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8. Medulloblastoma Incidence has not Changed Over
Time: A Cbtrus Study
Curran EK, Gem ML, Propp JM, Cobb KL, Fisher PG
(Palo Alto, CA; Fremont, CA; Chicago, IL)
Background: Previous medulloblastoma (MB) studies
present conflicting claims about declines and rises in MB incidence, possibly due to misclassification. By using a strict
classification and a rigorous analysis, we aimed to determine
the incidence trends of MB over the last two decades. Methods: 441 MB patients diagnosed between 1985 and 2002
were identified from the Central Brain Tumor Registry of
the United States (CBTRUS), representing approximately
5% of the U.S. population (6 registries). MB was strictly
defined and non-cerebellar embryonal tumors (primitive
neuro-ectodermal tumors [PNETs]) excluded, using histology and site codes. The estimated average annual percentage
change (EAPC) and sharp changes in incidence were determined using multiplicative Poisson regression and joinpoint
regression (Joinpoint Regression Program, version 3.0), respectively. Results: A slight but nonsignificant (p⫽.18) increase in medulloblastoma was demonstrated (EAPC ⫽ 1.1),
with no sharp changes in incidence (joinpoints ⫽ 0). A repeat analysis, with a less strict MB definition (including noncerebellar PNETs), identified 559 patients. Using this
broader classification scheme, there was a statistically significant increase in incidence (p⫽.02, EAPC ⫽ 1.6), but no
sharp changes in incidence (joinpoints ⫽ 0). Conclusion:
MB incidence does not appear to have changed since the
1980s. Incidence increased only when MB was not strictly
defined and misclassified by including non-cerebellar PNETs
in the analysis. The observed increase in the combined MB/
PNET classification may relate to the PNET hypothesis—a
proposal that all brain tumors of apparently undifferentiated
cells be considered a unique diagnostic group—popularized
in the 1980s and early 1990s.
DOI: 10.1002/ana.11472
9. A Dual PI3-kinase/mTOR Inhibitor Reveals
Emergent Efficacy in Glioma
Fan, QiWen, Knight ZA, Goldenberg DD, Wei Y,
Mostov KE, Stokoe D, Shokat KM, Weiss WA.
(San Francisco, CA)
The PI3-kinase family of lipid kinases promotes cell growth
and survival by generating the second messenger
phosphatidylinositol-3,4,5-trisphosphate (PIP3). The frequent activation of this pathway in glioma has focused intense interest on PI3-kinases as drug targets. Yet it remains
unclear which kinases in this family should be targeted in
glioma, in large part because the first selective inhibitors of
these enzymes have only recently been reported. We report a
novel strategy for pharmacological target validation, based on
screening an array of chemically diverse inhibitors that potently target the PI3-kinase family. To define targets critical
for cancers driven by activation of PI3-kinase, we screened a
biochemically-characterized and structurally diverse set of
drug-like molecules that target this entire family. These compounds include representatives from the majority of chemotypes and target selectivities currently in preclinical development by the pharmaceutical industry, and therefore preview
the biological activities of compounds that will ultimately enter clinical development. Surprisingly, we show here that a
single agent (PI-103) effected proliferative arrest in glioma
cells, despite the fact that many compounds were able to
Annals of Neurology
Vol 60 (suppl 3)
block PI3-kinase signaling through its downstream effecter,
Akt. The unique cellular activity of PI-103 was traced directly to its ability to inhibit both a growth-factor dependent
pathway (PI3-kinase alpha) and a nutrient-sensing pathway
(mTOR). PI-103 showed significant activity in xenografted
tumors with no observable toxicity. These data confirm the
importance of PI3-kinase alpha in cancer and demonstrate
an emergent efficacy due to combinatorial inhibition of
mTOR and PI3-kinase alpha in malignant glioma.
Injury and Repair of the
Developing Nervous System
Thursday, October 19, 2006
3:30 – 5:30 pm
10. Use of Magnetic Resonance Imaging in Rat Pups
to Monitor Iron-Labelled Neural Stem Cell Homing
After Hypoxia-Ischemia
Ashwal S, Obenaus A, Digicaylioglu M, Tone B, Robbins M,
Wang A, Tian H, Snyder E (Loma Linda, CA and
La Jolla, CA)
Neural stem cells (NSCs) have attracted increasing attention
as a potential treatment for neonatal hypoxic ischemic injury
(HII) and several studies have demonstrated a reparative effect on brain injury in rats after unilateral carotid ligation/8% hypoxia (Rice-Vannucci model, RVM). Although
multiple mechanisms, aside from neural replacement, have
been proposed to explain this reparative effect, it is realized
that developing non-invasive means to monitor NSC migration and homing to the site of injury would be extremely
helpful in understanding injury repair mechanisms. We have
implanted iron-labeled NSCs into the contralateral ventricle
of 10-day RVM and control rat pups and using an 11.7 T
magnetic resonance imaging scanner. NSC migration was
tracked for up to 28 days. As shown in the figure (at 14days
post implantation), NSCs remained within the ventricle in
control pups whereas in RVM pups, migration of NSCs towards the area of ischemic injury was seen by 4 days and
continued over the 28-day period of study. We also observed
that the apparent initial volume of NSCs changed over time,
suggesting that the NSCs spread out towards different regions of ischemic injury, possibly in response to different
homing signals released by injured tissue. Our findings demonstrate that iron-labeled NSCs can non-invasively be
tracked for extended periods of time in a rat pup RVM
model and that such methods can be used to develop the
optimal method for NSC implantation to maximize recovery
after neonatal HII.
11. Cerebral Palsy in a Term Population: Risk Factors
and Neuroimaging Findings
Wu YW, Shah SJ, Newman TB, Najjar DV, Croen LA
(San Francisco, CA)
Objective: To determine risk factors and neuroimaging
characteristics of cerebral palsy (CP) in term and near-term
infants. Methods: In a retrospective cohort study of
334,339 infants ⱖ36 weeks gestation born at Kaiser Permanente in northern California, 1991-2003, we identified
infants with CP and obtained clinical data from electronic
and medical records. Risk factors for CP among infants
with different brain abnormalities were compared using
polytomous logistic regression. Results: Of 377 infants
with CP (prevalence 1.1/1,000), 72% received either a head
MRI (n⫽227) or CT only (n⫽46). Abnormalities included
focal arterial infarction (22%), brain malformation (14%)
and periventricular white matter (PVWM) abnormalities
(12%). Independent risk factors for CP were maternal age
⬎35 (OR 1.9, 95% CI 1.5-2.5), black race (OR 1.4,
95%CI 1.01-1.9) and intrauterine growth restriction (OR
4.3, 95% CI 2.6-7.2). Intrauterine growth restriction was
more strongly associated with PVWM injury (OR 17.5,
95% CI 6.8-45.3) than with other neuroimaging findings
(OR 3.5, 95% CI 1.7-7.1; P⬍0.01 for the difference).
Nighttime delivery was associated with CP accompanied by
generalized brain atrophy (OR 3.6, 95% CI 1.4-9.3), but
not with CP accompanied by other brain lesions (OR 0.9,
95% CI 0.7-1.2, P ⬍ 0.01 for the difference). Motor abnormalities were more likely to resolve by age three in the
setting of a normal head image (11% vs. 1%, P⬍0.001).
Conclusion: Focal arterial infarction and brain malformation represent the most common neuroimaging abnormalities in term and near-term infants with CP. Risk factors for
CP differ depending on type of underlying brain abnormality.
12. Minocycline is Neuroprotective against Acute
Bilirubin Toxicity in Jaundiced Gunn Rat Pups.
Geiger AS, Rice AC, Shapiro SM (Richmond, VA)
Acute severe hyperbilirubinemia is currently treated with
double volume exchange transfusion, which may take hours
to commence. A neuroprotective agent that could be administered prior to transfusion might be useful. Minocycline, an
agent with anti-inflammatory and anti-apoptotic effects, pre-
vents hyperbilirubinemia-induced cerebellar hypoplasia in
Gunn rats. We have described acute abnormalities of brainstem auditory evoked potentials (BAEPs) after giving sulfadimethoxine to 16-day-old jaundiced Gunn rats to displace
bilirubin into brain. We gave minocycline at 4 doses:
0.5mg/kg (N⫽4), 5mg/kg (N⫽9), 50mg/kg (N⫽9) and
500mg/kg (N⫽3) 15 minutes before sulfadimethoxine to determine whether it was neuroprotective 6 hours later. Controls received saline (0mg/kg minocycline) followed by either
sulfadimethoxine (N⫽13) or saline (N⫽7); all 3 animals
given 500mg/kg died. Total plasma bilirubin decreased from
0.70⫾0.35mg/dl (p⬍10-9) in all sulfadimethoxine-injected
groups as bilirubin was displaced into brain. Six hour amplitudes were 30⫾24%, 39⫾19%, 52⫾18%, and 73⫾30% of
baseline for BAEP wave II, and 9⫾10%, 16⫾17%,
36⫾21% and 88⫾24% of baseline for wave III in groups
given 0, 0.5, 5 and 50mg/kg minocycline vs. 6h wave II
amplitude 91⫾28% and III amplitude 86⫾20% of baseline
in controls. Similarily, there was complete protection against
a 26⫾13% (0.32⫾0.16msec) increase in I-II and 23⫾9%
(0.52⫾0.17msec) increase in I-III interwave intervals with
50mg/kg minocycline, and partial protection with lower
doses. The results show that pretreatment with minocycline
50mg/kg 15min prior to acute bilirubin neurotoxicity is neuroprotective in jaundiced Gunn rat pups. Further studies are
suggested to investigate the temporal course and mechanism
of neuroprotection.
13. Arterial Ischemic Stroke in Canadian Children
Canadian Paediatric Ischemic Stroke Study Group
Background: Epidemiological data on paediatric arterial
ischemic stroke (AIS) is necessary for clinical trial development. We report on a 10-year, population-based study of the
largest cohort reported to date of children with AIS from the
Canadian Paediatric Ischemic Stroke Registry. Methods:
Children (term birth to 18th birthday) with clinically and
radiographically confirmed AIS were identified from January
1992 to January 2002 across all 16 Canadian children’s hospitals. Results: We enrolled 1268 patients with AIS including 338 presumed pre/perinatal AIS and 234 neonates and
696 older infants and children with acute AIS. Of 930 patients diagnosed acutely with AIS, 45% were female. Presentations included seizures (neonates 88%; 37% older) and focal deficits (neonates 35%; 69% older) which were motor
(78%), speech (16%) visual (10%) or other (32%). Risk factors in neonates were acute systemic illness (55%) and cardiac disease (24%) and among older children were cardiac
disease (29%), arteriopathy (69% of 365 with vascular imaging), head and neck pathology (31%), acute systemic illness (26%), and prothrombotic disorders (22%). Infarct locations were anterior circulation (65%), left-hemisphere
(62%) and large-vessel distribution (64% neonates vs.38%
older). Hemorrhagic infarcts were more frequent in neonates
(24.4% vs.10.5% older). Only 10.3% of neonates received
antithrombotic treatment vs. 55% older children. Outcomes
included neurological deficits (42% neonates, 61% older),
death (7.2% neonates, 13% older) and subsequent recurrent
cerebral ischemia (1% neonates,13% older). Conclusions:
Adverse outcomes in 75% support clinical trials to determine
more effective treatments for paediatric AIS. These trials will
only be accomplished through multi-national collaboration.
Program and Abstracts, Child Neurology Society
14. Altered Temporal Expression of Aquaporin 4 in a
Model of Neonatal Stroke: Correlation with MRI
Badaut J, Ashwal S, Obenaus A (Lausanne, Switzerland and
Loma Linda, CA)
Neonatal stroke is diagnosed using MRI techniques including T2-weighted (T2WI) and diffusion weighted imaging
(DWI). Cerebral edema contributes to the morbidity and
mortality after stroke and recent studies suggest that aquaporins (water channels), particularly AQP4, is responsible
for modulating water movements in brain and plays a key
role in edema formation. We have previously demonstrated
that high field MRI can localize the evolution of neonatal
(10-day-old rat pup) stroke over 28 days after middle cerebral artery occlusion. Using this model, we examined DWI,
T2WI and AQP4 protein expression (immunohistochemistry). Injured tissue at 24 hours showed decreased apparent
diffusion coefficient (ADC) values and increased cortical/
striatal T2 values reflecting increased edema (Fig. A,B). We
also observed an increase in AQP4 expression at the lesion
border (adjacent to injured tissue, Fig. C). Striatal MR abnormalities continued to 72 hrs; however, AQP4 expression
normalized, findings that remained until 28 days. At the
lesion border, AQP4 staining revealed increased labeling in
astrocyte end-feet close to blood vessels in a decreasing gradient from the ischemic core. At 28 days there was a clear
demarcation between normal and injured necrotic tissue
with AQP4 staining in astrocytes, but virtually no staining
in ischemic tissue. Our results demonstrate an inverse relation between DWI and AQP4 and suggest that AQP4 participates in brain water movement after neonatal stroke, a
finding similar to that in adult stroke models but opposite
that reported after neonatal hypoxia-ischemia. These findings have implications regarding our understanding of the
mechanisms of brain injury and repair as well as new treatment approaches.
15. Reorganization of Language Processing Networks
in Pediatric Stroke
Gaillard WD, Berl MM, Ritzl ER, Rosenberger LR,
Moore EN, Weber D, Vaidya C, Ratner N, Gioia G,
Vezina, LG (Washington, DC; Bethesda, MD;
College Park, MD)
Objective: To examine reorganization of language functions
in children with left hemisphere stroke. Methods: Ten children (7 male, 3 female), all left handed with left hemisphere
localization related seizures (mean age onset 4.4 (range 0.115)), were studied at mean age 14.4 years (range 8.7-20) with
structural MRI (1.5T), EEG, and EPI BOLD fMRI (3T).
Paradigms, adjusted for cognitive level, included auditory
based single word semantic decision, auditory description decision, listening, and reading tasks. Data were analyzed using
SPM and were visually rated compared to normal data from
88 children/young adults (p⬍0.05 corrected). Results: Seven
children had left MCA cortical infarcts, two had left lenticular
infarcts, one had a left thalamic venous infarct with hemorrhage. Nine strokes were perinatal; one occurred at five years.
Annals of Neurology
Vol 60 (suppl 3)
Excluding the child with venous stroke/hemorrhage (VIQ
140, PIQ 90), mean VIQ was 79.5 (range 72-89) and PIQ
was 79 (range 65-87). All children showed atypical language;
five were right hemisphere dominant for language in Broca’s
and Wernicke’s areas, all with LMCA CVA; four showed right
Broca’s activation systems with varying degrees of preserved
left temporal language processing. One child, (stroke at age
five), had bilateral activation. All activation occurred in right
hemisphere homologues of left activation patterns seen in normal controls. Patients showed greater activation in supramarginal/angular gyrus compared to normals. Conclusions: Language functions are sustained in the right hemisphere
homologues following early injury to left hemisphere. Shift to
right hemisphere may be incomplete and reflect local insult to
language cortex, especially in frontal regions.
16. Developmental and Functional Outcomes of
Children with Congenital Heart Defects at School
Majnemer A, Limperopoulos C, Shevell M, Rohlicek C,
Rosenblatt B, Tchervenkov C (Montreal, Quebec, Canada)
Objective: To describe long-term developmental (cognitive,
language, behavior) and functional outcomes in children with
a congenital heart defect (CHD) who required open-heart surgery. Methods: In this prospective study, young infants with
CHD who underwent early surgical repair were recruited and
assessed intermittently for developmental outcome. At 5 years,
subjects were blindly reassessed by a psychologist and occupational therapist using the Wechsler Preschool Primary Scale of
Intelligence (IQ), Peabody Picture Vocabulary Test (receptive
language), Child Behavior Checklist, Vineland Adaptive Behavior Scale (VABS) and WeeFIM (functional independence).
Results: A total of 94 children were re-evaluated at
64.2⫾11.3 months. Mean verbal (90.2⫾19.3), performance
(93.7⫾20.9), and total (91.0⫾20.7) IQ were low average with
19-22%⬍80. Receptive language was in the normal range
(103.6⫾14.4). For internalizing behaviors (52.4⫾9.8), 31%
were borderline or abnormal compared to 17% for externalizing behaviors (53.0⫾10.4). Functional limitations (⬍1.5 SD
on VABS) in socialization (93.0⫾17.1), daily living skills
(94.6⫾16.4), communication (90.0⫾14.1) and adaptive behavior (92.1⫾15.8) were noted in 11-17%. Using WeeFIM,
20 -22% were more dependent in self-care and problemsolving, although few (4.5%) had mobility limitations. Predictors (p⬍.05) of developmental difficulties and functional
limitations included: abnormal postoperative neurologic examination, microcephaly at surgery, increased deep hypothermic
circulatory arrest time, palliation, and low maternal education.
Conclusion: Following open-heart surgery, most children
with CHD will have a favorable outcome. However, a subset
exhibit intellectual and behavioral difficulties, enhancing risk
for learning challenges. Children with a history of microcephaly and neurologic abnormalities in infancy are at greater risk
for developmental delays and limitations in everyday activities.
17. The Effects of Caffeine and Morphine on the
Developing Premature Brain
Pandya S, Terepocki A, Armstrong EA, Yager JY
(Edmonton, Alberta)
Background: Caffeine is frequently used in neonatal intensive
care units for the treatment of apnea of prematurity. Morphine is often given in conjunction with caffeine to alleviate
the discomfort of invasive procedures, and the pain associated
with chronic intubation. This study investigates the potential
neurotoxicity of these drugs on the developing nervous system,
when administered alone or in combination. Methods: Newborn rats were given a subcutaneous single injection on day 3
of life (P3) of either: 1) saline, 2) caffeine (100mg/kg), 3)
morphine (10mg/kg) or 4) both medications combined.
Twenty-four hours post-injection rats were euthanized and the
brains were quick frozen in iso-pentane. Sections were stained
using Fluoro-jade B to identify and quantify neuronal death in
specific brain areas. Positive staining cells in the cortex, caudate/putamen, nucleus accumbens, globus pallidus, thalamus,
hypothalamus, superior colliculus and hippocampus were
counted, and the extent of cell death determined per mm3.
Results: Weight gain in those rat pups receiving both caffeine
and morphine was significantly less over the 24 hours postinjection than was the control group, or in those rats receiving
either of the drugs alone (p⬍0.05). The neocortical regions
did not show any significant increase in cell death. Morphine
alone, did not cause an increase in cell death in any of the
regions examined. Caffeine alone resulted in a significant increase in cell death, compared to control, in all areas examined
(p⬍0.001), with the exception of the thalamus and caudate/
putamen. In combination, a significant increase in cell death
was seen over control in the hypothalamus, the thalamus and
the hippocampus (p⬍0.01). Conclusions: Medications commonly utilized in the treatment of premature infants may not
be benign. Caffeine in particular causes an increase in cell
death. The ramifications of these drugs long term on brain
development and behavior need further investigation.
DOI: 10.1002/ana.11473
Thursday, October 19, 3:30 –
5:30 pm
18. Low Dose Vs. High Dose ACTH Treatment in
Infantile Spasms -A Reappraisal of “dose” of ACTH
Sivaswamy L, Asano,E. (Detroit, MI)
Objective: To compare the response rate and the incidence
of side effects in children with infantile spasms between ‘lowdose’ and ‘high-dose’ ACTH therapies. Methods: Thirty-two
children with infantile spasms, who presented to a tertiary
epilepsy center, were retrospectively analyzed. 15 subjects
were treated with ACTH 30-40 IU /day i.e. 3.8 to 5 IU/ kg,
whereas 17 were given 60-80 IU i.e. 8-16 IU/kg. The average duration of treatment was 6 weeks with a range from 4
to 8 weeks. Response to ACTH was defined as absence of
spasms by long-term video-EEG monitoring done 8 weeks
after the cessation of treatment. The incidence of side effects
including hypertension (systolic or diastolic more than 2
standard deviations from the mean), gastrointestinal bleed,
irritability or an infectious event was also assessed. Results:
There was no difference in the response rate between ‘lowdose’ and ‘high-dose’ groups (response rate: 52% vs 48%;
p⫽1.0; Fisher exact probability test). The adverse effects except for hypertension were equally distributed in both groups
(p⬎0.05). Hypertension was present in 47% of ‘high-dose’
group as opposed to 13.3% in ‘low-dose’ group. Discussion:
The present study failed to demonstrate the difference in efficacy or adverse effects between ‘low-dose’ and ‘high-dose’
therapies. We will discuss whether a lower-dose ACTH therapy, as used in some countries is warranted to minimize the
incidence of side effects while maintaining the efficacy in
children with infantile spasms.
19. Pre-Operative Factors Predict Success of Resective
Epilepsy Surgery in Children
Poduri A, Schomer M, Said R, Bergin AM, Duffy FH,
Bourgeois BFD, Madsen JR, Black PM, Riviello JJ
(Boston, MA; Philadelphia, PA; Dallas, TX)
Objective: To determine whether the outcome of epilepsy
surgery, measured by post-operative Engel score (4-point
scale, with lower score meaning better outcome), can be predicted by patient age, duration of epilepsy, gender, presence
of a lesion on MRI, cognitive status, or history of prior epilepsy surgery. Methods: Patients who underwent invasive
subdural EEG monitoring and/or focal resection for epilepsy
were identified in a database. Pre-operative data and Engel
scores were obtained by retrospective chart review; Engel
score was assigned if not reported. We performed univariate
and multivariable linear regression analyses of the above preoperative factors, adjusting for year of surgery and treating
Engel score as a continuous variable. We attempted to assess
whether MRI lesion type predicted outcome. Results: Of
224 patients in the database, outcome data were available for
196, with mean follow-up time of 25 months. By univariate
analyses, presence of an MRI lesion and normal cognition
were associated with lower Engel score (p⬍.05). Linear regression revealed that, when adjusted for year of surgery, the
presence of an MRI lesion was associated with Engel score
0.45 lower than no lesion (p⬍.05); normal cognition with
Engel score 0.51 lower than mental retardation (p⬍.005);
and history of prior epilepsy surgery with Engel score 0.56
lower than no prior surgery (p⬍.05). There was insufficient
power to stratify outcome by type of MRI lesion. Conclusions: In patients considered candidates for epilepsy surgery,
the presence of an MRI lesion, normal intelligence, and history of prior epilepsy surgery each predicts favorable postoperative seizure outcome.
20. Causes and Precedents of Childhood Epilepsy
Associated with Mental Retardation
Camfield P, Camfield C (Halifax, Nova Scotia)
Objectives: To determine the causes of childhood epilepsy
associated with mental retardation (MR). Methods: We selected all patients with MR from the Nova Scotia
population-based childhood epilepsy cohort (n⫽692) with
epilepsy onset between 1977-85. Causes and family history
were determined after 19⫾8 years of follow up. Results:
Overall 148 patients had MR ⫹ epilepsy (21% of all childhood epilepsy). Standard psychological testing was available
57%, 38.5% were too impaired for testing, leaving 4% with
the degree of MR assessed clinically. Severe/ profound MR
predominated (mild MR 24%, moderate 23%, severe/profound 53%). 59% had additional severe neurologic deficits,
especially associated with severe MR (p⬍0.001). Epilepsy
syndromes were: symptomatic generalized (n⫽75), partial
(n⫽52), other (n⫽21). 85% had a CT scan, 9% an MRI.
61.5% had a definite etiology; 38.5% were cause unknown.
A defined etiology was more likely in those with severe MR
(60/78 versus 31/65 p⫽0.001). Identified causes were pre-
Program and Abstracts, Child Neurology Society
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