The clinical, imaging, pathological and genetic landscape of bottom-of-sulcus dysplasia.

Bottom-of-sulcus dysplasia (BOSD) is increasingly recognized as a cause of drug-resistant, surgically-remediable, focal epilepsy, often in seemingly MRI-negative patients. We describe the clinical manifestations, morphological features, localization patterns and genetics of BOSD, with the aims of improving management and understanding pathogenesis. We studied 85 patients with BOSD diagnosed between 2005-2022. Presenting seizure and EEG characteristics, clinical course, genetic findings and treatment response were obtained from medical records. MRI (3 T) and 18F-FDG-PET scans were reviewed systematically for BOSD morphology and metabolism. Histopathological analysis and tissue genetic testing were performed in 64 operated patients. BOSD locations were transposed to common imaging space to study anatomical location, functional network localization and relationship to normal MTOR gene expression. All patients presented with stereotyped focal seizures with rapidly escalating frequency, prompting hospitalization in 48%. Despite 42% patients having seizure remissions, usually with sodium channel blocking medications, most eventually became drug-resistant and underwent surgery (86% seizure-free). Prior developmental delay was uncommon but intellectual, language and executive dysfunction were present in 24%, 48% and 29% when assessed preoperatively, low intellect being associated with greater epilepsy duration. BOSDs were missed on initial MRI in 68%, being ultimately recognized following repeat MRI, 18F-FDG-PET or image postprocessing. MRI features were grey-white junction blurring (100%), cortical thickening (91%), transmantle band (62%), increased cortical T1 signal (46%) and increased subcortical FLAIR signal (26%). BOSD hypometabolism was present on 18F-FDG-PET in 99%. Additional areas of cortical malformation or grey matter heterotopia were present in eight patients. BOSDs predominated in frontal and pericentral cortex and related functional networks, mostly sparing temporal and occipital cortex, and limbic and visual networks. Genetic testing yielded pathogenic mTOR pathway variants in 63% patients, including somatic MTOR variants in 47% operated patients and germline DEPDC5 or NPRL3 variants in 73% patients with familial focal epilepsy. BOSDs tended to occur in regions where the healthy brain normally shows lower MTOR expression, suggesting these regions may be more vulnerable to upregulation of MTOR activity. Consistent with the existing literature, these results highlight (i) clinical features raising suspicion of BOSD; (ii) the role of somatic and germline mTOR pathway variants in patients with sporadic and familial focal epilepsy associated with BOSD; and (iii) the role of 18F-FDG-PET alongside high-field MRI in detecting subtle BOSD. The anatomical and functional distribution of BOSDs likely explain their seizure, EEG and cognitive manifestations and may relate to relative MTOR expression.

Structural and functional abnormalities and cognitive profiles in older adults with early-onset and late-onset focal epilepsy.

This study aimed to determine the patterns of changes in structure, function, and cognitive ability in early-onset and late-onset older adults with focal epilepsy (OFE). This study first utilized the deformation-based morphometry analysis to identify structural abnormalities, which were used as the seed region to investigate the functional connectivity with the whole brain. Next, a correlation analysis was performed between the altered imaging findings and neuropsychiatry assessments. Finally, the potential role of structural-functional abnormalities in the diagnosis of epilepsy was further explored by using mediation analysis. Compared with healthy controls (n = 28), the area of reduced structural volume was concentrated in the bilateral cerebellum, right thalamus, and right middle cingulate cortex, with frontal, temporal, and occipital lobes also affected in early-onset focal epilepsy (n = 26), while late-onset patients (n = 31) displayed cerebellar, thalamic, and cingulate atrophy. Furthermore, correlation analyses suggest an association between structural abnormalities and cognitive assessments. Dysfunctional connectivity in the cerebellum, cingulate cortex, and frontal gyrus partially mediates the relationship between structural abnormalities and the diagnosis of early-onset focal epilepsy. This study identified structural and functional abnormalities in early-onset and late-onset focal epilepsy and explored characters in cognitive performance. Structural-functional coupling may play a potential role in the diagnosis of epilepsy.

Widespread, depth-dependent cortical microstructure alterations in pediatric focal epilepsy.

OBJECTIVE: Tissue abnormalities in focal epilepsy may extend beyond the presumed focus. The underlying pathophysiology of these broader changes is unclear, and it is not known whether they result from ongoing disease processes or treatment-related side effects, or whether they emerge earlier. Few studies have focused on the period of onset for most focal epilepsies, childhood. Fewer still have utilized quantitative magnetic resonance imaging (MRI), which may provide a more sensitive and interpretable measure of tissue microstructural change. Here, we aimed to determine common spatial modes of changes in cortical architecture in children with heterogeneous drug-resistant focal epilepsy and, secondarily, whether changes were related to disease severity. METHODS: To assess cortical microstructure, quantitative T1 and T2 relaxometry (qT1 and qT2) was measured in 43 children with drug-resistant focal epilepsy (age range = 4-18 years) and 46 typically developing children (age range = 2-18 years). We assessed depth-dependent qT1 and qT2 values across the neocortex, as well as their gradient of change across cortical depths. We also determined whether global changes seen in group analyses were driven by focal pathologies in individual patients. Finally, as a proof-of-concept, we trained a classifier using qT1 and qT2 gradient maps from patients with radiologically defined abnormalities (MRI positive) and healthy controls, and tested whether this could classify patients without reported radiological abnormalities (MRI negative). RESULTS: We uncovered depth-dependent qT1 and qT2 increases in widespread cortical areas in patients, likely representing microstructural alterations in myelin or gliosis. Changes did not correlate with disease severity measures, suggesting they may represent antecedent neurobiological alterations. Using a classifier trained with MRI-positive patients and controls, sensitivity was 71.4% at 89.4% specificity on held-out MRI-negative patients. SIGNIFICANCE: These findings suggest the presence of a potential imaging endophenotype of focal epilepsy, detectable irrespective of radiologically identified abnormalities.

Combining magnetic resonance fingerprinting with voxel-based morphometric analysis to reduce false positives for focal cortical dysplasia detection.

OBJECTIVE: We aim to improve focal cortical dysplasia (FCD) detection by combining high-resolution, three-dimensional (3D) magnetic resonance fingerprinting (MRF) with voxel-based morphometric magnetic resonance imaging (MRI) analysis. METHODS: We included 37 patients with pharmacoresistant focal epilepsy and FCD (10 IIa, 15 IIb, 10 mild Malformation of Cortical Development [mMCD], and 2 mMCD with oligodendroglial hyperplasia and epilepsy [MOGHE]). Fifty-nine healthy controls (HCs) were also included. 3D lesion labels were manually created. Whole-brain MRF scans were obtained with 1 mm3 isotropic resolution, from which quantitative T1 and T2 maps were reconstructed. Voxel-based MRI postprocessing, implemented with the morphometric analysis program (MAP18), was performed for FCD detection using clinical T1w images, outputting clusters with voxel-wise lesion probabilities. Average MRF T1 and T2 were calculated in each cluster from MAP18 output for gray matter (GM) and white matter (WM) separately. Normalized MRF T1 and T2 were calculated by z-scores using HCs. Clusters that overlapped with the lesion labels were considered true positives (TPs); clusters with no overlap were considered false positives (FPs). Two-sample t-tests were performed to compare MRF measures between TP/FP clusters. A neural network model was trained using MRF values and cluster volume to distinguish TP/FP clusters. Ten-fold cross-validation was used to evaluate model performance at the cluster level. Leave-one-patient-out cross-validation was used to evaluate performance at the patient level. RESULTS: MRF metrics were significantly higher in TP than FP clusters, including GM T1, normalized WM T1, and normalized WM T2. The neural network model with normalized MRF measures and cluster volume as input achieved mean area under the curve (AUC) of .83, sensitivity of 82.1%, and specificity of 71.7%. This model showed superior performance over direct thresholding of MAP18 FCD probability map at both the cluster and patient levels, eliminating ≥75% FP clusters in 30% of patients and ≥50% of FP clusters in 91% of patients. SIGNIFICANCE: This pilot study suggests the efficacy of MRF for reducing FPs in FCD detection, due to its quantitative values reflecting in vivo pathological changes. © 2024 International League Against Epilepsy.

Why did my seizures start now? Influences of lesion connectivity and genetic etiology on age at seizure onset in focal epilepsy.

OBJECTIVE: Patients with focal, lesional epilepsy present with seizures at variable ages. Larger lesion size and overlap with sensorimotor or default mode network (DMN) have been associated with younger age at seizure onset in cohorts with mixed types of focal cortical dysplasia (FCD). Here, we studied determinants of age at seizure onset in patients with bottom-of-sulcus dysplasia (BOSD), a discrete type of FCD with highly localized epileptogenicity. METHODS: Eighty-four patients (77% operated) with BOSD were studied. Demographic, histopathologic, and genetic findings were recorded. BOSD volume and anatomical, primary versus association, rostral versus caudal, and functional network locations were determined. Normative functional connectivity analyses were performed using each BOSD as a region of interest in resting-state functional magnetic resonance imaging data of healthy children. Variables were correlated with age at seizure onset. RESULTS: Median age at seizure onset was 5.4 (interquartile range = 2-7.9) years. Of 50 tested patients, 22 had somatic and nine had germline pathogenic mammalian target of rapamycin (mTOR) pathway variants. Younger age at seizure onset was associated with greater BOSD volume (p = .002), presence of a germline pathogenic variant (p = .04), DMN overlap (p = .04), and increased functional connectivity with the DMN (p < .05, false discovery rate corrected). Location within sensorimotor cortex and networks was not associated with younger age at seizure onset in our relatively small but homogenous cohort. SIGNIFICANCE: Greater lesion size, pathogenic mTOR pathway germline variants, and DMN connectivity are associated with younger age at seizure onset in small FCD. Our findings strengthen the suggested role of DMN connectivity in the onset of FCD-related focal epilepsy and reveal novel contributions of genetic etiology.

Anti-seizure medication response and the glymphatic system in patients with focal epilepsy.

BACKGROUND AND PURPOSE: We aimed to evaluate (i) glymphatic system function in patients with focal epilepsy in comparison with healthy controls, and (ii) the association between anti-seizure medication (ASM) response and glymphatic system function by using diffusion tensor image analysis along the perivascular space (DTI-ALPS). METHODS: We retrospectively enrolled 100 patients with focal epilepsy who had normal brain magnetic resonance imaging (MRI) findings, and classified them as "poor" or "good" ASM responders according to their seizure control at the time of brain MRI. We also included 79 age- and sex-matched healthy controls. All patients and healthy controls underwent conventional brain MRI and diffusion tensor imaging. The DTI-ALPS index was calculated using the DSI studio program. RESULTS: Of the 100 patients with focal epilepsy, 38 and 62 were poor and good ASM responders, respectively. The DTI-ALPS index differed significantly between patients with focal epilepsy and healthy controls and was significantly lower in patients with focal epilepsy (1.55 vs. 1.70; p < 0.001). The DTI-ALPS index also differed significantly according to ASM response and was lower in poor ASM responders (1.48 vs. 1.59; p = 0.047). Furthermore, the DTI-ALPS index was negatively correlated with age (r = -0.234, p = 0.019) and duration of epilepsy (r = -0.240, p = 0.016) in patients with focal epilepsy. CONCLUSION: Our study is the first to identify, in focal epilepsy patients, a greater reduction in glymphatic system function among poor ASM responders compared to good responders. To confirm our results, further prospective multicenter studies with large sample sizes are needed.

Multi-scale structural alterations of the thalamus and basal ganglia in focal epilepsy using 7T MRI.

Focal epilepsy is characterized by repeated spontaneous seizures that originate from cortical epileptogenic zone networks (EZN). Analysis of intracerebral recordings showed that subcortical structures, and in particular the thalamus, play an important role in seizure dynamics as well, supporting their structural alterations reported in the neuroimaging literature. Nonetheless, between-patient differences in EZN localization (e.g., temporal vs. non-temporal lobe epilepsy) as well as extension (i.e., number of epileptogenic regions) might impact the magnitude as well as spatial distribution of subcortical structural changes. Here we used 7 Tesla MRI T1 data to provide an unprecedented description of subcortical morphological (volume, tissue deformation, and shape) and longitudinal relaxation (T1 ) changes in focal epilepsy patients and evaluate the impact of the EZN and other patient-specific clinical features. Our results showed variable levels of atrophy across thalamic nuclei that appeared most prominent in the temporal lobe epilepsy group and the side ipsilateral to the EZN, while shortening of T1 was especially observed for the lateral thalamus. Multivariate analyses across thalamic nuclei and basal ganglia showed that volume acted as the dominant discriminator between patients and controls, while (posterolateral) thalamic T1 measures looked promising to further differentiate patients based on EZN localization. In particular, the observed differences in T1 changes between thalamic nuclei indicated differential involvement based on EZN localization. Finally, EZN extension was found to best explain the observed variability between patients. To conclude, this work revealed multi-scale subcortical alterations in focal epilepsy as well as their dependence on several clinical characteristics.

Novel noninvasive identification of patient-specific epileptic networks in focal epilepsies: Linking single-photon emission computed tomography perfusion during seizures with resting-state magnetoencephalography dynamics.

Single-photon emission computed tomography (SPECT) during seizures and magnetoencephalography (MEG) during the interictal state are noninvasive modalities employed in the localization of the epileptogenic zone in patients with drug-resistant focal epilepsy (DRFE). The present study aims to investigate whether there exists a preferentially high MEG functional connectivity (FC) among those regions of the brain that exhibit hyperperfusion or hypoperfusion during seizures. We studied MEG and SPECT data in 30 consecutive DRFE patients who had resective epilepsy surgery. We parcellated each ictal perfusion map into 200 regions of interest (ROIs) and generated ROI time series using source modeling of MEG data. FC between ROIs was quantified using coherence and phase-locking value. We defined a generalized linear model to relate the connectivity of each ROI, ictal perfusion z score, and distance between ROIs. We compared the coefficients relating perfusion z score to FC of each ROI and estimated the connectivity within and between resected and unresected ROIs. We found that perfusion z scores were strongly correlated with the FC of hyper-, and separately, hypoperfused ROIs across patients. High interictal connectivity was observed between hyperperfused brain regions inside and outside the resected area. High connectivity was also observed between regions of ictal hypoperfusion. Importantly, the ictally hypoperfused regions had a low interictal connectivity to regions that became hyperperfused during seizures. We conclude that brain regions exhibiting hyperperfusion during seizures highlight a preferentially connected interictal network, whereas regions of ictal hypoperfusion highlight a separate, discrete and interconnected, interictal network.

Actigraphic correlates of neuropsychiatric symptoms in adults with focal epilepsy.

OBJECTIVES: Disability in patients with epilepsy (PWEs) is multifactorial: beyond seizure frequency/severity, PWEs are prone to a range of neuropsychiatric, cognitive, and somatic comorbidities that significantly affect quality of life. Here, we explored how variations in seizure severity and the burden of self-reported somatic/neuropsychiatric symptoms correlate with disruptions to 24 h activity patterns (rest-activity rhythms [RARs]), determined through wrist accelerometry/actigraphy. METHODS: Multiday wrist-actigraphy recordings were obtained from 59 adult patients with focal epilepsy (44% male, ages 18-72), who contemporaneously responded to validated psychometric instruments to measure anxiety, depression, sleepiness, and somatic symptoms. We conducted a similar in silico psychometric-actigraphic correlation in a publicly available data set of 1747 Hispanic subjects (35% male, ages 18-65) from the Study of Latinos (SOL) Sueño Ancillary Study. RARs were analyzed via a sigmoidally-transformed cosine model (quantifying amplitude, steepness, acrophase, and robustness) and nonparametric measures to estimate RAR stability, fragmentation, and sleep. RESULTS: Compared with matched SOL subjects, RARs from PWE subjects featured a significantly lower amplitude, a wider rest phase, and significantly more total daily sleep. Within PWEs, similar RAR distortions were associated with seizure intractability and/or anticonvulsant polytherapy, whereas high anxiety, depression, and somatic symptom scores were associated with lower RAR robustness and acrophase delay. We applied the SOL data set to train logistic regression models to dichotomously classify subjective anxiety, depression, and sleepiness symptoms using demographic and RAR parameters. When tested on PWEs, these models predicted prevalent anxiety and depression symptom burden (accuracy ~70%) but failed to predict subjective sleepiness. SIGNIFICANCE: Together these results demonstrate that RAR features may encode prevalent depression and anxiety symptoms in patients with focal epilepsy, potentially offering wearable-derived endpoints to adjunct clinical care and drug/device trials. With larger PWE-specific actigraphic-psychometric data sets, we may identify RAR signatures that may more precisely correlate with varying seizure frequency, the burden of anticonvulsant therapy, and prevalent mood/anxiety symptoms.

Evaluating whole-brain tissue-property changes in MRI-negative pharmacoresistant focal epilepsies using MR fingerprinting.

OBJECTIVE: We aim to quantify whole-brain tissue-property changes in patients with magnetic resonance imaging (MRI)-negative pharmacoresistant focal epilepsy by three-dimensional (3D) magnetic resonance fingerprinting (MRF). METHODS: We included 30 patients with pharmacoresistant focal epilepsy and negative MRI by official radiology report, as well as 40 age- and gender-matched healthy controls (HCs). MRF scans were obtained with 1 mm3 isotropic resolution. Quantitative T1 and T2 relaxometry maps were reconstructed from MRF and registered to the Montreal Neurological Institute (MNI) space. A two-sample t test was performed in Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) to evaluate significant abnormalities in patients comparing to HCs, with correction by the threshold-free cluster enhancement (TFCE) method. Subgroups analyses were performed for extra-temporal epilepsy/temporal epilepsy (ETLE/TLE), and for those with/without subtle abnormalities detected by morphometric analysis program (MAP), to investigate each subgroup's pattern of MRF changes. Correlation analyses were performed between the mean MRF values in each significant cluster and seizure-related clinical variables. RESULTS: Compared to HCs, patients exhibited significant group-level T1 increase ipsilateral to the epileptic origin, in the mesial temporal gray matter (GM) and white matter (WM), temporal pole GM, orbitofrontal GM, hippocampus, and amygdala, with scattered clusters in the neocortical temporal and insular GM. No significant T2 changes were detected. The ETLE subgroup showed a T1-increase pattern similar to the overall cohort, with additional involvement of the ipsilateral anterior cingulate GM. The subgroup of MAP+ patients also showed a T1-increase pattern similar to the overall cohort, with additional cluster in the ipsilateral lateral orbitofrontal GM. Higher T1 was associated with younger seizure-onset age, longer epilepsy duration, and higher seizure frequency. SIGNIFICANCE: MRF revealed group-level T1 increase in limbic/paralimbic structures ipsilateral to the epileptic origin, in patients with pharmacoresistant focal epilepsy and no apparent lesions on MRI, suggesting that these regions may be commonly affected by seizures in the epileptic brain. The significant association between T1 increase and higher seizure burden may reflect progressive tissue damage.

Altered amygdala volumes and microstructure in focal epilepsy patients with tonic-clonic seizures, ictal, and post-convulsive central apnea.

OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death for patients with epilepsy; however, the pathophysiology remains unclear. Focal-to-bilateral tonic-clonic seizures (FBTCS) are a major risk factor, and centrally-mediated respiratory depression may increase the risk further. Here, we determined the volume and microstructure of the amygdala, a key structure that can trigger apnea in people with focal epilepsy, stratified by the presence or absence of FBTCS, ictal central apnea (ICA), and post-convulsive central apnea (PCCA). METHODS: Seventy-three patients with focal impaired awareness seizures without FBTC seizures (FBTCneg group) and 30 with FBTCS (FBTCpos group) recorded during video electroencephalography (VEEG) with respiratory monitoring were recruited prospectively during presurgical investigations. We acquired high-resolution T1-weighted anatomic and multi-shell diffusion images, and computed neurite orientation dispersion and density imaging (NODDI) metrics in all patients with epilepsy and 69 healthy controls. Amygdala volumetric and microstructure alterations were compared between three groups: healthy subjects, FBTCneg and FBTCpos groups. The FBTCpos group was further subdivided by the presence of ICA and PCCA, verified by VEEG. RESULTS: Bilateral amygdala volumes were significantly increased in the FBTCpos cohort compared to healthy controls and the FBTCneg group. Patients with recorded PCCA had the highest increase in bilateral amygdala volume of the FBTCpos cohort. Amygdala neurite density index (NDI) values were decreased significantly in both the FBTCneg and FBTCpos groups relative to healthy controls, with values in the FBTCpos group being the lowest of the two. The presence of PCCA was associated with significantly lower NDI values vs the non-apnea FBTCpos group (p = 0.004). SIGNIFICANCE: Individuals with FBTCpos and PCCA show significantly increased amygdala volumes and disrupted architecture bilaterally, with greater changes on the left side. The structural alterations reflected by NODDI and volume differences may be associated with inappropriate cardiorespiratory patterns mediated by the amygdala, particularly after FBTCS. Determination of amygdala volumetric and architectural changes may assist identification of individuals at risk.

A phase 1 open-label trial evaluating focused ultrasound unilateral anterior thalamotomy for focal onset epilepsy.

OBJECTIVE: Focused ultrasound ablation (FUSA) is an emerging treatment for neurological and psychiatric diseases. We describe the initial experience from a pilot, open-label, single-center clinical trial of unilateral anterior nucleus of the thalamus (ANT) FUSA in patients with treatment-refractory epilepsy. METHODS: Two adult subjects with treatment-refractory, focal onset epilepsy were recruited. The subjects received ANT FUSA using the Exablate Neuro (Insightec) system. We determined the safety and feasibility (primary outcomes), and changes in seizure frequency (secondary outcome) at 3, 6, and 12 months. Safety was assessed by the absence of side effects, that is, new onset neurological deficits or performance deterioration on neuropsychological testing. Feasibility was defined as the ability to create a lesion within the anterior nucleus. The monthly seizure frequency was compared between baseline and postthalamotomy. RESULTS: The patients tolerated the procedure well, without neurological deficits or serious adverse events. One patient experienced a decline in verbal fluency, attention/working memory, and immediate verbal memory. Seizure frequency reduced significantly in both patients; one patient was seizure-free at 12 months, and in the second patient, the frequency reduced from 90-100 seizures per month to 3-6 seizures per month. SIGNIFICANCE: This is the first known clinical trial to assess the safety, feasibility, and preliminary efficacy of ANT FUSA in adult patients with treatment-refractory focal onset epilepsy.

Associations between testing and treatment pathways in lesional temporal or extratemporal epilepsy: A census survey of NAEC center directors.

OBJECTIVE: The evaluation to determine candidacy and treatment for epilepsy surgery in persons with drug-resistant epilepsy (DRE) is not uniform. Many non-invasive and invasive tests are available to ascertain an appropriate treatment strategy. This study examines expert response to clinical vignettes of magnetic resonance imaging (MRI)-positive lesional focal cortical dysplasia in both temporal and extratemporal epilepsy to identify associations in evaluations and treatment choice. METHODS: We analyzed annual report data and a supplemental epilepsy practice survey reported in 2020 from 206 adult and 136 pediatric epilepsy center directors in the United States. Non-invasive and invasive testing and surgical treatment strategies were compiled for the two scenarios. We used chi-square tests to compare testing utilization between the two scenarios. Multivariable logistic regression modeling was performed to assess associations between variables. RESULTS: The supplemental survey response rate was 100% with 342 responses included in the analyses. Differing testing and treatment approaches were noted between the temporal and extratemporal scenarios such as chronic invasive monitoring selected in 60% of the temporal scenario versus 93% of the extratemporal scenario. Open resection was the most common treatment choice; however, overall treatment choices varied significantly (p < .001). Associations between non-invasive testing, invasive testing, and treatment choices were present in both scenarios. For example, in the temporal scenario stereo-electroencephalography (SEEG) was more commonly associated with fluorodeoxyglucose-positron emission tomography (FDG-PET) (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.06-3.29; p = .033), magnetoencephalography (MEG) (OR 2.90; 95% CI 1.60-5.28; p = <.001), high density (HD) EEG (OR 2.80; 95% CI 1.27-6.24; p = .011), functional MRI (fMRI) (OR 2.17; 95% CI 1.19-4.10; p = .014), and Wada (OR 2.16; 95% CI 1.28-3.66; p = .004). In the extratemporal scenario, choosing SEEG was associated with increased odds of neuromodulation over open resection (OR 3.13; 95% CI 1.24-7.89; p = .016). SIGNIFICANCE: In clinical vignettes of temporal and extratemporal lesional DRE, epilepsy center directors displayed varying patterns of non-invasive testing, invasive testing, and treatment choices. Differences in practice underscore the need for comparative trials for the surgical management of DRE.

Verbal fluency functional magnetic resonance imaging detects anti-seizure effects and affective side effects of perampanel in people with focal epilepsy.

Perampanel, a noncompetitive antagonist of the postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor, is effective for controlling focal to bilateral tonic-clonic seizures but is also known to increase feelings of anger. Using statistical parametric mapping-derived measures of activation and task-modulated functional connectivity (psychophysiologic interaction), we investigated 14 people with focal epilepsy who had verbal fluency functional magnetic resonance imaging (fMRI) twice, before and after the add-on treatment of perampanel. For comparison, we included 28 people with epilepsy, propensity-matched for clinical characteristics, who had two scans but no change in anti-seizure medication (ASM) regimen in-between. After commencing perampanel, individuals had higher task-related activations in left orbitofrontal cortex (OFC), fewer task-related activations in the subcortical regions including the left thalamus and left caudate, and lower task-related thalamocaudate and caudate-subtantial nigra connectivity. Decreased task-related connectivity is observed between the left OFC and precuneus and left medial frontal lobe. Our results highlight the brain regions associated with the beneficiary therapeutic effects on focal to bilateral tonic-clonic seizures (thalamus and caudate) but also the undesired affective side effects of perampanel with increased anger and aggression (OFC).

A multi-scale cortical wiring space links cellular architecture and functional dynamics in the human brain.

The vast net of fibres within and underneath the cortex is optimised to support the convergence of different levels of brain organisation. Here, we propose a novel coordinate system of the human cortex based on an advanced model of its connectivity. Our approach is inspired by seminal, but so far largely neglected models of cortico-cortical wiring established by postmortem anatomical studies and capitalises on cutting-edge in vivo neuroimaging and machine learning. The new model expands the currently prevailing diffusion magnetic resonance imaging (MRI) tractography approach by incorporation of additional features of cortical microstructure and cortico-cortical proximity. Studying several datasets and different parcellation schemes, we could show that our coordinate system robustly recapitulates established sensory-limbic and anterior-posterior dimensions of brain organisation. A series of validation experiments showed that the new wiring space reflects cortical microcircuit features (including pyramidal neuron depth and glial expression) and allowed for competitive simulations of functional connectivity and dynamics based on resting-state functional magnetic resonance imaging (rs-fMRI) and human intracranial electroencephalography (EEG) coherence. Our results advance our understanding of how cell-specific neurobiological gradients produce a hierarchical cortical wiring scheme that is concordant with increasing functional sophistication of human brain organisation. Our evaluations demonstrate the cortical wiring space bridges across scales of neural organisation and can be easily translated to single individuals.

Structural brain network analysis in occipital lobe epilepsy.

BACKGROUND: This study aimed to analyze the structural brain network in patients with occipital lobe epilepsy (OLE) and investigate the differences in structural brain networks between patients with OLE and healthy controls. METHODS: Patients with OLE and healthy controls with normal brain MRI findings were enrolled. They underwent diffusion tensor imaging using a 3.0T MRI scanner, and we computed the network measures of global and local structural networks in patients with OLE and healthy controls using the DSI studio program. We compared network measures between the groups. RESULTS: We enrolled 23 patients with OLE and 42 healthy controls. There were significant differences in the global structural network between patients with OLE and healthy controls. The assortativity coefficient (-0.0864 vs. -0.0814, p = 0.0214), mean clustering coefficient (0.0061 vs. 0.0064, p = 0.0203), global efficiency (0.0315 vs. 0.0353, p = 0.0086), and small-worldness index (0.0001 vs. 0.0001, p = 0.0175) were lower, whereas the characteristic path length (59.2724 vs. 53.4684, p = 0.0120) was higher in patients with OLE than those in the healthy controls. There were several nodes beyond the occipital lobe that showed significant differences in the local structural network between the groups. In addition, the assortativity coefficient was negatively correlated with the duration of epilepsy (r=-0.676, p = 0.001).

Interpretable surface-based detection of focal cortical dysplasias: a Multi-centre Epilepsy Lesion Detection study.

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted 'gold-standard' subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy.

Novel GATOR1 variants in focal epilepsy.

INTRODUCTION: Variants in GATOR1 genes are well established in focal epilepsy syndromes. A strong association of GATOR1 variants with drug-resistant epilepsy as well as an increased risk of sudden unexplained death in epilepsy warrants developing strategies to facilitate the identification of patients who could potentially benefit from genetic testing and precision medicine. We aimed to determine the yield of GATOR1 gene sequencing in patients with focal epilepsy typically referred for genetic testing, establish novel GATOR1 variants and determine clinical, electroencephalographic, and radiological characteristics of variant carriers. PATIENTS AND METHODS: Ninety-six patients with clinical suspicion of genetic focal epilepsy with previous comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia, were included in the study. Sequencing was performed using a custom gene panel encompassing DEPDC5, NPRL2, and NPRL3. Variants of interest (VOI) were classified according to criteria proposed by the American College of Medical Genetics and the Association for Molecular Pathology. RESULTS: Four previously unreported VOI in 4/96 (4.2%) patients were found in our cohort. Three likely pathogenic variants were determined in 3/96 (3.1%) patients, one frameshift variant in DEPDC5 in a patient with nonlesional frontal lobe epilepsy, one splicogenic DEPDC5 variant in a patient with nonlesional posterior quadrant epilepsy, and one frameshift variant in NPRL2 in a patient with temporal lobe epilepsy associated with hippocampal sclerosis. Only one VOI, a missense variant in NPRL3, found in 1/96 (1.1%) patients, was classified as a variant of unknown significance. CONCLUSION: GATOR1 gene sequencing was diagnostic in 3.1% of our cohort and revealed three novel likely pathogenic variants, including a previously unreported association of temporal lobe epilepsy with hippocampal sclerosis with an NPRL2 variant. Further research is essential for a better understanding of the clinical scope of GATOR1 gene-associated epilepsy.

Use of sulthiame as add-on therapy in children with non-self-limited focal epilepsies of childhood.

PURPOSE: This retrospective study aimed to evaluate the efficacy and tolerability of sulthiame (STM) as an add-on treatment in 49 patients with non-self-limited focal epilepsies of childhood (non-SeLFE) resistant to other antiseizure medications (ASM) and/or non-pharmacological treatment. METHODS: Patients with non-SeLFE who had failed to respond to at least five previous ASM, alone or in combination, were included in the study. All patients underwent neurological examination, brain magnetic resonance imaging repeated prolonged electroencephalography (EEG) or video-EEG studies, and neurometabolic studies. School achievements and/or performance on neuropsychological tests were also assessed. Sulthiame was added in doses ranging from 10 to 40 mg/kg/day. Efficacy was measured by comparing seizure frequency before and after initiating STM therapy. RESULTS: Twenty-nine of 49 patients (59.1%) who received STM as add-on therapy had a greater than 50% decrease in seizures after a mean follow-up of 35 months. One patient (2%) became seizure-free. Fourteen patients (40%) had a 25-50% seizure reduction. The mean time of response was 5 months (range, 3.5 to 6 months). No differences were found either between patients with a response of more or less than 50% or between the response of the focal seizure types (motor or non-motor, with or without consciousness impairment). CONCLUSION: In our study, STM was found to be effective and well-tolerated in children and adolescents with non-SeLFE. In the patients who responded, improvement in the EEG was seen.

Ictal semiology of gelastic seizures.

Gelastic seizures are rare epileptic manifestations characterized by laughter or a smile. The main etiology is represented by hypothalamic hamartoma, but also focal localization of the epileptogenic zone is described. We reviewed a group of patients with gelastic seizures to describe the semiology and to establish any difference related to diverse epilepsy etiologies. Thirty-five seizures from 16 patients (6 females) were reviewed. The study confirms that hypothalamic hamartoma is the more frequent etiology associated with gelastic seizures. Laughter represented the majority of gelastic ictal signs, while the ictal smile was less frequent. In 87.5% of patients, the manifestation of laughter or smile was the only ictal phenomenon, or the first and the most important clinical sign. Interestingly, it has been observed that patients with a lesion localized in the hypothalamic region had more frequently laughter with emotional involvement and that laughter was the only manifestation of the seizure. On the contrary, patients with lesions localized outside the hypothalamic region had more often seizures with laugh without emotional involvement, resembling a more mechanical action, and associated with other semeiological signs. It, therefore, seems possible to assume that the emotional involvement and the expression of mirth during the seizure, especially in children, are more frequently associated with hypothalamic hamartoma. On the contrary, when the semiology includes less conveyed emotion similar to a mechanical action and other symptoms, an extra hypothalamic localization should be considered.