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Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, specific electroencephalogram (EEG) patterns, and significant cognitive and behavioral impairments. To date, eight anti-seizure medications (ASMs) have been specifically approved by the U.S. Food and Drug Administration (FDA) for the treatment of LGS: clonazepam, felbamate, lamotrigine, topiramate, rufinamide, clobazam, cannabidiol, and fenfluramine. Additionally, several other ASMs, including valproate, are frequently used off-label for LGS management. As the therapeutic landscape for LGS expands, clinicians are increasingly faced with complex decisions regarding optimal ASM selection. This narrative review explores evolving treatment strategies, offering a consensus-based treatment algorithm designed by a panel of U.S.- based experts. We analyze both FDA-approved and off-label ASMs, drawing on data from randomized controlled trials, open-label extensions, and real-world studies to assess each drug's efficacy and safety profile. A key challenge in comparing ASMs lies in the heterogeneity of study designs and outcome measures. This review addresses these limitations and considers crucial factors influencing ASM selection, such as seizure outcomes, safety profiles, cognitive and behavioral outcomes, drug-drug interactions, and rational polypharmacy. Barriers to access, including economic and regulatory hurdles, are also discussed. The proposed treatment algorithm emphasizes a personalized approach to LGS management, recommending valproate or clobazam as first-line treatments, followed by individualized combinations based on the specific patient profile and associated comorbidities., 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. MSP servs as a consultant for Stoke Therapeutics, Neurelis, UCB, Pyros, Azurity, Marinus, and Jazz. Research funding has been provided to MSP’s institution by Takeda, UCB, Stoke, Encoded, Neurocrine, and Biocodex. MSP also holds unpaid board memberships with the Child Neurology Foundation, Pediatric Epilepsy Research Consortium, Lennox-Gastaut Foundation, and Dravet Syndrome Foundation. The other authors declare no potential conflicts of interest with respect to the research, authorship, and publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Neuromodulation techniques, including vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS), have emerged as important treatment options for patients with LGS who do not respond adequately to antiseizure medications. This review, developed with input from the Pediatric Epilepsy Research Consortium (PERC) LGS Special Interest Group, provides practical guidance for clinicians on the use of these neuromodulation approaches in patients with LGS. We discuss patient selection criteria, expected seizure and non-seizure outcomes, potential complications, and device management considerations for each technique. The review also covers initiation and titration strategies, ongoing care requirements, and emerging data on combining multiple neuromodulation modalities. While all three approaches can reduce seizure frequency in patients with LGS, with commonly reported responder rates ranging from 50 % to 60 %, their impacts on cognition, behavior and quality of life are more variable. Careful patient selection, individualized programming, and long-term follow-up are essential to optimize outcomes with neuromodulation in this challenging patient population. Further research is needed to identify optimal candidates, determine the ideal timing during patients' clinical course to consider neuromodulation, develop standardized outcome measures, and evaluate the comparative effectiveness and cost-effectiveness of different neuromodulation techniques for LGS., (Copyright © 2025 Elsevier B.V. All rights reserved.)

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., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Objectives: A supraclavicular insertion approach for vagus nerve stimulation (VNS) may permit a wider range of VNS settings compared to traditional insertion techniques due to increased anatomic distance between VNS leads and the recurrent laryngeal nerve. Beyond potential technical advantages, this approach could offer greater cosmetic satisfaction for patients. However, the safety and efficacy of the supraclavicular approach is uncertain. We compared safety and efficacy of supraclavicular versus mid-neck insertion techniques for VNS in the treatment of pediatric drug-resistant epilepsy (DRE)., Methods: Single-center retrospective analysis of children with epilepsy (< 21 years of age) who received VNS via supraclavicular or mid-neck insertion from May 2017 to December 2022. Continuous variables were compared using Wilcoxon rank-sum tests, while categorical variables were analyzed with Fisher's exact tests., Results: The study included a total of 88 patients (Male/Female:38/50), with 18 having supraclavicular and 70 mid-neck VNS insertions. No significant differences between groups were found in demographics, clinical/seizure characteristics, VNS settings, side-effect profile related to VNS surgery or stimulation, or seizure outcomes at last follow up., Conclusions: The supraclavicular approach to VNS does not differ from the mid-neck method in terms of efficacy and overall safety profile. Future research with a larger cohort and longer-term follow-up is needed to explore the clinical significance of VNS settings in the context of different lead locations., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical statement: 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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Developmental and epileptic encephalopathies (DEEs) are a group of childhood-onset epilepsy syndromes characterized by frequent seizures, severe cognitive and behavioral impairments, and poor long-term outcomes. These conditions are typically refractory to currently available medical therapies, prompting recent exploration of neuromodulation treatments such as deep brain stimulation (DBS) and responsive neurostimulation (RNS), which aim to modulate epileptic networks spanning cortical and subcortical regions. These advances have occurred alongside an improved understanding of syndrome-specific and interictal epileptiform discharge/seizure-specific brain networks. By targeting key nodes within these networks, DBS and RNS hold promise for influencing seizures and associated cognitive and behavioral comorbidities. Initial experiences with centromedian (CM) thalamic DBS for Lennox-Gastaut syndrome (LGS) have shown modest efficacy across multiple seizure types. Reports also indicate the application of DBS and RNS across various genetic and structural etiologies commonly associated with DEEs, with mixed success. Although DBS and RNS are increasingly used in LGS and other DEEs, their mixed efficacy highlights a knowledge gap in understanding why some patients with LGS do not respond and which neuromodulation approach is most effective for other DEEs. To address these issues, this review first discusses recent neuroimaging studies showing similarities and differences in the epileptic brain networks underlying various DEEs, revealing the common involvement of the thalamus and the default-mode network (DMN) across multiple DEEs. We then examine thalamic DBS for LGS to illustrate how such network insights may be used to optimize neuromodulation. Although network-based neuromodulation is still in its infancy, the LGS model may serve as a framework for other DEEs, where optimal treatment necessitates consideration of the underlying epileptic networks. Lastly, the review suggests future research directions, including individualized connectivity assessment and biomarker identification through collaborative efforts, which may enhance the therapeutic potential of neuromodulation for individuals living with DEEs., 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.)

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.)

Disorders of consciousness (DoC) are states of impaired arousal or awareness. Deep brain stimulation (DBS) is a potential treatment, but outcomes vary, possibly due to differences in patient characteristics, electrode placement, or stimulation of specific brain networks. We studied 40 patients with DoC who underwent DBS targeting the thalamic centromedian-parafascicular complex. Better-preserved gray matter, especially in the striatum, correlated with consciousness improvement. Stimulation was most effective when electric fields extended into parafascicular and subparafascicular nuclei-ventral to the centromedian nucleus, near the midbrain-and when it engaged projection pathways of the ascending arousal network, including the hypothalamus, brainstem, and frontal lobe. Moreover, effective DBS sites were connected to networks similar to those underlying impaired consciousness due to generalized absence seizures and acquired lesions. These findings support the therapeutic potential of DBS for DoC, emphasizing the importance of precise targeting and revealing a broader link between effective DoC treatment and mechanisms underlying other conscciousness-impairing conditions., Competing Interests: COMPETING INTERESTS AELW, MR, HF, FLWVJS, JT, SBS, JL, MMJC, KB, MUF, RJ, JEI, PWC, DF, ADB, BLE, and DC have no competing interests to report. MDF has intellectual property on the use of brain connectivity imaging to analyze lesions and guide brain stimulation, has consulted for Magnus Medical, Soterix, Abbott, Boston Scientific, and Tal Medical, and has received research funding from Neuronetics. AH reports lecture fees for Boston Scientific and is a consultant for Neuromodulation and Abbott. JDR has received past consulting payments from Medtronic, Corlieve, ClearPoint, Medtronic, and NeuroPace, and currently consults for Turing Medical.

Importance: Drug-resistant temporal lobe epilepsy (TLE) has been associated with hippocampal pathology. Most surgical treatment strategies, including resection and responsive neurostimulation (RNS), focus on this disease epicenter; however, imaging alterations distant from the hippocampus, as well as emerging data from responsive neurostimulation trials, suggest conceptualizing TLE as a network disorder., Objective: To assess whether brain networks connected to areas of atrophy in the hippocampus align with the topography of distant neuroimaging alterations and RNS response., Design, Setting, and Participants: This retrospective case-control study was conducted between July 2009 and June 2022. Data collection for this multicenter, population-based study took place across 4 tertiary referral centers in Montréal, Canada; Querétaro, México; Nanjing, China; and Salt Lake City, Utah. Eligible patients were diagnosed with TLE according to International League Against Epilepsy criteria and received either neuroimaging or neuroimaging and RNS to the hippocampus. Patients with encephalitis, traumatic brain injury, or bilateral TLE were excluded., Main Outcomes and Measures: Spatial alignment between brain network topographies., Results: Of the 110 eligible patients, 94 individuals diagnosed with TLE were analyzed (51 [54%] female; mean [SD] age, 31.3 [10.9] years). Hippocampal thickness maps in TLE were compared to 120 healthy control individuals (66 [55%] female; mean [SD] age, 29.8 [9.5] years), and areas of atrophy were identified. Using an atlas of normative connectivity (n = 1000), 2 brain networks were identified that were functionally connected to areas of hippocampal atrophy. The first network was defined by positive correlations to temporolimbic, medial prefrontal, and parietal regions, whereas the second network by negative correlations to frontoparietal regions. White matter changes colocalized to the positive network (t93 = -3.82; P = 2.44 × 10-4). In contrast, cortical atrophy localized to the negative network (t93 = 3.54; P = 6.29 × 10-3). In an additional 38 patients (20 [53%] female; mean [SD] age, 35.8 [11.3] years) treated with RNS, connectivity between the stimulation site and atrophied regions within the negative network was associated with seizure reduction (t212 = -2.74; P = .007)., Conclusions and Relevance: The findings in this study indicate that distributed pathology in TLE may occur in brain networks connected to the hippocampal epicenter. Connectivity to these same networks was associated with improvement following RNS. A network approach to TLE may reveal therapeutic targets outside the traditional target in the hippocampus.

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.)

Objective: Deep brain stimulation (DBS) of the centromedian nucleus (CM) is used to treat diverse brain diseases including epilepsy, Tourette syndrome, and disorders of consciousness. However, the CM is challenging to visualize on routine MRI. Many surgeons use an indirect targeting method based on established stereotactic coordinates. The authors aimed to quantify how often a DBS electrode's contacts were positioned within the CM using this approach, and to identify alternative indirect coordinates that are more accurate., Methods: Indirect targeting of the CM was performed on 100 MR images obtained in healthy adults, and the resulting coordinates were warped to a common brain template. To estimate positions of DBS contacts along this trajectory, the authors developed a probable electrode location (PEL) mask, modeled on trajectory angles obtained from prior clinical cases. Euclidean and x, y, and z distances between the centroids of the PEL mask and an atlas-based CM mask were measured and defined as error. The percentage of overlaps between the PEL mask and nearby thalamic nuclei was determined. To assess the clinical utility of this methodology, the analysis was validated using 20 MR images obtained in patients with generalized epilepsy, a common clinical indication for CM-DBS., Results: Using standard indirect coordinates, the authors found the average Euclidean error to be 4.40 ± 1.05 mm, and the x, y, and z errors were 4.19 ± 0.97 mm, 0.73 ± 0.65 mm, and 0.66 ± 0.69 mm, respectively. The PEL mask overlap was 52% with the CM and 65% with the ventral posteromedial nucleus. Variation in third ventricular width was the dominant contributor to these errors (r = -0.71). To overcome this variation, the authors developed alternative indirect coordinates: 4.5 mm lateral to the posterolateral corner of the third ventricle at the level of the posterior commissure. With this refinement, the average Euclidean error was reduced to 1.24 ± 0.5 mm, with 84% of the PEL mask within the CM., Conclusions: The unavailability of advanced MRI for direct targeting limits access to CM-DBS in resource-constrained neurosurgical programs. Standard indirect coordinates do not provide optimal targeting of the CM, with most contacts laterally placed in the sensory thalamus. The proposed indirect approach may therefore increase the accuracy and availability of CM-DBS, while reducing side effects.

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.)

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.

Objective: Patients with focal, lesional epilepsy present with seizures at variable ages. Larger lesion size and overlap with sensorimotor or default mode network (DMN) have been associated with younger age at seizure onset in cohorts with mixed types of focal cortical dysplasia (FCD). Here, we studied determinants of age at seizure onset in patients with bottom-of-sulcus dysplasia (BOSD), a discrete type of FCD with highly localized epileptogenicity., Methods: Eighty-four patients (77% operated) with BOSD were studied. Demographic, histopathologic, and genetic findings were recorded. BOSD volume and anatomical, primary versus association, rostral versus caudal, and functional network locations were determined. Normative functional connectivity analyses were performed using each BOSD as a region of interest in resting-state functional magnetic resonance imaging data of healthy children. Variables were correlated with age at seizure onset., Results: Median age at seizure onset was 5.4 (interquartile range = 2-7.9) years. Of 50 tested patients, 22 had somatic and nine had germline pathogenic mammalian target of rapamycin (mTOR) pathway variants. Younger age at seizure onset was associated with greater BOSD volume (p = .002), presence of a germline pathogenic variant (p = .04), DMN overlap (p = .04), and increased functional connectivity with the DMN (p < .05, false discovery rate corrected). Location within sensorimotor cortex and networks was not associated with younger age at seizure onset in our relatively small but homogenous cohort., Significance: Greater lesion size, pathogenic mTOR pathway germline variants, and DMN connectivity are associated with younger age at seizure onset in small FCD. Our findings strengthen the suggested role of DMN connectivity in the onset of FCD-related focal epilepsy and reveal novel contributions of genetic etiology., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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

This paper outlines the therapeutic rationale and neurosurgical targeting technique for bilateral, closed-loop, thalamocortical stimulation in Lennox-Gastaut syndrome, a severe form of childhood-onset epilepsy. Thalamic stimulation can be an effective treatment for Lennox-Gastaut syndrome, but complete seizure control is rarely achieved. Outcomes may be improved by stimulating areas beyond the thalamus, including cortex, but the optimal targets are unknown. We aimed to identify a cortical target by synthesizing prior neuroimaging studies, and to use this knowledge to advance a dual thalamic (centromedian) and cortical (frontal) approach for closed-loop stimulation. Multi-modal brain network maps from three group-level studies of Lennox-Gastaut syndrome were averaged to define the area of peak overlap: simultaneous EEG-functional MRI of generalized paroxysmal fast activity, [ 18 F]fluorodeoxyglucose PET of cortical hypometabolism and diffusion MRI structural connectivity associated with clinical efficacy in a previous trial of thalamic deep brain stimulation. The resulting 'hotspot' was used as a seed in a normative functional MRI connectivity analysis to identify connected networks. Intracranial electrophysiology was reviewed in the first two trial patients undergoing bilateral implantations guided by this hotspot. Simultaneous recordings from cortex and thalamus were analysed for presence and synchrony of epileptiform activity. The peak overlap was in bilateral premotor cortex/caudal middle frontal gyrus. Functional connectivity of this hotspot revealed a distributed network of frontoparietal cortex resembling the diffuse abnormalities seen on EEG-functional MRI and PET. Intracranial electrophysiology showed characteristic epileptiform activity of Lennox-Gastaut syndrome in both the cortical hotspot and thalamus; most detected events occurred first in the cortex before appearing in the thalamus. Premotor frontal cortex shows peak involvement in Lennox-Gastaut syndrome and functional connectivity of this region resembles the wider epileptic brain network. Thus, it may be an optimal target for a range of neuromodulation therapies, including thalamocortical stimulation and emerging non-invasive treatments like focused ultrasound or transcranial magnetic stimulation. Compared to thalamus-only approaches, the addition of this cortical target may allow more rapid detections of seizures, more diverse stimulation paradigms and broader modulation of the epileptic network. A prospective, multi-centre trial of closed-loop thalamocortical stimulation for Lennox-Gastaut syndrome is currently underway., Competing Interests: A.E.L.W., M.P.H., L.J.D., E.M.-L., F.L.W.V.J.S., L.A.H., H.S. and K.L.B. have no competing interests to report. C.R.B. has recently served as a consultant for NeuraModix and Abbott and holds intellectual property related to neuromodulation therapy. J.S.A. has received honoraria from Medtronic. R.E.G. received research support from NeuroPace, Medtronic and Boston Scientific, and consulting payments from Medtronic, Boston Scientific, Abbott Labs and Nia Therapeutics, and holds equity interest in Nia Therapeutics; the arrangements are all approved by Emory University. L.J. and M.J.M. have equity ownership with NeuroPace and are employees of NeuroPace, Inc. J.D.R. has received consulting payments from Medtronic, Corlieve and NeuroPace., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Bottom-of-sulcus dysplasia (BOSD) is increasingly recognized as a cause of drug-resistant, surgically-remediable, focal epilepsy, often in seemingly MRI-negative patients. We describe the clinical manifestations, morphological features, localization patterns and genetics of BOSD, with the aims of improving management and understanding pathogenesis. We studied 85 patients with BOSD diagnosed between 2005-2022. Presenting seizure and EEG characteristics, clinical course, genetic findings and treatment response were obtained from medical records. MRI (3 T) and 18F-FDG-PET scans were reviewed systematically for BOSD morphology and metabolism. Histopathological analysis and tissue genetic testing were performed in 64 operated patients. BOSD locations were transposed to common imaging space to study anatomical location, functional network localization and relationship to normal MTOR gene expression. All patients presented with stereotyped focal seizures with rapidly escalating frequency, prompting hospitalization in 48%. Despite 42% patients having seizure remissions, usually with sodium channel blocking medications, most eventually became drug-resistant and underwent surgery (86% seizure-free). Prior developmental delay was uncommon but intellectual, language and executive dysfunction were present in 24%, 48% and 29% when assessed preoperatively, low intellect being associated with greater epilepsy duration. BOSDs were missed on initial MRI in 68%, being ultimately recognized following repeat MRI, 18F-FDG-PET or image postprocessing. MRI features were grey-white junction blurring (100%), cortical thickening (91%), transmantle band (62%), increased cortical T1 signal (46%) and increased subcortical FLAIR signal (26%). BOSD hypometabolism was present on 18F-FDG-PET in 99%. Additional areas of cortical malformation or grey matter heterotopia were present in eight patients. BOSDs predominated in frontal and pericentral cortex and related functional networks, mostly sparing temporal and occipital cortex, and limbic and visual networks. Genetic testing yielded pathogenic mTOR pathway variants in 63% patients, including somatic MTOR variants in 47% operated patients and germline DEPDC5 or NPRL3 variants in 73% patients with familial focal epilepsy. BOSDs tended to occur in regions where the healthy brain normally shows lower MTOR expression, suggesting these regions may be more vulnerable to upregulation of MTOR activity. Consistent with the existing literature, these results highlight (i) clinical features raising suspicion of BOSD; (ii) the role of somatic and germline mTOR pathway variants in patients with sporadic and familial focal epilepsy associated with BOSD; and (iii) the role of 18F-FDG-PET alongside high-field MRI in detecting subtle BOSD. The anatomical and functional distribution of BOSDs likely explain their seizure, EEG and cognitive manifestations and may relate to relative MTOR expression., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Current applications of neurostimulation for generalized epilepsy use a one-target-fits-all approach that is agnostic to the specific epilepsy syndrome and seizure type being treated. The authors describe similarities and differences between the 2 "archetypes" of generalized epilepsy-Lennox-Gastaut syndrome and Idiopathic Generalized Epilepsy-and review recent neuroimaging evidence for syndrome-specific brain networks underlying seizures. Implications for stimulation targeting and programming are discussed using 5 clinical questions: What epilepsy syndrome does the patient have? What brain networks are involved? What is the optimal stimulation target? What is the optimal stimulation paradigm? What is the plan for adjusting stimulation over time?, Competing Interests: Disclosure A.E.L. Warren, Steven Tobochnik, Melissa M.J. Chua, Hargunbir Singh, and Michaela A. Stamm have no disclosures to report. John D. Rolston has received consulting payments from Medtronic, Corlieve, and NeuroPace., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The number of intracranial depth electrodes implanted in stereoelectroencephalography (SEEG) investigations is primarily driven by the preimplantation hypothesis about SOZ location. Targeting is not standardized and highly variable between centers. Whether some of these electrodes may prove redundant, or target low-yield areas too frequently, is uncertain., Methods: We identified a retrospective multi-institutional cohort implanted with depth electrodes for iEEG monitoring between 2003 and 2022. We collected preoperative clinical features and iEEG investigation parameters, including the number of depth electrodes and contacts implanted. We built a propensity-matched cohort with respect to these covariates and evaluated outcomes, which included (1) the likelihood of SOZ localization, (2) complications, and (3) seizure-free outcomes as a function of electrode contact coverage. In addition, we aimed to identify brain regions commonly explored in conjunction with each other and identify the likelihood of a region being implicated in initial electroclinical seizure onset., Results: One hundred and sixty-seven patients were followed for a median of 3.8 (range 2, 18) years after SEEG. Propensity-matched cohorts demonstrated that a higher number of implanted contacts were associated with a greater likelihood of proceeding to treatment, but were not associated with SOZ localization, seizure freedom (Engel I), favorable seizure outcomes (Engel I/II), or complications, per Bayes factor analysis. Lateral orbitofrontal, supramarginal, posterior cingulate, inferior parietal, and inferior temporal areas were least likely to be implicated in initial electrographic onset, whereas hippocampus, caudal middle frontal, pericalcarine, and parahippocampal areas were most likely when controlling for electrode coverage., Conclusions: SEEG effectively localizes the SOZ in both lesional and non-lesional etiologies, and clinicians are generally optimizing the electrode coverage for hypothetical SOZ localization, leading to further therapeutic surgeries that may confer seizure freedom. Nevertheless, several areas are possibly being explored despite low likelihood (<2.5%) of participation within the SOZ., (© 2024 S. Karger AG, Basel.)

Functional magnetic resonance images (fMRI) acquired using echo planar sequences typically suffer from spatial distortions due to susceptibility induced off-resonance fields, which may cause geometric mismatch with structural images and affect subsequent quantification and localization of brain function. State-of-the art distortion correction methods (for example, using FSL's topup or AFNI's 3dQwarp algorithms) require the collection of additional scans - either field maps or images with reverse phase encoding directions (i.e., blip-up/blip-down acquisitions) - to estimate and correct distortions. However, not all imaging protocols acquire these additional data and thus cannot take advantage of these post-acquisition corrections. In this study, we aim to enable state-of-the art processing of historical or limited datasets that do not include specific sequences for distortion correction by using only the acquired functional data and a single commonly acquired structural image. To achieve this, we synthesize an undistorted image with contrast similar to the fMRI data and use the non-distorted synthetic image as an anatomical target for distortion correction. We evaluate the efficacy of this approach, named SynBOLD-DisCo (Synthetic BOLD contrast for Distortion Correction), and show that this distortion correction process yields fMRI data that are geometrically similar to non-distorted structural images, with distortion correction virtually equivalent to acquisitions that do contain both blip-up/blip-down images. Our method is available as a Singularity container, source code, and an executable trained model to facilitate evaluation and integration into existing fMRI preprocessing pipelines., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Here, we report a retrospective, single-center experience with a novel deep brain stimulation (DBS) device capable of chronic local field potential (LFP) recording in drug-resistant epilepsy (DRE) and explore potential electrophysiological biomarkers that may aid DBS programming and outcome tracking., Methods: Five patients with DRE underwent thalamic DBS, targeting either the bilateral anterior (n = 3) or centromedian (n = 2) nuclei. Postoperative electrode lead localizations were visualized in Lead-DBS software. Local field potentials recorded over 12-18 months were tracked, and changes in power were associated with patient events, medication changes, and stimulation. We utilized a combination of lead localization, in-clinic broadband LFP recordings, real-time LFP response to stimulation, and chronic recordings to guide DBS programming., Results: Four patients (80%) experienced a >50% reduction in seizure frequency, whereas one patient had no significant reduction. Peaks in the alpha and/or beta frequency range were observed in the thalamic LFPs of each patient. Stimulation suppressed these LFP peaks in a dose-dependent manner. Chronic timeline data identified changes in LFP amplitude associated with stimulation, seizure occurrences, and medication changes. We also noticed a circadian pattern of LFP amplitudes in all patients. Button-presses during seizure events via a mobile application served as a digital seizure diary and were associated with elevations in LFP power., Significance: We describe an initial cohort of patients with DRE utilizing a novel sensing DBS device to characterize potential LFP biomarkers of epilepsy that may be associated with seizure control after DBS in DRE. We also present a new workflow utilizing the Percept device that may optimize DBS programming using real-time and chronic LFP recording., (© 2023 International League Against Epilepsy.)

Introduction: Lennox Gastaut syndrome (LGS) can be conceptualised as a "secondary network epilepsy", in which the shared electroclinical manifestations reflect epileptic recruitment of a common brain network, despite a range of underlying aetiologies. We aimed to identify the key networks recruited by the epileptic process of LGS using interictal 2-deoxy-2-( 18 F)fluoro-D-glucose positron emission tomography ( 18 F-FDG-PET)., Methods: Group analysis of cerebral 18 F-FDG-PET, comparing 21 patients with LGS (mean age = 15 years) and 18 pseudo-controls (mean age = 19 years), studied at Austin Health Melbourne, between 2004 and 2015. To minimise the influence of individual patient lesions in the LGS group, we only studied brain hemispheres without structural MRI abnormalities. The pseudo-control group consisted of age- and sex-matched patients with unilateral temporal lobe epilepsy, using only the hemispheres contralateral to the side of epilepsy. Voxel-wise permutation testing compared 18 F-FDG-PET uptake between groups. Associations were explored between areas of altered metabolism and clinical variables (age of seizure onset, proportion of life with epilepsy, and verbal/nonverbal ability). Penetrance maps were calculated to explore spatial consistency of altered metabolic patterns across individual patients with LGS., Results: Although not always readily apparent on visual inspection of individual patient scans, group analysis revealed hypometabolism in a network of regions including prefrontal and premotor cortex, anterior and posterior cingulate, inferior parietal lobule, and precuneus (p < 0.05, corrected for family-wise error). These brain regions tended to show a greater reduction in metabolism in non-verbal compared to verbal LGS patients, although this difference was not statistically significant. No areas of hypermetabolism were detected on group analysis, although ∼25 % of individual patients showed increased metabolism (relative to pseudo-controls) in the brainstem, putamen, thalamus, cerebellum, and pericentral cortex., Discussion: Interictal hypometabolism in frontoparietal cortex in LGS is compatible with our previous EEG-fMRI and SPECT studies showing that interictal bursts of generalised paroxysmal fast activity and tonic seizures recruit similar cortical regions. This study provides further evidence that these regions are central to the electroclinical expression of LGS., Competing Interests: Conflict of Interests disclosure None of the authors has any conflict of interest relevant to this study to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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 18 F-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. 18 F-FDG PET and ECoG abnormalities in surrounding cortex seem to be secondary phenomena., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: Prompt dissemination of clinical trial results is essential for ensuring the safety and efficacy of intracranial neurostimulation treatments, including deep brain stimulation (DBS) and responsive neurostimulation (RNS). However, the frequency and completeness of results publication, and reasons for reporting delays, are unknown. Moreover, the patient populations, targeted anatomical locations, and stimulation parameters should be clearly reported for both reproducibility and to identify lacunae in trial design. Here, we examine DBS and RNS trials from 1997 to 2022, chart their characteristics, and examine rates and predictors of results reporting., Methods: Trials were identified using ClinicalTrials.gov. Associated publications were identified using ClinicalTrials.gov and PubMed.gov. Pearson's χ2 tests were used to assess differences in trial characteristics between published and unpublished trials., Results: Across 449 trials, representing a cumulative cohort of 42,769 patient interventions, there were 37 therapeutic indications and 44 stimulation targets. The most common indication and target were Parkinson's disease (40.55%) and the subthalamic nucleus (35.88%), respectively. Only 0.89% of trials were in pediatric patients (11.58% were mixed pediatric and adult). Explored targets represented 75% of potential basal ganglia targets but only 29% of potential thalamic targets. Allowing a 1-year grace period after trial completion, 34/169 (20.12%) had results reported on ClinicalTrials.gov, and 107/169 (63.31%) were published. ∼80% of published trials included details about stimulation parameters used. Published and unpublished trials did not significantly differ by trial characteristics., Conclusion: We highlight key knowledge and performance gaps in DBS and RNS trial research. Over one-third of trials remain unpublished &gt;1 year after completion; pediatric trials are scarce; most of the thalamus remains unexplored; about one-in-five trials fail to report stimulation parameters; and movement disorders comprise the most studied indications., (© 2023 S. Karger AG, Basel.)

Objective: Epilepsy treatment trials typically rely on seizure diaries to determine seizure frequency, but these are time-consuming and difficult to maintain accurately. Fast, reliable, and objective biomarkers of treatment response are needed, particularly in Lennox-Gastaut syndrome (LGS), where high seizure frequency and comorbid cognitive and behavioral issues are additional obstacles to accurate diary-keeping. Here, we measured generalized paroxysmal fast activity (GPFA), a key interictal electrographic feature of LGS, and correlated GPFA burden with seizure diaries during a thalamic deep brain stimulation (DBS) treatment trial (Electrical Stimulation of the Thalamus in Epilepsy of Lennox-Gastaut Phenotype [ESTEL])., Methods: GPFA and electrographic seizure counts from intermittent, 24-h electroencephalograms (EEGs) were compared to 3-month diary-recorded seizure counts in 17 young adults with LGS (mean age ± SD = 24.9 ± 6.6) in the ESTEL study, a randomized clinical trial of DBS lasting 12 months (comprising a 3-month baseline and 9 months of postimplantation follow-up)., Results: Baseline median seizures measured by diaries numbered 2.6 (interquartile range [IQR] = 1.4-5) per day, compared to 284 (IQR = 120.5-360) electrographic seizures per day, confirming that diaries capture only a small fraction of seizure burden. Across all patient EEGs, the average number of GPFA discharges per hour of sleep was 138 (IQR =72-258). GPFA duration and frequency, quantified over 2-h windows of sleep EEG, were significantly associated with diary-recorded seizure counts over 3-month intervals (p < .001, η 2 p  = .30-.48). For every GPFA discharge, there were 20-25 diary seizures witnessed over 3 months. There was high between-patient variability in the ratio between diary seizure burden and GPFA burden; however, within individual patients, the ratio was similar over time, such that the percentage change from pre-DBS baseline in seizure diaries strongly correlated with the percentage change in GPFA., Significance: When seeking to optimize treatment in patients with LGS, monitoring changes in GPFA may allow rapid titration of treatment parameters, rather than waiting for feedback from seizure diaries., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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.)

Objective: Deep brain stimulation (DBS) can reduce seizures in Lennox-Gastaut syndrome (LGS). However, little is known about the optimal target and whether efficacy depends on connectivity of the stimulation site. Using outcome data from the ESTEL trial, we aimed to determine the optimal target and connectivity for DBS in LGS., Methods: A total of 20 patients underwent bilateral DBS of the thalamic centromedian nucleus (CM). Outcome was percentage seizure reduction from baseline after 3 months of DBS, defined using three measures (monthly seizure diaries, 24-hour scalp electroencephalography [EEG], and a novel diary-EEG composite). Probabilistic stimulation mapping identified thalamic locations associated with higher/lower efficacy. Two substitute diffusion MRI datasets (a normative dataset from healthy subjects and a "disease-matched" dataset from a separate group of LGS patients) were used to calculate structural connectivity between DBS sites and a map of areas known to express epileptic activity in LGS, derived from our previous EEG-fMRI research., Results: Results were similar across the three outcome measures. Stimulation was most efficacious in the anterior and inferolateral "parvocellular" CM border, extending into the ventral lateral nucleus (posterior subdivision). There was a positive association between diary-EEG composite seizure reduction and connectivity to areas of a priori EEG-fMRI activation, including premotor and prefrontal cortex, putamen, and pontine brainstem. In contrast, outcomes were not associated with baseline clinical variables., Interpretation: Efficacious CM-DBS for LGS is linked to stimulation of the parvocellular CM and the adjacent ventral lateral nucleus, and is associated with connectivity to, and thus likely modulation of, the "secondary epileptic network" underlying the shared electroclinical manifestations of LGS. ANN NEUROL 2022;92:61-74., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Prior uncontrolled studies have reported seizure reductions following deep brain stimulation (DBS) in patients with Lennox-Gastaut syndrome (LGS), but evidence from randomized controlled studies is lacking. We aimed to formally assess the efficacy and safety of DBS to the centromedian thalamic nucleus (CM) for the treatment of LGS., Methods: We conducted a prospective, double-blind, randomized study of continuous, cycling stimulation of CM-DBS, in patients with LGS. Following pre- and post-implantation periods, half received 3 months of stimulation (blinded phase), then all received 3 months of stimulation (unblinded phase). The primary outcome was the proportion of participants with ≥50% reduction in diary-recorded seizures in stimulated versus control participants, measured at the end of the blinded phase. A secondary outcome was the proportion of participants with a ≥50% reduction in electrographic seizures on 24-hour ambulatory electroencephalography (EEG) at the end of the blinded phase., Results: Between November 2017 and December 2019, 20 young adults with LGS (17-37 years;13 women) underwent bilateral CM-DBS at a single center in Australia, with 19 randomized (treatment, n = 10 and control, n = 9). Fifty percent of the stimulation group achieved ≥50% seizure reduction, compared with 22% of controls (odds ratio [OR] = 3.1, 95% confidence interval [CI] = 0.44-21.45, p = 0.25). For electrographic seizures, 59% of the stimulation group had ≥50% reduction at the end of the blinded phase, compared with none of the controls (OR= 23.25, 95% CI = 1.0-538.4, p = 0.05). Across all patients, median seizure reduction (baseline vs study exit) was 46.7% (interquartile range [IQR] = 28-67%) for diary-recorded seizures and 53.8% (IQR = 27-73%) for electrographic seizures., Interpretation: CM-DBS in patients with LGS reduced electrographic rather than diary-recorded seizures, after 3 months of stimulation. Fifty percent of all participants had diary-recorded seizures reduced by half at the study exit, providing supporting evidence of the treatment effect. ANN NEUROL 2022;91:253-267., (© 2021 American Neurological Association.)

Objective: To determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD)., Methods: We reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG., Results: Thirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0-14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasia (FCD) type IIb in 29 patients and FCDIIa in 9. Dysmorphic neurons were present in the bottom of the sulcus but not the top or the gyral crown in 17 of 22 patients. Six (16%) patients required reoperation for postoperative seizures and residual dysplasia; reoperation was not correlated with ECoG, neuroimaging, or histologic abnormalities in the gyral crown. At a median 6.3 (IQR 4.8-9.9) years of follow-up, 33 (87%) patients are seizure-free, 31 off antiseizure medication., Conclusion: BOSD can be safely and effectively resected with MRI and ECoG guidance, corticectomy potentially being limited to the dysplastic sulcus, without need for intracranial EEG monitoring and functional mapping., Classification of Evidence: This study provides Class IV evidence that 1-stage, limited corticectomy for BOSD is safe and effective for control of seizures., (© 2021 American Academy of Neurology.)

Objective: Markup of generalized interictal epileptiform discharges (IEDs) on EEG is an important step in the diagnosis and characterization of epilepsy. However, manual EEG markup is a time-consuming, subjective, and the specialized task where the human reviewer needs to visually inspect a large amount of data to facilitate accurate clinical decisions. In this study, we aimed to develop a framework for automated detection of generalized paroxysmal fast activity (GPFA), a generalized IED seen in scalp EEG recordings of patients with the severe epilepsy of Lennox-Gastaut syndrome (LGS)., Methods: We studied 13 children with LGS who had GPFA events in their interictal EEG recordings. Time-frequency information derived from manually marked IEDs across multiple EEG channels was used to automatically detect similar events in each patient's interictal EEG. We validated true positives and false positives of the proposed spike detection approach using both standalone scalp EEG and simultaneous EEG-functional MRI (EEG-fMRI) recordings., Results: GPFA events displayed a consistent low-high frequency arrangement in the time-frequency domain. This 'bimodal' spectral feature was most prominent over frontal EEG channels. Our automatic detection approach using this feature identified EEG events with similar time-frequency properties to the manually marked GPFAs. Brain maps of EEG-fMRI signal change during these automatically detected IEDs were comparable to the EEG-fMRI brain maps derived from manual IED markup., Conclusion: GPFA events have a characteristic bimodal time-frequency feature that can be automatically detected from scalp EEG recordings in patients with LGS. The validity of this time-frequency feature is demonstrated by EEG-fMRI analysis of automatically detected events, which recapitulates the brain maps we have previously shown to underlie generalized IEDs in LGS., Significance: This study provides a novel methodology that enables a fast, automated, and objective inspection of generalized IEDs in LGS. The proposed framework may be extendable to a wider range of epilepsy syndromes in which monitoring the burden of epileptic activity can aid clinical decision-making and faster assessment of treatment response and estimation of future seizure risk., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: We aimed to assess the roles of the cortex and thalamus (centromedian nucleus [CM]) during epileptic activity in Lennox-Gastaut syndrome (LGS) patients undergoing deep brain stimulation (DBS) surgery as part of the ESTEL (Electrical Stimulation of the Thalamus for Epilepsy of Lennox-Gastaut Phenotype) trial., Methods: Twelve LGS patients (mean age = 26.8 years) underwent bilateral CM-DBS implantation. Intraoperatively, simultaneous electroencephalogram (EEG) was recorded (range = 10-34 minutes) from scalp electrodes and bilateral thalamic DBS electrodes. Temporal onsets of epileptic discharges (generalized paroxysmal fast activity [GPFA] and slow spike-and-wave [SSW]) were manually marked on recordings from scalp (ie, "cortex") and thalamus (ie, CM-DBS electrodes). Phase transfer entropy (PTE) analysis quantified the degree of information transfer from cortex to thalamus within different frequency bands around GPFA events., Results: GPFA was captured in eight of 12 patients (total event number across patients = 168, cumulative duration = 358 seconds). Eighty-six percent of GPFA events were seen in both scalp and thalamic recordings. In most events (83%), onset occurred first at scalp, with thalamic onset lagging by a median of 98 milliseconds (interquartile range = 78.5 milliseconds). Results for SSW were more variable and seen in 11 of 12 patients; 25.4% of discharges were noted in both scalp and thalamus. Of these, 74.5% occurred first at scalp, with a median lag of 75 milliseconds (interquartile range = 228 milliseconds). One to 0.5 seconds and 0.5-0 seconds before GPFA onset, PTE analysis showed significant energy transfer from scalp to thalamus in the delta (1-3 Hz) frequency band. For alpha (8-12 Hz) and beta (13-30 Hz) frequencies, PTE was greatest 1-0.5 seconds before GPFA onset., Significance: Epileptic activity is detectable in CM of thalamus, confirming that this nucleus participates in the epileptic network of LGS. Temporal onset of GPFA mostly occurs earlier at the scalp than in the thalamus. This supports our prior EEG-functional magnetic resonance imaging results and provides further evidence for a cortically driven process underlying GPFA in LGS., (© 2020 International League Against Epilepsy.)

Head motion is a significant barrier to functional MRI (fMRI) in patients who are unable to tolerate awake scanning, including young children or those with cognitive and behavioural impairments. General anaesthesia minimises motion and ensures patient comfort, however the optimal anaesthesia regimen for fMRI in the paediatric setting is unknown. In this study, we tested the feasibility of anaesthetised fMRI in 11 patients (mean age = 9.8 years) with Lennox-Gastaut syndrome, a severe form of childhood-onset epilepsy associated with intellectual disability. fMRI was acquired during clinically-indicated MRI sessions using a synergistic anaesthesia regimen we typically administer for epilepsy neurosurgery: combined low-dose isoflurane (≤ 0.8% end-tidal concentration) with remifentanil (≤ 0.1 mcg/kg/min). Using group-level independent component analysis, we assessed the presence of resting-state networks by spatially comparing results in the anaesthetised patients to resting-state network templates from the 'Generation R' study of 536 similarly-aged non-anaesthetised healthy children (Muetzel et al. in Hum Brain Mapp 37(12):4286-4300, 2016). Numerous resting-state networks commonly studied in non-anaesthetised healthy children were readily identifiable in the anaesthetised patients, including the default-mode, sensorimotor, and frontoparietal networks. Independent component time-courses associated with these networks showed spectral characteristics suggestive of a neuronal origin of fMRI signal fluctuations, including high dynamic range and temporal frequency power predominantly below 0.1 Hz. These results demonstrate the technical feasibility of anaesthetised fMRI in children, suggesting that combined isoflurane-remifentanil anaesthesia may be an effective strategy to extend the emerging clinical applications of resting-state fMRI (for example, neurosurgical planning) to the variety of patient groups who may otherwise be impractical to scan.

Objectives: Deep brain stimulation (DBS) of the centromedian thalamic nucleus (CM) is an emerging treatment for multiple brain diseases, including the drug-resistant epilepsy Lennox-Gastaut syndrome (LGS). We aimed to improve neurosurgical targeting of the CM by: (1) developing a structural MRI approach for CM visualisation, (2) identifying the CM's neurophysiological characteristics using microelectrode recordings (MERs) and (3) mapping connectivity from CM-DBS sites using functional MRI (fMRI)., Methods: 19 patients with LGS (mean age=28 years) underwent presurgical 3T MRI using magnetisation-prepared 2 rapid acquisition gradient-echoes (MP 2 RAGE) and fMRI sequences; 16 patients proceeded to bilateral CM-DBS implantation and intraoperative thalamic MERs. CM visualisation was achieved by highlighting intrathalamic borders on MP 2 RAGE using Sobel edge detection. Mixed-effects analysis compared two MER features (spike firing rate and background noise) between ventrolateral, CM and parafasicular nuclei. Resting-state fMRI connectivity was assessed using implanted CM-DBS electrode positions as regions of interest., Results: The CM appeared as a hyperintense region bordering the comparatively hypointense pulvinar, mediodorsal and parafasicular nuclei. At the group level, reduced spike firing and background noise distinguished CM from the ventrolateral nucleus; however, these trends were not found in 20%-25% of individual MER trajectories. Areas of fMRI connectivity included basal ganglia, brainstem, cerebellum, sensorimotor/premotor and limbic cortex., Conclusions: In the largest clinical trial of DBS undertaken in patients with LGS to date, we show that accurate targeting of the CM is achievable using 3T MP 2 RAGE MRI. Intraoperative MERs may provide additional localising features in some cases; however, their utility is limited by interpatient variability. Therapeutic effects of CM-DBS may be mediated via connectivity with brain networks that support diverse arousal, cognitive and sensorimotor processes., Competing Interests: Competing interests: WT has received honoraria from Medtronic and Boston Scientific., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To identify brain regions underlying interictal generalized paroxysmal fast activity (GPFA), and their causal interactions, in children and adults with Lennox-Gastaut syndrome (LGS)., Methods: Concurrent scalp EEG-fMRI was performed in 2 separately analyzed patient groups with LGS: 10 children (mean age 8.9 years) scanned under isoflurane-remifentanil anesthesia and 15 older patients (mean age 31.7 years) scanned without anesthesia. Whole-brain event-related analysis determined GPFA-related activation in each group. Results were used as priors in a dynamic causal modeling (DCM) analysis comparing evidence for different neuronal hypotheses describing initiation and propagation of GPFA between cortex, thalamus, and brainstem., Results: A total of 1,045 GPFA events were analyzed (cumulative duration 1,433 seconds). In both pediatric and older groups, activation occurred in distributed association cortical areas, as well as the thalamus and brainstem ( p < 0.05, corrected for family-wise error). Activation was similar across individual patients with structural, genetic, and unknown etiologies of epilepsy, particularly in frontoparietal cortex. In both groups, DCM revealed that GPFA was most likely driven by prefrontal cortex, with propagation occurring first to the brainstem and then from brainstem to thalamus., Conclusions: We show reproducible evidence of a cortically driven process within the epileptic network of LGS. This network is present early (in children) and late (in older patients) in the course of the syndrome and across diverse etiologies of epilepsy, suggesting that LGS reflects shared "secondary network" involvement. A cortical-to-subcortical hierarchy is postulated whereby GPFA rapidly propagates from prefrontal cortex to the brainstem via extrapyramidal corticoreticular pathways, whereas the thalamus is engaged secondarily., (© 2019 American Academy of Neurology.)

Objective: To identify abnormal thalamocortical circuits in the severe epilepsy of Lennox-Gastaut syndrome (LGS) that may explain the shared electroclinical phenotype and provide potential treatment targets., Methods: Twenty patients with a diagnosis of LGS (mean age = 28.5 years) and 26 healthy controls (mean age = 27.6 years) were compared using task-free functional magnetic resonance imaging (MRI). The thalamus was parcellated according to functional connectivity with 10 cortical networks derived using group-level independent component analysis. For each cortical network, we assessed between-group differences in thalamic functional connectivity strength using nonparametric permutation-based tests. Anatomical locations were identified by quantifying spatial overlap with a histologically informed thalamic MRI atlas., Results: In both groups, posterior thalamic regions showed functional connectivity with visual, auditory, and sensorimotor networks, whereas anterior, medial, and dorsal thalamic regions were connected with networks of distributed association cortex (including the default-mode, anterior-salience, and executive-control networks). Four cortical networks (left and right executive-control network; ventral and dorsal default-mode network) showed significantly enhanced thalamic functional connectivity strength in patients relative to controls. Abnormal connectivity was maximal in mediodorsal and ventrolateral thalamic nuclei., Significance: Specific thalamocortical circuits are affected in LGS. Functional connectivity is abnormally enhanced between the mediodorsal and ventrolateral thalamus and the default-mode and executive-control networks, thalamocortical circuits that normally support diverse cognitive processes. In contrast, thalamic regions connecting with primary and sensory cortical networks appear to be less affected. Our previous neuroimaging studies show that epileptic activity in LGS is expressed via the default-mode and executive-control networks. Results of the present study suggest that the mediodorsal and ventrolateral thalamus may be candidate targets for modulating abnormal network behavior underlying LGS, potentially via emerging thalamic neurostimulation therapies., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

We previously observed that adults with Lennox-Gastaut syndrome (LGS) show abnormal functional connectivity among cognitive networks, suggesting that this may contribute to impaired cognition. Herein we report network reorganization following seizure remission in a child with LGS who underwent functional magnetic resonance imaging (fMRI) before and after resection of a cortical dysplasia. Concurrent electroencephalography (EEG) was acquired during presurgical fMRI. Presurgical and postsurgical functional connectivity were compared using (1) graph theoretical analyses of small-world network organization and node-wise strength; and (2) seed-based analyses of connectivity within and between five functional networks. To explore the specificity of these postsurgical network changes, connectivity was further compared to nine children with LGS who did not undergo surgery. The presurgical EEG-fMRI revealed diffuse activation of association cortex during interictal discharges. Following surgery and seizure control, functional connectivity showed increased small-world organization, stronger connectivity in subcortical structures, and greater within-network integration/between-network segregation. These changes suggest network improvement, and diverged sharply from the comparison group of nonoperated children. Following surgery, this child with LGS achieved seizure control and showed extensive reorganization of networks that underpin cognition. This case illustrates that the epileptic process of LGS can directly contribute to abnormal network organization, and that this network disruption may be reversible., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)