| Abstract|| |
Focal cortical dysplasias (FCDs) represent the third most frequent cause of drug-resistant focal epilepsy in adults (after hippocampal sclerosis and tumours) submitted to surgery, and the most common in the pediatric age group. The International League Against Epilepsy (ILAE) classification of focal cortical dysplasia is still a reference and consists of a three-tiered system: FCD type I refers to isolated abnormalities in cortical layering; FCD type II refers to cases with abnormalities in cortical architecture and dysmorphic neurons with or without balloon cells; and FCD type III refers to abnormalities in cortical layering associated with other lesions. Recent studies have demonstrated that somatic mutations occurring post-zygotically during embryonal development and leading to mosaicism, underlie most brain malformations. The molecular pathogenesis of FCD type II is associated with activation of the mTOR pathway. Pathogenic variants in this pathway are recognized in up to 63% of cases and may occur both through single activating variants in activators of the mTOR signaling pathway or double-hit inactivating variants in repressors of the signaling pathway. The newly described mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy, has been found to show recurrent pathogenic variants in SLC35A2 with mosaicism. The present review describes the lesions of FCD and discusses the molecular pathogenesis and proposal for a revised classification.
Keywords: Epilepsy, focal cortical dysplasia, genetics, malformations of cortical development, neuropathology
|How to cite this article:|
Pinheiro J, Honavar M. Focal cortical dysplasia: Updates. Indian J Pathol Microbiol 2022;65, Suppl S1:189-97
| Introduction|| |
Drug resistant epilepsy is a recognised clinical feature of a large number and variety of malformations of the brain and is frequently associated with developmental delay and neurological deficits. It is estimated that cerebral malformations are found in up to 40% of pathologically examined brain tissue of subjects with epilepsy. Malformations arise from disturbance of the complex process of cerebral development during one or more of its three principal steps: cell proliferation in the periventricular germinal layer, neuronal migration using glial cell guides, and post-migration organization. These steps overlap, with continued neural cell proliferation as migration occurs and migration continues with precision as neuronal organization takes place and connections are made. This process may be disrupted by genetic abnormalities or by external influences, which include maternal diabetes, infections, alcohol, teratogenic drugs and toxins and irradiation or a combination of factors.
Advances in neuroimaging have played an important role in recognizing the importance of cerebral malformations as a cause of seizure disorders., Furthermore, they have contributed significantly to understanding the underlying structural abnormalities responsible for the clinical picture.,,
Malformations associated with chronic epilepsy are those of cerebral cortical development, involving neuronal and glial cells. Vascular malformations located in the cerebral hemispheres may also cause chronic epilepsy. The classification of these malformations from a pathological perspective has been based on the gross or microscopic location in the cerebral hemispheres, such as hemispheric, cortical, or heterotopic. However, the classification most used currently in clinical and neuroradiological practise is based on the stage of neurodevelopment first disrupted, using pathological and neuroimaging characteristics and when available genetic information. It was first proposed in 1996 and has been updated in keeping with newer findings, using the broad framework below,,:
Group I – Malformations secondary to abnormal neuronal and glial proliferation or apoptosis
Group II – Malformations due to abnormal cell migration
Group III – Malformations secondary to abnormal post-migrational development
The current classification includes almost all characterised cerebral cortical malformations and subtypes.
As surgery became available as a therapeutic option for resectable causes of drug resistant chronic epilepsy, attention was drawn to localised abnormalities resulting from malformations of cortical development (MCD), which were termed focal cortical dysplasia (FCD). According to a large multi-center surgical series, these lesions represented the third most frequent cause of drug-resistant focal epilepsy submitted to surgery, after hippocampal sclerosis and tumours, comprising up to 19.8% of cases. Moreover, it is the most common structural abnormality in pediatric age, representing 39.3% of resected lesions. In a recent series from a single tertiary care centre in India, FCD was observed in 14.9% drug resistant epilepsy submitted to surgery, and was the predominant pathology in extratemporal epilepsy specimens, representing 29.1% of these cases.
The aim of this article is to review the histopathological classification of focal cortical dysplasia and present updates in our knowledge of the genetic and epigenetic origins of these focal malformations.
| Histopathological Classification of Focal Cortical Dysplasia|| |
The term focal cortical dysplasia was initially introduced by Taylor et al. in 1971, in a seminal paper describing the pathological findings in 10 lobectomy specimens of patients submitted to surgery for the treatment of chronic epilepsy. They described localized areas of disrupted normal cortical architecture associated with the presence of large bizarre (dysmorphic) neurons distributed throughout the affected cortex but sparing the first cortical layer and, in a subset of cases, “grotesque” balloon cells were described. A histological similarity was drawn to the tubers of tuberous sclerosis, but they lacked the other clinical stigmata of the disease, and additional histological differences, such as reduced cortical cellularity, subpial wheat-sheaf like glial bundles, calcifications, and cyst formation.
Since this original paper, the improvements in imaging and electroencephalographic techniques in the assessment of patients with epilepsy, resections of drug-resistant epilepsy lesions have become increasingly more common.,,, Consequently, a variety of other and more subtle abnormalities of cortical layering have been identified histologically and have been designated cortical dysplasia, and a variety of terms have been utilized for similar cortical abnormalities. Responding to the need for uniform nomenclature and histopathological diagnostic criteria, different classification schemes have been proposed,,, based on the recognition of abnormalities of cortical architecture and the types of cells involved and their cytomorphology and location [Table 1].
|Table 1: Comparison of the two most used classification systems for focal cortical dysplasia|
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In 2011, the ILAE assembled a task force to create a consensus on the histological classification of the focal cortical dysplasia. A three tiered classification system was proposed, largely based on the classification previously published by Palmini et al.
According to the 2011 ILAE classification, focal cortical dysplasia Type I is a malformation characterized by abnormal cortical layering, without evidence of dysmorphic neurons or balloon cells and is further subdivided in three subtypes [Figure 1]. FCD type Ia is characterized by the presence of multiple vertical microcolumns, each of eight or more neurons, most frequently in cortical layer 3 and resembling the radial columns formed during cortical development. FCD type Ib results from abnormal tangential composition of the neocortex resulting in absence of any recognizable layering that can affect the total thickness of the neocortex or may present with abnormalities restricted to layer 2 and/or layer 4. The combination of both variants is classified as FCD Type Ic. In addition, the dysplastic cortex may contain hypertrophic pyramidal neurons outside layer 5 or small immature neurons.
|Figure 1: (a) Focal cortical dysplasia type Ia, with loss of cortical laminar architecture and featuring vertical microcolumns of neurons (NeuN, 40×). (b) Fragmented and poorly oriented specimen presenting scattered microcolumns of neurons, suggestive of a FCD type Ia (NeuN 40×). No other abnormality was encountered in the resection specimen|
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Focal cortical dysplasia Type II is a malformation presenting with loss of cortical lamination and specific cytologic abnormalities and is subdivided into FCD Type IIa with dysmorphic neurons and FCD Type IIb with dysmorphic neurons and balloon cells [Figure 2]. Dysmorphic neurons are defined as large neurons with abnormal morphology, nuclear enlargement, abnormalities in Nissl substance distribution and the accumulation of phosphorylated neurofilament protein. Balloon cells are large cells with abundant glassy eosinophilic cytoplasm and one or more eccentric nuclei; they are characterized by the accumulation of intermediate filaments in the cytoplasm. Co-expression of neural and glial markers has been demonstrated in both cell types, although more commonly in balloon cells.,, They can be positive for vimentin, nestin, glial fibrillary acidic protein (GFAP), neurofilaments, and immature neuronal proteins MAP1 and MAP2 by immunohistochemistry and immunofluorescence. In both FCD type IIa and IIb, there is blurring of the gray/white matter junction, with prominent myelin pallor of the underlying white matter and heterotrohic neurons. Balloon cells extend deep into the white matter.
|Figure 2: Focal cortical dysplasia type IIb (Taylor type). (a) Absence of cortical organization and pallor of subcortical white matter (A - LFB/-Nissl, 20×). (b) NeuN immunohistochemistry demonstrating large dysmorphic neurons and balloon cells scattered throughout the cortex (100×). (c) Large dysmorphic neurons (H&E, 400×). (d) Balloon cells (H&E, 200×). (e) Phosphorylated neurofilaments demonstrating dysmorphic neurons with coarse processes. (200×). (f) GFAP expression in balloon cells (400×); (g) Vimentin expression in balloon cells (400×)|
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Finally, focal cortical dysplasia Type III refers to cortical lamination abnormalities present in association with a principal lesion, usually adjacent to or affecting the same cortical area/lobe [Figure 3]. Four variants should be distinguished: FCD Type IIIa associated with hippocampal sclerosis; FCD Type IIIb associated with tumors; FCD Type IIIc associated with vascular malformations; and FCD Type IIId associated with any other principal lesion acquired during early life.
|Figure 3: Focal cortical dysplasia type III. (a) Epilepsy associated paediatric type low grade glioma with cortex above (H&E. 20×); (b) Adjacent cortex of the same case shows altered architecture: hypoplasia and dyslamination with loss of six-layered structure (NeuN, 20×). (c) Focal cortical dysplasia type IIId in a patient with history of difficult delivery. The cortical ribbon is thin and lacks lamination other than a cellular deep layer (NeuN, 40×). (d) Focal cortical dysplasia type IIId at the periphery of a porencephalic cyst, composed of clusters of large neurons within the region of the cortical ribbon (NeuN, 40×)|
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The present classification relies only on histological features, both architectural and cytological and correct orientation of the cortex in the neuropathological preparations is essential. Fragmentation of the surgical specimen often represents a further challenge and may make an adequate diagnosis impossible, particularly in cases of FCD types I and FCD types III. Insufficient representation of cortex adjacent to other lesions of FCD type III, in the material submitted to neuropathology, further increases the difficulty. Additional stains, namely luxol fast blue/Nissl histochemistry and NeuN immunohistochemistry help to delineate details of cortical cytoarchitecture. Immunohistochemistry with antibodies to phosphorylated neurofilaments, GFAP and vimentin are useful to identify the dysmorphic neurons and balloon cells of FCD type II, synaptophysin to demonstrate synaptic plexi and Ki 67 for evidence of proliferative activity. There has been relatively little published on FCD types I and III since the ILAE classification in 2011 and a critical review published in 2018 questions whether FCD types Ib and Ic are true developmental entities and whether they occur as isolated lesions; attention was drawn to the lack of reliable neurophysiological, imaging and neuropathological features or genetic markers for FCD type III.
| Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy|| |
A new form of cortical malformation, with more subtle histological alterations, was described in 2017 by Schurr et al., and was termed mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE). The description was achieved on a review of epilepsy surgery specimens, suspected on imaging to be FCD, with histology previously called non-lesional. All the cases occurred in patients with early onset drug-resistant surgery originating in the frontal lobe.
On histology, a blurring of the gray-white matter junction was observed, with significantly increased numbers of oligodendrocytes in the deep cortex and subcortical white matter which showed decreased myelin staining density. Heterotopic neurons were seen in the subcortical white matter, but not deep white matter [Figure 4]. Unusually, the oligodendroglial cells demonstrated proliferative activity, as evaluated by Ki67 immunohistochemistry, a feature that appears to diminish with age. In contrast to previously described FCD, no significant abnormalities in cortical laminar architecture were present and dysmorphic neurons or balloon cells were not observed., Since the initial description, other case reports of the entity have been published, including two cases in the temporal lobe.
|Figure 4: Mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE). (a) Globally preserved cortical laminar architecture; note the presence of heterotopic neurons in the white matter (NeuN, 40×); (b) Increased cellularity in the subcortical white matter, due to hyperplasia of oligodendroglial cells (H&E, 40×). (c) Heterotopic neurons with normal morphology (arrows) in the white matter with increased cellularity (H&E, 200×). (d) Diffuse Olig2 expression in oligodendroglial cells (Olig2, 200×)|
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The magnetic resonance imaging (MRI) features of MOGHE were described later,, and were subdivided in two subtypes with a clear age dependent distribution. The subtype I occurred between 1.5 and 5.1 years (median 2.6 years) and showed increased laminar T2 and fluid attenuated inversion recovery (FLAIR) signal at the corticomedullary junction; the subtype II occurred between 3.4 and 20.7 years (median 14.1 years) and disclosed reduced corticomedullary differentiation because of increased signal of the adjacent white matter. These variable MRI findings were related to maturational processes between 3 and 6 years.
| Clues to the Molecular Origin of Focal Cortical Dysplasia|| |
Prenatal cortical development is a complex process and includes: cell proliferation in the germinal zones; migration of cells to the cortex; and vertical and horizontal organization of cells within the cortex with the establishment of axonal and dendritic connections. The vast majority of neurons are produced prenatally and retained for the entire lifespan. Most terminally differentiated neurons are not believed to undergo mitosis.
Recent studies have demonstrated that somatic variants that arise post-zygotically underlie most brain malformations.,,, These somatic brain mutations lead to mosaicism, a mixture of variant-positive and variant-negative cells, which may affect one or more tissue or cell type, depending on the timing and location of the mutational event. In this context, there is evidence that somatic mutations linked to focal cortical malformations must occur early during development, in cells that migrate during brain development, resulting from mutations in genes critical for neuronal migration.
Recent investigations have been focusing on the genetic and epigenetic changes of focal brain malformations, and distinct etiopathogenesis have been discovered for FCD type II, FCD type I, and MOGHE.
| Genetics of Focal Cortical Dysplasia Type II|| |
An investigation by immunohistochemistry of Notch and WNT signaling pathways in FCD type IIb, both important in cell fate determination and differentiation and cell migration, demonstrated significant abnormalities suggesting a contribution to development of the morphological features of the disorder.
Many of the histological features described in FCD type IIb are shared with cortical tubers of tuberous sclerosis and with hemimegalencephaly. Although clinically distinct conditions, the three disorders share features of cortical dyslamination, dysmorphic neurons, and balloon cells. Drawing on this similarity, previous attempts to demonstrate a genetic causal link between tuberous sclerosis and FCD by studying allelic loss in the two genes responsible for molecular basis of tuberous sclerosis, hamartin – TSC1 and tuberin – TSC2 failed to show conclusive evidence of such a link.,
Focal cortical dysplasia is considered a sporadic disorder, but there does appear to be some evidence for genetic susceptibility with rare cases of familial FCD., In a report including two pairs of siblings with FCD type II, and one pair with FCD type II and hemimegalencephaly, two pedigrees in which there were first cousins with FCD and ganglioglioma and dysembryoplastic neuroepithelial tumour, respectively, it was suggested that these disorders might share molecular mechanisms.
Recent molecular studies featuring targeted gene sequencing further highlight the possibility that FCD type IIb, tubers and hemimegalencephaly may share a common molecular pathogenesis through activation of the mammalian target of rapamycin (mTOR) pathway. The mTOR signaling pathway appears to have important roles in neuronal differentiation, migration, and myelination., MTOR hyperactivity is thought to interfere in brain cell growth, neuronal connectivity, and neuronal excitability.
To date, nine genes in the pathway have been associated with cases of focal cortical dysplasia type 2: AKT3, DEPDC5, MTOR, NPRL2, NPRL3, PIK3CA, RHEB, TSC1, and TSC2 [Figure 5].,,,,,, It appears that two types of mutational events might explain the abnormal cell population in focal cortical dysplasia type II: (1) single activating variants in activators of the mTOR signaling pathway; (2) double-hit inactivating variants in repressors of the signaling pathway.
|Figure 5: Schematic representation of the mTOR signaling pathway, representing the global diagnostic yield among HME and FCT type II, considering the percentage of patients carrying pathogenic variants of each gene according Baldassari et al. 2019.|
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Most cases of focal cortical dysplasia type II and of hemimegalencephaly are associated with missense mutations in the mTOR gene or, more rarely, in other genes in the signaling pathway, namely AKT3, PIK3CA, or RHEB. Moreover, it has been further demonstrated by analysis of microdissected cells that both dysplastic neurons and balloon cells carry these pathogenic variants., As there is evidence that both FCD type II and hemimegalencephaly are mTORopathies, it has been suggested that they may represent a spectrum of the same disease. The phenotypic variability may be related to the embryonic stage in which the postzygotic mutational event occurs. The earlier the somatic mutation occurs during brain development, the larger the mutational burden is likely to be and hence, the extent of the malformation, as in hemimegalencephaly. In contrast, FCD type II is restricted as a smaller number of cells carry the mutation and appears to be related to events later during brain development.
Cortical tubers in tuberous sclerosis, on the other hand, are usually the result of double-hit inactivating variants in the mTOR repressors TSC1 and TSC2. However, somatic mutations in TSC1 and TSC2 have also been reported in cases of FCD type II. More recently, germline variants in the mTOR pathway repressor gene DEPDC5 were also described in FCD type II. For these mTOR repressors, a two-hit mutational mechanism (similar to the Knudson's two-hit model of tumorigenesis) is assumed to be necessary to get biallelic inactivation and cause focal cortical dysplasia. The somatic second event can occur by a missense single nucleotide mutation or by loss of heterozygosity (LOH). The latter mechanism of a second-hit event has been demonstrated in a patient with type II FCD and a germ-line variant of DEPDC5.,
Current targeted gene sequencing studies have only revealed a molecular culprit in up to 63% of cases of FCD type II. However, by immunohistochemistry, panel negative FCD type II also displayed strong expression of phospo-S6 immunostaining, a downstream marker of mTOR hyperactivity, suggesting that these “molecularly negative cases” are also mTORopathies, possibly associated with somatic variants in genes of the mTOR cascade in which the current molecular knowledge is insufficient to disclose their underlying genetic alteration.
Finally, no significant molecular differences have been found between the subtypes FCD types IIA and IIB. Similarly, no correlation has been demonstrated between the mutated genes and post-surgical outcome. Probably other factors are more important in this context, such age of onset, disease extent, and location of the lesion.
| Genetics of Focal Cortical Dysplasia, Type I|| |
FCD type I is a more challenging subject. The validity of the subtypes proposed by the ILAE in 2011 as lesions of developmental origin is being questioned, with FCD type Ia persisting as the only credible subtype., The fetal cortex exhibits radial microcolumnar architecture, from initiation of radial migration at 7–8 weeks' gestation until midgestation, and it has been proposed that FCD type Ia may be a maturational arrest of a physiological state of cortical plate in the first half of gestation. The persistence of microcolumnar architecture is observed not only in FCD type Ia, but also in a more widespread distribution in a variety of genetic and metabolic diseases, including DiGeorge syndrome (22q11.2 deletion), tubers of tuberous sclerosis, and methylmalonic acidaemia. Additional support for a developmental origin of FCD Ia (and FCD II) is the presence of excessive neuronal heterotopia and their complex synaptic plexi in the U-fibre layer beneath the affected cortex. On the other hand, it appears to be doubtful that FCD type Ib and FCD type Ic, are true malformations of cortical development and probably represent architectural disturbances arising as a consequence of ischemic or toxic encephalopathies, congenital infections, or other perinatal insults.
No specific molecular markers/genetic mutations have as yet been consistently identified in FCD type I in targeted panel sequencing studies. Mutations have not been identified in any of the genes of the mTOR signaling pathway in FCD type I. Brain somatic mutations in the SLC35A2 gene (see section below) were demonstrated in fewer than 20% of cases of FCD type I and a single case of West syndrome with FCD type Ic., However, deoxyribonucleic acid (DNA) methylation analysis was able to distinguish FCD type Ia from other FCD variants.
| Genetics Of Moghe|| |
Although this is a recently described entity, there are already important clues to their etiology. Recently, Bonduelle et al., performing gene panel sequencing in a single center cohort of 20 patients, identified inactivating somatic pathogenic variants in the SLC35A2 gene n 45% of cases (9/20), with mosaic rates from 4 to 52%. Moreover, using laser capture microdissection, the same study found evidence that both oligodendroglial and heterotopic neurons may be the carriers of these pathogenic variant.
Somatic pathogenic variants in SLC35A2 had been recognized previously, in cases of non-lesional focal epilepsy, FCD type I, and in cases of minor malformations of cortical development, which from the published neuropathological description appear to be MOGHE.
Germline variants of SLC35A2, occurring as de novo mutations, were also described in a very rare X-linked dominant form of congenital disorder of glycosylation type IIm (MIM #300896), primarily presenting with epileptic encephalopathy, seizures, severe psychomotor developmental delay, and delayed myelination. SLC35A2 encodes an UDP-galactose from the cytosol into Golgi vesicles, where it serves as a glycosyl donor for the generation of glycans. N-glycosylation is a key post-translational process; modified glycan structures may affect protein folding, stability, and integration with other molecules. However, it remains to be further investigated how primary defects in glycosylation in neuroglia precursors can lead to the histopathological features of MOGHE.
| DNA-Methylation Based Classification of Cortical Malformation|| |
Genome-wide array-based methylation profiling has been proving a valuable tool in the process of reviewing the classification of brain tumours, as recognized by the 2021 WHO classification of Central Nervous System Tumors., The application of the same methodology in the research of malformations in cortical development has been evaluated in a pair of studies, with promising results. A report by Kobow et al. highlighted that differential hierarchical cluster analysis of DNA methylation was able to distinguish major FCD subtypes (Ia, IIa, and IIb) from epileptogenic cortex that did not demonstrate architectural abnormalities.
A more extensive study on the DNA-methylation-based classification of focal cortical malformations has been recently published. A reference cohort of 239 tissue samples histopathologically classified as MCD was achieved, including 12 major entities. This was followed by a test cohort of 43 independent surgical samples from different epilepsy centers, all samples from the cohort were accurately assigned to their disease classes by the algorithm, including cases of FCD types I and II and of MOGHE. These data demonstrate the suitability of DNA methylation-based MCD classification across major histopathological entities amenable to epilepsy surgery and thus lead to an integrated diagnostic classification scheme for epilepsy-associated MCD.
| Future Directions|| |
With the recent advances in the knowledge of focal cortical dysplasia, particularly with respect molecular information, the 2011 ILAE classification for focal cortical dysplasia was found wanting. Moreover, significant interobserver variability in the classification of focal cortical dysplasia has been reported. Although diagnostic criteria for FCD type II are more straightforward, the diagnoses of FCD types I and III and the classification and clinical relevance of mMCD remain challenging and the routine use of appropriate immunohistochemistry is recommended to establish diagnosis, by demonstrating alterations in cortical cytoarchitecture and abnormal cytomorphology. The current discussion also centres on how genetic findings should be incorporated to obtain a comprehensive, reliable, and integrative genotype–phenotype diagnosis of focal cortical dysplasia. In addition to sequencing studies, the use of immunohistochemical markers of mTOR pathway activation (such as phospho-P70S6 kinase, S6 ribosomal protein, and Stat3) should be considered. To address these, a panel of experts discussed these challenges, aiming to get consensus toward further refine the classification of focal cortical displasia [Table 2]. The new classification scheme reintroduces the concept of mild malformations in cortical development of the classification of Palmini et al., with predominantly white matter lesions, where MOGHE is included. In addition, to respond to the absence of pathology in specimens resected in the clinical and radiological setting of FCD, the term “no FCD” has been introduced. Although the classification is still based of morphological features, it is recognized that a panel of immunohistochemical stains may increase the histopathological diagnostic accuracy and hence agreement in FCD classification. Moreover, adding the level of genetic findings to obtain a comprehensive, reliable, and integrative genotype–phenotype is also discussed but has not yet been incorporated into the new classification.
The surgical outcome of epilepsy surgery is still variable, and dependent on both clinical and pathological factors. In most recent series, overall seizure freedom (Engel class I) is achieved in 50% to 75%.,, Positive prognostic indicators related to clinical parameters include lesser extent of disease, complete resection of the epileptogenic area, lower age at surgery, and shorter duration of epilepsy. It is known that more severe pathologic features are related to better outcome: patients with FCD type IIA or IIB have a higher chance to be seizure free after surgery, than patients with mMCD and FCD type I., In the case series of MOGHE, only a third of the patients became seizure free after surgery.
In addition to improving criteria for diagnosis and understanding the pathogenesis of these lesions, the importance of identifying the causative genetic mutation is to open the path to new targeted therapy for these patients with poorly controlled epilepsy. The mTOR pathway can be pharmacologically targeted by rapamycin derivatives, such as everolimus. This pharmacological approach has been proven to be partially effective for seizure control in patients with tuberous sclerosis. Currently, there are ongoing clinical trials evaluating the clinical efficacy of everolimus for seizure control in patients with focal cortical dysplasia type II and refractory seizures (NCT03198949).
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Department of Anatomic Pathology, Hospital Pedro Hispano, Rua Dr. Eduardo Torres, 4464-513 Matosinhos
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]