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Aim: To assess the relationship of surface area of the cerebral cortex to intracranial volume (ICV) in syndromic craniosynostosis., Method: Records of 140 patients (64 males, 76 females; mean age 8y 6mo [SD 5y 6mo], range 1y 2mo-24y 2mo) with syndromic craniosynostosis were reviewed to include clinical and imaging data. Two hundred and three total magnetic resonance imaging (MRI) scans were evaluated in this study (148 patients with fibroblast growth factor receptor [FGFR], 19 patients with TWIST1, and 36 controls). MRIs were processed via FreeSurfer pipeline to determine total ICV and cortical surface area (CSA). Scaling coefficients were calculated from log-transformed data via mixed regression to account for multiple measurements, sex, syndrome, and age. Educational outcomes were reported by syndrome., Results: Mean ICV was greater in patients with FGFR (1519cm 3 , SD 269cm 3 , p=0.016) than in patients with TWIST1 (1304cm 3 , SD 145cm 3 ) or controls (1405cm 3 , SD 158cm 3 ). CSA was related to ICV by a scaling law with an exponent of 0.68 (95% confidence interval [CI] 0.61-0.76) in patients with FGFR compared to 0.81 (95% CI 0.50-1.12) in patients with TWIST1 and 0.77 (95% CI 0.61-0.93) in controls. Lobar analysis revealed reduced scaling in the parietal (0.50, 95% CI 0.42-0.59) and occipital (0.67, 95% CI 0.54-0.80) lobes of patients with FGFR compared with controls. Modified learning environments were needed more often in patients with FGFR., Interpretation: Despite adequate ICV in FGFR-mediated craniosynostosis, CSA development is reduced, indicating maldevelopment, particularly in parietal and occipital lobes. Modified education is also more common in patients with FGFR., (© 2021 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Introduction: Neurodevelopmental delay is more common in children born with congenital heart defects (CHD), even with optimal perinatal and peri-operative care. It is hypothesized that fetuses with CHD are prone to neurological impairment in utero due to their cardiac defect, possibly leading to delayed cortical development., Methods: Cerebral cortical maturation was assessed with advanced neurosonographic examinations every 4 weeks in fetuses with CHD and compared to control fetuses. Five different primary fissures and four areas were scored (ranging 0-5) by blinded examiners using a cortical maturation scheme., Results: Cortical staging was assessed in 574 ultrasound examinations in 85 CHD fetuses and 61 controls. Small differences in grading were seen in Sylvian and cingulate fissures. (Sylvian fissure: -0.12 grade, 95% CI (-0.23; -0.01) p = 0.05, cingulate fissure: -0.24 grade, 95% CI (-0.38; -0.10) p = <0.001. Other cortical areas showed normal maturation as compared to control fetuses., Conclusion: Small differences were seen in three of the nine analyzed cortical areas in CHD fetuses, in contrast to previous reports on progressive third-trimester delay. The clinical implications of the small differences however, remain unknown., (© 2021 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Malformations of cortical development (MCD) represent a group of rare diseases with severe clinical presentation as epileptic and pharmacoresistant encephalopathies. Morphological studies in tissue from MCD patients have revealed reduced GABAergic efficacy and increased intracellular chloride concentration in neuronal cells as important pathophysiological mechanisms in MCD. Also, in various animal models, alterations of GABAergic inhibition have been postulated as a predominant factor contributing to perilesional hyperexcitability. Along with this line, the NKCC1 inhibitor bumetanide has been postulated as a potential drug for treatment of epilepsy, mediating its antiepileptic effect by reduction of the intracellular chloride and increased inhibitory efficacy of GABAergic transmission. In the present study, we focused on the focal freeze-lesion model of MCD to compare antiepileptic drugs with distinct mechanisms of action, including NKCC1 inhibition by bumetanide. For this purpose, we combined electrophysiological and optical methods in slice preparations and assessed the properties of seizure like events (SLE) induced by 4-aminopyridine. In freeze-lesioned but not control slices, SLE onset was confined to the perilesional area, confirming that this region is hyperexcitable and likely triggers pathological activity. Bumetanide selectively reduced epileptic activity in lesion-containing slices but not in slices from sham-treated control rats. Moreover, bumetanide caused a shift in the SLE onset site away from the perilesional area. In contrast, effects of other antiepileptic drugs including carbamazepine, lacosamide, acezatolamide and zonisamide occurred mostly independently of the lesion and did not result in a shift of the onset region. Our work adds evidence for the functional relevance of chloride homeostasis in the pathophysiology of microgyrus formation as represented in the focal freeze-lesion model. Further studies in different MCD models and human tissue will be required to validate the effects across different MCD subtypes and species and to assess the translational value of our findings., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are related malformations with shared etiologies. We report three patients with a spectrum of cortical malformations associated with pathogenic brain-specific somatic Ras homolog enriched in brain (RHEB) variants. The somatic variant load directly correlated with the size of the malformation, with upregulated mTOR activity confirmed in dysplastic tissues. Laser capture microdissection showed enrichment of RHEB variants in dysmorphic neurons and balloon cells. Our findings support the role of RHEB in a spectrum of cortical malformations confirming that FCD and HME represent a disease continuum, with the extent of dysplastic brain directly correlated with the somatic variant load., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Abnormal levels of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) have been detected in various neurological disorders. The potent impact of FGF-FGFR in multiple embryonic developmental processes makes it challenging to elucidate their roles in postmitotic neurons. Taking an alternative approach to examine the impact of aberrant FGFR function on glutamatergic neurons, we generated a FGFR gain-of-function (GOF) transgenic mouse, which expresses constitutively activated FGFR3 (FGFR3 K650E ) in postmitotic glutamatergic neurons. We found that GOF disrupts mitosis of radial-glia neural progenitors (RGCs), inside-out radial migration of post-mitotic glutamatergic neurons, and axonal tract projections. In particular, late-born CUX1-positive neurons are widely dispersed throughout the GOF cortex. Such a cortical migration deficit is likely caused, at least in part, by a significant reduction of the radial processes projecting from RGCs. RNA-sequencing analysis of the GOF embryonic cortex reveals significant alterations in several pathways involved in cell cycle regulation and axonal pathfinding. Collectively, our data suggest that FGFR3 GOF in postmitotic neurons not only alters axonal growth of postmitotic neurons but also impairs RGC neurogenesis and radial glia processes.

By using the Cre-mediated genetic switch technology, we were able to successfully generate a conditional knock-in mouse, bearing the KIF2A p.His321Asp missense point variant, identified in a subject with malformations of cortical development. These mice present with neuroanatomical anomalies and microcephaly associated with behavioral deficiencies and susceptibility to epilepsy, correlating with the described human phenotype. Using the flexibility of this model, we investigated RosaCre-, NestinCre- and NexCre-driven expression of the mutation to dissect the pathophysiological mechanisms underlying neurodevelopmental cortical abnormalities. We show that the expression of the p.His321Asp pathogenic variant increases apoptosis and causes abnormal multipolar to bipolar transition in newborn neurons, providing therefore insights to better understand cortical organization and brain growth defects that characterize KIF2A-related human disorders. We further demonstrate that the observed cellular phenotypes are likely to be linked to deficiency in the microtubule depolymerizing function of KIF2A., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aim: To evaluate gross motor function and associated factors in children with congenital Zika syndrome (CZS)., Method: Fifty-nine children (30 males, 29 females) with CZS at a mean (SD) age of 14.7 (3.9), months (range 5-29mo) were evaluated using the Gross Motor Function Measure (GMFM) and classified according to the Gross Motor Function Classification System (GMFCS). Neurological damage was evaluated by neuroimaging. The mothers' sociodemographic characteristics and general data on the children were obtained from interviews with the mothers and from the children's medical records. Correlational and multiple regression analyses were performed to identify factors associated with these children's motor function., Results: In 81% of the children, motor function impairment was severe, classified as GMFCS level V. The overall GMFM score ranged from 5 to 210 (median 18; interquartile range 11), with only four children receiving scores in the D and E dimensions. The factors found to affect motor function were the presence of severe malformations of cortical development and small head circumference at birth., Interpretation: Although motor impairment may be mild in some children, it is generally severe. Severe malformations of cortical development and small head circumference at birth were factors associated with poorer motor function, reflecting the greater severity of brain damage., What This Paper Adds: Motor impairment is severe in most children with congenital Zika syndrome (CZS). Motor skills are adequate or close to adequate for age in 7% of children with CZS. Severe malformations of cortical development are associated with poor motor control. Small head circumference at birth is also associated with poor motor control., (© 2019 Mac Keith Press.)

Background: Type IIIb dysplasia is a subtype of focal cortical dysplasia associated with a tumor, most frequently with gangliogliomas then with dysembryoplastic neuroepithelial tumors (DNETs). Their preoperative diagnosis often remains equivocal since specific features are missing. The functional results (i.e., seizure free) is good with 81%-87% of Engel Ia at 5-year follow-up., Case Description: A 4-year-old boy presented with a 1-year history of severe, invalidating, drug-resistant epilepsy. Imaging workup demonstrated a huge left limbic lesion, of which diagnosis remained speculative. Because of worsening neurological status, resective surgery was recommended after multidisciplinary discussion. The resection was performed through left transtemporal approach under neuronavigation (C.R.). Postoperative magnetic resonance imaging assessed uncomplicated near-total resection. Histopathological analysis showed combined features of a DNET of nonspecific type and a focal cortical dysplasia., Conclusion: We describe a rare condition of type IIIb dysplasia combining a focal cortical dysplasia with a DNET. Preoperative diagnosis of the lesion was of utmost difficultly, thereby rendering mandatory a thorough histopathological examination of resected specimen in the vast majority of cases. Increased recognition of the condition brings up the hypothesis of a genetic continuum or linkage between the 2 conditions. Functional results on seizure activity after ablative surgery are good and maximal safe resection should be the goal., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Our objective is to examine the layer and spectrotemporal architecture and laminar distribution of high-frequency oscillations (HFOs) in a neonatal freeze lesion model of focal cortical dysplasia (FCD) associated with a high prevalence of spontaneous spike-wave discharges (SWDs). Electrophysiological recording of local field potentials (LFPs) in control and freeze lesion animals were obtained with linear micro-electrode arrays to detect presence of HFOs as compared to changes in spectral power, signal coherence, and single-unit distributions during "hyper-excitable" epochs of anesthesia-induced burst-suppression (B-S). Result were compared to HFOs observed during spontaneous SWDs in animals during sleep. Micro-electrode array recordings from the malformed cortex indicated significant increases in the presence of HFOs above 100 Hz and associated increases in spectral power and altered LFP coherence of recorded signals across cortical lamina of freeze-lesioned animals with spontaneous bursts of high-frequency activity, confined predominately to granular and supragranular layers. Spike sorting of well-isolated single-units recorded from freeze-lesioned cortex indicated an increase in putative excitatory cell activity in the outer cortical layers that showed only a weak association with HFOs while deeper inhibitory units were strongly phase-locked to high-frequency ripple (HFR) oscillations (300-800 Hz). Both SWDs and B-S show increases in HFR activity that were phase-locked to the high-frequency spike pattern occurring at the trough of low frequency oscillations. The spontaneous cyclic spiking of cortical inhibitory cells appears to be the driving substrate behind the HFO patterns associated with SWDs and a hyperexcitable supragranular layer near the malformed cortex may play a key role in epileptogenesis in our model. These data, derived from a mouse model with a distinct focal cortical malformation, support recent clinical data that HFOs, particularly fast ripples, is a biomarker to help define the cortical seizure zone, and provide limited insights toward understanding cellular level changes underlying the HFOs.

Background: Prenatal infection is a substantial risk factor for neurodevelopmental disorders such as autism in offspring. We have previously reported that influenza vaccination (VAC) during early pregnancy contributes to neurogenesis and behavioral function in offspring., Results: Here, we probe the efficacy of VAC pretreatment on autism-like behaviors in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) mouse model. We show that VAC improves abnormal fetal brain cytoarchitecture and lamination, an effect associated with promotion of intermediate progenitor cell differentiation in MIA fetal brain. These beneficial effects are sufficient to prevent social deficits in adult MIA offspring. Furthermore, whole-genome analysis suggests a strong interaction between Ikzf1 (IKAROS family zinc-finger 1) and neuronal differentiation. Intriguingly, VAC rescues excessive microglial Ikzf1 expression and attenuates microglial inflammatory responses in the MIA fetal brain., Conclusions: Our study implies that a preprocessed influenza vaccination prevents maternal bacterial infection from causing neocortical lamination impairments and autism-related behaviors in offspring.

Background: Catastrophic epilepsy results in severe neurodevelopmental delay in infants because of frequent and/or long seizures. Therefore, consideration of early epilepsy surgery is essential for neurodevelopmental outcome. Once an infant with catastrophic seizures is identified as a surgical candidate, it is important that the surgical plan be carefully defined based on detailed presurgical evidence to minimize surgical complications in this age group., Case Description: We present 2 infants with catastrophic epilepsy, epileptic spasms, and bihemispheric electroencephalographic abnormalities who underwent one-stage disconnection surgery based on a sound hypothesis of the epileptogenic zone. Each patient underwent an extensive noninvasive presurgical investigation followed by stereotactic disconnection leucotomy in a single stage. After the 2 children were followed for 24-36 months. A seizure reduction by at least 90% (Engel class I) was achieved in both cases with subsequent improvement in neurodevelopmental progress. There were no perioperative complications. Both patients had widespread cortical dysplasia on pathologic evaluation., Conclusions: Careful consideration of the noninvasive presurgical workup can identify focal onset even in the presence of catastrophic epilepsy with widespread bilateral abnormalities. Single-stage lobar leucotomy for disconnection of the epileptogenic zone can lead to excellent outcome in these patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Epilepsy is a common neurologic disorder resulting in spontaneous, recurrent seizures. About 30-40% of patients are not responsive to pharmacologic therapies. This may be due to the differences between individual patients such as etiology, underlying pathophysiology, and seizure focus, and it highlights the importance of new drug discovery and testing in this field. Our goal was to determine the efficacy of lacosamide (LCM), a drug approved for the treatment of focal seizures, in a model of generalized epilepsy with cortical dysplasia (CD). We sought to compare LCM to levetiracetam (LEV), a drug that is currently used for the treatment of both partial and generalized epilepsy and to test its proficiency., Methods: Pregnant rats were irradiated to produce pups with malformed cortices in a model of CD, which will be referred to as the "first hit." Adult animals, developed normally (NL) and irradiated (XRT), were surgically implanted with electroencephalography (EEG) electrodes. Baseline EEG was recorded on all rats prior to pretreatments with either LCM, LEV, or placebo (PBO). After 30 min, all rats were injected with a subconvulsive dose of pentylenetetrazole (PTZ), a γ-aminobutyric acid receptor A (GABA A ) antagonist used to provoke generalized seizures as a "second hit.", Results: LCM and LEV were both effective against seizures induced by PTZ. XRT rats had a higher seizure incidence with longer and more severe seizures than NL rats. Seizure duration was decreased with both LCM and LEV in all animals. In XRT rats, there was a significant reduction in acute seizure incidence and severity with both LCM and LEV after PTZ injection., Significance: Our results suggest that LCM could be used as a potential treatment option for generalized epilepsy with CD as the underlying pathology., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Background and Purpose: Brain AVM, cerebral abscess, and ischemic stroke are among the well known neurologic manifestations of hereditary hemorrhagic telangiectasia. However, recently reported data suggest an additional association with malformations of cortical development. The purpose of this study was to determine the prevalence of malformations of cortical development in a population of pediatric patients with hereditary hemorrhagic telangiectasia., Materials and Methods: A retrospective review of brain MRIs from 116 pediatric patients was performed. Each patient was referred from our institution's Hereditary Hemorrhagic Telangiectasia Clinic. Each MRI included a 3D sequence, most frequently MPRAGE. The 3D sequence was evaluated by a neuroradiology fellow, with specific attention to the presence or absence of malformations of cortical development. Positive studies were subsequently reviewed by 2 attending neuroradiologists, who rendered a final diagnosis., Results: Fourteen of 116 (12.1%) patients were found to have a malformation of cortical development. Among these 14, there were 12 cases of polymicrogyria and 2 cases of bifrontal periventricular nodular heterotopia., Conclusions: Pediatric patients with hereditary hemorrhagic telangiectasia have a relatively high prevalence of malformations of cortical development, typically perisylvian polymicrogyria., (© 2017 by American Journal of Neuroradiology.)

Focal cortical dysplasia (FCD) is one of the most important causes of drug-resistant epilepsy in paediatric patients, particularly in those below the age of 3. Even though over 40 years have passed since the first description of the entity by Taylor, the exact mechanisms causing these cortical abnormalities remain unelucidated. In this review, we summarise the current knowledge on clinical and histopathological aspects, taking into account the new classification system proposed by the International League Against Epilepsy. We focus on the clinicopathological associations and differences in post-surgical outcome among FCD subtypes, in particular isolated FCD vs. FCD associated with principal lesions, which have not been summarised to date. We also recapitulate genetic studies, pointing to the possible mechanisms of the cortical dysregulation and drug resistance, and summarise novel factors which may contribute to epileptogenesis in FCD. Furthermore, we compare FCD type IIB (FCDIIB) with brain tumours found in a neurocutaneous disorder, tuberous sclerosis, as we evaluate the hypothesis that FCD IIB may be a local form of this disease.

Objective: To examine if mice with focal cortical dysplasia (FCD) develop spontaneous epileptic seizures and, if so, determine the key electroencephalography (EEG) features., Methods: Unilateral single freeze lesions to the S1 region (SFLS1R) were made in postnatal day 0-1 pups to induce a neocortical microgyrus in the right cortical hemisphere. Continuous 24-h recordings with intracranial EEG electrodes and behavioral tests were performed in adult SFLS1R and sham-control mice to assess neurologic status., Results: A high percentage of adult SFLS1R animals (89%, 40/45) exhibited at least one or more spontaneous nonconvulsive seizure events over the course of 24 h. Of these animals, 60% (27/45) presented with a chronic seizure state that was persistent throughout the recording session, consisting of bursts of rhythmic high-amplitude spike-wave activities and primarily occurring during periods of slow-wave sleep. In comparison, none of the control, age-matched, mice (0/12) developed seizures. The epileptic discharge pattern closely resembled a pattern of continuous spike-waves during slow-wave sleep (CSWS) of the human syndrome described as an electrical status epilepticus during slow-wave sleep (ESES). Key findings in the SFLS1R model indicated that the observed CSWS (1) were more prevalent in female (18/23) versus male (9/22, p < 0.05), (2) were strongest in the right S1 region although generalized to other brain regions, (3) were associated with significant cognitive and behavioral deficits, (4) were temporarily alleviated by ethosuximide treatment or optogenetic activation of cortical γ-aminobutyric acid (GABA)ergic neurons, and (5) theta and alpha band rhythms may play a key role in the generalization of spike-wave activities., Significance: This is the first report of an in vivo animal FCD model that induces chronic spontaneous electrographic brain seizures. Further characterization of the abnormal oscillations in this mouse model may lead to a better understanding of the mechanisms of CSWS/ESES., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Hyaline protoplasmic astrocytopathy is a rare disorder marked by an accumulation of protein material in the cytoplasm of astrocytic cells, mostly in the cortex. The finding has been described in Aicardi syndrome (agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms) as well as in patients with pharmacoresistant epilepsy and in association with focal cortical dysplasia, polymicrogyria and nodular heterotopia. This report describes the first case of this entity described in a patient with tuberous sclerosis. The patient was a 3-year-old boy who presented at age 2months with medically intractable seizures. Has mother has a tuberous sclerosis 2 (TSC 2) gene abnormality and a diagnosis of tuberous sclerosis. On imaging, he was noted to have multiple lesions in the left parietal and temporal lobes consistent with focal cortical dysplasia and a subependymal nodule. He additionally had two hypopigmented lesions on the skin. He underwent resection of the left parietal lobe 32months after seizure onset. Histopathologic examination showed eosinophilic cytoplasmic inclusions within astrocytes in the cortex and superficial white matter focally accompanied by a disordered cortical architecture with dysmorphic neurons and balloon cells, consistent with focal cortical dysplasia classified as type IIb according to International League Against Epilepsy classification criteria (ILAE type IIb). At the time of most recent follow-up, 93months postoperatively, he is still experiencing seizures with overall worthwhile improvement while on seizure medication., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Resective epilepsy surgery is an established treatment option in patients with pharmacoresistant, lesion related epilepsy. Yet, if the presurgical work-up proves multi-focal organization of the epileptogenic zone, or the area of intended resection is close to eloquent brain areas, patients may decide against resections because of an unfavorable risk-benefit-ratio. We assess if lesion guided cortical stereotactic radiofrequency thermocoagulation (L-RFTC) is a potential surgical alternative in these patients., Methods: We performed seven procedures of L-RFTC. Three patients had monofocal epilepsy arising close to eloquent structures; in four, invasive pre-surgical workup documented monofocal seizure onset but strong interictal epileptic activity also independent and distant from the seizure onset zone. L-RFTC was restricted to the lesional area (=seizure onset site)., Results: 12 to 37 months after RFTC worthwhile seizure improvement was achieved in 6 patients. One patient became seizure free following complete coagulation of a focal cortical dysplasia, two had had 1-2 auras under tapered but not under continued medication. In one patient only subclinical seizures persisted. In one patient hypermotor seizures were transformed into milder short tonic seizures and another one had a seizure reduction by 50%. Only one patient did not profit at all. One patient developed a persisting neurological deficit., Significance: In patients with complex epileptogenic zones L-RFTC can lead to worthwhile seizure reduction. This qualifies this procedure as a palliative surgical technique with potential good risk-benefit ratio. In patients with small focal cortical dysplasias L-RFTC may even allow minimal-invasive surgery with curative intention., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We report a rare case of a 22-year-old woman with biopsy-proven pigmented ganglioglioma. The patient initially underwent a right temporal lobectomy for intractable seizures at the age of 9 and remained seizure free for several years but subsequently developed complex partial seizures. Due to enhancement of a left mesial occipital lesion on preoperative MRI of the brain, the patient underwent a left subdural electrode placement and simultaneous biopsy of the left mesial occipital lesion. Biopsy results revealed a rare pigmented ganglioglioma, World Health Organization Grade I. The seizure focus was identified in the left mesial occipital lobe and the patient underwent tumor resection. An extensive literature search revealed that our patient is the fourth case of pigmented ganglioglioma described in the literature and was positive for BRAF V600E mutation by molecular studies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Epilepsy surgery is increasingly used to treat children with medically intractable epilepsy. This study investigates the aetiology and seizure outcome in Danish children operated between 1996 and 2010., Methods: Retrospectively collected data on structural magnetic resonance imaging (MRI) diagnoses, surgical procedures and seizure outcomes classified according to the Engel Classification were used. Changes over time grouped as 1996-2000, 2001-2005 and 2006-2010 were analysed., Results: A total of 95 children underwent epilepsy surgery. Sixty-three operations were performed in Denmark and 50 abroad. In all, 14 children needed reoperation. The median follow-up period was four years. At the latest follow-up, Engel class I (indicating no disabling seizures) was found in 67% of the patients. Cortical dysplasia, mesial temporal sclerosis and tumour were the most common MRI findings. The percentage of tumours operated decreased over time, and frontal lobe resections increased. In the 2006-2010 period, resections with normal MRI were performed, resulting in a less favourable Engel outcome. Persistent, unexpected complications were seen in three of 113 operations., Conclusions: The majority of children who undergo epilepsy surgery have a good, worthwhile seizure outcome. The seizure outcome for Danish children corresponds to that of other epilepsy surgery centres. The clinical criteria for selection of patients changed over time., Funding: none., Trial Registration: The Danish Data Protection Agency approved the project with record number: 2013-41-2459.

Purpose: To examine the cognition, spontaneous epilepsy, and electroencephalography (EEG) characteristics of rats with malformations of cortical development (MCD) and their use as an animal model for investigating the pathogenesis of intractable epilepsy and screening novel antiepileptic drugs., Methods: An epileptic rat model of MCD was established with the F1 generation of pregnant rats after X-irradiation with 175 cGy (Group L), 195 cGy (Group M), or 215 cGy (Group H). Long-term video-EEG monitoring was used to record the seizures in the rats with MCD. Cognition was assessed with the Morris water maze. The EEGs were recorded and analyzed in the frontal and parietal lobes and hippocampi of adult rats. Finally, the brain tissues were processed for Nissl staining., Results: The model groups exhibited markedly prolonged escape latencies and distinct decrements in the percent distance traveled in the target quadrant and platform-crossing frequency. These findings were dose-dependent. Frequent interictal epileptiform discharges were observed in the frontal and parietal lobes and hippocampi of adult rats, and their incidences were markedly higher in the model groups compared with that in the normal controls, with Group M having the highest incidence. Spontaneous seizures were observed in the model groups (mean incidence, 46.7%). The daily mean frequency of seizures and the incidence of spontaneous seizures were highest in Group M. Nissl staining revealed a dose-dependent pattern of hippocampal abnormalities, cortical and subcortical nodular heterotopia, and callosal agenesis in the model groups., Conclusion: The 195 cGy dose was most appropriate for establishing an epileptic model of MCD with X-irradiation., (Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

One of the most prominent features of the cerebral cortex of higher mammals is the presence of gyri. Because malformations of the cortical gyri are associated with severe disability in brain function, the mechanisms underlying malformations of the cortical gyri have been of great interest. Combining gyrencephalic carnivore ferrets and genetic manipulations using in utero electroporation, here we successfully recapitulated the cortical phenotypes of thanatophoric dysplasia (TD) by expressing fibroblast growth factor 8 in the ferret cerebral cortex. Strikingly, in contrast to TD mice, our TD ferret model showed not only megalencephaly but also polymicrogyria. We further uncovered that outer radial glial cells (oRGs) and intermediate progenitor cells (IPs) were markedly increased. Because it has been proposed that increased oRGs and/or IPs resulted in the appearance of cortical gyri during evolution, it seemed possible that increased oRGs and IPs underlie the pathogenesis of polymicrogyria. Our findings should help shed light on the molecular mechanisms underlying the formation and malformation of cortical gyri in higher mammals.

Pediatric epilepsy has a wide variety of etiology and severity. A recent epidemiological study suggested that surgery might be indicated in as many as 5% of the pediatric epilepsy population. Now, we know that effective epilepsy surgery can result in seizure freedom and improvement of psychomotor development. Seizure control is the most effective way to improve patients neurologically and psychologically. In this review, we look over the recent evidence related to pediatric epilepsy surgery, and try to establish the optimal surgical timing for patients with intractable epilepsy. Appropriate surgical timing depends on the etiology and natural history of the epilepsy to be treated. The most common etiology of pediatric intractable epilepsy patients is malformation of cortical development (MCD) and early surgery is recommended for them. Patients operated on earlier than 12 months of age tended to improve their psychomotor development compared to those operated on later. Recent progress in neuroimaging and electrophysiological studies provide the possibility of very early diagnosis and comprehensive surgical management even at an age before 12 months. Epilepsy surgery is the only solution for patients with MCD or other congenital diseases associated with intractable epilepsy, therefore physicians should aim at an early and precise diagnosis and predicting the future damage, consider a surgical solution within an optimal timing.

Developmental cortical malformations are associated with a high incidence of drug-resistant epilepsy. The underlying epileptogenic mechanisms, however, are poorly understood. In rodents, cortical malformations can be modeled using neonatal freeze-lesion (FL), which has been shown to cause in vitro cortical hyperexcitability. Here, we investigated the therapeutic potential of gabapentin, a clinically used anticonvulsant and analgesic, in preventing FL-induced in vitro and in vivo hyperexcitability. Gabapentin has been shown to disrupt the interaction of thrombospondin (TSP) with α2δ-1, an auxiliary calcium channel subunit. TSP/α2δ-1 signaling has been shown to drive the formation of excitatory synapses during cortical development and following injury. Gabapentin has been reported to have neuroprotective and anti-epileptogenic effects in other models associated with increased TSP expression and reactive astrocytosis. We found that both TSP and α2δ-1 were transiently upregulated following neonatal FL. We therefore designed a one-week GBP treatment paradigm to block TSP/α2δ-1 signaling during the period of their upregulation. GBP treatment prevented epileptiform activity following FL, as assessed by both glutamate biosensor imaging and field potential recording. GBP also attenuated FL-induced increases in mEPSC frequency at both P7 and 28. Additionally, GBP treated animals had decreased in vivo kainic acid (KA)-induced seizure activity. Taken together these results suggest gabapentin treatment immediately after FL can prevent the formation of a hyperexcitable network and may have therapeutic potential to minimize epileptogenic processes associated with developmental cortical malformations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: In epilepsy, the diagnosis of mild Malformation of Cortical Development type II (mMCD II) predominantly relies on the histopathological assessment of heterotopic neurons in the white matter. The exact diagnostic criteria for mMCD II are still ill-defined, mainly because findings from previous studies were contradictory due to small sample size, and the use of different stains and quantitative systems. Advance in technology leading to the development of whole slide imaging with high-throughput, automated quantitative analysis (WSA) may overcome these differences, and may provide objective, rapid, and reliable quantitation of white matter neurons in epilepsy. This study quantified the density of NeuN immunopositive neurons in the white matter of up to 142 epilepsy and control cases using WSA. Quantitative data from WSA was compared to two other systems, semi-automated quantitation, and the widely accepted method of stereology, to assess the reliability and quality of results from WSA., Results: All quantitative systems showed a higher density of white matter neurons in epilepsy cases compared to controls (P = 0.002). We found that, in particular, WSA with user-defined region of interest (manual) was superior in terms of larger sampled size, ease of use, time consumption, and accuracy in region selection and cell recognition compared to other methods. Using results from WSA manual, we proposed a threshold value for the classification of mMCD II, where 78% of patients now classified with mMCD II were seizure-free at the second post-operatively follow up., Conclusion: This study confirms the potential role of WSA in future quantitative diagnostic histology, especially for the histopathological diagnosis of mMCD.

A macrocephalic girl presented with generalised epilepsy due to focal cortical dysplasia. She later developed multiple hamartomatous lesions and was diagnosed to have Cowden syndrome. The diagnosis was confirmed by identification of a novel frameshift mutation in the PTEN gene of the patient.

Neuronal hyperexcitability plays an important role in epileptogenesis. Conditions of low extracellular calcium (Ca) or magnesium (Mg) can induce hyperexcitability and epileptiform activity with unclear mechanisms. Transient receptor potential canonical type 3 (TRPC3) channels play a pivotal role in neuronal excitability and are activated in low-Ca and/or low-Mg conditions to depolarize neurons. TRPC3 staining was highly enriched in immature, but very weak in mature, control cortex, whereas it was strong in dysplastic cortex at all ages. Depolarization and susceptibility to epileptiform activity increased with decreasing Ca and Mg. Combinations of low Ca and low Mg induced larger depolarization in pyramidal neurons and greater susceptibility to epileptiform activity in immature and dysplastic cortex than in mature and control cortex, respectively. Intracellular application of anti-TRPC3 antibody to block TRPC3 channels and bath application of the selective TRPC3 inhibitor Pyr3 greatly diminished depolarization in immature control and both immature and mature dysplastic cortex with strong TRPC3 expression. Epileptiform activity was initiated in low Ca and low Mg when synaptic activity was blocked, and Pyr3 completely suppressed this activity. In conclusion, TRPC3 primarily mediates low Ca- and low Mg-induced depolarization and epileptiform activity, and the enhanced expression of TRPC3 could make dysplastic and immature cortex more hyperexcitable and more susceptible to epileptiform activity.

Background: Human cytomegalovirus, a major cause of permanent neurodevelopmental disability in children, frequently produces intracranial abnormalities, including calcifications and polymicrogyria, in infants with congenital cytomegalovirus infections. This report describes the features of cerebral cortical clefting, including schizencephaly, in children with congenital cytomegalovirus infection., Methods: This is a retrospective review of the medical records of infants and children with congenital cytomegalovirus infection evaluated at Primary Children's Medical Center, Salt Lake City, Utah, between 1999 and 2008., Findings: Twenty-five children with congenital cytomegalovirus infection were identified during this 10-year period; 23 (92%) had computed tomography and 17 (68%) had magnetic resonance imaging. Imaging was obtained at a median age of 6 months (mode 1 month or less). Of 15 children with confirmed congenital infections, 10 (66%) had polymicrogyria or abnormal gyral patterns, five (33%) had cleft cortical dysplasia, and two (13%) had schizencephaly. Of 10 children with suspected congenital cytomegalovirus infection, eight (80%) had polymicrogyria, two (20%) had cleft cortical dysplasia, and one (10%) had bilateral schizencephaly with calcifications. Seventeen of the 25 infants (68%) had intracranial calcifications., Interpretation: These results indicate that clefting, either as cleft cortical dysplasia or schizencephaly, is an important feature of congenital cytomegalovirus infection., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This study aimed to identify the effect of early hemispherotomy on development in a consecutive series of 12 infants with hemimegalencephaly (HME) demonstrating epileptic encephalopathy. Mean age at onset was 20.4 days (range, 1-140), mean age at surgery was 4.3 months (range, 2-9), and mean follow-up time was 78.8 months (range, 36-121). Eleven patients had a history of early infantile epileptic encephalopathy. Vertical parasagittal hemispherotomy was performed without mortality or severe morbidities. At follow-up, seizure freedom was obtained in 8 patients (66.7%), who showed significantly higher postoperative developmental quotient (DQ) (mean, 31.3; range, 7-61) than those with seizures (mean, 5.5; range, 3-8) (p=0.02). Within the seizure-free group, postoperative DQ correlated with preoperative seizure duration (r=-0.811, p=0.01). Our results showed that shorter seizure duration during early infancy could provide better postoperative DQ in infants with HME and epileptic encephalopathy., (© 2013.)

To identify pathologic characteristics that are associated with outcome, we performed a retrospective analysis of the clinical, radiologic, and pathologic features of 44 children with isolated focal cortical dysplasia (FCD) after epilepsy surgery. Based on the International League Against Epilepsy Classification, 16 patients had FCD Type I and 28 subjects had FCD Type II. A significantly higher percentage of subjects with FCD Type IIb versus Types I and IIa were seizure-free after surgery. Akt (also known as protein kinase B) is the main downstream target of phosphatidylinositol 3'-kinase and has been implicated in epilepsy pathogenesis. Semiquantitative analysis of cortical gliosis and quantitation of Akt1-immunoreactive neurons indicated that individuals with FCD Type II were more likely to have diffuse astrogliosis and higher counts of Akt1-positive neurons versus those with FCD Type I. A logistic regression model, including Akt1-positive neurons, age at surgery, and the interaction of these factors, was significantly associated with seizure-free outcome. This study provides evidence that astrogliosis and overexpression of neuronal Akt1 protein may be important factors in the pathogenesis of FCD and suggests that the pathogenesis of FCD Type I may differ from that of FCD Type II in children.

In order to study how the formation of focal cortical malformations is attributed to perturbation of developmentally multimodal γ-aminobutyric acid (GABA) functions, we made a focal cortical freeze-lesion on a rodent cerebral cortex at P0 (postnatal day 0). The microgyrus was formed at P7. GABA neurons were accumulated in the region surrounding necrosis at P4. Cortical plate cells born at E17.5 gathered, surrounding the GABA neurons, forming the cell dense portions in layer 2 of the microgyrus. Ambient GABA level was increased in the area corresponding to populated GABA neurons at P4. A KCC2 expression was downregulated, whereas an NKCC1 expression was upregulated in both the gathering GABA and cortical plate neurons, suggesting these cells had high intracellular Cl(-) concentration rendering GABA action depolarizing. GABAA receptor activation was involved in Ca(2+) oscillation in these gathering cells. In vivo blockade of GABAA receptor prevented the above characteristic pattern of cell accumulation and hence microgyrus formation. Thus, neonatal freeze-lesion causes characteristic accumulation of differential populations of neurons preceded by characteristic release of GABA at an early stage, which induces GABAA receptor-mediated depolarization and Ca(2+) oscillation. This paracrine/autocrine GABA may underlie the formation of neocortical malformations such as polymicrogyria., (© 2013 Japanese Society of Neuropathology.)

Schizencephaly is a rare malformation of cortical development characterized by congenital clefts extending from the pial surface to the lateral ventricle that are lined by heterotopic gray matter. The clinical presentation is variable and can include motor or cognitive impairment and epilepsy. The causes of schizencephaly are heterogeneous and can include teratogens, prenatal infection, or maternal trauma. Reported genetic causes include chromosomal aneuploidy, EMX2 mutations, and possible autosomal recessive familial cases based on recurrence in siblings. In an effort to identify risk factors for schizencephaly, we conducted a survey of 48 parents or primary caretakers of patients with schizencephaly born between 1983 and 2004. We discovered that young maternal age, lack of prenatal care, and alcohol use were all significantly associated with risk of schizencephaly. Our results suggest that there are important nongenetic, intrauterine events that predispose to schizencephaly.

Objective: Focal cortical dysplasia type IIB (FCDIIB) is a sporadic developmental malformation of the cerebral cortex highly associated with pediatric epilepsy. Balloon cells (BCs) in FCDIIB exhibit constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Recently, the high-risk human papillomavirus type 16 oncoprotein E6 was identified as a potent activator of mTORC1 signaling. Here, we test the hypothesis that HPV16 E6 is present in human FCDIIB specimens., Methods: HPV16 E6 protein expression was assayed by immunohistochemistry in FCDIIB specimens (n = 50) and control brain specimens (n = 36). HPV16 E6 DNA was assayed by polymerase chain reaction (PCR) and in situ hybridization; HPV16 E6 mRNA was assayed by reverse transcriptase PCR. HPV16 E6 was transfected into fetal mouse brains by in utero electroporation to test the effects of E6 on cortical development., Results: HPV16 E6 protein was robustly expressed in all FCDIIB specimens in BCs, but not in regions without BCs or in control tissue specimens including normal brain, lymphoblasts, and fibroblasts, cortical tubers, and U87 glioma cells. E6 expression in FCDIIB colocalized with phosphoactivated S6 protein, a known mTORC1 substrate. HPV16 E6 DNA and mRNA were detected in representative specimens of FCDIIB but not control cortex, and were confirmed by sequencing. Transfection of E6 into fetal mouse brains caused a focal cortical malformation in association with enhanced mTORC1 signaling., Interpretation: Our results indicate a new association between HPV16 E6 and FCDIIB and demonstrate for the first time HPV16 E6 in the human brain. We propose a novel etiology for FCDIIB based on HPV16 E6 expression during fetal brain development., (Copyright © 2012 American Neurological Association.)

The epidermal nevus syndrome (ENS) is an uncommon neurocutaneous disorder in which epidermal nevi are found in association with congenital abnormalities of the brain, eye, and/or skeleton. The association of epidermal nevi and neurologic abnormalities was comprehensively described by Schimmelpenning in 1957. Pavone et al. (1991) identified a homogeneous variant of ENS with hemimegalencephaly, gyral malformation, mental retardation, seizures and facial hemihypertrophy. A 13-year-old boy with the neurologic variant of ENS with hemimegalencephaly, facial asymmetry, febrile seizures and mental retardation is reported. Additionally, we performed a literature review using the search terms "epidermal nevus syndrome" and "hemimegalencephaly", including secondary sources of data such as reference lists of articles reviewed. We found 57 previously reported cases with the hemimegalencephalic variant of epidermal nevus syndrome, in which the most frequent associated features are severe epilepsy, in about half of cases with neonatal onset, mental retardation/developmental delay, ocular/visual involvement, and facial abnormalities., (Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Purpose:   Memory impairment is a common comorbidity in people with epilepsy-associated malformations of cortical development. We studied spatial memory performance and hippocampal synaptic plasticity in an animal model of cortical dysplasia., Methods:   Embryonic day 17 rats were exposed to 2.25 Gy external radiation. One-month-old rats were tested for spatial recognition memory. After behavioral testing, short-term and long-term synaptic plasticity in the hippocampal CA1 region was studied in an in vitro slice preparation., Key Findings:   Behavioral assessments showed impaired hippocampal CA1-dependent spatial recognition memory in irradiated rats. Neurophysiologic assessments showed that baseline synaptic transmission was significantly enhanced, whereas paired-pulse facilitation, long-term potentiation, and long-term depression of the field excitatory postsynaptic potential (fEPSP) slope at Schaffer collateral/commissural fiber-CA1 synapses were significantly reduced in the irradiated rats. Histologic observations showed dysplastic cortex and dispersed hippocampal pyramidal neurons., Significance:   This study has shown that prenatally irradiated rats with cortical dysplasia exhibit a severe impairment of spatial recognition memory accompanied by disrupted short-term and long-term synaptic plasticity and may help to guide development of potential therapeutic interventions for this important problem., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Objectives: To highlight a case series of 3 cases of focal cortical dysplasia that were unrecognized for many years though the patients were seen by various neurologists and received the appropriate neuroimaging studies, and to retrospectively characterize the clinical elements, neuroimaging, electroencephalography, and pathologic findings in these cases., Design: Retrospective descriptive study., Setting: Tertiary urban and suburban neurology and epilepsy outpatient and inpatient clinic settings and hospitals., Patients: We analyze retrospectively 3 patients in whom magnetic resonance images were previously deemed as normal, who, in fact, exhibited subtle gyral abnormalities and who underwent focal surgical resections of these regions after invasive electroencephalography monitoring or electrocorticography and were cured of their epilepsy., Main Outcome Measures: Clinical semiology and neuroimaging findings., Results: Focal cortical dysplasias may present with subtle gyral abnormalities. These gyral abnormalities may guide invasive electroencephalography or electrocorticography and may delineate seizure onsets with precision. Resection of these areas in 3 such patients resulted in excellent surgical outcomes., Conclusions: Subtle gyral abnormalities may be associated with intractable epilepsy and seizure onsets. Focal resection after appropriate evaluations in selected patients may be curative. The magnetic resonance imaging features of focal cortical dysplasia can be subtle and require a high index of suspicion based on ictal semiology and clinical presentation.

Objectives: To establish the prevalence and antenatal diagnosis of schizencephaly in the UK., Methods: Data on schizencephaly were extracted from six regional congenital anomaly registers., Results: Thirty-eight cases of schizencephaly were identified in 2 567 165 livebirths and stillbirths, giving a total prevalence of 1.48/100 000 births (95% CI, 1.01-1.95). Eighteen (47% (95% CI, 31-63%)) of the 38 cases were identified antenatally. No affected fetus had an abnormal karyotype identified. A high proportion of cases of schizencephaly occurred in younger mothers: 63% were aged 24 years or less, significantly higher (P < 0.0001) than the corresponding proportion (26%) of mothers in England and Wales. The majority of cases were not identified until after 22 weeks of pregnancy. Additional anomalies associated with vascular disruption sequences were found in eight cases which had septo-optic dysplasia or absent septum pellucidum, one of which also had gastroschisis., Conclusions: Schizencephaly occurs more frequently in the fetuses of younger mothers. It is often associated with septo-optic dysplasia, suggesting that the two conditions may share a common origin, arising as a result of destructive processes that cause changes in the brain which only become apparent on ultrasound in the second half of pregnancy., (Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.)

Aim: The effects on neural repair of intraparenchymal nerve growth factor (NGF) administration were evaluated in neonate Wistar rats with experimentally induced focal microgyria., Methods: A freezing focal polymicrogyric lesion was induced on the frontal cortex in 35 newborn Wistar rats on postnatal day 1. NGF was administered in 15 cases, with 20 pups as controls. Animals were sacrificed at 72 h and 7 days after NGF administration. Real-time PCR was used for the quantification of the expression of TrkA, p75, and doublecortin (DCX) at the level of the cortical lesion in seven different groups of animals: control 72 h (n = 5), control 7 days (n = 5), microgyria 72 h (n = 5), microgyria 7 days (n = 5), microgyria + NGF 72 h (n = 5), microgyria + NGF 7 days (n = 5), and control + NGF (n = 5)., Results: A significant increase in TrkA expression was found in the microgyria + NGF 7 days group compared to the others. TrkA upregulation was already visible 72 h after NGF administration. Unlike TrkA, p75 expression increased in animals subjected to the experimental focal microgyria and decreased markedly after NGF administration. DCX expression in injured animals was observed to increase strongly 7 days after NGF administration compared with other groups., Conclusions: NGF administration interferes with neural repair mechanisms at the polymicrogyric lesion site by means of TrkA and DCX upregulation which possibly counteracts the process of apoptosis caused by the brain injury.

Purpose: Developmental delay and cognitive impairment are common comorbidities in people with epilepsy associated with malformations of cortical development (MCDs). We studied cognition and behavior in an animal model of diffuse cortical dysplasia (CD), in utero irradiation, using a battery of behavioral tests for neuromuscular and cognitive function., Methods: Fetal rats were exposed to 2.25 Gy external radiation on embryonic day 17 (E17). At 1 month of age they were tested using an open field task, a grip strength task, a grid walk task, inhibitory avoidance, an object recognition task, and the Morris water maze task., Key Findings: Rats with CD showed reduced nonlocomotor activity in the open field task and impaired motor coordination for grid walking but normal grip strength. They showed a reduced tendency to recognize novel objects and reduced retention in an inhibitory avoidance task. Water maze testing showed that learning and memory were impaired in irradiated rats for both cue discrimination and spatially oriented tasks. These results demonstrate significant deficits in cortex- and hippocampus-dependent cognitive functions associated with the diffuse abnormalities of cortical and hippocampal development that have been documented in this model., Significance: This study documents multimodal cognitive deficits associated with CD and can serve as the foundation for future investigations into the mechanisms of and possible therapeutic interventions for this problem., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

In this case report we describe the presence of a unilateral watershed infarction in a preterm born infant. Structural imaging in the neonatal period and in adolescence confirmed a typical lesion pattern compatible with watershed infarction in term born infants. Though the resulting parasagittal cleft transected the primary motor cortex, motor function of the affected hand was relatively spared. Functional MRI and transcranial magnetic stimulation revealed an important role for the unaffected hemisphere in motor control of the affected hand, showing once again that early cortical reorganization may lead to a near normal hand function., (Copyright © 2011 European Paediatric Neurology Society. All rights reserved.)

Background: Epilepsy surgery for magnetic resonance imaging (MRI)-negative patients has a less favorable outcome., Objective: Detection of subclinical abnormal gyration (SAG) patterns and their potential contribution to assessment of the topography of the epileptogenic zone (EZ) is addressed in MRI-negative patients with frontal lobe epilepsy., Methods: Between September 1998 and July 2005, 12 MRI-negative frontal lobe epilepsy patients underwent stereoelectroencephalography with postcorticectomy follow-up of longer than 1 year (average, 3.3 years). Original software (BrainVISA/Anatomist, http://brainvisa.info) trained on a database of normal volunteers was used to determine which sulci had morphology out of the normal range (SAG). Topography of the EZ, SAG pattern, corticectomy, postoperative seizure control, and histopathology were analyzed., Results: At last follow-up, 8 of 12 patients (66.7%) were Engel class I (7 IA and 1 IB), 2 class II, and 2 class IV. Small focal cortical dysplasia was histologically diagnosed in 9 of the 12 patients (75%), including 7 of 8 seizure-free patients (87.5%). A SAG pattern was found to be in the EZ area in 9 patients (75%), in the ipsilateral frontal lobe out of the EZ in 2, and limited to the contralateral hemisphere in 1., Conclusion: SAG patterns appear to be associated with the topography of the EZ in MRI-negative frontal lobe epilepsy and may have a useful role in preoperative assessment. Small focal cortical dysplasia not detected with MRI is often found on histopathological examination, particularly in the depth of the posterior part of the superior frontal sulcus and intermediate frontal sulcus, suggesting a specific developmental critical zone in these locations.

One of the most common and serious co-morbidities in patients with epilepsy is cognitive impairment. While early-life seizures are considered a major cause for cognitive impairment, it is not known whether it is the seizures, the underlying neurological substrate or a combination that has the largest impact on eventual learning and memory. Teasing out the effects of seizures from pre-existing neurological disorder is critical in developing therapeutic strategies. We therefore investigated the additional cognitive effects of seizures on rodents with malformations of cortical development induced with methylazoxymethanol acetate. Pregnant rats were injected with saline or methylazoxymethanol acetate at embryonic Day 15 or 17 to induce differing malformation severity. From the day of birth to 9 days of age, half the pups received 50 flurothyl-induced seizures. All rats underwent testing in the Morris water maze to test spatial memory at 25 days of age (immediate post-weaning) or during adolescence at 45 days of age. Post-weaning rats had severe spatial cognitive deficits in the water maze and seizures worsened performance. In contrast, in animals tested during adolescence, there was no longer an additional adverse effect of seizures. We also investigated whether the severity of the structural abnormality and seizures impacted brain weight, cortical thickness, hippocampal area and cell dispersion area. The mean brain weight in control animals was greater than in rats exposed to methylazoxymethanol acetate at embryonic Day 17, which was greater than rats exposed to methylazoxymethanol acetate at embryonic Day 15. Rats exposed to methylazoxymethanol acetate at embryonic Day 15 had a thinner cortical mantle compared with rats exposed at embryonic Day 17 and control animals. The hippocampal area was similar in rats exposed at embryonic Days 15 and 17 but was smaller compared with controls. Methylazoxymethanol at embryonic Day 17 caused dispersion of the CA1-4 cell layers in the hippocampus, whereas methylazoxymethanol at embryonic Day 15 caused focal nodules in or above the CA1 layer, but the CA1-4 layers were intact and similar to control. Early-life seizures did not have a significant impact on any of these parameters. These observations indicate that the major factor responsible for the cognitive impairment in the rats with cortical dysplasia was the underlying brain substrate, not seizures. These findings have significant implications for the understanding of cognitive impairments in childhood epilepsy and suggest that early aggressive therapy of seizures alone may not be an adequate strategy for minimizing cognitive effects.

Malformations of cortical development (MCD) result from disruptions in the complex process of the human brain cortex formation and are highly associated to severe epilepsy, neurodevelopmental delay and motor dysfunction. Nowadays, magnetic resonance imaging (MRI) is the cornerstone of the work-up of patients with epilepsy and modern advanced imaging techniques have improved not only our ability to detect and characterize cortical malformations, but also in identifying associated functional abnormalities that are far beyond the structural visualized lesions. Herein, we address the most currently used classifications of MCD and make a concise review of the embryological process of cortical development. Our main goal is to summarize recent advances and new trends in diagnostic imaging techniques concerning MCD. Thereafter, follows a brief discussion of specific disorders and their radiological features.

Periventricular nodular heterotopia (PVNH) is a malformation of cortical development associated with epilepsy. It is unclear whether the epileptogenic focus is the nodule, overlying cortex, or both. We performed electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) in a patient with bilateral PVNH, capturing 45 "left temporal" epileptiform discharges. The relative time at which fMRI-involved regions became active was assessed. Additionally, nodule-cortex interactions were explored using fMRI functional connectivity. There was EEG-fMRI activity in specific periventricular nodules and overlying cortex in the left temporoparietal region. In both nodules and cortex, the peak BOLD response to epileptiform events occurred earlier than expected from standard fMRI hemodynamic modeling. Functional connectivity showed nodule-cortex interactions to be strong in this region, even when the influence of fMRI activity fluctuations due to spiking was removed. Nonepileptogenic, contralateral nodules did not show connectivity with overlying cortex. EEG-fMRI and functional connectivity can help identify which of the multiple abnormal regions are epileptogenic in PVNH., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The diagnostic criteria for focal cortical dysplasia type I (FCD I) remain to be well and consistently defined. Cortical layer-specific markers (CLM) provide a potential tool for the objective assessment of any dyslamination. We studied expression patterns of recognised CLM using immunohistochemistry for N200, ER81, Otx1, Map1b (subsets of V/VI projection neurones), Pax6, Tbr1, Tbr2 (differentially expressed in cortical neurones from intermediate progenitor cells), Cux 1 (outer cortical layers) and MASH1 (ventricular zone progenitors). Dysplasia subtypes included FCD I and II, dysplasias adjacent to hippocampal sclerosis (HS) or dysembryoplastic neuroepithelial tumours (DNTs); all were compared to neonatal and adult controls. Laminar expression patterns in normal cortex were observed with Tbr1, Map1b, N200 and Otx1. FCDI cases in younger patients were characterised by abnormal expression in layer II for Tbr1 and Otx1. FCDII showed distinct labelling of balloon cells (Pax6, ER81 and Otx1) and dysmorphic neurones (Tbr 1, N200 and Map1b) supporting origins from radial glia and intermediate progenitor cells, respectively. In temporal lobe sclerosis cases with dysplasia adjacent to HS, Tbr1 and Map1b highlighted abnormal orientation of neurones in layer II. Dyslamination was not confirmed in the perilesional cortex of DNT with CLM. Finally, immature cell types (Otx1, Pax6 and Tbr2) were noted in varied pathologies. One possibility is activation of progenitor cell populations which could contribute to the pathophysiology of these lesions.

Purpose: Expression of the protein subunits that make up the γ-aminobutyric acid (GABA)(A) receptor pentamer is known to change during postnatal brain development in animal models. In the present study, analysis of cortical GABA(A) subunit expression was performed in control human tissue obtained from infancy through adolescence, and was compared to that from similarly aged children with intractable focal epilepsy., Methods: Twenty frozen pediatric control and 25 epileptic neocortical specimens were collected. The membrane fractions were isolated and subjected to quantitative western blot analysis. Subunit expression was correlated with clinical factors including age, pathology, and medication exposure., Results: In control cortical samples, α₁ and γ₂ GABA(A) receptor subunits exhibited low expression in infancy, which increased over the first several years of life and then stabilized through adolescence. In contrast, α₄ subunit expression was higher in infants than in older children. The level of the chloride transporter KCC2 increased markedly with age, whereas that of NKCC1 decreased. These patterns were absent in the children with epilepsy, both in those with focal cortical dysplasia and in those with cortical gliosis. Although there was marked variability in GABA(A) receptor subunit expression among the children with epilepsy, identifiable patterns of subunit expression were found in each individual child., Discussion: Maturation of cortical GABA(A) receptor subunit expression continues over the first several years of postnatal human development. Intractable focal epilepsy in children is associated with disruption of this normal developmental pattern. These findings have significant implications for the treatment of children with medications that modulate GABA(A) receptor function., (Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.)

Purpose: Cortical dysplasia (CD) is a major cause of epilepsy in children and adults, but underlying mechanisms of epileptogenesis in this disorder are poorly understood. We have utilized the irradiated rat model to study an injury-based form of diffuse CD in rats. Prior studies in this model have shown reduced numbers of γ-aminobutyric acid (GABA)ergic interneurons and reduced inhibitory synaptic currents in pyramidal cells in CD. We analyzed the number of excitatory and inhibitory presynaptic terminals in the neocortex of irradiated rats to better characterize altered connectivity in experimental CD., Methods: Antibodies to vesicular glutamate transporter 1 (VGLUT1), vesicular glutamate transporter 2 (VGLUT2), vesicular GABA transporter (VGAT), and parvalbumin (PV) were used to quantify glutamatergic and GABAergic presynaptic terminals in control and dysplastic cortex., Results: We found that the density of VGLUT1 terminals was increased in CD in comparison to layers IV, V, and VI in control cortex. VGLUT2 terminals were increased in CD compared to layers IV and VI. VGAT terminals were reduced in CD compared to layers II/III, IV, and V in controls as were PV-immunoreactive somata and terminals., Discussion: These findings suggest an overall increase in excitatory synaptic connectivity and decrease in inhibitory synaptic connectivity in CD in irradiated rat. We propose that these changes contribute to hyperexcitability in these animals and may contribute to epileptogenicity in some forms of human CD., (Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.)

In epileptic patients, focal cortical dysplasia (FCD) is pathologically characterized by irregular cortical lamination, blurring of the grey and white matter border and the occurrence of dysplastic cells in the cerebral cortex. Here, we report the case of a 42-year-old male showing developmental delay, transient repetition of hypoglycemic attack and cortical dysplasia, partly mimicking FCD. He had no family history of neurological disorders. He had never been able to stand independently and had always been unable to speak. He developed generalized convulsion in infancy, and then, in the absence of predisposing factors, suffered from repetitive hypoglycemic attacks between the ages of 27 and 38. Various endocrine tests, abdominal CT and brain MRI failed to demonstrate abnormalities. He died of peritonitis. At autopsy, no changes were observed in the pancreas, liver, kidneys, endocrine organs or hypothalamus. In the insular and frontal cortices, many large bizarre cells in the deep layer were observed and perivascular oligodendrocyte satellitosis was present in the adjacent white matter. Unlike FCD, the cortical lamination and the grey-white matter interface were preserved. A well-demarcated pilocytic astrocytoma was present in the brainstem. The cortical dysplasia, consisting of the diffuse occurrence of bizarre cells and the preservation of cortical lamination, is unique and has not been previously reported. Repetition of hypoglycemic attacks within a certain period is also noteworthy, although the relationship of this with the cortical dysplasia is unknown., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

Purpose: Cortical dysplasia (CD) is one of the most frequent causes of pharmacoresistent focal epilepsy. Despite significant advances in various diagnostic and therapeutic methods, the basic mechanisms of higher susceptibility for seizures in patients with CD are unknown. Animal models of CD present with a lower threshold for seizure induction. The purpose of this study is to further characterize the animal model of in utero radiation-induced CD and to illustrate the effect of a late postnatal second hit (low dose of pentylenetetrazole, PTZ) on the development of spontaneous seizures., Methods: Pregnant Sprague-Dawley rats were irradiated on E17 (145 cGy; control group was left untreated). Litters were implanted with bifrontal epidural and hippocampal depth electrodes. After baseline electroencephalography (EEG) recording, animals received 30 mg/kg PTZ and were chronically monitored. Histopathology of the brains was verified., Results: No seizures were detected in animals that did not receive PTZ. PTZ-injected irradiated (XRT) rats showed severe prolonged, repetitive seizures during the acute period. During the chronic period, XRT rats had recurrent seizures and epileptiform spikes. PTZ-injected control animals exhibited milder and fewer acute seizures and did not show seizures during the chronic period. Histology was consistent with cortical and hippocampal dysplasia., Conclusions: This study shows that a single treatment with a low dose of PTZ renders XRT rats (but not age-matched controls) epileptic, exhibiting spontaneous epileptiform spikes and seizures on EEG. These results might mirror the natural history of patients with CD thought to be caused by prenatal/congenital or perinatal insults.