Focal Cortical Dysplasia Patients Research Articles

Evaluating intraoperative ultrasound (IOUS) in focal cortical dysplasia (FCD) resection surgery: A systematic review.

Surgery is the best approach to treating focal cortical dysplasia (FCD)-related epilepsy; yet, it has suboptimal outcomes because distinguishing the boundaries between the FCD region and normal brain tissue intraoperatively poses a challenge. The use of intraoperative ultrasound (IOUS) helps demarcate FCD lesion borders leading to more accurate intraoperative resection. In this review, the use of IOUS for the resection of FCD was evaluated. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Medline, Embase, Cochrane Library, Scopus Library, and Dynamed Library databases were searched, and two independent reviewers examined the articles. The search terms related to "drug-resistant epilepsy" and "intraoperative ultrasound." The results between January 2008 and April 2022 were abridged for FCD type, ultrasound resolution, extent of lesion resection, correction of brain shift, postoperative neurological deficits, and postoperative seizure freedom (Engel classification). Ten articles were included in the study. The parameters used to assess the efficacy of IOUS in FCD surgery were ultrasound resolution, demarcation of lesion boundaries, correction of brain shift, postoperative neurological deficits, and seizure freedom. Most studies have shown that IOUS produces high-resolution images. Surgery for Type 2 FCD patients had better outcomes than surgery for Type 1 FCD patients due to better visualization by IOUS. Patients were classified as Engel class 1 or class 2 postoperatively. Eight studies found that IOUS was superior to magnetic resonance imaging in brain shift correction. The preliminary results look promising, especially for the international league against epilepsy class 2 FCD. However, there is a need for more high-quality research evaluating the use of IOUS in FCD and comparing it to other intraoperative imaging modalities.

Hypometabolic patterns are related to post-surgical seizure outcomes in focal cortical dysplasia: A semi-quantitative study.

Fluorine-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) is routinely used for presurgical evaluation in many epilepsy centers. Hypometabolic characteristics have been extensively examined in prior studies, but the metabolic patterns associated with specific pathological types of drug-resistant epilepsy remain to be fully defined. This study was developed to explore the relationship between metabolic patterns or characteristics and surgical outcomes in type I and II focal cortical dysplasia (FCD) patients based on results from a large cohort. Data from individuals who underwent epilepsy surgery from 2014 to 2019 with a follow-up duration of over 3 years and a pathological classification of type I or II FCD in our hospital were retrospectively analyzed. Hypometabolic patterns were quantitatively identified via statistical parametric mapping (SPM) and qualitatively analyzed via visual examination of PET-MRI co-registration images. Univariate analyses were used to explore the relationship between metabolic patterns and surgical outcomes. In total, this study included data from 210 patients. Following SPM calculations, four hypometabolic patterns were defined including unilobar, multi-lobar, and remote patterns as well as cases where no pattern was evident. In type II FCD patients, the unilobar pattern was associated with the best surgical outcomes (p = 0.014). In visual analysis, single gyrus (p = 0.032) and Clear-cut hypometabolism edge (p = 0.040) patterns exhibited better surgery outcomes in the type II FCD group. PET metabolic patterns are well-correlated with the prognosis of type II FCD patients. However, similar correlations were not observed in type I FCD, potentially owing to the complex distribution of the epileptogenic region. In this study, we demonstrated that FDG-PET was a crucial examination for patients with FCD, which was a common cause of epilepsy. We compared the surgical prognosis for patients with different hypometabolism distribution patterns and found that clear and focal abnormal region in PET was correlated with good surgical outcome in type II FCD patients.

Cortical surface analysis for focal cortical dysplasia diagnosis by using PET images

Focal cortical dysplasia (FCD) is a neurological disorder distinguished by faulty brain cell structure and development. Repetitive and uncontrollable seizures may be linked to FCD's aberrant cortical thickness, gyrification, and sulcal depth. Quantitative cortical surface analysis is a crucial alternative to ineffective visual inspection. This study recruited 42 subjects including 22 FCD patients who underwent surgery and 20 healthy controls (HC). For the FCD patients, T1-weighted and PET images were obtained by a PET-MRI scanner, and the confirmed epileptogenic zone (EZ) was collected from postsurgical follow-up. For the HCs, CT and PET images were obtained by a PET-CT scanner. Cortical thickness, gyrification index, and sulcal depth were calculated using a computational anatomical toolbox (CAT12). A cluster-based analysis is carried out to determine each FCD patient's aberrant cortical surface. After parcellating the cerebral cortex into 68 regions by the Desikan-Killiany atlas, a region of interest (ROI) analysis was conducted to know whether the feature in the FCD group is significantly different from that in the HC group. Finally, the features of all ROIs were utilised to train a support vector machine classifier (SVM). The classification performance is evaluated by the leave-one-out cross-validation. The cluster-based analysis can localize the EZ cluster with the highest accuracy of 54.5 % (12/22) for cortical thickness, 40.9 % (9/22) and 13.6 % (3/22) for sulcal depth and gyrification, respectively. Moderate concordance (Kappa, 0.6) is observed between the confirmed EZs and identified clusters by using the cortical thickness. Fair concordance (Kappa, 0.3) and no concordance (Kappa, 0.1) is found by using sulcal depth and gyrification. Significant differences are found in 46 of 68 regions (67.7 %) for the three measures. The trained SVM classifier achieved a prediction accuracy of 95.5 % for the cortical thickness, while the sulcal depth and the gyrification obtained 86.0 % and 81.5 %. Cortical thickness, as determined by quantitative cortical surface analysis of PET data, has a greater ability than sulcal depth and gyrification to locate aberrant EZ clusters in FCD. Surface measures might be different in many regions for FCD and HC. By integrating machine learning and cortical morphologies features, individual prediction of FCD seems to be feasible.

Expression profiles of α-synuclein in cortical lesions of patients with FCD IIb and TSC, and FCD rats.

Focal cortical dysplasia (FCD) IIb and tuberous sclerosis complex (TSC) are common causes of drug-resistant epilepsy in children. However, the etiologies related to the development of FCD IIb and TSC are not fully understood. α-synuclein (α-syn) is a member of synucleins family that plays crucial roles in modulating synaptic transmission in central nervous system. Here, we explored the expression profiles and potential pathogenic functions of α-syn in cortical lesions of epileptic patients with FCD IIb and TSC. Surgical specimens from epileptic patients with FCD IIb and TSC, as well as FCD rats generated by in utero X-ray-radiation were adopted in this study and studied with immunohistochemistry, immunofluorescence, western blotting, and co-immunoprecipitation etc. molecular biological techniques. Our results showed that α-syn expression was reduced in FCD IIb and TSC lesions. Specifically, α-syn protein was intensely expressed in dysplastic neurons (DNs) and balloon cells (BCs) in FCD IIb lesions, whereas was barely detected in DNs and giant cells (GCs) of TSC lesions. Additionally, p-α-syn, the aggregated form of α-syn, was detected in DNs, BCs, GCs, and glia-like cells of FCD IIb and TSC lesions. We previous showed that the function of N-methyl-D-aspartate receptor (NMDAR) was enhanced in FCD rats generated by X-ray-radiation. Here, we found the interaction between α-syn and NMDAR subunits NMDAR2A, NMDAR2B were augmented in cortical lesions of FCD patients and FCD rats. These results suggested a potential role of α-syn in the pathogenesis of FCD IIb and TSC by interfering with NMDAR.

Limbic network co-localization predicts pharmacoresistance in dysplasia-related epilepsy.

To evaluate the role of focal cortical dysplasia co-localization to cortical functional networks in the development of pharmacoresistance. One hundred thirty-six focal cortical dysplasia patients with 3.0 T or 1.5 T MRI were identified from clinical databases at Children's National Hospital. Clinico-radio-pathologic factors and network co-localization were determined. Using binomial logistic regression, limbic network co-localization (odds ratio 4.164 95% confidence interval 1.02-17.08, p = 0.048), and focal to bilateral tonic-clonic seizures (4.82, 1.30-18.03, p = 0.019) predicted pharmacoresistance. These findings provide clinicians with markers to identify patients with focal cortical dysplasia-related epilepsy at high risk of developing pharmacoresistance and should facilitate earlier epilepsy surgical evaluation.

Clinical and anatomical analysis of the epileptogenic spread patterns in focal cortical dysplasia patients.

Focal cortical dysplasia (FCD) is one of the main causes of intractable epilepsy, which is amendable by surgery. During the surgical management of FCD, the understanding of its epileptogenic foci, interconnections, and spreading pathways is crucial for attaining a good postoperative seizure free outcome. We retrospectively evaluated 54 FCD patients operated in Federal Center of Neurosurgery, Tyumen, Russia. The electroencephalogram findings were correlated to the involved brain anatomical areas. Subsequently, we analyzed the main white matter tracts implicated during the epileptogenic spreading in some representative cases. We prepared 10 human hemispheres using Klinger's method and dissected them through the fiber dissection technique. The clinical results were displayed and the main white matter tracts implicated in the seizure spread were described in 10 patients. Respective FCD foci, interconnections, and ectopic epileptogenic areas in each patient were discussed. A strong understanding of the main implicated tracts in epileptogenic spread in FCD patient remains cardinal for neurosurgeons dealing with epilepsy. To achieve meaningful seizure freedom, despite the focal lesion resection, the interconnections and tracts should be understood and somehow disconnected to stop the spreading.

An Assessment of the Pathological Classification and Postoperative Outcome of Focal Cortical Dysplasia by Simultaneous Hybrid PET/MRI

The purpose of this research was to investigate whether MRI and Simultaneous Hybrid PET/MRI images were consistent in the histological classification of patients with focal cortical dysplasia. Additionally, this research aimed to evaluate the postoperative outcomes with the MRI and Simultaneous Hybrid PET/MRI images of focal cortical dysplasia. A total of 69 cases in this research were evaluated preoperatively for drug-resistant seizures, and then surgical resection procedures of the epileptogenic foci were performed. The postoperative result was histopathologically confirmed as focal cortical dysplasia, and patients then underwent PET and MRI imaging within one month of the seizure. In this study, head MRI was performed using a 3.0 T magnetic resonance scanner (Philips) to obtain 3D T1WI images. The Siemens Biograph 16 scanner was used for a routine scanning of the head to obtain PET images. BrainLAB's iPlan software was used to fuse 3D T1 images with PET images to obtain PET/MRI images. Focal cortical dysplasia was divided into three types according to ILAE: three patients were classified as type I, twenty-five patients as type II, and forty-one patients as type III. Patients age of onset under 18 and age of operation over 18 had a longer duration (p = 0.036, p = 0.021). MRI had a high lesion detection sensitivity of type III focal cortical dysplasia (p = 0.003). Simultaneous Hybrid PET/MRI showed high sensitivity in detecting type II and III focal cortical dysplasia lesions (p = 0.037). The lesions in Simultaneous Hybrid PET/MRI-positive focal cortical dysplasia patients were mostly located in the temporal and multilobar (p = 0.005, 0.040). Simultaneous Hybrid PET/MRI has a high accuracy in detecting the classification of focal cortical dysplasia. The results of this study indicate that patients with focal cortical dysplasia with positive Simultaneous Hybrid PET/MRI have better postoperative prognoses.

Application of data harmonization and tract-based spatial statistics reveals white matter structural abnormalities in pediatric patients with focal cortical dysplasia

Our study assessed diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) in pediatric subjects with epilepsy secondary to Focal Cortical Dysplasia (FCD) to improve our understanding of structural network changes associated with FCD related epilepsy. We utilized a data harmonization (DH) approach to minimize confounding effects induced by MRI protocol differences. We also assessed correlations between DTI metrics and neurocognitive measures of the fluid reasoning index (FRI), verbal comprehension index (VCI), and visuospatial index (VSI). Data (n = 51) from 23 FCD patients and 28 typically developing controls (TD) scanned clinically on either 1.5T, 3T, or 3T-wide-bore MRI were retrospectively analyzed. Tract-based spatial statistics (TBSS) with threshold-free cluster enhancement and permutation testing with 100,000 permutations were used for statistical analysis. To account for imaging protocol differences, we employed non-parametric data harmonization prior to permutation testing. Our analysis demonstrates that DH effectively removed MRI protocol-based differences typical in clinical acquisitions while preserving group differences in DTI metrics between FCD and TD subjects. Furthermore, DH strengthened the association between DTI metrics and neurocognitive indices. Fractional anisotropy, MD, and RD metrics showed stronger correlation with FRI and VSI than VCI. Our results demonstrate that DH is an integral step to reduce the confounding effect of MRI protocol differences during the analysis of white matter tracts and highlights biological differences between FCD and healthy control subjects. Characterization of white matter changes associated with FCD-related epilepsy may better inform prognosis and treatment approaches.

Endoplasmic reticulum stress and unfolded protein accumulation correlate to seizure recurrence in focal cortical dysplasia patients.

Epileptic seizures occur due to an imbalance between excitatory and inhibitory neurosignals. The excitotoxic insults promote the accumulation of reactive oxygen species (ROS), unfolded proteins (UFP) aggregation, and sometimes even cell death. The epileptic brain samples in our study showed significant changes in the quantity of UFP accumulation. This part explored the efficiency of ER stress and autophagy responses at neutralizing the UFP using resected epileptic brain tissue samples. Meanwhile, we regularly observed these patients' post-surgical clinical data to find the recurrence of seizures. According to International League against Epilepsy (ILAE) suggestions, we classified the patients (n = 26) as class 1 (completely seizure-free), class 2 (less frequent seizures or auras), and class 3 (auras with < 3 seizures per year). The classification helped us understand the reason for variations in the UFP accumulation in patient samples. We have observed the protein levels of ER chaperone, glucose-regulated protein 78kDa (GRP78/BiP), inositol-requiring enzyme 1α (IRE1α), X box-binding protein 1s (XBP1s), eukaryotic translation initiation factor 2α (peIF2α), C/EBP homologous protein (CHOP), NADPH oxidase (NOX2), and autophagy proteins like BECLIN1, ATG 7, 12, 5, 16, p62, and LC3. Our results suggested that ER stress response limitation may contribute to seizure recurrence in epilepsy patients, particularly in classes 2 and 3. In addition, we have observed significant upregulation of ER stress-dependent apoptosis initiation factor CHOP in these patients. These results indicate that understanding the ER stress response pattern infers the possibility of post-surgical outcomes in focal cortical dysplasia (FCD) patients.

Superficial and deep white matter diffusion abnormalities in focal epilepsies.

This study was undertaken to evaluate superficial-white matter (WM) and deep-WM magnetic resonance imaging diffusion tensor imaging (DTI) metrics and identify distinctive patterns of microstructural abnormalities in focal epilepsies of diverse etiology, localization, and response to antiseizure medication (ASM). We examined DTI data for 113 healthy controls and 113 patients with focal epilepsies: 51 patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) refractory to ASM, 27 with pharmacoresponsive TLE-HS, 15 with temporal lobe focal cortical dysplasia (FCD), and 20 with frontal lobe FCD. To assess WM microstructure, we used a multicontrast multiatlas parcellation of DTI. We evaluated fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), and assessed within-group differences ipsilateral and contralateral to the epileptogenic lesion, as well as between-group differences, in regions of interest (ROIs). The TLE-HS groups presented more widespread superficial- and deep-WM diffusion abnormalities than both FCD groups. Concerning superficial WM, TLE-HS groups showed multilobar ipsilateral and contralateral abnormalities, with less extensive distribution in pharmacoresponsive patients. Both the refractory TLE-HS and pharmacoresponsive TLE-HS groups also presented pronounced changes in ipsilateral frontotemporal ROIs (decreased FA and increased MD, RD, and AD). Conversely, FCD patients showed diffusion changes almost exclusively adjacent to epileptogenic areas. Our findings add further evidence of widespread abnormalities in WM diffusion metrics in patients with TLE-HS compared to other focal epilepsies. Notably, superficial-WM microstructural damage in patients with FCD is more restricted around the epileptogenic lesion, whereas TLE-HS groups showed diffuse WM damage with ipsilateral frontotemporal predominance. These findings suggest the potential of superficial-WM analysis for better understanding the biological mechanisms of focal epilepsies, and identifying dysfunctional networks and their relationship with the clinical-pathological phenotype. In addition, lobar superficial-WM abnormalities may aid in the diagnosis of subtle FCDs.

Sage Against the Machine: Promise and Challenge of Artificial Intelligence in Epilepsy.

Multicenter Validation of a Deep Learning Detection Algorithm for Focal Cortical Dysplasia Gill RS, Lee HM, Caldairou B, et al. Neurology. 2021 Oct 19;97(16):e1571-e1582. doi:10.1212/WNL.0000000000012698. Epub 2021 Sep 14. PMID: 34521691; PMCID: PMC8548962.Background and Objective:To test the hypothesis that a multicenter-validated computer deep learning algorithm detects MRI-negative focal cortical dysplasia (FCD).Methods:We used clinically acquired 3-dimensional (3D) T1-weighted and 3D fluid-attenuated inversion recovery MRI of 148 patients (median age 23 years [range 2-55 years]; 47% female) with histologically verified FCD at 9 centers to train a deep convolutional neural network (CNN) classifier. Images were initially deemed MRI-negative in 51% of patients, in whom intracranial EEG determined the focus. For risk stratification, the CNN incorporated bayesian uncertainty estimation as a measure of confidence. To evaluate performance, detection maps were compared to expert FCD manual labels. Sensitivity was tested in an independent cohort of 23 cases with FCD (13 ± 10 years). Applying the algorithm to 42 healthy controls and 89 controls with temporal lobe epilepsy disease tested specificity.Results:Overall sensitivity was 93% (137 of 148 FCD detected) using a leave-one-site-out cross-validation, with an average of 6 false positives per patient. Sensitivity in MRI-negative FCD was 85%. In 73% of patients, the FCD was among the clusters with the highest confidence; in half, it ranked the highest. Sensitivity in the independent cohort was 83% (19 of 23; average of 5 false positives per patient). Specificity was 89% in healthy and disease controls.Discussion:This first multicenter-validated deep learning detection algorithm yields the highest sensitivity to date in MRI-negative FCD. By pairing predictions with risk stratification, this classifier may assist clinicians in adjusting hypotheses relative to other tests, increasing diagnostic confidence. Moreover, generalizability across age and MRI hardware makes this approach ideal for presurgical evaluation of MRI-negative epilepsy. Classification of evidence: This study provides Class III evidence that deep learning on multimodal MRI accurately identifies FCD in patients with epilepsy initially diagnosed as MRI negative.

499 Seizures in a Dish: Demonstrating and Analyzing Coordinated Network Activity in Human and Mouse Brain Slice with Calcium Imaging

INTRODUCTION: Childhood epilepsy is a common and often devastating disease, and chronic seizures lead to a significant increase in premature mortality and developmental delay. Focal cortical dysplasia (FCD), a malformation of cortical development, is the primary cause of pharmacoresistant epilepsy in children undergoing resective surgery. There are no targeted medical or surgical therapies for FCD patients who have failed surgery or who are not surgical candidates. METHODS: Human tissue from patients with MCDs was resected during epilepsy surgery. Comparison tissue from CD1 mouse brains was also used. 400-µm brain slices were made with a vibratome. The slices were then incubated the slices in Fluo-8L, a low-affinity calcium-sensitive indicator for 40-180 minutes. Slices were imaged using an sCMOS imager at 15 fps on an upright microscope and standard patch-clamp rig with a custom-built temperature-controlled chamber with high aCSF flow rate (5-15mL per minute) to optimize tissue oxygenation. Network bursts are induced with a pro-ictal ACSF containing high potassium (8 mM) and 4-aminopyridine (100 micromolar). RESULTS: We developed a workflow for calcium imaging in human tissue as follows. Preliminary semi-manual analysis on each image stack was performed using ImageJ. Image stacks were motion corrected using the NoRMCorre algorithm and then processed using the calcium imaging analysis workflow (CaImAn) appropriate for 1-photon imaging. Hundreds of cells can be analyzed simultaneously. Ictal network activity may be induced with the pro-ictal ACSF, or with gabazine (1 mM, a GABA-A receptor antagonist, data not shown). CONCLUSION: We have demonstrated the feasibility of performing ex vivo calcium imaging to directly study the aberrant epileptic networks in human MCD tissue resected from children with intractable epilepsy. In future work, we will use this novel technique to uncover network anomalies underlying the epileptic networks in this disorder.

Hippocampal Malrotation Could Be Less Significant in Epilepsy Caused by Focal Cortical Dysplasia Type I and Type II.

ObjectivesDebates over the relationship between hippocampal malrotation (HIMAL) and epilepsy continue without consensus. This study explores the role of HIMAL in a cohort of epilepsy caused by focal cortical dysplasia (FCD).MethodsIn this study, 90 patients with epilepsy caused by FCD type I and type II and 48 healthy adults underwent a 3 Tesla MRI following a dedicated epilepsy protocol for the analysis of the prevalence and morphologic features of HIMAL. In addition, numerous clinical characteristics and hippocampal volumes were evaluated.ResultsThe cohort included a total of 90 patients (32 were HIMAL, 58 were non-HIMAL). Among these patients, 32 (35.6%) had HIMAL (22 left, four right, and six bilateral), which did not differ from the 48 controls, where 16 (33.3%) had HIMAL (12 left, two right, and two bilateral). Neither the quantitative features of HIMAL (diameter ratio, dominant inferior temporal sulcus height ratio, medial distance ratio, dominant inferior temporal sulcus angle, and parahippocampal angle), nor the accompanying characteristics of HIMAL (vertical dominant inferior temporal sulcus, enlarged temporal horn, and a low position of ipsilateral fornix) showed differences between patients with FCD and controls. No statistical difference in the clinical characteristics between FCD patients with HIMAL and those without was found. Neither the side nor the existence of HIMAL was correlated with the lateralization and location of FCD. As to the hippocampal volume, there was no difference between FCD patients with HIMAL and those without.ConclusionHippocampal malrotation is a common morphologic variant in healthy controls as well as in patients with epilepsy caused by FCD type I and type II. Hippocampal malrotation could be less significant in epilepsy caused by FCD type I and type II.

Mechanistic Analysis of Micro-Neurocircuits Underlying the Epileptogenic Zone in Focal Cortical Dysplasia Patients.

We aim to explore the microscopic neurophysiology of focal cortical dysplasia (FCD) induced epileptogenesis in specific macroscopic brain regions, therefore mapping a micro-macro neuronal network that potentially indicates the epileptogenic mechanism. Epileptic and relatively non-epileptic temporal neocortex specimens were resected from FCD and mesial temporal lobe epilepsy (mTLE) patients, respectively. Whole-cell patch-clamping was performed on cells from the seizure onset zone (SOZ) and non-SOZ inside the epileptogenic zone (EZ) of FCD patients, as well as the non-epileptic neocortex of mTLE patients. Microscopic data were recorded, including membrane characteristics, spontaneous synaptic activities, and evoked action potentials. Immunohistochemistry was also performed on parvalbumin-positive (PV+) interneurons. We found that SOZ interneurons exhibited abnormal neuronal expression and distribution as well as reduced overall function compared with non-SOZ and mTLE interneurons. The SOZ pyramidal cells experienced higher excitation but lower inhibition than the mTLE controls, whereas the non-SOZ pyramidal cells exhibited intermediate excitability. Action potential properties of both types of neurons also suggested more synchronized neuronal activity inside the EZ, particularly inside the SOZ. Together, our research provides evidence for a potential neurocircuit underlying SOZ epileptogenesis and non-SOZ seizure susceptibility. Further investigation of this microscopic network may promote understanding of the mechanism of FCD-induced epileptogenesis.

Mass spectrometry-based lipidomic analysis reveals altered lipid profile in brain tissues resected from patients with focal cortical dysplasia (FCD)

Focal cortical dysplasia (FCD) is a common pathology responsible for drug-resistant epilepsy (DRE). Failure to precisely localize the epileptogenic zones (EZs) is a major reason for poor surgical outcome in FCD. Currently, there are no molecular or cellular biomarkers available which can aid in defining the EZs in FCD. Phospholipid alterations between healthy and malignant tumor tissues are reported and have been used for marking tumor margins. In this study, we utilize liquid chromatography and tandem mass spectrometry to identify altered lipids in resected brain specimens from FCD patients compared to non-epileptic controls. Based on these results, we propose that a similar approach utilizing unique lipid mass spectra can be used for defining the EZs in FCD. The observed distinct lipid mass spectra of cortical tissues from FCD patients could be used for real-time guidance during surgery as well as for ex vivo examination of resected tissues for diagnostic purposes.

Effective connectivity differs between focal cortical dysplasia types I and II.

To determine whether brain connectivity differs between focal cortical dysplasia (FCD) types I and II. We compared cortico-cortical evoked potentials (CCEPs) as measures of effective brain connectivity in 25 FCD patients with drug-resistant focal epilepsy who underwent intracranial evaluation with stereo-electroencephalography (SEEG). We analyzed the amplitude and latency of CCEP responses following ictal-onset single-pulse electrical stimulation (iSPES). In comparison to FCD type II, patients with type I demonstrated significantly larger responses in the electrodes near the ictal-onset zone (<50mm). These findings persisted when controlling for the location of the epileptogenic zone, as noted in patients with temporal lobe epilepsies, as well as controlling for seizure type, as noted in patients with focal to bilateral tonic-clonic seizures (FBTCS). In type II, the root mean square (RMS) of CCEP responses dropped substantially from the early segment (10-60ms) to the middle and late segments (60-600ms). The middle and late CCEP latency segments showed the largest differences between FCD types I and II. Focal cortical dysplasia type I may have a greater degree of cortical hyperexcitability as compared with FCD type II. In addition, FCD type II displays a more restrictive area of hyperexcitability in both temporal and spatial domains. In patients with FBTCS and type I FCD, the increased amplitudes of RMS in the middle and late CCEP periods appear consistent with the cortico-thalamo-cortical network involvement of FBTCS. The notable differences in degree and extent of hyperexcitability may contribute to the different postsurgical seizure outcomes noted between these two pathological substrates.

Multicenter Validation of a Deep Learning Detection Algorithm for Focal Cortical Dysplasia.

To test the hypothesis that a multicenter-validated computer deep learning algorithm detects MRI-negative focal cortical dysplasia (FCD). We used clinically acquired 3-dimensional (3D) T1-weighted and 3D fluid-attenuated inversion recovery MRI of 148 patients (median age 23 years [range 2-55 years]; 47% female) with histologically verified FCD at 9 centers to train a deep convolutional neural network (CNN) classifier. Images were initially deemed MRI-negative in 51% of patients, in whom intracranial EEG determined the focus. For risk stratification, the CNN incorporated bayesian uncertainty estimation as a measure of confidence. To evaluate performance, detection maps were compared to expert FCD manual labels. Sensitivity was tested in an independent cohort of 23 cases with FCD (13 ± 10 years). Applying the algorithm to 42 healthy controls and 89 controls with temporal lobe epilepsy disease tested specificity. Overall sensitivity was 93% (137 of 148 FCD detected) using a leave-one-site-out cross-validation, with an average of 6 false positives per patient. Sensitivity in MRI-negative FCD was 85%. In 73% of patients, the FCD was among the clusters with the highest confidence; in half, it ranked the highest. Sensitivity in the independent cohort was 83% (19 of 23; average of 5 false positives per patient). Specificity was 89% in healthy and disease controls. This first multicenter-validated deep learning detection algorithm yields the highest sensitivity to date in MRI-negative FCD. By pairing predictions with risk stratification, this classifier may assist clinicians in adjusting hypotheses relative to other tests, increasing diagnostic confidence. Moreover, generalizability across age and MRI hardware makes this approach ideal for presurgical evaluation of MRI-negative epilepsy. This study provides Class III evidence that deep learning on multimodal MRI accurately identifies FCD in patients with epilepsy initially diagnosed as MRI negative.

Increased levels of α4-containing GABAA receptors in focal cortical dysplasia: A possible cause of benzodiazepine resistance

Benzodiazepines are the first choice of anti-epileptic drugs used to treat seizures. However, it has been seen that their efficacy decreases with time leading to drug insensitivity, plausibly caused by an alteration in the expression of the benzodiazepine biding site on GABAA receptors. This study was designed to investigate if the differential expression of GABAA receptor subunits α1/α4/γ2/δ across the postsynaptic sites could contribute to benzodiazepine resistance in patients with focal cortical dysplasia (FCD), the most common cause of drug resistant epilepsy in pediatric population. Differential gene and cellular expression of GABAA receptor subunits α1, α4, γ2 and δ were evaluated and validated using qPCR and immunohistochemistry. Whole cell patch clamp studies were performed on pyramidal neurons of resected cortical FCD samples to measure the spontaneous GABAA receptor activity. Upregulation of α4-and γ2-subunits containing GABAA receptors were observed at both mRNA and protein level. α1-and δ-subunits containing GABAA receptors did not show any significant changes. Flumazenil treatment did not affect the kinetics of GABAergic events in FCD; however, it significantly reduced the frequency and amplitude of spontaneous GABAergic activity in non-seizure control samples. Our results demonstrate the enhanced expression of α4-containing GABAA receptors and GABAergic activity in pyramidal neurons which in turn may contribute to benzodiazepine resistance in FCD patients.

Detrended fluctuation analysis in the presurgical evaluation of parietal lobe epilepsy patients

ObjectiveTo examine the usability of long-range temporal correlations (LRTCs) in non-invasive localization of the epileptogenic zone (EZ) in refractory parietal lobe epilepsy (RPLE) patients. MethodsWe analyzed 10 RPLE patients who had presurgical MEG and underwent epilepsy surgery. We quantified LRTCs with detrended fluctuation analysis (DFA) at four frequency bands for 200 cortical regions estimated using individual source models. We correlated individually the DFA maps to the distance from the resection area and from cortical locations of interictal epileptiform discharges (IEDs). Additionally, three clinical experts inspected the DFA maps to visually assess the most likely EZ locations. ResultsThe DFA maps correlated with the distance to resection area in patients with type II focal cortical dysplasia (FCD) (p<0.05), but not in other etiologies. Similarly, the DFA maps correlated with the IED locations only in the FCD II patients. Visual analysis of the DFA maps showed high interobserver agreement and accuracy in FCD patients in assigning the affected hemisphere and lobe. ConclusionsAberrant LRTCs correlate with the resection areas and IED locations. SignificanceThis methodological pilot study demonstrates the feasibility of approximating cortical LRTCs from MEG that may aid in the EZ localization and provide new non-invasive insight into the presurgical evaluation of epilepsy.

Crossed cerebellar diaschisis: risk factors and prognostic value in focal cortical dysplasia by 18F-FDG PET/CT.

Crossed cerebellar diaschisis (CCD) has been widely studied in hemispheric stroke but is less characterized in epilepsy. In this study, we used 18F-FDG PET/CT to investigate the risk factors for CCD and its prognostic value for intractable epilepsy caused by focal cortical dysplasia (FCD). One hundred medically intractable epilepsy patients pathologically diagnosed with FCD postoperatively were included and classified into two groups: CCD+ and CCD-. PET/CT images were analyzed qualitatively by visual assessment and semi-quantitatively using the absolute asymmetry index (|AI|). Clinical factors, including age, sex, body mass index (BMI), age at seizure onset, epilepsy duration, seizure type, seizure frequency, electroencephalography (EEG) and brain magnetic resonance imaging (MRI), were retrospectively assessed from medical records. Follow-up outcomes were evaluated according to the Engel classification at 3, 6, 12, 24 and 36months postoperatively. Of the 100 patients, 77 (77.0%) were classified as CCD-, and 23 (23.0%) were classified as CCD + . CCD+ patients had a higher number of lobes involved on PET (3.61 ± 2.16 vs 2.26 ± 1.01, P < 0.001) than CCD- patients. CCD- patients showed more negative MRI results than CCD + patients (P = 0.02). At 12months postoperatively, 70.7% (29/41) of CCD- patients and 30.8% (4/13) of CCD + patients presented a favourable prognosis (P = 0.02). Significant differences in the average |AI| values in the posterior frontal and anterior temporal lobes were found between CCD+ and CCD- patients (P < 0.05). The number of lobes involved on PET, structural anomalies on MRI, the |AI| values in the posterior frontal and anterior temporal lobes may be predisposing factors for CCD. CCD occurrence may help predict the prognosis of FCD patients at 12months postoperatively.