Targeting thalamocortical circuits for closed-loop stimulation in Lennox-Gastaut syndrome.

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, [18F]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.

Frontoparietal 18F-FDG-PET hypo-metabolism in Lennox-Gastaut syndrome: Further evidence highlighting the key network.

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-(18F)fluoro-D-glucose positron emission tomography (18F-FDG-PET). METHODS: Group analysis of cerebral 18F-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 18F-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.

Paroxysmal fast activity is a biomarker of treatment response in deep brain stimulation for Lennox-Gastaut syndrome.

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, η2 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.

Cognition, adaptive skills and epilepsy disability/severity in patients with Lennox-Gastaut syndrome undergoing deep brain stimulation for epilepsy in the ESTEL trial.

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.

The Optimal Target and Connectivity for Deep Brain Stimulation in Lennox-Gastaut Syndrome.

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.

DBS of Thalamic Centromedian Nucleus for Lennox-Gastaut Syndrome (ESTEL Trial).

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.

Cortex leads the thalamic centromedian nucleus in generalized epileptic discharges in Lennox-Gastaut syndrome.

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.

Combined Isoflurane-Remifentanil Anaesthesia Permits Resting-State fMRI in Children with Severe Epilepsy and Intellectual Disability.

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.

The epileptic network of Lennox-Gastaut syndrome: Cortically driven and reproducible across age.

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.

Hemiconvulsion-hemiplegia-epilepsy evolving to contralateral hemi-Lennox-Gastaut-like phenotype.

BACKGROUND: Hemiconvulsion-hemiplegia-epilepsy (HHE) involves infantile-onset acute hemiconvulsive febrile status epilepticus with subsequent unilateral cerebral atrophy and hemiparesis. Chronic epilepsy later develops, typically involving refractory focal seizures; however, the underlying pathophysiology of this epilepsy is not well understood. PATIENT: We present a boy who had a typical acute presentation of HHE at 23 months, but an unusual evolution to chronic epilepsy in which the initially unaffected hemisphere was significantly abnormal. His initial acute presentation was right-sided hemiconvulsive febrile status epilepticus, with subsequent left cerebral hemiatrophy and hemiparesis affecting the right face, arm and leg. Focal seizures began at 5 years and were refractory to medical treatment. At 9 years, video EEG monitoring showed a striking pattern of interictal slow spike-wave and paroxysmal fast activity, maximal over the right, initially unaffected, hemisphere. He had primarily focal tonic seizures involving left-sided stiffening, also appearing to originate from the right hemisphere. Following left functional hemispherotomy he became seizure-free and parents reported improved cognitive function, attention and quality of life. DISCUSSION: This boy had classic features of Lennox-Gastaut syndrome, but expressed almost exclusively over the right hemisphere, which was initially unaffected in his acute presentation of HHE. His evolution to "hemi-Lennox-Gastaut-like phenotype" illustrates the importance of monitoring chronic epilepsy in patients with HHE; early surgical intervention might prevent pathologic recruitment of bilateral secondary networks leading to the refractory seizures and cognitive impairment associated with Lennox-Gastaut syndrome.

Intraoperative definition of bottom-of-sulcus dysplasia using intraoperative ultrasound and single depth electrode recording - A technical note.

Bottom of sulcus dysplasias (BOSDs) are localized focal cortical dysplasias (FCDs) centred on the bottom of a sulcus that can be highly epileptogenic, but difficult to delineate intraoperatively. We report on a patient with refractory epilepsy due to a BOSD, successfully resected with the aid of a multimodal surgical approach using neuronavigation based on MRI and PET, intraoperative ultrasound (iUS) and electrocorticography (ECoG) using depth electrodes. The lesion could be visualized on iUS showing an increase in echogenicity at the grey-white matter junction. IUS demonstrated the position of the depth electrode in relation to the lesion. Depth electrode recording showed almost continuous spiking. Thus, intraoperative imaging and electrophysiology helped confirm the exact location of the lesion. Post-resection ultrasound demonstrated the extent of the resection and depth electrode recording did not show any epileptiform activity. Thus, both techniques helped assess completeness of resection. The patient has been seizure free since surgery. Using a multimodal approach including iUS and ECoG is a helpful adjunct in surgery for BOSD and may improve seizure outcome.

Thalamocortical functional connectivity in Lennox-Gastaut syndrome is abnormally enhanced in executive-control and default-mode networks.

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.

Refractory focal motor seizures controlled with intramuscular botulinum toxin.

Patients with recurrent focal motor seizures present a management dilemma, as anti-convulsants are often ineffective, and resective surgery poses a high risk of motor deficit. We describe three patients with recurrent focal motor seizures that remained refractory despite numerous anti-convulsant trials. All patients showed either hyperperfusion on Single-Photon Emission Computerised Tomography (SPECT) or hypermetabolism on Positron Emission Tomography (PET) in primary motor cortex during periods of sustained jerking, although EEG abnormalities were uncommon. After botulinum toxin (BoT) injection there was a rapid and dramatic reduction in seizure frequency in all patients despite minimal limb weakness. Seizure freedom persisted for 3-6 months following treatment in the injected area. Repeat BoT injections following seizure recurrence were again efficacious in one case. Combining data from our cases with those previously reported, it appears that BoT may be a useful therapeutic tool for recurrent focal motor seizures. We hypothesise that the toxin disrupts or down-regulates an epileptic circuit between motor cortex and muscle, in which volleys of information from muscle spindles have been perpetuating seizure discharges in the cortex.

Cognitive network reorganization following surgical control of seizures in Lennox-Gastaut syndrome.

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.

Targeted therapeutic mild hypercapnia after cardiac arrest: A phase II multi-centre randomised controlled trial (the CCC trial).

BACKGROUND: In intensive care observational studies, hypercapnia after cardiac arrest (CA) is independently associated with improved neurological outcome. However, the safety and feasibility of delivering targeted therapeutic mild hypercapnia (TTMH) for such patients is untested. METHODS: In a phase II safety and feasibility multi-centre, randomised controlled trial, we allocated ICU patients after CA to 24h of targeted normocapnia (TN) (PaCO2 35-45mmHg) or TTMH (PaCO2 50-55mmHg). The primary outcome was serum neuron specific enolase (NSE) and S100b protein concentrations over the first 72h assessed in the first 50 patients surviving to day three. Secondary end-points included global measure of function assessment at six months and mortality for all patients. RESULTS: We enrolled 86 patients. Their median age was 61 years (58, 64 years) and 66 (79%) were male. Of these, 50 patients (58%) survived to day three for full biomarker assessment. NSE concentrations increased in the TTMH group (p=0.02) and TN group (p=0.005) over time, with the increase being significantly more pronounced in the TN group (p(interaction)=0.04). S100b concentrations decreased over time in the TTMH group (p<0.001) but not in the TN group (p=0.68). However, the S100b change over time did not differ between the groups (p(interaction)=0.23). At six months, 23 (59%) TTMH patients had good functional recovery compared with 18 (46%) TN patients. Hospital mortality occurred in 11 (26%) TTMH patients and 15 (37%) TN patients (p=0.31). CONCLUSIONS: In CA patients admitted to the ICU, TTMH was feasible, appeared safe and attenuated the release of NSE compared with TN. These findings justify further investigation of this novel treatment.

Abnormal cognitive network interactions in Lennox-Gastaut syndrome: A potential mechanism of epileptic encephalopathy.

OBJECTIVE: In patients with Lennox-Gastaut syndrome (LGS), recurrent epileptic activity is thought to contribute to impaired cognition (epileptic encephalopathy). Using concurrent electroencephalography-functional magnetic resonance imaging (EEG-fMRI), we recently showed that epileptiform discharges in LGS recruit large-scale networks that normally support key cognitive processes. In LGS, given that epileptic activity engages cognitive networks, and cognition is pervasively impaired, we hypothesized that cognitive network interactions in LGS are persistently abnormal. METHODS: We studied 15 LGS patients (mean age ± 1 standard deviation [SD] = 28.7 ± 10.6 years) and 17 healthy controls (mean age ± 1 SD = 27.6 ± 6.6 years) using task-free EEG-fMRI. Four networks of interest (default-mode, dorsal attention, executive control, and anterior salience) were defined using group-level independent components analysis (ICA). Functional connectivity within and between networks was determined for each subject, and then LGS network interactions were compared to network behavior in the control group. To test whether group differences were present in periods without scalp-detectable epileptiform discharges (i.e., persistent), we separately assessed discharge-affected and discharge-unaffected epochs in six patients with sufficient data for this analysis. RESULTS: In LGS, cognitive networks showed (1) reduced within-network integration, including weaker connectivity within the default-mode network, and (2) impaired between-network segregation, including stronger connectivity between the default-mode and dorsal attention networks. Abnormal interactions were present during fMRI periods with and without discharges, indicating that impaired network behavior may endure during periods without scalp-detectable epileptic activity. SIGNIFICANCE: In LGS, cognitive network interactions are persistently abnormal. Given that cognition typically worsens with the onset of LGS, and may improve after seizure control, our findings are consistent with the hypothesis that the epileptic process in LGS may initiate and perhaps sustain abnormal network behavior. We propose that epileptic encephalopathy may be a consequence of persistently disrupted cognitive network interactions.

Pontine and cerebral atrophy in Lennox-Gastaut syndrome.

OBJECTIVES: Lennox-Gastaut syndrome (LGS) is a severe epilepsy of childhood onset associated with intellectual disability and multiple seizure types. Characteristic interictal electrographic discharges include generalized paroxysmal fast activity and slow spike and wave, which we have previously shown recruit widespread areas of association cortex. We wished to determine whether patients with Lennox-Gastaut syndrome (LGS) have changes in cerebral volumes that match this pattern of cortical recruitment. METHODS: High resolution T1 weighted structural MRI was collected from 10 patients with LGS and 10 age and sex matched controls. Voxel-based morphometry (VBM) was used to compare tissue volumes across the whole brain (grey matter, white matter and CSF) and pontine volume between patients and controls, as well as to identify other regions of maximal tissue loss. RESULTS: LGS patients showed a significant decrease in whole brain volume compared to controls. Cortical atrophy was prominent in the mesial frontal region and bilateral anterior temporal poles. White matter atrophy was widespread and included peri-central and premotor regions. Atrophy was prominent in the pons, particularly in the region of the reticular formation. Grey matter atrophy trended to progress with age. SIGNIFICANCE: Grey and white matter atrophy are a feature of Lennox-Gastaut syndrome. Grey matter atrophy is apparent in the mesial frontal lobe suggesting this region may be an important node in the epilepsy network of LGS. Atrophy maximal in the pons and cerebellum mimics the patterns of seizure spread that has been previously observed during tonic seizures. This supports the idea that the pons is a key part of the epilepsy network in LGS.