Trends in management of patients with new-onset refractory status epilepticus (NORSE) from 2016 to 2023: An interim analysis.

In response to the evolving treatment landscape for new-onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy-seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second-line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second-line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1-1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3-2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second-line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3-8.9)-particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3-21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5-20.1)-than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second-line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes.

Comparative analysis of patients with new onset refractory status epilepticus preceded by fever (febrile infection-related epilepsy syndrome) versus without prior fever: An interim analysis.

Febrile infection-related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non-FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non-FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non-FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non-infection-related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein-1 alpha (MIP-1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non-FIRES NORSE are very similar conditions.

Distinct signatures of loss of consciousness in focal impaired awareness versus tonic-clonic seizures.

Loss of consciousness is a hallmark of many epileptic seizures and carries risks of serious injury and sudden death. While cortical sleep-like activities accompany loss of consciousness during focal impaired awareness seizures, the mechanisms of loss of consciousness during focal to bilateral tonic-clonic seizures remain unclear. Quantifying differences in markers of cortical activation and ictal recruitment between focal impaired awareness and focal to bilateral tonic-clonic seizures may also help us to understand their different consequences for clinical outcomes and to optimize neuromodulation therapies. We quantified clinical signs of loss of consciousness and intracranial EEG activity during 129 focal impaired awareness and 50 focal to bilateral tonic-clonic from 41 patients. We characterized intracranial EEG changes both in the seizure onset zone and in areas remote from the seizure onset zone with a total of 3386 electrodes distributed across brain areas. First, we compared the dynamics of intracranial EEG sleep-like activities: slow-wave activity (1-4 Hz) and beta/delta ratio (a validated marker of cortical activation) during focal impaired awareness versus focal to bilateral tonic-clonic. Second, we quantified differences between focal to bilateral tonic-clonic and focal impaired awareness for a marker validated to detect ictal cross-frequency coupling: phase-locked high gamma (high-gamma phased-locked to low frequencies) and a marker of ictal recruitment: the epileptogenicity index. Third, we assessed changes in intracranial EEG activity preceding and accompanying behavioural generalization onset and their correlation with electromyogram channels. In addition, we analysed human cortical multi-unit activity recorded with Utah arrays during three focal to bilateral tonic-clonic seizures. Compared to focal impaired awareness, focal to bilateral tonic-clonic seizures were characterized by deeper loss of consciousness, even before generalization occurred. Unlike during focal impaired awareness, early loss of consciousness before generalization was accompanied by paradoxical decreases in slow-wave activity and by increases in high-gamma activity in parieto-occipital and temporal cortex. After generalization, when all patients displayed loss of consciousness, stronger increases in slow-wave activity were observed in parieto-occipital cortex, while more widespread increases in cortical activation (beta/delta ratio), ictal cross-frequency coupling (phase-locked high gamma) and ictal recruitment (epileptogenicity index). Behavioural generalization coincided with a whole-brain increase in high-gamma activity, which was especially synchronous in deep sources and could not be explained by EMG. Similarly, multi-unit activity analysis of focal to bilateral tonic-clonic revealed sustained increases in cortical firing rates during and after generalization onset in areas remote from the seizure onset zone. Overall, these results indicate that unlike during focal impaired awareness, the neural signatures of loss of consciousness during focal to bilateral tonic-clonic consist of paradoxical increases in cortical activation and neuronal firing found most consistently in posterior brain regions. These findings suggest differences in the mechanisms of ictal loss of consciousness between focal impaired awareness and focal to bilateral tonic-clonic and may account for the more negative prognostic consequences of focal to bilateral tonic-clonic.

Multi-shell connectome DWI-based graph theory measures for the prediction of temporal lobe epilepsy and cognition.

Temporal lobe epilepsy (TLE) is the most common epilepsy syndrome that empirically represents a network disorder, which makes graph theory (GT) a practical approach to understand it. Multi-shell diffusion-weighted imaging (DWI) was obtained from 89 TLE and 50 controls. GT measures extracted from harmonized DWI matrices were used as factors in a support vector machine (SVM) analysis to discriminate between groups, and in a k-means algorithm to find intrinsic structural phenotypes within TLE. SVM was able to predict group membership (mean accuracy = 0.70, area under the curve (AUC) = 0.747, Brier score (BS) = 0.264) using 10-fold cross-validation. In addition, k-means clustering identified 2 TLE clusters: 1 similar to controls, and 1 dissimilar. Clusters were significantly different in their distribution of cognitive phenotypes, with the Dissimilar cluster containing the majority of TLE with cognitive impairment (χ2 = 6.641, P = 0.036). In addition, cluster membership showed significant correlations between GT measures and clinical variables. Given that SVM classification seemed driven by the Dissimilar cluster, SVM analysis was repeated to classify Dissimilar versus Similar + Controls with a mean accuracy of 0.91 (AUC = 0.957, BS = 0.189). Altogether, the pattern of results shows that GT measures based on connectome DWI could be significant factors in the search for clinical and neurobehavioral biomarkers in TLE.

Evaluating the Impact of Point-of-Care Electroencephalography on Length of Stay in the Intensive Care Unit: Subanalysis of the SAFER-EEG Trial.

BACKGROUND: Electroencephalography (EEG) is needed to diagnose nonconvulsive seizures. Prolonged nonconvulsive seizures are associated with neuronal injuries and deleterious clinical outcomes. However, it is uncertain whether the rapid identification of these seizures using point-of-care EEG (POC-EEG) can have a positive impact on clinical outcomes. METHODS: In a retrospective subanalysis of the recently completed multicenter Seizure Assessment and Forecasting with Efficient Rapid-EEG (SAFER-EEG) trial, we compared intensive care unit (ICU) length of stay (LOS), unfavorable functional outcome (modified Rankin Scale score ≥ 4), and time to EEG between adult patients receiving a US Food and Drug Administration-cleared POC-EEG (Ceribell, Inc.) and those receiving conventional EEG (conv-EEG). Patient records from January 2018 to June 2022 at three different academic centers were reviewed, focusing on EEG timing and clinical outcomes. Propensity score matching was applied using key clinical covariates to control for confounders. Medians and interquartile ranges (IQRs) were calculated for descriptive statistics. Nonparametric tests (Mann-Whitney U-test) were used for the continuous variables, and the χ2 test was used for the proportions. RESULTS: A total of 283 ICU patients (62 conv-EEG, 221 POC-EEG) were included. The two populations were matched using demographic and clinical characteristics. We found that the ICU LOS was significantly shorter in the POC-EEG cohort compared to the conv-EEG cohort (3.9 [IQR 1.9-8.8] vs. 8.0 [IQR 3.0-16.0] days, p = 0.003). Moreover, modified Rankin Scale functional outcomes were also different between the two EEG cohorts (p = 0.047). CONCLUSIONS: This study reveals a significant association between early POC-EEG detection of nonconvulsive seizures and decreased ICU LOS. The POC-EEG differed from conv-EEG, demonstrating better functional outcomes compared with the latter in a matched analysis. These findings corroborate previous research advocating the benefit of early diagnosis of nonconvulsive seizure. The causal relationship between the type of EEG and metrics of interest, such as ICU LOS and functional/clinical outcomes, needs to be confirmed in future prospective randomized studies.

Unified topological inference for brain networks in temporal lobe epilepsy using the Wasserstein distance.

Persistent homology offers a powerful tool for extracting hidden topological signals from brain networks. It captures the evolution of topological structures across multiple scales, known as filtrations, thereby revealing topological features that persist over these scales. These features are summarized in persistence diagrams, and their dissimilarity is quantified using the Wasserstein distance. However, the Wasserstein distance does not follow a known distribution, posing challenges for the application of existing parametric statistical models. To tackle this issue, we introduce a unified topological inference framework centered on the Wasserstein distance. Our approach has no explicit model and distributional assumptions. The inference is performed in a completely data driven fashion. We apply this method to resting-state functional magnetic resonance images (rs-fMRI) of temporal lobe epilepsy patients collected from two different sites: the University of Wisconsin-Madison and the Medical College of Wisconsin. Importantly, our topological method is robust to variations due to sex and image acquisition, obviating the need to account for these variables as nuisance covariates. We successfully localize the brain regions that contribute the most to topological differences. A MATLAB package used for all analyses in this study is available at https://github.com/laplcebeltrami/PH-STAT.

Quantitative epileptiform burden and electroencephalography background features predict post-traumatic epilepsy.

BACKGROUND: Post-traumatic epilepsy (PTE) is a severe complication of traumatic brain injury (TBI). Electroencephalography aids early post-traumatic seizure diagnosis, but its optimal utility for PTE prediction remains unknown. We aim to evaluate the contribution of quantitative electroencephalograms to predict first-year PTE (PTE1). METHODS: We performed a multicentre, retrospective case-control study of patients with TBI. 63 PTE1 patients were matched with 63 non-PTE1 patients by admission Glasgow Coma Scale score, age and sex. We evaluated the association of quantitative electroencephalography features with PTE1 using logistic regressions and examined their predictive value relative to TBI mechanism and CT abnormalities. RESULTS: In the matched cohort (n=126), greater epileptiform burden, suppression burden and beta variability were associated with 4.6 times higher PTE1 risk based on multivariable logistic regression analysis (area under the receiver operating characteristic curve, AUC (95% CI) 0.69 (0.60 to 0.78)). Among 116 (92%) patients with available CT reports, adding quantitative electroencephalography features to a combined mechanism and CT model improved performance (AUC (95% CI), 0.71 (0.61 to 0.80) vs 0.61 (0.51 to 0.72)). CONCLUSIONS: Epileptiform and spectral characteristics enhance covariates identified on TBI admission and CT abnormalities in PTE1 prediction. Future trials should incorporate quantitative electroencephalography features to validate this enhancement of PTE risk stratification models.

Association of neighborhood deprivation with white matter connectome abnormalities in temporal lobe epilepsy.

OBJECTIVE: Social determinants of health, including the effects of neighborhood disadvantage, impact epilepsy prevalence, treatment, and outcomes. This study characterized the association between aberrant white matter connectivity in temporal lobe epilepsy (TLE) and disadvantage using a US census-based neighborhood disadvantage metric, the Area Deprivation Index (ADI), derived from measures of income, education, employment, and housing quality. METHODS: Participants including 74 TLE patients (47 male, mean age = 39.2 years) and 45 healthy controls (27 male, mean age = 31.9 years) from the Epilepsy Connectome Project were classified into ADI-defined low and high disadvantage groups. Graph theoretic metrics were applied to multishell connectome diffusion-weighted imaging (DWI) measurements to derive 162 × 162 structural connectivity matrices (SCMs). The SCMs were harmonized using neuroCombat to account for interscanner differences. Threshold-free network-based statistics were used for analysis, and findings were correlated with ADI quintile metrics. A decrease in cross-sectional area (CSA) indicates reduced white matter integrity. RESULTS: Sex- and age-adjusted CSA in TLE groups was significantly reduced compared to controls regardless of disadvantage status, revealing discrete aberrant white matter tract connectivity abnormalities in addition to apparent differences in graph measures of connectivity and network-based statistics. When comparing broadly defined disadvantaged TLE groups, differences were at trend level. Sensitivity analyses of ADI quintile extremes revealed significantly lower CSA in the most compared to least disadvantaged TLE group. SIGNIFICANCE: Our findings demonstrate (1) the general impact of TLE on DWI connectome status is larger than the association with neighborhood disadvantage; however, (2) neighborhood disadvantage, indexed by ADI, revealed modest relationships with white matter structure and integrity on sensitivity analysis in TLE. Further studies are needed to explore this relationship and determine whether the white matter relationship with ADI is driven by social drift or environmental influences on brain development. Understanding the etiology and course of the disadvantage-brain integrity relationship may serve to inform care, management, and policy for patients.

Real-world, long-term evaluation of the tolerability and therapy retention of Epidiolex® (cannabidiol) in patients with refractory epilepsy.

OBJECTIVE: Epidiolex® (CBD) is FDA-approved for seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC). Phase III studies suggest that certain adverse effects (AEs), possibly linked to pharmacokinetic/pharmacodynamic (PK/PD) interactions may be therapy-limiting. We sought to identify these factors that contribute to treatment success and retention of therapy. METHODS: A single-center, retrospective review of patients with refractory epilepsy taking Epidiolex® was performed. Kaplan-Meier analysis was performed to describe Epidiolex® retention, as a measure of overall effectiveness. RESULTS: One hundred and twelve patients were screened; 4 were excluded due to loss to follow-up or never starting Epidiolex®. Of 108 patients, mean age was 20.3 years (13.1, range 2 to 63), and 52.8% were female. Mean initial and maintenance doses were 5.3 mg/kg/day (1.3) and 15.3 mg/kg/day (5.8), respectively. At the final evaluation, 75% of patients remained on Epidiolex®. The 25th percentile for discontinuation was 19 months. 46.3% of patients experienced at least one treatment-emergent adverse effect (TEAE) with 14.5% d/c Epidiolex® due to treatment emerging adverse effects (TEAE). The most common reasons for discontinuation were lack of efficacy (37%), increased seizure activity (22%), worsened behavior (22%), and sedation (22%). One out of 27 discontinuations was due to liver function test (LFT) elevations (3.7%). At initiation, 47.2% were concurrently taking clobazam, and 39.2% of those patients had an initial clobazam dose decrease. 53% of patients were able to either discontinue or lower the dose of at least one other antiseizure medication. SIGNIFICANCE: Epidiolex® is generally well-tolerated and the majority continued long-term treatment. Patterns of adverse effects were similar to clinical trials, however gastrointestinal complaints, and significant LFT elevations were less common. Our data suggest most patients discontinue within the first several months of treatment and suggest that further studies designed to evaluate early identification and potential mitigation of adverse effects and including drug interactions are warranted.

Neurological Prognostication After Hypoglycemic Coma: Role of Clinical and EEG Findings.

BACKGROUND: Hypoglycemic coma (HC) is an uncommon but severe clinical condition associated with poor neurological outcome. There is a dearth of robust neurological prognostic factors after HC. On the other hand, there is an increasing body of literature on reliable prognostic markers in the postanoxic coma, a similar-albeit not identical-situation. The objective of this study was thus to investigate the use and predictive value of these markers in HC. METHODS: We conducted a retrospective, multicenter, cohort study within five centers of the Critical Care EEG Monitoring Research Consortium. We queried our electroencephalography (EEG) databases to identify all patients undergoing continuous EEG monitoring after admission to an intensive care unit with HC (defined as Glasgow Coma Scale < 8 on admission and a first blood glucose level < 50 mg/dL or not documented but in an obvious clinical context) between 01/01/2010 and 12/31/2020. We studied the association of findings at neurological examination (Glasgow Coma Scale motor subscale, pupillary light and corneal reflexes) and at continuous EEG monitoring(highly malignant patterns, reactivity, periodic discharges, seizures) with best neurological outcome within 3 months after hospital discharge, defined by the Cerebral Performance Category as favorable (1-3: recovery of consciousness) versus unfavorable (4-5: lack of recovery of consciousness). RESULTS: We identified 60 patients (30 [50%] women; age 62 [51-72] years). Thirty-one and 29 patients had a favorable and unfavorable outcome, respectively. The presence of pupillary reflexes (24 [100%] vs. 17 [81%]; p value 0.04) and a motor subscore > 2 (22 [92%] vs. 12 [63%]; p value 0.03) at 48-72 h were associated with a favorable outcome. A highly malignant EEG pattern was observed in 7 of 29 (24%) patients with unfavorable outcome versus 0 of 31 (0%) with favorable outcome, whereas the presence of EEG reactivity was observed in 28 of 31 (90%) patients with favorable outcome versus 13 of 29 (45%) with unfavorable outcome (p < 0.001 for comparison of all background categories). CONCLUSIONS: This preliminary study suggests that highly malignant EEG patterns might be reliable prognostic markers of unfavorable outcome after HC. Other EEG findings, including lack of EEG reactivity and seizures and clinical findings appear less accurate. These findings should be replicated in a larger multicenter prospective study.

A model of metabolic supply-demand mismatch leading to secondary brain injury.

Secondary brain injury (SBI) is defined as new or worsening injury to the brain after an initial neurologic insult, such as hemorrhage, trauma, ischemic stroke, or infection. It is a common and potentially preventable complication following many types of primary brain injury (PBI). However, mechanistic details about how PBI leads to additional brain injury and evolves into SBI are poorly characterized. In this work, we propose a mechanistic model for the metabolic supply demand mismatch hypothesis (MSDMH) of SBI. Our model, based on the Hodgkin-Huxley model, supplemented with additional dynamics for extracellular potassium, oxygen concentration, and excitotoxity, provides a high-level unified explanation for why patients with acute brain injury frequently develop SBI. We investigate how decreased oxygen, increased extracellular potassium, excitotoxicity, and seizures can induce SBI and suggest three underlying paths for how events following PBI may lead to SBI. The proposed model also helps explain several important empirical observations, including the common association of acute brain injury with seizures, the association of seizures with tissue hypoxia and so on. In contrast to current practices which assume that ischemia plays the predominant role in SBI, our model suggests that metabolic crisis involved in SBI can also be nonischemic. Our findings offer a more comprehensive understanding of the complex interrelationship among potassium, oxygen, excitotoxicity, seizures, and SBI.NEW & NOTEWORTHY We present a novel mechanistic model for the metabolic supply demand mismatch hypothesis (MSDMH), which attempts to explain why patients with acute brain injury frequently develop seizure activity and secondary brain injury (SBI). Specifically, we investigate how decreased oxygen, increased extracellular potassium, excitotoxicity, seizures, all common sequalae of primary brain injury (PBI), can induce SBI and suggest three underlying paths for how events following PBI may lead to SBI.

Regional and global resting-state functional MR connectivity in temporal lobe epilepsy: Results from the Epilepsy Connectome Project.

Temporal lobe epilepsy (TLE) has been conceptualized as focal disease with a discrete neurobiological focus and can respond well to targeted resection or ablation. In contrast, the neuro-cognitive deficits resulting from TLE can be widespread involving regions beyond the primary epileptic network. We hypothesize that this seemingly paradoxical findings can be explained by differences in connectivity between the primary epileptic region which is hyper-connected and its secondary influence on global connectome organization. This hypothesis is tested using regional and global graph theory metrics where we anticipate that regional mesial-temporal hyperconnectivity will be found and correlate with seizure frequency while global networks will be disorganized and be more closely associated with neuro-cognitive deficits. Resting-state fMRI was used to examine temporal lobe regional connectivity and global functional connectivity from 102 patients with TLE and 55 controls. Connectivity matrices were calculated for subcortical volumes and cortical parcellations. Graph theory metrics (global clustering coefficient (GCC), degree, closeness) were compared between groups and in relation to neuropsychological profiles and disease covariates using permutation testing and causal analysis. In TLE there was a decrease in GCC (p = 0.0345) associated with a worse neuropsychological profile (p = 0.0134). There was increased connectivity in the left hippocampus/amygdala (degree p = 0.0103, closeness p = 0.0104) and a decrease in connectivity in the right lateral temporal lobe (degree p = 0.0186, closeness p = 0.0122). A ratio between the hippocampus/amygdala and lateral temporal lobe-temporal lobe connectivity ratio (TLCR) revealed differences between TLE and controls for closeness (left p = 0.00149, right p = 0.0494) and for degree on left p = 0.00169; with trend on right p = 0.0567. Causal analysis suggested that "Epilepsy Activity" (seizure frequency, anti-seizure medications) was associated with increase in TLCR but not in GCC, while cognitive decline was associated with decreased GCC. These findings support the hypothesis that in TLE there is hyperconnectivity in the hippocampus/amygdala and hypoconnectivity in the lateral temporal lobe associated with "Epilepsy Activity." While, global connectome disorganization was associated with worse neuropsychological phenotype.

Behavioral phenotypes of childhood idiopathic epilepsies.

OBJECTIVE: To characterize the presence and nature of discrete behavioral phenotypes and their correlates in a cohort of youth with new and recent onset focal and generalized epilepsies. METHODS: The parents of 290 youth (age = 8-18 years) with epilepsy (n = 183) and typically developing participants (n = 107) completed the Child Behavior Checklist for children aged 6-18 from the Achenbach System of Empirically Based Assessment. The eight behavior problem scales were subjected to hierarchical clustering analytics to identify behavioral subgroups. To characterize the external validity and co-occurring comorbidities of the identified subgroups, we examined demographic features (age, gender, handedness), cognition (language, perception, attention, executive function, speed), academic problems (present/absent), clinical epilepsy characteristics (epilepsy syndrome, medications), familial factors (parental intelligence quotient, education, employment), neuroimaging features (cortical thickness), parent-observed day-to-day executive function, and number of lifetime-to-date Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnoses. RESULTS: Hierarchical clustering identified three behavioral phenotypes, which included no behavioral complications (Cluster 1, 67% of epilepsy cohort [n = 122]), nonexternalizing problems (Cluster 2, 11% of cohort [n = 21]), and combined internalizing and externalizing problems (Cluster 3, 22% of cohort [n = 40]). These behavioral phenotypes were characterized by orderly differences in personal characteristics, neuropsychological status, history of academic problems, parental status, cortical thickness, daily executive function, and number of lifetime-to-date DSM-IV diagnoses. Cluster 1 was most similar to controls across most metrics, whereas Cluster 3 was the most abnormal compared to controls. Epilepsy syndrome was not a predictor of cluster membership. SIGNIFICANCE: Youth with new and recent onset epilepsy fall into three distinct behavioral phenotypes associated with a variety of co-occurring features and comorbidities. This approach identifies important phenotypes of behavior problem presentations and their accompanying factors that serve to advance clinical and theoretical understanding of the behavioral complications of children with epilepsy and the complex conditions with which they co-occur.

Detecting Seizures and Epileptiform Abnormalities in Acute Brain Injury.

PURPOSE OF REVIEW: Acute brain injury (ABI) is a broad category of pathologies, including traumatic brain injury, and is commonly complicated by seizures. Electroencephalogram (EEG) studies are used to detect seizures or other epileptiform patterns. This review seeks to clarify EEG findings relevant to ABI, explore practical barriers limiting EEG implementation, discuss strategies to leverage EEG monitoring in various clinical settings, and suggest an approach to utilize EEG for triage. RECENT FINDINGS: Current literature suggests there is an increased morbidity and mortality risk associated with seizures or patterns on the ictal-interictal continuum (IIC) due to ABI. Further, increased use of EEG is associated with better clinical outcomes. However, there are many logistical barriers to successful EEG implementation that prohibit its ubiquitous use. Solutions to these limitations include the use of rapid EEG systems, non-expert EEG analysis, machine learning algorithms, and the incorporation of EEG data into prognostic models.

Electrographic seizures and ictal-interictal continuum (IIC) patterns in critically ill patients.

Critical care long-term continuous electroencephalogram (cEEG) monitoring has expanded dramatically in the last several decades spurned by technological advances in EEG digitalization and several key clinical findings: 1-Seizures are relatively common in the critically ill-large recent observational studies suggest that around 20% of critically ill patients placed on cEEG have seizures. 2-The majority (~75%) of patients who have seizures have exclusively "electrographic seizures", that is, they have no overt ictal clinical signs. Along with the discovery of the unexpectedly high incidence of seizures was the high prevalence of EEG patterns that share some common features with archetypical electrographic seizures but are not uniformly considered to be "ictal". These EEG patterns include lateralized periodic discharges (LPDs) and generalized periodic discharges (GPDs)-patterns that at times exhibit ictal-like behavior and at other times behave more like an interictal finding. Dr. Hirsch and colleagues proposed a conceptual framework to describe this spectrum of patterns called the ictal-interictal continuum (IIC). In the following years, investigators began to answer some of the key pragmatic clinical concerns such as which patients are at risk of seizures and what is the optimal duration of cEEG use. At the same time, investigators have begun probing the core questions for critical care EEG-what is the underlying pathophysiology of these patterns, at what point do these patterns cause secondary brain injury, what are the optimal treatment strategies, and how do these patterns affect clinical outcomes such as neurological disability and the development of epilepsy. In this review, we cover recent advancements in both practical concerns regarding cEEG use, current treatment strategies, and review the evidence associating IIC/seizures with poor clinical outcomes.

Neuroticism in temporal lobe epilepsy is associated with altered limbic-frontal lobe resting-state functional connectivity.

Neuroticism, a core personality trait characterized by a tendency towards experiencing negative affect, has been reported to be higher in people with temporal lobe epilepsy (TLE) compared with healthy individuals. Neuroticism is a known predictor of depression and anxiety, which also occur more frequently in people with TLE. The purpose of this study was to identify abnormalities in whole-brain resting-state functional connectivity in relation to neuroticism in people with TLE and to determine the degree of unique versus shared patterns of abnormal connectivity in relation to elevated symptoms of depression and anxiety. Ninety-three individuals with TLE (55 females) and 40 healthy controls (18 females) from the Epilepsy Connectome Project (ECP) completed measures of neuroticism, depression, and anxiety, which were all significantly higher in people with TLE compared with controls. Resting-state functional connectivity was compared between controls and groups with TLE with high and low neuroticism using analysis of variance (ANOVA) and t-test. In secondary analyses, the same analytics were performed using measures of depression and anxiety and the unique variance in resting-state connectivity associated with neuroticism independent of symptoms of depression and anxiety identified. Increased neuroticism was significantly associated with hyposynchrony between the right hippocampus and Brodmann area (BA) 9 (region of prefrontal cortex (PFC)) (p < 0.005), representing a unique relationship independent of symptoms of depression and anxiety. Hyposynchrony of connection between the right hippocampus and BA47 (anterior frontal operculum) was associated with high neuroticism and with higher depression and anxiety scores (p < 0.05), making it a shared abnormal connection for the three measures. In conclusion, increased neuroticism exhibits both unique and shared patterns of abnormal functional connectivity with depression and anxiety symptoms between regions of the mesial temporal and frontal lobe.

Validation of the 2HELPS2B Seizure Risk Score in Acute Brain Injury Patients.

BACKGROUND AND OBJECTIVE: Seizures are common after traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage (aSAH), subdural hematoma (SDH), and non-traumatic intraparenchymal hemorrhage (IPH)-collectively defined herein as acute brain injury (ABI). Most seizures in ABI are subclinical, meaning that they are only detectable with EEG. A method is required to identify patients at greatest risk of seizures and thereby in need of prolonged continuous EEG monitoring. 2HELPS2B is a simple point system developed to address this need. 2HELPS2B estimates seizure risk for hospitalized patients using five EEG findings and one clinical finding (pre-EEG seizure). The initial 2HELPS2B study did not specifically assess the ABI subpopulation. In this study, we aim to validate the 2HELPS2B score in ABI and determine its relative predictive accuracy compared to a broader set of clinical and electrographic factors. METHODS: We queried the Critical Care EEG Monitoring Research Consortium database for ABI patients age ≥ 18 with > 6 h of continuous EEG monitoring; data were collected between February 2013 and November 2018. The primary outcome was electrographic seizure. Clinical factors considered were age, coma, encephalopathy, ABI subtype, and acute suspected or confirmed pre-EEG clinical seizure. Electrographic factors included 18 EEG findings. Predictive accuracy was assessed using a machine-learning paradigm with area under the receiver operator characteristic (ROC) curve as the primary outcome metric. Three models (clinical factors alone, EEG factors alone, EEG and clinical factors combined) were generated using elastic-net logistic regression. Models were compared to each other and to the 2HELPS2B model. All models were evaluated by calculating the area under the curve (AUC) of a ROC analysis and then compared using permutation testing of AUC with bootstrapping to generate confidence intervals. RESULTS: A total of 1528 ABI patients were included. Total seizure incidence was 13.9%. Seizure incidence among ABI subtype varied: IPH 17.2%, SDH 19.1%, aSAH 7.6%, TBI 9.2%. Age ≥ 65 (p = 0.015) and pre-cEEG acute clinical seizure (p < 0.001) positively affected seizure incidence. Clinical factors AUC = 0.65 [95% CI 0.60-0.71], EEG factors AUC = 0.82 [95% CI 0.77-0.87], and EEG and clinical factors combined AUC = 0.84 [95% CI 0.80-0.88]. 2HELPS2B AUC = 0.81 [95% CI 0.76-0.85]. The 2HELPS2B AUC did not differ from EEG factors (p = 0.51), or EEG and clinical factors combined (p = 0.23), but was superior to clinical factors alone (p < 0.001). CONCLUSIONS: Accurate seizure risk forecasting in ABI requires the assessment of EEG markers of pathologic electro-cerebral activity (e.g., sporadic epileptiform discharges and lateralized periodic discharges). The 2HELPS2B score is a reliable and simple method to quantify these EEG findings and their associated risk of seizure.

Neuroanatomical correlates of personality traits in temporal lobe epilepsy: Findings from the Epilepsy Connectome Project.

Behavioral and personality disorders in temporal lobe epilepsy (TLE) have been a topic of interest and controversy for decades, with less attention paid to alterations in normal personality structure and traits. In this investigation, core personality traits (the Big 5) and their neurobiological correlates in TLE were explored using the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) and structural magnetic resonance imaging (MRI) through the Epilepsy Connectome Project (ECP). NEO-FFI scores from 67 individuals with TLE (34.6 ±â€¯9.5 years; 67% women) were compared to 31 healthy controls (32.8 ±â€¯8.9 years; 41% women) to assess differences in the Big 5 traits (agreeableness, openness, conscientiousness, neuroticism, and extraversion). Individuals with TLE showed significantly higher neuroticism, with no significant differences on the other traits. Neural correlates of neuroticism were then determined in participants with TLE including cortical and subcortical volumes. Distributed reductions in cortical gray matter volumes were associated with increased neuroticism. Subcortically, hippocampal and amygdala volumes were negatively associated with neuroticism. These results offer insight into alterations in the Big 5 personality traits in TLE and their brain-related correlates.

Time-dependent risk of seizures in critically ill patients on continuous electroencephalogram.

OBJECTIVE: Find the optimal continuous electroencephalographic (CEEG) monitoring duration for seizure detection in critically ill patients. METHODS: We analyzed prospective data from 665 consecutive CEEGs, including clinical factors and time-to-event emergence of electroencephalographic (EEG) findings over 72 hours. Clinical factors were selected using logistic regression. EEG risk factors were selected a priori. Clinical factors were used for baseline (pre-EEG) risk. EEG findings were used for the creation of a multistate survival model with 3 states (entry, EEG risk, and seizure). EEG risk state is defined by emergence of epileptiform patterns. RESULTS: The clinical variables of greatest predictive value were coma (31% had seizures; odds ratio [OR] = 1.8, p < 0.01) and history of seizures, either remotely or related to acute illness (34% had seizures; OR = 3.0, p < 0.001). If there were no epileptiform findings on EEG, the risk of seizures within 72 hours was between 9% (no clinical risk factors) and 36% (coma and history of seizures). If epileptiform findings developed, the seizure incidence was between 18% (no clinical risk factors) and 64% (coma and history of seizures). In the absence of epileptiform EEG abnormalities, the duration of monitoring needed for seizure risk of <5% was between 0.4 hours (for patients who are not comatose and had no prior seizure) and 16.4 hours (comatose and prior seizure). INTERPRETATION: The initial risk of seizures on CEEG is dependent on history of prior seizures and presence of coma. The risk of developing seizures on CEEG decays to <5% by 24 hours if no epileptiform EEG abnormalities emerge, independent of initial clinical risk factors. Ann Neurol 2017;82:177-185.

Cervical spinal canal narrowing in idiopathic syringomyelia.

INTRODUCTION: The cervical spine in Chiari I patient with syringomyelia has significantly different anteroposterior diameters than it does in Chiari I patients without syringomyelia. We tested the hypothesis that patients with idiopathic syringomyelia (IS) also have abnormal cervical spinal canal diameters. The finding in both groups may relate to the pathogenesis of syringomyelia. METHODS: Local institutional review boards approved this retrospective study. Patients with IS were compared to age-matched controls with normal sagittal spine MR. All subjects had T1-weighted spin-echo (500/20) and T2-weighted fast spin-echo (2000/90) sagittal cervical spine images at 1.5 T. Readers blinded to demographic data and study hypothesis measured anteroposterior diameters at each cervical level. The spinal canal diameters were compared with a Mann-Whitney U test. The overall difference was assessed with a Friedman test. Seventeen subjects were read by two reviewers to assess inter-rater reliability. RESULTS: Fifty IS patients with 50 age-matched controls were studied. IS subjects had one or more syrinxes varying from 1 to 19 spinal segments. Spinal canal diameters narrowed from C1 to C3 and then enlarged from C5 to C7 in both groups. Diameters from C2 to C4 were narrower in the IS group (p < 0.005) than in controls. The ratio of the C3 to the C7 diameters was also smaller (p = 0.004) in IS than controls. Collectively, the spinal canal diameters in the IS were significantly different from controls (Friedman test p < 0.0001). CONCLUSION: Patients with IS have abnormally narrow upper and mid cervical spinal canal diameters and greater positive tapering between C3 and C7.