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Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities., Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance., Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019., Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort., Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks., Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus). In all subjects, the median response ratio showed inhibition at all interstimulus intervals. Using a mixed linear-effects model, we compared the long-interval intracortical inhibition response ratios between the different subject types. We conducted two analyses; one including data from the four centres and one excluding data from Centre 2, as the methods in this centre differed from the others. In the first analysis, we found no differences in long-interval intracortical inhibition between the different subject types. In all subjects, the response ratios at interstimulus intervals 100 and 150 ms showed significantly more inhibition than the response ratios at 50, 200 and 250 ms. Our second analysis showed a significant interaction between interstimulus interval and subject type (P = 0.0003). Post hoc testing showed significant differences between controls and refractory focal epilepsy at interstimulus intervals of 100 ms (P = 0.02) and 200 ms (P = 0.04). There were no significant differences between controls and refractory generalized epilepsy groups or between the refractory generalized and focal epilepsy groups. Our results do not support the body of previous work that suggests that long-interval intracortical inhibition is significantly reduced in refractory focal and genetic generalized epilepsy. Results from the second analysis are even in sharper contrast with previous work, showing inhibition in refractory focal epilepsy at 200 ms instead of facilitation previously reported. Methodological differences, especially shorter intervals between the pulse pairs, may have contributed to our inability to reproduce previous findings. Based on our results, we suggest that long-interval intracortical inhibition as measured by transcranial magnetic stimulation and electromyography is unlikely to have clinical use as a biomarker of epilepsy., (© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Activation of the mTOR pathway has been linked to the cytopathology and epileptogenicity of malformations, specifically Focal Cortical Dysplasia (FCD) and Tuberous Sclerosis (TSC). Experimental and clinical trials have shown than mTOR inhibitors have anti-epileptogenic effects in TS. Dysmorphic neurones and balloon cells are hallmarks of FCDIIb and TSC, but similar cells are also occasionally observed in other acquired epileptogenic pathologies, including hippocampal sclerosis (HS) and Rasmussen's encephalitis (RE). Our aim was to explore mTOR pathway activation in a range of epilepsy-associated pathologies and in lesion-negative cases., Results: 50 epilepsy surgical pathologies were selected including HS ILAE type 1 with (5) and without dysmorphic neurones (4), FCDIIa (1), FCDIIb (5), FCDIIIa (5), FCDIIIb (3), FCDIIId (3), RE (5) and cortex adjacent to cavernoma (1). We also included pathology-negative epilepsy cases; temporal cortex (7), frontal cortex (2), paired frontal cortical samples with different ictal activity according to intracranial EEG recordings (4), cortex with acute injuries from electrode tracks (5) and additionally non-epilepsy surgical controls (3). Immunohistochemistry for phospho-S6 (pS6) ser240/244 and ser235/236 and double-labelling for Iba1, neurofilament, GFAP, GFAPdelta, doublecortin, and nestin were performed. Predominant neuronal labelling was observed with pS6 ser240/244 and glial labelling with pS6 ser235/236 in all pathology types but with evidence for co-expression in a proportion of cells in all pathologies. Intense labelling of dysmorphic neurones and balloon cells was observed in FCDIIb, but dysmorphic neurones were also labelled in RE and HS. There was no difference in pS6 labelling in paired samples according to ictal activity. Double-labelling immunofluorescent studies further demonstrated the co-localisation of pS6 with nestin, doublecortin, GFAPdelta in populations of small, immature neuroglial cells in a range of epilepsy pathologies., Conclusions: Although mTOR activation has been more studied in the FCDIIb and TSC, our observations suggest this pathway is activated in a variety of epilepsy-associated pathologies, and in varied cell types including dysmorphic neurones, microglia and immature cell types. There was no definite evidence from our studies to suggest that pS6 expression is directly related to disease activity.

Purpose: To investigate whether specific semi-quantitative 3T MRI parameters are associated with particular histological features in temporal lobe specimens in epilepsy surgery patients whose conventional MRI scan appeared normal. These MRI techniques have the potential to visualise subtle structural abnormalities currently undetected on conventional MRI; but correlation between pre-operative in vivo MRI and histopathology is needed to understand the basis of these MRI abnormalities. Predicting subtle histopathology with semi-quantitative MRI techniques could contribute to pre-surgical evaluation of epilepsy patients., Materials and Methods: MRI techniques: normalised FLAIR signal intensity (nFSI), grey matter probability and diffusion tensor imaging (DTI) were correlated with quantitative histopathological measures: NeuN (neuronal nuclear antigen); GFAP (glial fibrillary acidic protein) and MBP (myelin basic protein) field fractions and stereological neuronal densities obtained in grey and white matter regions in twenty-four patients who underwent anterior temporal lobe resections., Results: There were no significant correlations between the histopathological measurements and MRI values in grey or white matter in macroscopically normal appearing tissue., Conclusion: Findings suggest that in macroscopically normal appearing tissue, the studied semiquantitative MRI measurements are not significantly related to the measures of gliosis, neuronal loss/gain and myelin used in the current study. Studies of macroscopically abnormal tissue as well as improvements to the MRI techniques may increase the sensitivity of future correlative studies to improve our understanding of the histopathological basis of MRI signal characteristics., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Simple and complex forms of dysembryoplastic neuroepithelial tumors (DNTs) are readily recognizable but forms with diffuse growth pattern, and hybrid tumors, that is, mixed DNT and ganglioglioma (DNT/GG), are more contentious entities. Rare DNTs have shown aggressive behavior. We reviewed cortical growth patterns, immunophenotype (including CD34, nestin and calbindin), genetic profile, and outcome in 101 DNT in adults. Simple (n = 18), complex (n = 31), diffuse (n = 35) DNT, and mixed DNT/GG (n = 17) showed no difference in age of onset, associated seizure type, or outcome (67.5% free from seizure; mean follow-up, 6 years). CD34 was seen in 61%, calbindin in 57%, and nestin in 86% of all DNT types; these markers were less common in simple DNT. Peritumoral cortical changes (Layer I hypercellularity [61%], satellite nodules [51.6%]) were frequent, but dyslamination (cortical dysplasia) was not identified. Molecular genetic abnormalities identified in 17 cases were IDH1 mutation (n = 3), 1p/19q loss (n = 10), isolated loss 9q (n = 2), and PTEN loss (n = 3), which were not associated with tumor type or location, higher cell proliferation, or distinguishing clinical features (mean age of epilepsy onset, 9 years; age at surgery = 31 years; 69% free from seizure); none had progression on magnetic resonance imaging (mean follow-up, 6 years). No single feature was predictive of seizure-free outcome, but there was a trend for better outcome in CD34-positive tumors (p = 0.07). One case has shown transformation to a higher grade. This study supports the existence of a range of subtypes of DNT some with overlapping features with ganglioglioma; molecular genetic abnormalities were not predictive of atypical behavior.

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.

Voxel-based morphometry (VBM) has detected differences between brains of groups of patients with epilepsy and controls, but the sensitivity for detecting subtle pathological changes in single subjects has not been established. The aim of the study was to test the sensitivity of VBM using statistical parametric mapping (SPM5) to detect hippocampal sclerosis (HS) and cortical neuronal loss in individual patients. T1-weighted volumetric 1.5 T MR images from 13 patients with HS and laminar cortical neuronal loss were segmented, normalised and smoothed using SPM5. Both modulated and non-modulated analyses were performed. Comparisons of one control subject against the rest (n = 23) were first performed to ascertain the smoothing level with the lowest number of SPM changes in controls. Each patient was then compared against the whole control group. The lowest number of SPM changes in control subjects was found at a smoothing level of 10 mm full width half maximum for modulated and non-modulated data. In the patient group, no SPM abnormalities were found in the affected temporal lobe or hippocampus at this smoothing level. At lower smoothing levels there were numerous SPM findings in controls and patients. VBM did not detect any abnormalities associated with either laminar cortical neuronal loss or HS. This may be due to normalisation and smoothing of images and low statistical power in areas with larger inter-individual differences. This suggests that the methodology may currently not be suitable to detect particular occult abnormalities possibly associated with seizure onset zone in individual epilepsy patients with unremarkable standard structural MRI.

Focal cortical dysplasia (FCD) type II is an important cause of drug-resistant epilepsy. Clinical presentation is variable, and depends on age of onset of seizures and the location and size of lesion. As FCD type II cannot be diagnosed with certainty in the clinic, in vivo identification by use of MRI is important. Diagnosis will have a major effect on management of this pathology as it should prompt referral for specialist assessment. Drug treatment commonly proves ineffective, whereas appropriate surgical treatment can be curative in many cases. The dramatic cellular anomalies of FCD seen at histopathology indicate a widespread pattern of molecular disruption underpinning the structural disorganisation of the cortex. The cause for FCD has not been firmly established, and there are no explanations for its potent intrinsic ability to cause seizures. There seem to be both neurodevelopmental abnormalities and possible premature neurodegeneration in FCD. Understanding the coordination of the abnormal processes in FCD type II might help to promote improved detection in vivo, direct treatment strategies, and perhaps help explain the development, differentiation, and loss of brain cells, with broad implications for the epilepsies and other neurological disorders.

Focal cortical dysplasia (FCD) is the most common malformation of cortical development found in epilepsy surgical series. Characterised by cortical mislamination, dysplastic neurons and, in a subgroup of cases, balloon cells, FCD is potently epileptogenic. Despite decades of study, the underlying aetiology of FCD remains uncertain and research has been hampered by the lack of a good animal model in which to simulate the condition. In this article we review some of the potential molecular mechanisms that might underpin human FCD. In particular we examine the potential role of cyclin-dependent kinase 5 and its principal activator p35 in FCD and estimate the contribution that deregulation of cyclin-dependent kinase 5 might make to the pathogenesis of this condition., (Copyright (c) 2008 S. Karger AG, Basel.)

Purpose: Reactivation of neurodevelopmental processes may contribute to neurodegeneration. For example, the proteins cyclin dependent kinase 5 (cdk5) and glycogen synthase kinase 3 beta (GSK3beta), which are essential to normal cortical development, can hyperphosphorylate tau and might contribute to the pathogenesis of Alzheimer's disease. Focal cortical dysplasia (FCD) is an important neurodevelopmental cause of refractory human epilepsy within which dysplastic neurons exhibit increased immunoreactivity for cdk5 and GSK3beta as well as neurofilamentous accumulations. We therefore hypothesized that the developmentally abnormal cortex of FCD might be more susceptible to tau-mediated neurodegeneration than adjacent histologically normal cortex., Materials and Methods: We examined a series of 15 cases of FCD, spanning a wide age range, for beta-amyloid, pathologically phosphorylated tau and neurofibrillary tangles using silver staining, immunohistochemistry for tau, AT8, RD3, RD4 and two-dimensional cell counting., Results: Beta-amyloid plaques, aberrantly phosphorylated tau and neurofibrillary tangles are only found in older patients. The hyperphosphorylated tau tangles are confined to dysplastic neurons. Immunoreactivity for 3- and 4-repeat tau was again only detected within regions of FCD in older patients. With increasing age, the dysplastic cortex became hypocellular and a higher proportion of dysplastic neurons exhibited pathological tau phosphorylation., Conclusions: In older patients, FCD appears more susceptible to formation of pathologically phosphorylated tau neurofibrillary tangles than adjacent histologically normal cortex. Our results suggest a novel convergence of pathological neurodevelopment with pathological age-related neurodegeneration.

Balloon cells (BC) are the prominent and defining cellular component of type IIB Focal Cortical Dysplasia (FCD), a common cause of focal epilepsy in patients undergoing surgical treatment. BC are considered immature cells of uncommitted cellular differentiation having immunophenotypical characteristics of both neurones and glia. They are often located in the lower cortical layers and white matter underlying the dysplastic cortex, suggesting migratory arrest during development. We investigated the proliferative potential of BC in 15 cases of FCD from patients with a wide range of ages using immunohistochemistry for Mcm2 (mini chromosome maintenance protein) and Ki67. In the majority of cases, BC showed Mcm2 nuclear positivity. In addition, cells with intermediate neuronal-glial characteristics were labelled whilst the dysmorphic or hypertrophic pyramidal neuronal components of FCD were not. Ki67 labelled only occasional BC. These findings support the view that BC cells represent a pool of less differentiated glial cells with proliferative capacity which may have potential for delayed neuronal differentiation. Furthermore, as Mcm2 specifically identifies BC populations, this marker may be of diagnostic value in the subtyping of FCD lesions in patients with epilepsy.

Focal cortical dysplasia (FCD) is considered to represent a malformation due to abnormal cortical development (MCD) and is an important cause of focal epilepsy. The histopathological features include abnormal laminar architecture, the presence of hypertrophic and dysmorphic neurones in FCD type IIA and additional balloon cells in FCD type IIB. The events causing these sporadic lesions are unknown, but abnormal progenitor cell proliferation occurring late in corticogenesis has been proposed. FCD-like lesions have, however, also been described following a cerebral injury early in life. We carried out a stereological assessment on 15 cases of FCD on NeuN- and Nissl-stained sections from patients with a wide age range, and identified a significant reduction in the neuronal density in all cases in the region of dysplasia compared to the adjacent unaffected cortex (mean neuronal densities 19.2x10(3)/mm3 in the region of dysplasia; 42.8x10(3)/mm3 in the adjacent cortex). Relative differences in neuronal density and size in FCD cases between the superficial (layer I and II) and deep cortical laminae (layer V and VI) were similar to that observed in other pathologies including mild MCD, temporal neocortex adjacent to hippocampal sclerosis as well as in a non-epilepsy surgical control group. The lower overall neuronal densities observed in FCD may reflect neuropil expansion, a local failure of neuronal migration, proliferation or secondary neuronal loss. The preservation of relative differences in neuronal densities between cortical layers and laminar patterns of neurofilament staining in FCD would support the view that the temporal sequence of lamination is not affected.

Purpose: Grey matter heterotopia are well-defined malformations of the cortex often associated with severe epilepsy. Defects have been identified in genes, including DCX and FLN1, that influence radial migration of postmitotic cells from the ventricular zone to the cortical plate. A proportion of cortical gamma-aminobutyric acid (GABA)-containing interneurons may arise from the ganglionic eminence of the ventral telencephalon. We aimed to identify the subtypes and localisation of interneurons within grey matter heterotopia relative to cortex., Methods: By using quantitative immunohistochemistry, we studied the density and distribution of interneurons within six cases of grey matter heterotopia in postmortem tissue from patients with epilepsy., Results: In many cases, a suggestion of focal rudimentary laminar arrangement and small reelin-positive cells was identified within the heterotopia. Immunohistochemistry for glutamic acid decarboxylase(65/57), parvalbumin, calbindin, and calretinin showed inhibitory neurons of all subtypes represented within the heterotopia, and of normal morphology. The mean densities of interneurons were overall similar to those of the overlying cortex, but the interneurons showed less organisation and were more randomly orientated compared with cortex., Conclusions: Interneurons within heterotopia probably arise from the ventricular zone, but their abnormal local organization may influence the epileptogenicity of these lesions.

Malformations of cortical development (MCD) are important causes of chronic epilepsy in human beings. A blanket term, MCD encompasses many varied developmental disorders with diverse clinical manifestations in patients that neurologists, paediatricians, and learning disability psychiatrists will encounter. Advances in imaging and genetics have led to a significant increase in our understanding of MCD, which has in turn enriched our knowledge of human epileptogenesis and normal brain development and function. In this review, I discuss some of the most common or enlightening MCD: focal cortical dysplasia, periventricular heterotopia, polymicrogyria, band heterotopia and lissencephaly, dysembryoplastic neuroepithelial tumours, and microdysgenesis. Clinical and imaging features, genetic aetiologies, treatments, and the insights that have resulted from MCD study are covered. The burden of epilepsy due to MCD is significant and there is still much to learn about MCD.

Focal cortical dysplasia (FCD) and microdysgenesis (MD) are likely to represent abnormalities of radial neuronal migration during cortical development. We investigated the distribution of reelin-positive Cajal-Retzius cells, known to be important in the later stages of radial neuronal migration and cortical organization, in 12 surgical cases of both MD and FCD. Quantitation revealed significantly higher numbers of these cells in MD cases compared to controls. As the majority of cortical interneurones arise via tangential rather than radial migration, we studied the distribution and morphology of inhibitory interneuronal subsets immunolabelled for calbindin, parvalbumin and calretinin within these malformations. Frequent findings were a reduction of inhibitory interneurones in the region of FCD and abnormally localised hypertrophic or multipolar calbindin-positive interneurones in both FCD and MD. Neuropeptide Y immunostaining showed a striking increase in the density of the superficial plexus of fibres in both MD and FCD cases in addition to labelling of dysplastic neurones, which may represent an adaptive anti-convulsant mechanism to dampen down seizure propagation.

Focal cortical dysplasia (FCD) is an important cause of refractory epilepsy in humans. The origin of its pathognomonic abnormal cell types and the links between abnormal cell morphology and epileptogenicity remain unknown. The developmentally-regulated kinase cdk5 and its neuronal activator p35 are known to be central to a number of key components in neuronal development, cellular morphology, cytoskeletal function, synaptic plasticity and neurodegeneration. Here we examine eight cases of human FCD for expression of cdk5. We show abnormal cdk5 immunoreactivity and aggregation of protein suggesting alterations in cdk5 may also be involved in this important epileptogenic human pathology.

The authors report a novel human brain malformation characterized by the absence of the anterior commissure without callosal agenesis, but associated with gross unilateral panhemispheric malformation incorporating subependymal heterotopia, subcortical heterotopia, and gyral abnormalities including temporal malformation and polymicrogyria. In contrast, a normal anterior commissure was found in 125 control subjects and in 113 other subjects with a range of brain malformations.

Periventricular heterotopia (PH) is a human neuronal migration disorder in which many neurons destined for the cerebral cortex fail to migrate. Previous analysis showed heterozygous mutations in the X-linked gene filamin 1 (FLN1), but examined only the first six (of 48) coding exons of the gene and hence did not assess the incidence and functional consequences of FLN1 mutations. Here we perform single-strand conformation polymorphism (SSCP) analysis of FLN1 throughout its entire coding region in six PH pedigrees, 31 sporadic female PH patients and 24 sporadic male PH patients. We detected FLN1 mutations by SSCP in 83% of PH pedigrees and 19% of sporadic females with PH. Moreover, no PH females (0/7 tested) with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical PH. Surprisingly, 2/24 males analyzed with PH (9%) also carried FLN1 mutations. Whereas FLN1 mutations in PH pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with PH appear to cause either severe or partial loss of function. Neither male could be shown to be mosaic for the FLN1 mutation in peripheral blood lymphocytes, suggesting that some neurons in the intact cortex of PH males may be mutant for FLN1 but migrate adequately. These results demonstrate the sensitivity and specificity of DNA testing for FLN1 mutations and have important functional implications for models of FLN1 protein function in neuronal migration.

NMDA receptors (NR) are important in many neurological processes. Using a large series of human brain tissue, we show that the distribution of NR2A/B immunoreactivity varies according to position along a gyrus. For pyramidal neurons in laminae II and III, immunoreactivity is most marked at gyral crown and gyral lips, diminishes along sulcal wall, and is barely detectable in sulcal floor cortex. In contrast, in some cases, immunoreactivity in laminae V and VI pyramidal neurons shows the reverse pattern. Neurofilament and calretinin immunoreactivity do not show this phenomenon. The findings suggest novel functional regionalization at the sulcogyral level in normal human brain.

Malformations of cortical development (MCD) are responsible for many cases of refractory epilepsy in adults and children. The results of surgical treatment are difficult to assess from the published literature. Judging from the limited number of adequately reported cases, approximately 40% of all cases of MCD treated surgically may be rendered seizure-free over a minimum 2-year follow-up period. This figure is the same for focal cortical dysplasia (FCD), the most common variety of MCD in surgical reports. In comparison with outcome for epilepsy associated with hippocampal sclerosis, this figure is low. Part of the difference may be artificial and related to limited reporting. Much of the difference is likely to relate to the complex underlying biology of MCD. Analysis of epileptogenesis in MCD has been undertaken. Different types of MCD have different sequelae. Some varieties are intrinsically epileptogenic; these include FCD and heterotopia. Although in most cases, the visualized MCD lies within the region of brain responsible for generating seizures (the epileptogenic zone), it may not constitute the entire epileptogenic zone in all cases. For polymicrogyria and schizencephaly in particular, the visualized abnormalities are probably not the most important component of the epileptogenic zone. There is evidence that the epileptogenic zone is spatially distributed and also, in some cases, temporally distributed. These findings may explain poor surgical outcome and the inadequacy of current presurgical evaluative methods. New preoperative techniques offer the opportunity of improved presurgical planning and selection of cases more likely to be rendered seizure-free by current surgical techniques. Of paramount importance is improved reporting. The establishment of a central registry may facilitate this aim. Specific recommendations are made for surgical strategies based on current experience and understanding.

Purpose: To report a novel malformation in a male subject with refractory partial seizures., Methods: Magnetic resonance imaging (MRI) and data reformatting in a subject referred for management of partial seizures., Results: The patient had four distinct partial seizure types, without learning disability. MRI demonstrated the novel association of bilateral laminar subcortical heterotopia, bilateral temporal periventricular heterotopia, and hippocampal malformation., Conclusions: This previously unreported complex bilateral neocortical and archicortical malformation in a male patient cannot be explained by known genetic causes of heterotopia, raising the possibility of a novel gene involved in brain formation.

Drug resistance in epilepsy due to malformations of cortical development (MCD) is unexplained. P-glycoprotein is a mediator of drug resistance, and we propose that MCD lesions over-express P-glycoprotein. Because P-glycoprotein expression may be induced by some antiepileptic drugs (AEDs), we studied brain samples from MCD cases before the onset of seizures or treatment with AEDs. Sixteen MCD cases and 16 age-matched controls were examined using immunohistochemistry. Glial labelling, representing over-expression, was seen in 10 of 16 MCD samples and in two of 16 control samples (p = 0.003). Semiquantitative assessment showed many immunoreactive glia in five of 16 MCD and one of 16 controls. We conclude that there is constitutive over-expression of P-glycoprotein in many MCD.

Guided by a review of the anatomical literature, 36 sulci on the human cerebral cortical surface were designated as homologous. These sulci were assessed for visibility on 3-dimensional images reconstructed from magnetic resonance imaging scans of the brains of 20 normal volunteers by 2 independent observers. Those sulci that were found to be reproducibly identifiable were used to define 24 landmarks around the cortical surface. The interobserver and intraobserver variabilities of measurement of the 24 landmarks were calculated. These reliably reproducible landmarks can be used for detailed morphometric analysis, and may prove helpful in the analysis of suspected cerebral cortical structured abnormalities in patients with such conditions as epilepsy.

Using [11C]flumazenil-PET and statistical parametric mapping (SPM), we have shown recently that regions of increased and decreased benzodiazepine receptor density may be seen in patients with localization-related epilepsy due to malformations of cortical development. These abnormalities were seen both within and beyond lesions visually apparent on high-resolution MRI. We have also shown, using an interactive anatomical segmentation technique and volume-of-interest measurements, that subtle and unsuspected abnormalities of cortical grey matter volume were found in the same group of patients on high-resolution MRI, beyond the lesions visually apparent. In 10 patients with localization-related epilepsy and malformations of cortical development, we have now applied the automated and objective technique of SPM to the analysis of high-resolution structural MRI. Each individual patient was compared with 16 normal control subjects. We have then simultaneously compared the structural and functional data obtained for each individual patient with normal control high-resolution MRI and [11C]flumazenil-PET image using a novel technique. This comparison allowed the detection of functional abnormalities that were not accounted for by either visible or unsuspected structural abnormalities, in an automated and statistically rigorous manner. Five patients had abnormalities of cortical grey matter volume detected using SPM; only these five patients had been found abnormal using the previous volume-of-interest technique. Six of the 10 patients showed regions of cerebral cortex with disproportionate flumazenil binding compared with local grey matter volume. This included regions not found to have abnormal flumazenil binding on analysis of the PET data alone. Furthermore, regions found to have abnormal binding on examination of the PET data alone were, in some instances, shown to be accounted for by abnormalities of cortical grey matter volume. We conclude that the analysis of ligand PET data should always include a comparison with structural MRI; such comparisons are greatly facilitated by the novel approach described.

Cerebral cortical dysgenesis has been found by magnetic resonance imaging to be the second most common pathology underlying medically refractory chronic partial epilepsy. Patients with the latter condition form the largest group in specialist epilepsy clinics. The pathogenesis of the epilepsy in cortical dysgenesis remains largely obscure. The most popular current hypothesis holds neuronal misconnection secondary to neuronal malpositioning culpable for seizure activity. However, a review of the published literature of cortical dysgenesis and an analysis of newer magnetic resonance and histopathological data, suggests that this view is no longer tenable. A modified hypothesis is proposed in which neuronal connectivity itself is postulated to be the primary motive force in both cerebral morphogenesis and epileptogenesis in cases of cortical dysgenesis. This hypothesis leads to the generation of a model for cortical development and directly testable predictions of intercellular connectivity, as well as a potential tool for the prediction of the possibility of freedom from seizure activity after surgical resection of dysgenetic lesions in individual cases.

Cerebral cortical dysgenesis (CD), as revealed by MRI is the second commonest cause of medically refractory chronic partial epilepsy. Surgical treatment is often disappointing in these cases. This has been attributed to the probable diffuse nature of the condition but proof of this in the human brain is lacking. We have quantitatively analysed MRI scans of 30 neurologically normal control subjects and 18 patients with CD, examining the regional distribution of grey and subcortical matter volumes. In 15 out of the 18 patients, we have demonstrated abnormalities of this distribution beyond the margins of the visualized lesion. Nine out of 10 patients with dysgenetic lesions visualized only in one hemisphere had volumetric abnormality in the apparently normal contralateral hemisphere. These abnormalities were not visible on reinspection of the MRI scans. Such abnormalities were not found in 10 patients with isolated hippocampal sclerosis (HS) although the history of generalized seizure activity and duration of epilepsy did not differ between the two groups of patients. Thus there is evidence for the existence of extensive structural disorganization outside visually identified focal lesions in the brains of patients with CD and chronic partial epilepsy. This disruption is not due to the effects of the epilepsy and must instead be associated with its cause. Possible mechanisms producing the abnormalities are discussed. The methodology described may be applied to other cortical diseases.

Cerebral cortical dysgenesis (CD) is a heterogeneous disorder of cortical development and organization commonly associated with epilepsy, with a variety of subtypes. We reviewed the clinical, EEG and neuroimaging features in 100 adult patients with CD. There were 39 men and 61 women with a median age of 27 years (range 15-63 years). All patients were referred because of medically refractory epilepsy. Median age at seizure onset was 10 years (range 3 weeks to 39 years); in 30 patients, onset was in adulthood. The epilepsy was classified as generalized in 16 patients and localization-related in 84. Of the latter, the epileptic syndromes in decreasing frequency were frontal (32%), temporal (31%), parietal (14%) and occipital (7%). Only 15% of patients had a history of status epilepticus. Prenatal/perinatal problems were reported in 32 patients but these were severe in only four: exposure to drugs (three) and infection (one) during the first trimester. Delayed developmental milestones were seen in 10%, mental retardation in 9%, additional congenital abnormalities in 4% and neurological deficits in 14% of patients. Diagnosis of CD was based on neuroimaging in 70, pathology in four and both methods in the remaining 26. The following subcategories were identified: agyria/diffuse macrogyria (four patients), focal macrogyria (16), focal polymicrogyria (one), focal macrogyria/polymicrogyria associated with a cleft (11), minor gyral abnormalities (seven), subependymal grey matter heterotopia (20), bilateral subcortical laminar grey matter heterotopia (eight), tuberous sclerosis (five), focal cortical dysplasia/microdysgenesis (seven) and dysembryoplastic neuroepithelial tumours (DNT) (21). Sixty-eight percent of patients had normal CT and 19 out of 36 patients had normal previous conventional MRI. MRI-based hippocampal volume measurements in 47 patients revealed ratios (smaller: larger hippocampus) of < 0.90 in 16, 0.90-0.94 in 14 and > or = 0.95 in 17 patients. EEGs were normal in only five patients. Alpha rhythm was preserved in 78 patients, including one patient with bilateral posterior macrogyria. Localized polymorphic slow activity was present in 43 patients. Five of 68 patients with focal/unilateral CD had only bilateral independent/synchronous spiking and 14 out of 32 with diffuse/bilateral CD only focal/unilateral spiking. In 60 patients with nondiffuse CD or with abnormal gyration or DNT, the epileptiform abnormalities were less extensive than coextensive with the lesion in 28, more extensive than and overlapped the lesion in 18 and remote from the lesion in five; nine patients did not have epileptiform abnormalities. There was poor correlation between the epileptic syndromes and EEG abnormalities and the location/extent of CD as defined by MRI and pathology.(ABSTRACT TRUNCATED AT 400 WORDS)

Volumetric magnetic resonance imaging has become a routine investigation in the management of patients with chronic partial epilepsy. However, even with the use of reformatted images, an underlying cause for epilepsy cannot be found in many of these patients. We show that further processing of the data, including three-dimensional reconstruction and quantitative analysis of the volume and complexity of the images in three dimensions, reveals additional positive information in up to 75% of patients. This may be useful for surgical planning, prognostication, and understanding of the structure and development of the human brain.

The possible dual occurrence of hippocampal sclerosis (HS) and other structural lesions (especially cortical dysgenesis [CD]) is well established in patients with chronic partial epilepsy. We describe the frequency of additional CD in a series of 100 patients with evidence of HS, using volumetric MRI. Additional, often subtle, CD was present in 15 patients: subependymal heterotopia (six), forme fruste of tuberous sclerosis (two), focal macrogyria (two), focal cortical dysplasia (one), laminar heterotopia (one), bilateral schizencephaly (one), and simplified gyral patterns (two). In contrast, in 46 healthy volunteers, only one had possible CD (p < 0.05). Only 2 of 15 patients had a history of childhood febrile convulsions. HS is a heterogeneous condition; patients being evaluated for temporal lobe surgery should be carefully screened for additional CD using appropriate MR techniques.