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Focal cortical dysplasia is a malformation of cortical development, which is the most common cause of medically refractory epilepsy in the pediatric population and the second/third most common etiology of medically intractable seizures in adults.
Both genetic and acquired factors are involved in the pathogenesis of cortical dysplasia. Numerous classifications of the complex structural abnormalities of focal cortical dysplasia have been proposed – from Taylor et al. in 1971 to the last modification of Palmini classification made by Blumcke in 2011. In general, three types of cortical dysplasia are recognized.
Type I focal cortical dysplasia with mild symptomatic expression and late onset, is more often seen in adults, with changes present in the temporal lobe.
Clinical symptoms are more severe in type II of cortical dysplasia usually seen in children. In this type, more extensive changes occur outside the temporal lobe with predilection for the frontal lobes.
New type III is one of the above dysplasias with associated another principal lesion as hippocampal sclerosis, tumor, vascular malformation or acquired pathology during early life.
Brain MRI imaging shows abnormalities in the majority of type II dysplasias and in only some of type I cortical dysplasias.
The most common findings on MRI imaging include: focal cortical thickening or thinning, areas of focal brain atrophy, blurring of the gray-white junction, increased signal on T2- and FLAIR-weighted images in the gray and subcortical white matter often tapering toward the ventricle. On the basis of the MRI findings, it is possible to differentiate between type I and type II cortical dysplasia. A complete resection of the epileptogenic zone is required for seizure-free life. MRI imaging is very helpful to identify those patients who are likely to benefit from surgical treatment in a group of patients with drug-resistant epilepsy.
However, in type I cortical dysplasia, MR imaging is often normal, and also in both types the lesion seen on MRI may be smaller than the seizure-generating region seen in the EEG. The abnormalities may also involve vital for life brain parts, where curative surgery will not be an option. Therefore, other diagnostic imaging techniques such as FDG PET, MEG, DTI and intra-cranial EEG are widely used to establish the diagnosis and to decide on management.
With advances in both genetics and neuroimaging, we may develop a better understanding of patients with drug-resistant epilepsy, which will help us to provide more successful pharmacological and/or surgical treatment in the future.
Focal cortical dysplasia is not very well known and still rarely diagnosed in Poland. It is responsible for nearly half of intractable epilepsy cases in children and adults, and at the same time it is characterized by quite good treatment outcome. Focal cortical dysplasia was first distinguished from developmental malformations in 10 patients by Taylor and colleagues in 1971 and its classification has been subjected to several modifications ever since. The continuous improvement of neuroimaging techniques providing more precise assessment of pathological lesions creates a chance for good surgical treatment outcome. Rapid development of new branches of science, such as genetics and diagnostics, implicates the need for reconsideration of the disease, as nowadays treatment methods of this disease give patients hope for recovery.
Focal cortical dysplasia (FCD) forms a very heterogeneous group of cortical lesions. In the literature it is described as malformation of cortical development, cortical dysplasia, cortical dysgenesis or neuronal migration disorder. FCD encompasses multiple types of alterations:
Since the first description of this entity, several attempts have been made for the last 40 years to classify the huge variety of histopathological findings. The most widely accepted was the scheme according to Barkovich, recently modified in 2005 [3,4] classifying FCD among developmental malformations in group Ib – Non-neoplastic malformations due to abnormal neuronal and glial proliferation or apoptosis, and IIIb – Malformations due to abnormal cortical organization. The most commonly used histopathological classification until now [2,5] distinguished two types of focal cortical dysplasia. Type I (benign) – characterized by isolated architectural abnormality – Ia or with additional abnormal cells (such as hypertrophic cells and immature neurons) – Ib. Type II (Taylor) – encompassing larger abnormalities with dislayering and additional presence of dysmorphic neurons – type IIa or balloon cells – type IIb. Focal cortical dysplasia was frequently found in hippocampal atrophy  or neoplastic developmental tumors (DNET, ganglioglioma) or in posttraumatic and postischemic patients (Table 1).
Several months ago, an international group of experts  modified the recent Palmini classification, distinguishing three types of focal cortical dysplasia:
Genetic aspects of focal cortical dysplasia are not fully investigated, mainly due to the limited number of cases and lack of proper experimental model. More extensive future studies will certainly shed more light on this problem. There are reports of familial FCD  with early onset.
It can be assumed, however, that the cause is not a simple, single gene mutation, as it is in lissencephaly or focal periventricular heterotopias, taking into consideration the heterogeneity of histopathological changes and different mechanisms of abnormal migration, which are partially determined.
Some authors suggest that TSC1, characteristic for tuberous sclerosis, is involved in the formation of focal dysplasia [9,10] and FCD itself constitutes a form tuberous sclerosis without extracerebral symptoms. In both entities, despite different clinical manifestation, same balloon cells are found.
Changes in other proteins of Wnt and Notch signaling pathways, that are normally responsible for proper neuronal migration, are also found in focal cortical dysplasia . Mutations of genes encoding these proteins, however, are lethal, which disqualify them as a cause of FCD. Mutations altering regulatory mechanisms of the pathways could be a possible explanation.
There are reports coming from experimental studies indicating that irradiation and methylazoxymethanol may cause DNA damage leading to FCD model .
A comprehensive view on genetic changes leads to a conclusion that mutations of genes encoding regulatory proteins or mutations resulting in partial alteration of protein function are the possible cause of focal dysplasia .
Focal cortical dysplasia may involve any part of the brain, may vary in size and location and may be multifocal . Epilepsy is the main symptom of dysplasia, sometimes associated with mental retardation, particularly with early seizure onset. There are no significant neurological deficits despite large areas of brain tissue occupied by a lesion. Symptoms appear at any age, mostly in childhood, but also occur in adults. Epilepsy is usually drug-resistant.
Patients with FCD type II manifest earlier onset comparing to type I [2,15]. Similarly, earlier onset is observed in patients with a larger focus on brain MRI as compared to patients with smaller lesions. According to the literature, focal cortical dysplasia type I is related to temporal lobe seizures [5,16]. In patients with FCD type II, multilobar lesions are found, involving hemisphere, often with extratemporal location and mainly in the frontal lobe. Therefore seizures with early onset in neonatal period or childhood are more likely FCD type II with multilobar or hemispheric lesion, while FCD type I with a small focus, usually in the temporal lobe, predominates in adults [15,17]
The regular, surface EEG recording is characterized by low specificity for focal cortical dysplasia.
Most commonly used imaging technique for assessing brain pathology in focal cortical dysplasia is MRI. It is performed as a whole-brain study, transverse T2-weighted, coronal T2-weighted TSE, coronal FLAIR and coronal IR T1-weighted sequences. In most of the patients volume 3D-FSE T1 is also performed. If necessary, sagittal T2 and FLAIR sequences are obtained. Other techniques, well-defining the white matter – gray matter junction are also helpful, as well as the automatic computed methods like morphometry, allowing the assessment of atrophy and ill-defined lesions of increased signal intensity within cortex [18,19]. Occasionally, lesions within temporal lobe are examined – transverse images parallel and coronal images perpendicular to the long axis of hippocampus. In some patients, an i.v. contrast medium can be used if tumor is suspected, but it is not required for diagnosis [5,20].
Many authors tried to define specific MRI features for focal cortical dysplasia [5,7,16,20–27]. The characteristic findings are as follows: cortical thickening, blurring of white matter – gray matter junction with abnormal architecture of subcortical layer, altered signal from white matter with or without the penetration through cortex (transmantel sign), altered signal from gray matter, abnormal sulcal or gyral pattern and segmental and/or lobar hypoplasia/atrophy.
In each type of FCD, images are as follows:
There are no essential differences between MR images of type Ia and type Ib. However, type Ib is more often located outside the temporal lobe (for this reason, it is difficult to differentiate it from FCD type II) (Figure 2).
The increased signal from gray matter on T2-weighted images is more evident in type II than type I. Nevertheless cortex remains more hypointense than white matter. There are no features distinguishing type IIa and IIb despite more evident demarcation of type IIb lesion comparing to other types.
FCD type II is more often found in extratemporal locations with predilection towards frontal lobe.
Lesions in FCD associated with developmental tumors, such as DNET or ganglioglioma, are currently classified as IIIb according to Blumcke et al. 2011 and characterized by a positive mass effect, cystic component, various calcifications and contrast enhancement. Dysplastic lesions are usually located peripherally in relation to tumor. However they may be located within the main lesion (Figure 5).
Occasionally, FCD may remain invisible on MRI, usually in type I . Moreover, the affected area of the brain can be larger than lesion revealed by MRI, which can be a possible cause of poorer postoperative outcomes if surgery is based on the MRI data solely [29,30]. For that reason, despite MRI visualization of FCD, other methods of precise preoperative selection of patients are required.
Additionally, in recent years this method has been improved by FDG-PET/MR fusion technique that has resulted in higher sensitivity (up to 98%) for FCD, especially in patients with benign FCD type I and normal MRI . FDG-PET study has become a useful tool for preoperative FCD detection in patients with intractable epilepsy and normal or less specific findings on MRI. It has resulted in better surgery outcomes and longer seizure-free periods postoperatively .
There are also reports suggesting that ictal SPECT may localize a dysplastic focus in patients with normal MRI .
Non-invasive technique showing electric activity of brain by registration of the magnetic field induced by cortex has been used intraictally for brain mapping in order to find and assess the size of epileptogenic focus. In addition, the data obtain by MEG can be fused with MR images helping to localize abnormal discharges in patients with intractable epilepsy and normal results in other examinations. Some reports point that this method may also allow to differentiate FCD type I and II .
Moreover, MEG localizes anatomically the functional areas: sensory, motor and speech , which could be spared during operation in order to improve the quality of life after surgical treatment.
Analyzing the diffusion process of free water molecules in brain using MRI, we may assess a cerebral microstructure (diffusion is restricted due to crossing fibers, large number of cells, demyelination or gliosis) and track the fibers – tractography – (the perpendicular water diffusion is more restricted than parallel diffusion along the fibers orientation). Therefore DTI can be used for assessing the extension of cortical dysplasia (with disrupted white matter structure, abnormal myelination, gliosis and increased number of cells, such as heterotopic neurons) which often appears larger than lesion revealed by conventional MRI and in patients with normal MRI [40,41]. There is no possibility to differentiate between other abnormalities of cortical development, neither to assess the histopathological correlation between particular FCD types. It is also uninformative, whether revealed lesions are primary – causing dysplasia, or occurring as result of repeating seizures locally and along the epileptic network.
The second method, tractography, allows the neurosurgeon to plan the operation basing on the assessment of anatomical relations between dysplastic focus and fiber bundles of eloquent centers.
DWI technique is helpful in determining the microstructure of affected brain and fiber tracts. However, more a precise connection with histopathology of the lesion must be elaborated.
Intracranial EEG can be performed if methods described above are insufficient to determine the epileptogenic focus. Intracranial electrodes are implanted registering an ictal or interictal activity in order to find epileptogenic zone. This method is also used intraoperatively allowing a precise selection of tissue for resection.
Epileptic seizures in focal cortical dysplasia are difficult to control with pharmacological treatment and often intractable. Hence, the surgical treatment appears to be a next therapeutic procedure. The resection of lesion, lobectomies and even hemispherectomies are performed. More limited surgeries are performed in elderly patients, usually due to FCD type I, usually located within the temporal lobe . Younger patients usually have FCD type II, with more extensive lesions and extratemporal location, predominantly in the frontal areas. In these cases operation includes lobectomy/ies or even hemispherectomy . There is no prove for gender or side predilection .
According to the literature, 60–80% of patients remain seizure-free after surgery, depending on the study center . Most favorable prognostic factor is a total resection, defined as the resection of lesion visible on MRI or epileptic focus determined by intracranial EEG. Unfortunately, according to different authors, subtotal resection is seen in approximately 30% of patients [17,46] with seizure relapsing after only 6 months .
The most frequent cause of unsuccessful surgical treatment is lesions invisible on MRI or located within vital and neurologically important structures – sensomotoric or speech-related . Poorer outcome is also observed in extratemporal location of the lesion, ill-defined epileptic focus, secondarily generalized tonic-clonic seizures, intracranial electrodes application and extensive resections [45,46,48]. Postoperative mortality for these surgeries is low. The most common transient postoperative complications include small neurological deficits and infections.
Some of the initial reports suggest a preferable mental development in children operated on early in lifetime due to focal cortical dysplasia .
Despite well-developed methods of neuroimaging and quite effective surgical techniques, focal cortical dysplasia remains underdiagnosed. An issue emerges, how many patients with intractable epilepsy reveal unspecific changes on EEG with normal brain MRI, having no chances of surgical treatment. The hope for the future is MR imaging using magnetic field of higher intensity – 3T, the development of DTI technique, dynamic perfusion MRI, fMRI and computed analysis of white and gray matter abnormalities, as well as the new PET ligands and modified EEG using a higher number of electrodes.
Further studies regarding epileptogenesis in dysplasia may contribute to the development of new pharmacological therapies. A huge step forward in surgical treatment would be the possibility of removing the lesions from vital brain centers.
The rapid development and improvement in various fields of medicine provides hope that many of these issues may find their solution in the future.