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Focal Cortical Dysplasia
Focal Cortical Dysplasia NK Focke, University of Tu¨bingen and Hertie Institute of Clinical Brain Research, Tu¨bingen, Germany M Thom, UCL Institute of Neurology, London, UK ã 2015 Elsevier Inc. All rights reserved.
Focal cortical dysplasia (FCD) is an important cause of focal epilepsies. FCDs have intrinsic epileptogenic properties and in a very high percentage of patients give rise to epilepsy, which is often resistant to medical treatment. They were first described by Taylor et al. in the 1970s from a series of epilepsy surgery specimens (Taylor, Falconer, Bruton, & Corsellis, 1971). The confirmation and subclassification of FCDs still remain a histopathologic diagnosis although modern imaging techniques, magnetic resonance imaging (MRI) in particular, have greatly improved the detection rate of FCD and contributed to our understanding of these lesions regarding patient care as well as their underlying neurobiology. FCDs are regarded as a subtype of malformations of cortical development and are characterized by the disruption of cortical lamination and neuronal and glial differentiation to varying degrees. They can appear isolated but can also be multifocal in a single patient or be associated with a second lesion, e.g., benign developmental tumors like dysembryoplastic neuroepithelial tumor and ganglioglioma.
Etiology of FCDs FCDs are generally considered developmental disorders due to erroneous neuronal migration or differentiation. Rare reports of FCD accumulation suggest a genetic background at least in some families (Leventer et al., 2014). The histopathologic similarity of FCDs and tuberous sclerosis also hints towards a possible involvement of the mammalian target of rapamycin (mTOR) pathway (Lee et al., 2014; Ljungberg et al., 2006). However, the exact etiology of the disease remains elusive in the majority of cases.
Classification and Histopathology of FCDs Several classification systems for cortical dysplasias have evolved over the years. FCD was first described as a distinct neuropathologic entity in the seminal paper of Taylor and colleagues (Taylor et al., 1971) based on observations in ten patients operated in the early epilepsy surgical programs. The term ‘cortical dysplasia,’ literally meaning abnormal formation of the cortex, then became rather freely used in the neuroimaging literature for a spectrum of malformations from polymicrogyria to subtle microscopic abnormalities as microdysgenesis. Using neuropathology criteria as the standard, the first universally accepted classification scheme for FCDs was the Palmini system in 2004; this separated the dysplasias with abnormal cortical lamination only (‘architectural’ dysplasias) from those with additional abnormal neuronal cytology (‘cytoarchitectural’ dysplasias), and these were classified as FCD types I and II, respectively (Palmini et al., 2004); other malformations, including microdysgenesis or
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mild malformations of cortical development, were excluded. The revised 2011 ILAE classification has added a third tier of FCDIII (Blumcke et al., 2011), which distinguishes dysplasias intimately associated with a second epileptogenic pathology (hippocampal sclerosis, low-grade glioneuronal tumors, and early-acquired vascular-destructive and inflammatory lesions), which have different pathoetiologies; this group will not be further discussed here. In the macroscopic examination of surgical resections of typical FCDII, the dysplastic region may appear firmer (due to gliosis) with poorer definition between the gray matter and white matter as compared to the adjacent normal cortex (Figure 1(a) and 1(b)). Some FCDs II are centered on the bottom of a sulcus although the abnormality can extend over several adjacent gyri, or rarely, they can be multifocal. In terms of lobar involvement, distribution around the central sulcus and frontal and temporal lobes is more common in surgical series. In some cases, however, even where FCDII is histologically proven, the abnormal region is not apparent macroscopically. The hallmark microscopic feature of FCDII is the identification of dysmorphic neurons. These are large, hyperchromatic, abnormally shaped and orientated neurons, distributed through the cortical layers as well as white matter, resulting in a haphazard cortical laminar architecture apparent at low magnification (Figure 1(c)). The abnormal area merges with the normal cortex at the margins, and single dysmorphic neurons may be identified at some distance away from the main focus of FCD. In pediatric FCDII, a greater packing density of dysmorphic neurons may be observed compared to adult cases where a reduced neuronal density compared to the normal cortex can be appreciated (which may represent neuronal loss) (Figure 1(d) and 1(e)); superimposed neurodegeneration may also be accelerated in older patients with FCD (Iyer et al., 2014; Sen et al., 2007; Thom et al., 2005). FCDII is subdivided into types A and B on the basis of identification balloon cells in histological sections (Figure 1(f)). These large cells have abundant cytoplasm, have eccentrically placed nucleus or multinucleation, and are present in groups or clusters, typically trailing in the white matter beneath the abnormal cortex. The presence of balloon cells in the white matter is also often associated with abnormal myelination (Shepherd et al., 2013). Dysmorphic neurons can be confirmed with immunohistochemistry for NeuN and both phosphorylated and nonphosphorylated neurofilament proteins (Figure 1(g) and 1(h)), whereas balloon cells are usually negative with these markers. Dysmorphic neurons may additionally retain expression of developmentally regulated proteins such as doublecortin; they phenotypically mostly align with intermediate progenitor cells that give rise to mature cortical pyramidal cells (Hadjivassiliou et al., 2010; Lamparello et al., 2007). Some balloon cells label with GFAP, in support of astroglial
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Figure 1 Pathological features of FCDII. (a) In a frontal lobe surgical resection, in one slice, the gray matter appears well defined compared to the white matter (arrowed). (b) In an adjacent slice of the same resection, there was poor definition between the gray matter and white matter (curved arrow), which corresponded histologically to the dysplasia. (c) Dysmorphic neurons (arrow) appear larger than normal neurons, appear hyperchromatic, and have abnormal shapes (H&E stain). (d) NeuN section of the normal cortex outer layers (I–III) labeled with NeuN neuronal marker (e). By contrast in the same cortical layers in a case of FCDII, NeuN demonstrates that the cortical layers II and III are populated by large dysmorphic neurons, intermingled with more normal-sized neurons. (f) A typical balloon cell (H&E). (g) Neurofilament (nonphosphorylated) of normal laminated cortex as seen in (d). (h) Neurofilament staining of the cortex as shown in (e) with FCDII shows increased labeling of dysmorphic neurons and their processes compared to normal. (i) Using pS6 immunolabeling as an indicator of mTOR pathway activation, strong labeling of dysmorphic neurons is shown.
lineage, as well as developmentally regulated intermediate filaments as vimentin, nestin, and delta-GFAP supporting an immature glial phenotype. In addition, stem cell proteins, as CD133, beta-integrin, and CD34, may be expressed as well as neuronal markers, with evidence for cell-cycle arrest and pathological stem cell properties in vitro (Thom et al., 2007; Yasin et al., 2010). Evidence of mTOR pathway activation can be demonstrated in the abnormal cell types of FCDII using immunohistochemistry (Figure 1(i)) and is currently implicated in
the pathoetiology of these lesions, therefore linking these lesions with other cortical malformations, including the hamartomas associated with tuberous sclerosis (Baybis et al., 2004; Crino, 2011). In FCDI, the macroscopic findings are indistinct, and abnormal radial and/or tangential alignment of cortical neurons is seen microscopically but without significant abnormalities of neuronal morphology. Intra- and interobserver reproducibility for the diagnosis of FCDI is less than for
INTRODUCTION TO CLINICAL BRAIN MAPPING | Focal Cortical Dysplasia
FCDII, and there are sometimes diagnostic difficulties in distinguishing FCDI reliably from normal variations in cortical architecture (Coras et al., 2012).
Epidemiology FCDII is the most common malformation in epilepsy surgical series. Its precise incidence in the general population and in patients with epilepsy is unknown. Interestingly, there is evidence that FCD is more common in boys than girls (OrtizGonzalez et al., 2013).
Imaging in FCDs The most important imaging modality for FCD detection is structural MRI. Computed tomography lacks the necessary tissue contrast and is not sufficient to reliably detect or rule out FCDs. Functional imaging modalities like SPECT and PET cannot directly detect FCDs but have an established value in the presurgical evaluation particularly in MR negative cases and, thus, may aid in indirectly improving the detection rate of FCD (Goffin et al., 2010). The choice of an optimized MR imaging paradigm is important. Generally, coronal sections are advisable to allow for a more convenient comparison of both hemispheres. The paradigm should consist of a high-resolution T1-weighted and/or inversion recovery image yielding a good gray/white matter contrast. T2-weighted scans with cerebrospinal fluid (CSF) signal suppression (T2-FLAIR) are important to detect increased T2 signal in the cortex and reduce CSF partial volume effects. Given the artifact sensitivity of T2FLAIR, another T2-weighted scan without CSF suppression is advisable. T2*-weighted scans or susceptibility weighted imaging (SWI) are also useful to detect vascular malformations like cavernoma, as is a contrast-enhanced T1-weighted scan to detect coincident enhancing lesions. FCDs themselves do not enhance since the blood–brain barrier is intact. However, DNET or ganglioglioma that are commonly associated with an FCD can show T1-enhancement. It is recommended to use slice thickness of 3 mm or lower; 3-D scans usually with 1 mm cubic resolution are a good alternative enabling later reconstruction in any orientation needed. Guidelines for an MRI paradigm are presented by the ILAE (ILAE Neuroimaging Commission, 1997) and recently updated based on the expected prevalence of epileptogenic lesions with a focus on FCDs (Wellmer et al., 2013). Typical features of FCDs in MR imaging are blurring of the gray–white junction zone, alterations of cortical thickness (both increases and decreases), changes of cortical intensity (usually T2 increase and T1 decrease), and a subcortical T2 signal increase often tapering down to the ventricle, the socalled transmantle sign (Barkovich, Kuzniecky, Bollen, & Grant, 1997). These features can appear combined or exclusive and are not specific to FCDs but can also be present in other lesion, for example, low-grade glioma. Thus, the visual identification of FCDs can be challenging especially if the lesion in question is small. Also, measures like cortical thickness are surprisingly controversial; both increases and decreases have been described. Some of the heterogeneity of MR imaging
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features can be caused by suboptimal standardization of the histopathologic classification of FCDs that is the reference for any description of imaging features. FCD of type 1/mild MCD especially showed relatively poor intraobserver concordance (Chamberlain et al., 2009). The recently updated neuropathologic consensus classification of FCD will hopefully improve this issue in the future (Blumcke et al., 2011). Currently, there is no clear consensus which MRI features are typical for which FCD subtype or if such specificity even exists even in the relatively well-characterized FCD subtypes IIa and IIb (Sisodiya, Fauser, Cross, & Thom, 2009). In a recent study, Mu¨hleber et al. used detailed neuropathologic quantification of FCD tissue based on the 2011 ILAE classification and, in their sample, found the transmantle sign to be specific for FCD subtype IIb (Muhlebner et al., 2012). Moreover, they found decreased cortical thickness in FCD subtype IIa, but these changed did not reach statistical significance. All subtypes of FCD showed a blurred gray–white junction zone, making this feature probably a good candidate for FCD screening in MRI. Example MR images of FCDs are shown in Figure 2. Given the complex folding of the cortical gyri and the variability of individual anatomy, visual interpretation of MRI requires expertise, particularly in cases of subtle FCDs that can easily be overlooked by unspecialized radiologists (von Oertzen et al., 2002). To aid in visual detection of subtle FCDs and other difficult-to-see epileptogenic lesions, computer-based postprocessing methods have been devised. The most common methods rely on voxel-based morphometry (Ashburner & Friston, 2000), an automated statistical method that uses a mass-univariate approach to create parametric maps, that is, an ‘image’ of statistical values. This can be used to compare a single scan against a group of healthy controls that define a normative range of – most commonly – gray matter volume derived from high-resolution T1-weighted scans. An early study from the late 1990s showed the general feasibility of the method (Woermann, Free, Koepp, Ashburner, & Duncan, 1999). Later, more sophisticated processing methods were introduced that considered the cortical thickness, local image intensities, and the particularly important ‘junction zone’ between the gray matter and white matter (Bernasconi et al., 2001; Colliot, Antel, Naessens, Bernasconi, & Bernasconi, 2006, Colliot et al., 2006, 2006; Huppertz et al., 2005). This approach can also be used on other MR imaging modalities like diffusion-tensor imaging (Eriksson, Rugg-Gunn, Symms, Barker, & Duncan, 2001; Rugg-Gunn, Eriksson, Symms, Barker, & Duncan, 2001; Rugg-Gunn et al., 2002), whole-brain T2-relaxometry (Rugg-Gunn, Boulby, Symms, Barker, & Duncan, 2005), double-inversion recovery (Rugg-Gunn, Boulby, Symms, Barker, & Duncan, 2006), magnetization transfer imaging (Rugg-Gunn et al., 2003), and T2-FLAIR (Focke et al., 2009; Focke, Symms, Burdett, & Duncan, 2008). All of these methods have shown some value in detecting previously missed FCD cases, but this plethora of different MR modalities and processing algorithms available also makes it difficult to give clear recommendations which method is preferable, especially since direct comparisons of these methods are scarce. One of the very few studies that directly compared some quantitative MR modalities found that 16% of patients showed concordant focal changes in whole-brain T2 relaxometry and double-inversion recovery;
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INTRODUCTION TO CLINICAL BRAIN MAPPING | Focal Cortical Dysplasia
Figure 2 Typical MRI findings in FCD. (a) Focal lesion with blurring of the gray–white junction zone, some increased cortical thickness, and typical transmantle sign on T2-FLAIR (arrow). Resection showed FCD subtype IIb. (b) Again, some diffuse blurring of the gray–white junction zone otherwise unremarkable. Postprocessing revealed significantly increase gray matter concentration (pink), increases in T2-FLAIR signal (red-yellow), and broadened junction zone (blue) clearly facilitating the detection of the lesion. Resection showed FCD subtype IIa.
for magnetization transfer and ‘classical’ gray matter VBM, detection rates were lower (5% and 9%, respectively) (Salmenpera et al., 2007). However, all voxel-based studies suffer from false-positive findings, that is, statistically significant differences that do not represent true, clinically relevant differences. In the Salempera et al. study, such probably spurious findings were seen in 42% of cases with double-inversion recovery, 36% in whole-brain T2-relaxometry, 6% with magnetization transfer, and 7% with classical VBM. Therefore, all these postprocessing methods have to be balanced between a good sensitivity and an acceptable specificity, like all other diagnostic methods in medicine, and should be seen just as one aspect of the multimodal presurgical evaluation of epilepsy patients. Figure 2(b) shows an example of a VBM-based postprocessing.
thus, the resection of an FCD is impossible due to functional relevance. Multiple subpial transections are a possibility; however, success rates are lower than those with resective surgery (Obeid, Wyllie, Rahi, & Mikati, 2009). There is no specific drug treatment for patients with FCD; all types of antiepileptic drugs indicated for focal epilepsy can be used and can be efficacious although the overall rate of resistant patients is high. If the epilepsy is well controlled in individual cases, surgery is not indicated since FCDs do not progress. However, it is not always possible to rule out a low-grade glioma by imaging. Thus, at times, follow-up imaging and resection may still be indicated for non-epilepsy-related reasons.
Clinical Aspects
FCDs are a developmental malformation of cortical architecture and are commonly associated with refractory epilepsy. Resective surgery is often needed to improve the quality of life and seizure control. Therefore, it is of pivotal importance to detect FCDs in these patients and reliably identify the borders and extent of these malformations especially when close to the functionally relevant cortex. Some typical MRI features have been described, but further work is need to better link histopathologic classification and in vivo MRI. Postprocessing tools are helpful in detection of FCDs compared to expert
Epilepsy is commonly refractory to medical treatment if an FCD is the underlying cause. Hence, surgical resection is often the therapy of choice. Imaging has a pivotal role in this context; the detection of a focal lesion like an FCD is the most important predictive factor in this scenario (Tellez-Zenteno, Dhar, & Wiebe, 2005; Tellez-Zenteno, Hernandez Ronquillo, Moien-Afshari, & Wiebe, 2010). Areas of FCDs are not necessarily devoid of physiological function (Vitali et al., 2008);
Summary
INTRODUCTION TO CLINICAL BRAIN MAPPING | Focal Cortical Dysplasia
visual assessment but have to be carefully evaluated given the rather low specificity of current methods.
See also: INTRODUCTION TO ACQUISITION METHODS: Anatomical MRI for Human Brain Morphometry; Diffusion MRI; HighField Acquisition; INTRODUCTION TO ANATOMY AND PHYSIOLOGY: Cortical Surface Morphometry; Gyrification in the Human Brain; INTRODUCTION TO CLINICAL BRAIN MAPPING: Epilepsy Therapeutics; INTRODUCTION TO METHODS AND MODELING: Cortical Thickness Mapping; Manual Morphometry; Sulcus Identification and Labeling; Surface-Based Morphometry; Tissue Classification; Tissue Microstructure Imaging with Diffusion MRI; Voxel-Based Morphometry.
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Focal cortical dysplasia (FCD) is an important cause of focal epilepsies. FCDs have intrinsic epileptogenic properties and in a very high percentage of patients give rise to epilepsy, which is often resistant to medical treatment. They were first described by Taylor et al. in the 1970s from a series of epilepsy surgery specimens (Taylor, Falconer, Bruton, & Corsellis, 1971). The confirmation and subclassification of FCDs still remain a histopathologic diagnosis although modern imaging techniques, magnetic resonance imaging (MRI) in particular, have greatly improved the detection rate of FCD and contributed to our understanding of these lesions regarding patient care as well as their underlying neurobiology. FCDs are regarded as a subtype of malformations of cortical development and are characterized by the disruption of cortical lamination and neuronal and glial differentiation to varying degrees. They can appear isolated but can also be multifocal in a single patient or be associated with a second lesion, e.g., benign developmental tumors like dysembryoplastic neuroepithelial tumor and ganglioglioma.
Etiology of FCDs FCDs are generally considered developmental disorders due to erroneous neuronal migration or differentiation. Rare reports of FCD accumulation suggest a genetic background at least in some families (Leventer et al., 2014). The histopathologic similarity of FCDs and tuberous sclerosis also hints towards a possible involvement of the mammalian target of rapamycin (mTOR) pathway (Lee et al., 2014; Ljungberg et al., 2006). However, the exact etiology of the disease remains elusive in the majority of cases.
Classification and Histopathology of FCDs Several classification systems for cortical dysplasias have evolved over the years. FCD was first described as a distinct neuropathologic entity in the seminal paper of Taylor and colleagues (Taylor et al., 1971) based on observations in ten patients operated in the early epilepsy surgical programs. The term ‘cortical dysplasia,’ literally meaning abnormal formation of the cortex, then became rather freely used in the neuroimaging literature for a spectrum of malformations from polymicrogyria to subtle microscopic abnormalities as microdysgenesis. Using neuropathology criteria as the standard, the first universally accepted classification scheme for FCDs was the Palmini system in 2004; this separated the dysplasias with abnormal cortical lamination only (‘architectural’ dysplasias) from those with additional abnormal neuronal cytology (‘cytoarchitectural’ dysplasias), and these were classified as FCD types I and II, respectively (Palmini et al., 2004); other malformations, including microdysgenesis or
Brain Mapping: An Encyclopedic Reference
mild malformations of cortical development, were excluded. The revised 2011 ILAE classification has added a third tier of FCDIII (Blumcke et al., 2011), which distinguishes dysplasias intimately associated with a second epileptogenic pathology (hippocampal sclerosis, low-grade glioneuronal tumors, and early-acquired vascular-destructive and inflammatory lesions), which have different pathoetiologies; this group will not be further discussed here. In the macroscopic examination of surgical resections of typical FCDII, the dysplastic region may appear firmer (due to gliosis) with poorer definition between the gray matter and white matter as compared to the adjacent normal cortex (Figure 1(a) and 1(b)). Some FCDs II are centered on the bottom of a sulcus although the abnormality can extend over several adjacent gyri, or rarely, they can be multifocal. In terms of lobar involvement, distribution around the central sulcus and frontal and temporal lobes is more common in surgical series. In some cases, however, even where FCDII is histologically proven, the abnormal region is not apparent macroscopically. The hallmark microscopic feature of FCDII is the identification of dysmorphic neurons. These are large, hyperchromatic, abnormally shaped and orientated neurons, distributed through the cortical layers as well as white matter, resulting in a haphazard cortical laminar architecture apparent at low magnification (Figure 1(c)). The abnormal area merges with the normal cortex at the margins, and single dysmorphic neurons may be identified at some distance away from the main focus of FCD. In pediatric FCDII, a greater packing density of dysmorphic neurons may be observed compared to adult cases where a reduced neuronal density compared to the normal cortex can be appreciated (which may represent neuronal loss) (Figure 1(d) and 1(e)); superimposed neurodegeneration may also be accelerated in older patients with FCD (Iyer et al., 2014; Sen et al., 2007; Thom et al., 2005). FCDII is subdivided into types A and B on the basis of identification balloon cells in histological sections (Figure 1(f)). These large cells have abundant cytoplasm, have eccentrically placed nucleus or multinucleation, and are present in groups or clusters, typically trailing in the white matter beneath the abnormal cortex. The presence of balloon cells in the white matter is also often associated with abnormal myelination (Shepherd et al., 2013). Dysmorphic neurons can be confirmed with immunohistochemistry for NeuN and both phosphorylated and nonphosphorylated neurofilament proteins (Figure 1(g) and 1(h)), whereas balloon cells are usually negative with these markers. Dysmorphic neurons may additionally retain expression of developmentally regulated proteins such as doublecortin; they phenotypically mostly align with intermediate progenitor cells that give rise to mature cortical pyramidal cells (Hadjivassiliou et al., 2010; Lamparello et al., 2007). Some balloon cells label with GFAP, in support of astroglial
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Figure 1 Pathological features of FCDII. (a) In a frontal lobe surgical resection, in one slice, the gray matter appears well defined compared to the white matter (arrowed). (b) In an adjacent slice of the same resection, there was poor definition between the gray matter and white matter (curved arrow), which corresponded histologically to the dysplasia. (c) Dysmorphic neurons (arrow) appear larger than normal neurons, appear hyperchromatic, and have abnormal shapes (H&E stain). (d) NeuN section of the normal cortex outer layers (I–III) labeled with NeuN neuronal marker (e). By contrast in the same cortical layers in a case of FCDII, NeuN demonstrates that the cortical layers II and III are populated by large dysmorphic neurons, intermingled with more normal-sized neurons. (f) A typical balloon cell (H&E). (g) Neurofilament (nonphosphorylated) of normal laminated cortex as seen in (d). (h) Neurofilament staining of the cortex as shown in (e) with FCDII shows increased labeling of dysmorphic neurons and their processes compared to normal. (i) Using pS6 immunolabeling as an indicator of mTOR pathway activation, strong labeling of dysmorphic neurons is shown.
lineage, as well as developmentally regulated intermediate filaments as vimentin, nestin, and delta-GFAP supporting an immature glial phenotype. In addition, stem cell proteins, as CD133, beta-integrin, and CD34, may be expressed as well as neuronal markers, with evidence for cell-cycle arrest and pathological stem cell properties in vitro (Thom et al., 2007; Yasin et al., 2010). Evidence of mTOR pathway activation can be demonstrated in the abnormal cell types of FCDII using immunohistochemistry (Figure 1(i)) and is currently implicated in
the pathoetiology of these lesions, therefore linking these lesions with other cortical malformations, including the hamartomas associated with tuberous sclerosis (Baybis et al., 2004; Crino, 2011). In FCDI, the macroscopic findings are indistinct, and abnormal radial and/or tangential alignment of cortical neurons is seen microscopically but without significant abnormalities of neuronal morphology. Intra- and interobserver reproducibility for the diagnosis of FCDI is less than for
INTRODUCTION TO CLINICAL BRAIN MAPPING | Focal Cortical Dysplasia
FCDII, and there are sometimes diagnostic difficulties in distinguishing FCDI reliably from normal variations in cortical architecture (Coras et al., 2012).
Epidemiology FCDII is the most common malformation in epilepsy surgical series. Its precise incidence in the general population and in patients with epilepsy is unknown. Interestingly, there is evidence that FCD is more common in boys than girls (OrtizGonzalez et al., 2013).
Imaging in FCDs The most important imaging modality for FCD detection is structural MRI. Computed tomography lacks the necessary tissue contrast and is not sufficient to reliably detect or rule out FCDs. Functional imaging modalities like SPECT and PET cannot directly detect FCDs but have an established value in the presurgical evaluation particularly in MR negative cases and, thus, may aid in indirectly improving the detection rate of FCD (Goffin et al., 2010). The choice of an optimized MR imaging paradigm is important. Generally, coronal sections are advisable to allow for a more convenient comparison of both hemispheres. The paradigm should consist of a high-resolution T1-weighted and/or inversion recovery image yielding a good gray/white matter contrast. T2-weighted scans with cerebrospinal fluid (CSF) signal suppression (T2-FLAIR) are important to detect increased T2 signal in the cortex and reduce CSF partial volume effects. Given the artifact sensitivity of T2FLAIR, another T2-weighted scan without CSF suppression is advisable. T2*-weighted scans or susceptibility weighted imaging (SWI) are also useful to detect vascular malformations like cavernoma, as is a contrast-enhanced T1-weighted scan to detect coincident enhancing lesions. FCDs themselves do not enhance since the blood–brain barrier is intact. However, DNET or ganglioglioma that are commonly associated with an FCD can show T1-enhancement. It is recommended to use slice thickness of 3 mm or lower; 3-D scans usually with 1 mm cubic resolution are a good alternative enabling later reconstruction in any orientation needed. Guidelines for an MRI paradigm are presented by the ILAE (ILAE Neuroimaging Commission, 1997) and recently updated based on the expected prevalence of epileptogenic lesions with a focus on FCDs (Wellmer et al., 2013). Typical features of FCDs in MR imaging are blurring of the gray–white junction zone, alterations of cortical thickness (both increases and decreases), changes of cortical intensity (usually T2 increase and T1 decrease), and a subcortical T2 signal increase often tapering down to the ventricle, the socalled transmantle sign (Barkovich, Kuzniecky, Bollen, & Grant, 1997). These features can appear combined or exclusive and are not specific to FCDs but can also be present in other lesion, for example, low-grade glioma. Thus, the visual identification of FCDs can be challenging especially if the lesion in question is small. Also, measures like cortical thickness are surprisingly controversial; both increases and decreases have been described. Some of the heterogeneity of MR imaging
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features can be caused by suboptimal standardization of the histopathologic classification of FCDs that is the reference for any description of imaging features. FCD of type 1/mild MCD especially showed relatively poor intraobserver concordance (Chamberlain et al., 2009). The recently updated neuropathologic consensus classification of FCD will hopefully improve this issue in the future (Blumcke et al., 2011). Currently, there is no clear consensus which MRI features are typical for which FCD subtype or if such specificity even exists even in the relatively well-characterized FCD subtypes IIa and IIb (Sisodiya, Fauser, Cross, & Thom, 2009). In a recent study, Mu¨hleber et al. used detailed neuropathologic quantification of FCD tissue based on the 2011 ILAE classification and, in their sample, found the transmantle sign to be specific for FCD subtype IIb (Muhlebner et al., 2012). Moreover, they found decreased cortical thickness in FCD subtype IIa, but these changed did not reach statistical significance. All subtypes of FCD showed a blurred gray–white junction zone, making this feature probably a good candidate for FCD screening in MRI. Example MR images of FCDs are shown in Figure 2. Given the complex folding of the cortical gyri and the variability of individual anatomy, visual interpretation of MRI requires expertise, particularly in cases of subtle FCDs that can easily be overlooked by unspecialized radiologists (von Oertzen et al., 2002). To aid in visual detection of subtle FCDs and other difficult-to-see epileptogenic lesions, computer-based postprocessing methods have been devised. The most common methods rely on voxel-based morphometry (Ashburner & Friston, 2000), an automated statistical method that uses a mass-univariate approach to create parametric maps, that is, an ‘image’ of statistical values. This can be used to compare a single scan against a group of healthy controls that define a normative range of – most commonly – gray matter volume derived from high-resolution T1-weighted scans. An early study from the late 1990s showed the general feasibility of the method (Woermann, Free, Koepp, Ashburner, & Duncan, 1999). Later, more sophisticated processing methods were introduced that considered the cortical thickness, local image intensities, and the particularly important ‘junction zone’ between the gray matter and white matter (Bernasconi et al., 2001; Colliot, Antel, Naessens, Bernasconi, & Bernasconi, 2006, Colliot et al., 2006, 2006; Huppertz et al., 2005). This approach can also be used on other MR imaging modalities like diffusion-tensor imaging (Eriksson, Rugg-Gunn, Symms, Barker, & Duncan, 2001; Rugg-Gunn, Eriksson, Symms, Barker, & Duncan, 2001; Rugg-Gunn et al., 2002), whole-brain T2-relaxometry (Rugg-Gunn, Boulby, Symms, Barker, & Duncan, 2005), double-inversion recovery (Rugg-Gunn, Boulby, Symms, Barker, & Duncan, 2006), magnetization transfer imaging (Rugg-Gunn et al., 2003), and T2-FLAIR (Focke et al., 2009; Focke, Symms, Burdett, & Duncan, 2008). All of these methods have shown some value in detecting previously missed FCD cases, but this plethora of different MR modalities and processing algorithms available also makes it difficult to give clear recommendations which method is preferable, especially since direct comparisons of these methods are scarce. One of the very few studies that directly compared some quantitative MR modalities found that 16% of patients showed concordant focal changes in whole-brain T2 relaxometry and double-inversion recovery;
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INTRODUCTION TO CLINICAL BRAIN MAPPING | Focal Cortical Dysplasia
Figure 2 Typical MRI findings in FCD. (a) Focal lesion with blurring of the gray–white junction zone, some increased cortical thickness, and typical transmantle sign on T2-FLAIR (arrow). Resection showed FCD subtype IIb. (b) Again, some diffuse blurring of the gray–white junction zone otherwise unremarkable. Postprocessing revealed significantly increase gray matter concentration (pink), increases in T2-FLAIR signal (red-yellow), and broadened junction zone (blue) clearly facilitating the detection of the lesion. Resection showed FCD subtype IIa.
for magnetization transfer and ‘classical’ gray matter VBM, detection rates were lower (5% and 9%, respectively) (Salmenpera et al., 2007). However, all voxel-based studies suffer from false-positive findings, that is, statistically significant differences that do not represent true, clinically relevant differences. In the Salempera et al. study, such probably spurious findings were seen in 42% of cases with double-inversion recovery, 36% in whole-brain T2-relaxometry, 6% with magnetization transfer, and 7% with classical VBM. Therefore, all these postprocessing methods have to be balanced between a good sensitivity and an acceptable specificity, like all other diagnostic methods in medicine, and should be seen just as one aspect of the multimodal presurgical evaluation of epilepsy patients. Figure 2(b) shows an example of a VBM-based postprocessing.
thus, the resection of an FCD is impossible due to functional relevance. Multiple subpial transections are a possibility; however, success rates are lower than those with resective surgery (Obeid, Wyllie, Rahi, & Mikati, 2009). There is no specific drug treatment for patients with FCD; all types of antiepileptic drugs indicated for focal epilepsy can be used and can be efficacious although the overall rate of resistant patients is high. If the epilepsy is well controlled in individual cases, surgery is not indicated since FCDs do not progress. However, it is not always possible to rule out a low-grade glioma by imaging. Thus, at times, follow-up imaging and resection may still be indicated for non-epilepsy-related reasons.
Clinical Aspects
FCDs are a developmental malformation of cortical architecture and are commonly associated with refractory epilepsy. Resective surgery is often needed to improve the quality of life and seizure control. Therefore, it is of pivotal importance to detect FCDs in these patients and reliably identify the borders and extent of these malformations especially when close to the functionally relevant cortex. Some typical MRI features have been described, but further work is need to better link histopathologic classification and in vivo MRI. Postprocessing tools are helpful in detection of FCDs compared to expert
Epilepsy is commonly refractory to medical treatment if an FCD is the underlying cause. Hence, surgical resection is often the therapy of choice. Imaging has a pivotal role in this context; the detection of a focal lesion like an FCD is the most important predictive factor in this scenario (Tellez-Zenteno, Dhar, & Wiebe, 2005; Tellez-Zenteno, Hernandez Ronquillo, Moien-Afshari, & Wiebe, 2010). Areas of FCDs are not necessarily devoid of physiological function (Vitali et al., 2008);
Summary
INTRODUCTION TO CLINICAL BRAIN MAPPING | Focal Cortical Dysplasia
visual assessment but have to be carefully evaluated given the rather low specificity of current methods.
See also: INTRODUCTION TO ACQUISITION METHODS: Anatomical MRI for Human Brain Morphometry; Diffusion MRI; HighField Acquisition; INTRODUCTION TO ANATOMY AND PHYSIOLOGY: Cortical Surface Morphometry; Gyrification in the Human Brain; INTRODUCTION TO CLINICAL BRAIN MAPPING: Epilepsy Therapeutics; INTRODUCTION TO METHODS AND MODELING: Cortical Thickness Mapping; Manual Morphometry; Sulcus Identification and Labeling; Surface-Based Morphometry; Tissue Classification; Tissue Microstructure Imaging with Diffusion MRI; Voxel-Based Morphometry.
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von Oertzen, J., Urbach, H., Jungbluth, S., Kurthen, M., Reuber, M., Fernandez, G., et al. (2002). Standard magnetic resonance imaging is inadequate for patients with refractory focal epilepsy. Journal of Neurology, Neurosurgery and Psychiatry, 73(6), 643–647. Wellmer, J., Quesada, C. M., Rothe, L., Elger, C. E., Bien, C. G., & Urbach, H. (2013). Proposal for a magnetic resonance imaging protocol for the detection of epileptogenic lesions at early outpatient stages. Epilepsia, 54(11), 1977–1987. Woermann, F. G., Free, S. L., Koepp, M. J., Ashburner, J., & Duncan, J. S. (1999). Voxel-by-voxel comparison of automatically segmented cerebral gray matter – A rater-independent comparison of structural MRI in patients with epilepsy. NeuroImage, 10(4), 373–384. Yasin, S. A., Latak, K., Becherini, F., Ganapathi, A., Miller, K., Campos, O., et al. (2010). Balloon cells in human cortical dysplasia and tuberous sclerosis: Isolation of a pathological progenitor-like cell. Acta Neuropathologica, 120(1), 85–96.