Blood pressure in children with sickle cell disease is higher than in the general pediatric population.

BACKGROUND: Sickle cell disease (SCD) is associated with an increased risk of cardiovascular disease that may be due to a variety of possible risk factors, including abnormal blood pressure. Blood pressure (BP) of children and adolescents with SCD has been reported to be lower compared to the BP of the general pediatric population. METHODS: To confirm this prior observation, we compared reference BP values for children with SCD with reference BP values of the general pediatric population. We hypothesized that children with SCD do not have lower BPs than children without SCD. RESULTS: Systolic BP differed for both males and females, over the different age groups between pediatric subjects with and without SCD. Systolic BP was higher in children with SCD, in both obese and non-obese populations. Diastolic BP did not differ between the groups. CONCLUSIONS: Our analysis demonstrated that systolic BP values are indeed higher in children with SCD than in the general pediatric population. This finding is consistent with the most recent literature showing abnormal BP patterns in the SCD pediatric population utilizing 24-hour BP monitoring devices. This is an important step for recognizing abnormal BP as a risk factor for cardio- and neurovascular events in SCD.

Imaging Predictors of Neurologic Outcome After Pediatric Arterial Ischemic Stroke.

BACKGROUND AND PURPOSE: To assess whether initial imaging characteristics independently predict 1-year neurological outcomes in childhood arterial ischemic stroke patients. METHODS: We used prospectively collected demographic and clinical data, imaging data, and 1-year outcomes from the VIPS study (Vascular Effects of Infection in Pediatric Stroke). In 288 patients with first-time stroke, we measured infarct volume and location on the acute magnetic resonance imaging studies and hemorrhagic transformation on brain imaging studies during the acute presentation. Neurological outcome was assessed with the Pediatric Stroke Outcome Measure. We used univariate and multivariable ordinal logistic regression models to test the association between imaging characteristics and outcome. RESULTS: Univariate analysis demonstrated that infarcts involving uncinate fasciculus, angular gyrus, insular cortex, or that extended from cortex to the subcortical nuclei were significantly associated with poorer outcomes with odds ratios ranging from 1.95 to 3.95. All locations except the insular cortex remained significant predictors of poor outcome on multivariable analysis. When infarct volume was added to the model, the locations did not remain significant. Larger infarct volumes and younger age at stroke onset were significantly associated with poorer outcome, but the strength of the relationships was weak. Hemorrhagic transformation did not predict outcome. CONCLUSIONS: In the largest pediatric arterial ischemic stroke cohort collected to date, we showed that larger infarct volume and younger age at stroke were associated with poorer outcomes. We made the novel observation that the strength of these associations was modest and limits the ability to use these characteristics to predict outcome in children. Infarcts affecting specific locations were significantly associated with poorer outcomes in univariate and multivariable analyses but lost significance when adjusted for infarct volume. Our findings suggest that infarcts that disrupt critical networks have a disproportionate impact upon outcome after childhood arterial ischemic stroke.

Hypertension and childhood stroke.

Cerebrovascular disease (stroke) is one of the ten leading causes of death in children and adolescents. Multiple etiologies, from arteriopathies to prothrombic states, can cause stroke in youth. In adult stroke, hypertension has been shown to be the single most important modifiable risk factor. Although hypertension has not been strongly identified as a risk factor in childhood stroke to date, there is preliminary evidence that suggests that hypertension may also be associated with stroke in children. In this review, we summarize the literature that may link hypertension to stroke in the young. We have identified a series of barriers and limitations in the fields of pediatric hypertension and pediatric neurology that might explain why hypertension has been overlooked in childhood stroke. We suggest that hypertension may be a relevant risk factor that, alone or in combination with other multiple factors, contributes to the development of stroke in children. Currently, there are no consensus guidelines for the management of post-stroke hypertension in children. Thus, we recommend that blood pressure be assessed carefully in every child presenting with acute stroke in order to better understand the effects of hypertension in the development and the outcome of childhood stroke. We suggest a treatment algorithm to help practitioners manage hypertension after a stroke.

Prevalence and Risk Factors for Cerebral Palsy in Children With Congenital Heart Disease Based on Risk of Surgical Mortality.

BACKGROUND: Children with congenital heart disease (CHD) have a higher prevalence of motor impairment secondary to brain injury, resulting in cerebral palsy (CP). The purpose of this study is to determine the prevalence of CP in CHD in a single-center cohort, stratify risk based on surgical mortality using Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) categories and identify risk factors. METHODS: Retrospective cohort study of pediatric patients registered in the University of Florida (UF) Society of Thoracic Surgeons Congenital Heart Surgery database from 2006 to 2017 with a diagnosis of CHD who continued follow-up for more than two years at UF. RESULTS: A total of 701 children with CHD met inclusion criteria. Children identified to have CP were 54 (7.7%). Most common presentation was spastic hemiplegic CP with a Gross Motor Function Classification System of level 2. Analysis of surgical and intensive care factors between the two groups showed that children with CHD and CP had longer time from admission to surgery (P = 0.003), higher STAT categories 4 and 5 (P = 0.038), and higher frequency of brain injury and seizures (P < 0.001). Developmental disabilities and rehabilitation needs were significantly greater for children with CHD and CP when compared with those with CHD alone (P < 0.001). CONCLUSIONS: In our cohort, 7.7% children with CHD develop CP; this is significantly higher than the 2010 US population estimate of 0.3%. Our study suggests higher STAT categories, brain injury, and seizures are associated with developing CP in children with CHD.

Primary hypertension and neurocognitive and executive functioning in school-age children.

Data on neurocognitive function in hypertensive children are limited. In this review, we summarize recent preliminary, early studies that suggest that children with elevated blood pressure demonstrate evidence of worse performance on direct neurocognitive testing, as well as evidence of executive dysfunction based on parent ratings, compared with matched normotensive comparison groups. Furthermore, hypertensive children may have increased prevalence of learning disabilities as well as a blunted cerebrovascular reactivity compared with normotensive controls. Larger, prospective studies are needed to confirm and further explore these emerging but preliminary findings.

Hypertension impairs vascular reactivity in the pediatric brain.

BACKGROUND AND PURPOSE: Chronic hypertension impairs cerebrovascular regulation in adults, but its effects on the pediatric population are unknown. The objective of this study was to investigate cerebrovascular abnormalities in hypertensive children and adolescents. METHODS: Sixty-four children and adolescents aged 7 to 20 years underwent transcranial Doppler examinations of the middle cerebral artery at the time of rebreathing CO2. Time-averaged maximum mean cerebral blood flow velocity and end-tidal CO2 were used to quantify cerebrovascular reactivity during hypercapnia. Patients were clinically categorized as hypertensive, prehypertensive, or white coat hypertensive based on 24-hour ambulatory blood pressure measurements. Their reactivities were compared with 9 normotensive control subjects and evaluated against baseline mean blood pressure z-scores and loads. RESULTS: Untreated hypertensive children had significantly lower hypercapnic reactivity than normotensive children (2.556 +/- 1.832 cm/s x mm Hg versus 4.256 +/- 1.334 cm/s x mm Hg, P < 0.05). Baseline mean diastolic blood pressure z-scores (r = -0.331, P = 0.037) and diastolic blood pressure loads (r = -0.351, P = 0.026) were inversely related to reactivity. CONCLUSIONS: Untreated hypertensive children and adolescents have blunted reactivity to hypercapnia, indicating deranged vasodilatory reactivity. The inverse relationship between diastolic blood pressure indices and reactivity suggests that diastolic blood pressure may be a better predictor of cerebral end organ damage than systolic blood pressure.

Transcranial doppler ultrasonography (TCD) in infants with sickle cell anemia: baseline data from the BABY HUG trial.

BACKGROUND: Transcranial Doppler ultrasonography (TCD) is used to predict stroke risk in children with sickle cell anemia (SCA), but has not been adequately studied in children under age 2 years. PROCEDURE: TCD was performed on infants with SCA enrolled in the BABY HUG trial. Subjects were 7-17 months of age (mean 12.6 months). TCD examinations were successfully performed in 94% of subjects (n = 192). RESULTS: No patient had an abnormal TCD as defined in the older child (time averaged maximum mean TAMM velocity > or =200 cm/sec) and only four subjects (2%) had velocities in the conditional range (170-199 cm/sec). TCD velocities were inversely related to hemoglobin (Hb) concentration and directly related to increasing age. CONCLUSION: Determination of whether the TCD values in this very young cohort of infants with SCA can be used to predict stroke risk later in childhood will require analysis of exit TCD's and long-term follow-up, which is ongoing (ClinicalTrials.gov number, NCT00006400).

Papilledema in Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP): A Pediatric Case and Review of the Literature.

OBJECTIVE: To analyze the available literature on papilledema in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), report the first detailed pediatric case, and explore the underlying pathophysiology. METHODS: First, we conducted a comprehensive literature review of all cases of papilledema in CIDP. Next, we reviewed each case, incorporating only those including cerebrospinal fluid analysis into the results. Finally, we present our pediatric patient. RESULTS: Our literature review yielded a total of 9 adult and no pediatric cases. Cerebrospinal fluid protein and opening pressures were elevated in all cases. They were also elevated in our pediatric case. CONCLUSION: Prolonged periods of active immune-mediated inflammation is likely a cause of papilledema in adult CIDP, and possibly also in our pediatric case.

MRI abnormalities of the brain in one-year-old children with sickle cell anemia.

BACKGROUND: Sickle cell anemia (SCA) frequently results in damage to the central nervous system (CNS), but the age of onset of these effects is uncertain. We performed MRI examinations of the brain in infants with SCA, who were evaluated as part of the multicenter randomized double-blinded Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG). METHODS: Determination of eligibility for enrollment in the trial originally required baseline MRI and magnetic resonance angiography (MRA) of the brain. A standardized imaging protocol was utilized across eight clinical centers. MRI/MRA exams were reviewed by a panel of three neurology/neuroradiology readers and interpretations reported to the coordinating center. Results were correlated with patient age, gender, history, WBC count, platelet count, hemoglobin (Hb), HbF level, score on the Bayley Scales of Infant Development, and velocity on transcranial Doppler ultrasonography (TCD). RESULTS: Twenty-three subjects with HbSS were examined at average age 13.7 months (range 10-18 months); 13 were male. Three (13%, CI: 3-34%) had silent infarcts on MRI, two in the right frontal area and one bilaterally. None had MRA abnormalities. The lesions were correlated with increased right-sided TCD velocity and low HbF level, but not with age, history, Hb level, developmental score, or left-sided velocity. CONCLUSIONS: Silent brain infarcts occur in a small but significant number of infants with SCA as early as a year of age. This finding indicates a need for thorough evaluation of the CNS very early in life in children with SCA in order to develop timely intervention strategies.

Lacunar stroke and masked hypertension in an adolescent male.

Hypertension has not been strongly identified as a risk factor in childhood stroke. This report describes a case of a teenager with a lacunar stroke, the type often observed in adults with hypertensive-associated infarction, and masked hypertension. The patient had normal blood pressure on initial presentation, but on further investigation demonstrated ambulatory hypertension with evidence of hypertensive end-organ damage. This case suggests that hypertension may be a risk factor in children with stroke, especially in cases of lacunar infarct. Evaluation for possible hypertension should be undertaken thoroughly to identify children who may benefit from antihypertensive therapy and therefore, prevent recurrences.

Stroke and Hypertension in Children and Adolescents.

Hypertension is the single most important modifiable risk factor for adult stroke. Stroke mortality has significantly decreased over the last 5 decades; this decline has been mainly associated to improved blood pressure control. Though much less prevalent than in adults, stroke is an increasingly recognized cause of morbidity and mortality in children. Although hypertension has not been strongly identified as a risk factor in childhood stroke yet, there is preliminary evidence that suggests that elevated blood pressure may be associated with stroke in children. This review summarizes the literature that may link elevated blood pressure to the development of childhood ischemic and hemorrhagic stroke. The authors suggest that elevated blood pressure may be a significant risk factor that, alone or in combination with other multiple risk factors, leads to the development of stroke in childhood. It is therefore recommend that blood pressure be measured and assessed carefully in every child presenting with acute stroke.

Pediatric stroke: Opportunities and challenges in planning clinical trials.

A conference entitled "Towards the establishment of clinical trials in pediatric and newborn stroke" assembled stroke animal model researchers, pediatric stroke researchers, adult stroke trialists, and members of the Food and Drug Administration and National Institute of Neurological Disorders and Stroke to focus on the obstacles and opportunities for conducting randomized trials in pediatric stroke. The need for good prospective clinical data in newborn and pediatric stroke in regard to outcome and recurrence risk was stressed. For clinical trials, there should be a scientific rationale. Preclinical data should be as promising and as complete as possible. Adult data should be explored, both positive and negative. For medication trials, reasonable safety and bioavailability data for the agent in question should be available. Commitment of researchers, collaboration with colleagues in primary care, emergency rooms, and intensive care units, and most importantly the willingness to participate of children and their families will all be crucial. Most children with cancer in the United States are enrolled in clinical trials and have an outcome superior to the adult patient with cancer, who is less likely to be enrolled in a trial. We should strive for enrollment and outcome results in pediatric stroke similar to those found in pediatric oncology trials.

Lessons from adult stroke trials.

Before designing epidemiologic, genetic, or treatment trials in pediatric stroke, we should learn from adult trials which preceded. Adult trialists state that there is a need for improved animal models to mimic human disease. Dose-response curves with blinded outcome measures would improve preclinical data. Functional and histologic outcome measures would improve the animal model. In regard to human Phase 2 medication trials, safety, delivery, end points, and surrogate markers are necessary. The detection of biologic activity can be defined in Phase 2B trials. For Phase 3 trials, the experiment needs to be simple with global outcome measures as end points. New statistical designs such as futility analysis may improve and streamline trials in both adults and children. Clinical trials are a long process, and care needs to be incorporated at every step. Why is there a propensity of failed studies for acute ischemic stroke in adults? The reasons include (a) the animal model fails us, (b) the Phase 2 trials are ineffective in defining dose, and (c) the Phase 3 trials are poorly done. Because clinical trials, more often than not, fail to give positive (effective treatment) results, it seems reasonable to attempt to learn from others' past experiences before initiating pediatric stroke trials.

Spinal cord infarction in meningitis: polygenic risk factors.

We report a male with spinal cord infarction and tetraplegia after Streptococcus pneumoniae meningitis. He was subsequently found to have both a Chiari I malformation and factor V Leiden mutation. A literature search was conducted to identify previously reported cases of pediatric spinal cord infarction associated with acute bacterial meningitis, anatomic brain anomalies, and hypercoagulability disorders. This article is the first report of spinal cord infarction in a child with hypercoagulability disorder and structural brain anomaly in the setting of acute bacterial meningitis. The confluence of infection, inflammation, localized pressure, and predisposition to hypercoagulability produced unique conditions resulting in infarction of the cervical spine. This report emphasizes the polygenic nature of the expression of spinal cord infarction.

Young Patients With Diabetes Have Decreased Cerebrovascular Reactivity Under Hypercapneic Conditions.

OBJECTIVE: Adult diabetic patients have an abnormal cerebrovascular response to hypercapnia, but there are few studies focused on diabetes mellitus type 1 and cerebral blood flow in pediatric or adolescent patients. We hypothesize that young patients with diabetes exhibit a different response to hypercapnia than normal control counterparts. METHODS: Using transcranial Doppler techniques, we compared young diabetic patients with healthy controls by measuring cerebral blood velocity before and during carbon dioxide challenge. RESULTS: Subjects with diabetes had decreased cerebral blood velocity reactivity when compared with the control group (P = 0.005). CONCLUSION: Our results suggest cerebrovascular dysfunction in diabetic patients beginning at an early age. The possibility of long-term implications for cerebrovascular disease demonstrates the need for further studies in the pediatric and adolescent diabetic population to better understand this prevalent condition.

Brain imaging and electrophysiology biomarkers: is there a role in poverty and education outcome research?

BACKGROUND: Prekindergarten educational interventions represent a popular approach to improving educational outcomes, especially in children from poor households. Children from lower socioeconomic groups are at increased risk for delays in cognitive development that are important for school success. These delays, which may stem from stress associated with poverty, often develop before kindergarten. Early interventions have been proposed, but there is a need for more information on effectiveness. By assessing socioeconomic differences in brain structure and function, we may better be able to track the neurobiologic basis underlying children's cognitive improvement. METHODS: We conducted a review of the neuroimaging and electrophysiology literature to evaluate what is known about differences in brain structure and function as assessed by magnetic resonance imaging and electrophysiology and evoked response potentials among children from poor and nonpoor households. RESULTS: Differences in lower socioeconomic groups were found in functional magnetic resonance imaging, diffusion tensor imaging, and volumetric magnetic resonance imaging as well as electroencephalography and evoked response potentials compared with higher socioeconomic groups. CONCLUSIONS: The findings suggest a number of neurobiologic correlates for cognitive delays in children who are poor. Given this, we speculate that magnetic resonance imaging and electrophysiology parameters might be useful as biomarkers, after more research, for establishing the effectiveness of specific prekindergarten educational interventions. At the very least, we suggest that to level the playing field in educational outcomes, it may be helpful to foster communication and collaboration among all professionals involved in the care and education of children.

Executive function and cerebrovascular reactivity in pediatric hypertension.

Primary hypertension is associated with decreased performance on neurocognitive testing and a blunted cerebrovascular reactivity to hypercapnia. Parents of 14 children with hypertension and prehypertension completed the Behavior Rating Inventory of Executive Functions. Children underwent 24-hour ambulatory blood pressure monitoring and transcranial Doppler with reactivity measurement using time-averaged maximum mean velocity and end-tidal carbon dioxide during hypercapnia-rebreathing test. Comparing the reactivity slope for the patients to historical controls showed a statistically significant difference (t = -5.19, df = 13, P < .001), with lower slopes. Pearson correlations of the Behavior Rating Inventory of Executive Functions scores with the reactivity slopes showed a statistically significant inverse relationship with Behavioral Regulation Index (r = -.60, P = .02), Metacognition Index (r = -.40, P = .05), and the Global Executive Component (r = -.53, P = .05). Children with hypertension have decreased executive function, and this correlates to low transcranial Doppler-reactivity slopes, suggesting that the brain is a target organ in hypertensive children.