Platform Session 2: (#9 ? 16) 9. Development of a Semiquantitative Fetal Brain Maturation Score on MRI Licht DJ (Philadelphia, PA); Limperopoulos C (Montreal, Canada); Duplessis, AJ (Boston, MA); Gee, JC, Wu J, Hedstrom G, Putt ME, Vossough A (Philadelphia, PA) Objective: Assessment of fetal brain maturation in-utero may provide important prognostic data and facilitate the study of human brain development in high-risk fetuses. A valid, yet simple to use semiquantitative observational scale of fetal brain maturation that can be used in routine clinical fetal MRI is proposed. Methods: A semiquantitative scale and scoring system for assessing brain maturation was developed by major modifications to a previously validated ex-utero brain maturational score. Six visual indices, including myelination, presence and locations of the germinal matrix, frontal/occipital cortical folding, insular cortical folding, and sulcal depth of each of the superior and inferior temporal sulci were used. Normal fetal (n�) brains were assessed via fetal MRI by two independent raters. The cumulative maturational score was correlated with gestational age (GA) and manually segmented fetal brain volumes (BV). Regression models of GA and BV based on the indices were performed. The model was cross-validated by the leave-one-out method. Results: The interrater correlation was ICC�945 (p<0.001) for the maturational score assessment. The correlation of the score with GA and segmented BV was r�971 (p<0.001) and r�969 (p<0.001), respectively. The regression analyses for predicting GA and BV was r2�938 and r2�932, respectively. The model was accurate to 3.99 days. The cross-validation analysis demonstrated excellent validity with R�91 for GA and R�89 for BV. Conclusions: The fetal brain maturation scale is reproducible, accurate and simple to use. The fetal brain maturation scale has the potential to extend the evaluation of the fetal central nervous system. 10. Transient Increase in NKCC1 Expression and Altered Neuronal Chloride Reversal Potential in Bumetanide-sensitive Neonatal Seizures in the Rat Talos DM, Sun H, Jackson M, Jensen FE (Boston, MA) Objective: The NKCC1 inhibitor bumetanide suppresses seizures in the immature rodent and is currently in clinical trials in neonatal seizures. Overexpression of NKCC1 is linked to the presence of depolarizing GABA receptors that contribute to the refractoriness of neonatal seizures to conventional GABAergic antiepileptic drugs. Here we evaluated whether neonatal seizures caused further increases in NKCC1 expression and function. Methods: Seizures were induced by hypoxia in P10 rats. NKCC1 and KCC2 expression was assessed by western blot over the first week post-seizure. The gramicidin perforated patch recordings measured ECl (EGABA) in CA1 pyramidal neurons in hippocampal slices removed at 24h following seizures. EGABA was determined by recording currents evoked with brief GABA puffs at various membrane potentials. Results: Seizures resulted in a transient NKCC1 increase at 24h in cortex (163.5% of control, n� (p<0.05) and hippocampus (131% of control, n�; no changes were seen in KCC2 expression at these times. EGABA was posiC 2010 American Neurological Association S88 V tively shifted at 24h in hippocampal neurons in slices from seizure rats (58.5862.72 mV, n� versus controls (67.7063.26 mV, n�(p<0.05). Application of phenobarbital (100uM) and bumetanide (10uM) in vitro normalized EGABA (from 58.6161.28 mV to 64.5362.30 mV, n� p<0.05) in slices removed at 24h post-seizures. Conclusions: Seizures in neonatal rats induce increases in expression of the chloride transporter NKCC1 and altered EGABA at 24h, suggesting that NKCC1 inhibitors such as bumetanide may have anticonvulsant efficacy in the subacute period following a neonatal seizure. Clinical trials may need to include subacute repeated doses of bumetanide for optimal effect. 11. Bumetanide Augments the Neuroprotective Efficacy of Phenobarbital plus Hypothermia in a Neonatal Brain Injury Model Liu YQ, Shangguan Y, Barks JD, Silverstein FS (Ann Arbor, MI) Objective: The NaKCl cotransporter NKCC1 facilitates intraneuronal chloride accumulation in the developing brain (Nat Med 11:1205). Bumetanide, a clinically available diuretic, inhibits this developmentally regulated chloride transporter, and it augments the antiepileptic effects of phenobarbital (PB) in a neonatal rat seizure model (Ann Neurol 63:222). In a neonatal model of cerebral hypoxia-ischemia (HI), elicited by right carotid ligation, followed by 90 min 8% O2 exposure in 7 day-old (P7) rats, PB augments the neuroprotective efficacy of delayed-onset hypothermia (Pediatr Res, 2010, in press). In this study, we evaluated whether bumetanide would confer added benefit. Methods: P7 rats (n�) underwent HI; 15 min later, all received injections of phenobarbital (30 mg/kg). 10 min later, 1=2 received injections of bumetanide (10 mg/kg) (PBBUM) and 1/2 received saline (PB-SAL). One hour after HI, all were cooled (30 C, 3h). Sensorimotor function and neuropathology were evaluated 7 days later. Results: Contralateral forepaw function scores (vibrissae stimulation test; normal�/10) were better in the PBBUM group (9.361.5/10 vs. 7.361.6, p<0.005, t-test). Tissue damage was also reduced; right hemisphere %Damage declined from 28617 % (PB-SAL) to 20617 % (PBBUM) (p<0.05, Mann Whitney test), and 5/18 PB-BUM animals had <10% Damage, compared with 0/18 in the PB-SAL group (p<0.05, Fisher?s exact test). Conclusions: These results provide additional evidence that NKCCl inhibition amplifies PB bioactivity in the immature brain, and suggest that co-administration of phenobarbital and bumetanide may represent a clinically feasible therapy to augment the neuroprotective efficacy of therapeutic hypothermia in asphyxiated neonates. 12. Ethnic and Socioeconomic Disparities in Prevalence of Cerebral Palsy Wu YW, Xing G, Fuentes-Afflick (San Francisco, CA); Danielson B (Rocklin, CA); Smith LH, Gilbert WM (Sacramento, CA) Objective: Ethnic disparities in cerebral palsy (CP) have been documented but the underlying mechanism is poorly understood. We tested the effect of prematurity and socioeconomic factors as potential explanations for ethnic disparities in CP prevalence. Methods: We undertook a population-based, case-control study among 6.1 million infants born in California hospitals from 1991?2001. Case patients (n�946) comprised all infants with CP who qualified for services from the California Department of Health Services. We randomly selected four controls per case from the population. Results: African American infants had the highest rates of prematurity and were 34% more likely to have CP than whites (OR 1.34, 95% CI 1.23?1.46), while Asian infants had a decreased risk of CP (OR 0.76, 95% CI 0.69?0.83). After controlling only for gestational age, the elevated risk of CP among African American infants was no longer significant (OR 1.08, 95% CI 0.98?1.19). Logistic regression analysis controlling for gestational age and sociodemographic factors demonstrated several significant risk factors for CP: twin gestation (OR 1.33), male gender (OR 1.29), late onset of prenatal care (OR 1.29), and maternal age >35 years (OR 1.22). Factors associated with reduced risk of CP were Asian ethnicity (OR 0.75), Hispanic ethnicity (OR 0.90), and maternal education beyond high school (OR 0.85). Conclusions: The increased risk of CP among African American infants is largely explained by increased rates of prematurity. Understanding how maternal ethnicity, educational attainment, and use of prenatal care impact the risk of CP may inform new strategies to prevent CP. 13. Early Caffeine is Associated with Decreased IVH in Very Low Birth Weight Neonates Abbasi S (Philadelphia, PA); Aden U (Stockholm, SW); Allan W (Scarborough, ME) Bada H (Lexington, KY); Barks J (Ann Arbor, MI); Bauer C (Miami, FL); Bizzarro M (New Haven, CT); Carlo W (Birmingham, AL); Chen X (New Haven, CT); Cummings J (Greenville, NC); Ehrenkranz R (New Haven, CT); Eyal F (Mobile, AL); Faix R (Salt Lake City, UT); Fuller J (Albuquerque, NM); Hopper A (Loma Linda, CA); Inder T (St. Louis, MO); Kaiser J (Little Rock, AR); Karpen H (Houston, TX): Lifton R (New Haven, CT); Maller-Kesselman (New Haven, CT); Ment L (New Haven, CT); O?Shea T (Winston-Salem, NC); Poindexter B (Indianapolis, IN; Pourcyrous M (Memphis, TN); Sayman K (Goteborg, SW); Shankaran S (Detroit, MI); Vohr B (Providence, RI); Yoder B (Salt Lake CIty, UT); Zhang H (New Haven, CT) Objective: Preclinical data suggest that caffeine prevents hypoxic-ischemic injury in the developing preterm infant brain. We hypothesized that early caffeine exposure would be associated with lower incidence of grades 2?4 intraventricular hemorrhage (IVH) in preterm neonates. Methods: Retrospective data for 166 inborn preterm case/control pairs (Birthweight 500?1250 g) enrolled in the multicenter Gene Targets for IVH study were analyzed for risk associated with Gr 2?4 IVH. Risk factors in the conditional logistic regression model included: gestational age (GA), black race, preeclampsia, antenatal steroid (ANS) exposure, chorioamnionitis, intubation for birth resuscitation/ stabilization, prophylactic indomethacin and gender/indomethacin interaction, multiple birth and caffeine on postnatal day (PND) 1?2. Results: IVH risk was not associated with chorioamnionitis, indomethacin, multiple birth, black race or preeclampsia (p values all >0.06). However, each decreasing week of GA (OR 1.34, 95% CI [1.04,1.73], p�025) and intubation (OR 2.30, 95% CI [1.19,4.43], p�013) were significant predictors of increased risk of IVH. In contrast, a complete course of ANS (OR 0.33, 95% CI [0.16,0.68], p�003) and caffeine administered on PND 1-2 (OR 0.37, 95% CI [0.20,0.70], p�002) were associated with significantly lower risk for Gr 2?4 IVH. Conclusions: These findings support the association between decreased risk for IVH and exposure to a complete course of ANS. In addition, they suggest an association between early postnatal caffeine and lower risk for IVH in VLBW neonates. Additional studies are needed to confirm the association between early postnatal caffeine exposure and lowered risk for IVH in VLBW neonates. Supported by NS 053865. 14. Clinical Factors Associated with Abnormal Preterm Cerebellar Growth Tam EWY (San Francisco, CA); Chau V (Vancouver, BC); Ferriero DM, Studholme C (San Francisco, CA); Poskitt K (Vancouver, BC); Glidden D, Barkovich, AJ (San Francisco, CA); Miller SP (Vancouver, BC) Objective: To characterize the clinical factors associated with previously reported diminished cerebellar growth in preterm newborn. Methods: We evaluated a cohort of preterm neonates admitted to the intensive care nurseries at UCSF and UBC between June 2006 and February 2009. MRI was obtained soon after birth and, when possible, again near term-equivalent age. To understand the clinical factors associated with diminished cerebellar growth, generalized estimating equations accounting for repeated measures and two study sites were used to study the association between cerebellar volume and potential clinical risk factors, adjusting for postmenstrual age at time of MRI. A backwards selection model was used, and a factor was considered significant if it was associated with 0.5cm3 change in cerebellar volume with P<0.1. Results: A cohort of 172 preterm newborns who had 298 MRI scans were analyzed for potential clinical factors. Of those risk factors studied, grade 3-4 intraventricular hemorrhage (P<0.001), postnatal steroids (hydrocortisone P�006, dexamethasone P�02), duration of intubation (P�002), and patent ductus arteriosus (P�04) were significant. Chorioamnionitis, sepsis, antenatal steroids, hypotension, and supratentorial white matter injury were not associated with changes in cerebellar volume during the preterm period. Conclusions: Decreased cerebellar volume in preterm newborns appear to be associated with a variety of clinical factors. These factors tend to occur in the postnatal period and thus may be modifiable. 15. Symptomatic Neonatal Arterial Ischemic Stroke: Findings from the International Pediatric Stroke Study Kirton A (Calgary, AB); Armstrong-Wells J (Denver, CO); Chang T (Washington, DC); Hernandez M (Santiago, Chile); Carpenter J (Washington, DC); Rivkin M (Boston, MA); Yager J (Edmonton, AB); Lynch J (Bethesda, MD); Ferriero DM (San Francisco, CA); Members of the IPSS Objective: Neonatal arterial ischemic stroke (AIS) has emerged as a leading cause of perinatal brain injury, cerebral palsy, and life-long disability. Pathogenesis is poorly understood, limiting the development of treatment and prevention strategies. Multicentre studies must define the epidemiology, risk factors and outcomes to advance clinical trials and improve the adverse outcomes suffered by most survivors. Methods: The International Pediatric Stroke Study (IPSS) is a global research initiative of 149 co-investigators (30 centres, 10 countries). Patients with clinical and neuroimaging confirmation of acute, symptomatic neonatal AIS were enrolled between 2003 and 2007. Standardized, webbased data entry collected clinical presentations, risk factors, Program and Abstracts, Child Neurology Society S89 neuroimaging, investigations, treatments, and outcomes. Associations with outcomes of interest were assessed. Results: The study population comprised 248 neonates (57% male, 10% premature). Most presented with seizure (72%) and non-focal neurological signs were common (63%). MRI was completed in 92% though <50% had vascular imaging. Infarcts preferentially involved the anterior circulation and left hemisphere and were multifocal in 30%. Maternal health and pregnancies were usually normal. Many neonates required significant resuscitation (30%) and had acute systemic illnesses (23%). Cardiac and prothrombotic abnormalities were identified in <20%. Only 21% received antithrombotic therapy and treatment practices varied across geographical regions. Many (49%) had neurological deficits at discharge with long-term outcomes yet to be determined. Conclusions: A definitive cause for most cases of neonatal AIS can not be established. The IPSS can systematically collect the large scale data required to address many outstanding questions and initiate clinical trials in neonatal AIS. 16. The Role of Blood Oxygen Labelled (BOLD) Functional MRI in the Assessment of Stroke Risk in Children with Stenosing Arteriopathy Dlamini N, Dirks P, Logan W, Mikulis D, Armstrong D, Yau I, Abou-Hamden A, DeVeber G (Toronto, ON) Background: Moyamoya, a progressive stenosing arteriopathy, causes recurrent ischemic events and progressive neurological decline. Revascularization surgery may prevent this decline. However indicators for selection of patients and optimal timing of surgery are not established. Blood Oxygen S90 Annals of Neurology Vol 68 (suppl 14) 2010 Level Dependent (BOLD) MRI with hypercapnic challenge can demonstrate altered cerebrovascular reactivity (CVR), which predicts brain-at-risk for ischemia in steno-occlusive cerebral arteriopathy. Objective: To determine if BOLD MRI identifies children at risk of cerebral ischemic events and demonstrates changes associated with revascularization surgery in moyamoya. Methods: Prospectively studied children with moyamoya undergoing indirect revascularization surgery were assessed with BOLD MRI CVR pre and post-operatively. Results: Seven children underwent BOLD MRI CVR pre- and post-revascularization surgery (13 studies). Hypercapnia was accomplished via: breath-holding, inhalation of elevated CO2 gas mixture under anesthesia or, with a rebreathing circuit in awake children. Children had moderate to severe moyamoya (>50% stenosis on conventional angiography), (unilateral in 3) and presented with headache (5), recurrent TIAs (4) and stroke (1). Pre-surgical CVR was abnormal in hemispheres affected by moyamoya in all children and predicted de novo TIA/stroke development in 3 children prior to surgery. Hypercapnic challenge demonstrated ?vascular steal? in 5 children. CVR (1?6 months post-op) in 6 children demonstrated improved CVR in 5 (all with clinical improvement) and worsening in 1 child (with clinical and angiographic disease progression). CVR was 100% concordant with clinical course. Conclusions: CVR is a useful and feasible tool for evaluating ischemic risk in childhood moyamoya and demonstrates clinically meaningful CVR improvement post-revascularization in the majority.