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Background and purposeMR imaging studies and neuropathologic findings in individuals with 22q11.2 deletion syndrome show anomalous early brain development. We aimed to retrospectively evaluate cerebral abnormalities, focusing on gray matter heterotopia, and to correlate these with subjects' neuropsychiatric impairments.Materials and methodsThree raters assessed gray matter heterotopia and other morphologic brain abnormalities on 3D T1WI and T2*WI in 75 individuals with 22q11.2 deletion syndrome (27 females, 15.5 [SD, 7.4] years of age) and 53 controls (24 females, 12.6 [SD, 4.7] years of age). We examined the association among the groups' most frequent morphologic findings, general cognitive performance, and comorbid neuropsychiatric conditions.ResultsHeterotopia in the white matter were the most frequent finding in individuals with 22q11.2 deletion syndrome (n = 29; controls, n = 0; between-group difference, P < .001), followed by cavum septi pellucidi and/or vergae (n = 20; controls, n = 0; P < .001), periventricular cysts (n = 10; controls, n = 0; P = .007), periventricular nodular heterotopia (n = 10; controls, n = 0; P = .007), and polymicrogyria (n = 3; controls, n = 0; P = .3). However, individuals with these morphologic brain abnormalities did not differ significantly from those without them in terms of general cognitive functioning and psychiatric comorbidities.ConclusionsTaken together, our findings, periventricular nodular heterotopia or heterotopia in the white matter (possibly related to interrupted Arc cells migration), persistent cavum septi pellucidi and/or vergae, and formation of periventricular cysts, give clues to the brain development disorder induced by the 22q11.2 deletion syndrome. There was no evidence that these morphologic findings were associated with differences in psychiatric or cognitive presentation of the 22q11.2 deletion syndrome.

Introducción: Tanto en México como en el mundo, más de tres cuartas partes de los insumos que se usan en la producción de electricidad provienen de fuentes no renovables, en una realidad donde los techos de las edificaciones son responsables de un consumo importante de electricidad por aire acondicionado. Por lo anterior, el objetivo fue evaluar el aspecto térmico y la eficiencia en el consumo de electricidad de dos aires acondicionados colocados, bajo el Techo de concreto reforzado y el Techo verde, y a la vez utilizar a la geometría analítica como herramienta de análisis en el consumo de electricidad. Método: Aunque inicialmente la metodología de la climatología dinámica, fue desarrollada para el análisis térmico, en este trabajo se retomó para aplicarlo al consumo eléctrico y conjuntándolo con el apoyo de la geometría analítica, a través de ecuaciones de recta que representan promedios anuales, se evidenció las diferencias en el consumo. Resultados: Los resultados obtenidos demuestran que el Techo verde amortigua mejor las temperaturas exteriores, reduce la oscilación térmica y; en el consumo eléctrico, con una diferencia promedio anual de un 28%, el Techo Verde consumió menos energía eléctrica por aire acondicionado. Discusión o conclusión: Se demuestra que conviene el uso de techos verdes en el sitio de estudio y posibilita su aplicación en otros contextos. El trabajo se realizó en periodos de temperaturas extremas opuestas, invierno de 2014 y primavera de 2015.

Objective: To assess whether arterial spin labeling perfusion images of healthy controls can enhance ictal single-photon emission computed tomography analysis and whether the acquisition of the interictal image can be omitted., Methods: We developed 2 pipelines: The first uses ictal and interictal images and compares these to single-photon emission computed tomography and arterial spin labeling of healthy controls. The second pipeline uses only the ictal image and the analogous healthy controls. Both pipelines were compared to the gold standard analysis and evaluated on data of individuals with epilepsy who underwent ictal single-photon emission computed tomography imaging during presurgical evaluation between 2010 and 2022. Fifty healthy controls prospectively underwent arterial spin labeling imaging. The correspondence between the detected hyperperfusion and the postoperative resection cavity or the presumably affected lobe was assessed using Dice score and mean Euclidean distance. Additionally, the outcomes of the pipelines were automatically assigned to 1 of 5 concordance categories., Results: Inclusion criteria were met by 43 individuals who underwent epilepsy surgery and by 73 non-surgical individuals with epilepsy. Compared to the gold standard analysis, both pipelines resulted in significantly higher Dice scores and lower mean distances (p < 0.05). The combination of both provided localizing results in 85/116 cases, compared to 54/116 generated by the current gold standard analysis and the ictal image alone produced localizing results in 60/116 (52%) cases., Interpretation: We propose a new ictal single-photon emission computed tomography protocol; it finds relevantly more ictal hyperperfusion, and halves the radiation dose in about half of the individuals. ANN NEUROL 2024;96:1160-1173., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Hippocampal sclerosis (HS), the most common pathology associated with temporal lobe epilepsy (TLE), is not always visible on magnetic resonance imaging (MRI), causing surgical delays and reduced postsurgical seizure-freedom. We developed an open-source software to characterize and localize HS to aid the presurgical evaluation of children and adults with suspected TLE., Methods: We included a multicenter cohort of 365 participants (154 HS; 90 disease controls; 121 healthy controls). HippUnfold was used to extract morphological surface-based features and volumes of the hippocampus from T1-weighted MRI scans. We characterized pathological hippocampi in patients by comparing them to normative growth charts and analyzing within-subject feature asymmetries. Feature asymmetry scores were used to train a logistic regression classifier to detect and lateralize HS. The classifier was validated on an independent multicenter cohort of 275 patients with HS and 161 healthy and disease controls., Results: HS was characterized by decreased volume, thickness, and gyrification alongside increased mean and intrinsic curvature. The classifier detected 90.1% of unilateral HS patients and lateralized lesions in 97.4%. In patients with MRI-negative histopathologically-confirmed HS, the classifier detected 79.2% (19/24) and lateralized 91.7% (22/24). The model achieved similar performances on the independent cohort, demonstrating its ability to generalize to new data. Individual patient reports contextualize a patient's hippocampal features in relation to normative growth trajectories, visualise feature asymmetries, and report classifier predictions., Interpretation: Automated and Interpretable Detection of Hippocampal Sclerosis (AID-HS) is an open-source pipeline for detecting and lateralizing HS and outputting clinically-relevant reports. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: Artificial intelligence (AI) is thought to improve lesion detection. However, a lack of knowledge about human performance prevents a comparative evaluation of AI and an accurate assessment of its impact on clinical decision-making. The objective of this work is to quantitatively evaluate the ability of humans to detect focal cortical dysplasia (FCD), compare it to state-of-the-art AI, and determine how it may aid diagnostics., Materials and Methods: We prospectively recorded the performance of readers in detecting FCDs using single points and 3-dimensional bounding boxes. We acquired predictions of 3 AI models for the same dataset and compared these to readers. Finally, we analyzed pairwise combinations of readers and models., Results: Twenty-eight readers, including 20 nonexpert and 5 expert physicians, reviewed 180 cases: 146 subjects with FCD (median age: 25, interquartile range: 18) and 34 healthy control subjects (median age: 43, interquartile range: 19). Nonexpert readers detected 47% (95% confidence interval [CI]: 46, 49) of FCDs, whereas experts detected 68% (95% CI: 65, 71). The 3 AI models detected 32%, 51%, and 72% of FCDs, respectively. The latter, however, also predicted more than 13 false-positive clusters per subject on average. Human performance was improved in the presence of a transmantle sign ( P < 0.001) and cortical thickening ( P < 0.001). In contrast, AI models were sensitive to abnormal gyration ( P < 0.01) or gray-white matter blurring ( P < 0.01). Compared with single experts, expert-expert pairs detected 13% (95% CI: 9, 18) more FCDs ( P < 0.001). All AI models increased expert detection rates by up to 19% (95% CI: 15, 24) ( P < 0.001). Nonexpert+AI pairs could still outperform single experts by up to 13% (95% CI: 10, 17)., Conclusions: This study pioneers the comparative evaluation of humans and AI for FCD lesion detection. It shows that AI and human predictions differ, especially for certain MRI features of FCD, and, thus, how AI may complement the diagnostic workup., Competing Interests: Conflicts of interest and sources of funding: A.R. has received fees as a speaker from UCB Pharma and travel support from the Elisabeth und Helmut Uhl Stiftung. U.A. has received fees as a speaker for Siemens Healthineers and as clinical consultant for Bayer. A.R. lectures for Guerbet and Bayer, and is part of the Advisory Board for GE, Bracco, and Guerbet. R.S. has received personal fees as speaker or for serving on advisory boards from Angelini, Arvelle, Bial, Desitin, Eisai, Jazz Pharmaceuticals Germany GmbH, Janssen-Cilag GmbH, LivaNova, LivAssured B.V., Novartis, Precisis GmbH, Rapport Therapeutics, Tabuk Pharmaceuticals, UCB Pharma, UNEEG, and Zogenix. T.R. has received fees as a speaker from Eisai. None of the previously mentioned activities were related to the content of this manuscript. The remaining authors have nothing to declare. No external funding was received for this work., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The epileptogenic network in temporal lobe epilepsy (TLE) contains structures of the primary and secondary olfactory cortex such as the piriform and entorhinal cortex, the amygdala, and the hippocampus. Olfactory auras and olfactory dysfunction are relevant symptoms of TLE. This study aims to characterize olfactory function in TLE using olfactory testing and olfactory functional magnetic resonance imaging (fMRI). We prospectively enrolled 20 individuals with unilateral TLE (age 45 ± 20 years [mean ± SD], 65% female, 90% right-handed) and 20 healthy individuals (age 33 ± 15 years [mean ± SD], 35% female, 90% right-handed). In the TLE group, the presumed seizure onset zone was left-sided in 75%; in 45% of the individuals with TLE limbic encephalitis was the presumed etiology; and 15% of the individuals with TLE reported olfactory auras. Olfactory function was assessed with a Screening Sniffin' Sticks Test (Burkhart, Wedel, Germany) during a pre-assessment. During a pre-testing, all individuals were asked to rate the intensity, valence, familiarity, and associated memory of five different odors (eugenol, vanillin, phenethyl alcohol, decanoic acid, valeric acid) and a control solution. During the fMRI experiment, all individuals repeatedly smelled eugenol (positively valenced odor), valeric acid (negatively valenced odor), and the control solution and were asked to rate odor intensity on a five-point Likert scale. We acquired functional EPI sequences and structural images (T1, T2, FLAIR). Compared to healthy individuals, individuals with TLE rated the presented odors as more neutral (two-sided Mann-Whitney U tests, FDR-p < 0.05) and less familiar (two-sided Mann-Whitney U tests, FDR-p < 0.05). fMRI data analysis revealed a reduced response contrast in secondary olfactory areas (e.g., hippocampus) connected to the limbic system when comparing eugenol and valeric acid in individuals with TLE when compared with healthy individuals. However, no lateralization effect was obtained when calculating a lateralization index by the number of activated voxels in the olfactory system (two-sided Mann-Whitney U test; U = 176.0; p = 0.525). TLE is characterized by olfactory dysfunction and associated with hypoactivation of secondary olfactory structures connected to the limbic system. These findings contribute to our understanding of the pathophysiology of TLE. This study was preregistered on OSF Registries (www.osf.io)., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: High-field magnetic resonance imaging (MRI) is a standard in the diagnosis of epilepsy. However, high costs and technical barriers have limited adoption in low- and middle-income countries. Even in high-income nations, many individuals with epilepsy face delays in undergoing MRI. Recent advancements in ultra-low-field (ULF) MRI technology, particularly the development of portable scanners, offer a promising solution to the limited accessibility of MRI. In this study, we present and evaluate the imaging capability of ULF MRI in detecting structural abnormalities typically associated with epilepsy and compare it to high-field MRI at 3 T., Methods: Data collection was conducted within 3 consecutive weeks at the University Hospital Bonn. Inclusion criteria were a minimum age of 18 years, diagnosed epilepsy, and clinical high-field MRI with abnormalities. We used a .064 T Swoop portable MR Imaging System. Both high-field MRI and ULF MRI scans were evaluated independently by two experienced neuroradiologists as part of their clinical routine, comparing pathology detection and diagnosis completeness., Results: Twenty-three individuals with epilepsy were recruited. One subject presented with a dual pathology. Across the entire cohort, in 17 of 24 (71%) pathologies, an anomaly colocalizing with the actual lesion was observed on ULF MRI. For 11 of 24 (46%) pathologies, the full diagnosis could be made based on ULF MRI. Tumors and posttraumatic lesions could be diagnosed best on ULF MRI, whereas cortical dysplasia and other focal pathologies were the least well diagnosed., Significance: This single-center series of individuals with epilepsy demonstrates the feasibility and utility of ULF MRI for the field of epileptology. Its integration into epilepsy care offers transformative potential, particularly in resource-limited settings. Further research is needed to position ULF MRI within imaging modalities in the diagnosis of epilepsy., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Convolutional neural networks (CNN) show great promise for translating decades of research on structural abnormalities in temporal lobe epilepsy into clinical practice. Three-dimensional CNNs typically outperform two-dimensional CNNs in medical imaging. Here we explore for the first time whether a three-dimensional CNN outperforms a two-dimensional CNN for identifying temporal lobe epilepsy-specific features on MRI. Using 1178 T1-weighted images (589 temporal lobe epilepsy, 589 healthy controls) from 12 surgical centres, we trained 3D and 2D CNNs for temporal lobe epilepsy versus healthy control classification, using feature visualization to identify important regions. The 3D CNN was compared to the 2D model and to a randomized model (comparison to chance). Further, we explored the effect of sample size with subsampling, examined model performance based on single-subject clinical characteristics, and tested the impact of image harmonization on model performance. Across 50 datapoints (10 runs with 5-folds each) the 3D CNN median accuracy was 86.4% (35.3% above chance) and the median F 1-score was 86.1% (33.3% above chance). The 3D model yielded higher accuracy compared to the 2D model on 84% of datapoints (median 2D accuracy, 83.0%), a significant outperformance for the 3D model (binomial test: P < 0.001). This advantage of the 3D model was only apparent at the highest sample size. Saliency maps exhibited the importance of medial-ventral temporal, cerebellar, and midline subcortical regions across both models for classification. However, the 3D model had higher salience in the most important regions, the ventral-medial temporal and midline subcortical regions. Importantly, the model achieved high accuracy (82% accuracy) even in patients without MRI-identifiable hippocampal sclerosis. Finally, applying ComBat for harmonization did not improve performance. These findings highlight the value of 3D CNNs for identifying subtle structural abnormalities on MRI, especially in patients without clinically identified temporal lobe epilepsy lesions. Our findings also reveal that the advantage of 3D CNNs relies on large sample sizes for model training., Competing Interests: None of the authors have any conflict of interest to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: The piriform cortex is considered to be highly epileptogenic. Its resection during epilepsy surgery is a predictor for postoperative seizure freedom in temporal lobe epilepsy. Epilepsy is associated with a dysfunction of the blood-brain barrier. We investigated blood-brain barrier dysfunction in the piriform cortex of people with temporal lobe epilepsy using quantitative T1-relaxometry., Methods: Gadolinium-based contrast agent was administered ictally and interictally in 37 individuals before undergoing quantitative T1-relaxometry. Postictal and interictal images were co-registered, and subtraction maps were created as biomarkers for peri-ictal (∆qT1 interictal-postictal ) and interictal (∆qT1 noncontrast-interictal ) blood-brain barrier dysfunction. Values were extracted for the piriform cortex, hippocampus, amygdala, and the whole cortex., Results: In temporal lobe epilepsy (n = 14), ∆qT1 noncontrast-interictal was significantly higher in the piriform cortex than in the whole cortex (p = 0.02). In extratemporal lobe epilepsy (n = 23), ∆qT1 noncontrast-interictal was higher in the hippocampus than in the whole cortex (p = 0.05). Across all individuals (n = 37), duration of epilepsy was correlated with ∆qT1 noncontrast-interictal (ß = 0.001, p < 0.001) in all regions, while the association was strongest in the piriform cortex. Impaired verbal memory was associated with ∆qT1 noncontrast-interictal only in the piriform cortex (p = 0.04). ∆qT1 interictal-postictal did not show differences in any region., Interpretation: Interictal blood-brain barrier dysfunction occurs in the piriform cortex in temporal lobe epilepsy. This dysfunction is linked to longer disease duration and worse cognitive deficits, emphasizing the central role of the piriform cortex in the epileptogenic network of temporal lobe epilepsy., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Progressive inflammation of one hemisphere characterises Rasmussen's encephalitis (RE), but contralesional epileptiform activity has been repeatedly reported. We aimed to quantify contralesional epileptiform activity in RE and uncover its functional and structural underpinnings. We retrospectively ascertained people with RE treated between 2000 and 2018 at a tertiary centre (Centre 1) and reviewed all available EEG datasets. The temporal occurrence of preoperative contralesional epileptiform activity (interictal/ictal) was evaluated using mixed-effects logistic regression. Cases with/without contralesional epileptiform activity were compared for cognition, inflammation (ipsilesional brain biopsies), and MRI (cortical and fixel-based morphometry). EEG findings were validated in a second cohort treated at another tertiary centre (Centre 2) between 1995 and 2020. We included 127 people with RE and 687 EEG samples. Preoperatively, contralesional epileptiform activity was seen in 30/68 (44%, Centre 1) and 8/59 (14%, Centre 2). In both cohorts, this activity was associated with younger onset age (OR = 0.9; 95% CI 0.83-0.97; P = 0.006). At centre 1, contralesional epileptiform activity was associated with contralesional MRI alterations, lower intelligence (OR = 5.19; 95% CI 1.28-21.08; P = 0.021), and impaired verbal memory (OR = 10.29; 95% CI 1.97-53.85; P = 0.006). After hemispherotomy, 11/17 (65%, Centre 1) and 28/37 (76%, Centre 2) were seizure-free. Contralesional epileptiform activity was persistent postoperatively in 6/12 (50%, Centre 1) and 2/34 (6%, Centre 2). Preoperative contralesional epileptiform activity reduced the chance of postoperative seizure freedom in both cohorts (OR = 0.69; 95% CI 0.50-0.95; P = 0.029). Our findings question the concept of strict unilaterality of RE and provide the evidence of contralesional epileptiform activity as a possible EEG predictor for persisting postoperative seizures., (© 2024. The Author(s).)

Purpose: Neuroglial tumors are frequently associated with pharmacorefractory epilepsies. However, comprehensive knowledge about long-term outcomes after epilepsy surgery and the main prognostic factors for outcome is still limited. We sought to evaluate long-term outcomes and potential influencing factors in a large cohort of patients who underwent surgery for neuroglial tumors in a single-center setting., Methods: The study analyzed the outcomes of 107 patients who underwent epilepsy surgery for neuroglial tumors between 2001 and 2020 at the Department of Epileptology, University Hospital Bonn, in Germany. The outcomes were evaluated using Engel classification. Differences in outcome related to potential prognostic factors were examined using the Chi2-test, Fisher's exact test and sign test. Additionally, stepwise logistic regression analysis was employed to identify independent prognostic factors., Results: Complete seizure freedom (Engel Class IA) was achieved in 75% of the operated patients at 12 months, and 56% at the last follow-up visit (70.4 ± 6.2 months, median: 40 months). Completeness of resection was a crucial factor for both 12-month follow-up outcomes and the longest available outcomes, whereas lobar tumor localization, histology (ganglioglioma vs. dysembryoplastic neuroepithelial tumor), history of bilateral tonic-clonic seizures prior to surgery, invasive diagnostics, side of surgery (dominant vs. non-dominant hemisphere), age at epilepsy onset, age at surgery, and epilepsy duration did not consistently impact postsurgical outcomes. Among temporal lobe surgeries, patients who underwent lesionectomy and lesionectomy, including hippocampal resection, demonstrated similar outcomes., Conclusion: Neuroglial tumors present as excellent surgical substrates in treating structural epilepsy. To achieve an optimal postsurgical outcome, a complete lesion resection should be pursued whenever possible., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. RS has received personal fees as speaker or for serving on advisory boards from Angelini, Arvelle, Bial, Desitin, Eisai, Jazz Pharmaceuticals Germany GmbH, Janssen-Cilag GmbH, LivaNova, LivAssured B.V., Novartis, Precisis GmbH, Rapport Therapeutics, Tabuk Pharmaceuticals, UCB Pharma, UNEEG, and Zogenix. These activities were not related to the content of this manuscript. AR has received fees as speaker from UCB Pharma, and received travel support from the Elisabeth und Helmut Uhl Stiftung. These activities were not related to the content of this manuscript. Some authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rácz, Müller, Becker, Hoffmann, Rüber, Borger, Vatter, Surges and Elger.)

Objective: Interictal blood-brain barrier dysfunction in chronic epilepsy has been demonstrated in animal models and pathological specimens. Ictal blood-brain barrier dysfunction has been shown in humans in vivo using an experimental quantitative magnetic resonance imaging (MRI) protocol. Here, we hypothesized that interictal blood-brain barrier dysfunction is also present in people with drug-resistant epilepsy., Methods: Thirty-nine people (21 females, mean age at MRI ± SD = 30 ± 8 years) with drug-resistant epilepsy were prospectively recruited and underwent interictal T1-relaxometry before and after administration of a paramagnetic contrast agent. Likewise, quantitative T1 was acquired in 29 people without epilepsy (12 females, age at MRI = 48 ± 18 years). Quantitative T1 difference maps were calculated and served as a surrogate imaging marker for blood-brain barrier dysfunction. Values of quantitative T1 difference maps inside hemispheres ipsilateral to the presumed seizure onset zone were then compared, on a voxelwise level and within presumed seizure onset zones, to the contralateral side of people with epilepsy and to people without epilepsy., Results: Compared to the contralateral side, ipsilateral T1 difference values were significantly higher in white matter (corrected p < .05), gray matter (uncorrected p < .05), and presumed seizure onset zones (p = .04) in people with epilepsy. Compared to people without epilepsy, significantly higher T1 difference values were found in the anatomical vicinity of presumed seizure onset zones (p = .004). A subgroup of people with hippocampal sclerosis demonstrated significantly higher T1 difference values in the ipsilateral hippocampus and in regions strongly interconnected with the hippocampus compared to people without epilepsy (corrected p < .01). Finally, z-scores reflecting the deviation of T1 difference values within the presumed seizure onset zone were associated with verbal memory performance (p = .02) in people with temporal lobe epilepsy., Significance: Our results indicate a blood-brain barrier dysfunction in drug-resistant epilepsy that is detectable interictally in vivo, anatomically related to the presumed seizure onset zone, and associated with cognitive deficits., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

A crucial step in the clinical adaptation of an AI-based tool is an external, independent validation. The aim of this study was to investigate brain atrophy in patients with confirmed, progressed Huntington's disease using a certified software for automated volumetry and to compare the results with the manual measurement methods used in clinical practice as well as volume calculations of the caudate nuclei based on manual segmentations. Twenty-two patients were included retrospectively, consisting of eleven patients with Huntington's disease and caudate nucleus atrophy and an age- and sex-matched control group. To quantify caudate head atrophy, the frontal horn width to intercaudate distance ratio and the intercaudate distance to inner table width ratio were obtained. The software mdbrain was used for automated volumetry. Manually measured ratios and automatically measured volumes of the groups were compared using two-sample t-tests. Pearson correlation analyses were performed. The relative difference between automatically and manually determined volumes of the caudate nuclei was calculated. Both ratios were significantly different between the groups. The automatically and manually determined volumes of the caudate nuclei showed a high level of agreement with a mean relative discrepancy of - 2.3 ± 5.5%. The Huntington's disease group showed significantly lower volumes in a variety of supratentorial brain structures. The highest degree of atrophy was shown for the caudate nucleus, putamen, and pallidum (all p < .0001). The caudate nucleus volume and the ratios were found to be strongly correlated in both groups. In conclusion, in patients with progressed Huntington's disease, it was shown that the automatically determined caudate nucleus volume correlates strongly with measured ratios commonly used in clinical practice. Both methods allowed clear differentiation between groups in this collective. The software additionally allows radiologists to more objectively assess the involvement of a variety of brain structures that are less accessible to standard semiquantitative methods., (© 2024. The Author(s).)

Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group., Methods: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness., Results: Across all epilepsies, reduced total cerebellar volume was observed (d = .42). Maximum volume loss was observed in the corpus medullare (d max  = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (d max  = .47), crus I/II (d max  = .39), VIIIA (d max  = .45), and VIIIB (d max  = .40). Earlier age at seizure onset ( η ρ max 2  = .05) and longer epilepsy duration ( η ρ max 2  = .06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls., Significance: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Purpose: Voxel-based morphometry (VBM) studies of people with focal epilepsies revealed gray matter (GM) alterations in brain regions involved in cardiorespiratory regulation, which have been linked to the risk of sudden unexpected death in epilepsy (SUDEP). It remains unclear whether the type and localization of epileptogenic lesions influence the occurrence of such alterations., Methods: To test the hypothesis that VBM alterations of autonomic network regions are independent of epileptogenic lesions and that they reveal structural underpinnings of SUDEP risk, VBM was performed in 100 people with focal epilepsies without an epileptogenic lesion identifiable on MRI (mean age ± standard deviation = 35 ± 11 years, 56 female). The group was further stratified in high (sample size n = 29) and low risk of SUDEP (n = 71). GM volumes were compared between these two subgroups and to 100 matched controls., Results: People with epilepsy displayed higher GM volume in both amygdalae and parahippocampal gyri and lower GM volume in the cerebellum and occipital (p<.05, familywise error corrected). There were no significant volumetric differences between high and low SUDEP risk subgroups., Conclusion: Our findings confirm that autonomic networks are structurally altered in people with focal epilepsy and they question VBM as a suitable method to show structural correlates of the SUDEP risk score., (© 2023 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Rasmussen's encephalitis is characterized by drug-resistant focal seizures and chronic inflammation of one hemisphere leading to progressive loss of hemispheric volume. In this cohort study, we aimed to investigate subcortical grey matter volumes and asymmetries in Rasmussen's encephalitis longitudinally in clinically relevant subgroups. We retrospectively included all T 1 -weighted MRI scans of all people with Rasmussen's encephalitis who were treated at the University Hospital Bonn between 1995 and 2022 ( n = 56, 345 scans, median onset 8 years, 36 female). All cases were classified as type 1 (onset ≤ 6 years) or type 2 (onset > 6 years). Subcortical segmentations were performed using FreeSurfer. Longitudinal trajectories of subcortical volumes and hemispheric ratios (ipsi-/contralesional) were assessed using linear mixed-effect models. Unihemispheric cortical degeneration was accompanied by ipsilesional atrophy of the nucleus accumbens, caudate nucleus, putamen, thalamus and contralesional atrophy of the nucleus accumbens and caudate nucleus both in type 1 (all P ≤ 0.014) and type 2 (all P < 0.001). In type 1, however, contralesional volume increase of the amygdala, hippocampus, pallidum and thalamus was found (all P ≤ 0.013). Both ipsilesional and contralesional subcortical atrophies, like cortical atrophy, are most probably caused by neurodegeneration following chronic neuroinflammation. We speculate that contralesional volume increase in type 1 could be related to either neuroplasticity or ongoing acute neuroinflammation, which needs to be investigated in further studies., Competing Interests: A.R. lectures for Guerbet and Bayer and is part of the advisory board for GE, Bracco and Guerbet. C.H. has received fees as speaker from Eisai. R.S. has received fees as speaker or for serving on the advisory board from Angelini, Arvelle, Bial, Desitin, Eisai, Janssen-Cilag GmbH, LivaNova, Novartis, Precisis GmbH, UCB Pharma, UnEEG and Zogenix. T.R. has received fees as speaker from Eisai., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Rasmussen's encephalitis is an immune-mediated brain disorder characterised by progressive unilateral cerebral atrophy, neuroinflammation, drug-resistant seizures and cognitive decline. However, volumetric changes and epileptiform EEG activity were also observed in the contralateral hemisphere, raising questions about the aetiology of contralateral involvement. In this study, we aim to investigate alterations of white matter integrity, structural network topology and network efficiency in Rasmussen's encephalitis using diffusion-tensor imaging. Fourteen individuals with Rasmussen's encephalitis (11 female, median onset 6 years, range 4-22, median disease duration at MRI 5 years, range 0-42) and 20 healthy control subjects were included. All subjects underwent T1-weighted structural and diffusion-tensor imaging. Diffusion-tensor images were analysed using the fixel-based analysis framework included in the MRtrix3 toolbox. Fibre density and cross-section served as a quantitative measure for microstructural white matter integrity. T1-weighted structural images were processed using FreeSurfer, subcortical segmentations and cortical parcellations using the Desikan-Killiany atlas served as nodes in a structural network model, edge weights were determined based on streamline count between pairs of nodes and compared using network-based statistics. Global efficiency was used to quantify network integration on an intrahemispheric level. All metrics were compared cross-sectionally between individuals with Rasmussen's encephalitis and healthy control subjects using sex and age as regressors and within the Rasmussen's encephalitis group using linear regression including age at onset and disease duration as independent variables. Relative to healthy control subjects, individuals with Rasmussen's encephalitis showed significantly (family-wise-error-corrected P < 0.05) lower fibre density and cross-section as well as edge weights in intrahemispheric connections within the ipsilesional hemisphere and in interhemispheric connections. Lower edge weights were noted in the contralesional hemisphere and in interhemispheric connections, with the latter being mainly affected within the first 2 years after disease onset. With longer disease duration, fibre density and cross-section significantly (uncorrected P < 0.01) decreased in both hemispheres. In the contralesional corticospinal tract, fibre density and cross-section significantly (uncorrected P < 0.01) increased with disease duration. Intrahemispheric edge weights (uncorrected P < 0.01) and global efficiency significantly increased with disease duration in both hemispheres (ipsilesional r = 0.74, P = 0.001; contralesional r = 0.67, P = 0.012). Early disease onset was significantly (uncorrected P < 0.01) negatively correlated with lower fibre density and cross-section bilaterally. Our results show that the disease process of Rasmussen's encephalitis is not limited to the cortex of the lesioned hemisphere but should be regarded as a network disease affecting white matter across the entire brain and causing degenerative as well as compensatory changes on a network level., Competing Interests: C.Ho. reports personal fees from Eisai. A.R. has received fees as speaker or served on the advisory board of Bayer, Bracco, GE, Guerbet. C.He. has received fees as speaker or served on the advisory board of Eisai. R.S. has received fees as speaker or served on the advisory board of Angelini, Arvelle, Bial, Eisai, Livanova, Novartis, Janssen-Cilag GmbH, Novartis, Precisis GmbH, UCB Pharma, UnEEG and Zogenix. T.R. has received fees as a speaker from Eisai. These activities were not related to the content of this manuscript., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Hippocampal volumetry is an essential tool in researching and diagnosing mesial temporal lobe epilepsy (mTLE). However, it has a limited ability to detect subtle alterations in hippocampal morphometry. Here, we establish and apply a novel geometry-based tool that enables point-wise morphometric analysis based on an intrinsic coordinate system of the hippocampus. We hypothesized that this point-wise analysis uncovers structural alterations not measurable by volumetry, but associated with histological underpinnings and the neuropsychological profile of mTLE. We conducted a retrospective study in 204 individuals with mTLE and 57 age- and gender-matched healthy subjects. FreeSurfer-based segmentations of hippocampal subfields in 3T-MRI were subjected to a geometry-based analysis that resulted in a coordinate system of the hippocampal mid-surface and allowed for point-wise measurements of hippocampal thickness and other features. Using point-wise analysis, we found significantly lower thickness and higher FLAIR signal intensity in the entire affected hippocampus of individuals with hippocampal sclerosis (HS-mTLE). In the contralateral hippocampus of HS-mTLE and the affected hippocampus of MRI-negative mTLE, we observed significantly lower thickness in the presubiculum. Impaired verbal memory was associated with lower thickness in the left presubiculum. In HS-mTLE histological subtype 3, we observed higher curvature than in subtypes 1 and 2 (all p < .05). These findings could not be observed using conventional volumetry (Bonferroni-corrected p < .05). We show that point-wise measures of hippocampal morphometry can uncover structural alterations not measurable by volumetry while also reflecting histological underpinnings and verbal memory. This substantiates the prospect of their clinical application., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Automated detection of lesions using artificial intelligence creates new standards in medical imaging. For people with epilepsy, automated detection of focal cortical dysplasias (FCDs) is widely used because subtle FCDs often escape conventional neuroradiological diagnosis. Accurate recognition of FCDs, however, is of outstanding importance for affected people, as surgical resection of the dysplastic cortex is associated with a high chance of postsurgical seizure freedom. Here, we make publicly available a dataset of 85 people affected by epilepsy due to FCD type II and 85 healthy control persons. We publish 3D-T1 and 3D-FLAIR, manually labeled regions of interest, and carefully selected clinical features. The open presurgery MRI dataset may be used to validate existing automated algorithms of FCD detection as well as to create new approaches. Most importantly, it will enable comparability of already existing approaches and support a more widespread use of automated lesion detection tools., (© 2023. The Author(s).)

Background and Objectives: A new frontier in diagnostic radiology is the inclusion of machine-assisted support tools that facilitate the identification of subtle lesions often not visible to the human eye. Structural neuroimaging plays an essential role in the identification of lesions in patients with epilepsy, which often coincide with the seizure focus. In this study, we explored the potential for a convolutional neural network (CNN) to determine lateralization of seizure onset in patients with epilepsy using T1-weighted structural MRI scans as input., Methods: Using a dataset of 359 patients with temporal lobe epilepsy (TLE) from 7 surgical centers, we tested whether a CNN based on T1-weighted images could classify seizure laterality concordant with clinical team consensus. This CNN was compared with a randomized model (comparison with chance) and a hippocampal volume logistic regression (comparison with current clinically available measures). Furthermore, we leveraged a CNN feature visualization technique to identify regions used to classify patients., Results: Across 100 runs, the CNN model was concordant with clinician lateralization on average 78% (SD = 5.1%) of runs with the best-performing model achieving 89% concordance. The CNN outperformed the randomized model (average concordance of 51.7%) on 100% of runs with an average improvement of 26.2% and outperformed the hippocampal volume model (average concordance of 71.7%) on 85% of runs with an average improvement of 6.25%. Feature visualization maps revealed that in addition to the medial temporal lobe, regions in the lateral temporal lobe, cingulate, and precentral gyrus aided in classification., Discussion: These extratemporal lobe features underscore the importance of whole-brain models to highlight areas worthy of clinician scrutiny during temporal lobe epilepsy lateralization. This proof-of-concept study illustrates that a CNN applied to structural MRI data can visually aid clinician-led localization of epileptogenic zone and identify extrahippocampal regions that may require additional radiologic attention., Classification of Evidence: This study provides Class II evidence that in patients with drug-resistant unilateral temporal lobe epilepsy, a convolutional neural network algorithm derived from T1-weighted MRI can correctly classify seizure laterality., (© 2023 American Academy of Neurology.)

Retinal disease accounts significantly for visual impairment and blindness. An important role in the pathophysiology of retinal disease and aging is attributed to lipofuscin, a complex of fluorescent metabolites. Fundus autofluorescence (AF) imaging allows non-invasive mapping of lipofuscin and is a key technology to diagnose and monitor retinal disease. However, currently used short-wavelength (SW) excitation light has several limitations, including glare and discomfort during image acquisition, reduced image quality in case of lens opacities, limited visualization of the central retina, and potential retinal light toxicity. Here, we establish a novel imaging modality which uses red excitation light (R-AF) and overcomes these drawbacks. R-AF images are high-quality, high-contrast fundus images and image interpretation may build on clinical experience due to similar appearance of pathology as on SW-AF images. Additionally, R-AF images may uncover disease features that previously remained undetected. The R-AF signal increases with higher abundance of lipofuscin and does not depend on photopigment bleaching or on the amount of macular pigment. Improved patient comfort, limited effect of cataract on image quality, and lack of safety concerns qualify R-AF for routine clinical monitoring, e.g. for patients with age-related macular degeneration, Stargardt disease, or for quantitative analysis of AF signal intensity., (© 2023. The Author(s).)

The piriform cortex (PC) is located at the junction of the temporal and frontal lobes. It is involved physiologically in olfaction as well as memory and plays an important role in epilepsy. Its study at scale is held back by the absence of automatic segmentation methods on MRI. We devised a manual segmentation protocol for PC volumes, integrated those manually derived images into the Hammers Atlas Database (n = 30) and used an extensively validated method (multi-atlas propagation with enhanced registration, MAPER) for automatic PC segmentation. We applied automated PC volumetry to patients with unilateral temporal lobe epilepsy with hippocampal sclerosis (TLE; n = 174 including n = 58 controls) and to the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 151, of whom with mild cognitive impairment (MCI), n = 71; Alzheimer's disease (AD), n = 33; controls, n = 47). In controls, mean PC volume was 485 mm 3 on the right and 461 mm 3 on the left. Automatic and manual segmentations overlapped with a Jaccard coefficient (intersection/union) of ~0.5 and a mean absolute volume difference of ~22 mm 3 in healthy controls, ~0.40/ ~28 mm 3 in patients with TLE, and ~ 0.34/~29 mm 3 in patients with AD. In patients with TLE, PC atrophy lateralised to the side of hippocampal sclerosis (p < .001). In patients with MCI and AD, PC volumes were lower than those of controls bilaterally (p < .001). Overall, we have validated automatic PC volumetry in healthy controls and two types of pathology. The novel finding of early atrophy of PC at the stage of MCI possibly adds a novel biomarker. PC volumetry can now be applied at scale., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Objectives: Limbic encephalitis (LE) is an autoimmune disease often associated with temporal lobe epilepsy and subacute memory deficits. It is categorized into serologic subgroups, which differ in clinical progress, therapy response, and prognosis. Using longitudinal MRI analysis, we hypothesized that mesiotemporal and cortical atrophy rates would reveal serotype-specific patterns and reflect disease severity., Methods: In this longitudinal case-control study, all individuals with antibody-positive (glutamic acid decarboxylase 65 [GAD], leucine-rich glioma-inactivated protein 1 [LGI1], contactin-associated protein 2 [CASPR2], and N -methyl-d-aspartate receptor [NMDAR]) nonparaneoplastic LE according to Graus' diagnostic criteria treated between 2005 and 2019 at the University Hospital Bonn were enrolled. A longitudinal healthy cohort was included as the control group. Subcortical segmentation and cortical reconstruction of T1-weighted MRI were performed using the longitudinal framework in FreeSurfer. We applied linear mixed models to examine mesiotemporal volumes and cortical thickness longitudinally., Results: Two hundred fifty-seven MRI scans from 59 individuals with LE (34 female, age at disease onset [mean ± SD] 42.5 ± 20.4 years; GAD: n = 30, 135 scans; LGI1: n = 15, 55 scans; CASPR2: n = 9, 37 scans; and NMDAR: n = 5, 30 scans) were included. The healthy control group consisted of 128 scans from 41 individuals (22 female, age at first scan [mean ± SD] 37.7 ± 14.6 years). The amygdalar volume at disease onset was significantly higher in individuals with LE ( p ≤ 0.048 for all antibody subgroups) compared with that in healthy controls and decreased over time in all antibody subgroups, except in the GAD subgroup. We observed a significantly higher hippocampal atrophy rate in all antibody subgroups compared with that in healthy controls (all p ≤ 0.002), except in the GAD subgroup. Cortical atrophy rates exceeded normal aging in individuals with impaired verbal memory, while those who were not impaired did not differ significantly from healthy controls., Discussion: Our data depict higher mesiotemporal volumes in the early disease stage, most likely due to edematous swelling, followed by volume regression and atrophy/hippocampal sclerosis in the late disease stage. Our study reveals a continuous and pathophysiologically meaningful trajectory of mesiotemporal volumetry across all serogroups and provides evidence that LE should be considered a network disorder in which extratemporal involvement is an important determinant of disease severity., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Focal cortical dysplasias (FCDs) are malformations of cortical development and one of the most common pathologies causing pharmacoresistant focal epilepsy. Resective neurosurgery yields high success rates, especially if the full extent of the lesion is correctly identified and completely removed. The visual assessment of magnetic resonance imaging does not pinpoint the FCD in 30%-50% of cases, and half of all patients with FCD are not amenable to epilepsy surgery, partly because the FCD could not be sufficiently localized. Computational approaches to FCD detection are an active area of research, benefitting from advancements in computer vision. Automatic FCD detection is a significant challenge and one of the first clinical grounds where the application of artificial intelligence may translate into an advance for patients' health. The emergence of new methods from the combination of health and computer sciences creates novel challenges. Imaging data need to be organized into structured, well-annotated datasets and combined with other clinical information, such as histopathological subtypes or neuroimaging characteristics. Algorithmic output, that is, model prediction, requires a technically correct evaluation with adequate metrics that are understandable and usable for clinicians. Publication of code and data is necessary to make research accessible and reproducible. This critical review introduces the field of automatic FCD detection, explaining underlying medical and technical concepts, highlighting its challenges and current limitations, and providing a perspective for a novel research environment., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The blood-brain barrier (BBB) is a physiological barrier maintaining a specialized brain micromilieu that is necessary for proper neuronal function. Endothelial tight junctions and specific transcellular/efflux transport systems provide a protective barrier against toxins, pathogens, and immune cells. The barrier function is critically supported by other cell types of the neurovascular unit, including pericytes, astrocytes, microglia, and interneurons. The dysfunctionality of the BBB is a hallmark of neurological diseases, such as ischemia, brain tumors, neurodegenerative diseases, infections, and autoimmune neuroinflammatory disorders. Moreover, BBB dysfunction is critically involved in epilepsy, a brain disorder characterized by spontaneously occurring seizures because of abnormally synchronized neuronal activity. While resistance to antiseizure drugs that aim to reduce neuronal hyperexcitability remains a clinical challenge, drugs targeting the neurovasculature in epilepsy patients have not been explored. The use of novel imaging techniques permits early detection of BBB leakage in epilepsy; however, the detailed mechanistic understanding of causes and consequences of BBB compromise remains unknown. Here, we discuss the current knowledge of BBB involvement in temporal lobe epilepsy with the emphasis on the neurovasculature as a therapeutic target., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Ictal single photon emission computed tomography (SPECT) can be used as an advanced diagnostic modality to detect the seizure onset zone in the presurgical evaluation of people with epilepsy. In addition to visual assessment (VSA) of ictal and interictal SPECT images, postprocessing methods such as ictal-interictal SPECT analysis using SPM (ISAS) can visualize regional ictal blood flow differences. We aimed to evaluate and differentiate the diagnostic value of VSA and ISAS in the Bonn cohort., Methods: We included 161 people with epilepsy who underwent presurgical evaluation at the University Hospital Bonn between 2008 and 2020 and received ictal and interictal SPECT and ISAS. We retrospectively assigned SPECT findings to one of five categories according to their degree of concordance with the clinical focus hypothesis., Results: Seizure onset zones could be identified more likely on a sublobar concordance level by ISAS than by VSA (31% vs. 19% of cases; OR = 1.88; 95% Cl [1.04, 3.42]; P = 0.03). Both VSA and ISAS more often localized a temporal seizure onset zone than an extratemporal one. Neither VSA nor ISAS findings were predicted by the latency between seizure onset and tracer injection (P = 0.75). In people who underwent successful epilepsy surgery, VSA and ISAS indicated the correct resection site in 54% of individuals, while MRI and EEG showed the correct resection localization in 96% and 33% of individuals, respectively. It was more likely to become seizure-free after epilepsy surgery if ISAS or VSA had been successful. There was no MR-negative case with successful surgery, indicating that ictal SPECT is more useful for confirmation than for localization., Significance: The results of the most extensive clinical study of ictal SPECT to date allow an assessment of the diagnostic value of this elaborate examination and emphasize the importance of postprocessing routines., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Patients with anti-leucine-rich glioma-inactivated 1 protein (LGI1) or anti-contactin-associated protein 2 (CASPR2) antibody encephalitis typically present with frequent epileptic seizures. The seizures generally respond well to immunosuppressive therapy, and the long-term seizure outcome seems to be favorable. Consequentially, diagnosing acute symptomatic seizures secondary to autoimmune encephalitis instead of autoimmune epilepsy was proposed. However, published data on long-term seizure outcomes in CASPR2 and LGI1 antibody encephalitis are mostly based on patient reports, and seizure underreporting is a recognized issue. Clinical records from our tertiary epilepsy center were screened retrospectively for patients with LGI1 and CASPR2 antibody encephalitis who reported seizure freedom for at least 3 months and received video-electroencephalography (EEG) for >24 h at follow-up visits. Twenty (LGI1, n = 15; CASPR2, n = 5) of 32 patients with LGI1 (n = 24) and CASPR2 (n = 8) antibody encephalitis fulfilled these criteria. We recorded focal aware and impaired awareness seizures in four of these patients (20%) with reported seizure-free intervals ranging from 3 to 27 months. Our results question the favorable seizure outcome in patients with CASPR2 and LGI1 antibody encephalitis and suggest that the proportion of patients who have persistent seizures may be greater. Our findings underline the importance of prolonged video-EEG telemetry in this population., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Recently, we showed that resection of at least 27% of the temporal part of piriform cortex (PiC) strongly correlated with seizure freedom 1 year following selective amygdalo-hippocampectomy (tsSAHE) in patients with mesial temporal lobe epilepsy (mTLE). However, the impact of PiC resection on long-term seizure outcome following tsSAHE is currently unknown. The aim of this study was to evaluate the impact of PiC resection on long-term seizure outcome in patients with mTLE treated with tsSAHE., Methods: Between 2012 and 2017, 64 patients were included in the retrospective analysis. Long-term follow-up (FU) was defined as at least 2 years postoperatively. Seizure outcome was assessed according to the International League against Epilepsy (ILAE). The resected proportions of hippocampus, amygdala, and PiC were volumetrically assessed., Results: The mean FU duration was 3.75 ± 1.61 years. Patients with ILAE class 1 revealed a significantly larger median proportion of resected PiC compared to patients with ILAE class 2-6 [46% (IQR 31-57) vs. 16% (IQR 6-38), p = 0.001]. Resected proportions of hippocampus and amygdala did not significantly differ for these groups. Among those patients with at least 27% resected proportion of PiC, there were significantly more patients with seizure freedom compared to the patients with <27% resected proportion of PiC (83% vs. 39%, p = 0.0007)., Conclusions: Our results show a strong impact of the extent of PiC resection on long-term seizure outcome following tsSAHE in mTLE. The authors suggest the PiC to constitute a key target volume in tsSAHE to achieve seizure freedom in the long term., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features., Methods: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance., Results: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10 -16 ), age at onset (ρ = -.18, p = 9.82 × 10 -7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI., Significance: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes., (© 2022. The Author(s).)

Shape-based markers have entered the field of morphometric neuroimaging analysis as a second mainstay alongside conventional volumetric approaches. We aimed to assess the added value of shape description for the analysis of lesional and autoimmune temporal lobe epilepsy (TLE) focusing on hippocampus and amygdala. We retrospectively investigated MRI and clinical data from 65 patients with lesional TLE (hippocampal sclerosis (HS) and astrogliosis) and from 62 patients with limbic encephalitis (LE) with serologically proven autoantibodies. Surface reconstruction and volumetric segmentation were performed with FreeSurfer. For the shape analysis, we used BrainPrint, a tool that utilizes eigenvalues of the Laplace-Beltrami operator on triangular meshes to calculate intra-subject asymmetry. Psychometric tests of memory performance were ascertained, to evaluate clinical relevance of the shape descriptor. The potential benefit of shape in addition to volumetric information for classification was assessed by five-fold repeated cross validation and logistic regression. For the LE group, the best performing classification model consisted of a combination of volume and shape asymmetry (mean AUC = 0.728), the logistic regression model was significantly improved considering both modalities instead of just volume asymmetry. For lesional TLE, the best model only considered volumetric information (mean AUC = 0.867). Shape asymmetry of the hippocampus was largely associated with verbal memory performance only in LE patients (OR = 1.07, p = 0.02). For lesional TLE, shape description is robust, but redundant when compared to volumetric approaches. For LE, in contrast, shape asymmetry as a complementary modality significantly improves the detection of subtle morphometric changes and is further associated with memory performance, which underscores the clinical relevance of shape asymmetry as a novel imaging biomarker., Competing Interests: Conflicts of interest J.A.W. reports personal fees from Eisai. A.R. discloses lectures for Guerbet and Bayer and institutional study support by Guerbet and Bayer. C.E.E. has received fees as a speaker or consultant from UCB Pharma, Desitin, Bial, and Eisai. R.S. has received fees as a speaker or consultant from Bial, Cyberonics, Desitin, Eisai, LivaNova, Novartis, and UCB Pharma. None of the other authors has any conflict of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Here, we report a consanguineous family harboring a novel homozygous frame-shift mutation in ASPM leading to a truncation of the ASPM protein after amino acid position 1830. The phenotype of the patients was associated with microcephaly, epilepsy, and behavioral and cognitive deficits. Despite the obvious genetic similarity, the affected patients show a considerable phenotypic heterogeneity regarding the degree of mental retardation, presence of epilepsy and MRI findings. Interestingly, the degree of mental retardation and the presence of epilepsy correlates well with the severity of abnormalities detected in brain MRI. On the other hand, we detected no evidence for substantial nonsense-mediated ASPM transcript decay in blood samples. This indicates that other factors than ASPM expression levels are relevant for the variability of structural changes in brain morphology seen in patients with primary hereditary microcephaly caused by ASPM mutations.

Background and Purpose: MR imaging studies and neuropathologic findings in individuals with 22q11.2 deletion syndrome show anomalous early brain development. We aimed to retrospectively evaluate cerebral abnormalities, focusing on gray matter heterotopia, and to correlate these with subjects' neuropsychiatric impairments., Materials and Methods: Three raters assessed gray matter heterotopia and other morphologic brain abnormalities on 3D T1WI and T2*WI in 75 individuals with 22q11.2 deletion syndrome (27 females, 15.5 [SD, 7.4] years of age) and 53 controls (24 females, 12.6 [SD, 4.7] years of age). We examined the association among the groups' most frequent morphologic findings, general cognitive performance, and comorbid neuropsychiatric conditions., Results: Heterotopia in the white matter were the most frequent finding in individuals with 22q11.2 deletion syndrome ( n = 29; controls, n = 0; between-group difference, P < .001), followed by cavum septi pellucidi and/or vergae ( n = 20; controls, n = 0; P < .001), periventricular cysts ( n = 10; controls, n = 0; P = .007), periventricular nodular heterotopia ( n = 10; controls, n = 0; P = .007), and polymicrogyria ( n = 3; controls, n = 0; P = .3). However, individuals with these morphologic brain abnormalities did not differ significantly from those without them in terms of general cognitive functioning and psychiatric comorbidities., Conclusions: Taken together, our findings, periventricular nodular heterotopia or heterotopia in the white matter (possibly related to interrupted Arc cells migration), persistent cavum septi pellucidi and/or vergae, and formation of periventricular cysts, give clues to the brain development disorder induced by the 22q11.2 deletion syndrome. There was no evidence that these morphologic findings were associated with differences in psychiatric or cognitive presentation of the 22q11.2 deletion syndrome., (© 2021 by American Journal of Neuroradiology.)

Neuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat model of TLE. Magnetic susceptibility of the presumed seizure-onset zone from three patients with focal epilepsy was compared during and after seizure activity. Finally, the cellular effects of iron overload were studied in vitro using an acute mouse hippocampal slice preparation and cultured human fetal astrocytes. While iron-accumulating neurons had a pyknotic morphology, astrocytes appeared to acquire iron-sequestrating capacity as indicated by prominent ferritin expression and iron retention in the hippocampus of patients with SE or TLE. Interictal to postictal comparison revealed increased magnetic susceptibility in the seizure-onset zone of epilepsy patients. Post-SE rats had consistently higher hippocampal iron levels during the acute and chronic phase (when spontaneous recurrent seizures are evident). In vitro, in acute slices that were exposed to iron, neurons readily took up iron, which was exacerbated by induced epileptiform activity. Human astrocyte cultures challenged with iron and ROS increased their antioxidant and iron-binding capacity, but simultaneously developed a pro-inflammatory phenotype upon chronic exposure. These data suggest that seizure-mediated, chronic neuronal iron uptake might play a role in neuronal dysfunction/loss in TLE-HS. On the other hand, astrocytes sequester iron, specifically in chronic epilepsy. This function might transform astrocytes into a highly resistant, pro-inflammatory phenotype potentially contributing to pro-epileptogenic inflammatory processes., (© 2021. The Author(s).)

Objective: Using multimodal imaging, we tested the hypothesis that patients after hemispherotomy recruit non-primary motor areas and non-pyramidal descending motor fibers to restore motor function of the impaired limb., Methods: Functional and structural MRI data were acquired in a group of 25 patients who had undergone hemispherotomy and in a matched group of healthy controls. Patients' motor impairment was measured using the Fugl-Meyer Motor Assessment. Cortical areas governing upper extremity motor-control were identified by task-based functional MRI. The resulting areas were used as nodes for functional and structural connectivity analyses., Results: In hemispherotomy patients, movement of the impaired upper extremity was associated to widespread activation of non-primary premotor areas, whereas movement of the unimpaired one and of the control group related to activations prevalently located in the primary motor cortex (all p ≤ 0.05, FWE-corrected). Non-pyramidal tracts originating in premotor/supplementary motor areas and descending through the pontine tegmentum showed relatively higher structural connectivity in patients (p < 0.001, FWE-corrected). Significant correlations between structural connectivity and motor impairment were found for non-pyramidal (p = 0.023, FWE-corrected), but not for pyramidal connections., Interpretation: A premotor/supplementary motor network and non-pyramidal fibers seem to mediate motor function in patients after hemispherotomy. In case of hemispheric lesion, the homologous regions in the contralesional hemisphere may not compensate the resulting motor deficit, but the functionally redundant premotor network., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Purpose: Febrile-infection-related epilepsy syndrome (FIRES) is an exceedingly rare and devastating subtype of new-onset refractory status epilepticus, which causes refractory epilepsy and permanent neurocognitive impairment., Methods: This was a long-term follow-up of adult FIRES survivors treated between 2005 and 2018 as part of the EpiCARE initiative, a European Reference Network for rare and complex epilepsies. Clinical, electroencephalography, imaging and functional outcome measures are described using the Scores of Independence for Neurologic and Geriatric Rehabilitation, the modified Rankin Scale and the Global Assessment of Severity of Epilepsy Scale., Results: Six patients with refractory epilepsy following FIRES were evaluated. Despite general improvement after intensive care unit discharge, disease severity was still high at follow-up in all patients. The functional outcome, as assessed by the modified Rankin Scale, was moderately impaired in 2/6 patients. In contrast, the Scores of Independence for Neurologic and Geriatric Rehabilitation indicated a loss of independence in 5/6, serious problems in memory and planning/problem-solving in 4/6 and serious attentional problems in 3/6 patients., Conclusions: Febrile-infection-related epilepsy syndrome survivors may regain vital functions and mobility but experience a significant loss of independence and participation due to recurring seizures, structural brain damage and neurocognitive decline. Minimization of disastrous outcomes through the systematic evaluation of rescue therapies within a network of specialized centres is crucial., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Objective: Rasmussen encephalitis (RE) is characterized by its unilateral cerebral involvement. However, both ipsi- and contralesional cerebellar atrophy have been anecdotally reported raising questions about the nature and extent of infratentorial findings. Using MRI, we morphometrically investigated the cerebellum and hypothesized abnormalities beyond the effects of secondary atrophy, implicating a primary involvement of the cerebellum by RE., Methods: Voxel-based morphometry of the cerebellum and brainstem was conducted in 57 patients with RE and in 57 matched controls. Furthermore, patient-specific asymmetry indices (AIs) of cerebellar morphometry and fluid-attenuated inversion recovery (FLAIR) intensity were calculated. Using diffusion tensor imaging, the integrity of the cortico-ponto-cerebellar (CPC) tract was assessed. Finally, a spatial independent component analysis (ICA) was used to compare atrophy patterns between groups., Results: Patients with RE showed bilateral cerebellar and predominantly ipsilesional mesencephalic atrophy ( p < 0.01). Morphometric AIs revealed ipsilesional < contralesional asymmetry in 27 and ipsilesional > contralesional asymmetry in 30 patients. In patients with predominant ipsilesional atrophy, morphometric AIs strongly correlated with FLAIR intensity AIs ( r = 0.86, p < 0.0001). Fractional anisotropy was lower for ipsilesional-to-contralesional CPC tracts than opposite tracts ( T = 2.30, p < 0.05). ICA revealed bilateral and strictly ipsi- and contralesional atrophy components in patients with RE ( p < 0.05)., Discussion: We demonstrated atrophy of the ipsilesional-to-contralesional CPC pathway and, consequently, interpret the loss of contralesional gray matter as secondary crossed cerebellar atrophy. The ipsilesional cerebellar atrophy, however, defies this explanation. Based on FLAIR hyperintensities, we interpret ipsilesional atrophy to be due to inflammation in the scope of a primary involvement of the cerebellum by RE., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Oligonucleotide therapies offer precision treatments for a variety of neurological diseases, including epilepsy, but their deployment is hampered by the blood-brain barrier (BBB). Previous studies showed that intracerebroventricular injection of an antisense oligonucleotide (antagomir) targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in animal models of epilepsy. In this study, we used assays of serum protein and tracer extravasation to determine that BBB disruption occurring after status epilepticus in mice was sufficient to permit passage of systemically injected Ant-134 into the brain parenchyma. Intraperitoneal and intravenous injection of Ant-134 reached the hippocampus and blocked seizure-induced upregulation of miR-134. A single intraperitoneal injection of Ant-134 at 2 h after status epilepticus in mice resulted in potent suppression of spontaneous recurrent seizures, reaching a 99.5% reduction during recordings at 3 months. The duration of spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. In vivo knockdown of LIM kinase-1 (Limk-1) increased seizure frequency in Ant-134-treated mice, implicating de-repression of Limk-1 in the antagomir mechanism. These studies indicate that systemic delivery of Ant-134 reaches the brain and produces long-lasting seizure-suppressive effects after systemic injection in mice when timed with BBB disruption and may be a clinically viable approach for this and other disease-modifying microRNA therapies., Competing Interests: Declaration of interests D.C.H. reports patent US9803200 B2 “Inhibition of microRNA-134 for the treatment of seizure-related disorders and neurologic injuries,” and D.C.H. and C.R.R. report patent WO2019219723A1 “Pharmaceutical compositions for treatment of microRNA related diseases.” The remaining authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)