Introduction—Epileptogenic cortical dysplasia: Emerging trends in diagnosis, treatment, and pathogenesis (2009)

Focal cortical dysplasias (FCDs) are a common cause of refractory epilepsy in children and adults. These dysplasias, which represent abnormalities of cellular proliferation, migration, and differentiation, are thought to arise in early or midgestation when the cortical architecture is forming. The Palmini classification has been adopted most widely in order to categorize these heterogeneous lesions. Type 1 dysplasia refers to the most subtle alterations in cortical lamination and ectopic neurons in the white matter or immediately adjacent to layer 1, whereas type 2 dysplasia refers to areas of more extensive dyslamination outside of layer 1 with the absence (type 2a) or presence (type 2b) of cytomegalic or balloon cells (for review see Crino, 2009; Duchowny, 2009; this supplement). The etiology of these lesions is poorly understood, and has been postulated to be due to possible in utero focal insults to cortex or to genetic mutations responsible for disordered cell proliferation or differentiation. Tuberous sclerosis complex (TSC) represents a more specific form of type 2b FCD, with the presence of areas of dysplasia containing giant cytomegalic cells as well as dysplastic neurons and astrocytes, termed “tubers.” Tubers can be present singly or multiply in an affected individual, and are variably epileptogenic. In addition to a high rate of epilepsy, patients with TSC also have cognitive deficits such as autism, as well as subependymal giant cell astrocytomas (SEGAs). In the last decade, there has been astonishing progress in our understanding of the molecular and genetic underpinnings of TSC, and this has also shed light on the pathophysiology and epileptogenicity of non-TSC FCD. TSC1 and TSC2 are the genes that are found to be mutated in TSC, and encode for hamartin and tuberin, respectively. Hamartin and tuberin cooperatively inhibit excessive protein translation by acting to downregulate the mammalian target of rapamycin (mTOR). The mTOR pathway has been shown to be upregulated in TSC, and some of its components are also overactive in non-TSC FCD, suggesting that this pathway may be common to a wide range of cortical dysplasias (for review see Crino, 2009; this supplement). Dysplastic lesions appear to be epileptic foci, although it remains unclear as to whether the ictal stimulus arises in the cells within the dysplasia or the more normal neuropil immediately adjacent to the lesion. Source analysis from scalp electroencephalography (EEG) often localized ictal onset in the dysplasias. During the phase 2 presurgical work-up, electrocorticography (ECoG) is performed with grids and strips electrode arrays, and can show sharp delineation in excitability between the lesion area and the normal surround. Other functional mapping is obtained by [18F]-deoxyglucose positron emission tomography (PET), where heterotopic nodules often appear hypometabolic in the interictal state. It has become clear that dysplastic neural networks are functionally integrated with surrounding areas, as is evidenced by their responses in event-related potential testing, task-related changes in cerebral blood flow within dysplastic areas on functional magnetic resonance imaging (fMRI), and intraoperative ECoG mapping studies (for review see Duchowny, 2009; this supplement). In addition to advanced neurophysiologic techniques, the diagnosis and localization of individual dysplasias has benefited greatly from newer imaging techniques. High-resolution, high field strength (3 Tesla) MRI is responsible for detection of lesions that were previously undetected by computerized tomography (CT) scans and lower field strength MRIs. It is important to note that MRIs can now be performed in the fetus, allowing detection of dysplasias near the time they are thought to arise in midgestation. In addition to improved field strength, arterial spin labeling (ASL) and susceptibility weighted imaging (SWI) improve the sensitivity of the images (for review see Madan and Grant, 2009; this supplement). Further advances have come from the application of diffusion tensor imaging (DTI), where subtle changes in white matter tracts can be detected adjacent to the lesion, as well as areas of abnormal regional connectivity. Improved accuracy of detection also comes from the combination of functional studies such as PET with MRI, and this has the potential for differentiating between epileptogenic and nonepileptic dysplastic lesions. Because patients with pharmacoresistant and refractory epilepsy do come to surgery, there is often the opportunity to study the resected tissue that is not required by pathologists for diagnostic purposes. Recent advances from study of human genetic mapping as well as cellular and molecular studies of resected tissue are revealing details that will be important for validation of potential therapies and biomarkers of epileptogenesis. Resected tissue can be immediately frozen for analysis of gene or protein expression. In addition, resected tissue can be the source for primary cell cultures for in vitro assays, or this tissue can be rapidly transferred to oxygenated artificial cerebrospinal fluid so that electrophysiologic studies such as field potential and whole-cell patch-clamp recordings can be performed. Finally, biopsy tissue can also serve for histopathologic analysis of disordered morphology, or cellular localization of altered gene (in situ hybridization) and protein expression (immunocytochemistry) (for review see D’Archangelo, 2009; this supplement). Thus far, human tissue studies have shown that there are marked alterations of protein translation in cells in both TSC and various forms of FCD—namely, upregulated expression of PI3K/Akt/mTOR cascades. Notably, as a result, clinical trials are underway in TSC with an analog to the mTOR inhibitor rapamycin. In addition, human tissue studies have revealed that cells within the dysplasia are variably epileptogenic; dysplastic neurons have been shown to be hyperexcitable, yet giant cells and balloon cells appear electrically inert, with little synaptic to no synaptic connectivity. This heterogeneity of function is corroborated by the fact that altered neurotransmitter and transporter expression is present on many cells in the lesion. Interestingly, the patterns of expression have distinct similarities to the status of expression normally seen in fetal or neonatal brain, where hyperexcitability is required for activity-dependent synaptogenesis and plasticity. Better delineation of unique aspects of the dysplasias, such as unique neurotransmitter compositions, may allow for pharmacologic therapies directed at the dysplasia with little effect on the surrounding neuronal networks. The wealth of information emerging from human genetic, cellular, and molecular studies has provided a foundation for the development of in vitro and in vivo experimental animal models of FCD. These models can be used for pathophysiologic investigations as well as facilitate preclinical therapeutic trials. A variety of rodent models have emerged, both genetic and acquired (see Wong, 2009; this supplement). Transgenic mouse models have been made to alter expression of components and regulators of the mTOR cascade, such as TSC1, TSC2, and PTEN mutations. In addition, others have refined models of in utero cortical injury with trauma or mitogens to produce focal areas of dysplasia. These models have variable levels of epilepsy, learning deficits, and cortical dyslamination or dysplastic neurons and/or glia. Therapeutic trials are possible in these animals, and several researchers are now reporting that therapies addressed at modulation of the mTOR cascade may attenuate epileptogenesis and cognitive dysfunction. Surgery remains the mainstay of therapy for refractory epilepsy localized to a focal dysplasia, and review of the available literature suggests that approximately two-thirds of patients are seizure free at last follow-up (see Mathern, 2009; this supplement). Typing of dysplasias appears to be important for prognosis: The recurrence rate for epilepsy is higher for type 2 than type 1 dysplasia. Improved localization from advanced neuroimaging, functional, and neurophysiologic studies has contributed to reduction in morbidity and mortality. Clearly there is a need for improved sensitivity and specificity of presurgical localization to improve surgical outcome. In addition, knowledge gained from the study of human tissue and animal models may provide novel nonsurgical therapies for this population. Human studies are vital to informing the development of experimental models, yet it is most likely that novel therapeutic interventions will arise from testing in the animal and in vitro models. Successful progress can be made by the continued translation of information between human investigation and experimental models. I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Disclaimer: The author declares no conflicts of interest.