Neurovascular multiparametric MRI defines epileptogenic and seizure propagation regions in experimental mesiotemporal lobe epilepsy.

OBJECTIVE: Improving the identification of the epileptogenic zone and associated seizure-spreading regions represents a significant challenge. Innovative brain-imaging modalities tracking neurovascular dynamics during seizures may provide new disease biomarkers. METHODS: With use of a multi-parametric magnetic resonance imaging (MRI) analysis at 9.4 Tesla, we examined, elaborated, and combined multiple cellular and cerebrovascular MRI read-outs as imaging biomarkers of the epileptogenic and seizure-propagating regions. Analyses were performed in an experimental model of mesial temporal lobe epilepsy (MTLE) generated by unilateral intra-hippocampal injection of kainic acid (KA). RESULTS: In the ipsilateral epileptogenic hippocampi, tissue T1 and blood-brain barrier (BBB) permeability to gadolinium were increased 48-72 hours post-KA, as compared to sham and contralateral hippocampi. BBB permeability endured during spontaneous focal seizures (4-6 weeks), along with a significant increase of apparent diffusion coefficient (ADC) and blood volume fraction (BVf). Simultaneously, ADC and BVf were augmented in the contralateral hippocampus, a region characterized by electroencephalographic seizure spreading, discrete histological neurovascular cell modifications, and no tissue sclerosis. We next asked whether combining all the acquired MRI parameters could deliver criteria to classify the epileptogenic from the seizure-spreading and sham hippocampi in these experimental conditions and over time. To differentiate sham from epileptogenic areas, the automatic multi-parametric classification provided a maximum accuracy of 97.5% (32 regions) 48-72 hours post-KA and of 100% (60 regions) at spontaneous seizures stage. To differentiate sham, epileptogenic, and seizure-spreading areas, the accuracies of the automatic classification were 93.1% (42 regions) 48-72 hours post-KA and 95% (80 regions) at spontaneous seizure stage. SIGNIFICANCE: Combining multi-parametric MRI acquisition and machine-learning analyses delivers specific imaging identifiers to segregate the epileptogenic from the contralateral seizure-spreading hippocampi in experimental MTLE. The potential clinical value of our findings is critically discussed.

Risk of epilepsy in surgical patients undergoing general or neuraxial anaesthesia.

Limited information is available on the risks of epilepsy after surgery in patients receiving general or neuraxial anaesthesia. Using Taiwan's National Health Insurance Research Database, we identified 1,478,977 patients aged ≥ 20 years who underwent surgery (required general or neuraxial anaesthesia with hospitalisation for more than one day) between 2004 and 2011. We selected 235,066 patients with general anaesthesia and 235,066 patients with neuraxial anaesthesia using a frequency-matching procedure for age and sex. We did not study those with co-existing epilepsy-related risk factors. The adjusted rate ratios (RRs) and 95% confidence intervals (CIs) of newly diagnosed epilepsy 1 year after surgery associated with general anaesthesia were analysed in the multivariate Poisson regression model. The one-year incidence of postoperative epilepsy for patients with general anaesthesia and neuraxial anaesthesia were 0.41 and 0.32 per 1000 persons, respectively, and the corresponding RR was 1.27 (95%CI 1.15-1.41). The association between general anaesthesia and postoperative epilepsy was significant in men (RR = 1.22; 95%CI 1.06-1.40), women (RR = 1.33; 95%CI 1.15-1.55) and 20-39-year-old patients. The risk of postoperative epilepsy increased in patients with general anaesthesia who had co-existing medical conditions and postoperative complications.

In vivo imaging of epileptic foci in rats using a miniature probe integrating diffuse optical tomography and electroencephalographic source localization.

OBJECTIVE: The goal of this work is to establish a new dual-modal brain-mapping technique based on diffuse optical tomography (DOT) and electroencephalographic source localization (ESL) that can chronically/intracranially record optical/electroencephalography (EEG) data to precisely map seizures and localize the seizure-onset zone and associated epileptic brain network. METHODS: The dual-modal imaging system was employed to image seizures in an experimental acute bicuculline methiodide rat model of focal epilepsy. Depth information derived from DOT was used as constraint in ESL to enhance the image reconstruction. Groups of animals were compared based on localization of seizure foci, either at different positions or at different depths. RESULTS: This novel imaging technique successfully localized the seizure-onset zone in rat induced by bicuculline methiodide injected at a depth of 1, 2, and 3 mm, respectively. The results demonstrated that the incorporation of the depth information from DOT into the ESL image reconstruction resulted in more accurate and reliable ESL images. Although the ESL images showed a horizontal shift of the source localization, the DOT identified the seizure focus accurately. In one case, when the bicuculline methiodide (BMI) was injected at a site outside the field of view (FOV) of the DOT/ESL interface, ESL gave false-positive detection of the focus, while DOT showed negative detection. SIGNIFICANCE: This study represents the first to identify seizure-onset zone using implantable DOT. In addition, the combination of DOT/ESL has never been documented in neuroscience and epilepsy imaging. This technology will enable us to precisely measure the neural activity and hemodynamic response at exactly the same tissue site and at both cortical and subcortical levels.

Noninvasive real time tomographic imaging of epileptic foci and networks.

While brain imaging and electrophysiology play a central role in neuroscience research and in the evaluation of neurological disorders, a single noninvasive modality that offers both high spatial and temporal resolution is currently not available. Here we show in an acute epilepsy rat model that photoacoustic tomography (PAT) can noninvasively track seizure brain dynamics with both high spatial and temporal resolution, and at a depth that is clinically relevant. The noninvasive yet whole surface and depth capabilities of the PAT system allowed us to actually see what is happening during ictogenesis in terms of seizure onset and spread. Both seizure onset and propagation were tomographically detected at a spatial resolution of 150µm and a temporal resolution of 300ms, respectively. The current study lends support to the theory that seizure onset and spread involves a rich interplay between multiple cortical and subcortical brain areas during the onset and spread of epileptic seizures. Dynamical changes of vasculature during epileptiform events were also detected with high spatiotemporal resolution. Together, these findings suggest that PAT represents a powerful tool for noninvasively mapping seizure onset and propagation patterns, and the 'functional' connectivity within epileptic brain networks.

Tailoring Materials for Epilepsy Imaging: From Biomarkers to Imaging Probes.

Excising epileptic foci (EF) is the most efficient approach for treating drug-resistant epilepsy (DRE). However, owing to the vast heterogeneity of epilepsies, EF in one-third of patients cannot be accurately located, even after exhausting all current diagnostic strategies. Therefore, identifying biomarkers that truly represent the status of epilepsy and fabricating probes with high targeting specificity are prerequisites for identifying the "concealed" EF. However, no systematic summary of this topic has been published. Herein, the potential biomarkers of EF are first summarized and classified into three categories: functional, molecular, and structural aberrances during epileptogenesis, a procedure of nonepileptic brain biasing toward epileptic tissue. The materials used to fabricate these imaging probes and their performance in defining the EF in preclinical and clinical studies are highlighted. Finally, perspectives for developing the next generation of probes and their challenges in clinical translation are discussed. In general, this review can be helpful in guiding the development of imaging probes defining EF with improved accuracy and holds promise for increasing the number of DRE patients who are eligible for surgical intervention.

Localization of Epileptic Foci Based on Simultaneous EEG-fMRI Data.

Combining functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) enables a non-invasive investigation of the human brain function and evaluation of the correlation of these two important modalities of brain activity. This paper explores recent reports on using advanced simultaneous EEG-fMRI methods proposed to map the regions and networks involved in focal epileptic seizure generation. One of the applications of EEG and fMRI combination as a valuable clinical approach is the pre-surgical evaluation of patients with epilepsy to map and localize the precise brain regions associated with epileptiform activity. In the process of conventional analysis using EEG-fMRI data, the interictal epileptiform discharges (IEDs) are visually extracted from the EEG data to be convolved as binary events with a predefined hemodynamic response function (HRF) to provide a model of epileptiform BOLD activity and use as a regressor for general linear model (GLM) analysis of the fMRI data. This review examines the methodologies involved in performing such studies, including techniques used for the recording of EEG inside the scanner, artifact removal, and statistical analysis of the fMRI signal. It then discusses the results reported for patients with primary generalized epilepsy and patients with different types of focal epileptic disorders. An important matter that these results have brought to light is that the brain regions affected by interictal epileptic discharges might not be limited to the ones where they have been generated. The developed methods can help reveal the regions involved in or affected by a seizure onset zone (SOZ). As confirmed by the reviewed literature, EEG-fMRI provides information that comes particularly useful when evaluating patients with refractory epilepsy for surgery.

Localizing Epileptic Foci Before Surgery in Patients With MRI-Negative Refractory Epilepsy Using Statistical Parameter Mapping and Three-Dimensional Stereotactic Surface Projection Based on 18F-FDG PET.

Patients with refractory epilepsy are not only free of seizures after resecting epileptic foci, but also experience significantly improved quality of life. Fluorine-18-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) is a promising avenue for detecting epileptic foci in patients with magnetic resonance imaging (MRI)-negative refractory epilepsy. However, the detection of epileptic foci by visual assessment based on 18F-FDG PET is often complicated by a variety of factors in clinical practice. Easy imaging methods based on 18F-FDG PET images, such as statistical parameter mapping (SPM) and three-dimensional stereotactic surface projection (3D-SSP), can objectively detect epileptic foci. In this study, the regions of surgical resection of patients with over 1 year follow-up and no seizures were defined as standard epileptic foci. We retrospectively analyzed the sensitivity of visual assessment, SPM and 3D-SSP based on 18F-FDG PET to detect epileptic foci in MRI-negative refractory epilepsy patients and obtained the sensitivities of visual assessment, SPM and 3D-SSP are 57, 70 and 60% respectively. Visual assessment combined with SPM or 3D-SSP can improve the sensitivity of detecting epileptic foci. The sensitivity was highest when the three methods were combined, but decreased consistency, in localizing epileptic foci. We conclude that SPM and 3D-SSP can be used as objective methods to detect epileptic foci before surgery in patients with MRI-negative refractory epilepsy. Visual assessment is the preferred method for PET image analysis in MRI-negative refractory epilepsy. When the visual assessment is inconsistent with the patient's electroclinical information, SPM or 3D-SSP was further selected to assess the epileptic foci. If the combination of the two methods still fails to accurately locate the epileptic foci, comprehensive evaluation can be performed by combining the three methods.

Joint reconstruction of Ictal/inter-ictal SPECT data for improved epileptic foci localization.

PURPOSE: To improve the performance for localizing epileptic foci, we have developed a joint ictal/inter-ictal SPECT reconstruction method in which ictal and inter-ictal SPECT projections are simultaneously reconstructed to obtain the differential image. METHODS: We have developed a SPECT reconstruction method that jointly reconstructs ictal and inter-ictal SPECT projection data. We performed both phantom and patient studies to evaluate the performance of our joint method for epileptic foci localization as compared with the conventional subtraction method in which the differential image is obtained by subtracting the inter-ictal image from the co-registered ictal image. Two low-noise SPECT projection datasets were acquired using 99m Tc and a Hoffman head phantom at two different positions and orientations. At one of the two phantom locations, a low-noise dataset was also acquired using a 99m Tc-filled 3.3-cm sphere with a cold attenuation background identical to the Hoffman phantom. These three datasets were combined and scaled to mimic low-noise clinical ictal (three different lesion-to-background contrast levels: 1.25, 1.55, and 1.70) and inter-ictal scans. For each low-noise dataset, 25 noise realizations were generated by adding Poisson noise to the projections. The mean and standard deviation (SD) of lesion contrast in the differential images were computed using both the conventional subtraction and our joint methods. We also applied both methods to the 35 epileptic patient datasets. Each differential image was presented to two nuclear medicine physicians to localize a lesion and specify a confidence level. The readers' data were analyzed to obtain the localized-response receiver operating characteristic (LROC) curves for both the subtraction and joint methods. RESULTS: For the phantom study, the difference between the mean lesion contrast in the differential images obtained using the conventional subtraction versus our joint method decreases as the iteration number increases. Compared with the conventional subtraction approach, the SD reduction of lesion contrast at the 10th iteration using our joint method ranges from 54.7% to 68.2% (P < 0.0005), and 33.8% to 47.9% (P < 0.05) for 2 and 4 million total inter-ictal counts, respectively. In the patient study, our joint method increases the area under LROC from 0.24 to 0.34 and from 0.15 to 0.20 for the first and second reader, respectively. We have demonstrated improved performance of our method as compared to the standard subtraction method currently used in clinical practice. CONCLUSION: The proposed joint ictal/inter-ictal reconstruction method yields better performance for epileptic foci localization than the conventional subtraction method.

Activation of LILRB2 signal pathway in temporal lobe epilepsy patients and in a pilocarpine induced epilepsy model.

Temporal lobe epilepsy (TLE) is a frequent form of focal intractable epilepsy in adults, but the specific mechanism underlying the epileptogenesis of TLE is still unknown. Human leukocyte immunoglobulin-like receptor B2 (LILRB2) (the murine homolog gene called paired immunoglobulin-like receptor B, or PirB), participates in the process of synaptic plasticity and neurite growth in the central nervous system (CNS), suggesting a potential role of LILRB2 in epilepsy. However, the expression pattern of LILRB2 and the downstream molecular signal in intractable TLE remains poorly understood. In the present study, western blotting and immunohistochemistry results showed that LILRB2 expression was upregulated in the temporal neocortex of patients with TLE. Moreover, protein levels of LILRB2 negatively correlated with the frequency of seizures in TLE patients. In the pilocarpine-induced C57BL/6 mouse model, PirB upregulation in the hippocampus began 12h after status epilepticus (SE), reached a peak at 7days and then maintained a significantly high level until day 60. Similarly, we found a remarkable increase in PirB expression at 1day, 7days and30days post-SE in the temporal cortex. Double-labeled immunofluorescence showed that LILRB2/PirB were highly expressed in neurons and astrocytes but not microglia. In addition, protein levels of POSH, SHROOM3, ROCK1 and ROCK2, the important downstream factors of the LILRB2 pathway, were significantly increased in the epileptic foci of TLE patients and located on the NeuN-positive neurons and GFAP-positive astrocytes. Taken together, our results indicate that LILRB2/PirB may be involved in the process of TLE.

Enhanced slow waves at the periphery of human epileptic foci.

OBJECTIVE: Experimental epilepsy foci are surrounded by an enhanced inhibition zone. We looked for evidence of peripheral inhibition in human epilepsy foci by analyzing the waveforms of discharges. The sharp-wave of an epileptic discharge is thought to reflect EPSP synchronization, and the subsequent slow-wave to reflect inhibition. Ratios of amplitudes of the sharp- and slow-waves in human EEGs may show how excitatory and inhibitory processes relate to discharge spread implicating peripheral inhibition in human epilepsy, too. METHOD: In electrocorticography from 10 adult patients we compared amplitudes of sharp-waves and of slow-waves and their ratios in each electrodes as a function of their distance from the highest sharp-wave electrode. RESULTS: Sharp-wave amplitude decreases as a function of electrode distance from the highest sharp-wave electrode, but the slow-wave voltage exhibits a slight increase. The ratio slow-wave/sharp-wave increases several-fold within 2-3 cm from the highest sharp-wave electrode. CONCLUSION: In human cortex epileptic discharges at the periphery of a focus exhibit a prevalent slow-wave consistent with a possible local enhanced inhibition. SIGNIFICANCE: Waveform analysis of electrocorticography epileptic discharges suggests the presence in human neocortex of surround inhibition, a basic mechanism limiting the spread of epileptic activity, long studied in experimental models.

Localization of epileptic foci in Children with childhood absence epilepsy by magnetoencephalography combined with synthetic aperture magnetometry.

This present study was aimed to investigate the localizable diagnostic value of magnetoencephalography (MEG) combined with synthetic aperture magnetometry (SAM) in childhood absence epilepsy (CAE). Thirteen CAE patients underwent MEG detection at resting state and after hyperventilation, and then the epileptic foci were located by SAM. In the thirteen CAE patients, epileptic foci were found in five cases (38.5%), and they were all located in the bilateral frontal lobe, suggesting that the frontal lobe in some CAE patients may serve as the epileptic foci. Our findings indicate that MEG combined with SAM could be of diagnostic value in localizing the epileptic foci in certain CAE patients.

Exploración de las propiedades psicométricas de la Batería Montreal de Evaluación de Amusia en una muestra de sujetos con epilepsia de lóbulo temporal / Exploration of the psychometric properties of the Montreal Battery of Evaluation of Amusia in a sample with temporal lobe epilepsy

ANTECEDENTES: La Batería Montreal de Evaluación de Amusia (MBEA) es un instrumento de reciente creación, utilizado para evaluar percepción y memoria musical asociadas al funcionamiento de lóbulos temporales. La epilepsia de lóbulo temporal no sintomática (ELTns) es una condición de alta prevalencia en México; esto proporciona una oportunidad para evaluar la MBEA, considerando que las crisis epilépticas pueden producir alteraciones neuropsicológicas específicas según la localización lobular y la lateralización de foco epileptogénico (LFE). OBJETIVO: Explorar las propiedades psicométricas y diagnósticas de la MBEA. MÉTODO: Dos muestras no probabilística de 31 controles y 22 casos de epilepsia ELTns fueron evaluados con la MBEA. Se utilizaron asimismo los datos estandarizados originales de la MBEA para comparación de controles. RESULTADOS: El análisis con prueba t mostró desempeños significativamente menores de los casos en comparación con los controles y significativamente menores entre controles y la norma. No se encontraron diferencias significativas en los puntajes según LFE. El análisis por Curvas ROC mostró propiedades cuestionables de sensibilidad y especificidad en la MBEA utilizando la ELTns como variable de estado. DISCUSIÓN Y CONCLUSIÓN: Se hallaron alteraciones en funciones de percepción musical en los casos; sin embargo, se detectaron inconsistencias teóricas con respecto a la relación de funciones afectadas. Las diferencias entre el grupo control y la norma apuntan a continuar evaluando la MBEA en población mexicana. La MBEA parece ser una medida poco precisa en términos de sensibilidad y especificidad para las alteraciones amúsicas en la ELTns, y su utilidad como medida de apoyo en la determinación de LFE permanece incierta.

BACKGROUND: The Montreal Battery of Evaluation of Amusia (MBEA) is a newly developed instrument to assess music perception and memory, associated to temporal lobe functioning. The non-symptomatic temporal lobe epilepsy is a prevalent condition in Mexico, and it gives an opportunity to test the MBEA, considering the fact that epileptic seizures can cause neuropsychological impairment according to lobar localization and hemispherical lateralization of the epileptogenic foci. OBJECTIVE: To explore the psychometric and diagnostic properties of the MBEA. METHOD: Two non-probabilistic samples of 31 control subjects and 22 cases with non-symptomatic temporal lobe epilepsy were assessed with the MBEA. Data from the original validation were used to compare with the control group. RESULTS: Analysis with t test showed significantly lower performances in the case group relative to controls, and a general lower performance of controls compared to the norm. There was no significant difference in performance between cases with left epileptogenic foci and cases with right epileptogenic foci. ROC curve analysis showed questionable properties of sensitivity and specificity in the MBEA. DISCUSSION AND CONCLUSION: Impairments in music perception were found in cases, although theoretical inconsistences with respect to relation between impaired functions were also detected. The performance of the control group relative to the norm aims to the continuation of the validation process, considering cultural differences. The MBEA seems to be a poor measure in terms of sensibility and specificity for the detection of amusic impairments in subjects with non-symptomatic temporal lobe epilepsy, and its utility for determining hemispheric lateralization of epileptogenic foci remains uncertain.