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Platform Session 2 (#9 Ц 16).

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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.
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