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Background and purpose: Pre‐surgical evaluation of pediatric patients with drug‐resistant focal epilepsy and negative (non‐lesional) magnetic resonance imaging (MRI) is particularly challenging. Focal cortical dysplasia (FCD), a frequent pathological substrate in such setting, may be subtle on MRI and evade detection. The aim of this study was to use voxel‐based MRI postprocessing to improve the detection of subtle FCD in pediatric surgical candidates. Methods: A consecutive cohort of pediatric patients undergoing pre‐surgical evaluation with a negative MRI by visual analysis was included. MRI postprocessing was performed using a voxel‐based morphometric analysis program (MAP) on T1‐weighted volumetric MRI, with comparison to an age‐specific normal pediatric database. The pertinence of MAP‐positive areas was confirmed by surgical outcome and pathology. Results: A total of 78 patients were included. Forty‐four patients (56%) had positive MAP regions. Complete resection of the MAP‐positive regions was positively associated with seizure‐free outcome compared with the no/partial resection group (P < 0.001). Patients with no/partial resection of the MAP‐positive regions had worse seizure outcomes than the MAP‐negative group (P = 0.002). The MAP‐positive rate was 100%, 77%, 63% and 40% in the 3–5, 5–10, 10–15 and 15–21 year age groups, respectively. MAP‐positive rates were 45% in patients with temporal resection and 63% in patients with extratemporal resection. Complete resection of the MAP‐positive regions was positively associated with seizure‐free outcome in the extratemporal group (P = 0.001) but not in the temporal group (P = 0.070). Conclusion: Our data suggest the importance of using MRI postprocessing in the pre‐surgical evaluation process of pediatric epilepsy patients with apparently normal MRI. [ABSTRACT FROM AUTHOR]

A significant volume of research continues to be conducted on the inactivation of Cryptosporidium with ozone. In 1996, Montgomery Watson undertook a project to evaluate Cryptosporidium inactivation with ozone using 13 natural waters from throughout North America and Europe. The project was funded by the participating water agencies and the American Water Works Association Research Foundation. The objective of the testing was to develop a large data base on the inactivation of Cryptosporidium with ozone under natural-water conditions. For three of the waters included in the study, testing was conducted at multipletemperatures ranging from 3 deg. C to 23 deg. C. This paper presentsand analyses those results, and proposes a preliminary CT table for the inactivation of Cryptosporidium with ozone. The results of the other waters tested continue to be analysed. As such, the CT values presented in this paper may be modified based on the results of the global analysis of the results obtained from all the waters tested. [ABSTRACT FROM AUTHOR]

The majority of data on the inactivation of Giardia cysts with ozonewas obtained from tests conducted in pure water containing virtuallyno turbidity and/or ozone demand. This study focused on evaluating the inactivation of Giardia cysts with ozone in three natural water samples containing three different turbidity levels (1.3, 11 and 19 NTU). A bench-scale, continuous-flow ozone contactor was used in the study. All inactivation testing was conducted at 3 deg.C. The results showed that higher Giardia inactivation was achieved in the low turbidity water sample compared to that achieved in the medium and high turbidity water samples. [ABSTRACT FROM AUTHOR]

Objective: To develop a multiparametric machine-learning (ML) framework using high-resolution 3 dimensional (3D) magnetic resonance (MR) fingerprinting (MRF) data for quantitative characterization of focal cortical dysplasia (FCD)., Materials: We included 119 subjects, 33 patients with focal epilepsy and histopathologically confirmed FCD, 60 age- and gender-matched healthy controls (HCs), and 26 disease controls (DCs). Subjects underwent whole-brain 3 Tesla MRF acquisition, the reconstruction of which generated T1 and T2 relaxometry maps. A 3D region of interest was manually created for each lesion, and z-score normalization using HC data was performed. We conducted 2D classification with ensemble models using MRF T1 and T2 mean and standard deviation from gray matter and white matter for FCD versus controls. Subtype classification additionally incorporated entropy and uniformity of MRF metrics, as well as morphometric features from the morphometric analysis program (MAP). We translated 2D results to individual probabilities using the percentage of slices above an adaptive threshold. These probabilities and clinical variables were input into a support vector machine for individual-level classification. Fivefold cross-validation was performed and performance metrics were reported using receiver-operating-characteristic-curve analyses., Results: FCD versus HC classification yielded mean sensitivity, specificity, and accuracy of 0.945, 0.980, and 0.962, respectively; FCD versus DC classification achieved 0.918, 0.965, and 0.939. In comparison, visual review of the clinical magnetic resonance imaging (MRI) detected 48% (16/33) of the lesions by official radiology report. In the subgroup where both clinical MRI and MAP were negative, the MRF-ML models correctly distinguished FCD patients from HCs and DCs in 98.3% of cross-validation trials. Type II versus non-type-II classification exhibited mean sensitivity, specificity, and accuracy of 0.835, 0.823, and 0.83, respectively; type IIa versus IIb classification showed 0.85, 0.9, and 0.87. In comparison, the transmantle sign was present in 58% (7/12) of the IIb cases., Interpretation: The MRF-ML framework presented in this study demonstrated strong efficacy in noninvasively classifying FCD from normal cortex and distinguishing FCD subtypes. ANN NEUROL 2024;96:944-957., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Our study aimed to investigate the management of patients with medically refractory epilepsy related to temporal encephaloceles, focusing on the use of ancillary testing in the pre-surgical evaluation to optimize surgical outcomes., Methods: We conducted a retrospective analysis of electronic medical records from the Cleveland Clinic, covering the period from January 2000 to May 2020. Patients with drug-resistant temporal lobe epilepsy were included if they had temporal lobe encephaloceles and required surgical intervention. We reviewed the results of ancillary studies, including invasive EEG., Results: A total of 19 patients with temporal lobe encephaloceles underwent resection for drug-resistant epilepsy treatment. Among them, 63 % reported experiencing auras commonly associated with mesial temporal lobe epilepsy, such as autonomic, psychic, and abdominal symptoms, followed by dialeptic seizures. Ictal patterns were consistently ipsilateral, with high amplitude delta or medium amplitude theta activity at onset, predominantly localized to the frontotemporal region in more than half of the cases. In 35 % of these patients, encephaloceles were only diagnosed during surgery. Stereo-EEG evaluation revealed two distinct ictal patterns: one characterized by localized low voltage fast activity in the temporal pole evolving into a 3-4 Hz high amplitude diffuse spiky activity, and the other exhibiting low amplitude rhythmic theta activity in the temporal pole with late involvement of the amygdala/hippocampus. Surgical resection strategy was based on clinical history and ancillary data analysis. At one-year follow-up after resection, 63 % of the patients attained Engel I seizure control over an average duration of 44 months (ranging from 6 months to 7.3 years). Additionally, 18 % of the patients achieved an Engel II outcome., Significance: Tailored resection of the encephalocele and the surrounding temporal pole, while preserving the mesial temporal structures, can effectively control seizures in patients with temporal encephaloceles identified through MRI. Patients presenting with temporal lobe symptoms and scalp ictal patterns characterized by polymorphic high delta theta activity with frontotemporal evolution should be evaluated for temporal encephaloceles as a potential underlying cause of their seizures, especially when the MRI is otherwise unrevealing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: We aimed to analyze seizure outcomes and define ictal onset with intracranial electroencephalography (ICEEG) in patients with polymicrogyria (PMG)-related drug-resistant epilepsy (DRE), considering surrounding cortex and extent of surgical resection., Methods: Retrospective study of PMG-diagnosed patients (2001 to June 2018) at a single epilepsy center was performed. Primary outcome was complete seizure freedom (SF), based on Engel classification with follow-up of ≥ 1 year. Univariate analyses identified predictive clinical variables, later integrated into multivariate Cox proportional hazards models., Results: Thirty-five patients with PMG-related DRE (19 adults/16 pediatric: 20 unilateral/15 bilateral) were studied. In surgical group (n = 23), 52 % achieved SF (mean follow-up:47 months), whereas none in non-resective treatment group (n = 12) attained SF (mean follow-up:39.3 months) (p = 0.002). In surgical group, there were no significant differences in SF, based on the laterality of the PMG [uni or bilateral,p = 0.35], involvement of perisylvian region(p = 0.714), and extent of the PMG resection [total vs. partial,p = 0.159]. Patients with ictal ICEEG onset in both PMG and non-PMG cortices, and those limited to non- PMG cortices had a greater chance of achieving SF compared to those limited to the PMG cortices., Conclusion: Resective surgery guided by ICEEG for defining the epileptogenic zone (EZ), in DRE patients with PMG, leads to favorable seizure outcomes. ICEEG-guided focal surgical resection(s) may lead to SF in patients with bilateral or extensive unilateral PMG. ICEEG aids in EZ localization within and/or outside the MRI-identified PMG. Complete removal of PMG identified on MRI does not guarantee SF. Hence, developing preimplantation hypotheses based on epileptogenic networks evaluation during presurgical assessment is crucial in this patient population., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose. We confirm that we have read the journal's position on the ethical publication issues and affirm that this report is consistent with those guidelines. All authors were critical in this project's design, data gathering, and manuscript preparation. Additionally, ethical adherence was demonstrated throughout the entirety of this project., (Copyright © 2024. Published by Elsevier Ltd.)

Pupillary changes can be an important semiologic feature in focal epilepsy. Though the subcortical networks involving pupillomotor function have been described, cortical generators of pupillary dilation and constriction in humans are not well known. In this report, we describe a case of pupillary constriction occurring during seizures in a patient with drug resistant focal epilepsy. On stereoelectroencephalography, onset was noted within the posterior segment of the right intraparietal sulcus and direct cortical electrical stimulation of these electrode contacts reproduced pupillary constriction associated with habitual seizures. This is the first case report to describe ictal pupillary constriction during SEEG with confirmation of the cortical localization by direct cortical electrical stimulation. The posterior segment of the right intraparietal sulcus localization of pupillary constriction may aid in surgical evaluation patients with drug resistant focal epilepsy., (© 2024 International League Against Epilepsy.)

Objective. For medically-refractory epilepsy patients, stereoelectroencephalography (sEEG) is a surgical method using intracranial electrode recordings to identify brain networks participating in early seizure organization and propagation (i.e. the epileptogenic zone, EZ). If identified, surgical EZ treatment via resection, ablation or neuromodulation can lead to seizure-freedom. To date, quantification of sEEG data, including its visualization and interpretation, remains a clinical and computational challenge. Given elusiveness of physical laws or governing equations modelling complex brain dynamics, data science offers unique insight into identifying unknown patterns within high-dimensional sEEG data. We apply here an unsupervised data-driven algorithm, dynamic mode decomposition (DMD), to sEEG recordings from five focal epilepsy patients (three with temporal lobe, and two with cingulate epilepsy), who underwent subsequent resective or ablative surgery and became seizure free. Approach. DMD obtains a linear approximation of nonlinear data dynamics, generating coherent structures ('modes') defining important signal features, used to extract frequencies, growth rates and spatial structures. DMD was adapted to produce dynamic modal maps (DMMs) across frequency sub-bands, capturing onset and evolution of epileptiform dynamics in sEEG data. Additionally, we developed a static estimate of EZ-localized electrode contacts, termed the higher-frequency mode-based norm index (MNI). DMM and MNI maps for representative patient seizures were validated against clinical sEEG results and seizure-free outcomes following surgery. Main results. DMD was most informative at higher frequencies, i.e. gamma (including high-gamma) and beta range, successfully identifying EZ contacts. Combined interpretation of DMM/MNI plots best identified spatiotemporal evolution of mode-specific network changes, with strong concordance to sEEG results and outcomes across all five patients. The method identified network attenuation in other contacts not implicated in the EZ. Significance. This is the first application of DMD to sEEG data analysis, supporting integration of neuroengineering, mathematical and machine learning methods into traditional workflows for sEEG review and epilepsy surgical decision-making., (Creative Commons Attribution license.)

Introduction: Given the prevalence and staggering cost of neurological disorders, there is dire need for effective early detection and intervention tools. Emerging evidence suggests that multidisciplinary lifestyle interventions (MLI) may mitigate the risk and progression of neurological disorders. The objectives of this protocol are (1) to test the impact of MLI on the progression of neurological disorders and (2) to identify multi-omic biomarkers for early stages of neurological disease and the impact of MLIs on these biomarkers., Methods and Analysis: We present the Multidisciplinary lifestyle Interventions for Neurological Disorders during the Silent phase (MINDS) protocol, a randomized controlled trial of MLI in neurologically healthy older adults (≥ 50 years old) exhibiting elevated risk for common neurological disorders: stroke, epilepsy, Parkinson's Disease, or Alzheimer's disease and related dementias. Participants will be randomly assigned to intervention (n = 100) or control (n = 100) groups. The intervention group will receive 3 months of weekly 2-hour sessions on diet education, yoga, music therapy, and cognitive skills training. The participants' neurological health and engagement in relevant lifestyle practices will be assessed at regular intervals for 12 months. Neuroimaging and samples for multi-omic analyses will be collected at baseline, and at 3 months and 12 months after enrollment. Primary outcomes will be signs of progression of the neurological disorder risk that qualified them for study enrollment or a clinical diagnosis of the disorder. Secondary and exploratory outcomes will be based on self-reported health and multi-omic data. Data analysis will include between-group and longitudinal within-group analyses., Perspectives: The MINDS protocol and trial aims to clarify the impact of MLI on the progression of neurological disorder risk or diagnosis in older adults and to identify biomarkers that can be used to confirm MLI efficacy. The ability to validate the impact of MLI on neurological disorder progression based on biomarker data allows the identification of individuals most likely to benefit from such therapies in the early stages of neurological disease., Trial Registration: The trial is registered on the National Institutes of Health (NIH) ClinicalTrials.gov (NCT05984056) site. It was registered on August 2nd, 2023. The trial has full approval of the Cleveland Clinic Internal Review Board., (© 2024. The Author(s).)

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 mm 3 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., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Ictal Single Photon Emission Computed Tomography (SPECT) and stereo-electroencephalography (SEEG) are diagnostic techniques used for the management of patients with drug-resistant focal epilepsies. While hyperperfusion patterns in ictal SPECT studies reveal seizure onset and propagation pathways, the role of ictal hypoperfusion remains poorly understood. The goal of this study was to systematically characterize the spatio-temporal information flow dynamics between differently perfused brain regions using stereo-EEG recordings., Methods: We identified seizure-free patients after resective epilepsy surgery who had prior ictal SPECT and SEEG investigations. We estimated directional connectivity between the epileptogenic-zone (EZ), non-resected areas of hyperperfusion, hypoperfusion, and baseline perfusion during the interictal, preictal, ictal, and postictal periods., Results: Compared to the background, we noted significant information flow (1) during the preictal period from the EZ to the baseline and hyperperfused regions, (2) during the ictal onset from the EZ to all three regions, and (3) during the period of seizure evolution from the area of hypoperfusion to all three regions., Conclusions: Hypoperfused brain regions were found to indirectly interact with the EZ during the ictal period., Significance: Our unique study, combining intracranial electrophysiology and perfusion imaging, presents compelling evidence of dynamic changes in directional connectivity between brain regions during the transition from interictal to ictal states., Competing Interests: Conflicts of interest statement None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Understanding the clinical characteristics and medical treatment of individuals affected by genetic epilepsies is instrumental in guiding selection for genetic testing, defining the phenotype range of these rare disorders, optimizing patient care pathways and pinpointing unaddressed medical need by quantifying healthcare resource utilization. To date, a matched longitudinal cohort study encompassing the entire spectrum of clinical characteristics and medical treatment from childhood through adolescence has not been performed. We identified individuals with genetic and non-genetic epilepsies and onset at ages 0-5 years by linkage across the Cleveland Clinic Health System. We used natural language processing to extract medical terms and procedures from longitudinal electronic health records and tested for cross-sectional and temporal associations with genetic epilepsy. We implemented a two-stage design: in the discovery cohort, individuals were stratified as being 'likely genetic' or 'non-genetic' by a natural language processing algorithm, and controls did not receive genetic testing. The validation cohort consisted of cases with genetic epilepsy confirmed by manual chart review and an independent set of controls who received negative genetic testing. The discovery and validation cohorts consisted of 503 and 344 individuals with genetic epilepsy and matched controls, respectively. The median age at the first encounter was 0.1 years and 7.9 years at the last encounter, and the mean duration of follow-up was 8.2 years. We extracted 188,295 Unified Medical Language System annotations for statistical analysis across 9659 encounters. Individuals with genetic epilepsy received an earlier epilepsy diagnosis and had more frequent and complex encounters with the healthcare system. Notably, the highest enrichment of encounters compared with the non-genetic groups was found during the transition from paediatric to adult care. Our computational approach could validate established comorbidities of genetic epilepsies, such as behavioural abnormality and intellectual disability. We also revealed novel associations for genitourinary abnormalities (odds ratio 1.91, 95% confidence interval: 1.66-2.20, P = 6.16 × 10 -19 ) linked to a spectrum of underrecognized epilepsy-associated genetic disorders. This case-control study leveraged real-world data to identify novel features associated with the likelihood of a genetic aetiology and quantified the healthcare utilization of genetic epilepsies compared with matched controls. Our results strongly recommend early genetic testing to stratify individuals into specialized care paths, thus improving the clinical management of people with genetic epilepsies., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Responsive neurostimulation is a closed-loop neuromodulation therapy for drug resistant focal epilepsy. Responsive neurostimulation electrodes are placed near ictal onset zones so as to enable detection of epileptiform activity and deliver electrical stimulation. There is no standard approach for determining the optimal placement of responsive neurostimulation electrodes. Clinicians make this determination based on presurgical tests, such as MRI, EEG, magnetoencephalography, ictal single-photon emission computed tomography and intracranial EEG. Currently functional connectivity measures are not being used in determining the placement of responsive neurostimulation electrodes. Cortico-cortical evoked potentials are a measure of effective functional connectivity. Cortico-cortical evoked potentials are generated by direct single-pulse electrical stimulation and can be used to investigate cortico-cortical connections in vivo . We hypothesized that the presence of high amplitude cortico-cortical evoked potentials, recorded during intracranial EEG monitoring, near the eventual responsive neurostimulation contact sites is predictive of better outcomes from its therapy. We retrospectively reviewed 12 patients in whom cortico-cortical evoked potentials were obtained during stereoelectroencephalography evaluation and subsequently underwent responsive neurostimulation therapy. We studied the relationship between cortico-cortical evoked potentials, the eventual responsive neurostimulation electrode locations and seizure reduction. Directional connectivity indicated by cortico-cortical evoked potentials can categorize stereoelectroencephalography electrodes as either receiver nodes/in-degree (an area of greater inward connectivity) or projection nodes/out-degree (greater outward connectivity). The follow-up period for seizure reduction ranged from 1.3-4.8 years (median 2.7) after responsive neurostimulation therapy started. Stereoelectroencephalography electrodes closest to the eventual responsive neurostimulation contact site tended to show larger in-degree cortico-cortical evoked potentials, especially for the early latency cortico-cortical evoked potentials period (10-60 ms period) in six out of 12 patients. Stereoelectroencephalography electrodes closest to the responsive neurostimulation contacts (≤5 mm) also had greater significant out-degree in the early cortico-cortical evoked potentials latency period than those further away (≥10 mm) ( P < 0.05). Additionally, significant correlation was noted between in-degree cortico-cortical evoked potentials and greater seizure reduction with responsive neurostimulation therapy at its most effective period ( P < 0.05). These findings suggest that functional connectivity determined by cortico-cortical evoked potentials may provide additional information that could help guide the optimal placement of responsive neurostimulation electrodes., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Despite well-established benefits of skin-to-skin care (SSC) for preterm infants and parents, standardized guidelines for implementation do not exist. Furthermore, the literature offers little evidence-based information to guide best practice., Purpose: To discover whether SSC using a body wrap to hold preterm infants would increase the duration of SSC, decrease parental stress during SSC, and minimize adverse events to ensure that body wraps are safe and feasible., Methods: Twenty-nine dyads of parents and preterm infants younger than 34 weeks postmenstrual age were enrolled. The first 15 dyads to meet inclusion criteria were assigned to a standard of care group for SSC with no body wrap. The remaining 14 dyads were assigned to an experimental group for SSC with a body wrap. Each dyad performed 2 SSC holds. Parents completed the Parental Stressor Scale and Parent Feedback Form. Adverse events were also documented., Results: No statistically significant differences were found between the 2 groups in total SSC time ( P = .33), the number of adverse events ( P = .31 for major events; P = .38 for minor events), average parental stress ( P = .22), and parental confidence performing SSC ( P = .18)., Implications for Practice and Research: This study found that SSC with a body wrap is safe for preterm infants in a neonatal intensive care unit (NICU). This is the first study to explore the use, safety, and effectiveness of body wraps during SSC with preterm infants in an NICU. Future research should be conducted with larger sample sizes to further evaluate the safety and efficacy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 by The National Association of Neonatal Nurses.)

Objective: To assess the effectiveness and safety/tolerability of perampanel (PER) in people with epilepsy (PWE) treated in everyday clinical practice for focal and generalized seizures, both in the total cohort and by age group., Methods: The PERMIT Extension study was a pooled analysis of data from PWE included in two large previous clinical practice studies (PERMIT and PROVE). Retention was assessed over 12 months. Effectiveness was assessed based on total seizures and by seizure type (focal and generalized) after 3, 6, and 12 months of PER treatment and at final follow-up (last observation carried forward; "last visit"); assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the previous visit). Safety/tolerability was assessed throughout PER treatment by evaluating adverse events (AEs). All assessments were conducted for the total population and by age category (<12, ≥12 to <18, ≥18 to <65, and ≥65 years at baseline)., Results: Full Analysis Set included 6,822 PWE (51.1% female; mean age, 36.9 years; mean duration of epilepsy 21.4 years) with 6,433, 4,648, and 6,233 PWE assessed for retention, effectiveness, and safety/tolerability, respectively. The majority of PWE (81.1%) were aged 18-64 at baseline, with 4.5% aged <12 years, 8.4% aged 12-17 years, and 5.9% aged ≥65 years. In the overall population, retention rates at 3, 6, and 12 months were 88.0%, 77.6%, and 61.4%, respectively; responder rates at 12 months were 58.5% for total seizures, 54.6% for focal seizures, and 77.7% for generalized seizures, and corresponding seizure freedom rates were 23.6%, 19.0%, and 51.3%, respectively. PER was effective regardless of age category, although effectiveness was greatest in PWE aged ≥65 years, for both focal and generalized seizures. In the overall population, the incidence of AEs was 49.2% and the most frequent AEs (≥5% of PWE) were dizziness/vertigo (13.4%), somnolence (8.8%), irritability (7.3%), and behavioral disorders (5.3%); AEs led to treatment discontinuation in 18.3% of PWE over 12 months. The incidence of AEs and the discontinuation rate due to AEs increased with increasing age (55.0% and 23.9%, respectively, in PWE aged ≥65 years)., Conclusion: In this study, the largest pooled analysis of PER clinical practice data conducted to date, PER was shown to be effective and generally well tolerated when used to treat people with focal or generalized epilepsy in everyday clinical practice, regardless of age category. No new or unexpected side effects emerged following long-term use in the real-world setting., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JW has received grant support from Aquestive, Eisai, Greenwich, INSYS Inc., LivaNova, Mallinckrodt, Neurelis, NeuroPace, the Shainberg Foundation, and West; has served as a consultant for Aquestive, BioMarin, Eisai, Greenwich, Mallinckrodt, Neurelis, NeuroPace, Shire, Supernus, and Zogenix; and has received speaker bureau honoraria from BioMarin, Eisai, Greenwich, LivaNova, Mallinckrodt, and Supernus. RTW has been a clinical trial investigator for Aquestive, Biogen, Cavion, Cerevel, Eisai, Engage Pharma, Greenwich Biosciences, Lundbeck, Otsuka, Pfizer, SK Life Science, Sunovion, UCB Pharma, Xenon, and Zogenix; has served on advisory boards and/or carried out consulting work for Brain Sentinel, Cerevel, Eisai, Engage Pharma, Greenwich Biosciences, Lundbeck, Otsuka, SK Life Science, Sunovion, and UCB Pharma; has received speaker bureau honoraria from Aquestive, Eisai, Greenwich Biosciences, LivaNova, Neurelis, SK Life Science, Sunovion, and UCB Pharma; and is a member of the Epilepsy Study Consortium. PP has received Speakers Bureaus from Bureaus Jazz, Novartis, and UCB and advisory/consultant fees from LIVIS, Novartis and UCB. ES has received honoraria from Eisai, GW Pharma, Lundbeck, Neurelis, Nutricia, and Zogenix. MC has served as a consultant for, and has received grant support and/or speaker or advisory honoraria from, Aquestive, Eisai, GW Pharma, Mallinckrodt Zogenix, Marinus, Neurelis and UCB Pharma. AC has received speaker fees from EISAI and GW/Jazz pharmaceutical company and consultancy fees by GW/Jazz pharmaceutical Company, UCB, and BIAL. AD has no disclosures. WD’s salary is part-funded by The University of Melbourne and received honoraria and/or research funds from Eisai, GSK, LivaNova, Novartis, Pfizer, Sanofi, SciGen, Tilray, and UCB Pharma, and has equity interest in EpiMinder. IN received honoraria from Eisai. SC is an employee of Eisai. RSF is an employee of Eisai. VV has received honoraria and/or research funds from Angelini, Bial, Eisai, Jazz Pharmaceuticals, NewBridge, Novartis, Nutricia, Takeda, UCB Pharma and Zogenix., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Approximately 50% of individuals who undergo resective epilepsy surgery experience seizure recurrence. The heterogenous post-operative outcomes are not fully explained by clinical, imaging and electrophysiological variables. We hypothesized that molecular features may be useful in understanding surgical response, and that individuals with epilepsy can be classified into molecular subtypes that are associated with seizure freedom or recurrence after surgical resection. Pre-operative blood samples, brain tissue and post-operative seizure outcomes were collected from a cohort of 40 individuals with temporal lobe epilepsy, 23 of whom experienced post-operative seizure recurrence. Messenger RNA and microRNA extracted from the blood and tissue samples were sequenced. The messenger RNA and microRNA expression levels from the blood and brain were each subjected to a novel clustering approach combined with multiple logistic regression to separate individuals into genetic clusters that identify novel subtypes associated with post-operative seizure outcomes. We then compared the microRNAs and messenger RNAs from patient blood and brain tissue that were significantly associated with each subtype to identify signatures that are similarly over- or under-represented for an outcome and more likely to represent endophenotypes with common molecular aetiology. These target microRNAs and messenger RNAs were further characterized by pathway analysis to assess their functional role in epilepsy. Using blood-derived microRNA and messenger RNA expression levels, we identified two subtypes of epilepsy that were significantly associated with seizure recurrence (clusters A1 and B4) (adjusted P < 0.20). A total of 551 microRNAs and 2486 messenger RNAs were associated with clusters A1 and B4, respectively (adjusted P < 0.05). Clustering of brain-tissue messenger RNA expression levels revealed an additional subtype (C2) associated with seizure recurrence that had high overlap of dysregulated messenger RNA transcripts with cluster B4. Clusters A1, B4 and C2 also shared significant overlap of subjects, which altogether suggests a coordinated mechanism by which microRNA and messenger RNA transcripts may be related to seizure recurrence. Epileptic subtypes A1, B4 and C2 reveal both known and novel microRNA and messenger RNA targets in seizure recurrence. Furthermore, targets identified in A1 and B4 are quantifiable in pre-operative blood samples and could potentially serve as biomarkers for surgical resection outcomes., Competing Interests: D.M.R. holds an equity stake in Clarified Precision Medicine, LLC., and has received research support from Novo Nordisk and consulting honoraria from Interpares Biomedicine and Pharmazaam, LLC. C.E. is the Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy., (© 2023. The Author(s).)

Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 ± 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 ± 4 single-nucleotide variants) or hippocampal sclerosis (5.1 ± 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2, DEPDC5 and PTEN, germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed 'second hit' disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21-q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Quantitative magnetic resonance (MR) has been used to study cyto- and myelo-architecture of the human brain non-invasively. However, analyzing brain cortex using high-resolution quantitative MR acquisition can be challenging to perform using 3T clinical scanners. MR fingerprinting (MRF) is a highly efficient and clinically feasible quantitative MR technique that simultaneously provides T1 and T2 relaxation maps. Using 3D MRF from 40 healthy subjects (mean age = 25.6 ± 4.3 years) scanned on 3T magnetic resonance imaging, we generated whole-brain gyral-based normative MR relaxation atlases and investigated cortical-region-based T1 and T2 variations. Gender and age dependency of T1 and T2 variations were additionally analyzed. The coefficient of variation of T1 and T2 for each cortical-region was 3.5% and 7.3%, respectively, supporting low variability of MRF measurements across subjects. Significant differences in T1 and T2 were identified among 34 brain regions (P < 0.001), lower in the precentral, postcentral, paracentral lobule, transverse temporal, lateral occipital, and cingulate areas, which contain sensorimotor, auditory, visual, and limbic functions. Significant correlations were identified between age and T1 and T2 values. This study established whole-brain MRF T1 and T2 atlases of healthy subjects using a clinical 3T scanner, which can provide a quantitative and region-specific baseline for future brain studies and pathology detection., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

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 mm 3 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., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: This study was undertaken to better understand the long-term palliative and disease-modifying effects of surgical resection beyond seizure freedom, including frequency reduction and both late recurrence and remission, in patients with drug-resistant epilepsy., Methods: This retrospective database-driven cohort study included all patients with >9 years of follow-up at a single high-volume epilepsy center. We included patients who underwent lobectomy, multilobar resection, or lesionectomies for drug-resistant epilepsy; we excluded patients who underwent hemispherectomies. Our main outcomes were (1) reduction in frequency of disabling seizures (at 6 months, each year up to 9 years postoperatively, and at last follow-up), (2) achievement of seizure remission (>6 months, >1 year, and longest duration), and (3) seizure freedom at last follow-up., Results: We included 251 patients; 234 (93.2%) achieved 6 months and 232 (92.4%) experienced 1 year of seizure freedom. Of these, the average period of seizure freedom was 10.3 years. A total of 182 (72.5%) patients were seizure-free at last follow-up (defined as >1 year without seizures), with a median 11.9 years since remission. For patients not completely seizure-free, the mean seizure frequency reduction at each time point was 76.2%, and ranged from 66.6% to 85.0%. Patients decreased their number of antiseizure medications on average by .58, and 53 (21.2%) patients were on no antiseizure medication at last follow-up. Nearly half (47.1%) of those seizure-free at last follow-up were not seizure-free immediately postoperatively., Significance: Patients who continue to have seizures after resection often have considerable reductions in seizure frequency, and many are able to achieve seizure freedom in a delayed manner., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Purpose: Neurosurgery is an effective treatment option for pharmacoresistant epilepsy. Although post-surgical seizure freedom is considered the primary goal of epilepsy surgery, other factors that impact Quality of Life (QOL) are also important to consider, including post-surgical cognitive changes. This study aimed to examine the impact of post-surgical cognitive changes on QOL in the context of seizure outcomes., Methods: Participants were 196 adults with focal epilepsy who underwent either frontal (n = 27) or temporal (n = 169) lobe resection. Each participant completed pre- and post-surgical neuropsychological evaluations, and cognitive composites were constructed for the following domains: language, attention/processing speed, memory, executive function, and visuospatial skill. The Quality of Life in Epilepsy (QOLIE-10) questionnaire was used to assess QOL. Seizure outcome was determined by seizure status six months post-surgery., Results: Eighty-one percent of patients were seizure-free post-surgery and generally reported improved QOL. While a significant portion of patient's demonstrated declines in language and verbal memory following surgery, only a decline in verbal memory was associated with worse QOL; however, this relationship was no longer significant after controlling for seizure outcome. Instead, reduced post-surgical QOL was primarily observed in those who experienced both seizure recurrence and a decline in executive function. Notably, depression was a significant covariate in all of the models., Conclusions: The findings from this study improve our ability to counsel patients about the trade-off between cognitive decline and seizure remittance in the greater context of overall QOL. Reassuringly, it appears that QOL is improved regardless of cognitive changes when patients have good seizure outcomes. However, for those that experience a "double hit" (i.e., cognitive decline without seizure remission), post-surgical QOL may be reduced. Changes in depression also appear to play a crucial role in QOL outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Seizure outcomes after brain surgery for drug-resistant epilepsy (DRE) are very heterogeneous and difficult to predict with models utilizing the current clinical, imaging, and electrophysiological variables. In this pilot study, we investigated whether genetic and molecular biomarkers (e.g., genomic, transcriptomic) can provide additional insight into differential response to surgery., Methods: Post-operative seizure-outcomes were collected at last follow-up (>6 months) for 201 adult patients with DRE who underwent surgery between 2004 and 2020. Resected tissue was sent for miRNA sequencing ( n = 132) and mRNA sequencing ( n = 135). Following the selection of 10 genes ( SCN1A, NBEA, PTEN, GABRA1, LGL1, DEPDC5, IL1A, ABCB1, C3, CALHM1 ), we investigated SNPs in those 10 genes from previously acquired exome sequencing data ( n = 106). Logistic regression was performed to test for associations between individual features (mRNAs, miRNAs, and SNPs) and post-operative seizure-outcome with an exploratory FDR P < 0.25 as the threshold for significance. Post-operative time-to-seizure analyses were performed for each SNP using a Cox proportional hazards model., Results: The majority of patients (83%) had temporal lobe epilepsy. Mean age at surgery was 38.3 years, and 56% were female. Three SNPs (rs10276036, rs11975994, rs1128503) in multi-drug resistance gene, ABCB1 , were associated with post-operative seizure outcomes. Patients with alternate alleles in ABCB1 were more likely to be seizure-free at last follow-up (52-56% reduction in seizure recurrence; FDR P = 0.24). All three SNPs were in linkage disequilibrium and highly correlated with each other. Median post-operative time-to-seizure was 63 months for patients with 2 alternate alleles, 24-33 months with 1 alternate allele, and 10-11 months with 0 alternate alleles. These SNPs improved outcome prediction beyond MRI and sex alone. No independent miRNAs or mRNAs were significantly associated with seizure-outcome ( P > 0.05). However, pathway analysis identified "cancer drug resistance by drug efflux" (mir-154 and mir-379) as enriched ( P = 0.02), supporting the role of drug response genes in post-operative seizure recurrence., Significance: ABCB1 may have a role in epileptogenesis and surgery outcomes independent of its drug efflux activity necessitating further investigation. SNPs in ABCB1 may serve as independent predictors of post-operative outcome., Competing Interests: Author DR has an equity stake in Clarified Precision Medicine, LLC. DR has received research support from Novo Nordisk, consulting honoraria from Interpares Biomedicine and Pharmazaam, LLC. Author CE is the Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic. The remaining 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., (Copyright © 2022 Louis, Busch, Lal, Hockings, Hogue, Morita-Sherman, Vegh, Najm, Ghosh, Bazeley, Eng, Jehi and Rotroff.)

Polytherapy with antiseizure medications (ASMs) is often used to control seizures in patients suffering from epilepsy, where about 30% of patients are pharmacoresistant. While drug combinations are intended to be beneficial, the consequence of CYP-dependent drug interactions on apoptotic protein levels and mitochondrial function in the epileptic brain remains unclear. We examined the interactions of ASMs given prior to surgery in surgically resected brain tissues and of three ASMs (lacosamide, LCM; oxcarbazepine, OXC; levetiracetam LEV) in isolated brain cells from patients with drug-resistant epilepsy ( n = 23). We divided the patients into groups-those who took combinations of NON-CYP + CYP substrate ASMs, NON-CYP + CYP inducer ASMs, CYP substrate + CYP substrate or CYP substrate + CYP inducer ASMs-to study the 1) pro- and anti-apoptotic protein levels and other apoptotic signaling proteins and levels of reactive oxygen species (reduced glutathione and lipid peroxidation) in brain tissues; 2) cytotoxicity at blood-brain barrier epileptic endothelial cells (EPI-ECs) and subsequent changes in mitochondrial membrane potential in normal neuronal cells, following treatment with LCM + OXC (CYP substrate + CYP inducer) or LCM + LEV (CYP substrate + NON-CYP-substrate) after blood-brain barrier penetration, and 3) apoptotic and mitochondrial protein targets in the cells, pre-and post-CYP3A4 inhibition by ketoconazole and drug treatments. We found an increased BAX (pro-apoptotic)/Bcl-X L (anti-apoptotic) protein ratio in epileptic brain tissue after treatment with CYP substrate + CYP substrate or inducer compared to NON-CYP + CYP substrate or inducer, and subsequently decreased glutathione and elevated lipid peroxidation levels. Further, increased cytotoxicity and Mito-ID levels, indicative of compromised mitochondrial membrane potential, were observed after treatment of LCM + OXC in combination compared to LCM + LEV or these ASMs alone in EPI-ECs, which was attenuated by pre-treatment of CYP inhibitor, ketoconazole. A combination of two CYP-mediated ASMs on EPI-ECs resulted in elevated caspase-3 and cytochrome c with decreased SIRT3 levels and activity, which was rescued by CYP inhibition. Together, the study highlights for the first time that pro- and anti-apoptotic proteins levels are dependent on ASM combinations in epilepsy, modulated via a CYP-mediated mechanism that controls free radicals, cytotoxicity and mitochondrial activity. These findings lead to a better understanding of future drug selection choices offsetting pharmacodynamic CYP-mediated interactions., Competing Interests: EP received speaker and/or consultancy fees from Angelini, Arvelle, Biogen, Biopas, Eisai, GW Pharma, PMI Life Sciences, Sanofi group of companies, SKL Life Science, Takeda, UCB Pharma, Xenon Pharma and Zogenix, and royalties from Wiley, Elsevier, and Wolters Kluwers. IN serves on the Speaker’ bureau for Eisai, Inc., and as a member of ad hoc advisory board for Eisai, Inc. and Liva Nova. The remaining 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., (Copyright © 2022 Ghosh, Westcott, Perucca, Hossain, Bingaman and Najm.)

Objectives: Magnetic resonance fingerprinting (MRF) is a novel, quantitative, and noninvasive technique to measure brain tissue properties. We aim to use MRF for characterizing normal-appearing thalamic and basal ganglia nuclei in the epileptic brain., Methods: A three-dimensional (3D) MRF protocol (1 mm 3 isotropic resolution) was acquired from 48 patients with unilateral medically intractable focal epilepsy and 39 healthy controls (HCs). Whole-brain T1 and T2 maps (containing T1 and T2 relaxation times) were reconstructed for each subject. Ten subcortical nuclei in the thalamus and basal ganglia were segmented as regions of interest (ROIs), within which the mean T1 and T2 values, as well as their coefficient of variation (CV) were compared between the patients and HCs at the group level. Subgroup and correlation analyses were performed to examine the relationship between significant MRF measures and various clinical characteristics. Using significantly abnormal MRF measures from the group-level analyses, support vector machine (SVM) and logistic regression machine learning models were built and tested with 5-fold and 10-fold cross-validations, to separate patients from HCs, and to separate patients with left-sided and right-sided epilepsy, at the individual level., Results: MRF revealed increased T1 mean value in the ipsilateral thalamus and nucleus accumbens; increased T1 CV in the bilateral thalamus, bilateral pallidum, and ipsilateral caudate; and increased T2 CV in the ipsilateral thalamus in patients compared to HCs (p < .05, false discovery rate [FDR] corrected). The SVM classifier produced 78.2% average accuracy to separate individual patients from HCs, with an area under the curve (AUC) of 0.83. The logistic regression classifier produced 67.4% average accuracy to separate patients with left-sided and right-sided epilepsy, with an AUC of 0.72., Significance: MRF revealed bilateral tissue-property changes in the normal-appearing thalamus and basal ganglia, with ipsilateral predominance and thalamic preference, suggesting subcortical involvement/impairment in patients with medically intractable focal epilepsy. The individual-level performance of the MRF-based machine-learning models suggests potential opportunities for predicting lateralization., (© 2022 International League Against Epilepsy.)