Diagnostic Imaging & Radiology

Anna Penn

Protecting the fetal brain from harm

Anna Penn

Ongoing placental dysfunction and allopregnanolone loss, not the increase that was expected due to stress, may alter cortical development in complicated pregnancies and put babies at risk, says Anna Penn, M.D., Ph.D.

Researchers long have known that allopregnanolone (ALLO), a derivative of the hormone progesterone, is produced in adults’ brains during times of acute stress and modulates how easily the brain’s neurons fire. ALLO also is produced in the placenta during fetal development, one of more than 200 different hormones that each uniquely contribute to fostering a smooth pregnancy and maintaining a fetus’ overall health. Although ALLO is thought to protect the developing brain in pregnancies complicated by conditions that might harm it, such as high blood pressure, how its levels evolve during pregnancy and in newborns shortly after birth has remained unknown.

Now, a new study presented during the Pediatric Academic Societies (PAS) 2018 annual meeting suggests that the placenta ramps up ALLO production over the second trimester, peaking just as fetuses approach full term.

To investigate this phenomenon, Anna Penn, M.D., Ph.D., a neonatologist/neuroscientist at Children’s National Health System, and colleagues created a designer experimental model to study how premature loss of ALLO alters orderly brain development. Knowing more about the interplay between ALLO and normal development of the cortex, the outer layer of the cerebrum, is a first step that could lead to strategies to rescue this vital brain region.

“The cortex is basically the brain’s command-and-control center for higher functions. In our experimental model, it develops from the middle of gestation through to the end of gestation. If ALLO levels are disrupted just as these cells are being born, neurons migrating to the cortex are altered and the developing neural network is compromised,” says Dr. Penn, senior author of the research presented at PAS 2018. “We’re concerned this same phenomenon occurs in human infants whose preterm birth disrupts their supply of this essential hormone.”

To better understand the human placental hormone pattern, the research team analyzed cord blood or serum samples collected within the first 36 hours of life for 61 preterm newborns born between 24 to 36 gestational weeks. They compared those preemie samples with samples drawn from 61 newborns carried to term who were matched by race, gender, size for gestational age, delivery method and maternal demographics.

They used liquid-chromatography-tandem mass spectrometry, a technique that can precisely analyze trace levels of compounds, to compare levels of 27 different steroids, including ALLO and its precursors as well as better-known adrenal gland hormones, such as cortisol and 17-Hydroxyprogesterone.

“Pregnancies complicated by hypertension tended to correlate with lower ALLO levels, though this finding did not reach statistical significance. This suggests that ongoing placental dysfunction and ALLO loss, not the increase that we expected to be caused by stress, may alter cortical development in these pregnancies and put babies at risk,” Dr. Penn adds. “In addition, having the largest neonatal sample set to date in which multiple steroid hormones have been measured can provide insight into the shifting hormone patterns that occur around 36 weeks gestation, just prior to term. Hopefully, restoring the normal hormonal milieu for preemies or other at-risk newborns will improve neurological outcomes in the future.”

In addition to Dr. Penn, study co-authors include Caitlin Drumm, MedStar Georgetown University Hospital; Sameer Desale, MedStar Health Research Institute; and Kathi Huddleston, Benjamin Solomon and John Niederhuber, Inova Translational Medicine Institute.

Preemie Baby

Brain food for preemies

Preemie Baby

Babies born prematurely – before 37 weeks of pregnancy – often have a lot of catching up to do. Not just in size. Preterm infants typically lag behind their term peers in a variety of areas as they grow up, including motor development, behavior and school performance.

New research suggests one way to combat this problem. The study, led by Children’s researchers and presented during the Pediatric Academic Societies 2018 annual meeting, suggests that the volume of carbohydrates, proteins, lipids and calories consumed by very vulnerable premature infants significantly contributes to increased brain volume and white matter development, even though additional research is needed to determine specific nutritional approaches that best support these infants’ developing brains.

During the final weeks of pregnancy, the fetal brain undergoes an unprecedented growth spurt, dramatically increasing in volume as well as structural complexity as the fetus approaches full term.

One in 10 infants born in the U.S. in 2016 was born before 37 weeks of gestation, according to the Centers for Disease Control and Prevention. Within this group, very low birthweight preemies are at significant risk for growth failure and neurocognitive impairment. Nutritional support in the neonatal intensive care unit (NICU) helps to encourage optimal brain development among preterm infants. However, their brain growth rates still lag behind those seen in full-term newborns.

“Few studies have investigated the impact of early macronutrient and caloric intake on microstructural brain development in vulnerable preterm infants,” says Katherine Ottolini, lead author of the Children’s-led study. “Advanced quantitative magnetic resonance imaging (MRI) techniques may help to fill that data gap in order to better direct targeted interventions to newborns who are most in need.”

The research team at Children’s National Health System enrolled 69 infants who were born younger than 32 gestational weeks and weighed less than 1,500 grams. The infants’ mean birth weight was 970 grams and their mean gestational age at birth was 27.6 weeks.

The newborns underwent MRI at their term-equivalent age, 40 weeks gestation. Parametric maps were generated for fractional anisotropy in regions of the cerebrum and cerebellum for diffusion tensor imaging analyses, which measures brain connectivity and white matter tract integrity. The research team also tracked nutritional data: Grams per kilogram of carbohydrates, proteins, lipids and overall caloric intake.

“We found a significantly negative association between fractional anisotropy and cumulative macronutrient/caloric intake,” says Catherine Limperopoulos, Ph.D., director of Children’s Developing Brain Research Laboratory and senior author of the research. “Curiously, we also find significantly negative association between macronutrient/caloric intake and regional brain volume in the cortical and deep gray matter, cerebellum and brainstem.”

Because the nutritional support does contribute to cerebral volumes and white matter microstructural development in very vulnerable newborns, Limperopoulos says the significant negative associations seen in this study may reflect the longer period of time these infants relied on nutritional support in the NICU.

In addition to Ottolini and Limperopoulos, study co-authors include Nickie Andescavage, M.D., Attending, Children’s Neonatal-Perinatal Medicine; and Kushal Kapse.

Dorothy Bulas

Dorothy Bulas, M.D., receives the Society for Pediatric Radiology’s highest honor

Dorothy Bulas

Dorothy Bulas, M.D. F.A.C.R., F.A.I.U.M., F.S.R.U., chief of diagnostic imaging and radiology in the Division of Diagnostic Imaging and Radiology at Children’s National Health System, is being recognized at the 2018 Society for Pediatric Radiology Annual Meeting with their most distinguished honor, the Gold Medal.

The Society of Pediatric Radiology (SPR) Gold Medal is awarded to pediatric radiologists who have contributed greatly to the SPR and their subspecialty of pediatric radiology as a scientist, teacher, personal mentor and leader.

Initially, Dr. Bulas completed her residency in pediatrics. During a pediatric radiology rotation at John Hopkins University, she realized how much she loved problem solving and using emerging imaging modalities and went on to complete her radiology residency at Albert Einstein Hospital. Soon after, Dr. Bulas moved to Washington, D.C. to complete a pediatric radiology fellowship at her professional home, Children’s National.

Since the completion of her fellowship, Dr. Bulas views her role in the advancement of fetal imaging as her most significant professional contribution. She has published 131 papers, one of her most recent as a co-author on “Neuroimaging findings in normocephalic infants with Zika virus” in Pediatric Neurology. Dr. Bulas is also a co-author of the textbook entitled Fundamental and Advanced Fetal Imaging and has authored 35 book chapters.

She has served as program director of the Radiology Fellowship Program at Children’s National since 2005 where she has impacted medical students, residents and fellows from the United States and abroad.

As a previous chair member for numerous organizations, Dr. Bulas currently co-chairs the American College of Radiology’s pediatric radiology education committee. She is a founding member of the Image Gently Alliance, where she chaired the outreach campaign to parents and wrote brochures, web material and articles. Dr. Bulas is also a founder of the World Federation of Pediatric Imaging.

Dr. Bulas was honored as an outstanding teacher with the Edward Singleton-Hooshang Taybi Award for Excellence in Education from the SPR and this past fall and as the Outstanding Educator in 2017 by the Radiological Society of North America.

Sudeepta Basu

GABA concentration in pre-term brain increases with gestational age

Sudeepta Basu

“A more complete understanding of the diagnostic and prognostic importance of GABA and glutamate in the preterm brain will help us to direct treatment strategies for the most vulnerable preterm infants at risk of brain injury,” says Sudeepta K. Basu, M.D.

The major neurotransmitters gamma-aminobutyric acid (GABA) and glutamate are pivotal to fetal and newborn brain development and influence evolution of brain injury and repair following preterm birth. Magnetic resonance spectroscopy (MRS) enables in vivo measurement of brain metabolites. However, GABA and glutamate are found in the developing brain in low concentrations, and their weak signal can be swamped by the stronger signal of more dominant metabolites.

A Children’s research team reports findings from a pilot study utilizing an innovative technique of MRS to reliably measure in vivo GABA in the developing preterm brain. The groundbreaking research done by the team that includes Principal Investigator Sudeepta K. Basu, M.D., neonatology attending at Children’s National Health System, is very unique and original since there are no existing data of in vivo GABA concentrations in the developing cerebellum. Under the mentorship of Catherine Limperopoulos, Ph.D., director of Children’s Developing Brain Research Laboratory, the team of multi-disciplinary specialists is pursuing cutting-edge technologies in advanced MRI neuroimaging to explore brain development and injury in preterm infants.

The research, presented at the Eastern Society for Pediatric Research (ESPR) annual meeting by Dr. Basu, was honored with the “2018 Meritorious Poster Award.” The research titled “Distinct temporal trends of GABA and glutamate in the cerebellum and frontal cortex of preterm infants” reports, for the first time, positive temporal trends in the specific regions of the developing brain intricately involved in cognitive and motor functions. This work lays the foundation for developing novel ways to diagnose, monitor and investigative brain protective therapies for vulnerable prematurely born infants.

The Children’s team performed non-sedated MRS in 44 preterm infants whose mean gestational age at birth was 26.5 weeks, placing voxels at the middle of the cerebellum and the right frontal cortex. GABA and GIx (glutamate combined with glutamine) were positively correlated with post-menstrual age in the frontal cortex, but not the cerebellum.  At the ESPR meeting, the team also presented for the first time that caffeine, a neuroprotective agent in preemies, leads to increased in vivo GABA concentration in the developing frontal cortex.

“Open questions include whether these findings reflect varying paces of maturation and vulnerability to injury among specific regions of the brain. Also, the relationship between clinical factors and medication exposure and changes in the concentration of these neurotransmitters may guide brain protective therapies in future,” Dr. Basu says. “A more complete understanding of the diagnostic and prognostic importance of GABA and glutamate in the preterm brain will help us to direct treatment strategies for the most vulnerable preterm infants at risk of brain injury.”

Children’s senior fellows from Division of Neonatology made four platform presentations during the ESPR conference:

  • “Caffeine increases GABA/Cr ratio in frontal cortex of preterm infants on spectroscopy.” Aditi Gupta; Sudeepta K. Basu, M.D.; Mariam Said, M.D.; Subechhya Pradhan, Linda White; Kushal Kapse; Jonathan Murnick, M.D., Ph.D.; Taeun Chang, M.D.; and Catherine Limperopoulos, Ph.D.
  • “Impact of early nutrition on microstructural brain development in VLBW Infants.” Katherine M. Ottolini, Nickie Andescavage, M.D.; Kushal Kapse; and Catherine Limperopoulos, Ph.D.
  • “Direct measurement of neonatal cardiac output utilizing the CO status monitor.” Simranjeet S. Sran, Mariam Said, M.D.; and Khodayar Rais-Bahrami, M.D.
  • “Cerebro-cerebellar diaschisis in preterm infants following unilateral cerebral parenchymal injury.” Huma Mirza, Yao Wu, Kushal Kapse, Jonathan Murnick, M.D., Ph.D.; Taeun Chang, M.D.; and Catherine Limperopoulos, Ph.D.
Sarah Mulkey

MRI finds novel brain defects in Zika-exposed newborns

Sarah Mulkey

“Imaging is constantly helping us make new discoveries with this virus, and in these two cases we found things that had not been previously described,” says Sarah Mulkey, M.D., Ph.D.

Magnetic resonance imaging (MRI) has identified two brain abnormalities never before reported in newborns with prenatal exposure to the Zika virus. Children’s National Health System researchers reported these findings from a study of more than 70 fetuses or newborns with Zika exposure in utero. The study was published in the January 2018 edition of Pediatric Neurology.

The two novel defects – cranial nerve enhancement and cerebral infarction – may join the growing list of neurological findings associated with congenital Zika infection.

“Imaging is constantly helping us make new discoveries with this virus, and in these two cases we found things that had not been previously described,” says Sarah Mulkey, M.D., Ph.D., the study’s lead author and a fetal-neonatal neurologist at Children’s National. Dr. Mulkey works in Children’s Congenital Zika Virus Program, one of the nation’s first comprehensive, dedicated Zika programs.

The research team recommends that postnatal brain MRI be considered in addition to ultrasound for newborns exposed to Zika in utero. “Brain MRI can be performed in the newborn often without sedation and provides an opportunity to look for brain abnormalities we might not catch otherwise – or might not detect until much later,” says Dr. Mulkey.

Birth defects are seen in 6 to 11 percent of pregnancies affected by Zika, and some of the neurological complications in infants are not apparent until well after birth.

Of the two infants in which the new abnormalities were observed, both had normal head size at birth. Neither had smaller-than-normal head size (microcephaly), one of the more severe effects associated with congenital Zika syndrome.

One infant had a normal neurological evaluation at 2 days of age. However, a brain MRI conducted the following day, using gadolinium contrast due to concern of infection, showed enhancement of multiple cranial nerves. “Nerve root enhancement is very rare in a newborn and had not been described with Zika before,” Dr. Mulkey says. “Yet, there was no neurological deficit that we could identify by physical exam.”

The research team acknowledges that the clinical significance of this finding is not yet known.

In the second patient, brain MRI conducted without contrast at 16 days of age revealed a small area consistent with chronic infarction (ischemic stroke) that likely occurred during the third trimester.

“We followed the mother throughout her pregnancy, and both MRI and ultrasound imaging were normal at 28 weeks gestation,” Dr. Mulkey says. “A postnatal ultrasound was also normal, but the postnatal MRI showed a stroke that had occurred at least one month prior to the MRI and after the last fetal study.”

She adds: “This is the first published report of fetal stroke associated with Zika infection, and it may add to our knowledge of what can occur with congenital Zika infection.”

Unlike most congenital infections, Zika virus does not appear to cause viral-induced placental inflammation, which can lead to fetal stroke. So, the authors say they cannot be sure that congenital Zika contributed to the infarct in this case. However, they write, “Given the relatively low incidence of perinatal ischemic infarct and the lack of other maternal- or birth-related risk factors for this patient, Zika infection is considered a possible etiology.”

In both patients, neonatal brain MRI identified subclinical findings that had not previously been described as part of congenital Zika syndrome. As the body of evidence about the Zika virus has grown, the spectrum of associated brain abnormalities has expanded to include considerably more findings than isolated microcephaly.

Data gathered in 2017 from the Centers for Disease Control and Prevention’s Zika pregnancy and infant registry indicates that 25 percent of eligible U.S. infants receive recommended postnatal imaging. Dr. Mulkey said this represents many possible missed opportunities for earlier identification of brain abnormalities.

“Brain MRI should be considered in all newborns exposed to Zika virus in utero, even in the presence of normal birth head circumference, normal cranial ultrasound and normal fetal imaging,” she says. “In both of these patients, the changes we observed were not evident on cranial ultrasound or on fetal MRI and fetal ultrasound.”

In addition to Dr. Mulkey, Children’s co-authors include L. Gilbert Vezina, M.D., Neuroradiology Program director; Dorothy I. Bulas, M.D., chief of Diagnostic Imaging and Radiology; Zarir Khademian, M.D., radiologist; Anna Blask, M.D., radiologist; Youssef A. Kousa, M.S., D.O., Ph.D., child neurology fellow; Lindsay Pesacreta, FNP; Adré  J. du Plessis, M.B.Ch.B., M.P.H., Fetal Medicine Institute director; and Roberta L. DeBiasi, M.D., M.S., senior author and Pediatric Infectious Disease division chief; and Caitlin Cristante, B.S.

Financial support for this research was provided by the Thrasher Research Fund.

banner year

2017: A banner year for innovation at Children’s National

banner year

In 2017, clinicians and research faculty working at Children’s National Health System published more than 850 research articles about a wide array of topics. A multidisciplinary Children’s Research Institute review group selected the top 10 articles for the calendar year considering, among other factors, work published in high-impact academic journals.

“This year’s honorees showcase how our multidisciplinary institutes serve as vehicles to bring together Children’s specialists in cross-cutting research and clinical collaborations,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “We’re honored that the National Institutes of Health and other funders have provided millions in awards that help to ensure that these important research projects continue.”

The published papers explain research that includes using imaging to describe the topography of the developing brains of infants with congenital heart disease, how high levels of iron may contribute to neural tube defects and using an incisionless surgery method to successfully treat osteoid osteoma. The top 10 Children’s papers:

Read the complete list.

Dr. Batshaw’s announcement comes on the eve of Research and Education Week 2018 at Children’s National, a weeklong event that begins April 16, 2018. This year’s theme, “Diversity powers innovation,” underscores the cross-cutting nature of Children’s research that aims to transform pediatric care.

Kirsten-M.-Williams

Helpful, hopeful news for bone marrow transplant patients

Kirsten-M.-Williams

Research published online Dec. 13, 2017, by The Lancet Haematology and co-led by Kirsten M. Williams, M.D., suggests that a new imaging agent can safely show engraftment as early as days after transplant – giving a helpful and hopeful preview to patients and their doctors.

Leukemia can be a terrifying diagnosis for the more than 60,000 U.S. patients who are told they have this blood cancer every year. But the treatment for this disease can be just as frightening. For patients with certain forms of leukemia, the only chance they have for a cure is to receive a massive dose of radiation and chemotherapy that kills their hematopoietic stem cells (HSCs), the cells responsible for making new blood, and then receive new HSCs from a healthy donor.

While patients are waiting for these new cells to go to the bone marrow factory and begin churning out new blood cells, patients are left without an immune system. Devoid of working HSCs for two to four weeks – or longer, if a first transplant doesn’t take – patients are vulnerable to infections that can be just as deadly as their original cancer diagnosis.

As they wait in the protected confines of a hospital, patients who undergo HSC transplants receive blood tests every day to gauge successful engraftment, searching for the presence of immune cells called neutrophils, explains Kirsten M. Williams, M.D., blood and bone marrow transplant specialist at Children’s National Health System.

“As you head into week three post-transplant and a patient’s cell counts remain at zero, everyone starts to get nervous,” Dr. Williams says. The longer a patient goes without an immune system, the higher the chance that they’ll develop a life-threatening infection. Until recently, Dr. Williams says, there has been no way beyond those daily blood tests to assess whether the newly infused cells have survived and started to grow early healthy cells in the bone marrow, a process called engraftment.

A new study could change that paradigm. Research published online Dec. 13, 2017, by The Lancet Haematology and co-led by Dr. Williams suggests that a new imaging agent can safely show engraftment as early as days after transplant – giving a helpful and hopeful preview to patients and their doctors.

The study evaluated an investigational imaging test called 18F-fluorothymidine (18F-FLT). It’s a radio-labeled analogue of thymidine, a natural component of DNA. Studies have shown that this compound is incorporated into just three white blood cell types, including HSCs. Because it’s radioactive, it can be seen on various types of common clinical imaging exams, such as positron emission tomography (PET) and computed tomography (CT) scans. Thus, after infusion, the newly infused developing immune system and marrow is readily visible.

To see whether this compound can readily and safely visualize transplanted HSCs, Dr. Williams and colleagues tested it on 23 patients with various forms of high-risk leukemia.

After these patients received total-body irradiation to destroy their own HSCs, they received donor HSCs from relatives or strangers. One day before they were infused with these donor cells, and then at five or nine days, 28 days, and one year after transplantation, the patients underwent imaging with the novel PET/and CT scan imaging platform.

Each of these patients had successful engraftment, reflected in blood tests two to four weeks after their HSC transplants. However, the results of the imaging exams revealed a far more complicated and robust story.

With 18F-FLT clearly visible in the scans, the researchers saw that the cells took a complex journey as they engrafted. First, they migrated to the patients’ livers and spleens. Next, they went to the thoracic spine, the axial spine, the sternum, and the arms and legs. By one year, most of the new HSCs were concentrated in the bones that make up the trunk of the body, including the hip, where most biopsies to assess marrow function take place.

Interestingly, notes Dr. Williams, this pathway is the same one that HSCs take in the fetus when they first form. Although experimental model research had previously suggested that transplanted HSCs travel the same route, little was known about whether HSCs in human patients followed suit.

The study also demonstrated that the radiation in 18F-FLT did not adversely affect engraftment. Additionally, images could identify success of their engraftments potentially weeks faster than they would have through traditional blood tests – a definite advantage to this technique.

“Through the images we took, these patients could see the new cells growing in their bodies,” Dr. Williams says. “They loved that.”

Besides providing an early heads up about engraftment status, she adds, this technique also could help patients avoid painful bone marrow biopsies to make sure donor cells have taken residence in the bones or at the very least help target those biopsies. It also could be helpful for taking stock of HSCs in other conditions, such as aplastic anemia, in which the body’s own HSCs fade away. And importantly, if the new healthy cells don’t grow, this test could signal this failure to doctors, enabling rapid mobilization of new cells to avert life-threatening infections and help us save lives after transplants at high risk of graft failure.

“What happens with HSCs always has been a mystery,” Dr. Williams says. “Now we can start to open that black box.”

Dr. Williams’ co-authors include co-lead author Jennifer Holter-Chakrabarty, M.D., Quyen Duong, M.S., Sara K. Vesely, Ph.D., Chuong T. Nguyen, Ph.D., Joseph P. Havlicek, Ph.D., George Selby, M.D., Shibo Li, M.D., and Teresa Scordino, M.D., University of Oklahoma; Liza Lindenberg, M.D., Karen Kurdziel, M.D., Frank I. Lin, M.D., Daniele N. Avila, N.P., Christopher G. Kanakry, M.D., Stephen Adler, Ph.D., Peter Choyke, M.D., and senior author Ronald E. Gress, M.D., National Cancer Institute; Juan Gea-Banacloche, M.D., Mayo Clinic Arizona; and Catherine “Cath” M. Bollard, M.D., MB.Ch.B., Children’s National.

Research reported in this story was supported by the National Institutes of Health, Ben’s Run/Ben’s Gift, Albert and Elizabeth Tucker Foundation, Mex Frates Leukemia Fund, Jones Family fund and Oklahoma Center for Adult Stem Cell Research.

newborn in incubator

Tracking oxygen saturation with vital signs to identify vulnerable preemies

 

Khodayar-Rais-Bahrami

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What’s known

Critically ill infants in neonatal intensive care units (NICU) require constant monitoring of their vital signs. Invasive methods, such as using umbilical arterial catheters to check blood pressure, are the gold standard but pose significant health risks. Low-risk noninvasive monitoring, such as continuous cardiorespiratory monitors, can measure heart rate, respiratory rate and blood oxygenation. A noninvasive technique called near-infrared spectroscopy (NIRS) can gauge how well tissues, including the brain, are oxygenated. While NIRS long has been used to monitor oxygenation in conditions in which blood flow is altered, such as bleeding in the brain, how NIRS values relate to other vital sign measures in NICU babies was unknown.

What’s new

A research team led by Khodayar Rais-Bahrami, M.D., a neonatologist at Children’s National Health System, investigated this question in 27 babies admitted to Children’s NICU. The researchers separated these subjects into two groups: Low birth weight (LBW, less than 1.5 kg or 3.3 pounds) and moderate birth weight (MBW, more than 1.5 kg). Then, they looked for correlations between information extracted from NIRS, such as tissue oxygenation (specific tissue oxygen saturation, StO2) and the balance between oxygen supply and consumption (fractional tissue oxygen extraction, FTOE), and various vital signs. They found that StO2 increased with blood pressure for LBW babies but decreased with blood pressure for MBW babies. Brain and body FTOE in LBW babies decreased with blood pressure. In babies with abnormal brain scans, brain StO2 increased with blood pressure and brain FTOE decreased with blood pressure. Together, the researchers suggest, these measures could give a more complete picture of critically ill babies’ health.

Questions for future research

Q: Can NIRS data be used as a surrogate for other forms of monitoring?

Q: How could NIRS data help health care professionals intervene to improve the health of critically ill infants in the NICU?

Source: Significant correlation between regional tissue oxygen saturation and vital signs of critically ill infants.” B. Massa-Buck, V. Amendola, R. McCloskey and K. Rais-Bahrami. Published by Frontiers in Pediatrics Dec. 21, 2017.

Pregnant-Mom

MRI opens new understanding of fetal growth restriction

Pregnant-Mom

Quantitative MRI can identify placental dysfunction complicated by fetal growth restriction earlier, creating the possibility for earlier intervention to minimize harm to the developing fetus.

A team of researchers has found that quantitative magnetic resonance imaging (MRI) can identify pregnancies where placental dysfunction results in fetal growth restriction (FGR), creating the possibility for earlier FGR detection and intervention to augment placental function and thus minimize harm to the fetal brain.

The study, published online in the Journal of Perinatology, reports for the first time that in vivo placental volume is tied to global and regional fetal brain volumes.

Placental insufficiency is a known risk factor for impaired fetal growth and neurodevelopment. It may cause the fetus to receive inadequate oxygen and nutrients, making it difficult to grow and thrive. The earlier placental insufficiency occurs in a pregnancy, the more serious it can be. But detecting a failing placenta before the fetus is harmed has been difficult.

One additional challenge is that a fetus may be small because the placenta is not providing adequate nourishment. Or the fetus simply may be genetically predisposed to be smaller. Being able to tell the difference early can have a lifelong impact on a baby. Infants affected by FGR can experience behavioral problems, learning difficulties, memory and attention deficits, and psychiatric issues as the child grows into adolescence and adulthood.

“Our study proved that MRI can more accurately determine which pregnancies are at greater risk for impaired fetal health or compromised placenta function,” says Nickie Andescavage, M.D., the study’s lead author and a specialist in neonatology and neonatal neurology and neonatal critical care at Children’s National Health System. “The earlier we can identify these pregnancies, the more thoughtful we can be in managing care.”

Dr. Andescavage’s research focus has been how fetal growth affects labor, delivery and postnatal complications.

Nickie-Andescavage-Niforatos

“Our study proved that MRI can more accurately determine which pregnancies are at greater risk for impaired fetal health or compromised placenta function,” says Nickie Andescavage, M.D., the study’s lead author.

“We don’t have a good understanding of why FGR happens, but we do know it’s hard to identify during pregnancy because often there are no signs,” says Dr. Andescavage. “Even when detected, it’s hard to follow. But if we’re aware of it, we can better address important questions, like when to deliver an at-risk fetus.”

In the study, the team measured placental and fetal brain growth in healthy, uncomplicated pregnancies and in pregnancies complicated by FGR. A total of 114 women participated, undergoing ultrasound, Doppler ultrasound and MRI imaging to measure placental volume and fetal brain volume.

An ultrasound test is often what detects FGR, but the measurements generated by ultrasound can be non-specific. In addition, reproducibility issues with 3D sonography limit its use as a standalone tool for placental assessment. Once FGR is detected via ultrasound, this study showed that complementary MRI provides more accurate structural measures of the fetal brain, as well as more detail and insight into placental growth and function.

“Our team has studied FGR for a few years, using imaging to see that’s happening with the fetus in real time,” says Dr. Andescavage. “The relationship of placental volume and fetal brain development had not been previously studied in utero.”

In pregnancies complicated by FGR, MRI showed markedly decreased placental and brain volumes. The team observed significantly smaller placental, total brain, cerebral and cerebellar volumes in these cases than in the healthy controls. The relationship between increasing placental volume and increasing total brain volume was similar in FGR and in normal pregnancies. However, the study authors write “the overall volumes were smaller and thus shifted downward in pregnancies with FGR.”

In addition, FGR-complicated pregnancies that also showed abnormalities in Doppler ultrasound imaging had even smaller placental, cerebral and cerebellar volumes than pregnancies complicated by FGR that did not have aberrations in Doppler imaging.

Since this study showed that quantitative fetal MRI can accurately detect decreased placental and brain volumes when FGR is present, Dr. Andescavage believes this imaging technique may give doctors important new insights into the timing and possibly the mechanisms of brain injury in FGR.  “Different pathways can lead to FGR. With this assessment strategy, we could potentially elucidate those,” she adds.

Using quantitative MRI to identify early deviations from normal growth may create opportunities for future interventions to protect the developing fetal brain. New treatments on the horizon promise to address placental health. MRI could be used to investigate these potential therapies in utero. When those therapies become available, it could allow doctors to monitor treatment effects in utero.

Study co-authors include Adré J. du Plessis, M.B.Ch.B., M.P.H., Director of Children’s Fetal Medicine Institute; Marina Metzler; Dorothy Bulas, M.D., FACR, FAIUM, FSRU, Chief of Children’s Division of Diagnostic Imaging and Radiology; L. Gilbert Vezina, M.D., Director of Children’s Neuroradiology Program; Marni Jacobs; Catherine Limperopoulos, Ph.D., Director of Children’s Developing Brain Research Laboratory and study senior author; Sabah N. Iqbal, MedStar Washington Hospital Center; and Ahmet Alexander Baschat, Johns Hopkins Center for Fetal Therapy.

Research reported in this post was supported by the Canadian Institutes of Health Research, MOP-81116; the National Institutes of Health under award numbers UL1TR000075 and KL2TR000076; and the Clinical and Translational Science Institute at Children’s National.

Neonatal baby

Multidisciplinary experts help CDC’s Zika research

“We are very excited about this next phase in our Zika research,” says Roberta L. DeBiasi, M.D., M.S. “It is a natural extension of our earlier participation as subject matter experts assisting as the CDC developed and published guidelines to inform the care of Zika-exposed and Zika-infected infants across the nation and U.S. territories.”

The Centers for Disease Control and Prevention (CDC) is funding three multidisciplinary experts from the Congenital Zika Virus Program at Children’s National Health System to collaborate on two of the CDC’s longitudinal Zika research projects in Colombia, South America.

“Zika en embarazadas y niños en Colombia” (ZEN) is a research study jointly designed by Colombia’s Instituto Nacional de Salud (INS) and the CDC to evaluate the association between Zika virus infection and adverse maternal, fetal and infant health outcomes. The study is following a large cohort of Colombian women from the first trimester of pregnancy, their male partners and their infants.

Under the six-month contract, Roberta L. DeBiasi, M.D., M.S., Sarah B. Mulkey, M.D., Ph.D., and Cara Biddle, M.D., M.P.H., will serve as consultants for the ZEN study providing expertise in pediatric infectious diseases, neurology, neurodevelopment and coordination of the complex care needs of Zika-affected infants.

The federal funding will underwrite the consultants’ work effort, as well as travel to the CDC’s headquarters in Atlanta and to research sites in Colombia. To that end, Drs. DeBiasi, Mulkey and Biddle participated in a December 2017 kickoff meeting, joining ZEN team leaders based in the U.S. at the CDC, as well as the INS in Colombia, with whom they will conduct research and collaborate academically.

Cara-Biddle-and-Sarah-Mulkey

Cara Biddle, M.D., M.P.H., and Sarah B. Mulkey, M.D., Ph.D., also will serve as consultants for the ZEN study.

“We are very excited about this next phase in our Zika research,” says Dr. DeBiasi, chief of the Division of Pediatric Infectious Diseases and co-director of the Children’s Zika program. “It is a natural extension of our earlier participation as subject matter experts assisting as the CDC developed and published guidelines to inform the care of Zika-exposed and Zika-infected infants across the nation and U.S. territories.”

Children’s National is leading its own longitudinal studies in Colombia that explore such questions as whether Zika-exposed infants whose neuroimaging appears normal when they are born experience any longer-term neurological issues and the role of genetics in neurologic injury following congenital Zika virus exposure and infection.

Dr. Laura Olivieri holding a 3D printed heart

Cardiology and radiology experts to participate in CMR 2018

Later this month, the international cardiovascular magnetic resonance (CMR) community will gather in Barcelona, Spain, for CMR 2018, a joint meeting organized by the European Association of Cardiovascular Imaging (EACVI) and the Society for Cardiovascular Magnetic Resonance (SCMR). Among the many attendees will be several cardiology and radiology experts from Children’s National Heart Institute:

  • Pediatric cardiology fellow Ashish Doshi, M.D., will be giving a talk titled, “Subendocardial resting perfusion defect in a case of acute fulminant myocarditis,” and will also present a poster titled, “Native T1 measurements in pediatric heart transplant patients correlate with history of prior rejection episodes.”
  • Pediatric cardiology fellow Rohan Kumthekar, M.D., will present a poster titled, “Native T1 values can identify pediatric patients with myocarditis.”
  • Cardiologist Laura Olivieri, M.D., will present two posters: “Native T1 measurements from CMR identify severity of myocardial disease over time in patients with Duchenne muscular dystrophy on therapy,” and “Feasibility of noncontrast T1 and T2 parametric mapping in assessment of acute ventricular ablation lesions in children.”
  • Pediatric cardiology fellow Neeta Sethi, M.D., will present a poster titled, “Cardiac magnetic resonance T2 mapping in the surveillance of acute allograft rejection in pediatric cardiac transplant patients.”

Additionally, Drs. Doshi and Sethi and Ileen Cronin, FNP-BC, a nurse practitioner in the Cardiac Catheterization Laboratory/Interventional Cardiac Magnetic Resonance (ICMR) Program, received travel awards to attend the conference.

CMR 2018 will be held January 31-February 3, 2018 and will focus on the theme of “Improving Clinical Value by Technical Advances.” The meeting’s emphasis will be on the common goal of improving clinical outcomes in cardiovascular disease through innovation in basic MR development and medical engineering.

Volumetric imaging of upper airways

Preemies’ narrowed upper airways may explain higher OSA risk

Volumetric imaging of upper airways

The airway structures of interest to the Children’s National research team included the nasopharynx (labeled red), oropharynx (labeled purple), hypopharynx (labeled green), adenoids (labeled yellow) and tonsils (labeled blue). The team displayed the volumetric imaging in three perpendicular planes and a three-dimensional model.
Credit: A. Smitthimedhin, et al, Clinical Imaging.

Infants born preterm have significantly lower nasopharyngeal and oropharyngeal volumes, compared with newborn peers carried to full term, and those lower airway volumes are independent of the infants’ gender, ethnicity or weight, according to a study published online Dec. 16, 2017 in Clinical Imaging.

According to the Centers for Disease Control and Prevention, 1 in 10 babies born in the United States is preterm, or born prior to the 37th gestational week. Premature birth leaves these children more susceptible to disordered breathing while sleeping, including obstructive sleep apnea (OSA), an ailment characterized by increased upper-airway resistance that narrows airways.

“In addition to finding some airway volumes were smaller in preterm infants, our results indicated both sets of newborns had similar hypopharyngeal volumes. This suggests that risk factors that lead to OSA are confined to the uppermost airway and do not appear to be explained by enlarged adenoids and tonsils,” says Anilawan Smitthimedhin, a Children’s National Health System radiology research fellow at the time the study was performed and lead author of the paper.

In order to diagnose OSA, clinicians now use bronchoscopy, but the method has limitations, including the need to insert a lighted instrument into the airway, which can affect pressure and resistance within the airway.

The Children’s National research team theorized that magnetic resonance imaging (MRI) could offer a non-invasive way to evaluate the upper airway, determine its anatomy and dynamic function, while shielding infants from radiation exposure that can accompany other imaging techniques.

They enrolled 96 infants who had undergone brain MRIs as part of an unrelated study about neonatal brain development. The newborns had a range of medical conditions, including suspected hypoxic ischemic encephalopathy, cardiac disease and seizures/movement disorders.

Forty-nine of the infants were born preterm; at the time of the MRI, their corrected mean gestational age was 38.4 weeks. Forty-seven of the newborns were born full term; they received MRIs at 1.7 weeks of age. The airway structures of interest included the nasopharynx (the upper part of the pharynx), oropharynx (located at the back of the mouth behind the oral cavity), hypopharynx (the entrance into the esophagus), adenoids and tonsils. The team displayed the volumetric imaging in three perpendicular planes and a three-dimensional model.

“Nasopharyngeal volume of full-term infants was 495.6 mm, compared with 221.1 mm in preterm infants. Oropharyngeal volume of full-term infants was 313.6 mm, compared with 179.3 mm in preterm infants,” Smitthimedhin says.

Aided by volumetric 3D data that more accurately measures airway and lymphoid tissue, the team proposes to study a larger group of infants to determine whether narrowing of the uppermost airways predisposes very young children to experiencing OSA later in life.

“Ultimately, our goal is to incorporate dedicated, dynamic MR imaging of the airway while children sleep, which would provide real-time, detailed information about the changes associated with sleep. This innovation holds the promise of leading to more accurate, non-invasive diagnosis of OSA in infants,” says Dorothy Bulas, M.D., chief of Diagnostic Imaging and Radiology at Children’s National.

Children’s National study co-authors include Radiologist Matthew Whitehead, M.D.; University of Maryland student Mahya Bigdeli; Pulmonologist Gustavo Nino Barrera, M.D.; Pulmonologist Geovanny Perez, M.D,; and Hansel Otero, who was at Children’s National when the research work was performed but now works at Children’s Hospital of Philadelphia.

William Gaillard

Putting childhood epilepsy in the spotlight at American Epilepsy Society Meeting

William Gaillard

“We aim to build the evidence base for treatments that are effective specifically for children with epilepsy,” says William D. Gaillard, M.D., chief of Child Neurology, Epilepsy and Neurophysiology, and director of the Comprehensive Pediatric Epilepsy Program.

While epilepsy affects people of all ages, the unique way it manifests in infants, children and adolescents can be attributed in part to the complexities of the growing and developing brain. Researchers from the Children’s National Comprehensive Pediatric Epilepsy Program brought their expertise on the challenges of understanding and treating epilepsy in children to the recent American Epilepsy Society Annual Meeting, the largest professional gathering on epilepsy in the world.

“We aim to build the evidence base for treatments that are effective specifically for children with epilepsy,” says William D. Gaillard, M.D., chief of Child Neurology, Epilepsy and Neurophysiology, and director of the Comprehensive Pediatric Epilepsy Program. “We have learned much from studies in adult populations but technologies like functional MRI allow us to get in-depth understanding, often in non-invasive ways, of precisely how epilepsy is impacting a child.”

Dr. Gaillard was also recently elected to serve as the Second Vice President of the American Epilepsy Society. “The AES is the largest multidisciplinary professional and scientific society dedicated to the understanding, treatment and eradication of epilepsy and associated disorders, and I am honored to serve as the new Second Vice President,” he said.

The team’s presentations and poster sessions focused on several key areas in pediatric epilepsy:

Better ways to see, measure and quantify activity and changes in the brain for children with epilepsy before, during and after surgery

  • Novel applications of fMRI for children with epilepsy
    • Evaluation of an fMRI tool that tracks verbal and visual memory in children with epilepsy – one of the first to capture memory functions in this population of children using noninvasive fMRI;
    • Early study of the use of “resting-state” fMRI to map language skills before epilepsy surgery – an important first step toward noninvasively evaluating children who are too young or neurologically impaired to follow tasks in traditional MRI studies;
  • A study of whether intraoperative MRI, i.e. imaging during neurosurgery, allows for more complete removal of abnormal brain tissue associated with focal cortical dysplasia in children, which is a common cause of intractable epilepsy;
  • A preliminary case review of existing data to see if arterial spin labeling MRI, which measures blood flow to the brain, has potential to identify blood flow changes in specific locations of the brain where seizures occur;
  • An analysis of language laterality – the dominant side of the brain controlling language –  questioning the true reasons that the brains of children with epilepsy have differences in the hemisphere that predominantly controls language;
  • A review of some common assessments of language and working memory that are used pre- and post-operatively to gauge the impacts of pediatric epilepsy surgery. The study found that using multiple assessments, and studying results individually rather than as a group average, resulted in a more complete picture of the outcomes of surgery on these areas of brain function;
  • A preliminary study examining whether continuous EEG monitoring of neonates with hypoxic ischemic encephalopathy, or lack of oxygen to the brain, can be a reliable predictor of neurodevelopmental outcomes while the infant is undergoing therapeutic hypothermia.

“In order to expand our understanding of causes, impacts and outcomes, the range of research is broad given the complexity of epilepsy,” says Madison M. Berl, Ph.D. “This is the only way we can contribute to the goal of providing our colleagues and the families they serve with better resources to make informed decisions about how best to assess and treat pediatric epilepsy.”

The molecular, genetic and biological factors that contribute to onset and severity of pediatric epilepsy

  • A retrospective study of young patients with malformations in cortical development that are important causes of childhood epilepsy;
  • Investigation of a simple saliva test to effectively identify the presence of two common viral infections, human herpesvirus-6B and Epstein-Barr virus, that may be contributors to onset of epilepsy in otherwise normally functioning brains;
  • A preliminary review of the possible relationship between febrile infection-related epilepsy syndrome and the co-occurrence of another neuro-inflammatory condition – hemophagocytic lymphohistiocytosis.

Madison Berl, Ph.D., director of research in the Division of Pediatric Neuropsychology, and a pediatric neuropsychologist in the Comprehensive Pediatric Epilepsy Program, adds, “In order to expand our understanding of causes, impacts and outcomes, the range of research is broad given the complexity of epilepsy. This is the only way we can contribute to the goal of providing our colleagues and the families they serve with better resources to make informed decisions about how best to assess and treat pediatric epilepsy.”

the cerebral blood flow (CBF) maps, corresponding anatomical image aligned to the CBF map, and the regions of interest examined

Tracking preemies’ blood flow to monitor brain maturation

Blood is the conduit through which our cells receive much of what they need to grow and thrive. The nutrients and oxygen that cells require are transported by this liquid messenger. Getting adequate blood flow is especially important during the rapid growth of gestation and early childhood – particularly for the brain, the weight of which roughly triples during the last 13 weeks of a typical pregnancy. Any disruption to blood flow during this time could dramatically affect the development of this critical organ.

Now, a new study by Children’s National Health System researchers finds that blood flow to key regions of very premature infants’ brains is altered, providing an early warning sign of disturbed brain maturation well before such injury is visible on conventional imaging. The prospective, observational study was published online Dec. 4, 2017 by The Journal of Pediatrics.

“During the third trimester of pregnancy, the fetal brain undergoes an unprecedented growth spurt. To power that growth, cerebral blood flow increases and delivers the extra oxygen and nutrients needed to nurture normal brain development,” says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National and senior author of the study. “In full-term pregnancies, these critical brain structures mature inside the protective womb where the fetus can hear the mother and her heartbeat, which stimulates additional brain maturation. For infants born preterm, however, this essential maturation process happens in settings often stripped of such stimuli.”

The challenge: How to capture what goes right or wrong in the developing brains of these very fragile newborns? The researchers relied on arterial spin labeling (ASL) magnetic resonance (MR) imaging, a noninvasive technique that labels the water portion of blood to map how blood flows through infants’ brains in order to describe which regions do or do not receive adequate blood supply. The imaging work can be done without a contrast agent since water from arterial blood itself illuminates the path traveled by cerebral blood.

“In our study, very preterm infants had greater absolute cortical cerebral blood flow compared with full-term infants. Within regions, however, the insula (a region critical to experiencing emotion), anterior cingulate cortex (a region involved in cognitive processes) and auditory cortex (a region involved in processing sound) for preterm infants received a significantly decreased volume of blood, compared with full-term infants. For preterm infants, parenchymal brain injury and the need for cardiac vasopressor support both were correlated with decreased regional CBF,” Limperopoulos adds.

The team studied 98 preterm infants who were born June 2012 to December 2015, were younger than 32 gestational weeks at birth and who weighed less than 1,500 grams. They matched those preemies by gestational age with 104 infants who had been carried to term. The brain MRIs were performed as the infants slept.

Blood flows where it is needed most with areas of the brain that are used more heavily commandeering more oxygen and nutrients. Thus, during brain development, CBF is a good indicator of functional brain maturation since brain areas that are the most metabolically active need more blood.

the cerebral blood flow (CBF) maps, corresponding anatomical image aligned to the CBF map, and the regions of interest examined

This figure represents the cerebral blood flow (CBF) maps, corresponding anatomical image aligned to the CBF map, and the regions of interest examined. The scale indicates the quantitative value of the CBF map and is expressed in mL/100g/min. The data are from a preterm infant scanned at term age without evidence of brain injury. The insula (see black arrows in panel ‘D’) may be particularly vulnerable to the added stresses of the preterm infant’s life outside the womb.
Credit: M. Bouyssi-Kobar, et al., The Journal of Pediatrics.

“The ongoing maturation of the newborn’s brain can be seen in the distribution pattern of cerebral blood flow, with the greatest volume of blood traveling to the brainstem and deep grey matter,” says Marine Bouyssi-Kobar, M.S., the study’s lead author. “Because of the sharp resolution provided by ASL-MR images, our study finds that in addition to the brainstem and deep grey matter, the insula and the areas of the brain responsible for sensory and motor functions are also among the most oxygenated regions. This underscores the critical importance of these brain regions in early brain development. In preterm infants, the insula may be particularly vulnerable to the added stresses of life outside the womb.”

Of note, compromised regional brain structures in adults are implicated in multiple neurodevelopmental disorders. “Altered development of the insula and anterior cingulate cortex in newborns may represent early warning signs of preterm infants at greater risk for long-term neurodevelopmental impairments,” Limperopoulos says.

Research reported in this post was supported by the Canadian Institutes of Health Research, MOP-81116; the SickKids Foundation, XG 06-069; and the National Institutes of Health under award number R01 HL116585-01.

Dorothy Bulas

Congratulations to Dorothy Bulas, M.D. – 2017 RSNA Outstanding Educator recipient

Dorothy Bulas

Dorothy Bulas, M.D., section head of ultrasound and fetal imaging at Children’s National Health System, was honored with the RSNA 2017 Outstanding Educator award at the Radiological Society of North America’s (RSNA) Annual Meeting, held November 26 – December 1 in Chicago, Illinois.

The winner of the award is selected annually by the RSNA Board of Directors based on the awardee’s significant contributions and long-term commitment – 15 years or more – to radiologic education.

“In addition to being a talented clinician and an accomplished researcher, Dr. Bulas is an extraordinary teacher who has made tireless contributions to the educational programs of RSNA,” said RSNA President Richard L. Ehman, M.D. “For more than three decades, she has been a passionate and effective advocate for improving pediatric radiology worldwide – especially in poorly served countries – by participating in educational outreach.”

Javad Nazarian

Liquid biopsy spots aggressive brainstem cancer earlier

Javad Nazarian

A Children’s National research team led by Javad Nazarian, Ph.D., M.S.C., tested whether circulating tumor DNA in patients’ blood and cerebrospinal fluid would provide an earlier warning that pediatric brainstem tumors were growing.

A highly aggressive pediatric brain cancer can be spotted earlier and reliably by the genetic fragments it leaves in biofluids, according to a study presented by Children’s National Health System researchers at the Society for Neuro-Oncology (SNO) 2017 Annual Meeting. The findings may open the door to non-surgical biopsies and a new way to tell if these tumors are responding to treatment.

Children diagnosed with diffuse midline histone 3 K27M mutant (H3K27M) glioma face a poor prognosis with a median survival time of only nine months after the pediatric brainstem cancer is diagnosed. Right now, clinicians rely on magnetic resonance imaging (MRI) to gauge how tumors are growing, but MRI can miss very small changes in tumor size. The Children’s research team led by Javad Nazarian, Ph.D., M.S.C., scientific director of Children’s Brain Tumor Institute, tested whether circulating tumor DNA in patients’ blood and cerebrospinal fluid would provide an earlier warning that tumors were growing. Just as a detective looks for fingerprints left at a scene, the new genetic analysis technique can detect telltale signs that tumors leave behind in body fluids.

“We continue to push the envelope to find ways to provide hope for children and families who right now face a very dismal future. By identifying these tumors when they are small and, potentially more responsive to treatment, our ultimate aim is to help children live longer,” says Eshini Panditharatna, B.A., study lead author. “In addition, we are hopeful that the comprehensive panel of tests we are constructing could identify which treatments are most effective in shrinking these deadly tumors.”

The researchers collected biofluid samples from 22 patients with diffuse intrinsic pontine glioma (DIPG) who were enrolled in a Phase I, Pacific Pediatric Neuro-Oncology Consortium clinical trial. Upfront and longitudinal plasma samples were collected with each MRI at various stages of disease progression. The team developed a liquid biopsy assay using a sensitive digital droplet polymerase chain reaction system that precisely counts individual DNA molecules.

“We detected H3K27M, a major driver mutation in DIPG, in about 80 percent of cerebrospinal fluid and plasma samples,” Panditharatna says. “Similar to adults with central nervous system (CNS) cancers, cerebrospinal fluid of children diagnosed with CNS cancers has high concentrations of circulating tumor DNA. However, after the children underwent radiotherapy, there was a dramatic decrease in circulating tumor DNA for 12 of the 15 patients (80 percent) whose temporal plasma was analyzed.”

Nazarian, the study senior author adds: “Biofluids, like plasma and cerebrospinal fluid, are suitable media to detect and measure concentrations of circulating tumor DNA for this type of pediatric glioma. Liquid biopsy has the potential to complement tissue biopsies and MRI evaluation to provide earlier clues to how tumors are responding to treatment or recurring.”

Support for this liquid biopsy study was provided by the V Foundation, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, the Zickler Family Foundation, the Piedmont Community Foundation, the Musella Foundation, the Mathew Larson Foundation and Brain Tumor Foundation for Children.

Stanley Thomas Fricke

Using IR imaging to improve lead apron inspection

Stanley Thomas Fricke

“When I researched how lead aprons are inspected, I learned that a combination of tactile and visual inspection is considered the gold standard. But many of the smallest holes can be missed this way,” says Stanley Thomas Fricke, Nucl. Eng., Ph.D., radiation safety officer at Children’s National Health System and study senior author.

Workers inspecting the lead aprons that shield patients from radiation during imaging tend to use tactile and visual inspections to find defects, running their fingers over the aprons since fingertips can detect even subtle changes to a surface. Yet findings from a new study could influence changes in this approach to improve inspection performance and better protect patients and inspectors.

Infrared (IR) thermal imaging is a much better detective, with 50 percent of study participants picking out all holes intentionally drilled into a test apron compared with just 6 percent of participants who detected the same defects using the tactile method, according to research published online Nov. 8, 2017 in Journal of the American College of Radiology. In addition to being a more accurate way to detect subtle defects, the IR imaging technology also reduces ionizing radiation exposure for inspectors checking the protective power of lead aprons.

“When I researched how lead aprons are inspected, I learned that a combination of tactile and visual inspection is considered the gold standard. But many of the smallest holes can be missed this way,” says Stanley Thomas Fricke, Nucl. Eng., Ph.D., radiation safety officer at Children’s National Health System and study senior author. “Unlike the fingertips, infrared light can penetrate the lead apron’s protective outer fabric and illuminate defects that are smaller than the defect size now used to reject a protective apron. This work challenges conventional wisdom and offers an inexpensive, readily available alternative.”

According to the study team, a growing number of health care settings use radiation-emitting imaging, from the operating room to the dentist’s office. Lead aprons and gonadal shields lower radiation doses experienced by health care staff and patients. In compliance with regulators, these protective devices are inspected regularly. A layer of lead inside keeps patients’ exposure to ionizing radiation at the lowest detectable level. The aprons are covered with nylon or polyester fabric for the patients’ comfort and for ease of cleaning.

“It is standard for health care institutions to use a tactile-visual approach to inspect radiation protective apparel,” Fricke says. “While increasingly common, that inspection method can allow aprons with holes and tears to slip by undetected due to the large surface area that needs to be inspected, the outer fabric that encloses the protective apron and other factors.”

Fricke recalled a news clip from years ago about an IR camera used to film swimmers at the pool that, like Superman’s powerful vision, could see through pool-goers’ clothing. The manufacturer quickly recalled the camera. But the IR technology is a perfect fit for inspectors looking for defects hidden under a lead apron’s fabric cover.

To validate this inspection alternative, the team drilled a series of nine holes ranging from 2 mm to 35 mm in diameter into a “phantom” lead apron and enclosed it within fabric that typically covers the protective shielding. The research team stapled the phantom apron to a wooden frame and placed dry wall under the frame.

Two of 31 radiation workers picked out all nine holes by touch and recorded the holes and their locations on written questionnaires.

For the IR method, the team used an infrared light to illuminate the lead apron from behind and relied on an infrared imaging camera to record 10 seconds of video from which still images were exported. Ten of 20 radiation technologists, radiology nurses and medical doctors identified all nine holes using those color photographs and recorded their entries on a questionnaire. An additional 20 percent identified eight of nine intentional defects to the phantom apron.

In both the tactile and IR groups, all participants found the largest hole and correctly recorded its location.

“Using the tactile method for inspection, most staff who work regularly with radiation-emitting devices were able to identify defects that would cause a lead apron to be rejected, which is 11 mm holes for thyroid shields and 15 mm holes for aprons,” Fricke says. “However, it is standard for these well-used aprons to develop smaller holes—which, over time, become bigger holes. Here at Children’s National, we care about every photon that touches a child.”

In the next phase of the research, the team will explore infrared flash photography, cooling the apron material and the impact of high-resolution cameras with greater depth of field.

Adolescent brain scan from obesity study

Imaging captures obesity’s impact on the adolescent brain

Adolescent brain scan from obesity study

For the first time, a team of researchers led by Chandan Vaidya, Ph.D., chair of the Department of Psychology at Georgetown University, has used functional magnetic resonance imaging (fMRI) to capture the brain function of a small population of adolescents with obesity, both before and after bariatric surgery.

Obesity affects the whole body, from more obvious physical impacts on bones and joints to more subtle, internal impacts on organs like the brain.

For the first time, a team of researchers has used functional magnetic resonance imaging (fMRI) to capture the brain function of a small population of adolescents with obesity, both before and after bariatric surgery. The goal is to better understand the neural changes that occur when an adolescent is obese, and determine the effectiveness of interventions, such as vertical sleeve gastrectomy, at improving brain function as weight is lost.

The study, published as the November Editors’ Choice in the journal Obesity, found that executive and reward-related brain functions of study participants with obesity improved following the surgical procedure and initial weight loss.

How bariatric surgery changes the teenage brain from Research Square on Vimeo.

“We’ve known for some time that severe obesity has negative consequences on some neurocognitive function areas for adults,” says Chandan Vaidya, Ph.D., chair of the Department of Psychology at Georgetown University and a senior author of the study. “But for the first time, we’ve captured fMRI evidence in young patients, and also shown that surgical intervention and the resulting weight loss can reverse some of those deficits.”

“For me, this early evidence makes a strong case that when kids are struggling with severe obesity, we need to consider surgical intervention as an option sooner in the process,” notes Evan Nadler, M.D., director of the Bariatric Surgery Program at Children’s National Health System, who also contributed to the study. “The question that remains is whether the neurocognitive function improves more if surgery, and thus weight loss, happens earlier – and is there a time factor that should help us determine when to perform a procedure that will maximize improvements?”

The preliminary study included 36 participants and was conducted using patients recruited from the Children’s National Bariatric Surgery program, one of the first children’s hospitals to achieve national accreditation by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program.

“We asked these questions because we know that in the kids we see, their behavioral, brain, and physical health are all very closely related to one another and have an impact on each other,” adds Eleanor Mackey, Ph.D., study senior author and co-principal investigator on the National Institute of Diabetes and Digestive and Kidney Diseases grant that funded the project. “We expected that as physical health improves, we might see corresponding improvements in brain and behavior such as cognitive and school performance.”

The study also pointed out some technical and practical challenges to studying this particular young population. Anyone with a BMI greater than 50 was not able to fit within the MR bore used in the study, preventing fMRI participation by those patients.

“In addition to future studies with a larger sample size, we’d like to see if there are neuroimaging markers of plasticity differences in a population with BMI greater than 50,” says Dr. Vaidya. “Does the severity of the obesity change how quickly the brain can adapt following surgery and weight loss?”

The abstract was selected by the journal’s editors as one that provides insights into preventing and treating obesity. It was featured at the Obesity Journal Symposium during Obesity Week 2017 in Washington, D.C., as part of the Obesity Week recognition, and a digital video abstract was also released about the findings.

nurse holding newborn baby

Continuous EEG monitoring better predicts HIE outcomes

nurse holding newborn baby

For newborns who experience a serious complication that deprives their brain of oxygen, continuously monitoring brain activity and examining how the electrical signals evolve may be a more reliable way to identify infants most at risk for brain injury.

For newborns who experience a serious complication that deprives their brain of oxygen, continuously monitoring brain activity and examining how the electrical signals evolve may be a more reliable way to identify infants most at risk for brain injury, compared with doing evaluations at discreet intervals, according to a prospective cohort study led by Children’s National Health System research-clinicians.

Amplitude-integrated electroencephalogram (aEEG) is a bedside tool that permits clinicians to monitor the complex electrical activity of the child’s brain over time. It’s a positive sign when an aEEG shows babies beginning to sleep and wake normally by the time they are 3 days old. Conversely, severely abnormal aEEG readings in the first days of life predict poor outcomes.

The Children’s team used aEEG with infants born with hypoxic-ischemic encephalopathy (HIE), one of the most severe complications that can affect full-term infants. During pregnancy, birth or shortly after birth, a hypoxic-ischemic event can occur that impedes blood flow and oxygen delivery to the brain, resulting in destruction of brain tissue. Cooling (therapeutic hypothermia) is now standard for newborns with HIE in order to stave off life-long consequences, but deaths and neurodevelopmental disability still can occur.

“We know whole-body cooling – or lowering the body’s temperature by about 3 degrees Celsius – can help vulnerable newborns survive and can protect their brains from suffering profound injuries,” says An N. Massaro, M.D., a Children’s National neonatologist and senior author of the study published online Sept. 28, 2017 in the American Journal of Perinatology.  “What we were trying to determine with this study is whether evaluating the pattern of evolution of the aEEG as a whole provides more information compared with looking at snapshots in time.”

Eighty infants undergoing therapeutic cooling who met the inclusion criteria were enrolled in the five-year study, one of the largest such studies to date. The babies weighed more than 1,800 grams and were older than 35 weeks’ gestational age at birth, and either needed prolonged resuscitation after birth or had low APGAR scores – a measure of how well newborns fare outside the womb. Continuous recordings of EEG data occurred from the time of admission up to 12 hours after the infants’ temperatures were raised to normal and aEEG tracings were calculated.

After the therapeutic cooling blankets were removed, the infants underwent at least one magnetic resonance imaging (MRI) scan prior to discharge. During the routine follow-up check at about 18 months of age, the HIE survivors’ cognitive and motor skills were assessed using validated instruments.

Fifty-six of the infants in the study had favorable outcomes. Twenty-four infants had adverse outcomes, including 15 with severe brain injury detected by MRI and nine infants who died. These children had lower APGAR scores at five minutes, and were more likely to have severe HIE and to have experienced more frequent seizures.

“Infants whose aEEG abnormalities do not improve were at increased risk: Infants who do not reach a discontinuous background pattern by 15.5 hours of life, achieve cycling by 45.5 hours after birth and who fail to achieve continuous normal voltage by 78 hours after birth are most at risk for adverse outcomes,” Dr. Massaro says. “In addition to defining worrisome trends, we found that overall assessment of continuous aEEG readings through the course of hypothermia treatment provide the most meaningful predictive power. This means we can speak with families at the bedside with more confidence about their child’s outcomes after the infant undergoes cooling therapy.”

Related Resources

Roberta DeBiasi and Sarah Mulkey

Children’s National experts contribute to new Zika guidelines

Roberta DeBiasi and Sarah Mulkey

Roberta DeBiasi, M.D., M. S., and Sarah B. Mulkey, M.D., Ph.D., members of Children’s multidisciplinary Congenital Zika Virus Program, were among the experts invited to participate in a forum held in Atlanta at CDC headquarters in late August to formulate new Zika recommendations.

The Centers for Disease Control and Prevention (CDC) on Oct. 19, 2017 updated guidelines for evaluation of women, fetuses and infants exposed to the Zika virus during pregnancy. Although only women with symptoms will now be routinely tested, asymptomatic and symptomatic infants born to these women will still be tested for the Zika virus using blood and urine tests.

Infants who appear normal, whose mothers either had negative Zika results or who had not undergone testing, will not undergo Zika testing. These infants still will undergo a standard evaluation, including a detailed physical exam, hearing screen and routine developmental assessments. The revised Zika guidance includes input from practitioners on the front lines of the Zika epidemic, including Children’s National Health System clinicians.

“These changes in the recommendations for Zika testing should not be interpreted as Zika infection risks subsiding for pregnant women and their infants in the United States. It’s simply an acknowledgement of the limitations of current testing methods – which must occur within a narrow window after Zika exposure – and the poor predictive value of Zika testing right now,” says Roberta L. DeBiasi, M.D., M.S., chief of Children’s Division of Pediatric Infectious Diseases. Dr. DeBiasi and Sarah B. Mulkey, M.D., Ph.D., members of Children’s multidisciplinary Congenital Zika Virus Program, were among the experts invited to participate in the Zika forum held in Atlanta at CDC headquarters in late August to formulate the recommendations.

While all infants will receive a standard evaluation, expanded evaluations that include an ophthalmologic assessment, more detailed hearing evaluation and ultrasound of the newborn’s head will be reserved for infants born to mothers confirmed to be Zika positive or Zika probable, or for infants born with abnormalities potentially consistent with congenital Zika syndrome, regardless of maternal status.

The majority of U.S. infants who have been exposed to Zika in the womb appeared normal at birth, according to CDC registries. Now, the next wave of these normal-appearing babies will receive standard evaluations when they are born, including a newborn hearing screening. At each well-child visit, these infants will receive:

  • A comprehensive physical examination
  • An age-appropriate vision screening
  • Developmental monitoring and screening using validated tools

“This is a natural evolution in the diagnosis and screening strategy now that the peak of the first wave of Zika transmission appears to be over,” Dr. DeBiasi says. “While we continue to evaluate new possible cases of Zika infection among pregnant women in our practice, a sizable proportion of Children’s cases are Zika-exposed infants whose physical exam and neuroimaging appeared normal at birth. Through ongoing monitoring, we hope to learn more about these children’s long-term neurodevelopment outcomes.”