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Background: Hippocampal sclerosis (HS) is one of the major causes of intractable epilepsy. Astrogliosis in epileptic brain is a peculiar condition showing epileptogenesis and is thought to be different from the other pathological conditions. The aim of this study is to investigate the altered expression of astrocytic receptors, which contribute to neurotransmission in the synapse, and channels in HS lesions., Methods: We performed immunohistochemical and immunoblotting analyses of the P2RY1, P2RY2, P2RY4, Kir4.1, Kv4.2, mGluR1, and mGluR5 receptors and channels with the brain samples of 20 HS patients and 4 controls and evaluated the ratio of immunopositive cells and those expression levels., Results: The ratio of each immunopositive cell per glial fibrillary acidic protein-positive astrocytes and the expression levels of all 7 astrocytic receptors and channels in HS lesions were significantly increased. We previously described unique astrogliosis in epileptic lesions similar to what was observed in this study., Conclusion: This phenomenon is considered to trigger activation of the related signaling pathways and then contribute to epileptogenesis. Thus, astrocytes in epileptic lesion may show self-hyperexcitability and contribute to epileptogenesis through the endogenous astrocytic receptors and channels. These findings may suggest novel astrocytic receptor-related targets for the pharmacological treatment of epilepsy.

Epilepsy is one of the major neurologic diseases, and astrocytes play important roles in epileptogenesis. To investigate possible roles of astrocyte-related receptors in patients with intractable epilepsy associated with focal cortical dysplasia (FCD) and other conditions, we examined resected epileptic foci from 31 patients, including 23 with FCD type I, IIa, or IIb, 5 with tuberous sclerosis complex, and 3 with low-grade astrocytoma. Control samples were from 21 autopsied brains of patients without epilepsy or neurologic deficits and 5 patients with pathologic gliosis without epilepsy. Immunohistochemical and immunoblot analyses with antibodies against purinergic receptor subtypes P2RY1, P2RY2, P2RY4, potassium channels Kv4.2 and Kir4.1, and metabotropic receptor subtypes mGluR1 and mGluR5 were performed. Anti-glial fibrillary acidic protein, anti-NeuN, and anti-CD68 immunostaining was used to identify astrocytes, neurons, and microglia, respectively. Most glial fibrillary acidic protein-immunopositive astrocyte cells in the brain samples from patients with epilepsy were P2RY1-, P2RY2-, P2RY4-, Kv4.2-, Kir4.1-, mGluR1-, and mGluR5-positive, whereas samples from controls and pathologic gliosis showed lower expression levels of these astrocyte-related receptors. Our findings suggest that, although these receptors are necessary for astrocyte transmission, formation of the neuron-glia network, and other physiologic functions, overexpression in the brains of patients with intractable epilepsy may be associated with activation of intracellular and glio-neuronal signaling pathways that contribute to epileptogenesis.

The aim of this study is to analyze the characteristics of epilepsies as the sequelae of acute febrile encephalopathy with prolonged convulsions during childhood. Sixteen patients (M:F=9:7) aged 2-13years (mean 6.1years) with history of febrile acute encephalopathy were retrospectively reviewed. These patients experienced febrile encephalopathy at the age of 11months to 4years, with 11 individuals presenting with findings of a biphasic clinical course (n=5), frontal predominant (n=8) lesions, and/or reduced diffusivity in the cerebral white matter on magnetic resonance imaging (MRI; n=3). The remaining 5 patients had unilateral lesions that manifested the phenotype of hemiconvulsion-hemiplegia-epilepsy syndrome (HHES). Epilepsy emerged with a latent period of 2months to 2years after the acute phase of febrile encephalopathy. Head nodding or spasm with subsequent motion arrest and brief tonic seizures were the main seizure phenotypes. Ictal records of epileptic seizures were available in 9 patients. Epileptiform discharges with a focal or uneven distribution appeared at the seizure onset and lasted less than 1s in all patients; these were followed by either generalized attenuation or fast activity in 8 patients with head nodding, spasm, or brief tonic seizures, and by localized fast activity in 1 patient with versive tonic seizures. Notably, the seizure onset area was often located outside the severe lesions on MRI, i.e., in the parietal areas in patients with frontal predominant lesions, and in the spared hemisphere of HHES. Although phenobarbital, zonisamide, carbamazepine, clobazam, clonazepam, and clorazepate were partially effective in some patients, daily seizures persisted in 11 patients. Callosotomy was performed in 2 patients, and beneficial effects were observed in both. These characteristics suggested a broad distribution of augmented excitability in these patients, resulting in the rapid propagation of epileptic activity in the initial phase of ictal phenomena. Thus, this study investigates the most severe subgroup of epilepsy following febrile acute encephalopathy and provides the basis for further exploration of the pathogenesis and treatment of characteristic seizures in this population., (Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are major causes of intractable epilepsy in children. The probable pathogenesis of FCD and HMG is the abnormal migration and differentiation of neurons. The aim of the present study was to clarify the abnormal cytoarchitecture, based on neuronal immaturation. Tissue samples were obtained from 16 FCD and seven HME patients, aged between 2 months and 12 years, who had been diagnosed as typical FCD and HME, following surgical treatment for intractable epilepsy. Paraffin-embedded sections were stained with the antibodies of three layer-markers that are usually present only during the fetal period, namely SATB2 (expressed in the upper layer of the normal fetal neocortex), FOXP1 (expressed in the 5th layer), and TBR1 (expressed in the 6th layer). In FCD, SATB2-positive (+) cells located in the middle and deep regions of FCD Ia and Ib, but only in the superficial region of FCD IIa and IIb. FOXP1+ cells diffusely located in the neocortex, especially the upper layer of FCD IIa and IIb. TBR1+ cells mainly located in the middle and deep regions, and also white matter. In FCD IIb, TBR1+ cells were in the superficial region. In HME, SATB2+ and FOXP1+ cells were found diffusely. TBR1+ cells were in the middle and deep regions. On the basis of continued expression of fetal cortical layer-specific markers in FCD and HME brains, the abnormal neocortical formation in both is likely to be the result of disrupted neuronal migration and dysmaturation. The expression pattern is different between FCD and HME., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Purpose: To detect the epileptogenic region causing epileptic spasms in an infant with tuberous sclerosis (TS)., Methods: We applied a multiple band frequency analysis to video electroencephalographic (EEG) recordings of the infant's scalp. We also performed computed tomography (CT), magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and magnetoencephalography (MEG) of the brain in order to ascertain the epileptic focus., Results: During the periodic spasms, we identified fast ictal activity with frequencies of 60-70 Hz in the right centroparietal region. This region was part of the area surrounding the largest cortical tuber that was identified on CT and MRI and was located in the right frontal lobe. An area of increased blood perfusion that was observed with SPECT and dipole sources that were determined with interictal MEG were also located in this area. In addition, ictal frequency oscillations (FOs) with high gamma activity were identified over the cortex surrounding the largest tuber. After a lesionectomy of this tuber, the periodic spasms disappeared, and no FOs were detected over this area., Conclusions: Scalp EEG, which identified the ictal onset zone by detecting fast activity that was suggestive of FOs, was useful for detecting the epileptogenic region in an infant with TS.

To evaluate the effect of corpus callosotomy (CC) on attention deficit and behavioral problems in pediatric patients with intractable epilepsy, we retrospectively investigated sequential patients who had undergone CC to control seizures. Between August 2005 and April 2010, a total of 15 patients aged between 3.1 and 17.9 years underwent CC at our institute. All the patients experienced either drop attacks or head nodding, which were considered to be therapeutic targets of CC. A standardized instrument, the Child Behavior Checklist (CBCL), was used to assess behavioral and emotional problems before and after surgery. On postoperative EEGs, 8 (53%) showed improvement and 7 (47%) showed no change in epileptiform discharges. The Attention Problems scale and total score on the CBCL significantly improved in patients whose postoperative EEGs showed improvement. In addition to amelioration of target seizures, CC can improve attention impairments in association with improvement in the postoperative EEG., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The epileptogenesis of the striatum is unknown. We describe the case of a 12-year-old girl with intractable epilepsy who was treated by surgical interventions. Magnetic resonance imaging (MRI) showed ambiguous corticomedullary boundary in the left frontal lobe, and magnetoencephalography (MEG) revealed spike dipoles in the vicinity of the left ventral striatum. The epileptic seizures disappeared after partial resection of the frontal lobe, but recurred within 2 months and remained intractable. Neuropathological examination confirmed the presence of focal cortical dysplasia in the resected brain tissue. Ictal single photon emission computed tomography at this period displayed hyperperfusion of the left anterior striatum. At the second surgery, intraoperative electrocorticography exhibited spike discharges from the anterior striatum. After the removal of this structure and adjacent brain tissues, the patient remains seizure-free for 33 months, without any neurological deficits. Histopathological examination of the resected tissue revealed a large number of dysmorphic neurons distributed widely in the cerebral cortex, subcortical white matter, striatum, and insular cortex. These findings suggest that microscopic dysplasia of basal ganglia can accompany certain cases of focal cortical malformations, and may play a critical role in the epileptogenesis through their interaction with cortical structures., (Copyright 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Abstract: We describe two cases of complex partial seizures with ictal violent movements arising from the insular cortex. The first patient, a 14-year-old girl, presented with hyperkinetic behavior such as rolling, thrashing, and pedaling, and the second case, a 38-year-old woman, had been suffering from frequent daytime hyperkinetic seizures characterized by bizarre vocalization, jumping, and violent bimanual movements. Both patients showed a slight high signal change in the right posterior ventral insular cortex in fluid-attenuated inversion recovery (FLAIR) studies involving magnetic resonance imaging, and extensive subdural electroencephalographic monitoring revealed EEG seizure onset from the temporal lobe. The posterior ventral insular and lateral temporal cortices were resected, resulting in complete seizure freedom in both cases. The histological diagnoses were focal cortical dysplasia in the first case and gliosis in the second case. There may exist a group of patients with complex partial seizures with ictal violent automatism that can be ameliorated by the resection of epileptogenic lesions in the insular cortex. Careful inspection of the insular cortex is necessary to diagnose this type of epileptic seizure. [Copyright &y& Elsevier]