Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain.
To test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient.
Cross-sectional and cohort study of children with SCA screened by magnetic resonance imaging (MRI) of the brain for a randomized clinical trial.
Clinical trial setting in tertiary care centers.
Asymptomatic children with SCA without known stroke, neurologic injury, or epilepsy not receiving treatment with transfusions or hydroxyurea.
Main Outcome Measure
Incidence of ASCIEs calculated using single diffusion-weighted MRI scans (acute ischemic events that occurred within 10 days of the MRI).
Acute silent cerebral ischemic events were detected on 1.3% of MRIs (10 of 771) in 652 children (mean age, 10.0 years), with an incidence of 47.3 events per 100 patient-years (95% CI, 22.7–87.2). Two of 10 children with ASCIEs had follow-up MRIs of the brain; only 1 had silent cerebral infarction in the same location as the previously detected ASCIE.
Children with SCA experience ongoing (chronic, intermittent) cerebral ischemia, sometimes reversible, far more frequently than previously recognized. The brain in SCA is at constant threat of ischemia.
Previous studies of pediatric intracerebral hemorrhage have investigated isolated intraparenchymal hemorrhage. We investigated whether detailed assessment of intraventricular hemorrhage enhanced outcome prediction after intracerebral hemorrhage. We prospectively enrolled 46 children, full-term to 17 years, median age 2.7 years with spontaneous intraparenchymal hemorrhage and/or intraventricular hemorrhage. Outcome was assessed with the King’s Outcome Scale for Childhood Head Injury. Twenty-six (57%) had intraparenchymal hemorrhage, 10 (22%) had pure intraventricular hemorrhage, and 10 (22%) had both. There were 2 deaths, both with intraparenchymal hemorrhage + intraventricular hemorrhage volume ≥4% of total brain volume. Presence of intraventricular hemorrhage was not associated with poor outcome, but hydrocephalus showed a trend (p=0.09) toward poor outcome. In receiver operating characteristic curve analysis, combined intraparenchymal hemorrhage + intraventricular hemorrhage volume also showed a trend toward better outcome prediction than intraparenchymal hemorrhage volume alone. Although not an independent outcome predictor, future studies should assess intraventricular hemorrhage qualitatively and quantitatively.
intracerebral hemorrhage; pediatric hemorrhage; intraparenchymal hemorrhage; intraventricular hemorrhage
Clinical neurologic signs considered predictive of adverse outcome after pediatric cardiac arrest (CA) may have a different prognostic value in the setting of therapeutic hypothermia (TH). We aimed to determine the prognostic value of motor and pupillary responses in children treated with TH after CA.
Prospective cohort study.
Pediatric ICU in tertiary care hospital.
Children treated with TH after CA.
Measurements and Main Results
Thirty-five children treated with TH after CA were prospectively enrolled. Examinations were performed by emergency medicine physicians and intensive care unit bedside nurses. Examinations were performed after resuscitation, 1 hour after achievement of hypothermia, during the last hour of hypothermia, 1 hour after achievement of normothermia, after 24 hours of normothermia, and after 72 hours of normothermia. The primary outcome was unfavorable outcome at ICU discharge, defined as a Pediatric Cerebral Performance Category (PCPC) score of 4–6 at hospital discharge. The secondary outcome was death (PCPC = 6). The associations between exam responses and unfavorable outcomes (as both PCPC 4,5,6 and PCPC 6) are presented as positive predictive values (PPV), for both all subjects and subjects not receiving paralytics. Statistical significance for these comparisons was determined using Fisher’s exact test. At all examination times and examination categories PPV is higher for the unfavorable outcome PCPC 4,5,6 than PCPC 6. By normothermia hour 24, absent motor and pupil responses were highly predictive of unfavorable outcome (PCPC 4,5,6) (PPV 100% and p<0.03 for all categories), while at earlier times the predictive value was lower.
Absent motor and pupil responses are more predictive of unfavorable outcome when defined more broadly than when defined as only death. Absent motor and pupil responses during hypothermia and soon after return of spontaneous circulation were not predictive of unfavorable outcome while absent motor and pupil responses once normothermic were predictive of unfavorable short-term outcome. Further study is needed using more robust short-term and long-term outcome measures.
Therapeutic Hypothermia; Neurological Examination; Pediatric; Hypoxic Ischemic Encephalopathy; Cardiac Arrest; Prognosis
To define incidence of seizures as a presenting symptom of acute arterial ischemic stroke (AIS) in children and to determine whether younger age, infarct location, or AIS etiology were risk factors for seizure at AIS presentation.
Children aged 2 months to 18 years presenting with AIS from January 2005 to December 2008 were identified from a single center prospective pediatric stroke registry. Clinical data were abstracted, and a neuroradiologist reviewed imaging studies.
Among 60 children who met inclusion criteria, seizures occurred at stroke presentation in 13 (22%). Median age was significantly younger in children who presented with seizures than in those who did not (1.1 versus 10 years, p=0.0009). Seizures were accompanied by hemiparesis in all patients. Three of four children with clinically overt seizures at presentation also had non-convulsive seizures on continuous EEG monitoring.
About one-fifth of children with acute AIS present with seizures. Seizures were always accompanied by focal neurologic deficits. Younger age was a risk factor for seizures at presentation. Seizure at presentation was not associated with infarct location or etiology. Non-convulsive seizures may occur during the acute period.
EEG; non-convulsive seizures; hemiparesis
Background and Purpose: Larger infarct volume as a percent of supratentorial brain volume (SBV) predicts poor outcome and hemorrhagic transformation in childhood arterial ischemic stroke (AIS). In perinatal AIS, higher scores on a modified pediatric version of the Alberta Stroke Program Early CT Score using acute MRI (modASPECTS) predict later seizure occurrence. The objectives were to establish the relationship of modASPECTS to infarct volume in perinatal and childhood AIS and to establish the interrater reliability of the score. Methods: We performed a cross sectional study of 31 neonates and 40 children identified from a tertiary care center stroke registry with supratentorial AIS and acute MRI with diffusion weighted imaging (DWI) and T2 axial sequences. Infarct volume was expressed as a percent of SBV using computer-assisted manual segmentation tracings. ModASPECTS was performed on DWI by three independent raters. The modASPECTS were compared among raters and to infarct volume as a percent of SBV. Results: ModASPECTS correlated well with infarct volume. Spearman rank correlation coefficients (ρ) for the perinatal and childhood groups were 0.76, p < 0.001 and 0.69, p < 0.001, respectively. Excluding one perinatal and two childhood subjects with multifocal punctate ischemia without large or medium sized vessel stroke, ρ for the perinatal and childhood groups were 0.87, p < 0.001 and 0.80, p < 0.001, respectively. The intraclass correlation coefficients for the three raters for the neonates and children were 0.93 [95% confidence interval (CI) 0.89–0.97, p < 0.001] and 0.94 (95% CI 0.91–0.97, p < 0.001), respectively. Conclusion: The modified pediatric ASPECTS on acute MRI can be used to estimate infarct volume as a percent of SBV with a high degree of validity and interrater reliability.
modified pediatric ASPECTS; arterial ischemic stroke; MRI; infarct volume; childhood; perinatal
Background and Purpose
To describe the occurrence of hemorrhagic transformation (HT) among children with arterial ischemic stroke (AIS) within 30 days after symptom onset and to describe clinical factors associated with HT.
Sixty-three children age 1 month to 18 years with AIS between January 2005 and November 2008 were identified from a single center prospective pediatric stroke registry. All neuroimaging studies within 30 days of stroke were reviewed by a study neuroradiologist. Hemorrhage was classified according to the European Cooperative Acute Stroke Study-1 definitions. Association of HT with clinical factors, systemic anticoagulation, stroke volume, and outcome was analyzed.
HT occurred in 19 of 63 children (30%; 95%CI 19–43%), only 2 (3%) of whom were symptomatic. Hemorrhage classification was HI1 in 14, HI2 in 2, PH1 in 2, and PH2 in 1. HT was less common in children with vasculopathy (RR 0.27; 95%CI 0.07–1.06; p=0.04) than in those with other stroke mechanisms. HT was not significantly associated with anticoagulation versus antiplatelet therapy (RR 0.6; 95%CI 0.2–1.5; p=0.26) but was associated with larger infarct volumes (p=0.0084). In multivariable analysis, worse PSOM scores were associated with infarct volume ≥5% of total supratentorial brain volume (OR 4.0; 95%CI 1.1–15; p=0.04), and a trend existed toward association of worse PSOM scores with HT (OR 4.0; 95%CI 0.9–18; p=0.07).
HT occurred in 30% of children with AIS within 30 days. Most hemorrhages were petechial and asymptomatic. Infarct volume was associated with HT and worse outcome.
hemorrhagic transformation; arterial ischemic stroke; anticoagulation; pediatric
Background and Purpose
Stroke is an important cause of death and disability among children. Clinical trials for childhood stroke require a valid and reliable acute clinical stroke scale. We evaluated inter-rater reliability (IRR) of a pediatric adaptation of the NIH Stroke Scale (PedNIHSS).
The PedNIHSS was developed by pediatric and adult stroke experts by modifying each item of the adult NIH Stroke Scale (NIHSS) for children, retaining all exam items and scoring ranges of the NIHSS. Children 2–18 years with acute arterial ischemic stroke were enrolled in a prospective cohort study from 15 North American sites January 2007-October 2009. Examiners were child neurologists certified in the adult NIHSS. Each subject was examined daily for 7 days or until discharge. A subset of patients at 3 sites was scored simultaneously and independently by 2 study neurologists.
IRR testing was performed in 25 of 113 a median of 3 days (interquartile range [IQR] 2–4 days) after symptom onset. Patient demographics, total initial PedNIHSS scores, risk factors and infarct characteristics in the IRR subset were similar to the non-IRR subset. The two raters’ total scores were identical in 60% and within one point in 84%. IRR was excellent as measured by concordance correlation coefficient of 0.97 (95%CI; 0.94–0.99); ICC of 0.99 (95%CI 0.97–0.99); precision measured by Pearson ρ of 0.97; and accuracy measured by the bias correction factor (Cb) of 1.0.
There was excellent IRR of the PedNIHSS in a multicenter prospective cohort performed by trained child neurologists.
sischemic stroke; childhood; outcome; validation; stroke scale
Background and Purpose
To describe features of children with intracerebral hemorrhage (ICH) and to determine predictors of short-term outcome in a single-center prospective cohort study.
Single-center prospective consecutive cohort study of spontaneous ICH in children age 1-18 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 (PSOM) and King's Outcome Scale for Childhood Head Injury (KOSCHI). ICH volumes and total brain volumes (TBV) were measured by manual tracing.
Twenty-two patients, median age of 10.3 years (range 4.2-16.6 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 median follow-up of 3.5 months (range 0.3-7.5 months), 71% of survivors had neurological deficits; 55% had clinically significant disability. Outcome based on PSOM and KOSCHI scores was worse in patients with ICH volume >2% of TBV (p=0.023) and altered mental status at presentation (p = 0.005).
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.
intracerebral hemorrhage; outcome; childhood; vascular malformation
Cumulative effects of repetitive mild head injury in the pediatric population are unknown. We have developed a cognitive composite dysfunction score that correlates white matter injury severity in neonatal piglets with neurobehavioral assessments of executive function, memory, learning, and problem solving. Anesthetized 3- to 5-day-old piglets were subjected to single (n = 7), double one day apart (n = 7), and double one week apart (n = 7) moderate (190 rad/s) rapid non-impact axial rotations of the head and compared to instrumented shams (n = 7). Animals experiencing two head rotations one day apart had a significantly higher mortality rate (43%) compared to the other groups and had higher failures rates in visual-based problem solving compared to instrumented shams. White matter injury, assessed by β-APP staining, was significantly higher in the double one week apart group compared to that with single injury and sham. Worsening performance on cognitive composite score correlated well with increasing severity of white matter axonal injury. In our immature large animal model of TBI, two head rotations produced poorer outcome as assessed by neuropathology and neurobehavioral functional outcomes compared to that with single rotations. More importantly, we have observed an increase in injury severity and mortality when the head rotations occur 24 h apart compared to 7 days apart. These observations have important clinical translation to infants subjected to repeated inflicted head trauma.
axonal injury; neurobehavioral assessment; pediatric brain injury; traumatic brain injury
To investigate the feasibility and utility of arterial spin labeling (ASL) perfusion MRI in characterizing alterations of cerebral blood flow (CBF) in pediatric patients with arterial ischemic stroke (AIS).
Materials and Methods
Ten children with AIS were studied within 4–125 hours following symptom onset, using a pulsed ASL (PASL) protocol attached to clinically indicated MR examinations. The inter-hemisphere perfusion deficit (IHPD) was measured in predetermined vascular territories and infarct regions of restricted diffusion, which were compared with the degree of arterial stenosis and volumes of ischemic infarcts.
Interpretable CBF maps were obtained in all 10 patients, showing simple lesion in 9 patients (5 hypoperfusion, 2 hyperperfusion, and 2 normal perfusion) and complex lesions in one patient. Both acute and follow-up infarct volumes were significantly larger in cases with hypoperfusion than in either hyper-or normal perfusion cases. The IHPD was found to correlate with the degree of stenosis, diffusion lesion and follow-up T2 infarct volumes. Mismatch between perfusion and diffusion lesions was observed. Brain regions presenting delayed arterial transit effects were tentatively associated with positive outcome.
This study demonstrates the clinical utility of ASL in the neuroimaging diagnosis of pediatric AIS.
Ischemic stroke; Magnetic resonance imaging; Perfusion; Pediatrics
Neurobehavioral deficits in higher cortical systems have not been described previously in a large animal model of diffuse brain injury. Anesthetized 3–5 day old piglets were subjected to either mild (142 rad/sec) or moderate (188 rad/sec) rapid non-impact axial rotations of the head. Multiple domains of cortical function were evaluated 5 times during the 12 day post-injury period using tests of neurobehavioral function devised for piglets. There were no observed differences in neurobehavioral outcomes between mild injury pigs (N = 8) and instrumented shams (N = 4). Moderately injured piglets (N = 7) had significantly lower interest in exploring their environment and had higher failure rates in visual-based problem solving compared to instrumented shams (N = 5) on Day 1 and 4 after injury. Neurobehavioral functional deficits correlated with neuropathologic damage in the neonatal pigs after inertial head injury. Injured axons detected by immunohistochemistry (β-APP) were absent in mild injury and sham piglets, but were observed in moderately injured piglet brains. In summary, we have developed a quantitative battery of neurobehavioral functional assessments for large animals that correlate with neuropathologic axonal damage and may have wide applications in the fields of cardiac resuscitation, stroke, and hypoxic-ischemic brain injury.
head injury; neurobehavioral assessment; axonal injury
We developed the Recurrence and Recovery Questionnaire (RRQ) by converting the Pediatric Stroke Outcome Measure (PSOM) to a questionnaire for telephone interview and sought to validate the RRQ in a large cohort.
We analyzed parents' RRQ responses and same-day PSOM assessments for 232 children who had arterial ischemic stroke, cerebral sinovenous thrombosis, or presumed perinatal ischemic stroke. We assessed the agreement and consistency of the PSOM and RRQ, and we identified conditions that contributed to differences between the 2 measures. We tested selected factors as predictors of differences between the total PSOM and total RRQ (tPSOM and tRRQ) scores.
Median PSOM score was 1.5 and median RRQ score was 1.5. There was good agreement between tPSOM and tRRQ, and RRQ was a reliable estimator of PSOM at the total and component level. Preexisting neurologic deficits or chronic illnesses increased the difference between the tPSOM and tRRQ; the chronic illness effect was confirmed with univariate analysis.
The RRQ can characterize poststroke function when a child cannot return for examination. While the RRQ is not identical to the PSOM, the 2 measures likely assess closely related aspects of recovery. The RRQ is particularly useful when assessing outcomes of large cohorts, and will be useful in performing long-term follow-up studies of pediatric stroke.
Background and Purpose
The Pediatric National Institutes of Health Stroke Scale (PedNIHSS), an adaptation of the adult NIH Stroke Scale, is a quantitative measure of stroke severity shown to be reliable when scored prospectively. The ability to calculate the PedNIHSS score retrospectively would be invaluable in the conduct of observational pediatric stroke studies. The study objective was to assess the concurrent validity and reliability of estimating the PedNIHSS score retrospectively from medical records.
Neurological examinations from medical records of 75 children enrolled in a prospective PedNIHSS validation study were photocopied. Four neurologists of varying training levels blinded to the prospective PedNIHSS scores reviewed the records and retrospectively assigned PedNIHSS scores. Retrospective scores were compared among raters and to the prospective scores.
Total retrospective PedNIHSS scores correlated highly with total prospective scores (R2=0.76). Interrater reliability for the total scores was “excellent” (intraclass correlation coefficient of 0.95, 95% confidence interval 0.94–0.97). Interrater reliability for individual test items was “substantial” or “excellent” for 14 of 15 items.
The PedNIHSS score can be scored retrospectively from medical records with a high degree of concurrent validity and reliability. This tool can be used to improve the quality of retrospective pediatric stroke studies.
arterial ischemic stroke; pediatric; NIH stroke scale
Electroencephalographic (EEG) features may provide objective data regarding prognosis in children resuscitated from cardiac arrest (CA), but therapeutic hypothermia (TH) may impact its predictive value. We aimed to determine whether specific EEG features were predictive of short-term outcome in children treated with TH after CA, both during hypothermia and after return to normothermia.
Thirty-five children managed with a standard clinical TH algorithm after CA were prospectively enrolled. EEG recordings were scored in a standardized manner and categorized. EEG category 1 consisted of continuous and reactive tracings. EEG category 2 consisted of continuous but unreactive tracings. EEG category 3 included those with any degree of discontinuity, burst suppression, or lack of cerebral activity. The primary outcome was unfavorable short-term outcome defined as Pediatric Cerebral Performance Category score of 4–6 (severe disability, vegetative, death) at hospital discharge. Univariate analyses of the association between EEG category and outcome was performed using logistic regression.
For tracings obtained during hypothermia, patients with EEGs in categories 2 or 3 were far more likely to have poor outcome than those in category 1 (OR 10.7, P = 0.023 and OR 35, P = 0.004, respectively). Similarly, for tracings obtained during normothermia, patients with EEGs in categories 2 or 3 were far more likely to have poor outcomes than those in category 1 (OR 27, P = 0.006 and OR 18, P = 0.02, respectively).
A simple EEG classification scheme has predictive value for short-term outcome in children undergoing TH after CA.
Therapeutic hypothermia; Outcome; Pediatric; Hypoxic ischemic encephalopathy; Heart arrest; Prognosis
We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R = 0.89, p < 0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.
diffuse correlation spectroscopy (DCS); diffuse reflectance spectroscopy (DRS); cerebral hemodynamics; cerebral blood flow; traumatic brain injury; near—infrared spectroscopy (NIRS)