MR images (sagittal, coronal and axial) with and without overlaid FCD label. Details about sulcal
depth are given in Table 1.
no difference in the proportion of patients with ictal
activity concordant with the FCD between small and large
lesions (48% versus 64%, P = 0.6). There was a tendency to
perform more invasive SEEG recordings in patients with
small than large FCD lesions (33% versus 5%; P = 0.05).
Discussion
Clinical observations have prompted the recent addition of
the ‘bottom-of-sulcus dysplasia’ as a subtype of FCD with
balloon cells to the classification of malformations of cortical development (Barkovich et al., 2005). Here, we present
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Central area
Central, LB
Controls
Bottom of a sulcus cortical dysplasia
Bottom-of-a-sulcus dysplasia: potential
pathophysiological mechanisms
During the initial phase of brain development, the surface
of the hemispheres is smooth. Most sulci and gyri develop
during the third trimester, and the primary and secondary
fissures are visible at birth (Chi et al., 1977; Ono et al., 1990
Armstrong et al., 1995). The deepest parts of sulci form
early (Welker, 1990) and their appearance is less variable
than superficial folds that form later (Lohmann et al.,
2008). Importantly, sulcal bottoms are believed to play a
pivotal role in the ontogeny of human gyrification
(Armstrong et al., 1995; Ochiai et al., 2004; Regis et al.,
2005; Lohmann et al., 2008). Typically, the sulci continue to
develop after birth (Jernigan et al., 1991) and during early
childhood the degree of gyrification stabilizes (Zilles et al.,
1988). A variety of non-genetic factors, including intrauterine environment (Bartley et al., 1997; Mohr et al., 2004),
modulate hemispheric sulcal morphology, while data from
morphological analysis of individual sulci suggest genetic
encoding (Le Goualher et al., 2000).
Sulcal morphology and patterns are thought to be linked
to the underlying cytoarchitecture, and to be an effect of
the expansion of cortical grey matter and the development
of interconnecting circuits (Armstrong et al., 1995; Van
Essen, 1997; Hilgetag and Barbas, 2005). In these models,
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gyrification is influenced mainly by three factors: forces
generated by growing and migrating cells, local mechanical properties of tissue and extrinsic factors. More specifically, it has been postulated that cortical folding involves
forces resulting from different tension of growth between
early cortical strata (Caviness, 1975), tension along axons
connecting cortical areas (Van Essen, 1997) and changes in
subcortical connectivity (Rakic, 1988). The axonal tension
hypothesis (Van Essen, 1997) posits that the shape of
the brain reflects the viscoelastic tension exerted by fibres.
The convoluted cortical landscape is produced by the
global competition and resulting minimization of axonal
tension. In this scenario, gyri form between strongly
connected areas as axons draw them together, and sulci
arise between weakly linked or unconnected areas. Recent
studies based on the analysis of architectonic and connection data of primate prefrontal cortices (Hilgetag and
Barbas, 2005) provide quantitative evidence consistent
with a key role of these mechanical factors in the formation
of cortical convolutions through axonal tension.
The exact mechanisms responsible for the differential
vulnerability of the sulcal bottom to host small FCD lesions
are unclear. Van Essen’s theory (Van Essen, 1997)
postulates that weaker local interconnections may lead to
deep sulci due to the predominant traction exerted by the
long connections (i.e. thalamo–cortical or cortico–cortical).
This is supported by experimental data indicating that early
disruption in connectivity can lead to the emergence of
anomalous sulcation (Rakic, 1988). Thus, it is plausible that
the pattern observed in our patients may in part result from
a disturbed neuronal connectivity in areas adjacent or
distant to the FCD lesion. Indeed, dysplasias have been
shown to be associated with abnormal connectivity
(Sisodiya et al., 1995; Sisodiya and Free, 1997; Matsuda
et al., 2001; Lee et al., 2004) and decreased white matter
organization (Lee et al., 2005a).
Cytoarchitectonic differentiation, selective neuronal death
and progressive myelination are among the ‘micromechanic’ factors that also influence gyrification (Welker,
1990). Such factors are modified in large part by nongenetic influences (Lohmann et al., 1999). Neuronal density
has been shown to be decreased within the FCD lesion
compared to the adjacent unaffected cortex, possibly
reflecting neuropil expansion, local failure of neuronal
migration, proliferation or secondary neuronal loss (Thom
et al., 2005). Decreased neuronal density and the presence
of abnormal cytoarchitecture, including increased cellular
volume and abnormal dendrites (Alonso-Nanclares et al.,
2005), are likely to lead to changes in mechanical properties, such as increased elasticity (Lu et al., 2006; Smith et al.,
2007) and reduced anisotropy (Van Essen, 1997) of the
dysplastic cortex. In a recent morphogenetic computational
model, convolutions were found to be deeper in the
more elastic part of the cortical surface (Toro and Burnod,
2005). Thus, the co-occurrence of incomplete maturation,
decreased neuronal density and abnormal connectivity may
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for the first time a systematic evaluation of morphological
characteristics of Taylor-type FCD and the sulci harbouring
them. Our high-resolution MRI protocol combined with
advanced image processing enabled us to perform 3D
models of sulcal structure and shape, and the quantification
of their spatial characteristics. The results of this analysis
indicate that small FCD lesions are often located at the
bottom of a sulcus. Furthermore, the morphometric
analysis revealed that this sulcus is usually deeper than its
equivalent in healthy controls.
Accurate review of FCD images examples presented
in the literature shows that lesions may be located in
the inferior portion of a sulcus (Barkovich et al., 1997;
Chan et al., 1998; Bastos et al., 1999; Matsuda et al., 2001;
Usui et al., 2001; Urbach et al., 2002; Chassoux, 2003;
Colombo et al., 2003; Barkovich et al., 2005; Focke et al.,
2008). However, only one report on 24 FCD lesions
explicitly indicated that 4/19 (21%) of the rather small
dysplasias were located in the depth of a sulcus (Urbach
et al., 2002). This low incidence is most likely explained by
the use of low-resolution MR images with orthogonal
views, potentially leading to incorrect determination of
sulcal depth, connective patterns and interruptions. A small
lesion that affects the cortex in the depth of a sulcus,
however, is not easy to detect, mainly because of the complexity of the brain’s convolution. Mathematical models of
sulcal structure and shape can quantify cortical characteristics, and thus give diagnostic information not easily
available on visual observation.
Brain (2008), 131, 3246 ^3255
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create a local weakness within the developing cortical
mantle, particularly in the sulcal bottom. Fragility of the
fundi in neurodevelopmental disorders is also suggested by
quantitative cytoarchitectonic studies in schizophrenia that
have demonstrated reduced cell density in the bottom of
temporal lobe sulci (Chance et al., 2004). Moreover, we
previously demonstrated an abnormally deep collateral
sulcus in epileptic patients with developmental malformations of the hippocampus (Bernasconi et al., 2005).
Preferential location of small FCD lesions:
relevance to pharmacologically intractable
epilepsy
removal (Bailey and Von Bonin, 1951; Sanides, 1962).
In our patients, sulci harbouring small FCD lesions at
their bottom were easily identified macroscopically. In the
patient with a small lesion located at the crown of a gyrus,
neither careful visual inspection nor the automatic sulcal
extraction revealed the presence of microscopic gyration
at this location. Partial volume effects due to the relatively
low resolution of our 1 mm isotropic images most likely
preclude the distinction of microscopic sulci from the
surrounding grey matter. High-field MR imaging combined
with multiple phased arrays yielding images at submillimetre resolution may resolve such small-scale features
and thus allow exploring the subgyral architecture and its
relation to developmental lesions. This may be of particular
interest in patients with so-called non-lesional epilepsy.
In our cohort, active epileptic abnormalities were less
frequent in patients with small compared to those with
large FCD lesions, although the difference did not reach
statistical significance. This finding reflects the well-known
intrinsic epileptogenicity of dysplastic human cortex (Avoli
et al., 1999). The fact that scalp EEG enables the detection
of abnormal electrical activity even in some subtle deep
lesions suggests that the epileptogenic network in FCD
involves the peri-lesional areas (Raymond and Fish, 1996).
A more detailed evaluation of the relationship between
FCD location and EEG patterns would entail the exploration of the geometric correspondence between the folded
cortical surface and the rectilinear trajectory of depth
electrodes, a complex task that needs to be addressed
in future prospective studies using sophisticated EEG–MRI
co-registration methods and extensive SEEG coverage
(Munari, 1985; Munari et al., 1994).
Information about lesion localization is important
when planning invasive EEG recordings (Sisodiya, 2000).
Subdural electrodes are frequently used for evaluating
extra-temporal seizures (Jeha et al., 2007; Widdess-Walsh
et al., 2007) because they cover a large area of cortex and
allow functional mapping (Goldring and Gregorie, 1984;
Najm et al., 2002). However, the discrete ictal activity of
dysplastic lesions buried in the depth of a sulcus is more
likely to be detected when using depth electrodes (Talairach
et al., 1992; Chassoux et al., 2000; Privitera et al., 2000;
McGonigal et al., 2007), particularly when guided with
advanced imaging.
Accurate knowledge about the spatial location of subtle
FCD lesions may promote minimally invasive approaches
(Mikuni and Hashimoto, 2006) and is likely to increase the
sensitivity of novel intra-operative tools such as highresolution ultrasound to detect and delineate the surgical
target (Miller et al., 2008).
Funding
Canadian Institutes of Health Research (grant #203707MOP 57840).
Downloaded from http://brain.oxfordjournals.org/ by guest on September 30, 2016
Our approach based on a quantitative threshold in a
consecutive group of patients allowed us to determine that
FCD measuring 53 cm3 represent about 50% of cases,
indicating that small dysplastic lesions are indeed prevalent
in patients undergoing pre-surgical evaluation for intractable seizures of extra-temporal lobe origin.
The identification of FCD on MRI during presurgical
evaluation is of crucial clinical importance since the absence
of an identifiable lesion is likely to lead to a poor outcome
(Sisodiya, 2000). Although high-resolution MRI has made it
possible to visually identify malformations of cortical
development in an increasing number of patients with
neocortical epilepsy (Bernasconi, 2005), the identification of
small FCD lesions remains a difficult task, as shown by the
low detection rate (19%) on routine clinical imaging
reported in this study. Indeed, in recent retrospective
series, about 40% of patients with subtle, histopathologically proven Taylor-type FCD had an unrevealing MRI
(Matsuda et al., 2001; Hong et al., 2002; Tassi et al., 2002;
Colombo et al., 2003; Cossu et al., 2005; Lee et al., 2005b;
Jeha et al., 2007; McGonigal et al., 2007; Nobili et al.,
2007). Such cases are usually referred to as ‘MRI-negative’.
FCDs with balloon cells are not necessarily associated with
increased T2-signal (Chan et al., 1998). Moreover, 525% of
our patients with small FCD lesions at the bottom of a
sulcus had signs of transmantle dysplasia (Barkovich et al.,
1997). Therefore, we believe that prior knowledge of
preferential location of small FCD at the bottom of a
deep sulcus can direct the search for developmental
abnormalities, particularly in patients in whom large-scale
MRI features are only mildly abnormal or absent.
Moreover, this information should be kept in mind when
evaluating MRI data of infants, since signal changes related
to some Taylor-type FCD lesions may almost completely
regress with completion of myelination (Eltze et al., 2005).
A detailed histological examination of surgically resected
tissue of patients with pharmacoresistant epilepsy has
shown that major gyri may be composed of microscopic
gyri with corresponding sulci (Kaufmann et al., 1996).
These features, imperceptible by gross inspection, have been
described in anatomical atlases that paid particular attention to cortical surface characteristics after meningeal
P. Besson et al.
Bottom of a sulcus cortical dysplasia
3253
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