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Objective: To determine the association between brain MRI abnormalities and incident epilepsy in older adults. Methods: Men and women (ages 45–64 years) from the Atherosclerosis Risk in Communities study were followed up from 1987 to 2018 with brain MRI performed between 2011 and 2013. We identified cases of incident late‐onset epilepsy (LOE) with onset of seizures occurring after the acquisition of brain MRI. We evaluated the relative pattern of cortical thickness, subcortical volume, and white matter integrity among participants with incident LOE after MRI in comparison with participants without seizures. We examined the association between MRI abnormalities and incident LOE using Cox proportional hazards regression. Models were adjusted for demographics, hypertension, diabetes, smoking, stroke, and dementia status. Results: Among 1251 participants with brain MRI data, 27 (2.2%) developed LOE after MRI over a median of 6.4 years (25–75 percentile 5.8–6.9) of follow‐up. Participants with incident LOE after MRI had higher levels of cortical thinning and white matter microstructural abnormalities before seizure onset compared to those without seizures. In longitudinal analyses, greater number of abnormalities was associated with incident LOE after controlling for demographic factors, risk factors for cardiovascular disease, stroke, and dementia (gray matter: hazard ratio [HR]: 2.3, 95% confidence interval [CI]: 1.0–4.9; white matter diffusivity: HR: 3.0, 95% CI: 1.2–7.3). Interpretation: This study demonstrates considerable gray and white matter pathology among individuals with LOE, which is present prior to the onset of seizures and provides important insights into the role of neurodegeneration, both of gray and white matter, and the risk of LOE. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Traumatic brain injury (TBI) is a significant risk factor for epilepsy, but little work has explored whether risk of epilepsy after TBI may operate through intermediary mechanisms. The objective of this study was to statistically screen for potentially mediating effects among 64 comorbidities for epilepsy risk following TBI among Post‐9/11 U.S. veterans.This longitudinal matched cohort study used an established algorithm to identify veterans in Department of Defense (DoD) and Veterans Health Administration (VHA) records with a history of the primary exposure, TBI, between 2003 and 2023, who were demographically matched 1:1 with veterans without history of TBI exposure from the same cohort. In the observation time window after index date, mediation models estimated the proportion eliminated of the total TBI–epilepsy relationship by other factors. Cox proportional hazard models were implemented for 64 comorbidities determined using International Classification of Diseases, Ninth/Tenth Revision (ICD‐9/10) codes, each individually tested for the potential mediation of epilepsy onset after date of first TBI (index date), adjusting for demographic and military covariates. Age‐stratified mediation analyses were conducted. Biologically plausible mechanisms were investigated.Among N = 292 200 veterans in the TBI and matched groups, 8458 (2.9%) had an epilepsy diagnosis that met study criteria between 2003 and 2023. The adjusted hazard ratio (HR, 95% CI) for epilepsy given TBI was 6.76 [6.33–7.21]. The median duration between TBI documentation and epilepsy diagnosis was 3.3 years. In the observation time after index date (median duration: 12.2 years), Cox proportional hazard models identified the primary meditators of epilepsy risk after TBI as post‐concussive symptoms (10.3%), cognitive dysfunction (7.0%), suicidal ideation/attempt (5.1%), overdose and drug abuse (3.8%–4.8%), and stroke (3.8%).This study identified neurological conditions and symptoms that may play an intermediary role in the TBI–epilepsy relationship. Specific changes in health status after TBI may present useful targets for future trials and experimental approaches of PTE prevention. [ABSTRACT FROM AUTHOR]

Background: The piriform cortex has been implicated in the initiation, spread and termination of epileptic seizures. This understanding has extended to surgical management of epilepsy, where it has been shown that resection or ablation of the piriform cortex can result in better outcomes. How and why the piriform cortex may play such a crucial role in seizure networks is not well understood. To answer these questions, we investigated the functional and structural connectivity of the piriform cortex in both healthy controls and temporal lobe epilepsy (TLE) patients., Methods: We studied a retrospective cohort of 55 drug-resistant unilateral TLE patients and 26 healthy controls who received structural and functional neuroimaging. Using seed-to-voxel connectivity we compared the normative whole-brain connectivity of the piriform to that of the hippocampus, a region commonly involved in epilepsy, to understand the differential contribution of the piriform to the epileptogenic network. We subsequently measured the inter-piriform coupling (IPC) to quantify similarities in the inter-hemispheric cortical functional connectivity profile between the two piriform cortices. We related differences in IPC in TLE back to aberrations in normative piriform connectivity, whole brain functional properties, and structural connectivity., Results: We find that relative to the hippocampus, the piriform is functionally connected to the anterior insula and the rest of the salience ventral attention network (SAN). We also find that low IPC is a sensitive metric of poor surgical outcome (sensitivity: 85.71%, 95% CI: [19.12%, 99.64%]); and differences in IPC within TLE were related to disconnectivity and hyperconnectivity to the anterior insula and the SAN. More globally, we find that low IPC is associated with whole-brain functional and structural segregation, marked by decreased functional small-worldness and fractional anisotropy., Conclusions: Our study presents novel insights into the functional and structural neural network alterations associated with this structure, laying the foundation for future work to carefully consider its connectivity during the presurgical management of epilepsy., Competing Interests: Competing Interests The authors report no competing interests.

Background and Significance: Positron Emission Tomography (PET) using fluorodeoxyglucose (FDG-PET) is a standard imaging modality for detecting areas of hypometabolism associated with the seizure onset zone (SOZ) in temporal lobe epilepsy (TLE). However, FDG-PET is costly and involves the use of a radioactive tracer. Arterial Spin Labeling (ASL) offers an MRI-based quantification of cerebral blood flow (CBF) that could also help localize the SOZ, but its performance in doing so, relative to FDG-PET, is limited. In this study, we seek to improve ASL's diagnostic performance by developing a deep learning framework for synthesizing FDG-PET-like images from ASL and structural MRI inputs., Methods: We included 68 epilepsy patients, out of which 36 had well lateralized TLE. We compared the coupling between FDG-PET and ASL CBF values in different brain regions, as well as the asymmetry of these values across the brain. We additionally assessed each modality's ability to lateralize the SOZ across brain regions. Using our paired PET-ASL data, we developed FlowGAN, a generative adversarial neural network (GAN) that synthesizes PET-like images from ASL and T1-weighted MRI inputs. We tested our synthetic PET images against the actual PET images of subjects to assess their ability to reproduce clinically meaningful hypometabolism and asymmetries in TLE., Results: We found variable coupling between PET and ASL CBF values across brain regions. PET and ASL had high coupling in neocortical temporal and frontal brain regions (Spearman's r > 0.30, p < 0.05) but low coupling in mesial temporal structures (Spearman's r < 0.30, p > 0.05). Both whole brain PET and ASL CBF asymmetry values provided good separability between left and right TLE subjects, but PET (AUC = 0.96, 95% CI: [0.88, 1.00]) outperformed ASL (AUC = 0.81; 95% CI: [0.65, 0.96]). FlowGAN-generated images demonstrated high structural similarity to actual PET images (SSIM = 0.85). Globally, asymmetry values were better correlated between synthetic PET and original PET than between ASL CBF and original PET, with a mean correlation increase of 0.15 (95% CI: [0.07, 0.24], p <0.001, Cohen's d = 0.91). Furthermore, regions that had poor ASL-PET correlation (e.g. mesial temporal structures) showed the greatest improvement with synthetic PET images., Conclusions: FlowGAN improves ASL's diagnostic performance, generating synthetic PET images that closely mimic actual FDG-PET in depicting hypometabolism associated with TLE. This approach could improve non-invasive SOZ localization, offering a promising tool for epilepsy presurgical assessment. It potentially broadens the applicability of ASL in clinical practice and could reduce reliance on FDG-PET for epilepsy and other neurological disorders., Competing Interests: Competing Interests Thomas Campbell Arnold is an employee of Subtle Medical, but this work is unrelated to his work at the company. He contributed to this work during his time at the University of Pennsylvania. The rest of the authors report no competing or financial interests.

Background and Motivation: Functional gradients have been used to study differences in connectivity between healthy and diseased brain states, however this work has largely focused on the cortex. Because the subcortex plays a key role in seizure initiation in temporal lobe epilepsy (TLE), subcortical functional-connectivity gradients may help further elucidate differences between healthy brains and TLE, as well as differences between left (L)-TLE and right (R)-TLE., Methods: In this work, we calculated subcortical functional-connectivity gradients (SFGs) from resting-state functional MRI (rs-fMRI) by measuring the similarity in connectivity profiles of subcortical voxels to cortical gray matter voxels. We performed this analysis in 23 R-TLE patients and 32 L-TLE patients (who were otherwise matched for age, gender, disease specific characteristics, and other clinical variables), and 16 controls. To measure differences in SFGs between L-TLE and R-TLE, we quantified deviations in the average functional gradient distributions, as well as their variance, across subcortical structures., Results: We found an expansion, measured by increased variance, in the principal SFG of TLE relative to controls. When comparing the gradient across subcortical structures between L-TLE and R-TLE, we found that abnormalities in the ipsilateral hippocampal gradient distributions were significantly different between L-TLE and R-TLE., Conclusion: Our results suggest that expansion of the SFG is characteristic of TLE. Subcortical functional gradient differences exist between left and right TLE and are driven by connectivity changes in the hippocampus ipsilateral to the seizure onset zone.

Objective: To describe the clinical features of rapid eye movement (REM) sleep behavior disorder (RBD), evaluate treatment options, and discuss management of patients with comorbid diseases., Data Sources: A MEDLINE search (1977-April 2007) using the terms REM sleep behavior disorder, narcolepsy, parkinsonian disorders, levodopa, dopamine agonists, clonazepam, benzodiazepines, and melatonin was used to retrieve relevant articles. The reference sections of all articles and texts were scanned for additional literature., Study Selection and Data Extraction: All articles published in English were evaluated. There were no specific criteria for inclusion of articles in this review., Data Synthesis: RBD is characterized by enactment of dream content resulting from the loss of normal skeletal muscle atonia during REM sleep. RBD occurs mainly in geriatric patients and in patients with neurodegenerative diseases, especially parkinsonian diseases. The presence of idiopathic RBD may be a sign of an underlying parkinsonian syndrome. Development of RBD may be one of the first manifestations of Parkinson's disease or other parkinsonian syndromes. An acute form of RBD can be drug-induced or occur on drug withdrawal. The potential for injury to the patient and his or her bed partner is as high as 96%. Controlled trials are unavailable for most agents used in the treatment of RBD, although clonazepam is an effective first-line agent and can provide rapid and complete symptom remission based on evidence from 3 large case series. Patients who cannot tolerate clonazepam or who have a suboptimal response may benefit from melatonin alone or as an adjunct. Both drugs are generally well tolerated when taken at bedtime. Management of patients with RBD becomes complicated due to the high incidence of neurologic comorbidity., Conclusions: Clonazepam is the treatment of choice for patients with RBD. The drug is efficacious and has a low incidence of adverse effects. Melatonin is a viable second-line or adjunctive treatment.