Quantitative grey matter histological measures do not correlate with grey matter probability values from in vivo MRI in the temporal lobe.

Voxel-based morphometry (VBM) is commonly used to study systematic differences in brain morphology from patients with various disorders, usually by comparisons with control subjects. It has often been suggested, however, that VBM is also sensitive to variations in composition in grey matter. The nature of the grey matter changes identified with VBM is still poorly understood. The aim of the current study was to determine whether grey matter histopathological measurements of neuronal tissue or gliosis influenced grey matter probability values that are used for VBM analyses. Grey matter probability values (obtained using both SPM5 and FSL-FAST) were correlated with neuronal density, and field fraction of NeuN and GFAP immunopositivity in a grey matter region of interest in the middle temporal gyrus, in 19 patients undergoing temporal lobe resection for refractory epilepsy. There were no significant correlations between any quantitative neuropathological measure and grey matter probability values in normal-appearing grey matter using either segmentation program. The lack of correlation between grey matter probability values and the cortical neuropathological measures in normal-appearing grey matter suggests that intrinsic cortical changes of the type we have measured do not influence grey matter probability maps used for VBM analyses.

T2 relaxometry of the hippocampus at 3T.

BACKGROUND AND PURPOSE: T2 mapping is useful for identifying and quantifying abnormalities of the hippocampus and amygdala. It is particularly useful in the presurgical evaluation of patients with temporal lobe epilepsy and for the identification of bilateral hippocampal sclerosis (HS). The purpose of this study was to implement and validate a dual-echo method for producing coronal T2 maps with complete coverage of the hippocampus and the rest of the brain on a 3T MR imaging scanner. MATERIALS AND METHODS: T2 relaxation times were estimated on 10 occasions on 3 quality assessment Eurospin II (Diagnostic Sonar, Livingstone, Scotland) test objects with the use of conventional spin-echo (CSE), fast spin-echo, and fast recovery fast spin-echo (FRFSE) sequences on a 3T Excite MR imaging scanner (GE Healthcare, Milwaukee, Wis). Hippocampal T2 relaxation times were then measured in 15 healthy subjects and 20 subjects with clear-cut HS who were scanned at 1.5 T with a previously validated dual-echo CSE sequence and 3T with an FRFSE sequence. RESULTS: 3T FRFSE data were as reliable as CSE data at 1.5 T. Reliability of hippocampal T2 measures was good on healthy volunteers and subjects with HS. FRFSE images were suitable for qualitative radiologic reporting and with complete brain coverage, so no additional T2-weighted sequences were required. There was good correlation between the 3T hippocampal T2 measurements and values obtained with the previously validated technique at 1.5 T, with reliable identification of all of the subjects with HS. CONCLUSIONS: T2 mapping with an FRFSE 30/80 sequence may be readily applied at 3T and can produce reliable T2 values in vivo with contiguous 5-mm sections and in a much reduced scan time of 3 minutes 1 second compared with 10 minutes 30 seconds for the CSE sequence at 1.5 T.

Correlation of quantitative MRI and neuropathology in epilepsy surgical resection specimens--T2 correlates with neuronal tissue in gray matter.

Newer MRI methods can detect cerebral abnormalities not identified on routine imaging in patients with focal epilepsy. Correlation of MRI with histopathology is necessary to understand the basis of MRI abnormalities and subsequently predict histopathology from in vivo MRI. The aim of this study was to determine if particular quantitative MR parameters were associated with particular histological features. Nine patients with temporal lobe epilepsy were imaged at 1.5 T using standard presurgical volumetric and quantifiable sequences: magnetization transfer and FFT2. The resected temporal lobe was registered with the volumetric MRI data according to our previously described method to permit correlation of the modalities. Stereologically measured neuronal densities and field fraction of GFAP, MAP2, synaptophysin and NeuN immunohistochemistry were obtained. Analyses were performed in the middle temporal gyrus and compared with quantitative MRI data from the equivalent regions. There was a significant Spearman Rho negative correlation between NeuN field fraction and the T2 value in gray matter (correlation coefficient -0.72, p=0.028). There were no significant correlations between any neuropathological and MR measures in white matter. These preliminary findings suggest that T2 in gray matter is sensitive to the proportion of neuronal tissue. Novel quantitative MRI measures acquired with higher field strength magnets, and so with superior signal to noise ratios, may generate data that correlate with histopathological measures. This will enable better identification and delineation of the structural causes of refractory focal epilepsy, and will be of particular benefit in patients in whom current optimal MRI does not identify a relevant abnormality.

Methodological aspects of 3D and automated 2D analyses of white matter neuronal density in temporal lobe epilepsy.

White matter neuronal density has been correlated with clinical outcome after temporal lobectomy for refractory epilepsy. Both morphometric 2D (two-dimensional) and stereological 3D (three-dimensional) analyses of neuronal density have been performed. 3D analyses are thought to be more accurate than 2D counts, but more time-consuming. We compared 3D and automated 2D measurements in the same specimens. Adjacent 20-microm (for 3D analyses) and 5-microm (for 2D analyses) sections from 10 temporal lobectomies were stained for NeuN immunohistochemistry. Analysis of 100% of a region of interest (ROI) in deep white matter was performed using an image analysis system (Histometrix, Kinetic Imaging, UK). 3D analyses were undertaken using x 63 magnification (6 h/case). Automated 2D analyses were undertaken using automatic neuronal identification at x 10 magnification with three to four repeats (1.5 h/case). The range of neuronal densities for 3D measurements was 2120-4910 neurones/mm(3), and for automated 2D measurements 17.4-47.1 neurones/mm2. There was a linear correlation between the two methods with an r2 of 0.58. [corrected] Count-recount variability was 1.4-9.9% for the 3D and 5.1-36.6% for the automated 2D measurements. We found a wide range of white matter neuronal densities using either analysis. The low agreement between methods, and the high count-recount variability for the automated 2D analyses, indicate that despite being more time-consuming, rigorous 3D stereological analyses have to be performed to obtain reliable results. These findings have implications for studies requiring neuronal counts in normal and disease states.

Cognitive functioning in humans with mutations of the PAX6 gene.

Fourteen patients with PAX6 gene mutations and previously identified MRI abnormalities were administered tests of cognitive functioning. No deficits were found. A subgroup with agenesis of the anterior commissure performed significantly more poorly on measures of working memory than those without this abnormality, suggesting the anterior commissure may play a role in cognitive processing in addition to an earlier identified role in sensory development and processing.

Defective auditory interhemispheric transfer in a patient with a PAX6 mutation.

Heterozygous PAX6 mutation is associated with an absent or hypoplastic anterior commissure and a reduction in the area of the corpus callosum. The authors found deficient auditory interhemispheric transfer in a 53-year-old woman with a PAX6 mutation who had an absent anterior commissure but normal callosal volume.

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.

Bilateral isolated hippocampal malformation in temporal lobe epilepsy.

Hippocampal malformations in patients with epilepsy usually are reported in the context of widespread cortical malformations. Isolated hippocampal malformations are more rarely identified in MRI studies with little documentation of their pathologic appearance. Postmortem examination revealed abnormal position and complex convolutional malformations isolated to the hippocampal formation in an adult with temporal lobe epilepsy in whom MRI demonstrated bilateral hippocampal abnormalities.

Anterior commissure absence without callosal agenesis: a new brain malformation.

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.

Cerebellar volumes in newly diagnosed and chronic epilepsy.

Cerebellar atrophy is assumed to be a common finding in patients suffering from epilepsy. Anticonvulsants as well as seizure activity itself have been considered to be responsible for it but many studies have addressed these questions in specialised centres for epilepsy thus having a referral bias towards patients with severe epileptic syndromes. The purpose of this study was: 1. To develop a quantitative method on 3D-MRI data to achieve volume or planimetric measurements (of cerebrum, cerebellum and cerebellar substructures). 2. To investigate the prevalence of cerebellar atrophy (and substructure atrophy) in a prospectively investigated population-based cohort of patients with newly diagnosed and chronic epilepsy. 3. To quantify cerebellar atrophy in clinic-based patients, who had had atrophy previously diagnosed on routine visual MRI assessment. 4. To correlate the measures of atrophy with clinical features in both patient groups. A total of 57 patients with either newly diagnosed or chronic active epilepsy and 36 control subjects were investigated with a newly developed semiautomated method for cerebral as well as cerebellar volume measurements and substructure planimetry, corrected for intracranial volume. We did not find any significant atrophy in the population-based cohort of patients with newly diagnosed epilepsy or with chronic epilepsy. Visually diagnosed cerebellar atrophy was mostly confirmed and quantified by volumetric analysis. The clinical data suggested a correlation between cerebellar atrophy and the duration of the seizure disorder and also the total number of lifetime seizures experienced and the frequency of generalised tonic-clonic seizures per year. Volumetry on 3D-MRI yields reliable quantitative data which shows that cerebellar atrophy might be common in severe and/or longstanding epilepsy but not necessarily in unselected patient groups. The results do not support the proposition that cerebellar atrophy is a predisposing factor for epilepsy but rather are consistent with the view that cerebellar atrophy is the aftermath of epileptic seizures or anticonvulsant medication.

PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans.

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies.

Landmark-based morphometrics of the normal adult brain using MRI.

We describe the application of statistical shape analysis to homologous landmarks on the cortical surface of the adult human brain. Statistical shape analysis has a sound theoretical basis. Landmarks are identified on the surface of a 3-D reconstruction of the segmented cortical surface from magnetic resonance image (MRI) data. Using publicly available software (morphologika) the location and size dependence of the landmarks are removed and the differences in landmark distribution across subjects are analysed using principal component analysis. These differences, representing shape differences between subjects, can be visually assessed using wireframe models and transformation grids. The MRI data of 58 adult brains (27 female and 15 left handed) were examined. Shape differences in the whole brain are described which concern the relative orientation of frontal lobe sulci. Analysis of all 116 hemispheres revealed a statistically significant difference (P < 0.001) between left and right hemispheres. This finding was significant for right- but not left-handed subjects alone. No other significant age, gender, handedness, or brain-size correlations with shape differences were found.

Bilateral periventricular and subcortical heterotopia in a man with refractory epilepsy.

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.

Reduction of frontal neocortical grey matter associated with affective aggression in patients with temporal lobe epilepsy: an objective voxel by voxel analysis of automatically segmented MRI.

BACKGROUND: Interictal episodes of aggression are often reported in patients with epilepsy. Some have characteristics of what has been referred to as episodic dyscontrol or intermittent explosive disorder (IED). Although structural brain abnormalities are thought to play a part in the pathophysiology of aggression, there are few in vivo studies of structural cerebral changes in patients with epilepsy and aggression. Using quantitative MRI, subtle structural brain abnormalities can be investigated in subgroups of patients with both epilepsy and episodes of affective aggression. METHODS: After automated segmentation of cerebral grey matter from T1 weighted MRI, the objective technique of statistical parametric mapping (SPM) was applied to the analysis of 35 control subjects, 24 patients with temporal lobe epilepsy (TLE) with a history of repeated, interictal episodes of aggression, and 24 patients with TLE without episodes of aggression. Both TLE patient groups were compared with each other and with the control subjects on a voxel by voxel basis for increases and decreases of grey matter. RESULTS: The patients with TLE with aggressive episodes had a decrease of grey matter, most markedly in the left frontal lobe, compared with the control group and with patients with TLE without aggressive episodes. CONCLUSION: These findings suggest that a reduction of frontal neocortical grey matter might underly the pathophysiology of aggression in TLE. These voxel by voxel comparisons can guide further in vivo studies into aggression.

Abnormal cerebral structure in juvenile myoclonic epilepsy demonstrated with voxel-based analysis of MRI.

MRI scans of patients with idiopathic generalized epilepsy (IGE) are normal on visual assessment. Using an interactive anatomical segmentation technique and volume-of-interest measurements of MRI, we showed recently that patients with IGE had significantly larger cortical grey matter than control subjects. Further, 40% of individual patients with juvenile myoclonic epilepsy (JME), a syndrome of IGE in adolescence, had significant abnormalities of cerebral structure. In this study, we applied the automated and objective technique of statistical parametric mapping (SPM) to the analysis of structural MRI from 20 patients with JME and 30 control subjects. The cortical grey matter of each individual JME patient and the group of JME patients was contrasted with that of the group of 30 normal subjects. The voxel-based SPM comparison between the group of JME patients and the control subjects showed an increase in cortical grey matter in the mesial frontal lobes of the patients. Analysis of individual patients revealed significant abnormalities of cortical grey matter in five out of 20 JME patients, four of whom had been shown to have widespread abnormalities using the previous volume of interest technique. These findings indicate a structural cerebral abnormality in JME, with involvement of mesiofrontal cortical structures.

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.

Disproportion in the distribution of gray and white matter: neuropsychological correlates.

OBJECTIVE: To examine the relationship between measures of disproportion in the regional distribution of gray and white matter and preoperative neuropsychological function in temporal lobe epilepsy patients with proved hippocampal sclerosis (HS). BACKGROUND: Subtle cerebral structural disruption, not evident on routine inspection of high-resolution MRI, is associated with poor surgical outcome in patients with histologically proved HS. Preoperative global memory dysfunction is also associated with poor postoperative seizure control. The authors hypothesize that patients with HS and abnormal regional distributions of gray and white matter would show more diffuse neuropsychological deficits preoperatively than patients with isolated HS alone. METHODS: A total of 28 adults with lateralized temporal lobe epilepsy and hippocampal volume loss measured on MRI were assessed preoperatively on neuropsychological tests of general intellect and the learning and recall of both verbal and nonverbal material. Quantitative MRI analysis of the regional distribution of gray and white matter was performed. Chi-square analyses were used to examine the relation between the presence or absence of cerebral abnormalities and preoperative performance on the neuropsychological tests. RESULTS: A total of 15 of 28 patients had extrahippocampal abnormalities on quantitative MRI analysis. Thirteen patients had global memory impairment. Bilateral memory deficits were significantly associated with both the presence of cerebral abnormalities (p < 0.02) and poor postoperative seizure control (p < 0.05). CONCLUSIONS: Disproportion in the regional distribution of gray and white matter in patients with HS may form the structural basis of global memory disturbance in a distinct group of patients with temporal lobe epilepsy.

Evidence for nodular epileptogenicity and gender differences in periventricular nodular heterotopia.

OBJECTIVE: To determine whether clinical differences between the sexes seen in periventricular nodular heterotopia (PNH) have structural correlates on imaging. BACKGROUND: PNH is the most common dysgenesis associated with hippocampal sclerosis (HS). Women with PNH have normal intellect; men may have mental retardation and other changes. Familial PNH, seen in women, is linked to Xq28-a region also abnormal in a sporadic male infant with PNH and retardation-suggesting sexual differences in gene expression. Epilepsy associated with PNH may be refractory to drugs, and surgery for associated HS does not stop seizures, suggesting intrinsic epileptogenicity of PNH. METHODS: Quantitative MRI analysis was performed using established techniques for detecting subtle structural changes in 13 female patients (11 sporadic and two familial) and four male patients (sporadic). RESULTS: There is structural heterogeneity in PNH, even in patients with bilateral PNH. On MRI, men have more cerebral abnormalities beyond PNH than control subjects or female patients (p < 0.005). CONCLUSIONS: The findings support the concept of intrinsic epileptogenicity of PNH. There may be additional structural abnormalities relevant to seizure generation, especially in men. Structural heterogeneity, and widespread abnormalities, may need consideration when patients are referred for surgical treatment or when additional studies of patients with PNH are conducted.