Junctional instability in neuroepithelium and network hyperexcitability in a focal cortical dysplasia human model.

Focal cortical dysplasia is a highly epileptogenic cortical malformation with few treatment options. Here, we generated human cortical organoids from patients with focal cortical dysplasia type II. Using this human model, we mimicked some focal cortical dysplasia hallmarks, such as impaired cell proliferation, the presence of dysmorphic neurons and balloon cells, and neuronal network hyperexcitability. Furthermore, we observed alterations in the adherens junctions zonula occludens-1 and partitioning defective 3, reduced polarization of the actin cytoskeleton, and fewer synaptic puncta. Focal cortical dysplasia cortical organoids showed downregulation of the small GTPase RHOA, a finding that was confirmed in brain tissue resected from these patients. Functionally, both spontaneous and optogenetically-evoked electrical activity revealed hyperexcitability and enhanced network connectivity in focal cortical dysplasia organoids. Taken together, our findings suggest a ventricular zone instability in tissue cohesion of neuroepithelial cells, leading to a maturational arrest of progenitors or newborn neurons, which may predispose to cellular and functional immaturity and compromise the formation of neural networks in focal cortical dysplasia.

Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia.

OBJECTIVE: Focal cortical dysplasias (FCDs) are an important cause of drug-resistant epilepsy. In this work, we aimed to investigate whether abnormal gene regulation, mediated by microRNA, could be involved in FCD type II. METHODS: We used total RNA from the brain tissue of 16 patients with FCD type II and 28 controls. MicroRNA expression was initially assessed by microarray. Quantitative polymerase chain reaction, in situ hybridization, luciferase reporter assays, and deep sequencing for genes in the mTOR pathway were performed to validate and further explore our initial study. RESULTS: hsa-let-7f (p = 0.039), hsa-miR-31 (p = 0.0078), and hsa-miR34a (p = 0.021) were downregulated in FCD type II, whereas a transcription factor involved in neuronal and glial fate specification, NEUROG2 (p < 0.05), was upregulated. We also found that the RND2 gene, a NEUROG2-target, is upregulated (p < 0.001). In vitro experiments showed that hsa-miR-34a downregulates NEUROG2 by binding to its 5'-untranslated region. Moreover, we observed strong nuclear expression of NEUROG2 in balloon cells and dysmorphic neurons and found that 28.5% of our patients presented brain somatic mutations in genes of the mTOR pathway. INTERPRETATION: Our findings suggest a new molecular mechanism, in which NEUROG2 has a pivotal and central role in the pathogenesis of FCD type II. In this way, we found that the downregulation of hsa-miR-34a leads to upregulation of NEUROG2, and consequently to overexpression of the RND2 gene. These findings indicate that a faulty coupling in neuronal differentiation and migration mechanisms may explain the presence of aberrant cells and complete dyslamination in FCD type II. Ann Neurol 2018;83:623-635.

Concurrent mood and anxiety disorders are associated with pharmacoresistant seizures in patients with MTLE.

OBJECTIVE: To investigate whether mood disorders (MD) and anxiety disorders (AD) are associated with seizure control in patients with mesial temporal lobe epilepsy (MTLE). We compared patients without any current psychiatric disorder, patients with current MD and/or AD, patients with subsyndromic depression episodes (SSDE) and anxiety episodes (SSAE), and patients with family psychiatric history. METHODS: In a cross-sectional study, we included 144 consecutive patients with MTLE (82 pharmacoresistant and 62 treatment-responsive patients). Every patient underwent a psychiatric evaluation including the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) Axis I (SCID-I), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), and Interictal Dysphoric Disorder Inventory (IDDI). Patients were divided into four groups: PsychNeg (G1, n = 61), current SSDE and SSAE (G2, n = 26), Current MD or AD (G3, n = 25), and current mixed MD/AD (G4, n = 32). RESULTS: Among patients with pharmacoresistant MTLE, 68.3% (56/82) experienced symptoms of depression and/or anxiety (G2, G3, and G4) (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.41-5.53, p < 0.01). Patients with mixed MD/AD (G4, n = 24/32) were more likely to have pharmacoresistant MTLE (OR 4.04, 95% CI 1.57-10.42, p < 0.01) than psychiatric asymptomatic patients (G1, n = 26/61), and their seizure frequency was significantly higher (p < 0.01). Positive family psychiatric history was more frequent in pharmacoresistant patients (n = 27/82, OR 2.28, 95% CI 1.02-5.05, p = 0.04). Finally, 31.6% of patients with MD and or AD were not receiving psychiatric treatment. SIGNIFICANCE: Identification of comorbid MD/AD and of family psychiatric history is of the essence in patients with MTLE, as they appear to be associated with worse seizure control.

Electroencephalography Patterns and Prognosis in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: The prognostic significance of interictal epileptiform discharges (IED) and periodic patterns (PP) after ischemic stroke has not been assessed. We sought to test whether IED and PP, detected on standard Electroencephalography (EEG) performed during the acute phase of ischemic stroke are associated with a worse functional outcome. METHODS: One-hundred-fifty-seven patients 18 years or older with a diagnosis of acute ischemic stroke presenting within 72 h from stroke onset were prospectively enrolled and followed. Patients with a pre-stroke history of seizures or epilepsy, previous debilitating neurological disease or conditions that precluded the performance of EEG were excluded. Interpretation was performed by a blinded board certified neurophysiologist. IED and PP (grouped as epileptiform activity [EA]) were defined according to proposed guidelines. Univariable and multivariable analyses were used to identify predictors of outcome (modified Rankin Scale dichotomized ≤2 vs. ≥3) at 3 months. RESULTS: In the univariable analysis, admission NIHSS (OR 1.20, 95% CI 1.12-1.28, p = 0.001), age (OR 1.03, 95% CI 1.01-1.05, p = 0.02), and presence of EA (OR 2.94, 95% CI 1.51-5.88, p = 0.001) were significantly associated with the outcome at 3 months. In the multivariable analysis, only admission NIHSS (OR 1.19, 95% CI 1.11-1.28, p < 0.001) and the presence of EA (OR 2.27, 95% CI 1.04-5.00, p = 0.04) were independently associated with the prognosis. SIGNIFICANCE: The importance of EEG in the prognosis of acute ischemic stroke warrants additional research, examining the role of medication therapy on the outcome and the occurrence of seizures for those patients with specific EEG patterns.

EEG-fMRI in the presurgical evaluation of temporal lobe epilepsy.

OBJECTIVE: Drug-resistant temporal lobe epilepsy (TLE) often requires thorough investigation to define the epileptogenic zone for surgical treatment. We used simultaneous interictal scalp EEG-fMRI to evaluate its value for predicting long-term postsurgical outcome. METHODS: 30 patients undergoing presurgical evaluation and proceeding to temporal lobe (TL) resection were studied. Interictal epileptiform discharges (IEDs) were identified on intra-MRI EEG and used to build a model of haemodynamic changes. In addition, topographic electroencephalographic correlation maps were calculated between the average IED during video-EEG and intra-MRI EEG, and used as a condition. This allowed the analysis of all data irrespective of the presence of IED on intra-MRI EEG. Mean follow-up after surgery was 46 months. International League Against Epilepsy (ILAE) outcomes 1 and 2 were considered good, and 3-6 poor, surgical outcome. Haemodynamic maps were classified according to the presence (Concordant) or absence (Discordant) of Blood Oxygen Level-Dependent (BOLD) change in the TL overlapping with the surgical resection. RESULTS: The proportion of patients with good surgical outcome was significantly higher (13/16; 81%) in the Concordant than in the Discordant group (3/14; 21%) (χ(2) test, Yates correction, p=0.003) and multivariate analysis showed that Concordant BOLD maps were independently related to good surgical outcome (p=0.007). Sensitivity and specificity of EEG-fMRI results to identify patients with good surgical outcome were 81% and 79%, respectively, and positive and negative predictive values were 81% and 79%, respectively. INTERPRETATION: The presence of significant BOLD changes in the area of resection on interictal EEG-fMRI in patients with TLE retrospectively confirmed the epileptogenic zone. Surgical resection including regions of haemodynamic changes in the TL may lead to better postoperative outcome.

Progression of gray matter atrophy in seizure-free patients with temporal lobe epilepsy.

OBJECTIVES: To investigate the presence and progression of gray matter (GM) reduction in seizure-free patients with temporal lobe epilepsy (TLE). METHODS: We enrolled 39 consecutive TLE patients, seizure-free for at least 2 years--20 with magnetic resonance imaging (MRI) signs of hippocampal sclerosis (TLE-HS), 19 with normal MRI (TLE-NL), and 74 healthy controls. For longitudinal analysis, we included individuals who had a second MRI with minimum interval of 18 months: 21 patients (10 TLE-HS, 11 TLE-NL) and 11 controls. Three-dimensional (3D) T1 -weighted images acquired in 3 Tesla MRI were analyzed with voxel-based morphometry (VBM). The images of patients with right-sided interictal epileptogenic zone (EZ) were right-left flipped, as well as a comparable proportion of controls. Cross-sectional analysis: The patients' images from each group were compared to controls to investigate differences in GM volumes. Longitudinal analysis: The first and second images were compared in each group to look for decreased GM volume. RESULTS: Cross-sectional analysis: Patients with TLE-HS had diffuse GM atrophy, including hippocampus and parahippocampal gyrus, insula, frontal, and occipital lobes ipsilateral to EZ, bilateral thalamus and contralateral orbitofrontal gyrus, and caudate. In contrast, TLE-NL group did not present significant differences compared to controls. Longitudinal analysis: TLE-HS presented progressive GM reduction in ipsilateral insula and occipital lobe, contralateral motor area, and bilateral temporal and frontal lobes. TLE-NL had GM progression in ipsilateral hypothalamus and parietal lobe, contralateral cerebellum, and bilateral temporal lobe. Controls did not show changes in GM volume between MRIs. SIGNIFICANCE: Diffuse extrahippocampal GM atrophy is present in seizure-free patients with TLE-HS. In addition, there is progressive GM atrophy in patients with and without HS. These results demonstrate that not only ongoing seizures are involved in the progression of GM atrophy. An underlying pathologic mechanism could be responsible for progressive brain volume loss in TLE patients even in seizure-free periods.

Delineating behavioral and cognitive phenotypes in juvenile myoclonic epilepsy: Are we missing the forest for the trees?

INTRODUCTION: Patients with juvenile myoclonic epilepsy (JME) have executive dysfunction and impulsive traits. There are lines of evidence that JME is a heterogeneous epilepsy syndrome considering outcome. In this study, we aimed to analyze this heterogeneity beyond seizure control. The objective was to identify whether the pattern of cognitive dysfunction and impulse control is also heterogeneous, in an attempt to establish possible differences in patients with easy- and hard-to-control epilepsies. METHODS: Essentially, 57 patients with JME were compared with 44 controls. Patients and controls were assessed with a neuropsychological battery for executive, attention, and memory functions. The expression of impulsive traits was evaluated with the Temperament and Character Inventory - novelty seeking domain. Then, patients were categorized according to seizure control as having easy- and hard-to-control JME. RESULTS: Patients with hard-to-control JME showed worse performance in 12 out of 25 neuropsychological tests than those with easy-to-control JME. Patients with hard-to-control JME also demonstrated significantly higher scores in novelty seeking - subfactor impulsiveness (p=0.002). SIGNIFICANCE: Our study demonstrated the existence of distinct or more severe cognitive and psychiatric profiles in a subset of patients with JME. Patients with treatment-refractory seizures seem to present a broader impairment related to both cognitive deficits and impulsive traits. These findings suggest that patients with JME are not equally compromised by executive and memory deficits or dysfunction, neither by their impulsive traits. Thus, there is a need for a better characterization of patients with JME to include diverse phenotypes since our results suggest a possible existence of distinct groups of patients with JME.

White matter abnormalities associate with type and localization of focal epileptogenic lesions.

OBJECTIVE: To evaluate white matter (WM) integrity of distinct groups of patients with antiepileptic drug (AED)-resistant localization-related epilepsies. METHODS: We used diffusion tensor imaging (DTI) fiber-tractography and voxel-based morphometry (VBM) to investigate differences of WM micro- and macrostructural integrity in patients with different drug-resistant localization-related epilepsies: 17 with temporal lobe epilepsy with magnetic resonance imaging (MRI) signs of hippocampal sclerosis (TLE-HS), 17 with TLE and normal MRI (TLE-NL), 14 with frontal lobe epilepsy and subtle MRI signs of focal cortical dysplasia (FLE-FCD), and 112 healthy controls. We performed fiber-tractography using a semiautomatic deterministic method to yield average fractional anisotropy (FA), axial (AD), and radial (RD) diffusivity ipsilateral and contralateral to the epileptogenic zone of the following tracts based on their functional and anatomic relevance: body of fornix (BoF), body of cingulum (BoC), inferior frontal occipital (IFO), and uncinate fasciculi (UF). In addition, we performed VBM of the WM maps to assess macrostructural integrity differences among groups. RESULTS: TLE-HS had ipsilateral and contralateral decreased FA and increased RD for all tracts. VBM showed WM alterations mainly in the ipsilateral parahippocampal region and contralateral superior temporal gyrus. FLE-FCD showed bilateral FA decreases only in the BoC and ipsilateral RD increases also in the BoC. VBM showed WM reduction mainly in the ipsilateral precuneus and posterior and anterior cingulum. No significant WM alterations were found in the TLE-NL in DTI or VBM analysis. SIGNIFICANCE: WM abnormalities differ in distinct AED-resistant localization-related epilepsies. The diverse distribution of the WM damage in these patients suggests that the localization of the epileptic networks may play a role in the WM burden. However, the distinct degree of this damage, more accentuated in TLE-HS, also suggests that the underlying cause of the epilepsy is probably an additional factor to explain this WM damage.

Distinct functional and structural MRI abnormalities in mesial temporal lobe epilepsy with and without hippocampal sclerosis.

OBJECTIVE: We aimed to investigate patterns of electroencephalography-correlated functional MRI (EEG-fMRI) and subtle structural abnormalities in patients with mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (MTLE-HS) or normal MRI (MTLE-NL). METHODS: We evaluated EEG-fMRI acquisition of the 25 patients with diagnosis of MTLE who had interictal epileptiform discharges (IEDs) in the intra-MRI EEG: 13 MTLE-HS and 12 MTLE-NL. fMRI was performed using echo-planar images in a 3T MRI coupled with EEG acquired with 64 MRI-compatible electrodes. In the first level analyses, the time of the IEDs ipsilateral to the epileptogenic zone was used as the paradigm, and four contrasts maps were built according to the variation of the hemodynamic response function (HRF) peaks (0, +3, +5, and +7 s). Second level group analyses were performed combining the contrast maps of MTLE-HS or MTLE-NL patients with each different HRF obtained at the first level. Areas of gray matter atrophy were evaluated with voxel-based morphometry (VBM) in both groups. RESULTS: MTLE-HS and MTLE-NL had IED-related positive BOLD (posBOLD) detected in the ipsilateral anterior temporal lobe and insula. However, only MTLE-HS had significant posBOLD on contralateral hippocampus and anterior cingulate, whereas MTLE-NL had areas of posBOLD on ipsilateral frontal lobe. Both groups had significant IED-related negBOLD responses in areas of the default mode network (DMN), such as posterior cingulate and precuneus. There was no overlap of both posBOLD and negBOLD and areas of atrophy detected by VBM. SIGNIFICANCE: Similar IEDs have different patterns of hemodynamic responses in sub-groups of MTLE. In both MTLE-HS and MTLE-NL, there is a possible suppression of the DMN related to IEDs, as demonstrated by the negBOLD in these areas. The brain areas involved in the interictal related hemodynamic network are not the regions with the most significant gray matter atrophy in MTLE with or without MRI signs of HS.

Memory impairment is not necessarily related to seizure frequency in mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: To investigate the effect of seizure frequency on memory, we performed a cross sectional study comparing mesial temporal lobe epilepsy (MTLE) patients with frequent and infrequent seizures. METHODS: We performed magnetic resonance imaging (MRI) hippocampal volume (HV) measurements and neuropsychological assessment in 22 patients with frequent seizures (at least one dyscognitive seizure [DS] per month) that were refractory to antiepileptic drugs and 20 patients with infrequent seizures (three or less DS per year and no event evolving to a bilateral convulsive seizure), all with MRI signs of hippocampal sclerosis (HS) on visual analysis. We also included 29 controls for comparison of volumetric data. RESULTS: There was no difference in memory performance between patients with frequent seizures and infrequent seizures. We observed a significant bilateral reduction of HV in patients with MTLE when compared to controls (p < 0.001). The degree of hippocampal atrophy (HA) between patients with frequent and infrequent seizures was not different. There was a negative correlation between seizure frequency and HV, with r = -0.3 for the HV ipsilateral to the HS and r = -0.55 for the contralateral side, thus, explaining only 9% and 30% of the HV loss. There was a positive correlation between age of onset and degree of HA (r = 0.37). SIGNIFICANCE: Our data suggest that seizure frequency does not explain most of the HV loss or memory impairment in MTLE. Memory impairment appears to be more influenced by hippocampal damage than by seizure frequency. Further studies are necessary to identify the factors that influence memory decline in patients with MTLE.

Multimodal neuroimaging: potential biomarkers for response to antiepileptic drugs?

Neuroimaging techniques in epilepsy are used widely for definition of the epileptogenic lesion and surgical decision. However, its applications extend to the knowledge of epileptic mechanisms and include the identification of prognostic features that can help our decisions on the appropriate type of treatment on an individual basis. Structural neuroimaging may be able to identify patients more likely to respond to antiepileptic drug (AED) treatment and also patients who are better candidates for earlier surgical treatment. In the past decades, quantitative analyses have also improved our knowledge about epileptogenic lesions and networks as well as the following prognoses: seizure control, cognitive outcome, and comorbidities. New advanced neuroimaging techniques such as functional magnetic resonance imaging (MRI) and the development biotracers that could be associated with inflammation and specific genetic patterns will add further knowledge to the development of epilepsy treatments.

Epilepsy as progressive disorders: what is the evidence that can guide our clinical decisions and how can neuroimaging help?

There is evidence that some types of epilepsy progress over time, and an important part of this knowledge has derived from neuroimaging studies. Different authors have demonstrated structural damage more pronounced in individuals with a longer duration of epilepsy, and others have been able to quantify this progression over time. However, others have failed to demonstrate progression possibly due to the heterogeneity of individuals evaluated. Currently, temporal lobe epilepsy associated with hippocampal sclerosis is regarded as a progressive disorder. Conversely, for other types of epilepsy, the evidence is not so clear. The causes of this damage progression are also unknown although there is consistent evidence that seizure is one of the mechanisms. The conflicting data about epilepsy progression can be a challenge for clinical decisions for an individual patient. Studies with homogenous groups and longer follow-up are necessary for appropriate conclusions about the real burden of damage progression in epilepsies, and neuroimaging will be essential in this context.

Amygdala enlargement occurs in patients with mesial temporal lobe epilepsy and hippocampal sclerosis with early epilepsy onset.

Mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) is considered an electroclinical syndrome, and there is a debate whether it is a unique disease or an entity with distinct subtypes. Together with other mesial temporal structures, the amygdala is important in the epileptogenic network of patients with MTLE with HS. During automatic volumetric analysis of mesial structures in a group of 102 patients with MTLE with MRI signs of HS, we observed significant amygdala enlargement in 14 (14%) individuals compared to a group of 79 healthy subjects. The increased amygdala volume was contralateral to the epileptogenic zone and MRI signs of HS in 93% of these patients. Patients with MTLE with HS and enlarged amygdala had significantly earlier epilepsy onset than those without an increase of amygdala volumes. Mesial temporal lobe epilepsy with HS and enlarged amygdala may be a part of the spectrum of this condition.

Differences in Cortical Structure and Functional MRI Connectivity in High Functioning Autism.

Autism spectrum disorders (ASD) represent a complex group of neurodevelopmental conditions characterized by deficits in communication and social behaviors. We examined the functional connectivity (FC) of the default mode network (DMN) and its relation to multimodal morphometry to investigate superregional, system-level alterations in a group of 22 adolescents and young adults with high-functioning autism compared to age-, and intelligence quotient-matched 29 healthy controls. The main findings were that ASD patients had gray matter (GM) reduction, decreased cortical thickness and larger cortical surface areas in several brain regions, including the cingulate, temporal lobes, and amygdala, as well as increased gyrification in regions associated with encoding visual memories and areas of the sensorimotor component of the DMN, more pronounced in the left hemisphere. Moreover, patients with ASD had decreased connectivity between the posterior cingulate cortex, and areas of the executive control component of the DMN and increased FC between the anteromedial prefrontal cortex and areas of the sensorimotor component of the DMN. Reduced cortical thickness in the right inferior frontal lobe correlated with higher social impairment according to the scores of the Autism Diagnostic Interview-Revised (ADI-R). Reduced cortical thickness in left frontal regions, as well as an increased cortical thickness in the right temporal pole and posterior cingulate, were associated with worse scores on the communication domain of the ADI-R. We found no association between scores on the restrictive and repetitive behaviors domain of ADI-R with structural measures or FC. The combination of these structural and connectivity abnormalities may help to explain some of the core behaviors in high-functioning ASD and need to be investigated further.

Epilepsy for primary health care: a cost-effective Latin American E-learning initiative.

A lack of neurologists in Latin America forces primary health care providers to manage epilepsy. With the main goal of improving diagnostic and therapeutic management of patients with epilepsy through training of physicians in the primary health care level, the International League Against Epilepsy Education Commission (2013-2017) created a low-cost, regional, virtual course. The course, set-up in Moodle platform, was structured in eight modules, each lasting for a week. Teaching was based on written didactic material, videos, and interactive discussions, both in Spanish and Portuguese. Topics included epidemiology, diagnosis, classification, treatment, prognosis, social issues, and epilepsy policies. Each course was limited to 50 participants and priority was given to general practitioners. Certification was given to those approving the final examination. Since 2015, five courses have been developed, involving 143 participants from 17 countries and 21 tutors. Of the participants, 61% worked in primary health care services. A total of 129 participants (90%) completed the course, and 110 submitted the final examination with an approval rate of 95%. From 85 participants completing the course evaluation, 98% would recommend the course to other colleagues, and 99% showed interest in taking other similar courses. High self-confidence for the management of patients with epilepsy increased from 21% at baseline to 73% after the course. The online course on epilepsy for primary care physicians in Latin America was shown to be a cost-effective course, with good retention and excellent approval rates. Our current challenges include periodic updating, complete self-sustainability, and exploring different strategies to reach our target audience more effectively.

Asymptomatic carotid stenosis is associated with gray and white matter damage.

BACKGROUND: Cognitive deficits in patients with asymptomatic carotid stenosis have been reported. The ultimate mechanism of cognitive deficits remains unclear and might be related to subtle structural brain damage. AIMS: The aim of the present study was to evaluate the presence of subtle white and grey matter abnormalities associated with asymptomatic carotid stenosis. METHODS: Twenty-five patients with asymptomatic ≥70%/occlusion carotid stenosis and 25 healthy controls, matched for gender and age, underwent 3 Tesla brain magnetic resonance imaging. Gray and white matter macrostructural abnormalities were evaluated with voxel-based morphometry using spm8 software. White matter microstructural abnormalities were evaluated with diffusion tensor images with the Diffusion Toolbox package and tract-based spatial statistics from FMRIB Software Library. RESULTS: We observed significant macro- and microstructural white matter abnormalities, and these findings were diffuse and symmetrical in both hemispheres. In contrast, gray matter atrophy was observed in the areas corresponding to the anterior circulation of the hemisphere ipsilateral to the carotid stenosis. CONCLUSIONS: Patients with asymptomatic carotid stenosis have different patterns of gray and white matter abnormalities. While the white matter damage is diffuse, the gray matter atrophy is localized in the territory of anterior circulation ipsilateral to the stenosis. The role of asymptomatic carotid stenosis in the gray matter damage must be further investigated with longitudinal studies and comparison with neuropsychological evaluation.

Frequent seizures are associated with a network of gray matter atrophy in temporal lobe epilepsy with or without hippocampal sclerosis.

OBJECTIVE: Patients with temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) have diffuse subtle gray matter (GM) atrophy detectable by MRI quantification analyses. However, it is not clear whether the etiology and seizure frequency are associated with this atrophy. We aimed to evaluate the occurrence of GM atrophy and the influence of seizure frequency in patients with TLE and either normal MRI (TLE-NL) or MRI signs of HS (TLE-HS). METHODS: We evaluated a group of 172 consecutive patients with unilateral TLE-HS or TLE-NL as defined by hippocampal volumetry and signal quantification (122 TLE-HS and 50 TLE-NL) plus a group of 82 healthy individuals. Voxel-based morphometry was performed with VBM8/SPM8 in 3T MRIs. Patients with up to three complex partial seizures and no generalized tonic-clonic seizures in the previous year were considered to have infrequent seizures. Those who did not fulfill these criteria were considered to have frequent seizures. RESULTS: Patients with TLE-HS had more pronounced GM atrophy, including the ipsilateral mesial temporal structures, temporal lobe, bilateral thalami and pre/post-central gyri. Patients with TLE-NL had more subtle GM atrophy, including the ipsilateral orbitofrontal cortex, bilateral thalami and pre/post-central gyri. Both TLE-HS and TLE-NL showed increased GM volume in the contralateral pons. TLE-HS patients with frequent seizures had more pronounced GM atrophy in extra-temporal regions than TLE-HS with infrequent seizures. Patients with TLE-NL and infrequent seizures had no detectable GM atrophy. In both TLE-HS and TLE-NL, the duration of epilepsy correlated with GM atrophy in extra-hippocampal regions. CONCLUSION: Although a diffuse network GM atrophy occurs in both TLE-HS and TLE-NL, this is strikingly more evident in TLE-HS and in patients with frequent seizures. These findings suggest that neocortical atrophy in TLE is related to the ongoing seizures and epilepsy duration, while thalamic atrophy is more probably related to the original epileptogenic process.

Understanding the spectrum of temporal lobe epilepsy: contributions for the development of individualized therapies.

Mesial temporal lobe epilepsy (TLE) is a subtype of epilepsy in which individuals present with seizure semiology and electroencephalographic characteristics that point to an ictal onset in mesial temporal structures. The diagnosis of TLE involves different etiologies, the most common being hippocampal sclerosis, but up to 20% of TLE patients have no detectable structural lesions on modern MRIs. A variability of antiepileptic drug response and surgical prognosis is observed in TLE. The understanding of the differences among patients with TLE can facilitate the development of individualized and more efficient therapeutics. In this study, we will address the recent contributions of neuroimaging, neurophysiology, genetics and histopathology to the comprehension of the spectrum of TLE with and without MRI signs of hippocampal sclerosis and how the advances in these areas have helped to improve surgical treatments.

Análise comparativa do volume hipocampal e talâmico em pacientes com epilepsia de lobo temporal mesial com e sem resposta adequada ao tratamento farmacológico / Comparative analysis of thalamic and hippocampal volume in patients with mesial temporal lobe epilepsy responsive or not to drug therapy

OBJETIVO: Verificar variação no volume hipocampal e talâmico entre pacientes com epilepsia de lobo temporal mesial (ELTM) refratários ou responsivos ao tratamento medicamentoso. MÉTODOS: Foram analisados 26 pacientes com ELTM com boa resposta ao tratamento medicamentoso (grupo "benigno"), 25 refratários e 23 controles por meio do delineamento manual dos limites anatômicos do hipocampo e tálamo, em cortes sequenciais das imagens de RM. O Software DISPLAY foi utilizado. Análise estatística foi realizada com o programa Systat 9. RESULTADOS: Houve diferença estatística entre os controles e os grupos benigno e refratário para os volumes do tálamo ipsilateral ao foco epileptogênico (p=0,00004). Não houve diferença estatística entre os três grupos para os volumes de tálamo contralateral ao foco epileptogênico. Houve correlação significativa entre hipocampo ipsilateral e tálamo ipsilateral ao foco epileptogênico (r=0,35 e p=0,004). Quanto maior a idade, menor o volume talâmico ipsilateral (p=0,002 e r=-0,37). CONCLUSÃO: Os dados demonstraram que atrofia hipocampal está presente também em pacientes com ELTM e bom controle medicamentoso, sem diferença significativa com a atrofia de pacientes refratários. A atrofia do tálamo foi correlacionada com a idade dos pacientes, o que também pode indicar que outros fatores além da frequência de crises influenciam o grau de lesão nesta estrutura.

OBJECTIVE: To investigate the variation of thalamic and hippocampal volume in patients with mesial temporal lobe epilepsy (MTLE) refractory or responsive to drug therapy. METHODS: We analyzed 26 patients with MTLE responsive to drug therapy, 25 refractory and 23 controls through the manual delineation of anatomic limits of the hippocampus and thalamus, in sequential sections of MR images. The DISPLAY software was used. Statistical analysis was performed using the program Systat 9. RESULTS: There were statistically significant differences between controls and patients groups for thalamic volumes ipsilateral to epileptogenic focus (p=0.00004). There was no statistical difference between the 3 groups for the volumes of the thalamus contralateral to the epileptogenic focus. There was significant correlation between ipsilateral hippocampus and thalamus ipsilateral to epileptogenic focus (r=0.35, p=0.004). The older the age, the lower the ipsilateral thalamic volume (p=0.002 and r=-0.37). CONCLUSION: The data showed that hippocampal atrophy is also present in patients with TLE and good seizure control. The atrophy of thalamus was correlated with the age of patients, which may also indicate that other factors besides the seizure frequency influences the degree of damage of this structure.