The focal cortical dysplasias (FCDs) are localised malformations of cortical development, classically associated with drug-resistant epilepsies. Taylor et al. originally introduced the term FCD in a study that described the histological findings of the focal cortical malformation [1]. In patients with FCD, the seizures most commonly begin in the first decade of life and may be refractory to antiepileptic drug treatment. In such cases, surgery with resection of the dysplastic lesion and the epileptogenic zone is the best option for seizure control. In children with focal epilepsies undergoing surgery, FCDs are the most common histological substrate [2].

Since the initial description by Taylor et al. in 1971 [1], advances in the detailed knowledge of histology [3,4,5] has led to different proposals for classification of FCDs. However, considerable heterogeneity remained in the distinct descriptions of the histopathological findings by different authors [5]. Recently, the International League Against Epilepsy (ILAE) proposed an electro-clinical, imaging and histological classification for the FCDs [6]. This classification distinguishes isolated FCDs (types I and II) from FCDs associated with other potentially epileptogenic lesions (type III) (Table 1).

According to the current ILAE classification, the FCD type I is defined by abnormal formation of cortical layers, which can compromise the radial neuronal migration and maturation (FCD type Ia) or tangential composition of the six layers of the neocortex (FCD type Ib). The concomitant occurrence of these two histological findings is classified as FCD type Ic [6]. The type II FCD is defined by disorganised cortical lamination and specific histological abnormalities that differentiate the FCD type IIa (presence of dysmorphic neurons without balloon cells) and FCD type IIb (presence of dysmorphic neurons and balloon cells) [6]. The type III FCD represents alterations in cortical lamination associated with an adjacent main lesion, this can occur in combination with hippocampal sclerosis, tumours, and vascular malformation amongst others [6]. This classification also suggests that the term “microdysgenesis” [7], used heterogeneously by different studies to describe subtle abnormalities of intracortical architecture, should be abandoned.

The different types of FCDs have distinct cellular elements. As a group, the FCD histology presents focal brain areas with architectural abnormalities, immature or dysmorphic neurons and balloon cells [5]. The FCD type Ia (FCD with abnormal radial cortical lamination) is characterised by abundant micro-columnar organisation (more than eight neurons vertically aligned), more prominent inlayer 3. Cell abnormalities, such as small immature neurons or hypertrophic pyramidal neurons outside layer 5 can also be found [6]. The FCD type Ib (FCD with abnormal tangential cortical lamination) is characterised by failure in the tangential composition of the six layers of the isocortex. Small immature neurons or hypertrophic pyramidal neurons outside layer 5 can be found, as well as normal neurons with dendrites displaying irregular orientation [6]. In FCD type Ic, radial and tangential cortical lamination are both abnormal [6].

The FCD type IIa is characterized by the presence of dysmorphic neurons. Dysmorphic neurons are cells with aberrant shape, abnormal orientation, enlarged size, abnormal cytoskeletal structure and atypical dendritic processes. These cells have an accumulation of cytoplasmic neurofilaments [5,8]and there are no balloon cells present. Discrimination of the cortical layers, except for layer 1, is not possible [6]. Type IIb FCD is characterized by the presence of dysmorphic neurons and balloon cells. A balloon cell is an abnormal cellular structure with a thin membrane, eosinophilic cytoplasm and single or multiple nucleus. These cells have characteristics of both neurons and glia [5]. A detailed view of the cortical layers, except for layer 1, is not possible and the content of myelin may be abnormal in the adjacent subcortical white matter [6].

The FCD type III (changes of cortical lamination associated with an adjacent main lesion) can be classified into four variants: FCD associated with hippocampal sclerosis (type IIIa), FCD associated with tumours (type IIIb), FCD associated with vascular malformations (IIIc) or FCD associated with another main lesion acquired in early life [6].

The current main hypothesis regarding the pathogenesis of FCD is that it results from an impairment of neuronal proliferation, differentiation, or migration. According to the 2012-updated Barkovich's proposal of classification of malformations of cortical development, FCD type II is in fact a malformation due to abnormal proliferation and differentiation [9]. This classification is supported by the findings that FCD type II has progenitor proteins that appear early in development, similar to those found in pluripotent stem cells and due to the suggestion that balloon cells in FCD type IIb originate from glioneuronal progenitor cells [10,11]. Alternatively, FCDs type I and III are considered malformations due to abnormal post migration development. It is hypothesised that these may result from injury to the cortex during the late stages of cortical development [9]. Indeed, different studies have suggested the association of perinatal insults with the development of the dysplasias [12,13]. This concept suggests that FCD type I could be a heterogeneous group of disorders resulting from late insult to the developing cortex.

In vivo and ex vivo studies show that FCD has intrinsic epileptogenicity [14]. However, the intrinsic epileptogenicity of the dysplastic tissue varies according to the cell population. In vivo electrocorticographic recordings have shown that areas in the dysplasia containing balloon cells are less epileptogenic than the remaining dysplastic region [15,16]. The hypothesis in fact, is that balloon cells disrupt the structure of the surrounding cortex thus leading to excitability of the dysplastic tissue [17]. Distinctly, cytomegalic neurons show the most abnormal intrinsic electrophysiological properties [17]. In vitro studies have also shown an overall increase in expression of glutamate receptors and decreased expression of GABA receptors in surgical specimens of patients with FCD type IIb [8,18].

There is no particular antiepileptic drug treatment for epilepsy related to FCD and the medication must be prescribed according to the specificities of each individual patient, such as seizure type, age, sex and comorbidities [43].

According to the ILAE, drug-resistant epilepsies can be defined as the failure of achieving seizure-freedom after two adequate trials of antiepileptic drugs [44]. Although there is no epidemiological data on the percentage of patients with FCD and drug-resistant epilepsies, it is current knowledge that the majority of patients will fulfil the criteria of drug-re-sistant epilepsy, most possibly in the first years after seizure onset. For those individuals, epilepsy surgery is the best treatment option. One should also bear in mind that both the refractory seizures and the cognitive and developmental impairment, must be considered for the indication of surgical treatment of children with FCD. Due to the high morbidity and psychosocial consequences associated with the refractory seizures, the identification of refractoriness and indication for surgical treatment, whenever achievable, should be performed as early as possible [45].

As it is the case for any epilepsy surgery, the final goal is achieving seizure freedom by the removal of the epileptogenic zone, defined as the extent of cortex necessary to generate the clinical seizures [46]. In order to accomplish this objective an individual evaluation is necessary, including, at least, detailed semiology data, ictal and inter-ictal video-EEG monitoring and MRI. For some patients, other non-invasive (FDG-PET, ictal SPECT, MEG, functional MRI) or invasive (subdural EEG grids or depth electrodes) evaluations are necessary, especially for those with normal MRI or FCD in the proximity of eloquent cortex [47,48]. Therefore, patients with suspected FCD and drug-resistant seizures must be promptly referred to a specialised epilepsy surgery centre. The use of different EEG and/or imaging techniques in the pre-surgical workup will depend on the specific characteristics of each individual patient and also the expertise of the centres [49].

Despite the significant advantage of better seizure control and improved quality of life for patients with refractory epilepsy who undergo surgical treatment, the prognosis of seizure control in the long term after surgery is largely heterogeneous. In a large surgical series of patients with FCD type I, only 46% had seizure control [31]. Another surgical series of patients with type II FCD and long term follow-up showed seizure remission in 88% of patients with FCD type IIb and 74% of patients with FCD type IIa and worse outcome associated with multilobar dysplasia or incomplete resection due to the proximity of eloquent cortex [26]. It is a well-demonstrated fact that the main determinant of seizure remission after surgery in patients with FCD is the complete resection of the lesion [50,51]. Therefore, the detection of clear changes suggestive of FCD in the pre-operatory MRI and the lesion not invading the eloquent cortex are other important determinants of the surgical outcome [26,51]. A very recent large series including FCDs type I, II and III with long-term follow-up after surgery demonstrated that the seizure outcome remains stable after the first postoperative year. Also, in this series, complete resection of the epileptogenic area, lower age at surgery and unilobar localisation were indicators of long-term seizure-freedom [52].

FCD is a significant cause of epilepsy, especially amongst children who display drug resistant seizures. In recent decades, significant advances have been accomplished in expanding knowledge regarding the clinical presentation, neuroimaging findings and histological subtypes of FCD. Future studies are necessary for the better understanding of prevalence, long-term clinical prognosis and the clinical differences between the specific subtypes of FCD. Moreover, efforts must be made to recognise FCD early and treat the seizures to improve seizure control and outcomes both neuropsychological and social.