Seizures and Cognitive Outcome After Traumatic Brain Injury: A Post Hoc Analysis.

INTRODUCTION: Seizures and abnormal periodic or rhythmic patterns are observed on continuous electroencephalography monitoring (cEEG) in up to half of patients hospitalized with moderate to severe traumatic brain injury (TBI). We aimed to determine the impact of seizures and abnormal periodic or rhythmic patterns on cognitive outcome 3 months following moderate to severe TBI. METHODS: This was a post hoc analysis of the multicenter randomized controlled phase 2 INTREPID2566 clinical trial conducted from 2010 to 2016 across 20 United States Level I trauma centers. Patients with nonpenetrating TBI and postresuscitation Glasgow Coma Scale scores 4-12 were included. Bedside cEEG was initiated per protocol on admission to intensive care, and the burden of ictal-interictal continuum (IIC) patterns, including seizures, was quantified. A summary global cognition score at 3 months following injury was used as the primary outcome. RESULTS: 142 patients (age mean + / - standard deviation 32 + / - 13 years; 131 [92%] men) survived with a mean global cognition score of 81 + / - 15; nearly one third were considered to have poor functional outcome. 89 of 142 (63%) patients underwent cEEG, of whom 13 of 89 (15%) had severe IIC patterns. The quantitative burden of IIC patterns correlated inversely with the global cognition score (r = - 0.57; p = 0.04). In multiple variable analysis, the log-transformed burden of severe IIC patterns was independently associated with the global cognition score after controlling for demographics, premorbid estimated intelligence, injury severity, sedatives, and antiepileptic drugs (odds ratio 0.73, 95% confidence interval 0.60-0.88; p = 0.002). CONCLUSIONS: The burden of seizures and abnormal periodic or rhythmic patterns was independently associated with worse cognition at 3 months following TBI. Their impact on longer-term cognitive endpoints and the potential benefits of seizure detection and treatment in this population warrant prospective study.

The Relationship Between Seizures and Spreading Depolarizations in Patients with Severe Traumatic Brain Injury.

BACKGROUND: Both seizures and spreading depolarizations (SDs) are commonly detected using electrocorticography (ECoG) after severe traumatic brain injury (TBI). A close relationship between seizures and SDs has been described, but the implications of detecting either or both remain unclear. We sought to characterize the relationship between these two phenomena and their clinical significance. METHODS: We performed a post hoc analysis of a prospective observational clinical study of patients with severe TBI requiring neurosurgery at five academic neurotrauma centers. A subdural electrode array was placed intraoperatively and ECoG was recorded during intensive care. SDs, seizures, and high-frequency background characteristics were quantified offline using published standards and terminology. The primary outcome was the Glasgow Outcome Scale-Extended score at 6 months post injury. RESULTS: There were 138 patients with valid ECoG recordings; the mean age was 47 ± 19 years, and 104 (75%) were men. Overall, 2,219 ECoG-detected seizures occurred in 38 of 138 (28%) patients in a bimodal pattern, with peak incidences at 1.7-1.8 days and 3.8-4.0 days post injury. Seizures detected on scalp electroencephalography (EEG) were diagnosed by standard clinical care in only 18 of 138 (13%). Of 15 patients with ECoG-detected seizures and contemporaneous scalp EEG, seven (47%) had no definite scalp EEG correlate. ECoG-detected seizures were significantly associated with the severity and number of SDs, which occurred in 83 of 138 (60%) of patients. Temporal interactions were observed in 17 of 24 (70.8%) patients with both ECoG-detected seizures and SDs. After controlling for known prognostic covariates and the presence of SDs, seizures detected on either ECoG or scalp EEG did not have an independent association with 6-month functional outcome but portended worse outcome among those with clustered or isoelectric SDs. CONCLUSIONS: In patients with severe TBI requiring neurosurgery, seizures were half as common as SDs. Seizures would have gone undetected without ECoG monitoring in 20% of patients. Although seizures alone did not influence 6-month functional outcomes in this cohort, they were independently associated with electrographic worsening and a lack of motor improvement following surgery. Temporal interactions between ECoG-detected seizures and SDs were common and held prognostic implications. Together, seizures and SDs may occur along a dynamic continuum of factors critical to the development of secondary brain injury. ECoG provides information integral to the clinical management of patients with TBI.

Quantitative assessments of pupillary light reflexes in hospital-onset unresponsiveness.

BACKGROUND: Patients who develop hospital-onset unresponsiveness should be promptly managed in order to avoid clinical deterioration. Pupillary examination through pupillary light reflex is the gold standard method in the initial evaluation of unresponsive patients. However, the current method of shining light and subjective description often shows poor reliability. The objective of this study is to explore whether a quantitative measurement of pupillary light reflexes is useful in detecting brain herniation syndrome and predicting neurological outcomes in patients who developed hospital-onset unresponsiveness after admission for non-neurological reasons. METHODS: This was a registry-based observational study on patients who activated the neurological rapid response team at Asan Medical Center (Seoul, Korea). Hospital-onset unresponsiveness was defined as a newly developed unresponsive state as assessed by the ACDU (Alert, Confused, Drowsy, and Unresponsive) scale during the hospital stay. Demographics, comorbidities, pupillometry parameters including Neurological Pupil index, brain herniation syndrome, in-hospital mortality, and modified Rankin Scale at 3-months were analyzed. RESULTS: In 214 consecutive patients with hospital-onset unresponsiveness, 37 (17%) had brain herniation syndrome. The optimal cut-off value of Neurological Pupil index for detecting brain herniation syndrome was < 1.6 (specificity, 91% [95% confidence interval (CI) = 86-95]; sensitivity, 49% [95% CI = 32-66]). The in-hospital mortality rate was 28% (59/214); the Neurological Pupil index was negatively associated with in-hospital mortality after adjustments for the presence of brain herniation syndrome (adjusted odds ratio = 0.77, 95% CI = 0.62-0.96). Poor neurological outcomes (modified Rankin Scale ≥4) at 3 months was observed in 76% (152/201) of the patients; the Neurological Pupil index was negatively associated with poor neurological outcomes after adjustments for clinical variables (adjusted odds ratio = 0.67, 95% CI = 0.49-0.90). CONCLUSIONS: Quantitative measurements of pupillary light reflexes may be useful for early detection of potentially life-threatening neurological conditions in patients with hospital-onset unresponsiveness.

Continuous Electroencephalography After Moderate to Severe Traumatic Brain Injury.

OBJECTIVES: After traumatic brain injury, continuous electroencephalography is widely used to detect electrographic seizures. With the development of standardized continuous electroencephalography terminology, we aimed to describe the prevalence and burden of ictal-interictal patterns, including electrographic seizures after moderate-to-severe traumatic brain injury and to correlate continuous electroencephalography features with functional outcome. DESIGN: Post hoc analysis of the prospective, randomized controlled phase 2 multicenter INTREPID study (ClinicalTrials.gov: NCT00805818). Continuous electroencephalography was initiated upon admission to the ICU. The primary outcome was the 3-month Glasgow Outcome Scale-Extended. Consensus electroencephalography reviews were performed by raters certified in standardized continuous electroencephalography terminology blinded to clinical data. Rhythmic, periodic, or ictal patterns were referred to as "ictal-interictal continuum"; severe ictal-interictal continuum was defined as greater than or equal to 1.5 Hz lateralized rhythmic delta activity or generalized periodic discharges and any lateralized periodic discharges or electrographic seizures. SETTING: Twenty U.S. level I trauma centers. PATIENTS: Patients with nonpenetrating traumatic brain injury and postresuscitation Glasgow Coma Scale score of 4-12 were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 152 patients with continuous electroencephalography (age 34 ± 14 yr; 88% male), 22 (14%) had severe ictal-interictal continuum including electrographic seizures in four (2.6%). Severe ictal-interictal continuum burden correlated with initial prognostic scores, including the International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (r = 0.51; p = 0.01) and Injury Severity Score (r = 0.49; p = 0.01), but not with functional outcome. After controlling clinical covariates, unfavorable outcome was independently associated with absence of posterior dominant rhythm (common odds ratio, 3.38; 95% CI, 1.30-9.09), absence of N2 sleep transients (3.69; 1.69-8.20), predominant delta activity (2.82; 1.32-6.10), and discontinuous background (5.33; 2.28-12.96) within the first 72 hours of monitoring. CONCLUSIONS: Severe ictal-interictal continuum patterns, including electrographic seizures, were associated with clinical markers of injury severity but not functional outcome in this prospective cohort of patients with moderate-to-severe traumatic brain injury. Importantly, continuous electroencephalography background features were independently associated with functional outcome and improved the area under the curve of existing, validated predictive models.

Clinical and Polysomnographic Characteristics of Adult Patients with Suspected Obstructive Sleep Apnea from Different Sleep Clinics at a Single Tertiary Center.

INTRODUCTION: The characteristics of patients across different sleep clinics may vary because they selectively visit specific specialists on the basis of their primary symptoms. This study aimed to compare the clinical and polysomnography (PSG) features of patients with suspected obstructive sleep apnea (OSA) at three sleep specialty clinics (otolaryngology [ENT], neurology [NR], and psychiatry [PSY]). METHODS: We retrospectively analyzed the medical records and PSG reports of adult patients who underwent full-night PSG between January 2022 and June 2023 at a tertiary medical center. The demographic, questionnaire, and PSG variables were compared. RESULTS: Of the 407 patients, 83.0% exhibited sleep-disordered breathing (apnea-hypopnea index ≥ 5) with varying severity among the specialty pathways. Patients in the ENT group (n = 231) were the youngest and had the shortest sleep latency and most severe OSA markers with the highest positive airway pressure (PAP) acceptance, while those in the NR group (n = 79) had similar OSA-related PSG parameters to those in the ENT group but were older and had more OSA-related comorbidities, although their PAP acceptance was relatively low. The PSY group (n = 97) included a significant proportion of patients with normal or mild OSA, a female majority, high levels of depression, and subjective sleep distress. CONCLUSION: Our results highlight the multidisciplinary aspects of sleep medicine and diverse patients, and specialist needs for diagnosing sleep disorders and PAP acceptance. Exploring the potential differences in prognosis and treatment responses across various sleep specialty clinics would facilitate the development of personalized strategies.

Astemizole, a Second-Generation Histamine H1-Receptor Antagonist, Did Not Attenuate the Aggregation Process of α-Synuclein In Vitro.

The antihistamine astemizole has shown disease-modifying effects in several preclinical disease models of Parkinson's disease (PD). Astemizole also interacts with an anomalous aggregation of Alzheimer's disease-related amyloid-ß (Aß) peptide and has inhibitory activity on the human prion protein PrPSc. We hypothesized that the proposed preclinical benefits of astemizole on PD can be associated with the attenuation of pathological α-synuclein (α-syn) aggregation. We tested the effects of astemizole on the fibrillation processes of amyloid peptides using thioflavin T aggregation monitoring, Congo red spectral analysis, cell viability study, and transmission electron microscopic imaging. We found that astemizole did not inhibit α-syn aggregation in vitro even at a high molar ratio but inhibited the assembly of Aß aggregates. Our results suggest that the inhibitory effect of astemizole on amyloid formation is target-protein selective, and the proposed beneficial effects of this compound observed in translational PD models might not be due to its ameliorating effects on α-syn aggregation.

The Association of Nocturnal Seizures and Interictal Cardiac/Central Autonomic Function in Frontal Lobe Epilepsy: Heart Rate Variability and Central Autonomic Network Analysis.

Purpose: Patients with epilepsy frequently experience autonomic dysfunction, closely related to sudden unexplained death in epilepsy (SUDEP). SUDEP occurs most often at night or during sleep, and frequent nocturnal seizures are an established risk factor. This study investigated the influence of nocturnal seizures on autonomic dysfunction in epilepsy. Patients and Methods: This retrospective study enrolled frontal lobe epilepsy (FLE) patients who performed 24-hour EEG monitoring. All participants were divided into nocturnal FLE (NFLE, > 90% of seizures occurring during sleep) or diurnal FLE (DFLE) groups. EEG and ECG signals were simultaneously obtained during waking and sleep stages. EEG current density source and connectivity analysis of the autonomic network were performed. ECG was analyzed across time and frequency domains heart rate variability (HRV) analysis method was used. The obtained parameters were compared between the NFLE and DFLE groups. Results: Fifteen NFLE and 16 DFLE patients were enrolled with no significant difference in age, sex, disease duration, seizure frequency, or the number of anti-seizure medications between the two groups. During sleep, a decrease in HRV parameters and an increase of the beta-1 (13-22 Hz) current source density power in the bilateral paracentral lobule (BA4,5,6), precuneus (BA7), and cingulate (BA31) were observed in the NFLE group compared to DFLE group. The NFLE group also showed hyperconnectivity in the central autonomic (12 edges distributed over 10 nodes), sympathetic (2 edges distributed over 3 nodes), and parasympathetic (4 edges distributed over 6 nodes) beta-1 frequency band networks during sleep. During wakefulness, central and cardiac autonomic variables were not significantly different between the NFLE and DFLE groups. Conclusion: Interictal cardiac and central autonomic dysfunction occurred simultaneously and can be attributed to the brain-heart autonomic axis. Our findings suggest that nocturnal seizures may contribute to interictal autonomic dysfunction during sleep in people with epilepsy.

Privacy-preserving parallel kNN classification algorithm using index-based filtering in cloud computing.

With the development of cloud computing, interest in database outsourcing has recently increased. In cloud computing, it is necessary to protect the sensitive information of data owners and authorized users. For this, data mining techniques over encrypted data have been studied to protect the original database, user queries and data access patterns. The typical data mining technique is kNN classification which is widely used for data analysis and artificial intelligence. However, existing works do not provide a sufficient level of efficiency for a large amount of encrypted data. To solve this problem, in this paper, we propose a privacy-preserving parallel kNN classification algorithm. To reduce the computation cost for encryption, we propose an improved secure protocol by using an encrypted random value pool. To reduce the query processing time, we not only design a parallel algorithm, but also adopt a garbled circuit. In addition, the security analysis of the proposed algorithm is performed to prove its data protection, query protection, and access pattern protection. Through our performance evaluation, the proposed algorithm shows about 2∼25 times better performance compared with existing algorithms.

Correction: Privacy-preserving parallel kNN classification algorithm using index-based filtering in cloud computing.

[This corrects the article DOI: 10.1371/journal.pone.0267908.].

Continuous heart rate variability and electroencephalography monitoring in severe acute brain injury: a preliminary study.

BACKGROUND: Decreases in heart rate variability have been shown to be associated with poor outcomes in severe acute brain injury. However, it is unknown whether the changes in heart rate variability precede neurological deterioration in such patients. We explored the changes in heart rate variability measured by electrocardiography in patients who had neurological deterioration following severe acute brain injury, and examined the relationship between heart rate variability and electroencephalography parameters. METHODS: Retrospective analysis of 25 patients who manifested neurological deterioration after severe acute brain injury and underwent simultaneous electroencephalography plus electrocardiography monitoring. RESULTS: Eighteen electroencephalography channels and one simultaneously recorded electrocardiography channel were segmented into epochs of 120-second duration and processed to compute 10 heart rate variability parameters and three quantitative electroencephalography parameters. Raw electroencephalography of the epochs was also assessed by standardized visual interpretation and categorized based on their background abnormalities and ictalinterictal continuum patterns. The heart rate variability and electroencephalography parameters showed consistent changes in the 2-day period before neurological deterioration commenced. Remarkably, the suppression ratio and background abnormality of the electroencephalography parameters had significant reverse correlations with all heart rate variability parameters. CONCLUSIONS: We observed a significantly progressive decline in heart rate variability from the day before the neurological deterioration events in patients with severe acute brain injury were first observed.

Neurological and clinical status from early time point to long-term follow-up after in-hospital cardiac arrest.

AIM: We aimed to evaluate neurological profiles of patients with in-hospital cardiac arrest (IHCA) from early time points to long-term follow-up periods. METHODS: For this prospective cohort study, we established a neurological rapid response team, and serially evaluated the neurological status of patients with IHCA from the initial resuscitation to 12 months after the onset of IHCA. The primary outcome was good neurological status defined as a Clinical Performance Category score of 1-2 at 12 months after IHCA. The secondary outcomes included the awakening and neurological recovery during the first week, the survival and neurological status at hospital discharge, and the survival at 12 months. RESULTS: A total of 291 adult patients with IHCA were included. On the first day and during the first week after IHCA, the awakening was achieved in 61 (21.0 %) and 119 patients (40.9 %), respectively; and neurological recovery in 12 (4.1 %) and 46 patients (15.8 %), respectively. Epileptic seizures developed in 9.7 % following restoration of spontaneous circulation. At hospital discharge, 106 patients (36.4 %) had survived; among them, 63.2 % showed good neurological status. At 12 months, 63 (21.6 %) patients survived; among them, 81.7 % showed good neurological status (17.0 % among all patients with IHCA). Of patients without awakening during the first 3 and 7 days, 2.7 % and 1.2 % showed good neurological status at 12 months, respectively. CONCLUSIONS: Among patients with IHCA, awakening and neurological recovery were remarkable throughout the first week. Survival and good neurological status were substantial at 12 months after IHCA.

Neurological Emergencies in Patients Hospitalized With Nonneurological Illness.

OBJECTIVE: We aimed to present neurological profiles and clinical outcomes of patients with acute neurological symptoms, which developed during hospitalization with nonneurological illness. METHODS: We organized the neurological alert team (NAT), a neurological rapid response team, to manage in-hospital neurological emergencies. In this registry-based study, we analyzed the clinical profiles and outcomes of patients who were consulted to the NAT. We also compared the 3-month mortality of patients with acute neurological symptoms with that of patients without acute neurological symptoms. RESULTS: Among the 85,507 adult patients, 591 (0.7%) activated the NAT. The most common reason for NAT activation was stroke symptoms (37.6%), followed by seizures (28.6%), and sudden unresponsiveness (24.0%). The most common diagnosis by the NAT neurologists was metabolic encephalopathy (45.5%), followed by ischemic stroke (21.2%) and seizures or status epilepticus (21.0%). Patients with NAT activation had high rates in mortality before hospital discharge (22.5%) and at 3 months (34.7%), transfer to intensive care units (39.6%), and length of hospital stay (43.1 ± 57.1 days). They also had high prevalence of poor functional status (78.1%) and recurrence of neurological symptoms at 3 months (27.2%). In a Cox proportional hazards model, patients with in-hospital neurological emergencies had a hazard ratio of 13.2 in terms of mortality at 3 months (95% confidence interval, 11.5-15.3; P < 0.001). CONCLUSIONS: Occurrence of acute neurological symptoms during hospital admission was associated with high rate of mortality and poor functional status. These results call for enhanced awareness and hospital-wide strategies for managing in-hospital neurological emergencies.