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Background: Data from the early pandemic revealed that 0.62% of children hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had an acute arterial ischemic stroke (AIS). In a larger cohort from June 2020 to December 2020, we sought to determine whether our initial point estimate was stable as the pandemic continued and to understand radiographic and laboratory data that may clarify mechanisms of pediatric AIS in the setting of SARS-CoV-2. Methods: We surveyed international sites with pediatric stroke expertise to determine numbers of hospitalized SARS-CoV-2 patients Results: Sixty-one centers from 21 countries provided AIS data. Forty-eight centers (78.7%) provided SARS-CoV-2 hospitalization data. SARS-CoV-2 testing was performed in 335/373 acute AIS cases (89.8%) compared with 99/166 (59.6%) in March to May 2020, P P =0.78. Of the 22 of 23 AIS cases with SARS-CoV-2 in whom we could collect additional data, SARS-CoV-2 was the main stroke risk factor in 6 (3 with arteritis/vasculitis, 3 with focal cerebral arteriopathy), a contributory factor in 13, and incidental in 3. Elevated inflammatory markers were common, occurring in 17 (77.3%). From centers with SARS-CoV-2 hospitalization data, of 7231 pediatric patients hospitalized with SARS-CoV-2, 23 had AIS (0.32%) compared with 6/971 (0.62%) from March to May 2020, P =0.14. Conclusions: The risk of AIS among children hospitalized with SARS-CoV-2 appeared stable compared with our earlier estimate. Among children in whom SARS-CoV-2 was considered the main stroke risk factor, inflammatory arteriopathies were the stroke mechanism.

Tenecteplase is replacing alteplase as the fibrinolytic agent of choice for the acute management of ischemic stroke in many adult stroke centers due to practical and pharmacokinetic advantages in the setting of similar outcomes. Although thrombolytic use is increasing for acute childhood stroke, there is very limited experience with tenecteplase in children for any indication, and importantly, there are no data on safety, dosing, or efficacy of tenecteplase for childhood stroke. Changes in fibrinolytic capacity over childhood, pediatric pharmacological considerations such as age-specific differences in drug clearance and volume of distribution, and practical aspects of drug delivery such as availability in children’s hospitals may impact decisions about transitioning from alteplase to tenecteplase for acute pediatric stroke treatment. Pediatric and adult neurologists should prepare institution-specific guidelines and organize prospective data collection.

We provide evidence that stroke-induced gut breakdown results in bacteria translocation to the ischaemic mouse brain. Inhibition of sympathetic tone reduced bacterial load in the post-stroke brain and reduced functional deficits without altering cerebral apoptosis, neuroinflammation or infarct volume. These findings indicate that the activation of the sympathetic nervous system after stroke promotes gut-derived bacteria to enter to the brain, and this process worsens motor function in mice.Abstract Figure

Previous studies investigating innate leukocyte recruitment into the brain after cerebral ischemia have shown conflicting results. Using distinct cell surface and intracellular markers, the current study evaluated the contributions of innate immune cells to the poststroke brain following 1-h middle cerebral artery occlusion (tMCAO) or permanent MCAO (pMCAO), and assessed whether these cells ascribed to an inflammatory state. Moreover, we examined whether there is evidence for leukocyte infiltration into the contralateral (CL) hemisphere despite the absence of stroke infarct. We observed the recruitment of peripheral neutrophils, monocytes and macrophages into the hemisphere ipsilateral (IL) to the ischemic brain infarct at 24 and 96 h following both tMCAO and pMCAO. In addition, we found evidence of increased leukocyte recruitment to the CL hemisphere but to a lesser extent than the IL hemisphere after stroke. Robust production of intracellular cytokines in the innate immune cell types examined was most evident at 24 h after pMCAO. Specifically, brain-associated neutrophils, monocytes and macrophages demonstrated stroke-induced production of tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β, while only monocytes and macrophages exhibit a significant expression of arginase 1 (Arg1) after stroke. At 96 h after stroke, brain-resident microglia demonstrated production of TNF-α and IL-1β following both tMCAO and pMCAO. At this later timepoint, neutrophils displayed TNF-α production and brain-associated macrophages exhibited elevation of IL-1β and Arg1 after tMCAO. Further, pMCAO induced significant expression of Arg1 and IL-1β in monocytes and macrophages at 96 h, respectively. These results revealed that brain-associated innate immune cells display various stroke-induced inflammatory states that are dependent on the experimental stroke setting.

In stroke patients, infection is a significant contributor to morbidity and mortality. Moreover, older stroke patients show an increased risk of developing stroke-associated infection, although the mechanisms underlying this increased susceptibility to infection are unknown. In this study, using an experimental mouse model of ischemic stroke, we showed that older (12–15 mo of age) mice had elevated lung bacterial infection and inflammatory damage after stroke when compared with young (8–10 wk of age) counterparts, despite undergoing the same degree of brain injury. Intravital microscopy of the lung microvasculature revealed that in younger mice, stroke promoted neutrophil arrest in pulmonary microvessels, but this response was not seen in older poststroke mice. In addition, bacterial phagocytosis by neutrophils in the lung microvasculature was reduced by both aging and stroke, such that neutrophils in aged poststroke mice showed the greatest impairment in this function. Analysis of neutrophil migration in vitro and in the cremaster muscle demonstrated that stroke alone did not negatively impact neutrophil migration, but that the combination of increased age and stroke led to reduced effectiveness of neutrophil chemotaxis. Transcriptomic analysis of pulmonary neutrophils using RNA sequencing identified 79 genes that were selectively altered in the context of combined aging and stroke, and they were associated with pathways that control neutrophil chemotaxis. Taken together, the findings of this study show that stroke in older animals results in worsening of neutrophil antibacterial responses and changes in neutrophil gene expression that have the potential to underpin elevated risk of stroke-associated infection in the context of increased age.

ObjectiveTo contextualize the role of child neurologists and neurodevelopmentalists (CNs/NDDs) in cerebral palsy (CP) care, we review the changing landscape of CP diagnosis and survey stakeholder CNs/NDDs regarding their roles in CP care.MethodsThe optimal roles of the multiple specialties involved in CP care are currently unclear, particularly regarding CP diagnosis. We developed recommendations regarding the role of CNs/NDDs noting (1) increasing complexity of CP diagnosis given a growing number of genetic etiologies and treatable motor disorders that can be misdiagnosed as CP and (2) the views of a group of physician stakeholders (CNs/NDDs from the Child Neurology Society Cerebral Palsy Special Interest Group).ResultsCNs/NDDs felt that they were optimally suited to diagnose CP. Many (76%) felt that CNs/NDDs should always be involved in CP diagnosis. However, 42% said that their patients with CP were typically not diagnosed by CNs/NDDs, and 18% did not receive referrals to establish the diagnosis of CP at all. CNs/NDDs identified areas of their expertise critical for CP diagnosis including knowledge of the neurologic examination across development and early identification of features atypical for CP. This contrasts with their views on CP management, where CNs/NDDs felt that they could contribute to the medical team, but were necessary primarily when neurologic coexisting conditions were present.DiscussionGiven its increasing complexity, we recommend early referral for CP diagnosis to a CN/NDD or specialist with comparable expertise. This contrasts with current consensus guidelines, which either do not address or do not recommend specific specialist referral for CP diagnosis.

Objective: Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied. Methods: A prospective time-delayed crossover design trial of GS to assess the efficacy of GS as a first-line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS. Results: Thirty-four individuals were assessed at interim review. The genetic origin of 2 patient's leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed-GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 [56%] vs 0/9 [0%]; Wild–Seber, p < 0.005) and delayed (control) arms (14/23 [61%] vs 5/23 [22%]; Wild–Seber, p < 0.005). The time to diagnosis was significantly shorter in the immediate-GS group (log-rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8–89.3%) in

Down syndrome regression disorder (DSRD) is characterized by the sudden loss of adaptive function, cognitive-executive function, and language with abnormal sleep and/or motor control.Clinical, laboratory, and imaging data from three individuals with DSRD and iron on brain imaging were reviewed.Three patients with Down syndrome presented with new onset of flat affect, depression, reduced speech, and other neurological symptoms consistent with DSRD. Magnetic resonance imaging showed abnormal iron accumulation in the basal ganglia, as well as calcification in two cases. Molecular diagnostic testing for neurodegeneration with brain iron accumulation was negative in the two individuals tested.These individuals presented suggest that a subset of individuals with DSRD have abnormal brain iron accumulation. Motor control symptoms reported in DSRD, such as stereotypies and parkinsonism, may reflect this basal ganglia involvement. The presence of abnormal brain iron should not delay or preclude diagnosis and treatment for DSRD.

Background Cerebral palsy (CP) is the most common cause of childhood motor disability. However, there is limited guidance on training of child neurologists and neurodevelopmental disability specialists in the care of individuals with cerebral palsy. We sought to determine training program directors’ impressions of the importance and adequacy of training in the diagnosis and management of cerebral palsy. Methods In this cross-sectional study, all 82 child neurology and neurodevelopmental disability program directors were asked to complete a survey querying program characteristics, aspects of training in cerebral palsy, importance of cerebral palsy training, and perceived competence at graduation in cerebral palsy care. Results There were 35 responses (43% response rate). Nearly all program directors (91%) reported “learning to diagnose cerebral palsy” as very important, and most (71%) felt that “learning to manage cerebral palsy” was very important. Although most program directors reported trainees to be very or extremely competent in cerebral palsy diagnosis (77%), only 43% of program directors felt that trainees were very or extremely competent in cerebral palsy management. Time spent with cerebral palsy faculty was associated with higher reported competence in cerebral palsy diagnosis ( P = .03) and management ( P Conclusions Child neurology and neurodevelopmental disability program directors reported that training in cerebral palsy is important for residents; however, a significant proportion felt that residents were not very well prepared to manage cerebral palsy. The development of cerebral palsy curricula and exposure to cerebral palsy clinics may improve training, translating to better care of individuals with cerebral palsy.

Mechanisms underlying post-stroke immune impairments and subsequent development of fatal lung infection have been suggested to involve multiple pathways, including hyperactivation of the sympathetic nervous system (SNS), which results in the excessive release of catecholamines and activation of β-adrenergic receptors (βARs). Indeed, previous reports from experimental studies demonstrated that post-stroke infection can be inhibited with treatment of β-blockers. However, the effectiveness of β-blockers in reducing post-stroke infection has yielded mixed results in retrospective clinical trials and its use remain controversial. In this study, we performed mid-cerebral artery occlusion in mice either genetically deficient in β2-adrenergic receptor (β2AR) or treated with non-selective and selective βAR antagonists to explore the contributions of the SNS in the development of post-stroke lung infection. Stroke induced a systemic activation of the SNS as indicated by elevated levels of plasma catecholamines and UCP-1 activity. However, β2AR deficient mice showed similar degrees of post-stroke immune impairment and infection rate compared to wildtype counterparts, potentially due to compensatory mechanisms common in transgenic animals. To overcome this, we treated post-stroke wildtype mice with pharmacological inhibitors of the βARs, including the non-selective antagonist propranolol (PPL) and selective β2AR antagonist ICI-118551. Both pharmacological strategies to block the action of SNS signalling were unable to reduce infection in mice that underwent ischaemic stroke. Overall, our data suggests that other mechanisms independent or in combination with β2AR activation contribute to the development of post-stroke infection.

To describe the clinical course and outcomes of aggressive retinal astrocytic hamartoma (RAH) treated with oral mechanistic target of rapamycin inhibitors (mTORis).A retrospective clinical case series.Five patients with genetically confirmed tuberous sclerosis complex and visually significant RAH due to tumor growth or exudation.In this retrospective clinical case series, a review of electronic medical records was performed to determine baseline and follow-up ophthalmic examination characteristics, along with ancillary imaging findings, in patients receiving off-label treatment with either oral sirolimus or everolimus for symptomatic RAH.Visual acuity, change in tumor size, degree of exudation, and adverse effects of the mTORis were evaluated.The 5 patients in this series ranged in age from 8 months to 54 years. Four were treated with sirolimus, and 1 received everolimus. In all the cases, the tumor height was stable or decreased after the treatment (median follow-up duration, 39 months; range, 11-73 months). Exudation improved after the treatment in all the cases. In an 8-month-old infant, frequent upper respiratory tract infections prompted the cessation of treatment. In 1 patient, the mTORi was temporarily withheld because of elevated liver enzyme levels. No other significant adverse effects were noted.Sirolimus and everolimus should be considered in the management of vision-threatening RAH, particularly in the setting of exudative and rapidly growing tumors. Four of the 5 patients in this series tolerated the oral mTORi and continued with the therapy. There were no serious complications.

Adenosine deaminase 2 deficiency (OMIM #615688) is an autosomal recessive disorder characterized by a wide clinical spectrum, including small- and medium-sized vessel vasculopathies, but data focusing on the associated neuroimaging features are still scarce in the literature. Here, we describe the clinical neuroimaging features of 12 patients with genetically proven adenosine deaminase 2 deficiency (6 males; median age at disease onset, 1.3 years; median age at genetic diagnosis, 15.5 years). Our findings expand the neuroimaging phenotype of this condition demonstrating, in addition to multiple, recurrent brain lacunar ischemic and/or hemorrhagic strokes, spinal infarcts, and intracranial aneurysms, also cerebral microbleeds and a peculiar, likely inflammatory, perivascular tissue in the basal and peripontine cisterns. Together with early clinical onset, positive family history, inflammatory flares and systemic abnormalities, these findings should raise the suspicion of adenosine deaminase 2 deficiency, thus prompting genetic evaluation and institution of tumor necrosis factor inhibitors, with a potential great impact on neurologic outcome.

Rationale: Early evidence for the benefit of mechanical thrombectomy (MT) in pediatric patients with intracranial large vessel occlusion has been shown in previous retrospective cohorts. Higher-level evidence is needed to overcome the limitations of these studies such as the lack of a control group and the retrospective design. Randomized trials will very likely not be feasible, and several open questions remain, for example, the impact of arteriopathic etiologies or a possible lower age limit for MT. Save ChildS Pro therefore aims to demonstrate the safety and effectiveness of MT in pediatric patients compared to the best medical management and intravenous thrombolysis.Design: Save ChildS Pro is designed as a worldwide multicenter prospective registry comparing the safety and effectiveness of MT to the best medical care alone in the treatment of pediatric arterial ischemic stroke (AIS). It will include pediatric patients (Outcomes: The primary endpoint of Save ChildS Pro is the modified Rankin Scale score at 90 days post-stroke. Secondary endpoints will comprise the decrease of the Pediatric National Institutes of Health Stroke Scale score from admission to discharge and rate of complications.Discussion: Save ChildS Pro aims to provide high-level evidence for MT for pediatric patients with AIS, thereby improving functional outcome and quality of life and reducing the individual, societal, and economic burden of death and disability resulting from pediatric stroke.Clinical Trial Registration: Save ChildS Pro is registered at the German Clinical Trials Registry (DRKS; identifier: DRKS00018960).

Background:Pantothenate kinase–associated neurodegeneration is characterized by severe, progressive dystonia. This study aims to describe the reported usage of cannabis products among children with pantothenate kinase–associated neurodegeneration.Methods:A cross-sectional, 37-item survey was distributed in April 2019 to the families of 44 children who participate in a clinical registry of individuals with pantothenate kinase–associated neurodegeneration.Results:We received 18 responses (40.9% response rate). Children were a mean of 11.0 (SD 4.3) years old. The 15 respondents with dystonia or spasticity were on a median of 2 tone medications (range 0-9). Seven children had ever used cannabis (38.9%). The most common source of information about cannabis was other parents. Children who had ever used cannabis were on more tone medications, were more likely to have used opiates, were less likely to be able to roll, and less likely to sit comfortably, than children who had never used cannabis. Four children reported moderate or significant improvement in dystonia with cannabis. Other areas reported to be moderate or significantly improved were pain (n = 3), sleep (n = 4), anxiety (n = 3), and behavior (n = 2). Adverse effects included sadness (n = 1), agitation/behavior change (n = 1), and tiredness (n = 1).Conclusion:Cannabis use was commonly reported among children with pantothenate kinase–associated neurodegeneration whose parents responded to a survey, particularly when many other dystonia treatments had been tried. Physicians should be aware that parents may treat their child with severe, painful dystonia with cannabis. Placebo-controlled studies of products containing cannabidiol and 9-tetrahydrocannabinol are needed for pediatric tone disorders.

We describe the risk factors for peri-procedural and spontaneous arterial ischemic stroke (AIS) in children with cardiac disease.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.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.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.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5–37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden’s Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

Purpose: We present the first detailed ophthalmic description of a child with Helsmoortel-Van der Aa Syndrome (HVDAS), including longitudinal follow-up and analysis. Observations: After extensive workup, a young child with poor visual behavior, hypotonic cerebral palsy, intellectual disability, and global developmental delay was found to have a heterozygous de novo mutation in the ADNP gene and diagnosed with HVDAS. Ophthalmic findings were remarkable for progressive nystagmus, macular pigment mottling, mild foveal hypoplasia with abnormal macular laminations, persistent rod dysfunction with electronegative waveform, and progressive cone degeneration. Conclusions and importance: Patients with HVDAS are known to have abnormal visual behavior due to refractive or cortical impairment. However, we present the first description, to our knowledge, of an association with retinal mal-development and degeneration. Thus, patients with HVDAS should be referred for ophthalmic genetics evaluation, and HVDAS should be on the differential diagnosis for young children with global developmental delay who present with nystagmus, rod and cone dysfunction with electronegative waveform, and relative lack of severe structural degeneration on optical coherence tomography. Keywords: Helsmoortel-Van der Aa Syndrome, HVDAS, Activity-dependent neuroprotective protein, ADNP, Nystagmus, Retinal degeneration, Electronegative waveform, Optical coherence tomography

Cerebral palsy is a non-progressive neurological disorder occurring in early childhood affecting body movement and muscle control. Early identification can help improve outcome through therapy-based interventions. Absence of so-called "fidgety movements" is a strong predictor of cerebral palsy. Currently, infant limb movements captured through either video cameras or accelerometers are analyzed to identify fidgety movements. However both modalities have their limitations. Video cameras do not have the high temporal resolution needed to capture subtle movements. Accelerometers have low spatial resolution and capture only relative movement. In order to overcome these limitations, we have developed a system to combine measurements from both camera and sensors to estimate the true underlying motion using extended Kalman filter. The estimated motion achieved 84% classification accuracy in identifying fidgety movements using Support Vector Machine.

Research concerning eating disorders among adolescent and young adult male athletes is limited compared with female counterparts, but increasing evidence indicates that they may be at unique risk for unhealthy exercise and eating behavior. The current study aimed to characterize unhealthy exercise and eating behavior according to competitive athlete status, as well as per sport type. Collegiate male athletes (N = 611), each affiliated with one of the 10 National College Athletics Association (NCAA) Division I schools in the United States, completed an online survey, reporting on eating and extreme weight control behaviors, and reasons for exercise. Competitive athletes endorsed increased driven exercise and exercising when sick. Baseball players, cyclists, and wrestlers emerged as the sports with the most players reporting elevated Eating Disorder Examination-Questionnaire scores in a clinical range, and basketball players reported the highest rates of binge eating. overall, baseball players, cyclists, rowers, and wrestlers appeared to demonstrate the greatest vulnerability for unhealthy eating and exercise behavior. Findings revealed differences between competitive and non-competitive male athletes. Among competitive athletes, results identified unique risk for unhealthy eating and exercise behavior across a variety of sport categories and support continued examination of these attitudes and behaviors in a nuanced manner. Evidence obtained from well-designed controlled trials without randomization.

Endovascular therapy benefits selected adults with acute stroke while data are lacking for children. The purpose of this study was to assess physician practice and institutional preparedness for endovascular therapy in pediatric stroke. A link to an anonymous online survey was sent to members of the International Pediatric Stroke Study (IPSS) group about physician experience with endovascular therapy, likelihood of treatment for provided clinical vignettes, and institutional readiness for the delivery of endovascular therapy to children. Thirty-one pediatric physicians with a mean of 11 years (SD 7.1) of experience responded. All but two would consider endovascular therapy in a child, and 20 (64.5%) had recommended endovascular therapy for a child in the preceding year. Most (n = 19, 67.9%) did not commit to an age minimum for endovascular therapy. Sixteen (57.1%) would consider treatment up to 24 h after symptom onset with 19 (67.9%) respondents reporting that their practice changed after the 2018 American Heart Association guidelines extended the time window for endovascular therapy in adults. Seventeen (60.7%) preferred imaging that included perfusion in children presenting beyond 6 h. Nineteen (70.4%) had institutional endovascular therapy criteria. Physicians in larger pediatric groups had more “likely to treat” responses on the clinical vignettes than physicians working in smaller groups (11.7 vs. 6.1, p

Accurate and informative microbiological testing is essential for guiding diagnosis and management of pneumonia in patients who are critically ill. Sampling of tracheal aspirate (TA) is less invasive compared with mini-bronchoalveolar lavage (mBAL) and is now recommended as a frontline diagnostic approach in patients who are mechanically ventilated, despite the historical belief that TA was suboptimal due to contamination from oral microbes. Advancements in metagenomic next-generation sequencing (mNGS) now permit assessment of airway microbiota without a need for culture and, as such, provide an opportunity to examine differences between mBAL and TA at a resolution previously unachievable. Here, we engaged shotgun mNGS to assess quantitatively the airway microbiome in matched mBAL and TA specimens from a prospective cohort of critically ill adults. We observed moderate differences between sample types across all subjects; however, we found significant compositional similarity in subjects with bacterial pneumonia, whose microbial communities were characterized by dominant pathogens. In contrast, in patients with noninfectious acute respiratory illnesses, significant differences were observed between sample types. Our findings suggest that TA sampling provides a similar assessment of airway microbiota as more invasive testing by mBAL in patients with pneumonia.

Lower respiratory tract infections (LRTIs) lead to more deaths each year than any other infectious disease category. Despite this, etiologic LRTI pathogens are infrequently identified due to limitations of existing microbiologic tests. In critically ill patients, noninfectious inflammatory syndromes resembling LRTIs further complicate diagnosis. To address the need for improved LRTI diagnostics, we performed metagenomic next-generation sequencing (mNGS) on tracheal aspirates from 92 adults with acute respiratory failure and simultaneously assessed pathogens, the airway microbiome, and the host transcriptome. To differentiate pathogens from respiratory commensals, we developed a rules-based model (RBM) and logistic regression model (LRM) in a derivation cohort of 20 patients with LRTIs or noninfectious acute respiratory illnesses. When tested in an independent validation cohort of 24 patients, both models achieved accuracies of 95.5%. We next developed pathogen, microbiome diversity, and host gene expression metrics to identify LRTI-positive patients and differentiate them from critically ill controls with noninfectious acute respiratory illnesses. When tested in the validation cohort, the pathogen metric performed with an area under the receiver-operating curve (AUC) of 0.96 (95% CI, 0.86–1.00), the diversity metric with an AUC of 0.80 (95% CI, 0.63–0.98), and the host transcriptional classifier with an AUC of 0.88 (95% CI, 0.75–1.00). Combining these achieved a negative predictive value of 100%. This study suggests that a single streamlined protocol offering an integrated genomic portrait of pathogen, microbiome, and host transcriptome may hold promise as a tool for LRTI diagnosis.

Introduction: Endovascular therapy (ET) for pediatric stroke has been described through case reports and series. Hypothesis: We aimed to determine how pediatric stroke neurologists practice regarding ET, and institutional readiness for this therapy. Methods: A link to a REDCap survey was emailed to the members of the International Pediatric Stroke Study (IPSS), which includes 58 centers and approximately 150 investigators, requesting responses from physicians who manage acute stroke. Results: We received 42 responses, with 12 countries represented. Most respondents were pediatric neurologists (n=33), with a median 10 years of experience treating pediatric stroke (SD 6.8). Fourteen (33%) had never recommended/performed ET, 10 (24%) had treated 1-2 patients, and 17 (40%) had treated 3-10 patients. All but one respondent would consider ET in a child. The mean minimum age for consideration of ET was 3 years (range 2-12 years), however most (n=27) had no set minimum age. Most used a time-window of 6 (33%) or 8 (24%) hours for anterior circulation stroke, though 38% had no set time window. Only 7 respondents reported a minimum NIHSS (median NIHSS 6, range 4-15), with the remainder reporting that deficits needed to be significant or the decision would dependent on the clinical scenario. The institutional analyses included only the responses of the 25 IPSS principal investigators to ensure just one response per institution. Fifty-six percent reported that ET would be performed at a children’s hospitals, 36% at an adjacent hospital, and 4% reported that ET would be performed off-site, with 67% responding that patients would need to travel > 10 miles. Only 3 reported working with interventional neuroradiologists who primarily or exclusively treated children, however 22 (88%) worked with adult interventional neuroradiologists comfortable treating children. Twenty (80%) reported having institutional ET guidelines in place or in development. Conclusions: Pediatric stroke neurologists were largely willing to consider ET, though many had limited experience. With varied clinician expertise and hospital settings, consensus-based guidelines would need to include minimum requirements for institutions to perform ET.

Lower respiratory tract infections (LRTI) lead to more deaths each year than any other infectious disease category(1). Despite this, etiologic LRTI pathogens are infrequently identified due to limitations of existing microbiologic tests(2). In critically ill patients, non-infectious inflammatory syndromes resembling LRTI further complicate diagnosis. To address the need for improved LRTI diagnostics, we performed metagenomic next-generation sequencing (mNGS) on tracheal aspirates from 92 adults with acute respiratory failure and simultaneously assessed pathogens, the lung microbiome and the host transcriptome. To differentiate pathogens from respiratory commensals, we developed rules-based and logistic regression models (RBM, LRM) in a derivation cohort of 20 patients with LRTI or non-infectious acute respiratory illnesses. When tested in an independent validation cohort of 24 patients, both models achieved accuracies of 95.5%. We next developed pathogen, microbiome diversity, and host gene expression metrics to identify LRTI-positive patients and differentiate them from critically ill controls with non-infectious acute respiratory illnesses. When tested in the validation cohort, the pathogen metric performed with an AUC of 0.96 (95% CI = 0.86 - 1.00), the diversity metric with an AUC of 0.80 (95% CI = 0.63 – 0.98), and the host transcriptional classifier with an AUC of 0.91 (95% CI = 0.80 – 1.00). Combining all three achieved an AUC of 0.99 (95% CI = 0.97 – 1.00) and negative predictive value of 100%. This study suggests that a single streamlined protocol offering an integrated genomic portrait of pathogen, microbiome and host transcriptome may hold promise as a novel tool for LRTI diagnosis.SIGNIFICANCE STATEMENTLower respiratory tract infections (LRTI) are the leading cause of infectious disease-related death worldwide yet remain challenging to diagnose because of limitations in existing microbiologic tests. In critically ill patients, non-infectious respiratory syndromes that resemble LRTI further complicate diagnosis and confound targeted treatment. To address this, we developed a novel metagenomic sequencing-based approach that simultaneously interrogates three core elements of acute airway infections: the pathogen, lung microbiome and host response. We studied this approach in a prospective cohort of critically ill patients with acute respiratory failure and found that combining pathogen, microbiome and host gene expression metrics achieved accurate LRTI diagnosis and identified etiologic pathogens in patients with clinically identified infections but otherwise negative testing.FundingNHLBI K12HL119997 (Langelier C), NHLBI K23HL123778 (Christensen S), NIAID P01AI091575 and the Chan Zuckerberg Biohub (DeRisi JL), NHLBI K23 HL136844 (Moazed F), NHLBI R01HL110969, K24HL133390, R35HL140026 (Calfee C), Gladstone Institutes (Pollard KS).

Diagnostic delay hinders management of pediatric arterial ischemic stroke. Quick brain MRI with diffusion-weighted imaging sequences may provide a rapid diagnosis without the ionizing radiation of a computed tomography (CT) scan.This was a single center retrospective chart review of children one month to 18 years old with acute arterial ischemic stroke hospitalized between January 2010 and January 2017. We evaluated sensitivity and the time to diagnostic study based on the first imaging study (CT or quick brain MRI with diffusion-weighted imaging).Twenty-five patients were included. Eleven patients (44%) were initially assessed with CT, 10 (40%) with quick brain MRI with diffusion-weighted imaging, and four (16%) with a full MRI. Compared with children undergoing CT, children with quick brain MRI with diffusion-weighted imaging as first study were younger (5.8 versus 14.1 years, P 0.001) and were more likely to be hospitalized at stroke onset (70% versus 18.2%, P = 0.03). Quick brain MRI with diffusion-weighted imaging was more sensitive for ischemia than CT (100% versus 27.3%). The median time from presentation to diagnostic imaging was 4.3 hours, with no differences between CT and quick brain MRI with diffusion-weighted imaging groups, although the quick brain MRI with diffusion-weighted imaging group had a shorter median time from first imaging to diagnostic imaging (P = 0.002). There were no significant missed findings on quick brain MRI with diffusion-weighted imaging.Quick brain MRI with diffusion-weighted imaging was more sensitive than CT for detecting ischemia and may be considered as the first study for some children presenting with suspected arterial ischemic stroke.

Despite strong evidence for endovascular therapy in adults with acute arterial ischemic stroke, limited data exist in children. We aimed to describe endovascular therapy utilization and explore outcomes in a national sample of pediatric arterial ischemic stroke.We queried the 2012 Kids' Inpatient Database for children aged greater than 28 days to 20 years with the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for arterial ischemic stroke and evaluated groups based on the procedure code for endovascular therapy. Poor outcome was defined as need for tracheostomy or gastrostomy, discharge to rehabilitation facility, or death. Logistic regression evaluated the association between endovascular therapy and poor outcome, adjusted for age, disease severity (hemiplegia, critical care interventions, neurosurgical interventions), and comorbidities.We identified 3184 pediatric discharges with a diagnosis code for arterial ischemic stroke. Thirty-eight (1%) had an endovascular therapy procedure code. Endovascular therapy patients were older (10.2 versus 4.5 years, P 0.001) and more likely to have hemiplegia/paresis (relative risk [RR] 3.8, 95% confidence interval [CI] 2.0-7.4), aphasia (RR 5.3, 95% CI 2.8-10.1), and facial droop (RR 4.0, 95% CI 1.9-8.7). Endovascular therapy was not associated with critical care and neurosurgical interventions or intracranial hemorrhage. Length of hospitalization, mortality, and discharge disposition were similar between groups. In a multivariable model, endovascular therapy was not associated with poor outcome (adjusted odds ratio 1.7, 95%, CI 0.7-4.1).In a national sample of children with a diagnosis of arterial ischemic stroke, endovascular therapy was infrequently utilized. Patients with a procedure code for endovascular therapy had significant stroke-related deficits, but outcomes were similar to those in children who did not receive endovascular therapy. Our data, in conjunction with evidence of benefit in adults, support consideration of endovascular therapy for select children with acute stroke.

Lesch-Nyhan disease (LND) is an X-linked disorder of purine metabolism, associated with self-mutilation, dystonia, and chorea. Seizures are uncommon in LND. Patients with LND are at risk for sudden and unexpected death. The etiology of this is unknown, but appears to occur from a respiratory process. We propose that respiratory failure secondary to subclinical seizure may lead to sudden death in these patients.We report a case of an 11-year-old boy with LND who had two episodes of nocturnal gasping. The second event was immediately followed by a 10 min generalized seizure. Upon arrival at the hospital, an arterial blood gas test revealed a severe respiratory acidosis. Following aggressive treatment of his seizures, this patient did well, and was discharged home on oxcarbazepine with rectal diazepam. No further seizures have been noted in 1 year of follow-up.In this case report and review, we hypothesize that sudden death from respiratory failure in Lesch-Nyhan disease may in some cases be due to seizure-induced respiratory failure, akin to sudden unexpected death in epilepsy (SUDEP). We suggest screening for paroxysmal respiratory events; consideration of electroencephalography for patients with LND presenting in respiratory distress or failure; and consideration of more aggressive treatment of seizures in these patients. Brief Summary:We present an 11-year-old boy with Lesch-Nyhan disease (LND) who developed respiratory failure and severe respiratory acidosis from his first known seizure, which evolved to subclinical status epilepticus. We propose that patients with LND have a predisposition to respiratory failure and sudden death, which in some cases may be provoked by seizure (sudden unexpected death in epilepsy, or SUDEP).

Self-injurious behavior (SIB) is common among adolescents, and has been shown to be associated with eating disorders (ED). This study examines the prevalence of SIB and SIB screening in adolescents with ED, and associations with binge eating, purging, and diagnosis.Charts of 1,432 adolescents diagnosed with ED, aged 10-21 years, at an academic center between January 1997 and April 2008, were reviewed.Of patients screened, 40.8% were reported to be engaging in SIB. Patients with a record of SIB were more likely to be female, have bulimia nervosa, or have a history of binge eating, purging, co-morbid mood disorder, substance use, or abuse. Patients who engaged in both binge eating and purging were more likely to report SIB than those engaged in restrictive behavior or either behavior alone. Providers documented screening for SIB in fewer than half of the patients. They were more likely to screen patients who fit a profile of a self-injurer: older patients who binge, purge, or had a history of substance use.SIB was common in this population, and supports extant literature on associations with bulimia nervosa, mood disorders, binge eating, purging, abuse, and substance use. Providers may selectively screen patients.

The incidence of obesity and its related disorders are increasing at a rate of pandemic proportions. Understanding the mechanisms behind the maintenance of energy balance is fundamental in developing treatments for clinical syndromes including obesity and diabetes. A neural network located in the nucleus of the solitary tract-area postrema complex in the hindbrain and the hypothalamus in the forebrain has long been implicated in the control of energy balance. In the hypothalamus this central neuronal network consists of small populations of nuclei with distinct functions such as the arcuate nucleus (ARH), the paraventricular nuclei of the hypothalamus (PVH), the dorsomedial (DMH), the ventromedial (VMH) and the lateral hypothalamus (LH). These hypothalamic areas form interconnected neuronal circuits that respond to fluctuations in energy status by altering the expression of neuropeptides, leading to changes in energy intake and expenditure. Regulation of these hypothalamic nuclei involves the actions of orexigenic peptides (ie ghrelin), which act to stimulate energy intake and decrease energy expenditure, and anorexigenic peptides (ie. leptin and insulin), which act to reduce energy intake and stimulate energy expenditure. Here we review the role of the ARH, DMH and PVH in the control of energy homeostasis and how recent advances in research technologies (Cre-loxP technology, optogenetics and pharmacogenetics) have shed light on the role of these hypothalamic nuclei in the control of energy balance. Such novel findings include the implication of ARH POMC and AgRP neurons in the browning of white adipose tissue to regulate energy expenditure as well as the likely existence of divergent hypothalamic pathways in the DMH and PVH in the control of food intake and energy expenditure.

Background: Much concern has been raised over pro-eating disorder (pro-ED) website communities, but little quantitative research has been conducted on these websites and their users. Objective: To examine associations between levels of pro-ED website usage, disordered eating behaviors, and quality of life. Methods: We conducted a cross-sectional, Internet-based survey of adult pro-ED website users. Main outcomes were Eating Disorder Examination Questionnaire (EDE-Q) and Eating Disorder Quality of Life (EDQOL) scores. Results: We included responses from 1291 participants; 1254 (97.13%) participants were female. Participants had an average age of 22.0 years and a mean body mass index of 22.1 kg/m2; 24.83% (296/1192) were underweight; 20.89% (249/1192) were overweight or obese. Over 70% of participants had purged, binged, or used laxatives to control their weight; only 12.91% (163/1263) were in treatment. Mean EDE-Q scores were above the 90th percentile and mean EDQOL scores were in the severely impaired range. When compared with moderate and light usage, heavy pro-ED website usage was associated with higher EDE-Q global (4.89 vs 4.56 for medium and 4.0 for light usage, P < .001) and EDQOL total scores (1.64 vs 1.45 for medium and 1.25 for light usage, P < .001), and more extreme weight loss behaviors and harmful post-website usage activities. In a multivariate model, the level of pro-ED website usage remained a significant predictor of EDE-Q scores. Conclusions: Pro-ED website visitors reported many disordered eating behaviors, although few had been treated. Heavy users reported poorer quality of life and more disordered eating behaviors. [J Med Internet Res 2012;14(5):e148]

Clinical studies have demonstrated a strong relationship between visceral fat content and metabolic diseases, such as type 2 diabetes and liver steatosis. Obese mouse models are an excellent tool to study metabolic diseases; however, there are limited methods for the noninvasive measurement of fat distribution in mice. Although micromagnetic resonance imaging and microcomputed tomography are the “gold standards” in the measurement of fat distribution, more economical and accessible methods are required. Dual energy X-ray absorptiometry (DEXA) is an effective method in characterizing fat content; however, it cannot discriminate between visceral and subcutaneous fat depots. We demonstrate that an evaluation of abdominal fat content measured by DEXA through the selection of one localized abdominal area strongly correlates with visceral fat content in C57BL/6J mice. We found that DEXA is able to measure fat pad volume ex vivo with high accuracy; however, the measurement of visceral fat in vivo shows an overestimation caused by subcutaneous tissue interference. The overestimation is almost constant for a wide range of values, and thus it is possible to correct the data for a more accurate estimation of visceral fat content. We demonstrate the utility of this technique in characterizing phenotypes of several obese mouse models ( ob/ob, db/db, MC4R-KO, and DIO) and evaluating the effect of treatments on visceral fat content in longitudinal studies. Additionally, we also establish abdominal obesity as a potential biomarker for metabolic abnormalities (liver fat accumulation, insulin resistance/diabetes) in mice, similar to that described in humans.

Objectives. The Internet offers Web sites that describe, endorse, and support eating disorders. We examined the features of pro–eating disorder Web sites and the messages to which users may be exposed. Methods. We conducted a systematic content analysis of 180 active Web sites, noting site logistics, site accessories, “thinspiration” material (images and prose intended to inspire weight loss), tips and tricks, recovery, themes, and perceived harm. Results. Practically all (91%) of the Web sites were open to the public, and most (79%) had interactive features. A large majority (84%) offered pro-anorexia content, and 64% provided pro-bulimia content. Few sites focused on eating disorders as a lifestyle choice. Thinspiration material appeared on 85% of the sites, and 83% provided overt suggestions on how to engage in eating-disordered behaviors. Thirty-eight percent of the sites included recovery-oriented information or links. Common themes were success, control, perfection, and solidarity. Conclusions. Pro–eating disorder Web sites present graphic material to encourage, support, and motivate site users to continue their efforts with anorexia and bulimia. Continued monitoring will offer a valuable foundation to build a better understanding of the effects of these sites on their users.

OBJECTIVE: The objective of this study was to compare the medical severity of adolescents who had eating disorders not otherwise specified (EDNOS) with those who had anorexia nervosa (AN) and bulimia nervosa (BN). METHODS: Medical records of 1310 females aged 8 through 19 years and treated for AN, BN, or EDNOS were retrospectively reviewed. Patients with EDNOS were subcategorized into partial AN (pAN) and partial BN (pBN) when they met all Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria but 1 for AN or BN, respectively. Primary outcome variables were heart rate, systolic blood pressure, temperature, and QTc interval on electrocardiogram. Additional physiologically significant medical complications were also reviewed. RESULTS: A total of 25.2% of females had AN, 12.4% had BN, and 62.4% had EDNOS. The medical severity of patients with EDNOS was intermediate to that of patients with AN and BN in all primary outcomes. Patients with pAN had significantly higher heart rates, systolic blood pressures, and temperatures than those with AN; patients with pBN did not differ significantly from those with BN in any primary outcome variable; however, patients with pAN and pBN differed significantly from each other in all outcome variables. Patients with pBN and BN had longer QTc intervals and higher rates of additional medical complications reported at presentation than other groups. CONCLUSIONS: EDNOS is a medically heterogeneous category with serious physiologic sequelae in children and adolescents. Broadening AN and BN criteria in pediatric patients to include pAN and pBN may prove to be clinically useful.

OBJECTIVE. Pro–eating disorder Web sites are communities of individuals who engage in disordered eating and use the Internet to discuss their activities. Pro-recovery sites, which are less numerous, express a recovery-oriented perspective. This pilot study investigated the awareness and usage of pro–eating disorder Web sites among adolescents with eating disorders and their parents and explored associations with health and quality of life.PATIENTS AND METHODS. This was a cross-sectional study of 698 families of patients (aged 10–22 years) diagnosed with an eating disorder at Stanford between 1997 and 2004. Anonymous surveys were mailed and offered in clinic. Survey content included questions about disease severity, health outcomes, Web site usage, and parental knowledge of eating disorder Web site usage.RESULTS. Surveys were returned by 182 individuals: 76 patients and 106 parents. Parents frequently (52.8%) were aware of pro–eating disorder sites, but an equal number did not know whether their child visited these sites, and only 27.6% had discussed them with their child. Most (62.5%) parents, however, did not know about pro-recovery sites. Forty-one percent of patients visited pro-recovery sites, 35.5% visited pro–eating disorder sites, 25.0% visited both, and 48.7% visited neither. While visiting pro–eating disorder sites, 96.0% reported learning new weight loss or purging techniques. However, 46.4% of pro-recovery site visitors also learned new techniques. Pro–eating disorder site users did not differ from nonusers in health outcomes but reported spending less time on school or schoolwork and had a longer duration of illness. Users of both pro–eating disorder and pro-recovery sites were hospitalized more than users of neither site.CONCLUSIONS. Pro–eating disorder site usage was prevalent among adolescents with eating disorders, yet parents had little knowledge of this. Although use of these sites was not associated with other health outcomes, usage may have a negative impact on quality of life and result in adolescents’ learning about and adopting disordered eating behaviors.

Purpose: To compare the clinical presentation of children with eating disorders (ED) to that of adolescents with ED. Methods: Demographic, medical, and psychiatric data of all 959 in- and outpatients (85 males, 874 females) 8 -19 years of age diagnosed with ED that presented to an academic center between 1997 and 2005 were examined via retrospective record review. Young patients (n 109) were defined as aged 13 years at presentation, and older patients (n 850) 13 years and 20 years. Results: Compared with older adolescents (mean 15.6 years, SD 1.4), younger patients (mean 11.6 years, SD 1.2) were more likely to be male ( 2 9.25, p .005) or diagnosed with eating disorder not otherwise specified (EDNOS) ( 2 5.09, p .05), and less likely to be diagnosed with bulimia nervosa (BN) ( 2 13.45, p .001). There were no significant differences in anorexia nervosa (AN) diagnoses between groups. Young patients were less likely to report purging ( 2 26.21, p .001), binge eating ( 2 26.53, p .001), diet pill ( 2 13.31, p .001) or laxative use ( 2 6.82, p .001) when compared with older teens. Young patients weighed less in percentage ideal body weight (p .05), had a shorter duration of disease (p .001), and had lost weight more rapidly than older adolescent patients (p .001). Conclusions: There are important diagnostic and gender differences in younger patients. Young ED patients presented at a lower percentage of ideal body weight and had lost weight more rapidly, which may put them at higher risk for future growth sequelae than their older counterparts. © 2006 Society for Adolescent Medicine. All rights reserved.

for atherosclerotic cardiovascular disease (ASCVD). No such WC cut-offs have been identified in adolescents, despite the consensus that risk factors for ASCVD are present in adolescents. The current study aims to identify WC cut-offs that will distinguish AfricanAmerican males ages 12 to 19 years with central adiposity who are at risk for ASCVD as defined by meeting metabolic syndrome (MetS) criteria. Methods: This study is a secondary data analysis using data from the CDC Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). A subpopulation of African-American males, ages 12 to 19 years with records containing data on WC and at least three of the following variables, were included in this study: fasting glucose, high density lipoprotein (HDL), serum triglyceride (TG), systolic blood pressure (SBP) and diastolic blood pressure (DBP). This resulted in 428 participants, with a weighted sample size of 1,688,814 African-American males. Participants were scored and grouped based on ASCVD risk factors as defined by the American Heart Association, National Cholesterol Education Program (NCEP) Adult Treatment Panel III as modified by Cook, et al. These include: fasting glucose 110 mg/ dL, HDL 40 mg/ dL, TG 110 mg/ dL, SBP and DBP 95% for age and gender. Individuals were categorized as low risk ( 3 risk factors) or high risk ( 3 risk factors) for ASCVD. Using WC as the independent variable, receiver-operating characteristics curve (ROC) analysis was used for each year of age to identify the optimal WC measurements that identify high-risk individuals. Results: Initial linear regression models confirm that WC predicts abnormal values in all dependent variables except fasting glucose. Results of ROC analysis are pending. Conclusions: It is expected that waist circumference values that identify three or more risk factors (thus defining MetS) will be considered the optimal cut-off point at which a clinical provider should begin screening for MetS. Sources of Support: None.