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.

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.

Neurologic Outcome Predictors in Pediatric Intracerebral Hemorrhage: A Prospective Study.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage is a considerable source of morbidity and mortality. This 3-center study describes outcomes of pediatric intracerebral hemorrhage and identifies 2-year neurological outcome predictors. METHODS: Children 29 days to 18 years of age presenting with intracerebral hemorrhage from March 2007 to May 2015 were enrolled prospectively. Exclusion criteria included trauma; intracranial tumor; hemorrhagic transformation of arterial ischemic stroke or cerebral sinovenous thrombosis; isolated subdural, epidural, or subarachnoid hemorrhage; and abnormal baseline neurological function. Intracerebral hemorrhage and total brain volumes were measured on neuroimaging. The Pediatric Stroke Outcome Measure assessed outcomes. RESULTS: Sixty-nine children were included (median age: 9.7 years; interquartile range: 2.2-14). Six children (9%) died during hospitalization. Outcomes in survivors were assessed at early follow-up in 98% (median 3.1 months; interquartile range: 3.1-3.8) and at later follow-up in 94% (median: 2.1 years; interquartile range: 1.3-2.8). Over a third had a significant disability at 2 years (Pediatric Stroke Outcome Measure >2). Total Pediatric Stroke Outcome Measure score improved over time (P=0.0003), paralleling improvements in the sensorimotor subscore (P=0.0004). Altered mental status (odds ratio, 13; 95% confidence interval, 3.9-46; P<0.001), hemorrhage volume ≥4% of total brain volume (odds ratio, 17; 95% confidence interval, 1.9-156; P=0.01), and intensive care unit length of stay (odds ratio, 1.1; 95% confidence interval, 1.0-1.2; P=0.002) were significantly associated with poor 2-year outcome. CONCLUSIONS: Over one third of children experienced significant disability at 2 years. Improvements in outcomes were driven by recovery of sensorimotor function. Altered mental status, hemorrhage volume ≥4% of total brain volume, and intensive care unit length of stay were independent predictors of significant disability at 2 years.

Incidence of Recurrence in Posterior Circulation Childhood Arterial Ischemic Stroke.

Importance: Childhood arterial ischemic stroke (CAIS) affects approximately 1.6 per 100 000 children per year, while stroke recurs in up to 20% of patients at 5 years. Factors determining the risk of recurrence are incompletely understood. Objective: To investigate the incidence of the recurrence of CAIS in the posterior and anterior circulations to determine if the risk differs between the 2 locations. Design, Setting, and Participants: A retrospective analysis of CAIS was conducted among children enrolled in a single-center prospective consecutive cohort at The Children's Hospital of Philadelphia between January 1, 2006, and January 1, 2015. Children with confirmed CAIS occurring between 29 days and 17.99 years were evaluated for inclusion. Patients were excluded if infarcts were located in both the anterior and posterior distributions or if CAIS occurred as a complication of intracranial surgery or brain tumor. Main Outcomes and Measures: Stroke recurrence. Results: The study population included 107 patients (75 boys [70.1%] and 32 girls [29.9%]; median age at AIS, 7.7 years [interquartile range, 3.1-13.6 years]). Sixty-one children had anterior circulation CAIS (ACAIS) and 46 had posterior circulation CAIS (PCAIS). Median follow-up was 20.9 months (interquartile range, 8.7-40.4 months). For ACAIS, recurrence-free survival was 100% at 1 month and 96% (95% CI, 85%-99%) at 1 and 3 years. For PCAIS, recurrence-free survival was 88% (95% CI, 75%-95%) at 1 month and 81% (95% CI, 66%-90%) at 1 and 3 years. The hazard ratio for recurrence after PCAIS compared with ACAIS was 6.4 (95% CI, 1.4-29.8; P = .02) in univariable analysis and 5.3 (95% CI, 1.1-26.4; P = .04) after adjusting for sex and cervical dissection. Conclusions and Relevance: We identified a subgroup of patients that comprise more than 80% of recurrences of CAIS. Three years after incident stroke, 19% of children with PCAIS had a recurrence compared with 4% of patients with ACAIS. Different mechanisms of stroke may account for this difference. Children with PCAIS may warrant increased monitoring. This study highlights the necessity for further research focused on recurrence prevention.

Intracranial aneurysms in sickle cell anemia: clinical and imaging findings.

BACKGROUND: Cerebral aneurysm formation is one of the cerebrovascular complications of sickle cell disease. OBJECTIVE: To report the clinical and imaging findings of intracerebral aneurysms and their treatment in pediatric and adult patients with sickle cell disease. METHODS: Review of clinical data via chart abstraction and radiologic features at the University of Pennsylvania and Children's Hospital of Philadelphia from 2000 to 2014 and review of the literature since 1942. RESULTS: Nineteen patients with aneurysms (2.7%) were found in 709 imaged patients, including 1.2% of imaged children and 10.8% of adults. A total of 44 aneurysms were detected (52.6% with multiple aneurysms, overall 2.3 per patient), 35 (79.5%) in the anterior circulation and 9 in the posterior circulation (20.4%). Thirty-eight unruptured aneurysms ranging in size from 2 to 6 mm and six ruptured aneurysms ranging in size from 3 to 9 mm in diameter were found. Of the patients with ruptured aneurysms, two were treated by stent-assisted coiling, two by clipping, and one patient with coiling. In the group without a rupture, one patient was treated by coil embolization and one patient with a peripheral middle cerebral artery aneurysm was treated by aneurysmectomy. Three pediatric patients with a previously normal MR angiogram demonstrated new aneurysm formation during the study. CONCLUSIONS: Adult patients with sickle cell disease have a high prevalence of aneurysm formation. Both pediatric and adult patients with sickle cell disease tend to develop multiple aneurysms with frequent involvement of atypical locations, in both anterior and posterior circulations.

Pediatric cavernous sinus thrombosis: A case series and review of the literature.

OBJECTIVE: To describe clinical characteristics, imaging findings, morbidity, and mortality in a single-center cohort of 12 pediatric cavernous sinus thrombosis cases and to review all cases available in recent English literature. METHODS: Clinical data and radiographic studies on 12 cases from our institution were analyzed retrospectively. A literature search and review was conducted, with additional cases pooled with the new cohort for an aggregate analysis. RESULTS: Twelve cases of cavernous sinus thrombosis in children from the Children's Hospital of Philadelphia between January 1, 2000, and December 31, 2013, were reviewed. All patients survived to discharge; 3 of 12 (25%) experienced neurologic morbidity. Contrast-enhanced MRI and contrast-enhanced head CT were 100% sensitive for detecting cavernous sinus thrombosis, while noncontrast time-of-flight magnetic resonance venography (TOF MRV) and noncontrast head CT were 0% sensitive. Literature review produced an additional 40 cases, and the aggregate mortality rate was 4 of 52 (8%) and morbidity rate was 10 of 40 (25%). Outcomes did not vary by treatment or with unilateral vs bilateral cavernous sinus involvement. There was a trend toward worse outcomes with fungal infections. CONCLUSION: Our case series demonstrates low morbidity and mortality with early, aggressive surgical, antimicrobial, and anticoagulation therapies. Although anticoagulation and surgery were not associated with significantly different outcomes, more study is needed.

Thrombotic events in critically ill children with myocarditis.

BACKGROUND: Children with myocarditis have multiple risk factors for thrombotic events, yet the role of antithrombotic therapy is unclear in this population. We hypothesised that thrombotic events in critically ill children with myocarditis are common and that children with myocarditis are at higher risk for thrombotic events than children with non-inflammatory dilated cardiomyopathy. METHODS: This is a retrospective chart review of all children presenting to a single centre cardiac intensive care unit with myocarditis from 1995 to 2008. A comparison group of children with dilated cardiomyopathy was also examined. Antithrombotic regimens were recorded. The primary outcome of thrombotic events included intracardiac clots and any thromboembolic events. RESULTS: Out of 45 cases with myocarditis, 40% were biopsy-proven, 24% viral polymerase chain reaction-supported, and 36% diagnosed based on high clinical suspicion. There were two (4.4%) thrombotic events in the myocarditis group and three (6.7%) in the dilated cardiomyopathy group (p = 1.0). Neither the use of any antiplatelet or anticoagulation therapy, use of intravenous immune globulin, presence of any arrhythmia, nor need for mechanical circulatory support were predictive of thrombotic events in the myocarditis, dilated cardiomyopathy, or combined groups. CONCLUSIONS: Thrombotic events in critically ill children with myocarditis and dilated cardiomyopathy occurred in 6% of the combined cohort. There was no difference in thrombotic events between inflammatory and non-inflammatory cardiomyopathy groups, suggesting that the decision to use antithrombotic prophylaxis should be based on factors other than the underlying aetiology of a child's acute decompensated heart failure.

Neuropsychological status in children after repair of acyanotic congenital heart disease.

OBJECTIVES: The majority of previous studies that described the neuropsychological effects of cardiopulmonary bypass (CPB) in children were performed after surgery in infancy for complex congenital heart disease (CHD). We sought to limit confounding variables and isolate potential independent effects of CPB by describing neuropsychological function in school-aged children after repair of acyanotic CHD. METHODS: This was a prospective study of patients who were aged 5 to 18 years and undergoing repair of acyanotic CHD. Neuropsychological testing battery included assessment of intelligence, memory, motor, attention, executive function, and behavior before and 6 months after CPB. The independent effects of anesthesia, surgery, and hospitalization on neuropsychological function were assessed by testing a surgical control group of patients who were undergoing repair of pectus deformities. In addition, an outpatient group of children with mild CHD were enrolled to assess the practice effects of serial testing. RESULTS: Patients included CPB (n = 35), surgical control (n = 19), and nonsurgical (n = 12). Groups were comparable in age, gender, and race and demonstrated similar unadjusted group mean scores on baseline and 6-month follow-up neuropsychological testing. When adjusted for practice effects, the CPB group performed similar to the non-CPB groups in all assessed neuropsychological domains, with the exception of 1 of 4 tests of executive function. CONCLUSIONS: When controlling for the non-CPB effects of surgery (eg, hospitalization, anesthesia, thoracotomy) and the practice effects of serial testing, there were no consistent independent effects of CPB on neuropsychological status in a cohort of children and adolescents 6 months after repair of acyanotic CHD.

Design of the silent cerebral infarct transfusion (SIT) trial.

BACKGROUND: Silent cerebral infarct (SCI) is the most common cause of serious neurological disease in sickle cell anemia (SCA), affecting approximately 22% of children. The goal of this trial is to determine whether blood transfusion therapy will reduce further neurological morbidity in children with SCI, and if so, the magnitude of this benefit. PROCEDURE: The Silent Cerebral Infarct Transfusion (SIT) Trial includes 29 clinical sites and 3 subsites, a Clinical Coordinating Center, and a Statistical and Data Coordinating Center, to test the following hypothesis: prophylactic blood transfusion therapy in children with SCI will result in at least an 86% reduction in the rate of subsequent overt strokes or new or progressive cerebral infarcts as defined by magnetic resonance imaging (MRI) of the brain. The intervention is blood transfusion versus observation. Two hundred and four participants (102 in each treatment assignment) will ensure 85% power to detect the effect necessary to recommend transfusion therapy (86% reduction), after accounting for 10% drop out and 19% crossover rates. MRI examination of the brain is done at screening, immediately before randomization and study exit. Each randomly assigned participant receives a cognitive test battery at study entry, 12-18 months later, and study exit and an annual neurological examination. Blood is obtained from all screened participants for a biologic repository containing serum and a renewable source of DNA. CONCLUSION: The SIT Trial could lead to a change in standard care practices for children affected with SCA and SCI, with a consequent reduction in neurological morbidity.

Diagnosis and treatment of vein of Galen aneurysmal malformations.

INTRODUCTION: Vein of Galen aneurysmal malformations (VGAM) are rare but clinically significant intracranial arteriovenous shunt lesions that most often present in neonates and infants. METHODS: Retrospective clinical data were collected for patients evaluated with a diagnosis of VGAM from 1994 to 2007. RESULTS: Thirteen patients with VGAM were evaluated from 1994 to 2007. Seven patients presented emergently with medically intractable cardiac failure, and six were treated in the first 2 weeks of life. Five children treated after this period (1.5-31 months of age) manifested enlarging head circumference, abnormal development, or subarachnoid hemorrhage. Eleven patients were managed endovascularly. Four disease or procedure-related complications occurred. Two complications were associated with poor outcome, both of which occurred in patients treated at less than 2 weeks of age. Two other patients experienced transient neurological deficits with no evidence of permanent sequelae. Outcome in the six patients treated emergently in the first 2 weeks of life included two patients who developed normally, one with mild to moderate neurological deficits, one with severe neurological deficits, and two deaths. Outcome in the five older patients (treated between 1.5 and 31 months) was considerably better than in the group treated early and included three with normal outcome and two with mild neurological deficits. CONCLUSIONS: Contemporary endovascular techniques remain the preferred treatment for VGAM in all age groups. Early diagnosis and multimodality treatment are essential for the best management and treatment of the complex constellation of clinical problems often arising from this disorder.

Predictors of outcome in childhood intracerebral hemorrhage: a prospective consecutive cohort study.

BACKGROUND AND PURPOSE: The purposes of this study were to describe features of children with intracerebral hemorrhage (ICH) and to determine predictors of short-term outcome in a single-center prospective cohort study. METHODS: A single-center prospective consecutive cohort study was conducted of spontaneous ICH in children aged 1 to 18 years from January 2006 to June 2008. Exclusion criteria were inciting trauma; intracranial tumor; isolated epidural, subdural, intraventricular, or subarachnoid hemorrhage; hemorrhagic transformation of ischemic stroke; and cerebral sinovenous thrombosis. Hospitalization records were abstracted. Follow-up assessments included outcome scores using the Pediatric Stroke Outcome Measure and King's Outcome Scale for Childhood Head Injury. ICH volumes and total brain volumes were measured by manual tracing. RESULTS: Twenty-two patients, median age 10.3 years (range, 4.2 to 16.6 years), had presenting symptoms of headache in 77%, focal deficits 50%, altered mental status 50%, and seizures 41%. Vascular malformations caused hemorrhage in 91%. Surgical treatment (hematoma evacuation, lesion embolization or excision) was performed during acute hospitalization in 50%. One patient died acutely. At a median follow-up of 3.5 months (range, 0.3 to 7.5 months), 71% of survivors had neurological deficits; 55% had clinically significant disability. Outcome based on Pediatric Stroke Outcome Measure and King's Outcome Scale for Childhood Head Injury scores was worse in patients with ICH volume >2% of total brain volume (P=0.023) and altered mental status at presentation (P=0.005). CONCLUSIONS: Spontaneous childhood ICH was due mostly to vascular malformations. Acute surgical intervention was commonly performed. Although death was rare, 71% of survivors had persisting neurological deficits. Larger ICH volume and altered mental status predicted clinically significant disability.

Mimics of childhood stroke: characteristics of a prospective cohort.

BACKGROUND: Little is known about the clinical features and spectrum of diagnoses in children with "stroke mimics," those with acute neurologic deficits but without cerebrovascular diseases. OBJECTIVES: Our goal was to describe patients with stroke mimics and to determine if clinical features predict benign diagnoses. METHODS: Our stroke consult team registered a prospective consecutive cohort of 143 patients with acute presentations suspicious for cerebrovascular disease from November 2003 to November 2004. Cases in which stroke was ruled out (stroke mimics) were reviewed for clinical features and diagnostic test results and were classified "benign" if there was no structural brain lesion and there was an expectation of complete recovery. RESULTS: Of the 143 cases evaluated for suspected stroke, 30 (21%) had stroke mimics. Presenting signs included seizure (n = 11), headache (n = 9), mental status change (n = 6), focal weakness (n = 14), and focal sensory change (n = 7). Eleven patients had "benign" diagnoses (3 migraine, 3 psychogenic diagnoses, 3 musculoskeletal abnormalities, 1 delirium, and 1 episodic vital sign changes). Nineteen patients had "not-benign" diagnoses (3 reversible posterior leukoencephalopathy syndrome, 3 neonatal seizures, 2 vascular anomalies, 2 inflammatory disease, 2 intracranial infection, 2 epilepsy, 2 metabolic stroke, 1 tumor, 1 drug toxicity, and 1 idiopathic intracranial hypertension). Except for the presence of seizures, there were no significant differences in presentation or risk factors between benign and not-benign cases. CONCLUSIONS: Many disorders mimic childhood stroke. History and clinical presentation often do not distinguish the one third of patients with benign disorders from the two thirds with more serious problems, necessitating timely comprehensive investigations, especially brain MRI.