Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline.

White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05-0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorß and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE.

Diminished circadian and ultradian rhythms of human brain activity in pathological tissue in vivo.

Chronobiological rhythms, such as the circadian rhythm, have long been linked to neurological disorders, but it is currently unknown how pathological processes affect the expression of biological rhythms in the brain. Here, we use the unique opportunity of long-term, continuous intracranially recorded EEG from 38 patients (totalling 6338 hours) to delineate circadian (daily) and ultradian (minute to hourly) rhythms in different brain regions. We show that functional circadian and ultradian rhythms are diminished in pathological tissue, independent of regional variations. We further demonstrate that these diminished rhythms are persistent in time, regardless of load or occurrence of pathological events. These findings provide evidence that brain pathology is functionally associated with persistently diminished chronobiological rhythms in vivo in humans, independent of regional variations or pathological events. Future work interacting with, and restoring, these modulatory chronobiological rhythms may allow for novel therapies.

Vagus nerve stimulation for epilepsy: A narrative review of factors predictive of response.

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy. However, there is a lack of reliable predictors of VNS response in clinical use. The identification of factors predictive of VNS response is important for patient selection and stratification as well as tailored stimulation programming. We conducted a narrative review of the existing literature on prognostic markers for VNS response using clinical, demographic, biochemical, and modality-specific information such as from electroencephalography (EEG), magnetoencephalography, and magnetic resonance imaging (MRI). No individual marker demonstrated sufficient predictive power for individual patients, although several have been suggested, with some promising initial findings. Combining markers from underresearched modalities such as T1-weighted MRI morphometrics and EEG may provide better strategies for treatment optimization.

Delineating structural and metabolic abnormalities in amygdala and hippocampal subfields for different seizure-onset patterns via stereotactic electroencephalography.

AIMS: We aimed to investigate mesial temporal lobe abnormalities in mesial temporal lobe epilepsy (MTLE) patients with hypersynchronous (HYP) and low-voltage fast rhythms (LVF) onset identified by stereotactic electroencephalography (SEEG) and evaluate their diagnostic and prognostic value. METHODS: Fifty-one MTLE patients were categorized as HYP or LVF by SEEG. High-resolution MRI volume-based analysis and 18F-FDG-PET standard uptake values of hippocampal and amygdala subfields were quantified and compared with 57 matched controls. Further analyses were conducted to delineate the distinct pathological characteristics differentiating the two groups. Diagnostic and prognostic prediction performance of these biomarkers were assessed using receiver operating characteristic curves. RESULTS: LVF-onset individuals demonstrated ipsilateral amygdala enlargement (p = 0.048) and contralateral hippocampus hypermetabolism (p = 0.042), pathological results often accompany abnormalities in the temporal lobe cortex, while HYP-onset subjects had significant atrophy (p < 0.001) and hypometabolism (p = 0.013) in ipsilateral hippocampus and its subfields, as well as amygdala atrophy (p < 0.001), pathological results are highly correlated with hippocampal sclerosis. Severe fimbria atrophy was observed in cases of HYP-onset MTLE with poor prognosis (AUC = 0.874). CONCLUSION: Individuals with different seizure-onset patterns display specific morphological and metabolic abnormalities in the amygdala and hippocampus. Identifying these subfield abnormalities can improve diagnostic and prognostic precision, guiding surgical strategies for MTLE.

Quantitative MRI Measures and Cognitive Function in People With Drug-Resistant Juvenile Myoclonic Epilepsy.

BACKGROUND AND OBJECTIVES: Neuroimaging studies have so far identified structural changes in individuals with juvenile myoclonic epilepsy (JME) when compared with controls. However, the underlying mechanisms of drug-resistant JME remain unknown. In this study, we aimed at characterizing the structural underpinnings of drug-resistant JME using MRI-derived cortical morphologic markers. METHODS: In this prospective cross-sectional 2-center study, T1-weighted MRI and neuropsychological measures of verbal memory and executive function were obtained in individuals with drug-resistant and drug-responsive JME recruited from epilepsy outpatient clinics and healthy controls. We performed vertexwise measurements of cortical thickness, surface area, and local gyrification index (LGI). Vertexwise group comparisons were corrected for multiple comparisons at a familywise error (FWE) of 0.05. The neuropsychological profile of disease subgroups was analyzed through principal component analysis. RESULTS: We studied 42 individuals with drug-resistant JME (mean age 29 ± 11 years, 50% female), 37 with drug-responsive JME (mean age 34 ± 10, years, 59% female), and 71 healthy controls (mean age 21 ± 9 years, 61% female). Surface area was increased in participants with drug-resistant JME in the left temporal lobe (Cohen d = 0.82 [-0.52 to -1.12], pFWE < 0.05) when compared with the drug-responsive group. Although no cortical thickness changes were observed between disease subgroups, drug-resistant and drug-sensitive participants showed discrete cortical thinning against controls (Cohen d = -0.42 [-0.83 to -0.01], pFWE < 0.05; Cohen d = -0.57 [-1.03 to -0.11], pFWE < 0.05, respectively). LGI was increased in the left temporal and occipital lobes in drug-resistant participants (Cohen d = 0.60 [0.34-0.86], pFWE < 0.05) when contrasting against drug-sensitive participants, but not controls. The composite executive function score was reduced in drug-resistant individuals compared with controls and drug-sensitive individuals (-1.74 [-2.58 to -0.90], p < 0.001 and -1.29 [-2.25 to -0.33], p < 0.01, respectively). Significant correlations were observed between executive function impairment and increased surface area in the precuneus and medial prefrontal regions (r = -0.79, pFWE < 0.05) in participants with drug-resistant JME. DISCUSSION: We identified a developmental phenotype in individuals with drug-resistant JME characterized by changes in cortical surface area and folding complexity, the extent of which correlates with executive dysfunction. No association was observed between cortical thickness and disease severity. Our findings support a neurodevelopmental basis for drug resistance and cognitive impairment in JME.

Sodium valproate is associated with cortical thinning of disease-specific areas in juvenile myoclonic epilepsy.

BACKGROUND: Juvenile myoclonic epilepsy (JME) is associated with cortical thinning of the motor areas. The relative contribution of antiseizure medication to cortical thickness is unknown. We aimed to investigate how valproate influences the cortical morphology of JME. METHODS: In this cross-sectional study, individuals with JME with and without valproate, with temporal lobe epilepsy (TLE) with valproate and controls were selected through propensity score matching. Participants underwent T1-weighted brain imaging and vertex-wise calculation of cortical thickness. RESULTS: We matched 36 individuals with JME on valproate with 36 individuals with JME without valproate, 36 controls and 19 individuals with TLE on valproate. JME on valproate showed thinning of the precentral gyri (left and right, p<0.001) compared with controls and thinning of the left precentral gyrus when compared with JME not on valproate (p<0.01) or to TLE on valproate (p<0.001). Valproate dose correlated negatively with the thickness of the precentral gyri, postcentral gyri and superior frontal gyrus in JME (left and right p<0.0001), but not in TLE. CONCLUSIONS: Valproate was associated with JME-specific and dose-dependent thinning of the cortical motor regions. This suggests that valproate is a key modulator of cortical morphology in JME, an effect that may underlie its high efficacy in this syndrome.

Incomplete resection of the intracranial electroencephalographic seizure onset zone is not associated with postsurgical outcomes.

Delineation of seizure onset regions using intracranial electroencephalography (icEEG) is vital in the surgical workup of drug-resistant epilepsy cases. However, it is unknown whether the complete resection of these regions is necessary for seizure freedom, or whether postsurgical seizure recurrence can be attributed to the incomplete removal of seizure onset regions. To address this gap, we retrospectively analyzed icEEG recordings from 63 subjects, identifying seizure onset regions visually and algorithmically. We assessed onset region resection and correlated this with postsurgical seizure control. The majority of subjects had more than half of their onset regions resected (82.46% and 80.65% of subjects using visual and algorithmic methods, respectively). There was no association between the proportion of the seizure onset zone (SOZ) that was subsequently resected and better surgical outcomes (area under the receiver operating characteristic curve [AUC] < .7). Investigating the spatial extent of onset regions, we found no substantial evidence of an association with postsurgical seizure control (all AUC < .7). Although seizure onset regions are typically resected completely or in large part, incomplete resection is not associated with worse postsurgical outcomes. We conclude that postsurgical seizure recurrence cannot be attributed to an incomplete resection of the icEEG SOZ alone. Other network mechanisms beyond icEEG seizure onset likely contribute.

Predictors of long-term memory and network connectivity 10 years after anterior temporal lobe resection.

OBJECTIVE: Anterior temporal lobe resection (ATLR) effectively controls seizures in medically refractory temporal lobe epilepsy but risks significant episodic memory decline. Beyond 1 year postoperatively, the influence of preoperative clinical factors on episodic memory and long-term network plasticity remain underexplored. Ten years post-ATLR, we aimed to determine biomarkers of successful memory network reorganization and establish presurgical features' lasting impact on memory function. METHODS: Twenty-five ATLR patients (12 left-sided) and 10 healthy controls underwent a memory-encoding functional magnetic resonance imaging paradigm alongside neuropsychometry 10 years postsurgery. Generalized psychophysiological interaction analyses modeled network functional connectivity of words/faces remembered, seeding from the medial temporal lobes (MTLs). Differences in successful memory connectivity were assessed between controls and left/right ATLR. Multivariate regressions and mixed-effect models probed preoperative phenotypes' effects on long-term memory outcomes. RESULTS: Ten years post-ATLR, lower baseline functioning (verbal and performance intelligence quotient) and a focal memory impairment preoperatively predicted worse long-term memory outcomes. Poorer verbal memory was significantly associated with longer epilepsy duration and earlier onset age. Relative to controls, successful word and face encoding involved increased functional connectivity from both or remnant MTL seeds and contralesional parahippocampus/hippocampus after left/right ATLR. Irrespective of surgical laterality, successful memory encoding correlated with increased MTL-seeded connectivity to frontal (bilateral insula, right anterior cingulate), right parahippocampal, and bilateral fusiform gyri. Ten years postsurgery, better memory performance was correlated with contralateral frontal plasticity, which was disrupted with longer epilepsy duration. SIGNIFICANCE: Our findings underscore the enduring nature of functional network reorganizations to provide long-term cognitive support. Ten years post-ATLR, successful memory formation featured stronger connections near resected areas and contralateral regions. Preoperative network disruption possibly influenced effectiveness of postoperative plasticity. These findings are crucial for enhancing long-term memory prediction and strategies for lasting memory rehabilitation.

Brain Morphology Normative modelling platform for abnormality and Centile estimation: Brain MoNoCle.

Normative models of brain structure estimate the effects of covariates such as age and sex using large samples of healthy controls. These models can then be applied to smaller clinical cohorts to distinguish disease effects from other covariates. However, these advanced statistical modelling approaches can be difficult to access, and processing large healthy cohorts is computationally demanding. Thus, accessible platforms with pre-trained normative models are needed. We present such a platform for brain morphology analysis as an open-source web application https://cnnplab.shinyapps.io/normativemodelshiny/, with six key features: (i) user-friendly web interface, (ii) individual and group outputs, (iii) multi-site analysis, (iv) regional and whole-brain analysis, (v) integration with existing tools, and (vi) featuring multiple morphology metrics. Using a diverse sample of 3,276 healthy controls across 21 sites, we pre-trained normative models on various metrics. We validated the models with a small clinical sample of individuals with bipolar disorder, showing outputs that aligned closely with existing literature only after applying our normative modelling. Further validation with a cohort of temporal lobe epilepsy showed agreement with previous group-level findings and individual-level seizure lateralisation. Finally, with the ability to investigate multiple morphology measures in the same framework, we found that biological covariates are better explained in specific morphology measures, and for clinical applications, only some measures are sensitive to the disease process. Our platform offers a comprehensive framework to analyse brain morphology in clinical and research settings. Validations confirm the superiority of normative models and the advantage of investigating a range of brain morphology metrics together.

Complicated epilepsy surgery: importance of balancing benefit and deficit.

The risk-benefit ratio of epilepsy surgery needs careful consideration, is different for each individual and requires a careful, informed dialogue between the person concerned and their medical advisers. We illustrate this process with Virginia, who has had refractory focal epilepsy from age 1 year and a left hemiparesis. At the age of 45 years, we discussed the possibility of epilepsy surgery and went through non-invasive investigations with structural and functional MRI, tractography, scalp video-EEG telemetry, neuropsychological and neuropsychiatric evaluations. This was followed by a decision to carry out intracranial EEG to define the area of seizure onset and its relation to an area of focal cortical dysplasia, eloquent cortex and tracts. We agreed to carry out a focal resection in the knowledge that this would result in a loss of left-hand function. One year later, Virginia is seizure-free on reduced medication. We describe the steps in the process with Virginia's views.

Tolerability of tariquidar - A third generation P-gp inhibitor as add-on medication to antiseizure medications in drug-resistant epilepsy.

PURPOSE: P-glycoprotein (P-gp) has been hypothesized to be involved in drug-resistance of epilepsy by actively extruding antiseizure medications (ASMs) from the brain. The P-gp inhibitor tariquidar (TQD) has been shown to effectively inhibit P-gp at the human blood-brain barrier, improving brain entry of several ASMs. A potential strategy to overcome drug-resistance is the co-administration of P-gp inhibitors such as TQD to ASMs. Here we present data on the tolerability of single-dose TQD as a potential add-on medication to ASMs. METHODS: We performed a multi-centre cohort study including drug-resistant epilepsy patients and healthy controls from the United Kingdom and Austria. TQD was administered intravenously at five different doses (2 mg/kg or 3 mg/kg of TQD were given to drug-resistant epilepsy patients and healthy controls, higher doses of TQD at 4 mg/kg, 6 mg/kg and 8 mg/kg as well as a prolonged infusion aiming at a dose of 6 mg/kg were only given to healthy controls). Adverse events were recorded and graded using the Common Terminology Criteria (CTCAE) scale. Additionally, TQD plasma concentration levels were measured and compared between drug-resistant patients and healthy controls. RESULTS: In total, 108 participants received TQD once at variable doses and it was overall well tolerated. At doses of 2 or 3 mg/kg TQD, only two of the 19 drug-resistant epilepsy patients and a third of the healthy controls (n = 14/42) reported adverse events probably related to TQD. The majority of those adverse events (96 %) were reported as mild. One drug-resistant epilepsy patient reported adverse events 24-hours after TQD administration possibly related to TQD-induced increased ASMs levels in the brain. CONCLUSIONS: TQD is an effective and well tolerated P-gp inhibitor as a single dose and could potentially be used intermittently in conjunction with ASMs to improve efficacy. This promising strategy to overcome drug-resistance in epilepsy should be investigated further in clinical randomised controlled trials.

Naming fMRI-guided white matter language tract volumes influence naming decline after temporal lobe resection.

OBJECTIVE: The aim of this study was to explore the relation of language functional MRI (fMRI)-guided tractography with postsurgical naming decline in people with temporal lobe epilepsy (TLE). METHODS: Twenty patients with unilateral TLE (9 left) were studied with auditory and picture naming functional MRI tasks. Activation maxima in the left posterobasal temporal lobe were used as seed regions for whole-brain fibre tractography. Clinical naming performance was assessed preoperatively, 4 months, and 12 months following temporal lobe resection. Volumes of white matter language tracts in both hemispheres as well as tract volume laterality indices were explored as moderators of postoperative naming decline using Pearson correlations and multiple linear regression with other clinical variables. RESULTS: Larger volumes of white matter language tracts derived from auditory and picture naming maxima in the hemisphere of subsequent surgery as well as stronger lateralization of picture naming tract volumes to the side of surgery correlated with greater language decline, which was independent of fMRI lateralization status. Multiple regression for picture naming tract volumes was associated with a significant decline of naming function with 100% sensitivity and 93% specificity at both short-term and long-term follow-up. INTERPRETATION: Naming fMRI-guided white matter language tract volumes relate to postoperative naming decline after temporal lobe resection in people with TLE. This can assist stratification of surgical outcome and minimize risk of postoperative language deficits in TLE.

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.

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 (dmax = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax = .47), crus I/II (dmax = .39), VIIIA (dmax = .45), and VIIIB (dmax = .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.

Outcome of Epilepsy Surgery in MRI-Negative Patients Without Histopathologic Abnormalities in the Resected Tissue.

BACKGROUND AND OBJECTIVE: Patients with presumed nonlesional focal epilepsy-based on either MRI or histopathologic findings-have a lower success rate of epilepsy surgery compared with lesional patients. In this study, we aimed to characterize a large group of patients with focal epilepsy who underwent epilepsy surgery despite a normal MRI and had no lesion on histopathology. Determinants of their postoperative seizure outcomes were further studied. METHODS: We designed an observational multicenter cohort study of MRI-negative and histopathology-negative patients who were derived from the European Epilepsy Brain Bank and underwent epilepsy surgery between 2000 and 2012 in 34 epilepsy surgery centers within Europe. We collected data on clinical characteristics, presurgical assessment, including genetic testing, surgery characteristics, postoperative outcome, and treatment regimen. RESULTS: Of the 217 included patients, 40% were seizure-free (Engel I) 2 years after surgery and one-third of patients remained seizure-free after 5 years. Temporal lobe surgery (adjusted odds ratio [AOR]: 2.62; 95% CI 1.19-5.76), shorter epilepsy duration (AOR for duration: 0.94; 95% CI 0.89-0.99), and completely normal histopathologic findings-versus nonspecific reactive gliosis-(AOR: 4.69; 95% CI 1.79-11.27) were significantly associated with favorable seizure outcome at 2 years after surgery. Of patients who underwent invasive monitoring, only 35% reached seizure freedom at 2 years. Patients with parietal lobe resections had lowest seizure freedom rates (12.5%). Among temporal lobe surgery patients, there was a trend toward favorable outcome if hippocampectomy was part of the resection strategy (OR: 2.94; 95% CI 0.98-8.80). Genetic testing was only sporadically performed. DISCUSSION: This study shows that seizure freedom can be reached in 40% of nonlesional patients with both normal MRI and histopathology findings. In particular, nonlesional temporal lobe epilepsy should be regarded as a relatively favorable group, with almost half of patients achieving seizure freedom at 2 years after surgery-even more if the hippocampus is resected-compared with only 1 in 5 nonlesional patients who underwent extratemporal surgery. Patients with an electroclinically identified focus, who are nonlesional, will be a promising group for advanced molecular-genetic analysis of brain tissue specimens to identify new brain somatic epilepsy genes or epilepsy-associated molecular pathways.

Epileptogenic networks in extra temporal lobe epilepsy.

Extra temporal lobe epilepsy (eTLE) may involve heterogenous widespread cerebral networks. We investigated the structural network of an eTLE cohort, at the postulated epileptogenic zone later surgically removed, as a network node: the resection zone (RZ). We hypothesized patients with an abnormal connection to/from the RZ to have proportionally increased abnormalities based on topological proximity to the RZ, in addition to poorer post-operative seizure outcome. Structural and diffusion MRI were collected for 22 eTLE patients pre- and post-surgery, and for 29 healthy controls. The structural connectivity of the RZ prior to surgery, measured via generalized fractional anisotropy (gFA), was compared with healthy controls. Abnormal connections were identified as those with substantially reduced gFA (z < -1.96). For patients with one or more abnormal connections to/from the RZ, connections with closer topological distance to the RZ had higher proportion of abnormalities. The minority of the seizure-free patients (3/11) had one or more abnormal connections, while most non-seizure-free patients (8/11) had abnormal connections to the RZ. Our data suggest that eTLE patients with one or more abnormal structural connections to/from the RZ had more proportional abnormal connections based on topological distance to the RZ and associated with reduced chance of seizure freedom post-surgery.

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.

Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current cortico-centric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural MRI in 1,602 adults with epilepsy and 1,022 healthy controls across twenty-two 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 i) all epilepsies; ii) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS); iii) non-lesional temporal lobe epilepsy (TLE-NL); iv) genetic generalised epilepsy; and (v) extra-temporal 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=0.42). Maximum volume loss was observed in the corpus medullare (dmax=0.49) and posterior lobe grey matter regions, including bilateral lobules VIIB (dmax= 0.47), Crus I/II (dmax= 0.39), VIIIA (dmax=0.45) and VIIIB (dmax=0.40). Earlier age at seizure onset (ηρ2max=0.05) and longer epilepsy duration (ηρ2max=0.06) 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 grey matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in non-motor 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 cerebellum subregions into neurobiological models of epilepsy.

Interictal magnetoencephalography abnormalities to guide intracranial electrode implantation and predict surgical outcome.

Intracranial EEG is the gold standard technique for epileptogenic zone localization but requires a preconceived hypothesis of the location of the epileptogenic tissue. This placement is guided by qualitative interpretations of seizure semiology, MRI, EEG and other imaging modalities, such as magnetoencephalography. Quantitative abnormality mapping using magnetoencephalography has recently been shown to have potential clinical value. We hypothesized that if quantifiable magnetoencephalography abnormalities were sampled by intracranial EEG, then patients' post-resection seizure outcome may be better. Thirty-two individuals with refractory neocortical epilepsy underwent magnetoencephalography and subsequent intracranial EEG recordings as part of presurgical evaluation. Eyes-closed resting-state interictal magnetoencephalography band power abnormality maps were derived from 70 healthy controls as a normative baseline. Magnetoencephalography abnormality maps were compared to intracranial EEG electrode implantation, with the spatial overlap of intracranial EEG electrode placement and cerebral magnetoencephalography abnormalities recorded. Finally, we assessed if the implantation of electrodes in abnormal tissue and subsequent resection of the strongest abnormalities determined by magnetoencephalography and intracranial EEG corresponded to surgical success. We used the area under the receiver operating characteristic curve as a measure of effect size. Intracranial electrodes were implanted in brain tissue with the most abnormal magnetoencephalography findings-in individuals that were seizure-free postoperatively (T = 3.9, P = 0.001) but not in those who did not become seizure-free. The overlap between magnetoencephalography abnormalities and electrode placement distinguished surgical outcome groups moderately well (area under the receiver operating characteristic curve = 0.68). In isolation, the resection of the strongest abnormalities as defined by magnetoencephalography and intracranial EEG separated surgical outcome groups well, area under the receiver operating characteristic curve = 0.71 and area under the receiver operating characteristic curve = 0.74, respectively. A model incorporating all three features separated surgical outcome groups best (area under the receiver operating characteristic curve = 0.80). Intracranial EEG is a key tool to delineate the epileptogenic zone and help render individuals seizure-free postoperatively. We showed that data-driven abnormality maps derived from resting-state magnetoencephalography recordings demonstrate clinical value and may help guide electrode placement in individuals with neocortical epilepsy. Additionally, our predictive model of postoperative seizure freedom, which leverages both magnetoencephalography and intracranial EEG recordings, could aid patient counselling of expected outcome.

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.

Complementary structural and functional abnormalities to localise epileptogenic tissue.

BACKGROUND: When investigating suitability for epilepsy surgery, people with drug-refractory focal epilepsy may have intracranial EEG (iEEG) electrodes implanted to localise seizure onset. Diffusion-weighted magnetic resonance imaging (dMRI) may be acquired to identify key white matter tracts for surgical avoidance. Here, we investigate whether structural connectivity abnormalities, inferred from dMRI, may be used in conjunction with functional iEEG abnormalities to aid localisation of the epileptogenic zone (EZ), improving surgical outcomes in epilepsy. METHODS: We retrospectively investigated data from 43 patients (42% female) with epilepsy who had surgery following iEEG. Twenty-five patients (58%) were free from disabling seizures (ILAE 1 or 2) at one year. Interictal iEEG functional, and dMRI structural connectivity abnormalities were quantified by comparison to a normative map and healthy controls. We explored whether the resection of maximal abnormalities related to improved surgical outcomes, in both modalities individually and concurrently. Additionally, we suggest how connectivity abnormalities may inform the placement of iEEG electrodes pre-surgically using a patient case study. FINDINGS: Seizure freedom was 15 times more likely in patients with resection of maximal connectivity and iEEG abnormalities (p = 0.008). Both modalities separately distinguished patient surgical outcome groups and when used simultaneously, a decision tree correctly separated 36 of 43 (84%) patients. INTERPRETATION: Our results suggest that both connectivity and iEEG abnormalities may localise epileptogenic tissue, and that these two modalities may provide complementary information in pre-surgical evaluations. FUNDING: This research was funded by UKRI, CDT in Cloud Computing for Big Data, NIH, MRC, Wellcome Trust and Epilepsy Research UK.

Identification of different MRI atrophy progression trajectories in epilepsy by subtype and stage inference.

Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. Here we analyse a cross-sectional multicentre structural MRI dataset of 696 people with epilepsy and 118 control subjects. We use an innovative machine-learning algorithm, Subtype and Stage Inference, to develop a novel data-driven disease taxonomy, whereby epilepsy subtypes correspond to distinct patterns of spatiotemporal progression of brain atrophy.In a discovery cohort of 814 individuals, we identify two subtypes common to focal and idiopathic generalized epilepsies, characterized by progression of grey matter atrophy driven by the cortex or the basal ganglia. A third subtype, only detected in focal epilepsies, was characterized by hippocampal atrophy. We corroborate external validity via an independent cohort of 254 people and confirm that the basal ganglia subtype is associated with the most severe epilepsy.Our findings suggest fundamental processes underlying the progression of epilepsy-related brain atrophy. We deliver a novel MRI- and AI-guided epilepsy taxonomy, which could be used for individualized prognostics and targeted therapeutics.