Macroscopic changes in aquaporin-4 underlie blast traumatic brain injury-related impairment in glymphatic function.

Mild traumatic brain injury (mTBI) has emerged as a potential risk factor for the development of neurodegenerative conditions such as Alzheimer's disease and chronic traumatic encephalopathy. Blast mTBI, caused by exposure to a pressure wave from an explosion, is predominantly experienced by military personnel and has increased in prevalence and severity in recent decades. Yet the underlying pathology of blast mTBI is largely unknown. We examined the expression and localization of AQP4 in human post-mortem frontal cortex and observed distinct laminar differences in AQP4 expression following blast exposure. We also observed similar laminar changes in AQP4 expression and localization and delayed impairment of glymphatic function that emerged 28 days following blast injury in a mouse model of repetitive blast mTBI. In a cohort of veterans with blast mTBI, we observed that blast exposure was associated with an increased burden of frontal cortical MRI-visible perivascular spaces, a putative neuroimaging marker of glymphatic perivascular dysfunction. These findings suggest that changes in AQP4 and delayed glymphatic impairment following blast injury may render the post-traumatic brain vulnerable to post-concussive symptoms and chronic neurodegeneration.

Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus.

OBJECTIVE: This study was undertaken to evaluate benzodiazepine (BZD) administration patterns before transitioning to non-BZD antiseizure medication (ASM) in pediatric patients with refractory convulsive status epilepticus (rSE). METHODS: This retrospective multicenter study in the United States and Canada used prospectively collected observational data from children admitted with rSE between 2011 and 2020. Outcome variables were the number of BZDs given before the first non-BZD ASM, and the number of BZDs administered after 30 and 45 min from seizure onset and before escalating to non-BZD ASM. RESULTS: We included 293 patients with a median (interquartile range) age of 3.8 (1.3-9.3) years. Thirty-six percent received more than two BZDs before escalating, and the later the treatment initiation was after seizure onset, the less likely patients were to receive multiple BZD doses before transitioning (incidence rate ratio [IRR] = .998, 95% confidence interval [CI] = .997-.999 per minute, p = .01). Patients received BZDs beyond 30 and 45 min in 57.3% and 44.0% of cases, respectively. Patients with out-of-hospital seizure onset were more likely to receive more doses of BZDs beyond 30 min (IRR = 2.43, 95% CI = 1.73-3.46, p < .0001) and beyond 45 min (IRR = 3.75, 95% CI = 2.40-6.03, p < .0001) compared to patients with in-hospital seizure onset. Intermittent SE was a risk factor for more BZDs administered beyond 45 min compared to continuous SE (IRR = 1.44, 95% CI = 1.01-2.06, p = .04). Forty-seven percent of patients (n = 94) with out-of-hospital onset did not receive treatment before hospital arrival. Among patients with out-of-hospital onset who received at least two BZDs before hospital arrival (n = 54), 48.1% received additional BZDs at hospital arrival. SIGNIFICANCE: Failure to escalate from BZDs to non-BZD ASMs occurs mainly in out-of-hospital rSE onset. Delays in the implementation of medical guidelines may be reduced by initiating treatment before hospital arrival and facilitating a transition to non-BZD ASMs after two BZD doses during handoffs between prehospital and in-hospital settings.

Factors associated with long-term outcomes in pediatric refractory status epilepticus.

OBJECTIVE: This study was undertaken to describe long-term clinical and developmental outcomes in pediatric refractory status epilepticus (RSE) and identify factors associated with new neurological deficits after RSE. METHODS: We performed retrospective analyses of prospectively collected observational data from June 2011 to March 2020 on pediatric patients with RSE. We analyzed clinical outcomes from at least 30 days after RSE and, in a subanalysis, we assessed developmental outcomes and evaluated risk factors in previously normally developed patients. RESULTS: Follow-up data on outcomes were available in 276 patients (56.5% males). The median (interquartile range [IQR]) follow-up duration was 1.6 (.9-2.7) years. The in-hospital mortality rate was 4% (16/403 patients), and 15 (5.4%) patients had died after hospital discharge. One hundred sixty-six (62.9%) patients had subsequent unprovoked seizures, and 44 (16.9%) patients had a repeated RSE episode. Among 116 patients with normal development before RSE, 42 of 107 (39.3%) patients with available data had new neurological deficits (cognitive, behavioral, or motor). Patients with new deficits had longer median (IQR) electroclinical RSE duration than patients without new deficits (10.3 [2.1-134.5] h vs. 4 [1.6-16] h, p = .011, adjusted odds ratio = 1.003, 95% confidence interval = 1.0008-1.0069, p = .027). The proportion of patients with an unfavorable functional outcome (Glasgow Outcome Scale-Extended score ≥ 4) was 22 of 90 (24.4%), and they were more likely to have received a continuous infusion. SIGNIFICANCE: About one third of patients without prior epilepsy developed recurrent unprovoked seizures after the RSE episode. In previously normally developing patients, 39% presented with new deficits during follow-up, with longer electroclinical RSE duration as a predictor.

Super-Refractory Status Epilepticus in Children: A Retrospective Cohort Study.

OBJECTIVES: To characterize the pediatric super-refractory status epilepticus population by describing treatment variability in super-refractory status epilepticus patients and comparing relevant clinical characteristics, including outcomes, between super-refractory status epilepticus, and nonsuper-refractory status epilepticus patients. DESIGN: Retrospective cohort study with prospectively collected data between June 2011 and January 2019. SETTING: Seventeen academic hospitals in the United States. PATIENTS: We included patients 1 month to 21 years old presenting with convulsive refractory status epilepticus. We defined super-refractory status epilepticus as continuous or intermittent seizures lasting greater than or equal to 24 hours following initiation of continuous infusion and divided the cohort into super-refractory status epilepticus and nonsuper-refractory status epilepticus groups. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 281 patients (157 males) with a median age of 4.1 years (1.3-9.5 yr), including 31 super-refractory status epilepticus patients. Compared with nonsuper-refractory status epilepticus group, super-refractory status epilepticus patients had delayed initiation of first nonbenzodiazepine-antiseizure medication (149 min [55-491.5 min] vs 62 min [33.3-120.8 min]; p = 0.030) and of continuous infusion (495 min [177.5-1,255 min] vs 150 min [90-318.5 min]; p = 0.003); prolonged seizure duration (120 hr [58-368 hr] vs 3 hr [1.4-5.9 hr]; p < 0.001) and length of ICU stay (17 d [9.5-40 d] vs [1.8-8.8 d]; p < 0.001); more medical complications (18/31 [58.1%] vs 55/250 [22.2%] patients; p < 0.001); lower return to baseline function (7/31 [22.6%] vs 182/250 [73.4%] patients; p < 0.001); and higher mortality (4/31 [12.9%] vs 5/250 [2%]; p = 0.010). Within the super-refractory status epilepticus group, status epilepticus resolution was attained with a single continuous infusion in 15 of 31 patients (48.4%), two in 10 of 31 (32.3%), and three or more in six of 31 (19.4%). Most super-refractory status epilepticus patients (30/31, 96.8%) received midazolam as first choice. About 17 of 31 patients (54.8%) received additional treatments. CONCLUSIONS: Super-refractory status epilepticus patients had delayed initiation of nonbenzodiazepine antiseizure medication treatment, higher number of medical complications and mortality, and lower return to neurologic baseline than nonsuper-refractory status epilepticus patients, although these associations were not adjusted for potential confounders. Treatment approaches following the first continuous infusion were heterogeneous, reflecting limited information to guide clinical decision-making in super-refractory status epilepticus.

Sleep Measure Validation in a Pediatric Neurocritical Care Acquired Brain Injury Population.

BACKGROUND/OBJECTIVE: Lingering morbidities including physical, cognitive, emotional, and psychosocial sequelae, termed the Post-Intensive Care Syndrome, persist years after pediatric neurocritical care (PNCC) hospitalization. Sleep disturbances impact other Post-Intensive Care Syndrome domains and are under-evaluated to date due to a lack of appropriate measurement tools. The present study evaluated the validity of the Sleep Disturbance Scale for Children (SDSC) to address the growing need for assessing sleep problems after PNCC. METHODS: We conducted a prospective observational study of youth aged 3-17 years with acquired brain injury (N = 69) receiving care through longitudinal PNCC programs at two tertiary academic medical centers. Parents completed the SDSC and provided proxy reports of internalizing symptoms, health-related quality of life (HRQOL), fatigue, pain behavior, and cognitive function within 3 months of hospital discharge. Evidence for the validity of the SDSC was established by utilizing the full sample for psychosocial measure comparisons and by comparing SDSC outcomes by severity (Low Risk, Mild-Moderate Risk, and High Risk defined by reported standardized T-scores). RESULTS: Internal consistency of the SDSC was good (α = .81). Within the full sample, increased sleep disturbances on the SDSC were significantly correlated with Post-Intensive Care Syndrome measures, including worse physical (r = .65), psychological (r = .62), and cognitive (r = - .74) sequelae. Youth in the High Risk group evidenced greater dysfunction in mental acuity, pain behavior, internalizing symptoms, and social engagement. Findings revealed both statistically and clinically significant impacts of sleep disturbances as measured by the SDSC on HRQOL. CONCLUSIONS: The SDSC is a valid and reliable measure for assessing sleep disturbances in children after PNCC. Results support the use of the SDSC to measure sleep disturbances after PNCC. Targeted interventions for sleep disturbances may be key to overall patient recovery.

Early Heart Rate Variability and Electroencephalographic Abnormalities in Acutely Brain-Injured Children Who Progress to Brain Death.

OBJECTIVES: Heart rate variability is controlled by the autonomic nervous system. After brain death, this autonomic control stops, and heart rate variability is significantly decreased. However, it is unknown if early changes in heart rate variability are predictive of progression to brain death. We hypothesized that in brain-injured children, lower heart rate variability is an early indicator of autonomic system failure, and it predicts progression to brain death. We additionally explored the association between heart rate variability and markers of brain dysfunction such as electroencephalogram and neurologic examination between brain-injured children who progressed to brain death and those who survived. DESIGN: Retrospective case-control study. SETTING: PICU, single institution. PATIENTS: Children up to 18 years with a Glasgow Coma Scale score of less than 8 admitted between August of 2016 and December of 2017, who had electrocardiographic data available for heart rate variability analysis, were included. EXCLUSION CRITERIA: patients who died of causes other than brain death. Twenty-three patients met inclusion criteria: six progressed to brain death (cases), and 17 survived (controls). Five-minute electrocardiogram segments were used to estimate heart rate variability in the time domain (SD of normal-normal intervals, root mean square successive differences), frequency domain (low frequency, high frequency, low frequency/high frequency ratio), Poincaré plots, and approximate entropy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients who progressed to brain death exhibited significantly lower heart rate variability in the time domain, frequency domain, and Poincaré plots (p < 0.01). The odds of death increased with decreasing low frequency (odds ratio, 4.0; 95% CI, 1.2-13.6) and high frequency (odds ratio, 2.5; 95% CI, 1.2-5.4) heart rate variability power (p < 0.03). Heart rate variability was significantly lower in those with discontinuous or attenuated/featureless electroencephalogram versus those with slow/disorganized background (p < 0.03). CONCLUSIONS: These results support the concept of autonomic system failure as an early indicator of impending brain death in brain-injured children. Furthermore, decreased heart rate variability is associated with markers of CNS dysfunction such as electroencephalogram abnormalities.

Linking Traumatic Brain Injury, Sleep Disruption and Post-Traumatic Headache: a Potential Role for Glymphatic Pathway Dysfunction.

PURPOSE OF THE REVIEW: Traumatic brain injury (TBI) is a major public health concern in the USA and worldwide. Sleep disruption and headaches are two of the most common problems reported by patients after TBI. In this manuscript, we review the current knowledge regarding the relation between post-traumatic sleep disruption and headaches. We also describe the role of the glymphatic system as a potential link between TBI, sleep, and headaches. RECENT FINDINGS: Recent studies show a reciprocal relation between post-traumatic sleep disruption and headaches: patients with sleep disruption after TBI report more headaches, and post-traumatic headaches are a risk factor for developing disrupted sleep. Despite this clinical association, the exact mechanisms linking post-traumatic sleep disruption and headaches are not well understood. The glymphatic pathway, a newly described brain-wide network of perivascular spaces that supports the clearance of interstitial solutes and wastes from the brain, is active primarily during sleep, and becomes dysfunctional after TBI. We propose a model where changes in glymphatic function caused by TBI and post-traumatic sleep disruption may impair the clearance of neuropeptides involved in the pathogenesis of post-traumatic headaches, such as CGRP. The relation between TBI, post-traumatic sleep disruption, and post-traumatic headaches, although well documented in the literature, remains poorly understood. Dysfunction of the glymphatic system caused by TBI offers a novel and exiting explanation to this clinically observed phenomenon. The proposed model, although theoretical, could provide important mechanistic insights to the TBI-sleep-headache association.

Transcranial Doppler Identification of Neurologic Injury during Pediatric Extracorporeal Membrane Oxygenation Therapy.

BACKGROUND: We used transcranial Doppler to examine changes in cerebral blood flow velocity in children treated with extracorporeal membrane oxygenation. We examined the association between those changes and radiologic, electroencephalographic, and clinical evidence of neurologic injury. METHODS: This was a retrospective review and prospective observational study of patients 18 years old and younger at a single university children's hospital. Transcranial Doppler studies were obtained every other day during the first 7 days of extracorporeal membrane oxygenation, and 1 additional study following decannulation, in conjunction with serial neurologic examinations, brain imaging, and 6- to 12-month follow-up. RESULTS: The study included 27 patients, the majority (26) receiving veno-arterial extracorporeal membrane oxygenation. Transcranial Doppler velocities during extracorporeal membrane oxygenation were significantly lower than published values for age-matched healthy and critically ill children across different cerebral arteries. Neonates younger than 10 days had higher velocities than expected. Blood flow velocity increased after extracorporeal membrane oxygenation decannulation and was comparable with age-matched critically ill children. There was no significant association between velocity measurements of individual arteries and acute neurologic injury as defined by either abnormal neurologic examination, seizures during admission, or poor pediatric cerebral performance category. However, case analysis identified several patients with regional and global increases in velocities that corresponded to neurologic injury including stroke and seizures. CONCLUSIONS: Cerebral blood flow velocities during extracorporeal membrane oxygenation deviate from age-specific normal values in all major cerebral vessels and across different age groups. Global or regional elevations and asymmetries in flow velocity may suggest impending neurologic injury.

Pediatric neurocritical care in the 21st century: from empiricism to evidence.

PURPOSE OF REVIEW: Approximately one in five children admitted to a pediatric ICU have a new central nervous system injury or a neurological complication of their critical illness. The spectrum of neurologic insults in children is diverse and clinical practice is largely empirical, as few randomized, controlled trials have been reported. This lack of data poses a substantial challenge to the practice of pediatric neurocritical care (PNCC). PNCC has emerged as a novel subspecialty, and its presence is expanding within tertiary care centers. This review highlights the recent advances in the field, with a focus on traumatic brain injury (TBI), cardiac arrest, and stroke as disease models. RECENT FINDINGS: Variable approaches to the structure of a PNCC service have been reported, comprising multidisciplinary teams from neurology, critical care, neurosurgery, neuroradiology, and anesthesia. Neurologic morbidity is substantial in critically ill children and the increased use of continuous electroencephalography monitoring has highlighted this burden. Therapeutic hypothermia has not proven effective for treatment of children with severe TBI or out-of-hospital cardiac arrest. However, results of studies of severe TBI suggest that multidisciplinary care in the ICU and adherence to guidelines for care can reduce mortality and improve outcome. SUMMARY: There is an unmet need for clinicians with expertise in the practice of brain-directed critical care for children. Although much of the practice of PNCC may remain empiric, a focus on the regionalization of care, creating defined training paths, practice within multidisciplinary teams, protocol-directed care, and improved measures of long-term outcome to quantify the impact of such care can provide evidence to direct the maturation of this field.

Venous stroke and status epilepticus due to milk-induced anemia in a child.

The risk factors for cerebral sinus venous thrombosis include dehydration, infection, and anemia. The clinical presentation in children of venous strokes associated with cerebral venous thrombosis is variable and may include seizures. Acute management should focus on the treatment of the primary cause and anticoagulation or antiplatelet therapy if needed. Early recognition and targeted treatment is important because survivors are at increased risk for long-term neurologic complications. We report a case of a 4-year-old girl who presented with status epilepticus and was subsequently found to have a cerebral venous sinus thrombosis in the transverse and sigmoid sinus, with venous infarction in the temporal lobe. Laboratory results were significant for a microcytic anemia caused by excessive milk intake. Although iron deficiency anemia is a common pediatric disorder, this uncommon presentation demonstrates the potential for neurologic complications secondary to anemia, as well as the need for a high index of suspicion in order to identify venous stroke as a cause in children who present to the emergency department with seizures.

Perivascular Space Burden and Cerebrospinal Fluid Biomarkers in US Veterans With Blast-Related Mild Traumatic Brain Injury.

Blast-related mild traumatic brain injury (mTBI) is recognized as the "signature injury" of the Iraq and Afghanistan wars. Sleep disruption, mTBI, and neuroinflammation have been individually linked to cerebral perivascular space (PVS) dilatation. Dilated PVSs are putative markers of impaired cerebrospinal fluid (CSF) and interstitial fluid exchange, which plays an important role in removing cerebral waste. The aim of this cross-sectional, retrospective study was to define associations between biomarkers of inflammation and MRI-visible PVS (MV-PVS) burden in Veterans after blast-related mTBI (blast-mTBI) and controls. The CSF and plasma inflammatory biomarker concentrations were compared between blast-mTBI and control groups and correlated with MV-PVS volume and number per white matter cm3. Multiple regression analyses were performed with inflammatory biomarkers as predictors and MV-PVS burden as the outcome. Correction for multiple comparisons was performed using the Banjamini-Hochberg method with a false discovery rate of 0.05. There were no group-wise differences in MV-PVS burden between Veterans with blast-mTBI and controls. Greater MV-PVS burden was significantly associated with higher concentrations of several proinflammatory biomarkers from CSF (i.e., eotaxin, MCP-1, IL-6, IL-8) and plasma (i.e., MCP-4, IL-13) in the blast-mTBI group only. After controlling for sleep time and symptoms of post-traumatic stress disorder, temporal MV-PVS burden remained significantly associated with higher CSF markers of inflammation in the blast-mTBI group only. These data support an association between central, rather than peripheral, neuroinflammation and MV-PVS burden in Veterans with blast-mTBI independent of sleep. Future studies should continue to explore the role of blast-mTBI related central inflammation in MV-PVS development, as well as investigate the impact of subclinical exposures on MV-PVS burden.

Dynamic changes in perivascular space morphology predict signs of spaceflight-associated neuro-ocular syndrome in bed rest.

During long-duration spaceflight, astronauts experience headward fluid shifts and expansion of the cerebral perivascular spaces (PVS). A major limitation to our understanding of the changes in brain structure and physiology induced by spaceflight stems from the logistical difficulties of studying astronauts. The current study aimed to determine whether PVS changes also occur on Earth with the spaceflight analog head-down tilt bed rest (HDBR). We examined how the number and morphology of magnetic resonance imaging-visible PVS (MV-PVS) are affected by HDBR with and without elevated carbon dioxide (CO2). These environments mimic the headward fluid shifts, body unloading, and elevated CO2 observed aboard the International Space Station. Additionally, we sought to understand how changes in MV-PVS are associated with signs of Spaceflight Associated Neuro-ocular Syndrome (SANS), ocular structural alterations that can occur with spaceflight. Participants were separated into two bed rest campaigns: HDBR (60 days) and HDBR + CO2 (30 days with elevated ambient CO2). Both groups completed multiple magnetic resonance image acquisitions before, during, and post-bed rest. We found that at the group level, neither spaceflight analog affected MV-PVS quantity or morphology. However, when taking into account SANS status, persons exhibiting signs of SANS showed little or no MV-PVS changes, whereas their No-SANS counterparts showed MV-PVS morphological changes during the HDBR + CO2 campaign. These findings highlight spaceflight analogs as models for inducing changes in MV-PVS and implicate MV-PVS dynamic compliance as a mechanism underlying SANS. These findings may lead to countermeasures to mitigate health risks associated with human spaceflight.

Biological sex and BMI influence the longitudinal evolution of adolescent and young adult MRI-visible perivascular spaces.

Background and Purpose: An association recently emerged between magnetic resonance imaging (MRI)-visible perivascular spaces (MV-PVS) with intracerebral solute clearance and neuroinflammation, in adults. However, it is unknown how MV-PVS change throughout adolescence and what factors influence MV-PVS volume and morphology. This study assesses the temporal evolution of MV-PVS volume in adolescents and young adults, and secondarily evaluates the relationship between MV-PVS, age, sex, and body mass index (BMI). Materials and Methods: This analysis included a 783 participant cohort from the longitudinal multicenter National Consortium on Alcohol and Neurodevelopment in Adolescence study that involved up to 6 imaging visits spanning 5 years. Healthy adolescents aged 12-21 years at study entry with at least two MRI scans were included. The primary outcome was mean MV-PVS volume (mm 3 /white matter cm 3 ). Results: On average, males had greater MV-PVS volume at all ages compared to females. A linear mixed-effect model for MV-PVS volume was performed. Mean BMI and increases in a person's BMI were associated with increases in MV-PVS volume over time. In females only, changes in BMI correlated with MV-PVS volume. One unit increase in BMI above a person's average BMI was associated with a 0.021 mm 3 /cm 3 increase in MV-PVS volume (p<0.001). Conclusion: This longitudinal study showed sex differences in MV-PVS features during adolescence and young adulthood. Importantly, we report that increases in BMI from a person's mean BMI are associated with increases in MV-PVS volume in females only. These findings suggest a potential link between MV-PVS, sex, and BMI that warrants future study.

Repetitive Head Impacts and Perivascular Space Volume in Former American Football Players.

Importance: Exposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role. Objective: To investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associated neurodegeneration. Design, Setting, and Participants: This cross-sectional study was part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project, a 7-year multicenter study consisting of 4 US study sites. Data were collected from September 2016 to February 2020 and analyses were performed between May 2021 and October 2023. After controlling for magnetic resonance image (MRI) and processing quality, former American football players and unexposed asymptomatic control participants were included in analyses. Exposure: Prior exposure to RHI while participating in American football was estimated using the 3 cumulative head impact indices (CHII-G, linear acceleration; CHII-R, rotational acceleration; and CHII, number of head impacts). Main Outcomes and Measures: Individual PVS volume was calculated in the white matter of structural MRI. Cognitive impairment was based on neuropsychological assessment. Linear regression models were used to assess associations of PVS volume with neuropsychological assessments in former American football players. All analyses were adjusted for confounders associated with PVS volume. Results: Analyses included 224 participants (median [IQR] age, 57 [51-65] years), with 170 male former football players (114 former professional athletes, 56 former collegiate athletes) and 54 male unexposed control participants. Former football players had larger PVS volume compared with the unexposed group (mean difference, 0.28 [95% CI, 0.00-0.56]; P = .05). Within the football group, PVS volume was associated with higher CHII-R (ß = 2.71 × 10-8 [95% CI, 0.50 × 10-8 to 4.93 × 10-8]; P = .03) and CHII-G (ß = 2.24 × 10-6 [95% CI, 0.35 × 10-6 to 4.13 × 10-6]; P = .03). Larger PVS volume was also associated with worse performance on cognitive functioning in former American football players (ß = -0.74 [95% CI, -1.35 to -0.13]; P = .04). Conclusions and Relevance: These findings suggest that impaired perivascular brain clearance, as indicated by larger PVS volume, may contribute to the association observed between RHI exposure and neurodegeneration.

Nonconvulsive seizures are common in children treated with extracorporeal cardiac life support.

OBJECTIVES: The prevalence of electrographic seizures or nonconvulsive status epilepticus and the effect of such seizures in children treated with extracorporeal cardiac life support are not known. We investigated the occurrence of electrographic abnormalities, including asymmetries in amplitude or frequency of the background rhythm and interictal activity in children undergoing extracorporeal cardiac life support and their association with seizures. We compared mortality and radiologic evidence of neurologic injury between patients with seizures and those without seizures. DESIGN: Retrospective review of medical records and the Extracorporeal Life Support Organization database. SETTING: PICU at a single institution. PATIENTS: All pediatric patients up to 18 years old, who had extracorporeal cardiac life support and continuous electroencephalography monitoring between the years 2006 and 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nineteen patients treated with extracorporeal cardiac life support underwent continuous electroencephalography monitoring. Seizures occurred in four patients (21%) and were exclusively nonconvulsive in three patients. Two of these four patients had nonconvulsive status epilepticus. Interictal discharges on electroencephalography were associated with seizures (odds ratio, 19.5 [95% CI, 1.29-292.75]; p = 0.03). Only 50% of the seizures were detected in the first hour of monitoring, whereas all seizures were detected within 24 hours. All patients with seizures had structural abnormalities seen on neuroimaging. Seizures were not significantly associated with increased mortality. To evaluate for ascertainment bias, we compared outcomes between patients who underwent extracorporeal cardiac life support and received continuous electroencephalography monitoring and those patients who underwent extracorporeal cardiac life support during the study period but did not receive electroencephalography (n = 30). CONCLUSIONS: Seizures are common in children during extracorporeal cardiac life support, and most seizures are nonconvulsive. In patients undergoing extracorporeal cardiac life support, clinical features are unreliable indicators of the presence of seizures. The presence of seizures is suggestive of CNS injury. This study is limited by the exclusion of neonates, a feature of the clinical use of electroencephalography at our institution. Although seizures were not associated with increased mortality, further prospective studies in larger populations are needed to assess the long-term morbidity associated with seizures during extracorporeal cardiac life support.

Management of status epilepticus in childhood: a survey conducted at pediatric hospitals in the City of Buenos Aires. / Manejo del estado epiléptico en niños: encuesta en hospitales pediátricos de la Ciudad Autónoma de Buenos Aires.

Introduction. Status epilepticus is the most common neurological emergency. Although mortality in children is low, morbidity may exceed 20%. Objective. To evaluate the management of status epilepticus by pediatricians who usually treat this condition. Population and methods. Descriptive, cross-sectional study based on a survey administered to physicians from 3 pediatric hospitals in the City of Buenos Aires. Results. A total of 292 surveys were administered (complete response rate as high as 86%); 77% were administered to pediatricians and 16% to intensive care specialists. Forty-seven percent of the participants reported that they administer the first dose of a benzodiazepine within the correct timeframe; 56% use intrarectal diazepam when intravenous access is not available; 95% choose lorazepam as the initial benzodiazepine if an intravenous line is available; 58% initiate the administration of a second-line drug within the correct timeframe; 84% administer phenytoin as the first-choice, second-line drug; and 33% do not measure treatment time. Overall adherence to international recommendations was 17%. Conclusions. Our study highlights poor adherence of pediatricians to international guidelines, particularly in time-dependent decisions. Greater heterogeneity was observed in treatment approaches as the treatment algorithm progressed.

Introducción. El estado epiléptico constituye la emergencia neurológica más frecuente. Si bien la mortalidad en niños es baja, su morbilidad puede superar el 20 %. Objetivo. Conocer las pautas de manejo del estado epiléptico referidas por médicos pediatras que atienden esta patología en forma habitual. Población y métodos. Estudio descriptivo, transversal, basado en una encuesta a médicos de tres hospitales pediátricos monovalentes de gestión pública de la Ciudad Autónoma de Buenos Aires. Resultados. Se administraron 292 encuestas (la tasa de respuesta completa alcanzó el 86 %); el 77 % se administró a pediatras y el 16 %, a especialistas en cuidados intensivos. Un 47 % de los participantes refiere indicar la primera benzodiacepina en el tiempo correcto; el 56 % utilizar diazepam intrarrectal en ausencia de un acceso intravenoso; el 95 % elige lorazepam como benzodiacepina inicial en caso de contar con acceso intravenoso; el 58 % refiere iniciar la etapa de fármacos de segunda línea en tiempo adecuado; el 84 % opta por fenitoína como fármaco inicial de segunda línea, un 33 % no cronometra el tiempo durante el tratamiento. La adherencia global a las recomendaciones internacionales fue del 17 %. Conclusiones. Nuestro estudio advierte una baja adherencia referida de los pediatras a las guías internacionales, en particular en las decisiones tiempo-dependientes. También se observó mayor heterogeneidad en las conductas terapéuticas a medida que se avanza en el algoritmo de tratamiento.

Retinal mid-peripheral capillary free zones are enlarged in cognitively unimpaired older adults at high risk for Alzheimer's disease.

BACKGROUND: Compared to standard neuro-diagnostic techniques, retinal biomarkers provide a probable low-cost and non-invasive alternative for early Alzheimer's disease (AD) risk screening. We have previously quantified the periarteriole and perivenule capillary free zones (mid-peripheral CFZs) in cognitively unimpaired (CU) young and older adults as novel metrics of retinal tissue oxygenation. There is a breakdown of the inner retinal blood barrier, pericyte loss, and capillary non-perfusion or dropout in AD leading to potential enlargement of the mid-peripheral CFZs. We hypothesized the mid-peripheral CFZs will be enlarged in CU older adults at high risk for AD compared to low-risk individuals. METHODS: 20 × 20° optical coherence tomography angiography images consisting of 512 b-scans, 512 A-scans per b-scan, 12-µm spacing between b-scans, and 5 frames averaged per each b-scan location of the central fovea and of paired major arterioles and venules with their surrounding capillaries inferior to the fovea of 57 eyes of 37 CU low-risk (mean age: 66 years) and 50 eyes of 38 CU high-risk older adults (mean age: 64 years; p = 0.24) were involved in this study. High-risk participants were defined as having at least one APOE e4 allele and a positive first-degree family history of AD while low-risk participants had neither of the two criteria. All participants had Montreal Cognitive Assessment scores ≥ 26. The mid-peripheral CFZs were computed in MATLAB and compared between the two groups. RESULTS: The periarteriole CFZ of the high-risk group (75.8 ± 9.19 µm) was significantly larger than that of the low-risk group (71.3 ± 7.07 µm), p = 0.005, Cohen's d = 0.55. The perivenule CFZ of the high-risk group (60.4 ± 8.55 µm) was also significantly larger than that of the low-risk group (57.3 ± 6.40 µm), p = 0.034, Cohen's d = 0.42. There were no significant differences in foveal avascular zone (FAZ) size, FAZ effective diameter, and vessel density between the two groups, all p > 0.05. CONCLUSIONS: Our results show larger mid-peripheral CFZs in CU older adults at high risk for AD, with the potential for the periarteriole CFZ to serve as a novel retinal vascular biomarker for early AD risk detection.

Longitudinal Sleep Patterns and Cognitive Impairment in Older Adults.

Importance: Sleep disturbances and clinical sleep disorders are associated with all-cause dementia and neurodegenerative conditions, but it remains unclear how longitudinal changes in sleep impact the incidence of cognitive impairment. Objective: To evaluate the association of longitudinal sleep patterns with age-related changes in cognitive function in healthy older adults. Design, Setting, and Participants: This cross-sectional study is a retrospective longitudinal analyses of the Seattle Longitudinal Study (SLS), which evaluated self-reported sleep duration (1993-2012) and cognitive performance (1997-2020) in older adults. Participants within the SLS were enrolled as part of a community-based cohort from the Group Health Cooperative of Puget Sound and Health Maintenance Organization of Washington between 1956 and 2020. Data analysis was performed from September 2020 to May 2023. Main Outcomes and Measures: The main outcome for this study was cognitive impairment, as defined by subthreshold performance on both the Mini-Mental State Examination and the Mattis Dementia Rating Scale. Sleep duration was defined by self-report of median nightly sleep duration over the last week and was assessed longitudinally over multiple time points. Median sleep duration, sleep phenotype (short sleep, median ≤7 hours; medium sleep, median = 7 hour; long sleep, median ≥7 hours), change in sleep duration (slope), and variability in sleep duration (SD of median sleep duration, or sleep variability) were evaluated. Results: Of the participants enrolled in SLS, only 1104 participants who were administered both the Health Behavior Questionnaire and the neuropsychologic battery were included for analysis in this study. A total of 826 individuals (mean [SD] age, 76.3 [11.8] years; 468 women [56.7%]; 217 apolipoprotein E ε4 allele carriers [26.3%]) had complete demographic information and were included in the study. Analysis using a Cox proportional hazard regression model (concordance, 0.76) showed that status as a short sleeper (hazard ratio, 3.67; 95% CI, 1.59-8.50) and higher sleep variability (hazard ratio, 3.06; 95% CI, 1.14-5.49) were significantly associated with the incidence of cognitive impairment. Conclusions and Relevance: In this community-based longitudinal study of the association between sleep patterns and cognitive performance, the short sleep phenotype was significantly associated with impaired cognitive performance. Furthermore, high sleep variability in longitudinal sleep duration was significantly associated with the incidence of cognitive impairment, highlighting the possibility that instability in sleep duration over long periods of time may impact cognitive decline in older adults.

Instability in longitudinal sleep duration predicts cognitive impairment in aged participants of the Seattle Longitudinal Study.

Importance: Sleep disturbances and clinical sleep disorders are associated with all-cause dementia and neurodegenerative conditions. It remains unclear how longitudinal changes in sleep impact the incidence of cognitive impairment. Objective: To evaluate how longitudinal sleep patterns contribute to age-related changes in cognitive function in healthy adults. Design Setting Participants: This study utilizes retrospective longitudinal analyses of a community-based study within Seattle, evaluating self-reported sleep (1993-2012) and cognitive performance (1997-2020) in aged adults. Main Outcomes and Measures: The main outcome is cognitive impairment as defined by sub-threshold performance on 2 of 4 neuropsychological batteries: Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale, Trail Making Test, and Wechsler Adult Intelligent Scale (Revised). Sleep duration was defined through self-report of 'average nightly sleep duration over the last week' and assessed longitudinally. Median sleep duration, change in sleep duration (slope), variability in sleep duration (standard deviation, Sleep Variability), and sleep phenotype ("Short Sleep" median ≤7hrs.; "Medium Sleep" median = 7hrs; "Long Sleep" median ≥7hrs.). Results: A total of 822 individuals (mean age of 76.2 years [11.8]; 466 women [56.7%]; 216 APOE allele positive [26.3%]) were included in the study. Analysis using a Cox Proportional Hazard Regression model (concordance 0.70) showed that increased Sleep Variability (95% CI [1.27,3.86]) was significantly associated with the incidence of cognitive impairment. Further analysis using linear regression prediction analysis (R2=0.201, F (10, 168)=6.010, p=2.67E-07) showed that high Sleep Variability (ß=0.3491; p=0.048) was a significant predictor of cognitive impairment over a 10-year period. Conclusions and Relevance: High variability in longitudinal sleep duration was significantly associated with the incidence of cognitive impairment and predictive of decline in cognitive performance ten years later. These data highlight that instability in longitudinal sleep duration may contribute to age-related cognitive decline.