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.

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.

Use of Magnetic Resonance Imaging in Neuroprognostication After Pediatric Cardiac Arrest: Survey of Current Practices.

BACKGROUND: Use of magnetic resonance imaging (MRI) as a tool to aid in neuroprognostication after cardiac arrest (CA) has been described, yet details of specific indications, timing, and sequences are unknown. We aim to define the current practices in use of brain MRI in prognostication after pediatric CA. METHODS: A survey was distributed to pediatric institutions participating in three international studies. Survey questions related to center demographics, clinical practice patterns of MRI after CA, neuroimaging resources, and details regarding MRI decision support. RESULTS: Response rate was 31% (44 of 143). Thirty-four percent (15 of 44) of centers have a clinical pathway informing the use of MRI after CA. Fifty percent (22 of 44) of respondents reported that an MRI is obtained in nearly all patients with CA, and 32% (14 of 44) obtain an MRI in those who do not return to baseline neurological status. Poor neurological examination was reported as the most common factor (91% [40 of 44]) determining the timing of the MRI. Conventional sequences (T1, T2, fluid-attenuated inversion recovery, and diffusion-weighted imaging/apparent diffusion coefficient) are routinely used at greater than 97% of centers. Use of advanced imaging techniques (magnetic resonance spectroscopy, diffusion tensor imaging, and functional MRI) were reported by less than half of centers. CONCLUSIONS: Conventional brain MRI is a common practice for prognostication after CA. Advanced imaging techniques are used infrequently. The lack of standardized clinical pathways and variability in reported practices support a need for higher-quality evidence regarding the indications, timing, and acquisition protocols of clinical MRI studies.

The Bidirectional Link Between Sleep Disturbances and Traumatic Brain Injury Symptoms: A Role for Glymphatic Dysfunction?

Mild traumatic brain injury (mTBI), often referred to as concussion, is a major cause of morbidity and mortality worldwide. Sleep disturbances are common after mTBI. Moreover, subjects who develop subjective sleep complaints after mTBI also report more severe somatic, mental health, and cognitive impairment and take longer to recover from mTBI sequelae. Despite many previous studies addressing the role of sleep in post-mTBI morbidity, the mechanisms linking sleep to recovery after mTBI remain poorly understood. The glymphatic system is a brainwide network that supports fluid movement through the cerebral parenchyma and the clearance of interstitial solutes and wastes from the brain. Notably, the glymphatic system is active primarily during sleep. Clearance of cellular byproducts related to somatic, mental health, and neurodegenerative processes (e.g., amyloid-ß and tau, among others) depends in part on intact glymphatic function, which becomes impaired after mTBI. In this viewpoint, we review the current knowledge regarding the association between sleep disturbances and post-mTBI symptoms. We also discuss the role of glymphatic dysfunction as a potential link between mTBI, sleep disruption, and posttraumatic morbidity. We outline a model where glymphatic dysfunction and sleep disruption caused by mTBI may have an additive effect on waste clearance, leading to cerebral dysfunction and impaired recovery. Finally, we review the novel techniques being developed to examine glymphatic function in humans and explore potential interventions to alter glymphatic exchange that may offer a novel therapeutic approach to those experiencing poor sleep and prolonged symptoms after mTBI.

Simultaneous Heart Rate Variability and Electroencephalographic Monitoring in Children in the Emergency Department.

Changes in heart rate variability (HRV) and electroencephalographic (EEG) background are promising tools for risk stratification and outcome prediction in children seen in the Emergency Department (ED). Novel monitoring technologies offer an opportunity for determining the clinical value of these physiologic variables, however, studies evaluating these measurements obtained in the Pediatric ED are sparse. The current study used a single center, prospective, observational cohort study of HRV and EEG as early predictors of outcome in children with acute trauma. ECG and HRV data were successfully collected in 167 subjects and simultaneous collection of ECG and EEG data using a wireless monitoring device was piloted in 17 patients with 15 patients having EEG data rated as appropriate for clinical interpretation. The mean time from ED arrival to ECG and EEG recording start was 7.5 (SD 11.6) and 34.5 (SD 15.5) minutes, respectively. The mean time required for EEG electrode placement was 9.3 min (SD 5.8 min). Results showed recording early HRV and EEG is feasible in children with acute injury seen in the ED. This study suggests that high consent rates are possible with the adequate research infrastructure and physiologic variables may offer an early, non-invasive marker for injury stratification and prognosis in children.

Post-Intensive-Care Syndrome for the Pediatric Neurologist.

The number of children who survive critical illness has steadily increased. However, lower mortality rates have resulted in a proportional increase in post-intensive-care morbidity. Critical illness in childhood affects a child's development, cognition, and family functioning. The constellation of physical, emotional, cognitive, and psychosocial symptoms that begin in the intensive care unit and continue after discharge has recently been termed post-intensive-care syndrome. A conceptual model of the post-intensive-care syndrome experienced by children who survive critical illness, their siblings, and parents has been coined post-intensive-care syndrome in pediatrics. Owing to their prolonged hospitalizations, the use of sedative medications, and the nature of their illness, children with primary neurological injury are among those at the highest risk for post-intensive-care syndrome in pediatrics. The pediatric neurologist participates in the care of children with acute brain injury throughout their hospitalization and remains involved after the patient leaves the hospital. Hence it is important for pediatric neurologists to become versed in the early recognition and management of post-intensive-care syndrome in pediatrics. In this review, we discuss the current knowledge regarding post-intensive-care syndrome in pediatrics and its risk factors. We also discuss our experience establishing Pediatric Neurocritical Care Recovery Programs at two large academic centers. Last, we provide a battery of validated tests to identify and manage the different aspects of post-intensive-care syndrome in pediatrics, which have been successfully implemented at our institutions. Dissemination of this "road map" may assist others interested in establishing recovery programs, therefore mitigating the burden of post-intensive-care morbidity in children.

Sleep-Wake Disturbances After Acquired Brain Injury in Children Surviving Critical Care.

BACKGROUND: Sleep-wake disturbances are underevaluated among children with acquired brain injury surviving critical care. We aimed to quantify severity, phenotypes, and risk factors for sleep-wake disturbances. METHODS: We performed a prospective cohort study of 78 children aged ≥3 years with acquired brain injury within three months of critical care hospitalization. Diagnoses included traumatic brain injury (n = 40), stroke (n = 11), infectious or inflammatory disease (n = 10), hypoxic-ischemic injury (n = 9), and other (n = 8). Sleep Disturbances Scale for Children standardized T scores measured sleep-wake disturbances. Overall sleep-wake disturbances were dichotomized as any total or subscale T score ≥60. Any T score ≥70 defined severe sleep-wake disturbances. Subscale T scores ≥60 identified sleep-wake disturbance phenotypes. RESULTS: Sleep-wake disturbances were identified in 44 (56%) children and were classified as severe in 36 (46%). Sleep-wake disturbances affected ≥33% of patients within each diagnosis and were not associated with severity of illness measures. The most common phenotype was disturbance in initiation and maintenance of sleep (47%), although 68% had multiple concurrent sleep-wake disturbance phenotypes. One third of all patients had preadmission chronic conditions, and this increased risk for sleep-wake disturbances overall (43% vs 21%, P = 0.04) and in the traumatic brain injury subgroup (52% vs 5%, P = 0.001). CONCLUSIONS: Over half of children surviving critical care with acquired brain injury have sleep-wake disturbances. Most of these children have severe sleep-wake disturbances independent of severity of illness measures. Many sleep-wake disturbances phenotypes were identified, but most children had disturbance in initiation and maintenance of sleep. Our study underscores the importance of evaluating sleep-wake disturbances after acquired brain injury.

Hospital Mortality and Functional Outcomes in Pediatric Neurocritical Care.

OBJECTIVES: Pediatric neurocritical care (PNCC) outcomes research is scarce. We aimed to expand knowledge about outcomes in PNCC by evaluating death and changes in Functional Status Scale (FSS) from baseline among PNCC diagnoses. METHODS: We conducted a 2-year observational study of children aged 0 to 18 years admitted to the ICU with a primary neurologic diagnosis (N = 325). Primary outcomes were death and change in FSS from preadmission baseline to discharge. New disability was defined as an FSS change of ≥1 from baseline, and severe disability was defined as an FSS change of ≥3. Categorical results are reported as relative risk (RR) with 95% confidence interval (CI). RESULTS: Thirty (9%) patients died. New disability (n = 103; 35%) and severe disability (n = 37; 13%) were common in PNCC survivors. New disability (range 14%-54%) and severe disability (range 3%-33%) outcomes varied significantly among primary diagnoses (lowest in status epilepticus; highest in infectious and/or inflammatory and stroke cohorts). Disability occurred in all FSS domains: mental status (15%), sensory (52%), communication (38%), motor (48%), feeding (40%), and respiratory (12%). Most (64%) patients with severe disability had changes in ≥3 domains. Requiring critical care interventions (RR 2.1; 95% CI 1.5-3.1) and having seizures (RR 1.5; 95% CI 1.1-2.0) during hospitalization were associated with new disability. CONCLUSIONS: PNCC patients have high rates of death and new disability at discharge, varying significantly between PNCC diagnoses. Multiple domains of disability are affected, underscoring the ongoing multidisciplinary health care needs of survivors. Our study quantified hospital outcomes of PNCC patients that can be used to advance future research in this vulnerable population.

Postintensive Care Syndrome in Pediatric Critical Care Survivors: Therapeutic Options to Improve Outcomes After Acquired Brain Injury.

PURPOSE OF REVIEW: Children surviving the pediatric intensive care unit (PICU) with neurologic illness or injury have long-term morbidities in physical, cognitive, emotional, and social functioning termed postintensive care syndrome (PICS). In this article, we review acute and longitudinal management strategies available to combat PICS in children with acquired brain injury. RECENT FINDINGS: Few intervention studies in this vulnerable population target PICS morbidities. Small studies show promise for both inpatient- and outpatient-initiated therapies, mainly focusing on a single domain of PICS and evaluating heterogeneous populations. While evaluating the effects of interventions on longitudinal PICS outcomes is in its infancy, longitudinal clinical programs targeting PICS are increasing. A multidisciplinary team with inpatient and outpatient presence is necessary to deliver the holistic integrated care required to address all domains of PICS in patients and families. While PICS is increasingly recognized as a chronic problem in PICU survivors with acquired brain injury, few interventions have targeted PICS morbidities. Research is needed to improve physical, cognitive, emotional, and social outcomes in survivors and their families.

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.

Lacosamide in Pediatric Status Epilepticus.

Investigators from Baylor College of Medicine studied the efficacy of lacosamide in pediatric status epilepticus (SE).

Timing of Anticonvulsant Administration in Status Epilepticus.

Investigators from the Pediatric Status Epilepticus Research Group studied the time elapsed from onset of pediatric convulsive status epilepticus (SE) to administration of antiepileptic drugs (AED).

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.

Progressive intracranial fusiform aneurysms and T-cell immunodeficiency.

In the pediatric population, intracranial fusiform aneurysms have been associated with human immunodeficiency virus/acquired immunodeficiency syndrome and rarely with opportunistic infections related to other immunodeficiencies. The HIV virus and other infectious organisms have been implicated in the pathophysiology of these aneurysms. We present a child with T-cell immunodeficiency but no evidence of human immunodeficiency virus or opportunistic intracranial infections that developed progressive bilateral fusiform intracranial aneurysms. Our findings suggest a role of immunodeficiency or inflammation in the formation of some intracranial aneurysms.

Myoclonic seizures in a patient with Charcot-Marie-tooth disease.

Charcot-Marie-Tooth disease affects both motor and sensory peripheral nerves, with broad variability in its clinical and pathologic expression. The involvement of the central nervous system in this disease has been reported in the past, and on two occasions Charcot-Marie-Tooth disease was associated with myoclonic seizures. The previously reported patients with associated Charcot-Marie-Tooth disease and seizures developed a severe disease and died at a young age. This report describes a now 8-year-old male with Charcot-Marie-Tooth disease type 1A associated with myoclonic seizures and developmental delay. Genetic studies established for the first time the duplication of the PMP-22 gene in a patient with this unusual association, confirming the diagnosis. The patient was treated with carbamazepine, valproate, and lamotrigine, has been seizure-free for over 2 years, and was successfully weaned from his medications.