Understanding Early Childhood Arterial Ischemic Stroke, Dr. Heather Fullerton is a Strides for Strokes 2014 funding recipient

Dr. Heather FullertonThis year the proceeds from Strides for Strokes 2014 will be spilt between two categories; research and education. We have selected Dr. Heather Fullerton’s research study Understanding Early Childhood Arterial Ischemic Stroke to be the benefactor of this year’s research funding.

Dr. Heather Fullerton is pediatric vascular neurologist with an active clinical research program in childhood stroke. She is the Director of the University of California, San Fransisco (UCSF) Pediatric Stroke and Cerebrovascular Disease Center, which she established in 2006, and Director of the UCSF Stroke Sciences Group, a group of stroke investigators first established by Dr. Clay Johnston, an adult stroke neurologist and epidemiologist.  In 2001, she began collaborating with Dr. Johnston at UCSF using administrative data to describe the incidence and demographics of childhood stroke. She then obtained a grant from the American Heart Association to perform a population-based study of childhood stroke within Kaiser Permanente, a large managed care organization. This study led to NIH funding for another retrospective Kaiser study on the role of infection in the pathogenesis of childhood stroke. She is now the PI on an NIH-funded prospective 25-center international study entitled, The Vascular effects of Infection in Pediatric Stroke (VIPS). This study will determine the association between common infections and a focal cerebral arteriopathy that is commonly observed in previously healthy children presenting with an ischemic stroke. It will also provide data on recurrence rates after a first childhood stroke. Her long-term goal is to develop clinical trials for primary and secondary stroke prevention in children (ucsf.edu).

Dr. Heather Fullerson graciously shared her proposal with us, and after reading it we could not wait to share it with you! You will find a detailed outline of her Understanding Early Childhood Arterial Ischemic Stroke study in her own words.

Understanding Early Childhood Arterial Ischemic Stroke

Blockage of an artery to the brain causes focal brain injury: an arterial ischemic stroke. Compared to older children, infants and toddlers have a particularly high risk of stroke, accounting for a third of the ≈ 2,500 U.S. children afflicted by ischemic strokes every year. Early strokes have major consequences—cerebral palsy, developmental delay, school difficulties, and epilepsy—yet their etiologies remain elusive. While newborn ischemic brain injury has received considerable attention (particularly birth asphyxia, a condition of global ischemic brain injury), childhood stroke studies are far less common, and do not distinguish strokes in infants and toddlers from those in older children and adolescents. Furthermore, existing stroke studies often focus on diseases of arteries, yet such arteriopathies are likely uncommon in early childhood. As the childhood stroke field moves towards prevention and treatment trials, it is crucial to first characterize early childhood strokes separately from those of newborns or older children in terms of causes and outcomes. While hitherto virtually impossible, we now stand in a unique position to accomplish this.

In 2009, the NIH funded the first-ever large international prospective observational study of childhood stroke, the “Vascular effects of Infection in Pediatric Stroke (VIPS)” study, led by Dr. Heather Fullerton from the University of California, San Francisco (UCSF), and Dr. Gabrielle DeVeber from the Hospital for Sick Children, Toronto. The primary objective of VIPS was to study the role of infection in the cerebral arteriopathies seen in later childhood stroke; the secondary objective was to create a well characterized cohort of children with arterial ischemic stroke that could be used to test other hypotheses. The VIPS study closed enrollment in March, 2014, after the 40 VIPS centers enrolled their target of 350 stroke cases (ages 29 days-18 years) and 350 control children. Based on the age distribution of the first 335 cases analyzed, we anticipate the 350 cases will include 120 with early childhood stroke (0-4 years of age); hence, we now have enough subjects to study these early cases as a distinct subgroup. We propose to use the VIPS cohort to test the overall hypothesis: early childhood stroke is distinct from later childhood stroke in its presentation, etiologies and outcomes, including risk of recurrent stroke. Our specific aims are: (1) in a cross-sectional study, to determine whether early childhood strokes (occurring between 29 days through 4 years of life; n=120) differ from later childhood strokes (n=230) in their presentation, imaging characteristics (size and location of infarction), etiologies, and inflammatory markers; (2) in a case-control study, to determine whether risk factors for childhood stroke are different for children ≤4 years old; and (3) in a prospective cohort study, to determine whether 1-year neurological outcomes and rates of recurrent stroke are different for early childhood stroke.

The proposed study is an ancillary study capitalizing on the extensive data already collected by the parent VIPS study; the only additional primary data collection required is further detailed review of radiologic studies that have been collected in an imaging library. The study setting includes 40 academic institutions from 6 countries (U.S., Canada, Australia, UK, Chile, Philippines, and China). Case inclusion criteria are age 29 days through 18 years; an acute diagnosis of arterial ischemic stroke, fulfilling pre-established clinical and imaging criteria; parental consent to study participation; enrollment within 3 weeks of the stroke symptom onset;parent/guardian willingness to participate in a standardized interview; brain and blood vessel imaging performed; and a study blood sample.

Once a case was enrolled, the site completed on-line baseline forms and performed an extensive standardized interview of the parent/guardian. The site sent CDs of the brain and blood vessel imaging to the VIPS Imaging Core at UCSF. Every enrolled subject underwent a case confirmation process whereby a study pediatric stroke neurologist (H.J.F.) and study neuro-radiologist independently reviewed the imaging studies and clinical history to confirm that the case met pre-specified criteria for inclusion. A team of two study neuro-radiologists reviewed all brain and blood vessel imaging and described both the infarction and any diseased blood vessels. Blood samples were sent to the VIPS Laboratory Core at Columbia University where they are tested for markers of inflammation and recent viral infection. For the proposed study, a pediatric stroke neurologist (H.J.F.) will perform additional imaging review of early childhood stroke cases.

Follow-up assessments are on-going in VIPS through January, 2015 (12 months after the last case enrollment). The site performs an in-person (if the patient is returning for a clinical visit) or telephone follow-up assessment at 4 months, 8 months, and 12 months, and then annually until the study end. Follow-up assessments include a validated questionnaire designed to assess stroke outcomes, including both neurodevelopment and stroke recurrence. At 12 months, the site will also perform chart review using a standardized data collection form to abstract additional data regarding recovery and recurrence. All recurrent strokes will be subjected to a confirmation process that mirrors the initial case confirmation process with centralized review of imaging and clinical findings.

The VIPS Biostatistics Core at UCSF, which performs the analyses for the parent VIPS study, will perform all analyses proposed for this study of early childhood stroke. For the cross-sectional study (Aim 1), the study biostatistician (Nancy K. Hills, PhD) will perform descriptive and statistical analyses to compare features of early childhood stroke (29 days through 4 years of age) to those of later childhood stroke (≥5 years). This will include comparisons of inflammatory markers between the two different age groups. We will use t-tests, chi-square, and Fisher’s exact tests, as appropriate, and logistic regression models. For the case-control study (Aim 2), we will use logistic regression analyses to assess risk factors for early childhood stroke, and compare those to risk factors for later childhood stroke. For the prospective cohort study (Aim 3), we will use survival analysis techniques to compare recurrence rates, and predictors of recurrence, for early childhood stroke versus later childhood stroke. We will also compare neurodevelopmental outcomes between the two age groups.

The results of the proposed study may have an immediate impact on clinical practice by demonstrating that the etiologies of early childhood stroke are distinct; this will affect the etiologic work-up that physicians perform on a young child presenting with a stroke. Our data on outcomes will immediately help physicians counsel families of young children with stroke by providing them data specific to that age group. The results will also have important implications as the field of pediatric stroke now moves towards the design of stroke prevention and treatment clinical trials in children. In particular, they will determine whether it is rational to include both young and older children in the same clinical trial, versus designing trials to address early childhood stroke as a separate entity. (Dr. Heather Fullerton)

We are thrilled that the VIPS was able to collect so much data, and hope that research studies can use that data for years to come! We want to thank Dr. Fullerton for working diligently for children and their families who have been affected by pediatric strokes. We know the results of this study will be a great tool for physicians to use for treatment and prevention of pediatric strokes.

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