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Diffusion‐weighted imaging (DWI) has been frequently used to examine age‐related deterioration of white matter microstructure and its relationship to cognitive decline. However, typical tensor‐based analytical approaches are often difficult to interpret due to the challenge of decomposing and (mis)interpreting the impact of crossing fibers within a voxel. We hypothesized that a novel analytical approach capable of resolving fiber‐specific changes within each voxel (i.e., fixel‐based analysis [FBA])—would show greater sensitivity relative to the traditional tensor‐based approach for assessing relationships between white matter microstructure, age, and cognitive performance. To test our hypothesis, we studied 636 cognitively normal adults aged 65–80 years (mean age = 69.8 years; 71% female) using diffusion‐weighted MRI. We analyzed fixels (i.e., fiber‐bundle elements) to test our hypotheses. A fixel provides insight into the structural integrity of individual fiber populations in each voxel in the presence of multiple crossing fiber pathways, allowing for potentially increased specificity over other diffusion measures. Linear regression was used to investigate associations between each of three fixel metrics (fiber density, cross‐section, and density × cross‐section) with age and cognitive performance. We then compared and contrasted the FBA results to a traditional tensor‐based approach examining voxel‐wise fractional anisotropy. In a whole‐brain analysis, significant associations were found between fixel‐based metrics and age after adjustments for sex, education, total brain volume, site, and race. We found that increasing age was associated with decreased fiber density and cross‐section, namely in the fornix, striatal, and thalamic pathways. Further analysis revealed that lower fiber density and cross‐section were associated with poorer performance in measuring processing speed and attentional control. In contrast, the tensor‐based analysis failed to detect any white matter tracts significantly associated with age or cognition. Taken together, these results suggest that FBAs of DWI data may be more sensitive for detecting age‐related white matter changes in an older adult population and can uncover potentially clinically important associations with cognitive performance. [ABSTRACT FROM AUTHOR]

Objective: Lennox‐Gastaut syndrome (LGS) is a severe, childhood‐onset epilepsy that is typically refractory to treatment. We surveyed the current landscape of LGS treatment, aiming to identify challenges to the development of efficacious therapies, and to articulate corresponding priorities toward clinical trials that improve outcomes. Methods: The LGS Special Interest Group of the Pediatric Epilepsy Research Consortium integrated evidence from the literature and expert opinion, into a narrative review. Results: We provide an overview of approved and emerging medical, dietary, surgical and neuromodulation approaches for LGS. We note that quality of care could be improved by standardizing LGS treatment based on expert consensus and empirical data. Whereas LGS natural history is incompletely understood, prospective studies and use of large retrospective datasets to understand LGS across the lifespan would enable clinical trials that address these dynamics. Recent discoveries related to LGS pathophysiology should enable development of disease‐modifying therapies, which are currently lacking. Finally, clinical trials have focused chiefly on seizures involving "drops," but should incorporate additional patient‐centered outcomes, using emerging measures adapted to people with LGS. Interpretation: Clinicians and researchers should enact these priorities, with the goal of patient‐centered clinical trials that are tailored to LGS pathophysiology and natural history. [ABSTRACT FROM AUTHOR]

Status Epilepticus (SE), unresponsive to medical management, is associated with high morbidity and mortality. Surgical management is typically considered in these refractory cases. The best surgical approach for affected patients remains unclear; however, given the lack of controlled trials exploring the role of surgery. We performed a systematic review according to PRIMSA guidelines, including case reports and series describing surgical interventions for patients in SE. Cases (157 patients, median age 12.9 years) were followed for a median of 12 months. Patients were in SE for a median of 21 days before undergoing procedures including: focal resection (36.9%), functional hemispherectomy (21%), lobar resection (12.7%), vagus nerve stimulation (VNS) (12.7%), deep brain stimulation (DBS) (6.4%), multiple subpial transection (MST) (3.8%), responsive neurostimulation (RNS) (1.9%), and cortical stimulator placement (1.27%), with 24 patients undergoing multiple procedures. Multiple SE semiologies were identified. 47.8% of patients had focal seizures, and 65% of patients had focal structural abnormalities on MRI. SE persisted for 36.8 ± 47.7 days prior to surgical intervention. SE terminated following surgery in 81.5%, terminated with additional adjuncts in 10.2%, continued in 1.9%, and was not specified in 6.4% of patients. Long‐term seizure outcomes were favorable, with the majority improved and 51% seizure‐free. Eight patients passed away in follow‐up, of which three were in SE. Seizures emerging from one hemisphere were both more likely to immediately terminate (OR 4.7) and lead to long‐term seizure‐free status (OR 3.9) compared to nonunilateral seizures. No other predictors, including seizure focality, SE duration, or choice of surgical procedure, were predictors of SE termination. Surgical treatment of SE can be effective in terminating SE and leading to sustained seizure freedom, with many different procedures showing efficacy if matched appropriately with SE semiology and etiology. Plain Language Summary: Patients with persistent seizures (Status Epilepticus) that do not stop following medications can be treated effectively with surgery. Here, we systematically review the entirety of existing literature on surgery for treating status epilepticus to better identify how and when surgery is used and what patients do after surgery. [ABSTRACT FROM AUTHOR]

Objective: Favorable seizure outcome is reported following resection of bottom‐of‐sulcus dysplasia (BOSD). We assessed the distribution of epileptogenicity and dysplasia in and around BOSD to better understand this clinical outcome and the optimal surgical approach. Methods: We studied 27 children and adolescents with magnetic resonance imaging (MRI)‐positive BOSD who underwent epilepsy surgery; 85% became seizure‐free postresection (median = 5.0 years follow‐up). All patients had resection of the dysplastic sulcus, and 11 had additional resection of the gyral crown (GC) or adjacent gyri (AG). Markers of epileptogenicity were relative cortical hypometabolism on preoperative 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET), and spiking, ripples, fast ripples, spike–high‐frequency oscillation cross‐rate, and phase amplitude coupling (PAC) on preresection and postresection electrocorticography (ECoG), all analyzed at the bottom‐of‐sulcus (BOS), top‐of‐sulcus (TOS), GC, and AG. Markers of dysplasia were increased cortical thickness on preoperative MRI, and dysmorphic neuron density and variant allele frequency of somatic MTOR mutations in resected tissue, analyzed at similar locations. Results: Relative cortical metabolism was significantly reduced and ECoG markers were significantly increased at the BOS compared to other regions. Apart from spiking and PAC, which were greater at the TOS compared to the GC, there were no significant differences in PET and other ECoG markers between the TOS, GC, and AG, suggesting a cutoff of epileptogenicity at the TOS rather than a tapering gradient on the cortical surface. MRI and tissue markers of dysplasia were all maximal in the BOS, reduced in the TOS, and mostly absent in the GC. Spiking and PAC reduced significantly over the GC after resection of the dysplastic sulcus. Significance: These findings support the concept that dysplasia and intrinsic epileptogenicity are mostly limited to the dysplastic sulcus in BOSD and support resection or ablation confined to the MRI‐visible lesion as a first‐line surgical approach. 18F‐FDG PET and ECoG abnormalities in surrounding cortex seem to be secondary phenomena. [ABSTRACT FROM AUTHOR]

Lennox-Gastaut Syndrome (LGS) is a category of severe, disabling epilepsy, characterized by frequent, treatment-resistant seizures, and cognitive impairment. Electroencephalography(EEG) shows characteristic generalized epileptic activity that is similar in those with lesional, genetic, or unknown causes, suggesting a common underlying mechanism. The condition typically begins in young children, leaving many severely disabled with recurring seizures throughout their adult life. Scalp EEG of the tonic seizures of LGS is characterized by a diffuse high-voltage slow transient evolving into generalized low-voltage fast activity, likely reflecting sustained fast neuronal firing over a wide cortical area. The typical interictaldis charges (runs of slow spike-and-wave and bursts of generalized paroxysmal fast activity) also have a "generalized" electrical field, suggesting widespread cortical involvement. Recent brain mapping studies have begun to reveal which cortical and subcorticalregions are active during these "generalized" discharges. In this critical review, we examine findings from neuroimaging studies of LGS and place these in the context of the electrical and clinical features of the syndrome. We suggest that LGS can be conceptualized as "secondary network epilepsy," where the epileptic activity is expressed through large-scale brain networks, particularly the attention and default-mode networks. Cortical lesions, when present, appear to chronically interact with these networks to produce network instability rather than triggering each individual epileptic discharge. LGS can be considered as "secondary" network epilepsy because the epileptic manifestations of the disorder reflect the networks being driven, rather than the specific initiating process. In this review, we begin with a summation of the clinical manifestations of LGS and what this has revealed about the underlying etiology of the condition. We then undertake a systematic review of the functional neuroimaging literature in LGS, which leads us to conclude that LGS can best be conceptualized as "secondary network epilepsy." [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) is a standard treatment for movement disorders, epilepsy, and others, yet its influence on postprocedural sleep quality remains an under-researched topic., Study Objectives: We performed a systematic review and meta-analysis of all DBS effects on sleep., Methods: The use of preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA) was utilized. We extracted demographic data, disease type/duration, DBS target, stimulation laterality (unilateral vs bilateral), follow-up lengths, and sleep pre/post-op measurements with polysomnography or across four standard sleep scales. The Cochrane methodology for evaluating RCTs was employed using the risk of bias assessments, data synthesis, and statistical methods, including forest plots (risk ratio; M-H random effects; 95% CI)., Results: Sixty-three studies were included in the overall analysis, representing 3022 patients. In a subgroup meta-analysis of subthalamic nucleus (STN) DBS for Parkinson's disease (PD), patients showed significant sleep improvement at three but not 12 months postoperatively with PDSS, at 12 but not 3 months with Epworth sleep scale, and at 6 months with nonmotor symptom scale. Pittsburgh sleep quality index (PSQI) showed no significant improvement in sleep at any time. Bilateral DBS showed significantly more improvement than unilateral DBS in the PSQI at 6 but not 3 months. Polysomnography showed significant sleep improvement at 1 week but not at 3 or 6 months. Most studies showed no significant sleep improvement for globus pallidus internus, centromedian thalamus, and ventral intermediate nucleus DBS., Conclusions: STN-DBS for PD likely improves sleep; however, significant standardization in sleep scale outcome reporting and follow-up time is needed to effectively determine the target-dependent effects of DBS surgery on sleep., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Objectives: Traumatic brain injury (TBI) is associated with sleep deficits, but it is not clear why some report sleep disturbances and others do not. The objective of this study was to assess the associations between axonal injury, sleep, and memory in chronic and acute TBI., Methods: Data were acquired from two independent datasets which included 156 older adult veterans (69.8 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with prior moderate-to-severe TBIs and 90 (69.2 years) controls and 374 (39.6 years) from Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) with a recent mild TBI (mTBI) and 87 controls (39.6 years), all who completed an MRI, memory assessment, and sleep questionnaire., Results: Older adults with a prior TBI had a significant association between axonal injury and sleep disturbances [β = 9.52, 95% CI (4.1, 14.9), p = 0.01]. Axonal injury predicted changes in memory over 1-year in TBI [β = -8.72, 95% CI (-18, -2.7), p = 0.03]. We externally validated those findings in TRACK-TBI where axonal injury within 2 weeks after mTBI was significantly associated with higher sleep disturbances in the TBI group at 2 weeks[β = -7.2, 95% CI (-14, -0.50), p = 0.04], 6 months [β = -16, 95% CI (-24, -7.6), p ≤ 0.01], and 12 months post-injury [β = -11, 95% CI (-19, -0.85), p = 0.03]. These associations were not significant in controls., Interpretations: Axonal injury, specifically to the left anterior internal capsule is robustly associated with sleep disturbances in multiple TBI populations. Early assessment of axonal injury following mTBI could identify those at risk for persistent sleep disturbances following injury., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Infantile epileptic spasms syndrome (IESS) is a common developmental and epileptic encephalopathy with poor long-term outcomes. A substantial proportion of patients with IESS have a potentially surgically remediable etiology. Despite this, epilepsy surgery is underutilized in this patient group. Some surgically remediable etiologies, such as focal cortical dysplasia and malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE), are under-diagnosed in infants and young children. Even when a surgically remediable etiology is recognised, for example, tuberous sclerosis or focal encephalomalacia, epilepsy surgery may be delayed or not considered due to diffuse EEG changes, unclear surgical boundaries, or concerns about operating in this age group., Areas Covered: In this review, the authors discuss the common surgically remediable etiologies of IESS, their clinical and EEG features, and the imaging techniques that can aid in their diagnosis. They then describe the surgical approaches used in this patient group, and the beneficial impact that early epilepsy surgery can have on developing brain networks., Expert Opinion: Epilepsy surgery remains underutilized even when a potentially surgically remediable cause is recognized. Overcoming the barriers that result in under-recognition of surgical candidates and underutilization of epilepsy surgery in IESS will improve long-term seizure and developmental outcomes.

The centromedian (CM) nucleus of the thalamus is a promising target for a range of brain diseases including drug-resistant generalized and multifocal epilepsy. CM is highly connected to cortical and subcortical regions including frontoparietal/sensorimotor cortex, striatum, brainstem, and cerebellum, which are involved in some generalized epilepsy syndromes like Lennox-Gastaut syndrome (LGS). In this video, the authors describe their methodology for targeting CM for deep brain stimulation (DBS). Delineation of an optimal and consistent target will expand the efficacy of neuromodulation of CM in intractable epilepsy. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID245., Competing Interests: Disclosures Dr. Chen reports equity in Verge Genomics and Gravity Medical Technology.Dr. Chen reports equity in Verge Genomics and Gravity Medical Technology., (© 2024, The Authors.)

Purpose: We previously reported seizure and EEG outcomes of the ESTEL study (Electrical Stimulation of Thalamus for Epilepsy of Lennox-Gastaut phenotype). To assess potential cognitive and behavioral changes during chronic, duty-cycle stimulation of bilateral thalamic centromedian nucleus, we compared standardized cognitive and behavioral measurements, as well as caregiver assessments of disability/severity, before implantation and after 3-months stimulation., Methods: Twenty patients with LGS (17-37 years;13 females) were studied; one participant was not randomized due to DBS device removal, with outcomes of 19 remaining participants reported here. Cognitive and behavioral measurements were performed at baseline (i.e., before DBS implantation), at the end of the blinded stimulation phase, and at study exit. Instruments measured cognition (NIH toolbox cognitive battery, NIHTB-CB), adaptive skills (ABAS-3), epilepsy severity (GASE) and disability (GAD), quality of life (QOLIE-31), and depression (PHQ-9). Changes in scores after 3-months of stimulation relative to baseline were explored using Wilcoxon matched-pairs signed rank tests., Results: After 3-months of stimulation, caregiver-reported epilepsy severity (GASE) and disability (GAD) improved (p<0.05). No other instrument showed a significant change from baseline. Measurements that required direct participant involvement, rather than caregivers, was completed by only a subset of higher-functioning individuals (NIHTB-CB, n = 13; QOLIE-31, n = 3; and PHQ-9, n = 6). In addition to cognitive impairments, behavioral and physical limitations were common obstacles to instrument completion. Standardized scores were hindered by 'floor effects'; however, raw scores better reflected clinical impressions of participants' functioning and were more sensitive to caregiver-reported changes following treatment., Conclusion: DBS treatment is associated with reduced epilepsy severity and disability in young adults with LGS. Performing cognitive and behavioral outcome measurement in patients with cognitive impairment is challenging but possible and requires careful selection of instruments and modifications of score interpretation to avoid floor effects., Competing Interests: Declaration of Competing Interest JSA has received honoraria from Medtronic. KJB and WT are co-founders and hold shares and option in DBS Technologies Pty Ltd. KJB and WT are also named inventors on related patents, which are assigned to DBS Technologies Pty Ltd. WT has received honoraria from Medtronic and Boston Scientific. Medtronic and Boston Scientific are manufacturers of DBS equipment. The remaining authors have no conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2022. Published by Elsevier Ltd.)