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.

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.

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.

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.

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.

Cerebral Sinovenous Thrombosis.

Cerebral sinovenous thrombosis (CSVT) is a rare but serious cerebrovascular disorder affecting children from the newborn period through childhood and adolescence. The incidence is estimated at 0.6/100,000/year, with 30-50% occurring in newborns. Causes are diverse and are highly age dependent. Acute systemic illness is the dominant risk factor among newborns. In childhood CSVT, acute infections of the head and neck such as mastoiditis are most common, followed by chronic underlying diseases such as nephrotic syndrome, cancer, and inflammatory bowel disease. Signs and symptoms are also age related. Seizures and altered mental status are the commonest manifestations in newborns. Headache, vomiting, and lethargy, sometimes with 6th nerve palsy, are the most common symptoms in children and adolescents. Recent multicenter cohort studies from North America and Europe have provided updated information on risk factors, clinical presentations, treatment practices, and outcomes. While systemic anticoagulation is the most common specific treatment used, there are wide variations and many uncertainties even among experts concerning best practice. The treatment dilemma is especially pronounced for neonatal CSVT. This is due in part to the higher prevalence of intracranial hemorrhage among newborns on the one hand, and the clear evidence that newborns suffer greater long-term neurologic morbidity on the other hand. With the advent of widespread availability and acceptance of acute endovascular therapy for arterial ischemic stroke, there is renewed interest in this therapy for children with CSVT. Limited published evidence exists regarding the benefits and risks of these invasive therapies. Therefore, the authors of current guidelines advise reserving this therapy for children with progressive and severe disease who have failed optimal medical management. As research focused on childhood cerebrovascular disease continues to grow rapidly, the future prospects for improving knowledge about this disorder should be good.

Pediatric cerebral sinovenous thrombosis following cranial surgery.

PURPOSE: Pediatric cerebral sinovenous thrombosis (CSVT) is an important, though less common subtype of pediatric stroke. It has been linked to several risk factors, including cranial procedures, with few studies highlighting this relationship. The aim of this study was to characterize the diagnosis and treatment of CSVT after cranial surgery. METHODS: An institutional pediatric stroke research database was used to identify all CSVT cases diagnosed within 30 days of cranial surgery from November 2004 to December 2014. Thirteen subjects were retrospectively analyzed for clinical presentation, surgical details, radiographic characteristics, laboratory study results, treatment, and outcome. Diagnostic testing and treatment adhered to a consensus-based institutional stroke protocol. RESULTS: Cranial vault reconstruction, subdural empyema evacuation, and tumor resection were each observed in three subjects. Eleven (85%) subjects had sinus exposure during surgery, and eight (73%) developed thrombus in a sinus within or adjacent to the operative field. Two (15%) had documented iatrogenic sinus injury. On post-operative testing, ten (77%) subjects had prothrombotic abnormalities. Seven (54%) were treated with anti-coagulation therapy (ACT) starting on a median of post-operative day (POD) 3 (IQR 1-3) for a median of 2.9 months (IQR 2.4-5.4). Median time to imaging evidence of partial or complete recanalization was 2.4 months (IQR 0.7-5.1). No symptomatic hemorrhagic complications were encountered. CONCLUSIONS: Pediatric CSVT may be encountered after cranial surgery, and decisions related to anti-coagulation are challenging. The risk of CSVT should be considered in pre-surgical planning and post-operative evaluation of cases with known risk factors. In our study, judicious use of ACT was safe in the post-operative period.

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.

Moyamoya syndrome associated with Alagille syndrome: outcome after surgical revascularization.

Vasculopathy is well-described in Alagille syndrome (ALGS); however, few data exist regarding neurosurgical interventions. We report 5 children with ALGS with moyamoya who underwent revascularization surgery. Postsurgical complications included 1 stroke and 1 death from thalamic hemorrhage. Global function improved in survivors. Revascularization is reasonably safe in patients with ALGS and may improve neurologic outcomes.

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.

Headache as a risk factor for neurovascular events in pediatric brain tumor patients.

OBJECTIVE: To determine whether severe recurrent headache is a risk factor for neurovascular events in children who received radiation for brain tumors. METHODS: This is a retrospective cohort study of children with brain tumors who received cranial irradiation at a large tertiary care center, aged 0-21 years at diagnosis, with initial treatment between January 1, 1993 and December 31, 2002, and 2 or more follow-up visits. Patients were considered to have severe recurrent headache if this appeared as a complaint on 2 or more visits. Headaches attributed to tumor progression, shunt malfunction, or infection, or appearing at the end of life, were excluded. Medical records were reviewed for events of stroke or TIA. RESULTS: Of 265 subjects followed for a median of 6.0 years (interquartile range 1.7-9.2 years), stroke or TIA occurred in 7/37 (19%) with severe headaches compared to 6/228 (3%) without these symptoms (hazard ratio 5.3, 95% confidence interval 1.8-15.9, p = 0.003). Adjusting for multiple variables did not remove the significance of this risk. Median time to first neurovascular event for the entire cohort was 4.9 years (interquartile range 1.7-5.5 years). CONCLUSIONS: Severe recurrent headache appears to be a risk factor or predictor for subsequent cerebral ischemia in pediatric brain tumor survivors treated with radiation. This finding has clinical implications for both monitoring survivors and targeting a specific population for primary stroke prevention.

A novel mutation in the mitochondrial DNA cytochrome b gene (MTCYB) in a patient with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes syndrome.

Mutations in the mitochondrial DNA cytochrome b gene (MTCYB) have been commonly associated with isolated mitochondrial myopathy and exercise intolerance, rarely with multisystem disorders, and only once with a parkinsonism/mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) overlap syndrome. Here, we describe a novel mutation (m.14864 T>C) in MTCYB in a 15-year-old girl with a clinical history of migraines, epilepsy, sensorimotor neuropathy, and strokelike episodes, a clinical picture reminiscent of MELAS.  The mutation, which changes a highly conserved cysteine to arginine at amino acid position 40 of cytochrome b, was heteroplasmic in muscle, blood, fibroblasts, and urinary sediment from the patient but absent in accessible tissues from her asymptomatic mother. This case demonstrates that MTCYB must be included in the already long list of mitochondrial DNA genes that have been associated with the MELAS phenotype.

Cranial irradiation increases risk of stroke in pediatric brain tumor survivors.

BACKGROUND AND PURPOSE: The purposes of this study were to determine the incidence of neurovascular events as late complications in pediatric patients with brain tumor and to evaluate radiation as a risk factor. METHODS: Patients were ascertained using the tumor database of a pediatric tertiary care center. Included patients had a primary brain tumor, age birth to 21 years, initial treatment January 1, 1993, to December 31, 2002, and at least 2 visits with neuro-oncology. Radiation exposure included: whole brain, whole brain plus a focal boost, or focal brain. The primary outcome was stroke or transient ischemic attack. RESULTS: Of 431 subjects, 14 had 19 events of stroke or transient ischemic attack over a median follow-up of 6.3 years. The incidence rate was 548/100 000 person-years. Overall, 61.5% of subjects received radiation, including 13 of 14 subjects with events. Median time from first radiation to first event was 4.9 years. The stroke/transient ischemic attack hazard ratio for any brain irradiation was 8.0 (95% CI, 1.05-62; P=0.045); for the circle of Willis, radiation was 9.0 (95% CI, 1.2-70; P=0.035); and for focal noncircle of Willis, radiation was 3.4 (95% CI, 0.21-55; P=0.38). CONCLUSIONS: The incidence of neurovascular events in this population is 100-fold higher than in the general pediatric population and cranial irradiation is an important risk factor. By defining the incidence of this late effect, physicians are better able to counsel parents regarding treatment, monitor patients at risk, and target a population for primary stroke prevention in future studies.

Bleeding and thrombotic emergencies in pediatric cardiac intensive care: unchecked balances.

Children in the cardiac intensive care unit (CICU) with congenital or acquired heart disease are at risk for hematologic complications, both hemorrhage and thrombosis. The overall incidence of hematologic complications in the CICU is unknown, but risk factors and target groups have been identified where the essential physiologic balance between bleeding and clotting has been disrupted. Although the best management of life-threatening bleeding and clotting is prevention, the cardiac intensivist is often faced with managing life-threatening hematologic events involving patients from within the unit or those who present from outside. Part I of this review deals with the propensity of children with congenital and acquired heart disease to complications of both bleeding and clotting, and includes discussions of perioperative bleeding, thromboses in single-ventricle patients, clotting of Blalock-Taussig shunts and thrombotic complications of mechanical valves. Part II deals with the subject of stroke in children with heart disease. Part III reviews monitoring the effectiveness of anticoagulation and thrombolysis in the CICU. Currently available diagnostics modalities, medications and management strategies are reviewed and future directions discussed.

Outcome following decompressive craniectomy for malignant middle cerebral artery infarction in children.

AIM: Mortality from malignant middle cerebral artery infarction (MMCAI) approaches 80% in adult series. Although decompressive craniectomy decreases mortality and leads to an acceptable outcome in selected adult patients, there are few data on MMCAI in children with stroke. This study evaluated the frequency of MMCAI and the use of decompressive craniectomy in children. METHOD: We retrospectively reviewed cases of MMCAI from five pediatric tertiary care centers. RESULTS: Ten children (two females, eight males; median age 9y 10mo, range 22mo-14y) had MMCAI, with a median Glasgow Coma Scale score of 6 (range 3-9). MMCAI represented fewer than 2% of cases of pediatric arterial ischemic stroke. Three patients who did not undergo decompression, all of whom had monitoring of intracranial pressure, developed intractable intracranial hypertension, and fulfilled criteria for brain death. In contrast, seven patients underwent decompressive craniectomy and survived, with rapid improvement in their level of consciousness postoperatively. All seven survivors now walk independently with mild to moderate residual hemiparesis and speak fluently, even though four had left-sided infarcts. INTERPRETATION: Decompressive craniectomy can lead to a moderately good outcome for children with MMCAI and should be considered, even with symptomatic stroke and deep coma. Monitoring of intracranial pressure may delay life-saving treatment.

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.