Malformations Of Cortical Development Patients Research Articles

Differential electrographic seizure patterns in malformations of cortical development, early life brain injury, and later life brain injury

Structural epilepsy is a chronic neurologic condition that may be caused by in utero malformations of cortical development (MCD) or post-natal brain injuries resulting in encephalomalacia. We hypothesized that the timing of epileptogenic insult would lead to distinct electrographic seizure patterns. Specifically, we predicted that later life insults would lead to longer duration seizures with higher proportion of focal: focal to bilateral tonic-clonic (FBTC) seizures and low rates of bihemispheric onset seizures, as compared to early life insults. We performed a retrospective chart review of 70 adult patients – 33 with epilepsy secondary to brain injury (9 with injury occurring before 16 years and 24 with injury occurring at or after 16 years) with resultant encephalomalacia on MR imaging and 37 with epilepsy secondary to MCD – admitted to the University of Pittsburgh Epilepsy Monitoring Unit for presurgical evaluation. There were no significant differences in duration of epilepsy or number of trialed seizure medications between the groups. We examined scalp EEG data for all patients, as well as intracranial EEG data in a subset. We analyzed seizure duration, seizure frequency, and seizure type (focal, FBTC, and bihemispheric onset) in three cohorts: MCD patients, patients with brain injury occurring in early life (<16 years old), and patients with brain injury occurring in later life (≥16 years old). Patients with later life brain injury had significantly longer and less frequent seizures as compared to MCD cohorts. There were no differences between MCD and early life brain injury cohorts. Seizure duration findings were corroborated in a subset of patients who additionally underwent intracranial EEG monitoring. Additionally, later life brain injury patients had significantly different seizure types as compared to MCD cohorts, with high rates of FBTC and low rates of bihemispheric onset. Again, there was no significant differences in seizure type between early life brain injury and MCD cohorts. These novel findings indicate the relevance of timing of epileptogenic insult on the electrophysiological characteristics of structural epilepsies.

CNS autoimmune response in the MAM/pilocarpine rat model of epileptogenic cortical malformation

The development of seizures in epilepsy syndromes associated with malformations of cortical development (MCDs) has traditionally been attributed to intrinsic cortical alterations resulting from abnormal network excitability. However, recent analyses at single-cell resolution of human brain samples from MCD patients have indicated the possible involvement of adaptive immunity in the pathogenesis of these disorders. By exploiting the MethylAzoxyMethanol (MAM)/pilocarpine (MP) rat model of drug-resistant epilepsy associated with MCD, we show here that the occurrence of status epilepticus and subsequent spontaneous recurrent seizures in the malformed, but not in the normal brain, are associated with the outbreak of a destructive autoimmune response with encephalitis-like features, involving components of both cell-mediated and humoral immune responses. The MP brain is characterized by blood-brain barrier dysfunction, marked and persisting CD8+ T cell invasion of the brain parenchyma, meningeal B cell accumulation, and complement-dependent cytotoxicity mediated by antineuronal antibodies. Furthermore, the therapeutic treatment of MP rats with the immunomodulatory drug fingolimod promotes both antiepileptogenic and neuroprotective effects. Collectively, these data show that the MP rat could serve as a translational model of epileptogenic cortical malformations associated with a central nervous system autoimmune response. This work indicates that a preexisting brain maldevelopment predisposes to a secondary autoimmune response, which acts as a precipitating factor for epilepsy and suggests immune intervention as a therapeutic option to be further explored in epileptic syndromes associated with MCDs.

Pathology-selective antiepileptic effects in the focal freeze-lesion rat model of malformation of cortical development

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.

Investigation of the most common clinical and imaging findings and the role of tubulin genes in the etiology of malformations of cortical development

Background/aimThe number of reports on the role of tubulin gene mutations ( TUBA1A, TUBB2B, and TUBB3 ) in etiology of malformations of cortical development has peaked in recent years. We aimed to determine tubulin gene defects on a patient population with simple and complex malformations of cortical development, and investigate the relationship between tubulin gene mutations and disease phenotype.Materials and methodsWe evaluated 47 patients with simple or complex malformations of cortical development, as determined by radiological examination, for demographic features, clinical findings and mutations on TUBA1A, TUBB2B, and TUBB3 genes.ResultsAccording to the magnetic resonance imaging findings, 19 patients (40.5%) had simple malformations of cortical development and 28 (59.5%) patients had complex malformations of cortical development. Focal cortical dysplasia was the most common simple malformation, lissencephaly was the most common coexisting cortical malformation, and corpus callosum anomalies were the most common coexisting extracortical neurodevelopmental abnormalities. None of the patients had genetic alterations on TUBA1A, TUBB2B, and TUBB3 genes causing protein dysfunction. On the other hand, the frequencies of some polymorphisms were higher when compared to the literature.ConclusionIt is crucial to identify the etiology in patients with malformations of cortical development in order to provide appropriate genetic counseling and prenatal diagnosis. We consider that multicenter studies with higher patient numbers and also including other malformations of cortical development-related genes are required to determine underlying etiological factors of malformations of cortical development patients.

Tensor-valued diffusion MRI differentiates cortex and white matter in malformations of cortical development associated with epilepsy.

Objective:Delineation of malformations of cortical development (MCD) is central in presurgical evaluation of drug-resistant epilepsy. Delineation using magnetic resonance imaging (MRI) can be ambiguous, however, because the conventional T1- and T2-weighted contrasts depend strongly on myelin for differentiation of cortical tissue and white matter. Variations in myelin content within both cortex and white matter may cause MCD findings on MRI to change size, become undetectable, or disagree with histopathology. The novel tensor-valued diffusion MRI (dMRI) technique maps microscopic diffusion anisotropy, which is sensitive to axons rather than myelin. This work investigated whether tensor-valued dMRI may improve differentiation of cortex and white matter in the delineation of MCD.Methods:Tensor-valued dMRI was performed on a 7 T MRI scanner in 13 MCD patients (age = 32 ± 13 years) featuring periventricular heterotopia, subcortical heterotopia, focal cortical dysplasia, and polymicrogyria. Data analysis yielded maps of microscopic anisotropy that were compared with T1-weighted and T2-fluid-attenuated inversion recovery images and with the fractional anisotropy from diffusion tensor imaging.Results:Maps of microscopic anisotropy revealed large white matter-like regions within MCD that were uniformly cortex-like in the conventional MRI contrasts. These regions were seen particularly in the deep white matter parts of subcortical heterotopias and near the gray-white boundaries of focal cortical dysplasias and polymicrogyrias.Significance:By being sensitive to axons rather than myelin, mapping of microscopic anisotropy may yield a more robust differentiation of cortex and white matter and improve MCD delineation in presurgical evaluation of epilepsy.

Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes.

Mutations in alpha- and beta-tubulins are increasingly recognized as a major cause of malformations of cortical development (MCD), typically lissencephaly, pachygyria and polymicrogyria; however, sequencing tubulin genes in large cohorts of MCD patients has detected tubulin mutations in only 1-13%. We identified patients with a highly characteristic cerebellar dysplasia but without lissencephaly, pachygyria and polymicrogyria typically associated with tubulin mutations. Remarkably, in seven of nine patients (78%), targeted sequencing revealed mutations in three different tubulin genes (TUBA1A, TUBB2Band TUBB3), occurring de novo or inherited from a mosaic parent. Careful re-review of the cortical phenotype on brain imaging revealed only an irregular pattern of gyri and sulci, for which we propose the term tubulinopathy-related dysgyria. Basal ganglia (100%) and brainstem dysplasia (80%) were common features. On the basis of in silico structural predictions, the mutations affect amino acids in diverse regions of the alpha-/beta-tubulin heterodimer, including the nucleotide binding pocket. Cell-based assays of tubulin dynamics reveal various effects of the mutations on incorporation into microtubules: TUBB3 p.Glu288Lys and p.Pro357Leu do not incorporate into microtubules at all, whereas TUBB2B p.Gly13Ala shows reduced incorporation and TUBA1A p.Arg214His incorporates fully, but at a slower rate than wild-type. The broad range of effects on microtubule incorporation is at odds with the highly stereotypical clinical phenotype, supporting differential roles for the three tubulin genes involved. Identifying this highly characteristic phenotype is important due to the low recurrence risk compared with the other (recessive) cerebellar dysplasias and the apparent lack of non-neurological medical issues.

Epileptogenic malformations of cortical development: when evolution goes awry

Background. Since the time of its origin in a mammalian ancestor, perhaps 250 million years ago, the neocortex has undergone expansion in both relative and absolute size. The complexity of the brain in vertebrates is proportional to the elaboration of the mechanisms controlling cortical development. Malformations of cortical development (MCD) are classified into three major groups that recapitulate the main developmental steps: cell proliferation, neuronal migration, or postmigrational cortical organization and connectivity. The main clinical manifestations of MCDs are epilepsy and / or intellectual disability. Seizures are the most common clinical feature, at least 75% of patients with MCDs will have epilepsy. Recent advances in neuroimaging techniques and revolutionary achievements in molecular biology led to an explosive increase in our knowledge of cerebral cortex development and malformations of cortical development (MCD). So far, more than 100 genes were associated with one or more types of MCD. However, the genetic cause still remains unidentified in the majority of cases. Conclusions. Investigations of human malformations of cortical development as of a model of impaired neurodevelopment gave a lot of important insights into normal and abnormal brain development processes and practical benefits to MCD patients and their families. Recent achievements in genetic technologies led to a real explosion in such knowledge and are expected to yield even more additional information in the near future.

Diffusion abnormalities of the corpus callosum in patients with malformations of cortical development and epilepsy

Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that can characterize white matter (WM) architecture and microstructure. DTI has demonstrated extensive WM changes in patients with several epileptic syndromes, but few studies have focused on patients with malformations of cortical development (MCD). Our aim was to investigate the quantitative diffusion properties of the corpus callosum (CC), a major commissural bundle critical in inter-hemispheric connectivity, in a large group of patients with MCD. Thirty-two MCD patients and 32 age and sex-matched control subjects were evaluated with DTI at 3.0 T. We analyzed the three major subdivisions of the CC (genu, body, and splenium) with deterministic tractography to yield fractional anisotropy (FA), mean diffusivity (MD), parallel diffusivity (λ||) and perpendicular diffusivity (λ⊥). We further assessed the CC with region of interest (ROI)-based analyses and evaluated different subgroups of MCD (polymicrogyria/schizencephaly, heterotopia, and cortical dysplasia). Partial correlations between diffusion changes and clinical parameters (epilepsy duration and age at disease onset) were also queried. There were significant reductions of FA, accompanied by increases in MD and λ⊥ in all segments of the CC in the patients group with both analytical methods. The absolute differences in FA were greater on ROI-analyses. There were no significant differences between the MCD subgroups, and no correlations between clinical parameters of epilepsy and FA. Our study indicates DTI abnormalities consistent with microstructural changes in the corpus callosum of MCD patients. The findings support the idea that patients with epilepsy secondary to cortical malformations present widespread WM changes that extend beyond the macroscopic MRI-visible lesions.

Widespread pH abnormalities in patients with malformations of cortical development and epilepsy: A phosphorus-31 brain MR spectroscopy study

Neuroimaging studies demonstrate that not only the lesions of malformations of cortical development (MCD) but also the normal-appearing parenchyma (NAP) present metabolic impairments, as revealed with (1)H-MRS. We have previously detected biochemical disturbances in MCD lesions with phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Our hypothesis is that pH abnormalities extend beyond the visible lesions. Three-dimensional 31P-MRS at 3.0 T was performed in 37 patients with epilepsy and MCD, and in 31 matched-control subjects. The patients were assigned into three main MCD subgroups: cortical dysplasia (n=10); heterotopia (n=14); schizencephaly/polymicrogyria (n=13). Voxels (12.5 cm3) were selected in five homologous regions containing NAP: right putamen; left putamen; frontoparietal parasagittal cortex; right centrum semiovale; and left centrum semiovale. Robust methods of quantification were applied, and the intracellular pH was calculated with the chemical shifts of inorganic phosphate (Pi) relative to phosphocreatine (PCr). In comparison to controls and considering a Bonferroni adjusted p-value <0.01, MCD patients presented significant reduction in intracellular pH in the frontoparietal parasagittal cortex (6.985±0.022), right centrum semiovale (7.004±0.029), and left centrum semiovale (6.995±0.030), compared to controls (mean values±standard deviations of 7.087±0.048, 7.096±0.042, 7.088±0.045, respectively). Dunnet and Dunn tests demonstrated that the differences in pH values remained statistically significant in all MCD subgroups. No significant differences were found for the putamina. The present study demonstrates widespread acidosis in the NAP, and reinforces the idea that MCD visible lesions are only the tip of the iceberg.

Independent contribution of individual white matter pathways to language function in pediatric epilepsy patients

Background and purposePatients with epilepsy and malformations of cortical development (MCDs) are at high risk for language and other cognitive impairment. Specific impairments, however, are not well correlated with the extent and locale of dysplastic cortex; such findings highlight the relevance of aberrant cortico-cortical interactions, or connectivity, to the clinical phenotype. The goal of this study was to determine the independent contribution of well-described white matter pathways to language function in a cohort of pediatric patients with epilepsy.Materials and methodsPatients were retrospectively identified from an existing database of pediatric epilepsy patients with the following inclusion criteria: 1. diagnosis of MCDs, 2. DTI performed at 3 T, and 3. language characterized by a pediatric neurologist. Diffusion Toolkit and Trackvis (http://www.trackvis.org) were used for segmentation and analysis of the following tracts: corpus callosum, corticospinal tracts, inferior longitudinal fasciculi (ILFs), inferior fronto-occipital fasciculi (IFOFs), uncinate fasciculi (UFs), and arcuate fasciculi (AFs). Mean diffusivity (MD) and fractional anisotropy (FA) were calculated for each tract. Wilcoxon rank sum test (corrected for multiple comparisons) was used to assess potential differences in tract parameters between language-impaired and language-intact patients. In a separate analysis, a machine learning algorithm (random forest approach) was applied to measure the independent contribution of the measured diffusion parameters for each tract to the clinical phenotype (language impairment). In other words, the importance of each tract parameter was measured after adjusting for the contribution of all other tracts.ResultsThirty-three MCD patients were included (age range: 3–18 years). Twenty-one patients had intact language, twelve had language impairment. All tracts were identified bilaterally in all patients except for the AF, which was not identified on the right in 10 subjects and not identified on the left in 11 subjects. MD and/or FA within the left AF, UF, ILF, and IFOF differed between language-intact and language-impaired groups. However, only parameters related to the left uncinate, inferior fronto-occipital, and arcuate fasciculi were independently associated with the clinical phenotype.ConclusionsScalar metrics derived from the left uncinate, inferior fronto-occipital, and arcuate fasciculi were independently associated with language function. These results support the importance of these pathways in human language function in patients with MCDs.

Functional MRI study of the brain with malformations of cortical development

Objective To explore the patterns of motor and linguistic activation in cortical and its correlations with abnormal gray matter in patients with malformations of cortical development(MCD)and epilepsy.Methods Seven MCD patients with epilepsy(2 patients with focal cortical dysplasia,2 heterotopia,2 schizencephaly,and 1 polymicrogyria)underwent blood-oxygen-level-dependent(BOLD)functional MRI(fMRI)in a 3 T MR scanner when practicing bilateral fingers tapping,toes twisting,verb generation,and picture naming.Functional images were post-processed by using SPM 5 software based on a general linear model(GLM)to generate activations above a uniform threshold with the cluster size (≥30 voxels,P ＜0.001 corrected).The activations were recognized and classified by two experienced neuroradiologists,and then compared with that in abnormal gray matter.Results The clusters and intensities of motor activations were mainly located in the sensormotor cortex(SMC)and premotor area (PMA).In linguistic tasks,activations produced by verb generation were found in language-associated cortical regions and PMA with higher activation in Wemicke area,picture naming significantly in the visual cortex,and language in Broca area.Combination of the two linguistic tasks produced significant clusters and intensities in language cortex.For MCD patients with abnormal cortical abnormalities,motor and language task could produce neuronal activities within normal as well as abnormal cortex regions.In 6 patients who underwent resective surgery,epileptic seizures decreased significantly,and the follow-up images demonstrated no new neurological dysfunctions and cognitive impairments.Conclusions fMRI can visualize neuronal activities in patients with MCD and epilepsy and demonstrate the motor and linguistic activations occurring in normal and abnormal gray matter.It should be cautious for surgery in patient with MCD and epilepsy. Key words: Cerebral cortex; Nervous system abnormalities; Grey matter heterotopia; Epileptic foci; Magnetic resonance imaging

Hippocampal abnormalities in malformations of cortical development

Hippocampal abnormalities may coexist with malformations of cortical development (MCD). This cross-sectional MRI study aimed at categorizing hippocampal abnormalities in a large group of MCD and comparing MCD patients with (group W) and without (group W/O) hippocampal abnormalities. Hippocampal anatomy, rotation, size, internal structure, and MRI signal alterations were assessed visually by 3 independent raters in patients with MCD and epilepsy. Four types of hippocampal abnormalities were examined in 220 patients (116 women, mean age 31 +/- 16.6, range 2-76 years): partially infolded/hypoplastic hippocampus (HH), hippocampal sclerosis (HS), malrotated hippocampus (MH), and enlarged hippocampus (EH). The commonest MCD in the cohort were focal cortical dysplasia (27%), polymicrogyria (PMG) (21%), developmental tumors (15%), and periventricular nodular heterotopia (PNH) (14%). Hippocampal abnormalities were seen in 69/220 (31%) patients: HH in 34/69 (49%); HS in 18/69 (26%); MH in 15/69 (22%); and EH in 2/69 (3%). PNH (21/30 [70%]) and PMG (22/47 [47%]) were most commonly associated with hippocampal abnormalities. Compared to the W/O group, patients in the W group had a higher rate of learning disability (W 41/69 [59%] vs W/O 56/151 [37%]; p = 0.003) and delayed developmental milestones (W 36/69 [52%] vs W/O 53/151 [35%]; p = 0.025); groups did not differ otherwise with regard to clinical presentation. HH was associated with symptomatic generalized epilepsies (11/34 [32%]) and high rate of learning disability (27/34 [79%]), neurologic deficits (25/34 [73%]), and delayed developmental milestones (23/34 [68%]). About a third of patients with malformations of cortical development had hippocampal abnormalities. Patients with hypoplastic hippocampus had the most severe clinical phenotype.

Temporal lobe epilepsy: neuropathological and clinical correlations in 243 surgically treated patients

The present study included analysis of data from 243 patients surgically treated for Temporal Lobe Epilepsy (TLE). Resection was confined to the temporal lobe, with at least two years of follow-up, and specimens sufficiently preserved to allow a precise evaluation of both lateral neocortex and hippocampus. The frequency of different types of lesion and hippocampal sclerosis (HS), isolated or associated with neocortical lesions, risk factors and surgical outcomes in relation to neuropathological findings were evaluated. We found tumours in 33% of patients, malformations of cortical development (MCD) in 45%, isolated HS in 14%, no lesion in 5% and less common lesions in 3%. HS was present in 8% of tumour cases and 70% of MCD. Statistical analysis of antecedents was significantly associated only with febrile seizures (FS). In MCD patients with no history of FS, a strong association between HS and duration of epilepsy was revealed. A Class I outcome was identified in 87% of cases with tumours and 79% in cases with MCD. In 93 patients the antiepileptic drug therapy was withdrawn. Our findings show that MCD, which is significantly associated with HS, is the most common lesion in TLE and support the concept that an optimal outcome is obtained when mesial and neocortical structures are removed. FS are particularly relevant in patients with focal cortical dysplasia and HS.

Different structures involved during ictal and interictal epileptic activity in malformations of cortical development: an EEG-fMRI study

Malformations of cortical development (MCDs) are commonly complicated by intractable focal epilepsy. Epileptogenesis in these disorders is not well understood and may depend on the type of MCD. The cellular mechanisms involved in interictal and ictal events are notably different, and could be influenced independently by the type of pathology. We evaluated the relationship between interictal and ictal zones in eight patients with different types of MCD in order to better understand the generation of these activities: four had nodular heterotopia, two focal cortical dysplasia and two subcortical band heterotopia (double-cortex). We used the non-invasive EEG-fMRI technique to record simultaneously all cerebral structures with a high spatio-temporal resolution. We recorded interictal and ictal events during the same session. Ictal events were either electrical only or clinical with minimal motion. BOLD changes were found in the focal cortical dysplasia during interictal and ictal epileptiform events in the two patients with this disorder. Heterotopic and normal cortices were involved in BOLD changes during interictal and ictal events in the two patients with double cortex, but the maximum BOLD response was in the heterotopic band in both patients. Only two of the four patients with nodular heterotopia showed involvement of a nodule during interictal activity. During seizures, although BOLD changes affected the lesion in two patients, the maximum was always in the overlying cortex and never in the heterotopia. For two patients intracranial recordings were available and confirm our findings. The dysplastic cortex and the heterotopic cortex of band heterotopia were involved in interictal and seizure processes. Even if the nodular gray matter heterotopia may have the cellular substrate to produce interictal events, the often abnormal overlying cortex is more likely to be involved during the seizures. The non-invasive BOLD study of interictal and ictal events in MCD patients may help to understand the role of the lesion in epileptogenesis and also determine the potential surgical target.

Analysis of shape and positioning of the hippocampal formation: an MRI study in patients with partial epilepsy and healthy controls

The purpose of this study was to evaluate systematically shape and positioning of the hippocampal formation (HF) in patients with partial epilepsy related to malformations of cortical development (MCD) and those with temporal lobe epilepsy (TLE). We studied 76 patients with MCD, including focal cortical dysplasia (n = 29; lesions located outside the temporal lobe in all), heterotopia (lesions outside of the temporal lobe, n = 14; lesions extending into the temporal lobe, n = 16), polymicrogyria (bilateral perisylvian, n = 14; unilateral perisylvian, n = 3) and 30 patients with TLE (hippocampal atrophy, n = 15; normal hippocampal volumes, n = 15). Shape and positioning of the HF were evaluated using a set of eight predefined morphological characteristics. In addition, the degree of hippocampal vertical orientation and medial positioning were assessed quantitatively. Patients were compared with 50 healthy controls. At least three criteria describing abnormal HF shape and positioning were found in 5/50 (10%) healthy controls, 37/76 (49%) MCD and 13/30 (43%) TLE patients. An association with all criteria was found in MCD and TLE, but not in healthy controls. In MCD there was no association between the side of HF shape abnormalities and the side of the cortical malformation or the EEG focus. Likewise, in TLE, HF abnormalities were not related to the side of the EEG focus. In both MCD and TLE patients who had hippocampal atrophy, no association was found between the side of HF shape abnormalities and the side of atrophy. Abnormal HF shape and positioning are found in a similar proportion in MCD and TLE. In TLE, they may be a marker of a more extensive disorder of brain development and may participate in the development of this condition.

Quantitative MRI detects abnormalities in relatives of patients with epilepsy and malformations of cortical development

Malformations of cortical development (MCD) are a common etiology for epilepsy. Laminar heterotopia, bilateral subependymal heterotopia, and lissencephaly have a genetic basis. No gene mutations have yet been identified in patients with focal cortical dysplasias. The aim of this study was to use quantitative morphometric tools to determine if there were gray matter abnormalities in relatives of patients with MCD. We studied 19 relatives of 13 probands with MCD and 58 healthy controls with high-resolution MRI. The relatives and controls had no neocortical abnormalities on visual inspection. MRI data were analyzed with voxel-based morphometry and autoblock analysis. Voxel-based morphometry showed significant increases of gray matter in 9 of 10 probands, 5 of 19 relatives, and 5 of 58 controls. The autoblock analysis showed significant abnormalities in 7 of 8 probands, 8 of 19 relatives, and 2 of 57 controls. This finding suggests structural abnormality in the brains of a greater number of relatives of MCD patients than would be expected, and in the context, a reasonable inference is that this reflects subtle genetically determined cerebral abnormalities, although acquired pathologies are possible and are not excluded.

Voxel-by-Voxel Comparison of Automatically Segmented Cerebral Gray Matter—A Rater-Independent Comparison of Structural MRI in Patients with Epilepsy

Quantitative evaluation of MRI in patients with epilepsy can give more information than qualitative assessment. Previously developed volume-of-interest-based methods identified subtle widespread structural changes in the neocortex beyond the visualized lesions in patients with malformations of cortical development (MCD) and hippocampal sclerosis (HS) and also in MRI-negative patients with juvenile myoclonic epilepsy (JME). This study evaluates a voxel-based automated analysis of structural MRI in epilepsy. After fully automated segmentation of cerebral gray matter from structural T1-weighted, high-resolution MRI scans, we applied the automated and objective technique of statistical parametric mapping (SPM) to the analysis of gray matter of 35 control subjects, 10 patients with partial seizures and MCD, 10 patients with left temporal lobe epilepsy (TLE) and HS, 10 patients with left TLE and normal MR quantitation of the hippocampus, and 20 patients with JME. At a corrected threshold of P < 0.05, significant abnormalities were found in 3/35 controls; in all 10 patients with MCD, 6 of whom had additional lesions beyond the margins of the visualized abnormalities; in 2/10 TLE patients with HS; in 2/10 MRI-negative TLE; and in 4/20 JME patients. Group comparisons between control subjects and HS patients identified the affected left temporal lobe with an increase in gray matter in the posterior temporal lobe, but did not identify hippocampal atrophy. The group of MRI-negative TLE patients showed no abnormalities compared with control subjects. Group comparison between control subjects and JME patients identified a mesial frontal increase in gray matter. The SPM-based voxel-by-voxel comparison of gray matter distribution identified MCD and abnormalities beyond the visualized lesion in individual MCD patients. The method did not reliably identify HS in individual patients or identify abnormalities in individual MRI-negative patients with TLE or JME in a proportion larger than the chance findings in the control group. Using group comparisons, structural abnormalities in the neocortical gray matter of patients with TLE and HS were lateralized to the affected temporal lobe. In patients with JME as a group, an increase in gray matter was localized to the mesial frontal area, corroborating earlier quantitative MRI findings.