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INTRODUCTION
Focal cortical dysplasia (FCD) is a heterogeneous group of disorders, which can be the cause of drug-resistant epilepsy or intractable epilepsy [12]. In medical practice, “dysplasia” is used as variable meanings, as pre-neoplastic (e.g., epithelial dysplasia of stomach), developmental anomaly (e.g., renal dysplasia) or etc. Originally “dysplasia” was a term used to refer an abnormality of development, alternation in size, shape and organization of adult cells [14,16]. Blümcke et al. [5] defined this terminology as “any tissue that is imperfectly developed in embryonic or fetal life. However, dysplasia is a diagnostic term used here to identify specific malformations of the cortex, the so-called FCDs, irrespective of their diverse histologic appearances that are addressed by this classification” in their paper [5]. Therefore, it is obvious that FCDs have a meaning of developmental abnormalities including cortical dyslamination, cytoarchitectural lesions, and underlying abnormalities of white matter [5,11].
THE SHORT HISTORY OF FCD
In 1971, Taylor et al. [13] reported the 10 patients with drugresistant epilepsy and described several histological findings, cortical disorganization, large bizarre neurons and balloon cells which are characteristic findings of the current classification of FCDs. In this paper, they described these features as “Focal dysplasias of cerebral cortex”. Previously, Crome had described three cases of intractable epilepsy. He described “dysmorphic neurons” as “giant nerve cells” in his cases [7].
After that, many researchers used different various terminologies in discussing FCDs. Although the etiology is exactly unknown, it is accepted that many lesions are related to the alteration of cortical development caused by a variety of mechanisms [12]. In 1992, Meencke and Veith [9] introduced “microdysgenesis” as a minor parenchymal malformation in patients with generalized epilepsy. They described many characteristic histological findings from their cases. These findings were largely overlapped with the features in current classification system of FCD. In 1996, the terminology of “malformation of cortical development (MCD)” was introduced to designate collectively a common group of disorders in children with developmental delay and young people with epilepsy [2]. They categorized these disorders as group I, II, and III. FCD was categorized as group III.B. In the past, MCDs have been defined as “neuronal migration disorder”; however, as not all the cortical abnormalities have been proven to be due to migrational derangements, the general term of MCDs was prefered [1].
In 2004, Palmini et al. [11] suggested FCD classification. After panel discussion, they proposed as follows : 1) a specific terminology for the different types of abnormal cells encountered in the cerebral cortex of patients with FCD; 2) a reappraisal of the different histopathologic abnormalities usually subsumed under the term “microdysgenesis,” and suggested that this terminology be abandoned; and 3) a more detailed yet straightforward classification of the various histopathologic features that usually are included under the heterogeneous term of “focal cortical dysplasia.”
Therefore, they classified the lesions as mild MCD (mild MCD) and FCD. In addition, they classified each entity into type I and II respectively (Table 1).
With advances in clinical, histological, radiological and genetic understanding of FCDs, International League Against Epilepsy (ILAE) Task Force proposed a three tiered classification system in 2011.
THE CURRENT ILAE CLASSIFICATION SYSTEM OF FCD
It is better to read the original paper [5] “point for point” for understanding of the detailed FCD classification system. In addition, the authors strongly recommend to read Najm et al.’s paper [10]. This paper dealt not only the original classification system, but also updated issue along the new data and prospective suggestions.
In this review paper, the authors would like to give helpful comments for better understanding of the current FCD classification.
Overview
The ILAE classification system of FCD is based on some several neurodevelopmental studies, especially on Cepeda et al.’s study [6] in a large portion. They suggested “dysmature cerebral developmental hypothesis” which is a partial failure in later phases of cortical development might show the distinctive histopathology, such as cortical dysplasia And local interactions of dysmature cells with normal postnatal neurons might promote seizures. Especially the basic concept of FCD type I was established from the Hildebrandt et al.’s morphometric study [8].
On contrary to Palmini et al.’s system [11], The ILAE classification system of FCD has a three-tier system. This system composed of isolated FCDs (FCD type I and II) and variants associated with other (potentially) epileptogenic lesions (FCD type III). The definition of FCD type III was cortical dyslamination abnormalities associated with a principal lesion, usually adjacent to or affecting the same cortical area/lobe [3]. The basic concept of type III seems to base on that there were some disturbances of normal cortical six layers adjacent the main lesion. In addition, it might be very difficult to identify these “subtle” cortical abnormalities from the histologic changes of “secondary reactive process, resulting from the main lesions.
Meanwhile, the mild MCD (mMCD) was not included the current system [3]. Therefore, the mMCDs in Blümcke et al.’s paper [4] were classified according to the Palmini et al.’s classification [11].
To get the best possible histologic assessment and reduce sampling errors, the standardized procedures for inspection, distribution and processing of epileptogenic brain tissue are very important [3]. Especially, the surgical procedures, resulting on piecemeal fragmentations of tissue should be avoided for pathologic diagnosis. The Task Force of ILAE commission on Diagnostic Methods suggested the International recommendation for a comprehensive neuropathologic workup of epilepsy surgery brain tissue [3]. They emphasized an en-bloc resection, anatomical oriented landmarks and 5 mm serial cutting, perpendicular to the pia. The immunohistochemical staining had become a routine procedure for the diagnosis. For example, the neuronal markers (e.g., NeuN) are essential to diagnosis certain type of FCD, especially in type I.
They defined the words, “dual pathology” and “double pathology”. They proposed the “dual pathology” as only in hippocampal sclerosis (HS), a second principal lesion affecting the brain, that is, tumor, vascular malformation, glial scar, limbic/Rasmussen encephalitis, or MCD (including FCD type IIa/IIb) [5]. If there is an architectural abnormality in the temporal lobe in HS patients, we should diagnosis as FCD type IIIa, instead of FCD type I or dual pathology. The double pathology meant that two independent lesions affecting one or multiple lobe, without HS. It meant that both lesions might originate from independent pathogenesis. For example; cavernous angioma in right temporal lobe and ganglioglioma in left temporal lobe.
In summary, 1) If HS plus FCD type I features in the temporal lobe is FCD type IIIa. 2) If HS plus other lesion (FCD type II, tumor, scar, or encephalitis) is a dual pathology. And 3) lesion A (except HS) plus lesion B (except HS) is a double pathology.
The clinico-radiologic-pathological correlation is very essential in diagnosis. For example, the histological features of hemimegalencephaly, tuberous sclerosis or schizencephaly could be overlapped with FCD type II [5]. Comprehensive review of patient clinical information would provide a diagnostic clue.
FCD type I
FCD Type I is a malformation characterized by abnormal cortical layering, which is caused by abnormal process in either radial migration of neurons (FCD type Ia) or the six-layered tangential composition of the neocortex (FCD type Ib). The combination of both conditions will be classified as FCD type Ic [5]. Before the understanding of the pathology of FCD type Ia, we have to remind what are “radial” and “tangential” (Fig. 1). Because the neuronal progenitor cells migrate along the radial glial cells, the radial migration looks like the bones of “a folding pan (Fig. 1, inlet)” in the microscopic examination (Fig. 1, white lines). And it is important to understand the definition of “microcolumn” [5]. The definition of “microcolumn” is more than eight neurons aligned in a vertical direction (Figs. 2 and 3). The concept of microcolumn was firstly introduced in Hildebrandt et al.’s paper [8]. On their observation, the cells of microcolumn had smaller perikarya. During the developmental period, primitive neuronal cells start to differentiate to several types and sizes after 22-weeks of gestation and the microcolumns begin to disappear [10]. The pattern of microcolumn is unusual histological findings in postnatal controls [8] (Fig. 1), except for occipital area. These findings suggested that the cortical maturation arrest may cause FCD type Ia.
The tangential compositions of the neocortex are completed after the radial migration. The tangential composition looks like “concentric lamella” (Fig. 1, red lines). Usually The FCD type Ib shows the derangements of cortical six-layers (Fig. 4).
The FCD type Ic is the combination of both variants. Even the neuropathologic experts doubts whether it is real entity or not.
FCD type II
These are undoubtedly definite categories. Also in Palmini et al.’s classification [11], these entities were almost the same. The hallmark of these FCD variants were presence of cortical dyslamination and dysmorphic neurons without (FCD type IIa) (Fig. 5) or with balloon cells (FCD type IIb) (Fig. 6) [5]. In the ILAE classification of FCD, the detailed morphological definitions of dysmorphic neurons (cell size 16–43 μm, nucleus diameter 15–28 μm, the characteristic Nissl substance and immunohistochemical stainings) [5] were emphasized. Moreover, the morphological and immunohistochemical features of balloon cells were detailed [5].
FCD type III
The FCD type III is classified into four subcategories (Table 2) based on histological features of principal lesion. If histological examination is not available, it is recommended to use Not Otherwise Specified (NOS). The concept of FCD type III can be simply defined as FCD type I adjacent to another principal lesion. For understanding of this concept, it is better to mention “Temporal lobe sclerosis” [15]. Thom et al. [15] reported approximately 10% of HS cases showed a horizontal cortical dyslamination with neuronal loss in temporal neocortex. Ref lecting their frequent association, co-existence of HS and FCD type I are classified as FCD IIIa (Fig. 7), but not as concurrent type I and type III. Similarly, FCD type I associated with other lesions (such as tumor, vascular lesion, and etc.) were classified as FCD type IIIb (Fig. 8), IIIc, and IIId, respectively.
It is not well known about the pathogenesis of FCD type III. As noted above, it is very difficult to differentiate whether the cortical dyslamination was primary or secondary.
Limitations, genetic progress and prospect
In our opinion, major limitation of this system is low interobserver agreement, especially, occurring in the assessment of type I and III. In addition, the definition of mMCD was still not clearly established. Nowadays, a lot of research papers regarding genetic information in FCD are published. Detailed review of the updates in genetics of FCD is beyond the purpose of this paper. Briefly, recent genomic data suggests that alteration of mammalian target of rapamycin (mTOR) pathway and mutations of Tuberous sclerosis (TSC) gene play an important role in pathogenesis of FCD [9,10]. With the advanced knowledge in genetics, it is needed to update the current classification [10]. The concept of integrated diagnosis upon clinicopathological and molecular findings has been recently suggested (Table 3). The authors carefully expect that the next classification system of FCD might be similar to the current World Health Organization (WHO) central nervous system (CNS) tumor classification.
There is no “perfect” disease classification system. According to technical progressions and disease paradigm changes, it should be updated. This virtuous cycle will be essential to make better disease classification. This effort will provide a better medical care for patient with epilepsy.
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