Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized, placebo-controlled phase II feasibility/pilot study.

Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-ß0-thalassemia subtypes of SCD age 12-48 months with normal neurological examination, MRI of the brain, and cerebral blood flow velocity. We hypothesized that hydroxyurea would reduce by 50% the incidence of CNS injury. Two outcomes were compared: primary-a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke; secondary-a weighted score estimating the risk of suffering the consequences of stroke (the Stroke Consequences Risk Score-SCRS), based on the same outcome events. Six participants were randomized to each group. One participant in the hydroxyurea group had a primary outcome vs. four in the placebo group (incidence rate ratio [90% CI] 0.216 [0.009, 1.66], p = .2914) (~80% reduction in the hydroxyurea group). The mean SCRS score was 0.078 (SD 0.174) in the hydroxyurea group, 0.312 (SD 0.174) in the placebo group, p = .072, below the p-value of .10 often used to justify subsequent phase III investigations. Serious adverse events related to study procedures occurred in 3/41 MRIs performed, all related to sedation. These results suggest that hydroxyurea may have profound neuroprotective effect in children with SCD and support a definitive phase III study to encourage the early use of hydroxyurea in all infants with SCD.

A prospective multicenter feasibility study of a miniaturized implantable continuous flow ventricular assist device in smaller children with heart failure.

BACKGROUND: There is no FDA-approved left ventricular assist device (LVAD) for smaller children permitting routine hospital discharge. Smaller children supported with LVADs typically remain hospitalized for months awaiting heart transplant-a major burden for families and a challenge for hospitals. We describe the initial outcomes of the Jarvik 2015, a miniaturized implantable continuous flow LVAD, in the NHLBI-funded Pumps for Kids, Infants, and Neonates (PumpKIN) study, for bridge-to-heart transplant. METHODS: Children weighing 8 to 30 kg with severe systolic heart failure and failing optimal medical therapy were recruited at 7 centers in the United States. Patients with severe right heart failure and single-ventricle congenital heart disease were excluded. The primary feasibility endpoint was survival to 30 days without severe stroke or non-operational device failure. RESULTS: Of 7 children implanted, the median age was 2.2 (range 0.7, 7.1) years, median weight 10 (8.2 to 20.7) kilograms; 86% had dilated cardiomyopathy; 29% were INTERMACS profile 1. The median duration of Jarvik 2015 support was 149 (range 5 to 188) days where all 7 children survived including 5 to heart transplant, 1 to recovery, and 1 to conversion to a paracorporeal device. One patient experienced an ischemic stroke on day 53 of device support in the setting of myocardial recovery. One patient required ECMO support for intractable ventricular arrhythmias and was eventually transplanted from paracorporeal biventricular VAD support. The median pump speed was 1600 RPM with power ranging from 1-4 Watts. The median plasma free hemoglobin was 19, 30, 19 and 30 mg/dL at 7, 30, 90 and 180 days or time of explant, respectively. All patients reached the primary feasibility endpoint. Patient-reported outcomes with the device were favorable with respect to participation in a full range of activities. Due to financial issues with the manufacturer, the study was suspended after consent of the eighth patient. CONCLUSION: The Jarvik 2015 LVAD appears to hold important promise as an implantable continuous flow device for smaller children that may support hospital discharge. The FDA has approved the device to proceed to a 22-subject pivotal trial. Whether this device will survive to commercialization remains unclear because of the financial challenges faced by industry seeking to develop pediatric medical devices. (Supported by NIH/NHLBI HHS Contract N268201200001I, clinicaltrials.gov 02954497).

Pediatric Cerebral Sinovenous Thrombosis and Risk for Epilepsy.

BACKGROUND: Cerebral sinovenous thrombosis (CSVT) is a rare form of pediatric stroke with significant morbidity. We determined cumulative incidence and predictors of acute seizures, remote seizures, and epilepsy after pediatric CSVT. METHODS: Retrospective analysis of 131 neonates and children with neuroimaging-confirmed CSVT enrolled between 2008 and 2020 from a single-center prospective consecutive cohort. Acute seizures occurred within 7 days of CSVT. Remote seizures occurred >7 days after CSVT. Epilepsy was defined as 2 or more remote seizures at least 24 hours apart. Survival methods determined the incidence of and risk factors for remote seizures and epilepsy. RESULTS: Acute seizures occurred in 14/33 neonates (42%) and 19/98 children (19%). Among children, hemorrhage predicted acute seizures (OR 6.6, 95% CI 1.9 to 22.4, P = 0.003). Remote seizures occurred in six neonates; five developed epilepsy. Remote seizures occurred in 14 children; 10 developed epilepsy. In neonates, 1- and 3-year epilepsy-free survival were 86% (95% CI 62% to 95%) and 66% (95% CI 32% to 87%). One- and 3-year epilepsy-free survival in children were 88% (95% CI 76% to 92%) and 84% (95% CI 59% to 86%). In multivariable analysis for children, acute seizures predicted epilepsy (HR 3.8, 95% CI 1.1-13.3, P = 0.039). In both cohorts, Pediatric Stroke Outcome Measure scores at last follow-up were worse in those with epilepsy compared to those without. CONCLUSIONS: Acute seizures occurred in approximately one quarter of our cohort and are an epilepsy risk factor in children with CSVT. Neonates and children with epilepsy had worse outcomes than those without.

Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement.

Importance: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. Objective: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. Evidence Review: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. Findings: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. Conclusions and Relevance: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.

Walking speed influences spatiotemporal but not symmetry measures of gait in children and adolescents with hemiplegia.

BACKGROUND: The measurement of gait is likely influenced by walking speed in children with hemiplegia, but this relationship is not well characterized. RESEARCH QUESTION: What is the influence of walking speed on spatiotemporal and symmetry measures of gait in children with hemiplegia, with consideration of side and footwear condition? METHODS: Children with hemiparetic gait due to stroke were recruited for a small pilot intervention study. Participants walked at self-selected and fast speeds while barefoot and while wearing shoes. Data from baseline sessions were included in this analysis. The influence of walking speed on five spatiotemporal gait measures was determined using a generalized estimating equation to calculate the proportion of variability in the gait measures that was explained by walking speed. Differences between sides and footwear conditions, and the relationships between walking speed and two symmetry measures, are also reported. RESULTS: A total of 820 steps were analyzed from ten children (11.2 ± 4.1 years). Walking velocity significantly influenced all spatiotemporal measures of gait. As speed increased, step length increased and all temporal measures decreased, on both paretic and nonparetic sides. Wearing shoes increased step length and stance time for both paretic and nonparetic sides, and slowed step time on the nonparetic side. Regardless of footwear, the paretic side demonstrated slower step and swing times, and faster stance and single support times. We did not observe significant relationships between walking speed and gait symmetry. SIGNIFICANCE: Our observations suggest that walking speed alone influences the spatiotemporal measurement of gait in children with hemiplegia and should be considered in the interpretation of walking function. Yet, controlling for walking speed is often not feasible or not preferred in this population. We offer suggestions for clinicians and researchers who seek to measure gait during overground walking at freely-selected speeds.

Language and developmental plasticity after perinatal stroke.

The mature human brain is lateralized for language, with the left hemisphere (LH) primarily responsible for sentence processing and the right hemisphere (RH) primarily responsible for processing suprasegmental aspects of language such as vocal emotion. However, it has long been hypothesized that in early life there is plasticity for language, allowing young children to acquire language in other cortical regions when LH areas are damaged. If true, what are the constraints on functional reorganization? Which areas of the brain can acquire language, and what happens to the functions these regions ordinarily perform? We address these questions by examining long-term outcomes in adolescents and young adults who, as infants, had a perinatal arterial ischemic stroke to the LH areas ordinarily subserving sentence processing. We compared them with their healthy age-matched siblings. All participants were tested on a battery of behavioral and functional imaging tasks. While stroke participants were impaired in some nonlinguistic cognitive abilities, their processing of sentences and of vocal emotion was normal and equal to that of their healthy siblings. In almost all, these abilities have both developed in the healthy RH. Our results provide insights into the remarkable ability of the young brain to reorganize language. Reorganization is highly constrained, with sentence processing almost always in the RH frontotemporal regions homotopic to their location in the healthy brain. This activation is somewhat segregated from RH emotion processing, suggesting that the two functions perform best when each has its own neural territory.

Normalizing step-to-step variability to age in children and adolescents with hemiplegia.

BACKGROUND: Children with hemiplegia often demonstrate gait deviations including increased variability and asymmetry. Step-to-step gait variability decreases over childhood and increases in the presence of neurologic dysfunction. Gait variability in children with hemiplegia should therefore be interpreted in reference to age-related norms RESEARCH QUESTION: Does conversion of the enhanced gait variability index (eGVI) to age-normalized z-scores improve interpretation of gait variability in children with hemiplegia? METHODS: Ten children (11.2 +/- 4.1 years) with hemiparetic gait due to stroke were recruited for a small prospective pilot intervention study. Participants walked at self-selected speed over an instrumented walkway while barefeet and while wearing shoes. eGVI values from baseline sessions were calculated and converted to age-normalized z-scores (eGVIz) based on published norms. Differences in gait variability between sides and footwear conditions, and its relationship to walking speed, were examined. RESULTS: There were no differences in raw eGVI or eGVIz between paretic and nonparetic sides (eGVI p = 0.31; eGVIz p = 0.31) or between footwear conditions (eGVI p = 0.62; eGVIz p = 0.33). Average raw eGVI values were just over two standards deviations above the reference mean of 100 (121.2, 122.1, 120.3 for mean (average of both limbs), nonparetic side and paretic side, respectively), indicating significantly greater step-to-step gait variability than in typical gait. However, when converted to age-normalized z-scores (eGVIz), variability deviated less from the normative sample, averaging just over one standard deviation above the reference mean (1.2, 1.3, 1.1 for mean, nonparetic side and paretic side, respectively). We also observed a relationship between eGVIz and walking speed in our sample. SIGNIFICANCE: We suggest that eGVI values in children be converted to z-scores or otherwise age-normalized so as not to inflate the degree of variability reported in clinical pediatric populations. Future work with larger samples will offer greater insight into gait variability in various clinical pediatric populations.

Characteristics of Moyamoya Syndrome in Pediatric Patients With Neurofibromatosis Type 1.

BACKGROUND: Moyamoya syndrome (MMS) is a progressive cerebral arteriopathy with increased incidence in children with neurofibromatosis type 1 (NF1). Despite the potential for significant neurological morbidity including stroke, little is known about the natural history, and no guidelines exist for screening and management of NF1-associated MMS. METHODS: We identified 152 literature cases of children aged ≤18 years with NF1-associated MMS. A meta-analysis was performed evaluating clinical and neuroimaging findings and patient outcomes. Data from 19 patients with NF1-associated MMS from our center treated from January 1995 to July 2020 were abstracted via chart review and similarly analyzed for clinical and neuroimaging features. RESULTS: Meta-analysis of literature cases showed a median age of MMS diagnosis of 6 years (interquartile range 3 to 10.8 years). Optic pathway gliomas were more common in patients with MMS (42%) compared with historical prevalence. Stroke or transient ischemic attack (TIA) was present at diagnosis in 46%. TIA and stroke were more common in patients with bilateral versus unilateral MMS (62% vs 34%, P = 0.001) and in children aged <4 years versus those aged ≥4 years (61% vs 40%, P = 0.02). Compared with the literature cases, our cohort was more frequently asymptomatic (42% vs 25%) and less likely to present with TIA or stroke (32% vs 46%) at diagnosis. CONCLUSIONS: These data suggest there is an aggressive form of MMS in children with NF1 <4 years of age. Therefore, early screening should be considered to facilitate early detection and treatment of cerebral arteriopathy.

Arterial spin labeling as an ancillary assessment to postoperative conventional angiogram in pediatric moyamoya disease.

OBJECTIVE: Digital subtraction angiography (DSA) is commonly performed after pial synangiosis surgery for pediatric moyamoya disease to assess the degree of neovascularization. However, angiography is invasive, and the risk of ionizing radiation is a concern in children. In this study, the authors aimed to identify whether arterial spin labeling (ASL) can predict postoperative angiogram grading. In addition, they sought to determine whether patients who underwent ASL imaging without DSA had similar postoperative outcomes when compared with patients who received ASL imaging and postoperative DSA. METHODS: The medical records of pediatric patients who underwent pial synangiosis for moyamoya disease at a quaternary children's hospital were reviewed during a 10-year period. ASL-only and ASL+DSA cohorts were analyzed. The frequency of preoperative and postoperative symptoms was analyzed within each cohort. Three neuroradiologists assigned a visual ASL grade for each patient indicating the change from the preoperative to postoperative ASL perfusion sequences. A postoperative neovascularization grade was also assigned for patients who underwent DSA. RESULTS: Overall, 21 hemispheres of 14 patients with ASL only and 14 hemispheres of 8 patients with ASL+DSA were analyzed. The groups had similar rates of MRI evidence of acute or chronic stroke preoperatively (61.9% in the ASL-only group and 64.3% in the ASL+DSA group). In the entire cohort, transient ischemic attack (TIA) (p = 0.027), TIA composite (TIA or unexplained neurological symptoms; p = 0.0006), chronic headaches (p = 0.035), aphasia (p = 0.019), and weakness (p = 0.001) all had decreased frequency after intervention. The authors found a positive association between revascularization observed on DSA and the visual ASL grading (p = 0.048). The visual ASL grades in patients with an angiogram indicating robust neovascularization demonstrated improved perfusion when compared with the ASL grades of patients with a poor neovascularization. CONCLUSIONS: Noninvasive ASL perfusion imaging had an association with postoperative DSA neoangiogenesis following pial synangiosis surgery in children. There were no significant postoperative stroke differences between the ASL-only and ASL+DSA cohorts. Both cohorts demonstrated significant improvement in preoperative symptoms after surgery. Further study in larger cohorts is necessary to determine whether the results of this study are validated in order to circumvent the invasive catheter angiogram.

Children with perinatal stroke are at increased risk for autism spectrum disorder: Prevalence and co-occurring conditions within a clinically followed sample.

OBJECTIVE: Children with perinatal stroke are at increased risk for developmental language disorders, learning difficulties, and other mental health conditions. However to date, autism (ASD) prevalence in this group has not been reported. Given that early identification of ASD is essential to promoting optimal outcomes, our goal was to establish prevalence of ASD in children with perinatal stroke. METHOD: A prospectively enrolled, single-center stroke registry maintained at our institution since 2005 was queried for all potentially eligible patients with a history of perinatal stroke. Information regarding stroke features, ASD diagnosis/concern, intellectual disability/global developmental delay, cerebral palsy/hemiparesis, epilepsy, and language disorder were collected via retrospective chart review from electronic health records. RESULTS: 311 children were identified, of which 201 complete records were analyzed. Twenty-three cases were formally diagnosed with ASD (11.4%). First concerns were noted in toddlerhood (Mage = 2.66 years), yet the average age of diagnosis was 6.26 years. Children with ASD were more likely to have earlier diagnoses of intellectual disability/global developmental delay or a mixed receptive-expressive language disorder (ps < .001) but did not differ on CP/hemiplegia or epilepsy diagnoses. Risk for ASD increased with accumulating diagnoses. DISCUSSION: Children with perinatal stroke have an increased prevalence of ASD (11.4%) than in the general population. ASD concerns arise at a similar age as the general population, yet ASD is diagnosed almost two years later than the general population and 3.60 years after first concerns present. Co-occurring neurological conditions are common. Clinicians must be aware of increased prevalence and implement screening as part of routine care for all pediatric patients with perinatal stroke.

Prevalence of Patent Foramen Ovale in a Cohort of Children With Cryptogenic Ischemic Stroke.

BACKGROUND AND OBJECTIVES: To determine the significance of patent foramen ovale (PFO) in childhood stroke, we compared PFO prevalence, PFO features, and stroke recurrence risk in 25 children with cryptogenic arterial ischemic stroke (AIS), 54 children with AIS from a known etiology, and 209 healthy controls. METHODS: We performed a case-control analysis of a 14-year prospectively enrolled single-center cohort of children with AIS who underwent transthoracic echocardiogram (TTE) and compared them to TTEs of otherwise healthy children evaluated for benign cardiac concerns. Stroke patients 29 days to 18 years of age at stroke ictus with confirmed acute AIS on imaging, availability of complete diagnostic studies of stroke risk factors, including TTE images available for central review, and at least 1 follow-up evaluation after index stroke were included. Presence of PFO and high-risk PFO features were assessed by 2 independent, blinded reviewers and compared between groups with the Fisher exact test. Stroke/TIA recurrence risk was determined from Cox proportional hazards models. RESULTS: Of 154 children with first-ever AIS, 79 were eligible; 25 had cryptogenic AIS, and 54 had a known cause. PFO prevalence was higher in the cryptogenic group (7, 28%) compared to both the known stroke etiology group (3, 5.6%, p = 0.009) and controls without stroke (24, 11.5%, p = 0.03). There were no significant differences in presence of right-to-left shunt and atrial septal aneurysm. Median follow-up time for entire stroke cohort was 20.9 months. Stroke-free recurrence at 2-years did not differ between children with and without PFO (HR 2.0, 95% CI 0.4-9.3, p = 0.39). DISCUSSION: PFO prevalence was higher in children with cryptogenic stroke compared to patients with AIS with known etiology and healthy controls. PFO was not associated with increased recurrence risk. Optimal secondary preventive treatment in children with cryptogenic stroke and PFO remains uncertain and requires further study. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that children with cryptogenic ischemic stroke have an increased frequency of PFO compared to children with ischemic stroke of known etiology and healthy controls.

Association of Pediatric ASPECTS and NIH Stroke Scale, Hemorrhagic Transformation, and 12-Month Outcome in Children With Acute Ischemic Stroke.

OBJECTIVE: We aimed to determine whether a modified pediatric Alberta Stroke Program Early CT Score (modASPECTS) is associated with clinical stroke severity, hemorrhagic transformation, and 12-month functional outcomes in children with acute AIS. METHODS: Children (29 days to <18 years) with acute AIS enrolled in two institutional prospective stroke registries at Children's Hospital of Philadelphia and Royal Children's Hospital Melbourne, Australia were retrospectively analyzed to determine whether modASPECTS, in which higher scores are worse, correlated with acute Pediatric NIH Stroke Scale (PedNIHSS) scores (children ≥2 years of age), was associated with hemorrhagic transformation on acute MRI, and correlated with 12-month functional outcome on the Pediatric Stroke Outcome Measure (PSOM). RESULTS: 131 children were included; 91 were ≥2 years of age. Median days from stroke to MRI was 1 (interquartile range [IQR] 0-1). Median modASPECTS was 4 (IQR 3-7). ModASPECTS correlated with PedNIHSS (rho=0.40, P=0.0001). ModASPECTS was associated with hemorrhagic transformation (OR 1.13 95% CI 1.02-1.25, P=0.018). Among children with follow-up (N=128, median 12.2 months, IQR 9.5-15.4 months), worse outcomes were associated with higher modASPECTS (common OR 1.14, 95%CI 1.04-1.24, P=0.005). The association between modASPECTS and outcome persisted when we adjusted for age at stroke ictus and the presence of tumor or meningitis as stroke risk factors (common OR 1.14, 95%CI 1.03-1.25, P=0.008). CONCLUSIONS: ModASPECTS correlates with PedNIHSS scores, hemorrhagic transformation, and 12-month functional outcome in children with acute AIS. Future pediatric studies should evaluate its usefulness in predicting symptomatic intracranial hemorrhage and outcome after acute revascularization therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the modified pediatric ASPECTS on MRI is associated with stroke severity (as measured by the baseline pediatric NIH Stroke Scale), hemorrhagic transformation, and 12-month outcome in children with acute supratentorial ischemic stroke.

Endovascular and thrombolytic treatment eligibility in childhood arterial ischemic stroke.

AIM: To describe factors affecting eligibility for, and rates of utilization of, hyperacute therapy in children with acute ischemic stroke (AIS) following establishment of our institutional acute stroke treatment pathway in 2005. METHODS: A retrospective analysis of a prospectively enrolled, single-center cohort was performed including children age 2 - <18 years with acute AIS from 2005 through 2017. Descriptive statistics were used to summarize clinical characteristics, presentation data, and Pediatric NIH Stroke Scale (PedNIHSS) scores that were abstracted from medical records. Assessment for eligibility and administration of hyperacute therapy was determined at the time of presentation according to the institutional stroke pathway. RESULTS: Of 90 children (median age at presentation 11.3 years, 36% female) with acute AIS, 5 (6%) received hyperacute therapy: 3 received intravenous tissue plasminogen activator (IV-tPA) alone, 1 received endovascular therapy (EVT) alone, and 1 received IV-tPA and EVT. Of 54 children (60%) who presented within 4.5 h of time last seen well, 6 had PedNIHSS scores 6-24, no medical contraindication to IV-tPA, and a partial or complete vessel occlusion. Of 7 children >3 years old who presented after EVT became available at our hospital and within 6 h of time last seen well with a PedNIHSS score 6-24, 3 (43%) had a large vessel occlusion (LVO). Two patients underwent EVT and the other patient was not transferred until >6 h from time last seen well. CONCLUSIONS: Delay to presentation and diagnosis of childhood acute AIS, mild neurologic deficits at presentation, medical contraindications to IV-tPA, and lack of vessel occlusion on acute neuroimaging contribute to low rates of hyperacute treatment in children with acute AIS.

Serial Neurologic Assessment in Pediatrics (SNAP): A New Tool for Bedside Neurologic Assessment of Critically Ill Children.

OBJECTIVES: We developed a tool, Serial Neurologic Assessment in Pediatrics, to screen for neurologic changes in patients, including those who are intubated, are sedated, and/or have developmental disabilities. Our aims were to: 1) determine protocol adherence when performing Serial Neurologic Assessment in Pediatrics, 2) determine the interrater reliability between nurses, and 3) assess the feasibility and acceptability of using Serial Neurologic Assessment in Pediatrics compared with the Glasgow Coma Scale. DESIGN: Mixed-methods, observational cohort. SETTING: Pediatric and neonatal ICUs. SUBJECTS: Critical care nurses and patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serial Neurologic Assessment in Pediatrics assesses Mental Status, Cranial Nerves, Communication, and Motor Function, with scales for children less than 6 months, greater than or equal to 6 months to less than 2 years, and greater than or equal to 2 years old. We assessed protocol adherence with standardized observations. We assessed the interrater reliability of independent Serial Neurologic Assessment in Pediatrics assessments between pairs of trained nurses by percent- and bias- adjusted kappa and percent agreement. Semistructured interviews with nurses evaluated acceptability and feasibility after nurses used Serial Neurologic Assessment in Pediatrics concurrently with Glasgow Coma Scale during routine care. Ninety-eight percent of nurses (43/44) had 100% protocol adherence on the standardized checklist. Forty-three nurses performed 387 paired Serial Neurologic Assessment in Pediatrics assessments (149 < 6 mo; 91 ≥ 6 mo to < 2 yr, and 147 ≥ 2 yr) on 299 patients. Interrater reliability was substantial to near-perfect across all components for each age-based Serial Neurologic Assessment in Pediatrics scale. Percent agreement was independent of developmental disabilities for all Serial Neurologic Assessment in Pediatrics components except Mental Status and lower extremity Motor Function for patients deemed "Able to Participate" with the assessment. Nurses reported that they felt Serial Neurologic Assessment in Pediatrics, compared with Glasgow Coma Scale, was easier to use and clearer in describing the neurologic status of patients who were intubated, were sedated, and/or had developmental disabilities. About 92% of nurses preferred to use Serial Neurologic Assessment in Pediatrics over Glasgow Coma Scale. CONCLUSIONS: When used by critical care nurses, Serial Neurologic Assessment in Pediatrics has excellent protocol adherence, substantial to near-perfect interrater reliability, and is feasible to implement. Further work will determine the sensitivity and specificity for detecting clinically meaningful neurologic decline.

A review of current controversies in determining death by neurologic criteria in children.

PURPOSE OF REVIEW: Death by neurologic criteria (DNC) is the irreversible cessation of all functions of the entire brain, including the brainstem. It is legally recognized as equivalent to cardiopulmonary death. Legal and ethical controversies surrounding DNC have emerged as a result of several highly publicized cases that have eroded public trust in our ability to declare DNC accurately. In this review, we focus on recently published primary data about DNC and address some of these controversies. RECENT FINDINGS: Approximately 21% of children who die in pediatric intensive care units (PICU) are declared DNC. Although 60% of physicians report that they have been asked to maintain organ support after DNC declaration, less than 1% of patients remain physically present in the PICU more than 5 days after DNC declaration. We discuss strategies for safely conducting the apnea test, indications and prevalence of ancillary testing, and objections to DNC, including issues of consent and requests for ongoing organ support. SUMMARY: In order to maintain public trust, published guidelines must be followed to accurately and consistently diagnose DNC. We must develop strategies to respond to objections to DNC determination. Ongoing research is needed to improve the safety of apnea testing and indications for and interpretation of ancillary testing.

Assessment of midazolam pharmacokinetics in the treatment of status epilepticus.

OBJECTIVES: Refractory status epilepticus (RSE) is often treated with midazolam boluses and continuous infusions, but there is considerable variability in dosing and efficacy. We aimed to evaluate the performance of a clinical midazolam dose escalation pathway for the treatment of pediatric RSE that was designed based on a novel midazolam pharmacokinetic model. DESIGN: Prospective pharmacokinetic study of midazolam bolus and escalation of continuous midazolam infusion. SETTING: Pediatric Intensive Care Unit in quaternary-care academic hospital. SUBJECTS: Children between two months to seventeen years of age who received clinically-indicated midazolam infusion for treatment of RSE. INTERVENTION: Blood sampled at regular intervals during treatment. Main study outcome measure was the accuracy of a pharmacokinetic model to predict serum midazolam concentrations. MEASUREMENTS AND MAIN RESULTS: We analysed data from six subjects. Three subjects had serum midazolam concentrations close to those predicted by our initial model (accuracy 88.9-170.2 %) which incorporates body weight, hepatic function, and renal function. For the other three subjects, all of whom were receiving pre-existing chronic benzodiazepine therapy prior to the RSE episode, the model grossly overestimated serum concentrations (predictive error 420.3-722.5 %). Once the model was corrected for the impact of pre-existing chronic benzodiazepine use on clearance, predicted concentrations more closely reflected those measured in subjects. CONCLUSION: We evaluated a clinical midazolam RSE treatment pathway but discovered that the model on which the pathway was based was not accurate for all patients. We therefore developed a novel pharmacokinetic midazolam model in children with RSE treated with continuous midazolam infusion. This model incorporates body weight, hepatic and renal function, and importantly, a correction factor for pre-existing chronic benzodiazepine use. Once validated, this model may guide dosing and drive the development of more effective treatment pathways for continuous midazolam in RSE.

Outcome Trajectories after Primary Perinatal Hemorrhagic Stroke.

BACKGROUND: Perinatal hemorrhagic stroke in late preterm and term neonates is understudied. We describe two-month and two-year neurological outcomes in a prospective cohort. METHODS: Neonates ≥36 weeks' gestation with spontaneous hemorrhagic stroke (parenchymal and intraventricular) presenting at age ≤28 days were enrolled between March 2007 and May 2015 at three tertiary pediatric centers. Hemorrhagic transformation of arterial ischemic stroke or cerebral sinovenous thrombosis was excluded. The Pediatric Stroke Outcome Measure (PSOM) assessed outcomes. Wilcoxon signed-rank tests evaluated change over time. RESULTS: Twenty-six neonates were included (median age: 1 day, interquartile range [IQR] 0 to 16; median gestational age: 38.3 weeks, IQR 37.0 to 39.0). Hemorrhage was isolated intraventricular in seven (27%), isolated intraparenchymal in six (23%), and a combination in 10 (39%). Three neonates (12%) died during hospitalization; one died later due to cardiac disease. Among 22 survivors, outcomes were assessed at a median of 2.1 months (IQR 1.7 to 3.3) in 96% and 1.9 years (IQR 1.3 to 2.0) in 73%. Median PSOM scores were 0.0 (IQR 0.0 to 1.0) and 0.25 (IQR 0.0 to 1.3), respectively. At two years, 45% of patients had no or nonimpairing deficits (PSOM <1.0), 30% had mild deficits (PSOM 1.0 to 2.0), and 5% had moderate deficits (PSOM 2.5 to 4.5). Over time, 31% worsened and 6% improved. Although total PSOM scores did not change significantly (P = 0.08), language subscores worsened (P = 0.009). No child developed epilepsy. CONCLUSIONS: Perinatal hemorrhagic stroke survivors had favorable outcomes in early childhood; at two years moderate to severe deficits occurred in 5%. Language deficits may emerge over time, warranting close follow-up.

Risk of Intracranial Hemorrhage Following Intravenous tPA (Tissue-Type Plasminogen Activator) for Acute Stroke Is Low in Children.

Background and Purpose- Data regarding the safety and efficacy of intravenous tPA (tissue-type plasminogen activator) in childhood acute arterial ischemic stroke are inadequate. The TIPS trial (Thrombolysis in Pediatric Stroke; National Institutes of Health grant R01NS065848)-a prospective safety and dose-finding trial of intravenous tPA in acute childhood stroke-was closed for lack of accrual. TIPS sites have subsequently treated children with acute stroke in accordance with established institutional protocols supporting data collection on outcomes. Methods- Data on children treated with intravenous tPA for neuroimaging-confirmed arterial ischemic stroke were collected retrospectively from 16 former TIPS sites to establish preliminary safety data. Participating sites were required to report all children who were treated with intravenous tPA to minimize reporting bias. Symptomatic intracranial hemorrhage (SICH) was defined as ECASS (European Cooperative Acute Stroke Study) II parenchymal hematoma type 2 or any intracranial hemorrhage associated with neurological deterioration within 36 following tPA administration. A Bayesian beta-binomial model for risk of SICH following intravenous tPA was fit using a prior distribution based on the risk level in young adults (1.7%); to test for robustness, the model was also fit with uninformative and conservative priors. Results- Twenty-six children (age range, 1.1-17 years; median, 14 years; 12 boys) with stroke and a median pediatric National Institutes of Health Stroke Scale score of 14 were treated with intravenous tPA within 2 to 4.5 hours (median, 3.0 hours) after stroke onset. No patient had SICH. Two children developed epistaxis. Conclusions- The estimated risk of SICH after tPA in children is 2.1% (95% highest posterior density interval, 0.0%-6.7%; mode, 0.9%). Regardless of prior assumption, there is at least a 98% chance that the risk is <15% and at least a 93% chance that the risk is <10%. These results suggest that the overall risk of SICH after intravenous tPA in children with acute arterial ischemic stroke, when given within 4.5 hours after symptom onset, is low.

Arterial Ischemic Stroke Secondary to Cardiac Disease in Neonates and Children.

OBJECTIVE: We describe the risk factors for peri-procedural and spontaneous arterial ischemic stroke (AIS) in children with cardiac disease. METHODS: We identified children with cardiac causes of AIS enrolled in the International Pediatric Stroke Study registry from January 2003 to July 2014. Isolated patent foramen ovale was excluded. Peri-procedural AIS (those occurring during or within 72 hours of cardiac surgery, cardiac catheterization, or mechanical circulatory support) and spontaneous AIS that occurred outside of these time periods were compared. RESULTS: We identified 672 patients with congenital or acquired cardiac disease as the primary risk factor for AIS. Among these, 177 patients (26%) had peri-procedural AIS and 495 patients (74%) had spontaneous AIS. Among non-neonates, spontaneous AIS occurred at older ages (median 4.2 years, interquartile range 0.97 to 12.4) compared with peri-procedural AIS (median 2.4 years, interquartile range 0.35 to 6.1, P < 0.001). About a third of patients in both groups had a systemic illness at the time of AIS. Patients who had spontaneous AIS were more likely to have a preceding thrombotic event (16 % versus 9 %, P = 0.02) and to have a moderate or severe neurological deficit at discharge (67% versus 33%, P = 0.01) compared to those with peri-procedural AIS. CONCLUSIONS: Children with cardiac disease are at risk for AIS at the time of cardiac procedures but also outside of the immediate 72 hours after procedures. Many have acute systemic illness or thrombotic event preceding AIS, suggesting that inflammatory or prothrombotic conditions could act as a stroke trigger in this susceptible population.

Inter-Rater Reliability Between Critical Care Nurses Performing a Pediatric Modification to the Glasgow Coma Scale.

OBJECTIVES: Estimate the inter-rater reliability of critical care nurses performing a pediatric modification of the Glasgow Coma Scale in a contemporary PICU. DESIGN: Prospective observation study. SETTING: Large academic PICU. PATIENTS/SUBJECTS: All 274 nurses with permanent assignments in the PICU were eligible to participate. A subset of 18 nurses were selected as study registered nurses. All PICU patients were eligible to participate. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PICU nurses were educated and demonstrated proficiency on a pediatric modification of the Glasgow Coma Scale we created to make it more applicable to a diverse PICU population that included patients who are sedated, mechanically ventilated, and/or have developmental disabilities. Each study registered nurse observed a sample of nurses perform the Glasgow Coma Scale, and they independently scored the Glasgow Coma Scale. Patients were categorized as having developmental disabilities if their preillness Pediatric Cerebral Performance Category score was greater than or equal to 3. Fleiss' Kappa (κ), intraclass correlation coefficient, and percent agreement assessed inter-rater reliability for each Glasgow Coma Scale component (eye, verbal, motor) and age-specific scale (≥ 2 and < 2-yr-old). The overall percent agreement between study registered nurses and nurses was 89% for the eye, 91% for the verbal, and 79% for the motor responses. Inter-rater reliability ranged from good (intraclass correlation coefficient = 0.75) to excellent (intraclass correlation coefficient = 0.96) for testable patients. Agreement on the motor response was significantly lower for children with developmental disabilities (< 2 yr: 59% vs 95%; p = 0.0012 and ≥ 2 yr: 55% vs 91%; p = 0.0012). Agreement was significantly worse for intermediate range Glasgow Coma Scale motor responses compared with responses at the extremes (e.g., motor responses 2, 3, 4 vs 1, 5, 6; p < 0.05). CONCLUSIONS: A pediatric modification of the Glasgow Coma Scale performed by trained PICU nurses has excellent inter-rater reliability, although reliability was reduced in patients with developmental disabilities and for intermediate range Glasgow Coma Scale responses. Further research is needed to determine the effectiveness of this Glasgow Coma Scale modification to detect clinical deterioration.