Lori Jordan - Current Funding 7/18/11
4/1/08 – 3/30/13
Predictors of recovery from intracerebral hemorrhage in children, K23NS062110
Sponsor: NINDS/NIH
Total direct costs: $824,751
PI: Lori Jordan M.D., Ph.D. (79% effort)
Mentor: Argye Hillis M.D. M.A.
Abstract:
Stroke is among the top ten causes of death in children. Hemorrhagic stroke represents 50% of
stroke and two-thirds of the mortality in childhood. The most common form of hemorrhagic
stroke is spontaneous (non-traumatic) intracerebral hemorrhage (ICH). ICH in children has
been vastly understudied and potential therapies in adults may not be applicable to children.
Before interventional trials and prognostic studies can be undertaken, it is essential to first
determine the clinical and pathophysiological factors that affect outcome. In preliminary
research by the applicant, odds of death after ICH increased 1.85 (95%CI: 1.07-3.20) for every
additional 10cc of hemorrhage volume when adjusted for age. ICH locations that were
associated poor outcome included the 4th ventricle and the frontotemporal regions. Based on
preliminary data, we propose to do the following:
AIM 1. To conduct a prospective longitudinal study of ICH in children to assess time to
presentation, etiology, hemorrhage size and other potential predictors of outcome. Hypotheses:
a. Outcome will be worse in children who have larger hemorrhages and in those who have
intraventricular hemorrhage. b. Hemorrhage location in patients with poor neurologic outcomes
will be distinct from hemorrhage location in those with good neurologic outcomes. c.
Hemorrhage size and location will be independent predictors of outcome. Therefore, scores for
both will be important for creating a formula that predicts outcome.
Public Health Relevance: This study will provide a better understanding of the factors that
predict neurologic outcome after childhood ICH, an important cause of mortality and life-long
disabilty in children, and will lay a foundation for further advances in patient care including
treatment trials.
9/1/09-8/31/14
Vascular effects of infection in pediatric stroke (VIPS), RO1NS062820
Sponsor: NINDS/NIH
Total direct costs: $21,227
PI: Heather Fullerton, University of California San Francisco
Role: Site PI, Vanderbilt, (1% effort)
Abstract:
The purpose of the study is to examine the association between infection and arterial ischemic
stroke (AIS) in children. A similar association has been described in adult stroke but is
generally attributed to atherosclerotic risk factors; typically not applicable to pediatric stroke
patients. Instead, arteriopathy—often for unknown reasons—is found frequently in pediatric
stroke. A subset of these has been termed Post-Varicella Angiopathy (PVA) due to stenosis
caused by the varicella zoster virus (VZV) invading arterial walls. Similar, non-progressing
stenosis is often noted but without a clear cause. This has been termed Transient Cerebral
Arteriopathy (TCA) or, more recently, Focal Cerebral Arteriopathy of childhood (FCA). Infection
can cause arteriopathy both by the direct invasion of the cell walls, as with PVA, or through
repeated inflammatory stress. This study will examine the relationship between infectious
1
markers and FCA, as well as the predictive utility of FCA for recurrent stroke in children. Blood
vessel abnormalities may cause as much as 80% of ischemic stroke in children and are the
major predictor of stroke recurrence. Stroke in children is an important problem; it is at least as
common as brain tumor, but is vastly understudied. This is the first major. multicenter NIH
funded study of stroke in children, outside of sickle cell disease.
10/1/05-11/30/13
The Silent Infarct Transfusion Trial- Multicenter Clinical Trial, U01-NS-042804
Sponsor: NINDS/NIH
Total direct costs: $293,811
PI: Michael DeBaun
Role: Co-investigator/Site Neurologist (1% effort)
Abstract:
Silent cerebral infarct (SCI) is the most common cause of serious neurological disease in sickle
cell anemia (SCA), affecting approximately 22% of children. The goal of this trial is to determine
whether blood transfusion therapy will reduce further neurological morbidity in children with SCI,
and if so, the magnitude of this benefit. The Silent Cerebral Infarct Transfusion (SIT) Trial
includes 29 clinical sites and 3 subsites, a Clinical Coordinating Center, and a Statistical and
Data Coordinating Center, to test the following hypothesis: prophylactic blood transfusion
therapy in children with SCI will result in at least an 86% reduction in the rate of subsequent
overt strokes or new or progressive cerebral infarcts as defined by magnetic resonance imaging
(MRI) of the brain. The intervention is blood transfusion versus observation. Two hundred and
four participants (102 in each treatment assignment) will ensure 85% power to detect the effect
necessary to recommend transfusion therapy (86% reduction), after accounting for 10% drop
out and 19% crossover rates. MRI examination of the brain is done at screening, immediately
before randomization and study exit. Each randomly assigned participant receives a cognitive
test battery at study entry, 12-18 months later, and study exit and an annual neurological
examination. Blood is obtained from all screened participants for a biologic repository containing
serum and a renewable source of DNA. The SIT Trial could lead to a change in standard care
practices for children affected with SCA and SCI, with a consequent reduction in neurological
morbidity.
Pending Funding (Just in Time paperwork submitted)
Hydroxyurea for the Prevention of Brain Injury in Sickle Cell Disease, R34
Sponsor: NHLBI/NIH
Total direct costs: $300,000
PI: James Casella
Role: Co-investigator/Head of Neurology Committee (5% effort)
Abstract:
Stroke, silent cerebral infarct (SCI), and cognitive impairment are frequent and highly morbid
complications of sickle cell disease (SCD) in children. Current approaches to the prevention
and treatment of neurological complications in SCD include screening by transcranial Doppler
ultrasound (TCD) to identify children with elevated cerebral blood flow velocity who are at
increased risk for strokes; these children are then typically treated with chronic transfusions
indefinitely. Hydroxyurea (HU) may have beneficial effects on central nervous system (CNS)
complications in SCD and reduces the frequency of painful crisis, acute chest syndrome and
transfusion. The safety of HU in infants and children has been suggested in a NIH sponsored
2
phase III trial; however, the exact indications for the use of HU in children remain unclear, as
well as its efficacy in preventing CNS complications of SCD. Our preliminary data suggest that,
if the cumulative frequency of abnormal TCD, SCI and stroke could be reduced by 50%, the
majority of pediatric hematologists would prescribe HU to all young children with SCD. The long
term goal of this project is to perform a primary prevention trial to demonstrate the
neuroprotective effect of HU and broaden the indications for HU in children. The goals of this
proposal are to: 1) conduct an internal pilot randomized placebo-controlled trial of HU to reduce
the CNS complications of SCD (the term internal pilot is used, as the results from the
participants in the pilot will be analyzed as part of a definitive phase III trial to follow); 2)
demonstrate the safety of hydroxyurea and study procedures in young children with SCD; and
3) create the leadership, network of clinical centers and other procedures necessary to conduct
a definitive phase III trial demonstrating the efficacy of HU for primary prevention of the
neurological complications of SCD. The primary endpoint for the internal pilot and definitive
phase III trials will be the development of abnormal TCD, SCI or stroke. To begin the internal
pilot trial, we have obtained CTSA support at Johns Hopkins and Washington University; over
the next two years, these sites will screen 40 participants 12-48 months of age and randomly
assign and follow 20 participants for two years. Two additional centers (Children’s Hospital of
Philadelphia and the University of Alabama, Birmingham) will begin enrollment during the
course of the R34 (20 patients screened and 10 participants randomly assigned per site), to
provide a total of 80 participants screened, 40 randomly assigned, and a minimum of 70
participant years of follow-up. Participants must have TCD measurements that are well below
transfusion thresholds and MRIs that are without evidence of SCI. Participants in the internal
pilot will continue into the proposed R34 and phase III trials, to complete 3 years on HU or
placebo. The information from the internal pilot trial will be used to improve the design of the
definitive phase III trial. The results of these studies could lead to true primary prevention of
CNS complications of SCD, including abnormal TCD, SCI, neurocognitive impairment and
stroke. In doing so, this study could also reduce the burden of chronic transfusions and change
clinical practice by broadening the indications for HU.
3