Focal Cortical Dysplasia Epilepsy Research Articles

Glucocorticoid receptors participate in epilepsy in FCDII patients and MP model rats: A potential therapeutic target for epilepsy in patients with focal cortical dysplasia II (FCDII)

ABSTRACT Background Glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) are involved in neuronal excitability, neurogenesis, and neuroinflammation. However, the roles of GRs and MRs in epilepsy in focal cortical dysplasia II (FCDII) have not been reported. Research Design and Methods We evaluated GRs and MRs expression and distribution in FCDII patients and methylazoxymethanol-pilocarpine-induced epilepsy model rats (MP rats), and the effects of a GR agonist on neurons in human FCDII and investigated the electrophysiological properties of rats’ neurons after lentivirus-mediated GR knockdown or overexpression and GR agonist or antagonist administration. Results GR expression (not MR) was decreased in specimens from FCDII patients and model rats. GR agonist dexamethasone reduced neuronal excitatory transmission and increased neuronal inhibitory transmission in FCDII. GR knockdown increased the excitability of cultured neurons, and GR overexpression rescued the hyperexcitability of MP-treated neurons. Moreover, dexamethasone decreased neuronal excitability and excitatory transmission in MP rats, while GR antagonist exerted the opposite effects. Dexamethasone reduced the seizure number and duration by approximately 85% and 60% in MP rats within one to two hours. Conclusions These results suggested that GRs play an important role in epilepsy in FCDII and GR activation may have protective and antiepileptic effects in FCDII.

Clinical and immunohistochemical characteristics of type II and type I focal cortical dysplasia.

Focal cortical dysplasia (FCD) II and I are major causes for drug-resistant epilepsy. In order to gain insight into the possible correlations between FCD II and FCD I, different clinical characteristics and immunohistochemical expression characteristics in FCD I and II were analyzed. The median age of onset and duration of epilepsy in FCD I and FCD II patients were 2.1 years and 5.3 years vs 2.4 years and 4.5 years. Therefore, the median age of onset and duration of epilepsy were similar in the two groups. Pathological lesions were predominantly located in frontal lobe in FCD II and temporal in FCD I. Significantly more signal abnormalities in FLAIR and T2 images were demonstrated in FCD II than FCD I. The rate of satisfied seizure outcome was relative higher in FCDII patients (95.12%) than that in FCDI group (84.6%). Furthermore, we detected expressions of progenitor cell proteins and the mammalian target of rapamycin (mTOR) cascade activation protein in FCDs. Results showed that sex-determiningregion Y-box 2(SOX2), Kruppel-likefactor 4 (KLF4) and phospho-S6 ribosomal proteins (ser240/244 or ser235/236) were expressed in FCDII group but not in FCD I. Overall, this study unveils FCD I and II exhibit distinct clinical and immunohistochemical expression characteristics, revealing different pathogenic mechanisms.

Non-invasive treatment options for focal cortical dysplasia.

Focal cortical dysplasia (FCD) presents a strong clinical challenge especially for the treatment of the associated epilepsy. Epilepsy in FCD is often treatment-resistant and constitutes 50% of treatment-resistant cases. Antiepileptic drugs (AEDs) have been widely used in the treatment of FCD. However, evidence to suggest their specific effect on the treatment of FCD remains to be established. In view of this resistance, several alternative treatments have been suggested. Although treatment currently involves surgical management, non-invasive treatments have been identified. The aim of the present review, was to assess non-invasive management strategies including, i) mammalian target of rapamycin (mTOR) inhibitors, ii) ketogenic diet (KD), and iii) vagus nerve stimulation (VNS). In addition, we discussed the literature available regarding the use of AEDs in FCD. Experiments conducted with mammals detailing rapamycin gene mutations in FCD have produced vital information for exploring treatment options using mTOR inhibitors. Of note is the importance of KD in children with FCD. This diet has been shown to modify disease progression by attenuating chromatin modification, a master regulator for gene expression and functional adaptation of the cell. FCD has also been studied widely with neurostimulation techniques. The outcomes of these techniques have been found to be variable. For widespread dysplasias, VNS has been shown to produce responder rates of >50%. Nevertheless, non-invasive cranial nerve stimulation techniques such as transcutaneous VNS and non-invasive VNS are gaining better patient compatibility, albeit their efficacy remains to be established.

Pathophysiologic characteristics of balloon cells in cortical dysplasia

Balloon cells are histopathological hallmarks of cortical malformations, i.e., focal cortical dysplasia (FCD) of the Taylor type or the cortical tubers of tuberous sclerosis, and they are believed to be the epileptogenic substrate and cause therapeutic drug resistant epilepsy in man. This study was carried out to investigate the developmental histogenesis and epileptogenesis of balloon cells in FCD. We used an immunohistochemical approach to examine the expressions of primitive neuroepithelial cell antigens (CD34, nestin, and vimentin), ionotrophic glutamate receptor subunits (NR1, NR2A/B, GluR1, GluR2, GluR3, GluR4, and GluR5/6/7), and P-glycoprotein in balloon cells from FCD and normal cerebral cortex epileptogenic lesions. Balloon cells presented in clusters or as scattered cells throughout FCD lesions involving the gray and white matter. We found the balloon cells to be classifiable into three subtypes based on glial fibrillary acidic protein (GFAP) and neurofilament protein (NF-L) immunohistochemistry, i.e., as neuronal, astrocytic, and uncommitted. Immunopositivity for nestin, CD34, and vimentin in balloon cells of FCD suggests that they may be derived from the abnormal development and differentiation of neural stem cells. Moreover, it appears that epileptogenesis in cortical dysplasia is partly caused by the upregulations of some glutamate receptor subunit proteins (NR1, NR2A/B, GluR1, and GluR3) in balloon cells and dysplastic neurons. We speculate that the presence of the drug resistance protein P-glycoprotein in balloon cells might explain medically refractory epilepsy in FCD.

Adult-onset epilepsy in focal cortical dysplasia of Taylor type

Focal cortical dysplasia of Taylor type (FCDT) usually presents with seizures at an early age, whereas adult onset of epilepsy is uncommon. We reviewed the medical records of 213 patients with FCDT. In 21 patients (10%), age at seizure onset ranged from 18 to 55 years (mean 25.3). The outcome of seizures in patients with FCDT and adult-onset epilepsy seems favorable vs childhood-onset seizures.

Characteristics of epilepsy in focal cortical dysplasia in infancy

To describe the poorly known characteristics of epilepsy during infancy in focal cortical dysplasia (FCD), one of the most frequent cause of infantile epilepsy. All 28 patients with FCD referred to two specialized centres were retrospectively studied regarding seizure characteristics, psychomotor evaluation, and response to medical and surgical treatment. All patients presented with early partial seizures. Semiology, but not the age of onset, depended on the topography of the dysplasia, with abnormal eye movements in all cases of posterior FCD. Eleven patients also developed infantile spasms (IS), mainly asymmetrical. IS were easily controlled with Vigabatrin or ACTH, but no partial seizures could be medically controlled except in one patient. All patients except one had abnormal neuropsychological findings. Fifteen patients had surgery, eight became seizure free, and seven were significantly improved regarding psychomotor development. Very early and refractory partial seizures, but easily controlled IS are the main characteristics of FCD in infancy. Only the focal ictal semiology may help differentiate the localization of FCD. Its intrinsic epileptogenicity could sustain this clinical pattern. Since the chances for medical control and normal neurodevelopment are poor, surgical treatment should be considered early in infants with FCD.