Local axonal architecture and spontaneous dynamic BOLD fluctuations in bottom-of-sulcus-dysplasia: a model of cryptogenic location related seizures

Epilepsy is one of the common neurologic syndromes with a lifetime incidence of
2-4% and about 50% of these patients suffer from partial seizures. Neuroimaging
is used to determine the origin of these seizures. However, in a large
proportion of these patients with partial seizures, MRI shows no abnormalities.
Even with state-of-the-art imaging techniques many localization-related
seizures remain cryptogenic. It is assumed that the majority of these patients
have a small cortical dysplasia. Detecting these lesions is of clinical
importance in patients with intractable epilepsy, because resection of these
focal lesions may be the only viable therapeutic option and there is an
excellent prognosis for seizure control following focal resection (Urbach
2002).
Different imaging strategies have been implemented to increase the sensitivity
for the detection of such small malformations. Advances in MRI technology have
certainly improved image quality and consequently increased the detection rate.
Despite these improvements, a large proportion of studies remain negative.
Post-processing techniques have also been applied to the imaging data to
improve the conspicuity and detection rate of small lesions.
These techniques employ voxel-based morphometry and parametric mapping of
cortical thickness and gray-white matter transition to increase the sensitivity
of MRI for the detection of malformations of cortical development. However,
these studies have not shown a consistently improved sensitivity compared with
visual image reading.
With visual assessment as gold standard the sensitivity of these techniques is
between 78 and 90% with a reported specificity between 50 and 100% (Antel 2002,
Huppertz 2005, Bonhilha 2006, Colliot 2006).
Another approach is to use novel imaging techniques that rely on different
intrinsic contrast mechanisms and may show previously unrevealed lesions. There
are a number of such novel MRI contrasts that have been shown to be more
sensitive for cerebral abnormalities than conventional MRI.
Two of these techniques are resting state functional MRI (rs-fMRI) and
diffusion tensor imaging (DTI).
DTI (Pierpaoli 1996 a&b, Helpern 1995) show reversible changes in active
regions during status epilepticus (e.g. Szabo 2005, Farina 2004, Hufnagel 2003,
Diehl 1999).
Although these reversible changes on MRI are most prominent in patients after
a status epilepticus and prolonged seizures and are rarely seen after a normal
seizure (Cianfoni ASNR 2009), this does have implications for patient
selection. Patients should be seizure free for at least a few days and they
should not have suffered from prolonged seizures or a status in the last two
month. However, the brain is a dynamic organ and when dealing with connectivity
there is no clear distinction between functional and structural changes. In
part, this distinction is not relevant as long as these techniques increase the
sensitivity for the detection of epileptogenic lesions.

DTI can also be used to show aberrant fibre connections in cerebral
malformations (Lee 2005). In post-traumatic brain injury regional DWI and DTI
parameters are more disturbed in patients with epilepsy as compared to those
without epilepsy (Gupta 2005). As such DTI provides data on the structural
connectivity and micro-structural integrity of the brain.
Rs-fMRI provides information about the (unconditional) synchronicity of
spontaneous temporal blood signal fluctuations between different brain regions
based on the blood oxygen level dependent (BOLD) effect and can be used to map
the functional connectivity as opposed to the structural (i.e. axonal)
connectivity as assessed by DTI.
There is however a fundamental problem with the application of these technique
for the detection of small malformations of cortical development. That is the
lack of a gold standard. Visual assessment of MRI scans is mainly based on
pattern recognition and if a cortical region has deviant morphological features
as compared to the surrounding cortex it is presumed abnormal. This technique
was proven to be specific, because a high correlation was found between
abnormalities on conventional MRI and the histopathology of the resected
lesions. Such pattern recognition is not yet possible in connectivity studies
because it is not clear yet which features distinguish normal from abnormal
cortex.
To this tackle this issue, we propose to use a very specific and well-defined
type of cortical dysplasia as a model to study small cortical malformations of
structural and functional connectivity.
A recently described archetype of focal cortical dysplasia may serve as such a
model for small cortical lesions. In the 2005 revision of the Barkovich
classification (Barkovich 2005), a new type of MCD was proposed;
bottom-of-sulcus dysplasia (BOSD) and it is classified in the group of
malformations due to abnormal proliferation, FCD with balloon cells. The lesion
may be difficult to detect on MRI and, even in expert centres*, is often missed
by experts on initial inspection of images. The imaging characteristics are
those of FCD of the Taylor type. However, the typical location of the dysplasia
at the bottom of a sulcus is infrequently seen in what we would normally call
typical FCD of the Taylor type. The pathological features of the resection
specimens are identical to those of any FCD. In FCD of Taylor type, the
dysplasia that probably overlaps with the BOSD, cortical laminar
disorganization, giant, ectopic and dysmorphic neurons is found. Gliosis is
also a prominent feature (Basto 1999). Hypomyelinated white matter and radially
orientated balloon cells are also reported (Urbach 2002). BOSD poses a
diagnostic challenge because of the small size and the location of the lesion.
The major problem with BOSD is that they can be subtle and easily missed on
initial examination of images. Diagnosis is greatly aided by having images with
excellent signal-to-noise ratio so that the blurring of the
grey-to-white-matter junction at the bottom of the sulcus can be properly
appreciated as well as the increased signal intensity of the cortex and
underlying white matter on T2-weighted images.

Furthermore, the post-surgical outcome appears to be excellent after complete
resection as reported (Urbach 2002). It appears that the disturbance is very
focal and the surrounding brain is not affected. With advancing imaging
techniques the detection rate of such small lesions is improved and a recent
publication showed that 68% of all FCDs were located in the depth of a sulcus
(Besson 2008). There is a continuum of increasing abnormalities in the
histology of cortical dysplasia from Palmini type IA to type IIB, and because
many of these lesions are in the ictal onset zone we postulate that the MR
image and connectivity characteristics also will show a continuum of increasing
abnormalities (Palmini 2004). Therefore, we propose to use BOSD, a Palminni
type IIB lesion, as a model for the up to now undetected cortical
malformations. BOSD is small, with only focal histological abnormalities, also
illustrated by the good outcome after focal resection of these apparently
highly epileptogenic lesions. Once this model type of dysplasia is fully
characterized in terms of rs-fMRI and DTI measures, more, thus far undetected,
small lesions may be become detectable.


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Primary objective: The ultimate goal is to achieve a more sensitive method for
detecting malformations of cortical development. This encompasses two steps:
the development of the method and the assessment of the sensitivity and
specificity of the method. The aim of the current project is to achieve a
characterization of the functional and structural connectivity of a specific
type of focal cortical dysplasia that can serve as a model for more subtle
dysplasias. When successful, the second step, the assessment of the new
technique on patient with location-related cryptogenic seizures will be the
subject of a subsequent separate study.

Using high-resolution DTI the local architecture of the normal and abnormal
cortex is imaged. During both image data acquisition as well as post-processing
the variable and complex anatomy is taken into account. Based on the DTI
analysis the different sub-regions of the abnormal gyrus will be segmented
based on the local tractographic topology. This is only possible with *high
angular resolution diffusion imaging* (HARDI), which encompasses 54-128
independent diffusion measurement directions.
The rs-fMRI will be used to characterize the spontaneous fluctuations of the
BOLD response in and around the BOSD and compare these results with the
controls. Spectral analysis will be applied in the assessment of rs-fMRI with
spectral density in the high (>80 mHz) and low frequency (<80 mHz) range will
be used as outcome variable.
Addendum 7 and 14
For DTI the quantitative outcome parameters will be the local Apparent
Diffusion Coefficient (ADC), Fractional Anisotropy (FA), and tract volume and
tract FA values seeded in the white matter region close to the BOSD. These
parameters will be obtained in the region close to the BOSD and the
corresponding contralateral (normal) regions.
For rs-fMRI the correlation coefficient will be determined between the rs-fMRI
time course signal from a region in the BOSD and all voxels in the rest of the
brain. The resulting map will be compared with the same analysis seeded to the
contralateral region. Besides the time courses, also the spectrum (Fourier
transformed signal) of the time courses will be analyzed. For this the
amplitudes of the spectral components in the high (> 80 mHz) and low (<80 mHz)
frequency ranges will be compared between the BOSD region and the contralateral
region.
DTI and rs-fMRI measures will be compared.

The MRI-techniques and questionnaire that are used in this study are
non-invasive. Therefore, the risks of participating in the study is minimal.
The risks of a MRI-scan are negligible because it is a magnetic field, does not
involve ionizing radiation and does not require contrast agents nor
anaesthetics.
Theoretically, it is possible that structural abnormalities will be found
during MRI in the healthy control group. Therefore, we will include only
subject who want to be informed whenever structural abnormalities are found
during imaging. All patients had a previous brain MRI which showed a focal
cortical dysplasia.

Benefit: There is no benefit for the patients or volunteers in this study,
however the potential benefit for epilepsy patients with a negative
conventional MRI is substantial; if a lesion is detected and a surgical
approach is possible, these patients may become seizure free.