Diagnostic Imaging and Radiology Research

Straightening out testicular torsion care

May 18, 2017

A new collaborative accelerated care pathway for testicular torsion assessment and treatment may save critical time between diagnosis and intervention.

The clock starts ticking for a child with testicular torsion as soon as the pain starts. To increase the likelihood of successfully salvaging the twisted testicle and spermatic cord, surgical intervention – which involves restoring blood flow to the testis – should ideally occur within six hours from the onset of pain.

That’s six hours for a parent to identify that there is a problem, bring a child to the emergency department (ED) and go through all the steps required to get the child to the operating room. This process starts with an emergency physician, who probably doesn’t see many cases of this relatively rare condition, being able to identify the potential issue and contact the pediatric urologist on call. Next, diagnostic imaging orders need to be placed and actual imaging needs to occur for the diagnosis to be made. Finally, the patient needs to be moved to the pre-operative area, assessed by the anesthesia team and then taken to surgery.

In April 2016, the Division of Urology at Children’s National launched a new, accelerated care pathway for testicular torsion assessment and treatment that was developed collaboratively with the Emergency Department, Diagnostic Imaging and Radiology, the Department of Anesthesiology, and the peri-operative and operating room team.

“What stood out to us when we looked at the total time from identifying the problem to getting to surgery, was the length of time from when the diagnosis was made in the emergency department to the operating room,” says Tanya Davis, M.D., a pediatric urologist who led this new initiative along with Harry Rushton, Jr., M.D., chief of the Division of Urology. “It was an area where we could easily identify and streamline the process to accelerate the time for a patient to get from arrival in the ED to the surgical suite.”

Now, when a patient presents in the emergency department with the symptoms of testicular torsion, there is a straightforward path mapped out for the physician. “Who you need to talk to, how to reach them, relevant phone numbers, details on when to communicate to the attending physician, the ideal order of activities, the ability for residents to quickly transport the patient rather than waiting for hospital transport to surgery, and, most important, making it clear to everyone involved that this condition is a true emergency when every second matters,” Dr. Davis adds.

Analysis of the streamlined care pathway, which emphasizes communication that the condition is a true emergency, has improved time from ED to OR within target ranges.

Since the initiative’s launch, 21 cases, from referrals and direct diagnosis, have come into the ED. The new protocol is working efficiently, reducing the mean time from the ED to the OR by more than an hour, now averaging below the team’s target goal of less than 2.5 hours from ED arrival to the OR.

Though salvage rates have not improved yet, the team will continue to collect data and monitor the impact of the accelerated pathway. Additionally, Dr. Davis says that a significant need remains for referring emergency and primary care physicians, as well as parents, to understand the condition and its need for urgent treatment. Children’s National urologists are developing handouts for both physicians and families to help raise awareness.

The hope is that more general knowledge of testicular torsion will allow parents, primary care doctors and emergency department staff to expedite diagnosis when a child complains of scrotal pain or has visible discoloration, further reducing the time from onset of pain to successful intervention. With such a short window of time for treatment, the accelerated care pathway is showing promising results.

Zika virus, one year later

April 21, 2017

A multidisciplinary team at Children’s National has consulted on 66 Zika-affected pregnancies and births since May 2016.

The first pregnant patient with worries about a possible Zika virus infection arrived at the Children’s National Health System Fetal Medicine Institute on Jan. 26, 2016, shortly after returning from international travel.

Sixteen months ago, the world was just beginning to learn how devastating the mosquito-borne illness could be to fetuses developing in utero. As the epidemic spread, a growing number of sun-splashed regions that harbor mosquitoes that efficiently spread the virus experienced a ballooning number of Zika-affected pregnancies and began to record sobering birth defects.

The Washington, D.C. patient’s concerns were well-founded. Exposure to Zika virus early in her pregnancy led to significant fetal brain abnormalities, and Zika virus lingered in the woman’s bloodstream months after the initial exposure — longer than the Centers for Disease Control and Prevention (CDC) then thought was possible.

The research paper describing the woman’s lengthy Zika infection, published by The New England Journal of Medicine, was selected as one of the most impactful research papers written by Children’s National authors in 2016.

In the intervening months, a multidisciplinary team at Children National has consulted on 66 pregnancies and infants with confirmed or suspected Zika exposure. Thirty-five of the Zika-related evaluations were prenatal, and 31 postnatal evaluations assessed the impact of in utero Zika exposure after the babies were born.

The continuum of Zika-related injuries includes tragedies, such as a 28-year-old pregnant woman who was referred to Children’s National after imaging hinted at microcephaly. Follow-up with sharper magnetic resonance imaging (MRI) identified severe diffuse thinning of the cerebral cortical mantle, evidence of parenchymal cysts in the white matter and multiple contractures of upper and lower extremities with muscular atrophy.

According to a registry of Zika-affected pregnancies maintained by the CDC, one in 10 pregnancies across the United States with laboratory-confirmed Zika virus infection has resulted in birth defects in the fetus or infant.

“More surprising than that percentage is the fact that just 25 percent of infants underwent neuroimaging after birth – despite the CDC’s recommendation that all Zika-exposed infants undergo postnatal imaging,” says Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-director of the Congenital Zika Virus Program at Children’s National. “Clinicians should follow the CDC’s guidance to the letter, asking women about possible exposure to Zika and providing multidisciplinary care to babies after birth. Imaging is an essential tool to accurately monitor the growing baby’s brain development.”

Adré du Plessis, M.B.Ch.B., M.P.H., director of the Fetal Medicine Institute and Congenital Zika Virus Program co-leader, explains the challenges: ”When it comes to understanding the long-term consequences for fetuses exposed to the Zika virus, we are still on the steepest part of the learning curve. Identifying those children at risk for adverse outcomes will require a sustained and concerted multidisciplinary effort from conception well beyond childhood.”

In addition to counseling families in the greater Washington, D.C. region, the Children’s research team is collaborating with international colleagues to conduct a clinical trial that has been recruiting Zika-infected women and their babies in Colombia. Pediatric Resident Youssef A. Kousa, D.O., Ph.D., M.S., and Neurologist Sarah B. Mulkey, M.D., Ph.D., will present preliminary findings during Research and Education Week 2017.

In Colombia as well as the District of Columbia, a growing challenge continues to be assessing Zika’s more subtle effects on pregnancies, developing fetuses and infants, says Radiologist Dorothy Bulas, M.D., another member of Children’s multidisciplinary Congenital Zika Virus Program.

The most severe cases from Brazil were characterized by interrupted fetal brain development, smaller-than-normal infant head circumference, brain calcifications, enlarged ventricles, seizures and limbs folded at odd angles. In the United States and many other Zika-affected regions, Zika-affected cases with such severe birth defects are outnumbered by infants who were exposed to Zika in utero but have imaging that appears normal.

In a darkened room, Dr. Bulas pores over magnified images of the brains of Zika-infected babies, looking for subtle differences in structure that may portend future problems.

“There are some questions we have answered in the past year, but a number of questions remain unanswered,” Dr. Bulas says. “For neonates, that whole area needs assessment. As the fetal brain is developing, the Zika virus seems to affect the progenitor cells. They’re getting hit quite early on. While we may not detect brain damage during the prenatal period, it may appear in postnatal images. And mild side effects that may not be as obvious early on still have the potential to be devastating.”

2016: A banner year for innovation

April 14, 2017

In 2016, clinicians and research scientists working at Children’s National Health System published more than 1,100 articles in high-impact journals about a wide array of topics. A Children’s Research Institute review group selected the top articles for the calendar year considering, among other factors, work published in top-tier journals with impact factors of 9.5 and higher.

“Conducting world-class research and publishing the results in prestigious journals represents the pinnacle of many research scientists’ careers. I am pleased to see Children’s National staff continue this essential tradition,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “While it was difficult for us to winnow the field of worthy contenders to this select group, these papers not only inform the field broadly, they epitomize the multidisciplinary nature of our research,” Dr. Batshaw adds.

The published papers explain research that includes discoveries made at the genetic and cellular levels, clinical insights and a robotic innovation that promises to revolutionize surgery:

Outcomes from supervised autonomous procedures are superior to surgery performed by expert surgeons
The Zika virus can cause substantial fetal brain abnormalities in utero, without microcephaly or intracranial calcifications
Mortality among injured adolescents was lower among patients treated at pediatric trauma centers, compared with adolescents treated at other trauma center types
Hydroxycarbamide can substitute for chronic transfusions to maintain transcranial Doppler flow velocities for high-risk children with sickle cell anemia
There is convincing evidence of the efficacy of in vivo genome editing in an authentic animal model of a lethal human metabolic disease
Sirt1 is an essential regulator of oligodendrocyte progenitor cell proliferation and oligodendrocyte regeneration after neonatal brain injury

Read the complete list.

Dr. Batshaw’s announcement comes on the eve of Research and Education Week 2017 at Children’s National, a weeklong event that begins April 24. This year’s theme, “Collaboration Leads to Innovation,” underscores the cross-cutting nature of Children’s research that aims to transform pediatric care.

Researchers tackle Zika’s unanswered questions

March 17, 2017

Youssef A. Kousa, D.O., Ph.D., M.S., is examining whether interplays between certain genes make some women more vulnerable to symptomatic Zika infections.

A Maryland woman traveled to the Dominican Republic early in her pregnancy, spending three weeks with family. She felt dizzy and tired and, at first, attributed the lethargy to jet lag. Then, she experienced a rash that lasted about four days. She never saw a bite or slapped a mosquito while in the Dominican Republic but, having heard about the Zika virus, asked to be tested.

Her blood tested positive for Zika.

Why was this pregnant woman infected by Zika while others who live year-round in Zika hot zones remain free of the infectious disease? And why was she among the slim minority of Zika-positive people to show symptoms?

Youssef A. Kousa, D.O., Ph.D., M.S., a pediatric resident in the child neurology track at Children’s National Health System, is working on a research study that will examine whether interplays between certain genes make some women more vulnerable to symptomatic Zika infections during pregnancy, leaving some fetuses at higher risk of developing microcephaly.

Dr. Kousa will present preliminary findings during Research and Education Week 2017 at Children’s National.

At sites in Puerto Rico, Colombia and Washington D.C., Dr. Kousa and his research collaborators are actively recruiting study participants and drawing blood from women whose Zika infections were confirmed in the first or second trimester of pregnancy. The blood is stored in test tubes with purple caps, a visual cue that the tube contains an additive that binds DNA, preventing it from being cut up. Additional research sites are currently being developed.

When the blood arrives at Children’s National, Dr. Kousa will use a centrifuge located in a sample preparation room to spin the samples at high speed for 11 minutes. The sample emerges from the centrifuge in three discrete layers, separated by weight. The rose-colored section that rises to the top is plasma. Plasma contains tell-tale signs of the immune system’s past battles with viruses and will be analyzed by Roberta L. DeBiasi, M.D., M.S., Chief of the Division of Pediatric Infectious Diseases at Children’s National, and Dr. Kousa’s mentor.

A slender line at the middle indicates white blood cells. The dark red layer is heavier red blood cells that sink to the bottom. This bottom half of the test tube, where the DNA resides, is where Dr. Kousa will perform his genetic research.

For years, Dr. Kousa has worked to identify genetic risk factors that influence which fetuses develop cleft lip and palate. In addition to genetic variances that drive disease, he looks at environmental overlays that can trigger genes to respond in ways that cause pediatric disease. When Zika infections raced across the globe, he says it was important to apply the same genetic analyses to the emerging disease. Genes make proteins that carry out instructions, but viral infection disrupts how genes interact, he says. Cells die. Other cells do not fully mature.

While certain poverty-stricken regions of Brazil have recorded the highest spikes in rates of microcephaly, more is at play than socioeconomics, he says. “It didn’t feel like all of the answers lie in the neighborhood. One woman with a Zika-affected child can live just down the street from a child who is more or less severely affected by Zika.”

As a father, Dr. Kousa is particularly concerned about how Zika stunts growth of the fetal brain at a time when it should expand exponentially. “I have three kids. You see them as they achieve milestones over time. It makes you happy and proud as a parent,” he says.

Sarah B. Mulkey, M.D., Ph.D., is studying whether infants exposed to Zika in utero achieve the same developmental milestones as uninfected infants.

While Dr. Kousa concentrates on Zika’s most devastating side effects, his colleague Sarah B. Mulkey, M.D., Ph.D., is exploring more subtle damage Zika can cause to fetuses exposed in utero. In the cohort of Colombian patients that Dr. Mulkey is researching, just 8 percent had abnormal fetal brain magnetic resonance images (MRIs). At first glance, the uncomplicated MRIs appear to be reassuring news for the vast majority of pregnant women.

Dr. Mulkey also will present preliminary findings during Research and Education Week 2017 at Children’s National.

In the fetus, the Zika virus makes a beeline to the developing brain where it replicates with ease and can linger after birth. “We need to be cautious about saying the fetal MRI is ‘normal’ and the infant is going to be ‘normal,’ ” Dr. Mulkey says. “We know with congenital cytomegalovirus that infected infants may not show symptoms at birth yet suffer long-term consequences, such as hearing deficits and vision loss.”

Among Zika-affected pregnancies in Colombia in which late-gestational age fetal MRIs were normal, Dr. Mulkey will use two different evaluation tools at 6 months and 1 year of age to gauge whether the babies accomplish the same milestones as peers. One evaluation tool is a questionnaire that has been validated in Spanish.

At 6 months and 1 year of age, the infants’ motor skills will be assessed, such as their ability to roll over in both directions, sit up, draw their feet toward their waist, stand, take steps independently and purposefully move their hands. Videotapes of the infants performing the motor skills will be scored by Dr. Mulkey and her mentor, Adre du Plessis, M.B.Ch.B., Chief of the Division of Fetal and Transitional Medicine at Children’s National. The Thrasher Research Fund is funding the project, “Neurologic outcomes of apparently normal newborns from Zika virus-positive pregnancies,” as part of its Early Career Award Program.

Both research projects are extensions of a larger multinational study co-led by Drs. du Plessis and DeBiasi that explores the impact of prolonged Zika viremia in pregnant women, fetuses and infants; the feasibility of using fetal MRI to describe the continuum of neurological impacts in Zika-affected pregnancies; and long-term developmental issues experienced by Zika-affected infants.

Treating osteoid osteoma with MR-HIFU

February 24, 2017

Karun Sharma, M.D., poses with two patients who participated in the MR-HIFU trial for pediatric osteoid osteoma.

Doctors from the Sheikh Zayed Institute for Pediatric Surgical Innovation and surgeons from Children’s National are the first in the U.S. to use Magnetic Resonance-Guided High-intensity Focused Ultrasound (MR-HIFU) to treat pediatric osteoid osteoma.

The trial, led by Principal Investigator Karun Sharma, M.D., Ph.D., Director of Interventional Radiology at Children’s National, began in 2015 and is demonstrating early success in establishing the safety and feasibility of noninvasive MR-HIFU as an alternative to the current, more invasive approaches to remove tumor tissue.

Osteoid osteoma is a painful, but benign, bone tumor that commonly occurs in children and young adults. Removal generally requires orthopaedic surgery to scrape the tumor from the bone or CT (computerized tomography) image-guided radiofrequency ablation (RFA), which is less invasive than surgery but is associated with ionizing radiation exposure and requires drilling through muscle and soft tissue into bone.

MR-HIFU, on the other hand, is a precise and controlled method that does not require a scalpel or needle, greatly reducing the risk of complications, including infections and bone fractures. Even better, it promises reduced procedure time, typically an hour or less.

“Our team set out to provide a noninvasive and radiation free treatment option for children with osteoid osteoma and our pilot feasibility and safety trial is almost completed. We have treated 9 patients and we’re very pleased with the success of the treatments so far. Although follow up will continue for another year, results to date that show that MR-HIFU may be a completely non-invasive and radiation free treatment for osteoid osteoma,” Dr. Sharma says. “Several of the children we treated were very active prior to the onset of their tumor, one a soccer player and the other a swimmer, but because of pain from the tumor, they were unable to enjoy their favorite activities, until now.”

“The use of MR-HIFU ablation of osteoid osteoma is a perfect example of our mission in the Sheikh Zayed Institute to make pediatric surgery more precise and less invasive,” adds Peter Kim, M.D., C.M., Ph.D., Vice President of the Sheikh Zayed Institute, who leads the Image Guided Non-Invasive Therapeutic Energy (IGNITE) program.

IGNITE is a joint clinical and research collaboration between the Sheikh Zayed Institute and the Divisions of Radiology, Oncology, Surgery, and Anesthesiology at Children’s National. MR-HIFU is also being used to treat pediatric refractory soft tissue tumors, a first-in-the-world clinical trial that is a collaboration between Children’s National and the NIH Center for Interventional Oncology directed by Bradford Wood, MD. Additionally, the IGNITE team has started preliminary work to explore applications of MR-HIFU for noninvasive ablation of growth plates and pediatric solid tumors.

In addition to Drs. Sharma and Kim, the team for the ablation of osteoid osteoma clinical trial includes: AeRang Kim, MD, PhD, pediatric oncologist; Matthew Oetgen, M.D., Division Chief of Orthopaedic Surgery and Sports Medicine; Kaleb Friend, M.D., pediatric orthopedic surgeon; Pavel Yarmolenko, Ph.D., Haydar Celik, Ph.D., and Avinash Eranki, biomedical engineers; Viktoriya Beskin, MR technologist; and Janish Patel, M.D., and Domiciano Santos, M.D., pediatric anesthesiologists.

Multidisciplinary approach to hydrocephalus care

February 23, 2017

Reflective of the myriad symptoms and complications that can accompany hydrocephalus, a multidisciplinary team at Children’s National works with patients and families for much of childhood.

The Doppler image on the oversized computer screen shows the path taken by blood as it flows through the newborn’s brain, with bright blue distinguishing blood moving through the middle cerebral artery toward the frontal lobe and bright red depicting blood coursing away. Pitch black zones indicate ventricles, cavities through which cerebrospinal fluid usually flows and where hydrocephalus can get its start.

The buildup of excess cerebrospinal fluid in the brain can begin in the womb and can be detected by fetal magnetic resonance imaging. Hydrocephalus also can crop up after birth due to trauma to the head, an infection, a brain tumor or bleeding in the brain, according to the National Institutes of Health. An estimated 1 to 2 per 1,000 newborns have hydrocephalus at birth.

When parents learn of the hydrocephalus diagnosis, their first question tends to be “Is my child going to be OK?” says Suresh Magge, M.D., a pediatric neurosurgeon at Children’s National Health System.

“We have a number of ways to treat hydrocephalus. It is one of the most common conditions that pediatric neurosurgeons treat,” Dr. Magge adds.

Unlike fluid build-up elsewhere in the body where there are escape routes, with hydrocephalus spinal fluid becomes trapped in the brain. To remove it, surgeons typically implant a flexible tube called a shunt that drains excess fluid into the abdomen, an interim stop before it is flushed away. Another surgical technique, called an endoscopic third ventriculostomy has the ability to drain excess fluid without inserting a shunt, but it only works for select types of hydrocephalus, Dr. Magge adds.

For the third year, Dr. Magge is helping to organize the Hydrocephalus Education Day on Feb. 25, a free event that offers parents an opportunity to learn more about the condition.

Reflective of the myriad symptoms and complications that can accompany hydrocephalus, such as epilepsy, cerebral palsy, cortical vision impairment and global delays, a multidisciplinary team at Children’s National works with patients and families for much of childhood.

Neuropsychologist Yael Granader, Ph.D., works with children ages 4 and older who have a variety of developmental and medical conditions. Granader is most likely to see children and adolescents with hydrocephalus once they become medically stable in order to assist in devising a plan for school support services and therapeutic interventions. Her assessments can last an entire day as she administers a variety of tasks that evaluate how the child thinks and learns, such as discerning patterns, assembling puzzles, defining words, and listening to and remembering information.

Neuropsychologists work with schools in order to help create the most successful academic environment for the child. For example, some children may struggle to visually track across a page accurately while reading; providing a bookmark to follow beneath the line is a helpful and simple accommodation to put in place. Support for physical limitations also are discussed with schools in order to incorporate adaptive physical education or to allow use of an elevator in school.

“Every child affected by hydrocephalus is so different. Every parent should know that their child can learn,” Granader says. “We’re going to find the best, most supportive environment for them. We are with them on their journey and, every few years, things will change. We want to be there to help with emerging concerns.”

Another team member, Justin Burton, M.D., a pediatric rehabilitation specialist, says rehabilitation medicine’s “piece of the puzzle is doing whatever I can to help the kids function better.” That means dressing, going to the bathroom, eating and walking independently. With babies who have stiff, tight muscles, that can mean helping them through stretches, braces and medicine management to move muscles smoothly in just the way their growing bodies want. Personalized care plans for toddlers can include maintaining a regular sleep-wake cycle, increasing attention span and strengthening such developmental skills as walking, running and climbing stairs. For kids 5 and older, the focus shifts more to academic readiness, since those youths’ “full-time job” is to become great students, Dr. Burton says.

The area of the hospital where children work on rehabilitation is an explosion of color and sounds, including oversized balance balls of varying dimensions in bright primary colors, portable basketball hoops with flexible rims at multiple heights, a set of foam stairs, parallel bars, a climbing device that looks like the entry to playground monkey bars and a chatterbox toy that lets a patient know when she has opened and closed the toy’s doors correctly.

“We end up taking care of these kids for years and years,” he adds. “I always love seeing the kids get back to walking and talking and getting back to school. If we can get them back out in the world and they’re doing things just like every other kid, that’s success.”

Meanwhile, Dr. Magge says research continues to expand the range of interventions and to improve outcomes for patients with hydrocephalus, including:

Fluid dynamics of cerebrospinal fluid
Optimal ways to drain excess fluid
Improving understanding of why shunts block
Definitively characterizing post-hemorrhagic ventricular dilation.

Unlike spina bifida, which sometimes can be corrected in utero at some health institutions, hydrocephalus cannot be corrected in the womb. “While we have come a long way in treating hydrocephalus, there is still a lot of work to be done. We continue to learn more about hydrocephalus with the aim of continually improving treatments,” Dr. Magge says.

During a recent office visit, 5-year-old Abagail’s head circumference had measured ¼ centimeter of growth, an encouraging trend, Robert Keating, M.D., Children’s Chief of Neurosurgery, tells the girl’s mother, Melissa J. Kopolow McCall. According to Kopolow McCall, who co-chairs the Hydrocephalus Association DC Community Network, it is “hugely” important that Children’s National infuses its clinical care with the latest research insights. “I have to have hope that she is not going to be facing a lifetime of brain surgery, and the research is what gives me the hope.”

MR-guided right heart catheterization live streams at SCMR scientific sessions

February 9, 2017

Interventional Cardiac Magnetic Resonance (ICMR) Program Team

The ICMR team who performed the livestream procedure during the member assembly session. The prestigious invitation came as a result of the innovative partnership between Children’s National and the NHLBI to form the Interventional Cardiac MR Program.

Cardiologists from the Interventional Cardiac Magnetic Resonance (ICMR) Program at Children’s successfully live streamed a right heart catheterization procedure guided by magnetic resonance (MR) imaging during the Member Assembly Session of the Society for Cardiac Magnetic Resonance Scientific Session in early February.

The ICMR program is a first-in-the-nation partnership between Children’s National and the National Heart, Lung, and Blood Institute that features a state-of-the-art dedicated cardiac specific MRI suite for diagnosis, evaluation and intervention for children with heart conditions. The program’s goal is to advance diagnostic and interventional cardiac magnetic resonance imaging techniques in pediatric cardiology and for adults with congenital heart disease. ICMR is cross-disciplinary, connecting researchers, clinicians, engineers and physicists to provide more precise and less invasive diagnostics and treatment options that also reduce radiation exposure for vulnerable patients.

Congenital heart disease and cortical growth

February 7, 2017

The cover of Science Translational Medicine features a new study of the cellular-level changes in the brain induced by congenital heart disease. Reprinted with permission from AAAS. Not for download

Disruptions in cerebral oxygen supply caused by congenital heart disease have significant impact on cortical growth, according to a research led by Children’s National Health System. The findings of the research team, which include co-authors from the National Institutes of Health, Boston Children’s Hospital and Johns Hopkins School of Medicine, appear on the cover of Science Translational Medicine. The subventricular zone (SVZ) in normal newborns’ brains is home to the largest stockpile of neural stem/progenitor cells, with newly generated neurons migrating from this zone to specific regions of the frontal cortex and differentiating into interneurons. When newborns experience disruptions in cerebral oxygen supply due to congenital heart disease, essential cellular processes go awry and this contributes to reduced cortical growth.

The preliminary findings point to the importance of restoring these cells’ neurogenic potential, possibly through therapeutics, to lessen children’s long-term neurological deficits.

“We know that congenital heart disease (CHD) reduces cerebral oxygen at a time when the developing fetal brain most needs oxygen. Now, we are beginning to understand the mechanisms of CHD-induced brain injuries at a cellular level, and we have identified a robust supply of cells that have the ability to travel directly to the site of injury and potentially provide help by replacing lost or damaged neurons,” says Nobuyuki Ishibashi, M.D., Director of the Cardiac Surgery Research Laboratory at Children’s National, and co-senior study author.

The third trimester of pregnancy is a time of dramatic growth for the fetal brain, which expands in volume and develops complex structures and network connections that growing children rely on throughout adulthood. According to the National Heart, Lung, and Blood Institute, congenital heart defects are the most common major birth defect, affecting 8 in 1,000 newborns. Infants born with CHD can experience myriad neurological deficits, including behavioral, cognitive, social, motor and attention disorders, the research team adds.

Cardiologists have tapped noninvasive imaging to monitor fetal hearts during gestation in high-risk pregnancies and can then perform corrective surgery in the first weeks of life to fix damaged hearts. Long term neurological deficits due to immature cortical development also have emerged as major challenges in pregnancies complicated by CHD.

“I think this is an enormously important paper for surgeons and for children and families who are affected by CHD. Surgeons have been worried for years that the things we do during corrective heart surgery have the potential to affect the development of the brain. And we’ve learned to improve how we do heart surgery so that the procedure causes minimal damage to the brain. But we still see some kids who have behavioral problems and learning delays,” says Richard A. Jonas, M.D., Chief of the Division of Cardiac Surgery at Children’s National, and co-senior study author. “We’re beginning to understand that there are things about CHD that affect the development of the brain before a baby is even born. What this paper shows is that the low oxygen level that sometimes results from a congenital heart problem might contribute to that and can slow down the growth of the brain. The good news is that it should be possible to reverse that problem using the cells that continue to develop in the neonate’s brain after birth.”

Among preclinical models, the spatiotemporal progression of brain growth in this particular model most closely parallels that of humans. Likewise, the SVZ cytoarchitecture of the neonatal preclinical model exposed to hypoxia mimics that of humans in utero and shortly after birth. The research team leveraged CellTracker Green to follow the path traveled by SVZ derived cells and to illuminate their fate, with postnatal SVZ supplying the developing cortex with newly generated neurons. SVZ derived cells were primarily neuroblasts. Superparamagnetic iron oxide nanoparticles supplied answers about long term SVZ migration, with SVZ derived cells making their way to the prefrontal cortex and the somatosensory cortex of the brain.

“We demonstrated that in the postnatal period, newly generated neurons migrate from the SVZ to specific cortices, with the majority migrating to the prefrontal cortex,” says Vittorio Gallo, Ph.D., Director of the Center for Neuroscience Research at Children’s National, and co-senior study author. “Of note, we revealed that the anterior SVZ is a critical source of newborn neurons destined to populate the upper layers of the cortex. We challenged this process through chronic hypoxia exposure, which severely impaired neurogenesis within the SVZ, depleting this critical source of interneurons.”

In the preclinical model of hypoxia as well as in humans, brains were smaller, weighed significantly less and had a significant reduction in cortical gray matter volume. In the prefrontal cortex, there was a significant reduction in white matter neuroblasts. Taken as a whole, according to the study authors, the findings suggest that impaired neurogenesis within the SVZ represents a cellular mechanism underlying hypoxia induced, region specific reduction in immature neurons in the cortex. The prefrontal cortex, the region of the brain that enables such functions as judgment, decision making and problem solving, is most impacted. Impairments in higher order cognitive functions involving the prefrontal cortex are common in patients with CHD.

Congenital heart disease and white matter injury

February 6, 2017

Although recent advances have greatly improved the survival of children with congenital heart disease, up to 55 percent will be left with injury to their brain’s white matter – an area that is critical for aiding connection and communication between various regions in the brain.

What’s known

Eight of every 1,000 children born each year have congenital heart disease (CHD). Although recent advances have greatly improved the survival of these children, up to 55 percent will be left with injury to their brain’s white matter – an area that is critical for aiding connection and communication between various regions in the brain. The resulting spectrum of neurological deficits can have significant costs for the individual, their family and society. Although studies have demonstrated that white matter injuries due to CHD have many contributing factors, including abnormal blood flow to the fetal brain, many questions remain about the mechanisms that cause these injuries and the best interventions.

What’s new

A Children’s National Health System research team combed existing literature, reviewing studies from Children’s as well as other research groups, to develop an article detailing the current state of knowledge on CHD and white matter injury. The scientists write that advances in neuroimaging – including magnetic resonance imaging, magnetic resonance spectroscopy, Doppler ultrasound and diffusion tensor imaging – have provided a wealth of knowledge about brain development in patients who have CHD. Unfortunately, these techniques alone are unable to provide pivotal insights into how CHD affects cells and molecules in the brain. However, by integrating animal models with findings in human subjects and in postmortem human tissue, the scientists believe that it will be possible to find novel therapeutic targets and new standards of care to prevent developmental delay associated with cardiac abnormalities.

For example, using a porcine model, the Children’s team was able to define a strategy for white matter protection in congenital heart surgery through cellular and developmental analysis of different white matter regions. Another study from Children’s combined rodent hypoxia with a brain slice model to replicate the unique brain conditions in neonates with severe and complex congenital heart disease. This innovative animal model provided novel insights into the possible additive effect of preoperative hypoxia on brain insults due to cardiopulmonary bypass and deep hypothermic circulatory arrest.

The Children’s research team also recently published an additional review article describing the key windows of development during which the immature brain is most vulnerable to CHD-related injury.

Questions for future research

Q: Can we create an animal model that recapitulates the morphogenic and developmental aspects of CHD without directly affecting other organs or developmental processes?
Q: What are the prenatal and neonatal cellular responses to CHD in the developing brain?
Q: What are the molecular mechanisms underlying white matter immaturity and vulnerability to CHD, and how can we intervene?
Q: How can we accurately assess the dynamic neurological outcomes of CHD and/or corrective surgery in animal models?
Q: Prenatal or postnatal insults to the developing brain: which is most devastating in regards to developmental and behavioral disabilities?
Q: How can we best extrapolate from, and integrate, neuroimaging findings/correlations in human patients with cellular/molecular approaches in animal models?

Source: Reprinted from Trends in Neurosciences, Vol. 38/Ed. 6, Paul D. Morton, Nobuyuki Ishibashi, Richard A. Jonas and Vittorio Gallo, “Congenital cardiac anomalies and white matter injury,” pp. 353-363, Copyright 2015, with permission from Elsevier.

New Children’s National and Inova collaboration

January 13, 2017

A new research collaboration will streamline completion of retrospective and prospective research studies, shedding light on myriad conditions that complicate pregnancies.

A new three-year, multi-million dollar research and education collaboration in maternal, fetal and neonatal medicine aims to improve the health of pregnant women and their children. The partnership between Children’s National Health System and Inova will yield a major, nationally competitive research and academic program in these areas that will leverage the strengths of both health care facilities and enhance the quality of care available for these vulnerable populations.

The collaboration will streamline completion of retrospective and prospective research studies, shedding light on a number of conditions that complicate pregnancies. It is one of several alliances between the two institutions aimed at improving the health and well-being of children in Northern Virginia and throughout the region.

“The Washington/Northern Virginia region has long had the capability to support a major, nationally competitive research and academic program in maternal and fetal medicine,” says Adre du Plessis, M.B.Ch.B., Director of the Fetal Medicine Institute at Children’s National and a co-Principal Investigator for this partnership. “The Children’s National/Inova maternal-fetal-neonatal research education program will fill this critical void.

“This new partnership will help to establish a closer joint education program between the two centers, working with the OB/Gyn residents at Inova and ensuring their involvement in Children’s National educational programs and weekly fetal case review meetings,” Dr. du Plessis adds.

Larry Maxwell, M.D., Chairman of Obstetrics and Gynecology at Inova Fairfax Medical Campus and a co-Principal Investigator for the collaboration, further emphasizes that “Inova’s experience in caring for women and children — combined with genomics- and proteomics-based research — will synergize with Children National’s leadership in neonatal pediatrics, placental biology and fetal magnetic resonance imaging (MRI) to create an unprecedented research consortium. This will set the stage for developing clinically actionable interventions for mothers and babies in metropolitan District of Columbia.”

Children’s National, ranked No. 3 nationally in neonatology, has expertise in pediatric neurology, fetal and neonatal neurology, fetal and pediatric cardiology, infectious diseases, genetics, neurodevelopment and dozens of additional pediatric medical subspecialties. Its clinicians are national leaders in next-generation imaging techniques, such as MRI. Eighteen specialties and 50 consultants evaluate more than 700 cases per year through its Fetal Medicine Institute. In mid-2016, Children’s National created a Congenital Zika Virus Program to serve as a dedicated resource for referring clinicians and pregnant women. The hospital performs deliveries in very high-risk, complex situations, but does not offer a routine labor and delivery program.

Inova Fairfax Medical Campus is home to both Inova Women’s Hospital and Inova Children’s Hospital. Inova Women’s Hospital is the region’s most comprehensive and highest-volume women’s hospital — delivering more than 10,000 babies in 2016. Inova Children’s Hospital serves as Northern Virginia’s children’s hospital —providing expert care in pediatric and fetal cardiology, cardiac surgery, genetics, complex general surgery, neurology, neurosurgery and other medical and surgical specialties. Its 108-bed Level IV neonatal intensive care unit is one of the largest and most comprehensive in the nation. Inova’s Translational Medicine Institute includes a genomics lab, as well as a research Institute focused on studies designed to build genetic models that help answer questions about individual disease. Each of these specialties is integrated into the Inova Fetal Care Center — which serves as a connection point between Inova Women’s and Children’s Hospitals. The Inova Fetal Care Center provides complex care coordination for women expecting infants with congenital anomalies or with other fetal concerns. Because Inova Women’s Hospital and Inova Children’s Hospital are co-located, women are able to deliver their babies in the same building where their children will receive care.

The research collaboration will support research assistants; tissue technicians; a placental biologist; as well as support for biomedical engineering, fetal-neonatal imaging, telemedicine, regulatory affairs and database management. The joint research projects that will take place under its auspices include:

Fetal growth restriction (FGR), which occurs when the failing placenta cannot support the developing fetus adequately. FGR is a major cause of stillbirth and death, and newborns who survive face numerous risks for multiple types of ailments throughout their lives. A planned study will use quantitative MRI to identify signs of abnormal brain development in pregnancies complicated by FGR.
Placental abnormalities, including placenta accreta. A planned study will combine quantitative MRI studies on the placenta during the third trimester and other points in time with formal histopathology to identify MRI signals of placenta health and disease.
Microcephaly, a condition that is characterized by babies having a much smaller head size than expected due to such factors as interrupted brain development or brain damage during pregnancy. While the global Zika virus epidemic has heightened awareness of severe microcephaly cases, dozens of pregnancies in the region in recent years have been complicated by the birth defect for reasons other than Zika infection. A planned study will examine the interplay between MRI within the womb and head circumference and weight at birth to examine whether brain volume at birth correlates with the baby’s developmental outcomes.

Using fMRI for assessment prior to neurosurgery

January 12, 2017

For more than 20 years, Children’s National has explored the use of non-invasive fMRI as an alternative to more invasive testing to assess children’s language and memory.

A new Practice Guideline Summary published in Neurology, the journal of the American Academy of Neurology, contains the first complete, objective assessment of available data on the efficacy of functional magnetic resonance imaging (fMRI) to assess baseline language and memory, brain hemisphere dominance and to predict postsurgical impacts prior to surgery in patients with epilepsy.

According to contributing author William D. Gaillard, M.D., chief of Child Neurology, Epilepsy and Neurophysiology, and director of the Comprehensive Pediatric Epilepsy Program at Children’s National Health System, the report outlines several cases in which fMRI presents an effective alternative to the current standard of care, intracarotid amobarbital procedure (IAP). In IAP, medication is injected through the carotid artery to isolate one hemisphere of the brain at a time, followed by the patient performing memory or language tasks. The approach requires catheterization via a major artery. While minimally invasive, the procedure still carries the standard risks of vascular catheter procedures and requires recovery time.

“This publication took six years to complete,” Dr. Gaillard notes, “but we are happy to finally have the practice parameters that will make the case for the use of fMRI in an evidence-based way.”

Though the Practice Guidelines focus on adults, the evidence assessment included all available pediatric data as well, says Dr. Gaillard. A great deal of that data were contributed by Children’s National faculty, who lead the nation in clinical applications of fMRI. More than 20 years ago, Dr. Gaillard and his team began studying fMRI as a viable alternative to IAP to collect accurate language assessments in children, particularly those with epilepsy. Today, Children’s National is at the forefront of clinical application of fMRI, having performed about 1,000 pediatric assessments in the last two decades — more than nearly every other institution.

An 11-member panel of international experts conducted the analyses for the Practice Guidelines. Overall, the report indicates:

fMRI is a viable option for measuring lateralized language functions in place of IAP in medial temporal lobe epilepsy, temporal epilepsy in general or extratemporal epilepsy.
Evidence was insufficient to recommend fMRI over IAP for patients with temporal neocortical epilepsy or temporal tumors.
Pre-surgical fMRI can serve as an adequate alternative to IAP memory testing for predicting verbal memory outcome.

In closing, the authors also explicitly recommend that clinicians carefully advise every patient of the risks and benefits of both fMRI and IAP before recommending either approach.

Down syndrome indicators in diverse populations

December 21, 2016

According to a large international study published in the American Journal of Medical Genetics, physical features vary in patients with Down syndrome across diverse populations. The study, led by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, used an objective digital facial analysis technology developed by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System to identify the most relevant facial features characteristic in Down syndrome in diverse populations from 12 countries. This study is the first to compare and contrast Down syndrome across diverse populations. It is the first in a series of studies to be used in the NIH’s Atlas of Human Malformation Syndromes in Diverse Populations, a free resource to help clinicians around the world diagnose birth defects and genetic diseases in people of diverse ancestry, and is the first in a series focused on different genetic syndromes.

Setting a baseline for healthy brain development

December 20, 2016

Catherine Limperopoulos, Ph.D., and colleagues performed the largest magnetic resonance imaging study of normal fetal brains in the second and third trimesters of pregnancy.

Starting as a speck barely visible to the naked eye and ending the in utero phase of its journey at an average weight of 7.5 pounds, the growth of the human fetus is one of the most amazing events in biology. Of all the organs, the fetal brain undergoes one of the most rapid growth trajectories, expanding over 40 weeks from zero to 100 billion neurons — about as many brain cells as there are stars in the Milky Way Galaxy.

This exponential growth is part of what gives humans our unique abilities to use language or have abstract thoughts, among many other cognitive skills. It also leaves the brain extremely vulnerable should disruptions occur during fetal development. Any veering off the developmental plan can lead to a cascade of results that have long-lasting repercussions. For example, studies have shown that placental insufficiency, or the inability of the placenta to supply the fetus with oxygen and nutrients in utero, is associated with attention deficit hyperactivity disorder, autism, and schizophrenia.

Recent research has identified differences in the brains of people with these disorders compared with those without. Despite the almost certain start of these conditions within the womb, they have remained impossible to diagnose until children begin to show clinical symptoms. If only researchers could spot the beginnings of these problems early in development, says Children’s National Health System researcher Catherine Limperopoulos, Ph.D., they might someday be able to develop interventions that could turn the fetal brain back toward a healthy developmental trajectory.

“Conventional tools like ultrasound and magnetic resonance imaging (MRI) can identify structural brain abnormalities connected to these problems, but by the time these differences become apparent, the damage already has been done,” Limperopoulos says. “Our goal is to be able to pick up very early deviations from normal in the high-risk pregnancy before an injury to the fetus might become permanent.”

Before scientists can recognize abnormal, she adds, they first need to understand what normal looks like.

In a new study published in Cerebral Cortex, Limperopoulos and colleagues begin to tackle this question through the largest MRI study of normal fetal brains in the second and third trimesters of pregnancy. While other studies have attempted to track normal fetal brain growth, that research has not involved nearly as many subjects and typically relied on data collected when fetuses were referred for MRIs for a suspected problem. When the suspected abnormality was ruled out by the scan, these “quasi-controls” were considered “normal” — even though they may be at risk for problems later in life, Limperopoulos explains.

By contrast, the study she led recruited 166 healthy pregnant women from nearby low-risk obstetrics practices. Each woman had an unremarkable singleton pregnancy and ended up having a normal full-term delivery, with no evidence of problems affecting either the mother or fetus over the course of 40 weeks.

At least one time between 18 and 39 gestational weeks, the fetuses carried by these women underwent an MRI scan of their brains. The research team developed complex algorithms to account for movement (since neither the mothers nor their fetuses were sedated during scans) and to convert the two-dimensional images into three dimensions. They used the information from these scans to measure the increasing volumes of the cerebellum, an area of the brain connected to motor control and known to mediate cognitive skills; as well as regions of the cerebrum, the bulk of the brain, that is pivotal for movement, sensory processing, olfaction, language, and learning and memory.

Their results in uncomplicated, full-term pregnancies show that over 21 weeks in the second half of pregnancy, the cerebellum undergoes an astounding 34-fold increase in size. In the cerebrum, the fetal white matter, which connects various brain regions, grows 22-fold. The cortical gray matter, key to many of cerebrum’s functions, grows 21-fold. And the deep subcortical structures (thalamus and basal ganglia), important for relaying sensory information and coordination of movement and behavior, grow 10-fold. Additional examination showed that the left hemisphere has a larger volume than the right hemisphere early in development, but sizes of the left and right brain halves were equal by birth.

By developing similar datasets on high-risk pregnancies or births—for example, those in which fetuses are diagnosed with a problem in utero, mothers experience a significant health problem during pregnancy, babies are born prematurely, or fetuses have a sibling diagnosed with a health problem with genetic risk, such as autism—Limperopoulos says that researchers might be able to spot differences during gestation and post-natal development that lead to conditions such as schizophrenia, attention deficit hyperactivity disorder and autism spectrum disorder.

Eventually, researchers may be able to develop fixes so that babies grow up without life-long developmental issues.

“Understanding ‘normal’ is really opening up opportunities for us to begin to precisely pinpoint when things start to veer off track,” Limperopolous says. “Once we do that, opportunities that have been inaccessible will start to present themselves.”

Altered blood flow may contribute to preemie brain injuries

December 20, 2016

A Children’s National research team for the first time mapped abnormalities in blood flow that may contribute to brain injury suffered by preterm infants.

Advanced noninvasive imaging permitted Children’s National Health System researchers to measure the lasting impact of abnormalities in blood flow on the immature brains of premature babies. Blood flow to the brain, or perfusion, has been studied previously to understand its role in other health conditions, but this is the first time a research team has mapped how these changes may contribute to brain injury suffered by babies born before 32 weeks’ gestation.

Preterm birth is a major risk factor for brain injury. The prospective study examined infants weighing less than 1,500 grams who were born prior to 32 gestational weeks.

Of 78 infants studied, 47 had structural brain injuries categorized as either mild or moderate to severe, and 31 had no brain injury. While global cerebral blood flow decreased with advancing postnatal age, the blood flow decreased more significantly among preterm infants with brain injury, says Eman S. Mahdi, M.D., M.B.Ch.B. Dr. Mahdi is a pediatric radiology fellow at Children’s National and lead author of the abstract.

“In addition to differences in global brain blood flow, we saw a marked decrease in regional blood flow to the thalamus and the pons, regions known to be metabolically active during this time,” Dr. Mahdi says. The thalamus helps to process information from the senses and relays it elsewhere within the brain. Located at the base of the brain, the pons is part of the central nervous system and also is a critical relay of information between the cerebrum and cerebellum. “These regional variations in blood flow reflect vulnerability of the cerebral-cerebellar circuitry,” she adds.

The Radiological Society of North America (RSNA) recognized Dr. Mahdi with its Trainee Research Prize. She presented the work, “Cerebral Perfusion Is Perturbed by Preterm Birth and Brain Injury,” during the RSNA Scientific Assembly and Annual Meeting, held from Nov. 27 to Dec. 2.

The findings point to the need for additional research to explore how cerebral blood flow trends evolve as preemies grow older and whether abnormal blood flow is linked to differences in health outcomes. In addition, the technique used by the research team, arterial spin labeling perfusion imaging – a type of magnetic resonance imaging – represents a useful and non-invasive technology for identifying early cerebral perfusion abnormalities in preterm infants, says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National and abstract senior author.

Premature birth may alter critical cerebellar development linked to learning and language

November 16, 2016

Diffusion tensor imaging teases out subtle injury to cerebral and cerebellar white matter that is not evident with conventional MRI, allowing researchers to quantify brain tissue microstructure and classify white matter integrity.

Premature birth can interrupt a key period of brain development that occurs in the third trimester, which has the potential to impact a child’s long-term learning, language, and social skills. A recent case-control study published in The Journal of Pediatrics applied diffusion tensor magnetic resonance imaging (DTI) to zoom in on the microstructures comprising the critical cerebellar neural networks related to learning and language, and found significant differences between preterm and full-term newborns.

“The third trimester, during which many premature births occur, is typically when the developing cerebellum undergoes its most dramatic period of growth. Normally, the cerebellar white matter tracts that connect to the deep nuclei are rich in pathways where nerve fibers cross. Those connections permit information to flow from one part of the brain to another. It is possible that premature birth leads to aberrant development of these critical neural networks,” says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National Health System and senior study author.

One in 10 American babies is born prematurely. The brain injury that infants born prematurely experience is associated with a range of neurodevelopmental disabilities, including some whose influence isn’t apparent until years later, when the children begin school. Nearly half of extremely preterm infants go on to experience long-term learning, social, and behavioral impairments.

While conventional magnetic resonance imaging (MRI) can detect many brain abnormalities in newborns, a newer technique called DTI can tease out even subtle injury to cerebral and cerebellar white matter that is not evident with conventional MRI. White matter contains axons, which are nerve fibers that transmit messages. With DTI, researchers can quantify brain tissue microstructure and describe the integrity of white matter.

The research team compared imaging from 73 premature infants born before 32 weeks gestation who weighed less than 1,500 grams with 73 healthy newborns born to mothers who delivered at full term after 37 weeks. After the newborns had been fed, swaddled, and fitted with double ear protection, the imaging was performed as they slept. Nurses monitored their heart rates and oxygen saturation. Their brain abnormalities were scored as normal, mild, moderate, or severe.

All of the full-term newborns had normal brain MRIs as did 44 (60.3 percent) of the preemies.

The preemies had significantly higher fractional anisotropy in the cerebellum, the part of the brain that processes incoming information from elsewhere in the brain, permitting coordinated movement as well as modulating learning, language, and social skills. Alterations in cerebellar microarchitecture was associated with markers for illness severe enough to require surgery – such as correcting abnormal blood flow caused by the failure of the ductus arteriosus to close after birth and to remedy a bowel disease known as necrotizing enterocolitis. The risk factors also are associated with compromised cardiorespiratory function and low Apgar score at five minutes, Limperopoulos and co-authors write. The Apgar score is a quick way to gauge, one minute after birth, how well the newborn withstood the rigors of childbirth. It is repeated at five minutes to describe how the newborn is faring outside of the womb.

“In previous studies, we and others have associated cerebellar structural injury in preterm infants with long-term motor, cognitive, and socio-affective impairments. This is one of the first studies to provide a detailed report about these unexpected alterations in cerebellar microstructural organization,” she adds. “We postulate that the combination of premature birth and early exposure of the immature developing cerebellum to the extrauterine environment results in disturbed micro-organization.”

Additional research is warranted in larger groups of patients as well as long-term follow up of this cohort of newborns to determine whether this microstructural disorganization predicts long-term social, behavioral, and learning impairments.

“A large number of these prematurely born newborns had MRI readings in the normal range. Yet, we know that these children are uniquely at risk for developing neurodevelopmental disabilities later in life. With additional study, we hope to identify interventions that could lower those risks,” Limperopoulos says.

Related resources: The Journal of Pediatrics editorial

Managing transposition of the great arteries in the womb

November 15, 2016

Monitoring and managing fetuses’ heart health in the womb can greatly improve their chances of living long and productive lives

Over the 22 years that Mary T. Donofrio, M.D., has been practicing fetal cardiology, the field has changed radically. The goal once had been simply to offer parents an accurate diagnosis and prepare them for sometimes devastating outcomes. Now, Dr. Donofrio, who directs the Fetal Heart Program and Critical Care Delivery Program at Children’s National Health System, says specialists can follow fetuses throughout the pregnancy and manage many conditions in the womb, greatly improving their chances of living long and productive lives.

Case in point: Transposition of the great arteries, a congenital defect characterized by reversal of the heart’s two main arteries—the aorta, which distributes oxygenated blood throughout the body, and the pulmonary artery, which carries deoxygenated blood from the heart to the lungs. The single abnormality means that the oxygenated “red” blood flows back to the lungs while deoxygenated “blue” blood flows out to the body.

After birth, when the cord is clamped and the connection to the placenta severed, the baby’s cardiovascular system must adjust. If the fetal connections between the two sides of the heart no longer remain, the brain and other organs in infants with this defect are severely deprived of oxygen. The condition may be fatal if something is not done immediately to reopen the fetal connections to stabilize the circulation before surgery can be done. But if the fetal cardiologist can keep tabs on what’s happening to the heart over time and prepare a specialty team of cardiologists to treat the problem immediately after birth, chances of survival are significantly improved.

More than a decade ago, as a young attending physician, Dr. Donofrio witnessed a case that has stuck with her to this day. The baby’s diagnosis of transposition of the great arteries was not made until shortly before birth. In addition, the two fetal blood flow connections that allow blood to circulate had closed, causing severe heart failure. Although the care team performed an emergency delivery and immediate cardiac procedure, including initiation of a heart-lung machine in the delivery room to try to stabilize the circulation, the baby ultimately died due to complications from a very low oxygen level. “I always wonder what happened,” Dr. Donofrio says. “Was the baby’s heart always that bad and nobody noticed it, or did it change over time?”

In a paper published recently in the Journal of Neonatal-Perinatal Medicine, she and colleagues illustrate the dramatic transformation in care that has taken place in the 14 years since this unforgettable case. The new publication describes the case of a different fetus diagnosed at 22 weeks gestation with transposition of the great arteries in 2015 at Children’s National. Unlike many congenital heart disorders, the heart’s four chambers appear misleadingly normal at the typical mid-pregnancy ultrasound. Despite the challenging diagnosis for many obstetricians, this fetus’ heart condition was recognized early by looking at the arteries leaving the heart in addition to the chambers.

While such a defect is fatal if left untreated, Dr. Donofrio explains there are two pathways that can allow the blood to get to where it needs to go such that the circulation is stabilized and the damage mitigated. One is the fetal blood vessel known as the ductus arteriosus that typically stays open for a day or two after birth. The second is an opening between the heart’s two upper chambers, known as the foramen ovale, which usually closes upon delivery. By keeping those two pathways open, blood can cross from one side of the heart to the other, buying time in the delivery room so that babies can be stabilized before they receive surgery to permanently move the arteries back to their normal position.

In the 2015 case, Dr. Donofrio and colleagues had the chance to monitor the fetus and the fetal heart at follow-up appointments every four weeks after diagnosis. What they saw completely changed the course of their treatment plan and likely saved the baby’s life. With each ultrasound, they saw that the ductus arteriosus and the foramen ovale—the critical connections needed for survival—were gradually closing.

Dr. Donofrio noted at the fetal evaluation at 38 weeks that the structures had closed, and the heart was showing signs that it was not functioning well. She and her team realized that the only way to save this baby was to deliver earlier than planned and to have cardiac specialists standing by ready to perform a life-saving procedure to open the connections right after the baby was separated from the placenta. The baby was delivered by Cesarean section in the cardiac operating room at Children’s. The cardiac intervention team immediately created a hole where the foramen ovale should have been by using a balloon to open the tissue that had closed. The care team also administered a prostaglandin infusion, a drug that can keep the ductus arteriosis open. This time, however, the medicine did not work. The baby was stabilized with several cardiac medications and, with little time to spare, the cardiac surgeons operated on the one-day-old baby to switch his great arteries back to the normal position, saving his life.

The baby is now 1-year-old, Dr. Donofrio says, and is healthy—a scenario that likely wouldn’t have happened had the fetal team not made the diagnosis and continually monitored the condition in the womb.

“I remember back to that first case when we were really scrambling to do everything we could at the last minute because we didn’t have the information we needed until the very end,” Dr. Donofrio says. “Now, we can spot problems early and do something about it. For me, that’s amazing. We’re making a difference, and that’s a really great thing.”

Every day fetuses remain in utero critical to preserving normal brain development

October 28, 2016

preemieimage

If it does not jeopardize the health of the pregnant mother or her fetus, pregnancies should be carried as close to full term as possible to avoid vulnerable preemies experiencing a delay in brain development, study results published October 28 in Pediatrics indicate.

Some 15 million infants around the world – and 1 in 10 American babies – are born prematurely. While researchers have known that preemies’ brain growth is disturbed when compared with infants born at full term, it remained unclear when preemies’ brain development begins to veer off course and how that impairment evolves over time, says Catherine Limperopoulos, Ph.D., Director of the Developing Brain Research Laboratory at Children’s National Health System and senior study author.

A look at the research

In order to shine a spotlight on this critical phase of fetal brain development, Limperopoulos and colleagues studied 75 preterm infants born prior to the 32th gestational week who weighed less than 1,500 grams who had no evidence of structural brain injury. These preemies were matched with 130 fetuses between 27 to 39 weeks gestational age.

The healthy fetal counterparts are part of a growing database that the Children’s National Developing Brain Research Laboratory has assembled. The research lab uses three-dimensional magnetic resonance imaging to carefully record week-by-week development of the normal in utero fetal brains as well as week-by-week characterizations of specific regions of the fetal brain.

The availability of time-lapsed images of normally developing brains offers a chance to reframe research questions in order to identify approaches to prevent injuries to the fetal brain, Limperopoulos says.

“Up until now, we have been focused on examining what is it about being born too early? What is it about those first few hours of life that leaves preemies more vulnerable to brain injury?” she says. “What is really unique about these study results is for the very first time we have an opportunity to better understand the ways in which we care for preemies throughout their hospitalization that optimize brain development and place more emphasis those activities.”

When the research team compared third-trimester brain volumes, preemies showed lower volumes in the cerebrum, cerebellum, brainstem, and intracranial cavity. The cerebrum is the largest part of the brain and controls speech, thoughts, emotions, learning, as well as muscle function. The cerebellum plays a role in learning and social-behavioral functions as well as complex motor functions; it also controls the balance needed to stand up and to walk. The brainstem is like a router, ferrying information between the brain, the cerebellum, and the spinal cord.

“What this study shows us is that every day and every week of in utero development is critical. If at all possible, we need to keep fetuses in utero to protect them from the hazards that can occur in the extra uterine environment,” she says.

Getting to the heart of cardiac malposition with fetal MRI

October 7, 2016

Mary T. Donofrio, M.D., Director of the Fetal Heart Program and Critical Care Delivery Program at Children’s National Health System

In a small percentage of pregnancies, the fetuses’ hearts develop in the wrong place. In the congenital anomaly known as heterotaxy syndrome that often includes a severe heart defect, the heart is often displaced from its usual position in the left chest. In other instances, the heart starts out in a normal position; however, it is pushed out of its normal position by a mass that grows in the chest cavity, by abnormal development of the lungs, or due to other causes. Although rare, babies born with cardiac malpositions associated with other congenital defects can be the most serious of all possible birth defects.

Sometimes, fetuses with these congenital problems die in the womb. Others do not survive long after birth. In some pregnancies, surgery is performed shortly after childbirth to stabilize the circulation so newborns even have a chance at life.

Correctly diagnosing these cardiac conditions during pregnancy can help doctors and parents alike make the most informed decisions and plan ahead.

However, the tools now used most often to reveal the overall anatomic details of cardiac malpositions — obstetrical ultrasound and fetal echocardiography — often don’t give a full picture. A clear view of the fetus can be obscured by the position of the fetus, insufficient amniotic fluid, or even a mother’s body habitus. Imaging techniques sometimes also have a hard time distinguishing between liver, bowel, and lung because the echogenicity of these tissues — the signature that sound waves make as they bounce back from their targets — is so similar.

“To be able to offer parents the best and most comprehensive counseling, and to begin planning for the type of intensive and multidisciplinary care that many of these babies will require, we need to have access to as much information as we can about each baby, not only relating to the heart but all the other organs as well,” says Mary T. Donofrio, M.D., a pediatric cardiologist who directs the Children’s National Health System Fetal Heart Program and Critical Care Delivery Program. “Unfortunately in some instances, obstetrical ultrasound and fetal echocardiography, the two diagnostic tools used most often in these cases, can be limited in what they tell us.”

What fetal MRI can show

An underutilized technique that gathers more details about the associated abnormalities that often accompany cardiac malposition during pregnancy is fetal magnetic resonance imaging, or fetal MRI, says Dr. Donofrio. Even though this technique is widely used to diagnose other fetal conditions, such as brain anomalies, it’s rarely used to better define the overall anatomy in cardiac malposition.

To determine whether fetal MRI is effective in complementing obstetrical ultrasound and fetal echocardiography, the current standard of care for this condition, Dr. Donofrio and colleagues took a retrospective look at all cases of cardiac malposition in which fetuses were evaluated using MRI between 2008 to 2013 at Children’s National. Their search turned up 42 cases.

Twenty-three cases had been diagnosed with obstetrical ultrasound and fetal echocardiography as having additional abnormalities beyond the heart’s changed position, and 19 had been given the diagnosis of heterotaxy syndrome. Each patient had been assigned to various known subtypes of these conditions, with some classified as having an unknown etiology for the findings.

After fetal MRI, the diagnoses of nearly one-third changed or were better delineated. Seven of the 23 cases of cardiac malposition attributed to an extra cardiac anomaly were reassigned to a cause different from the original diagnosis based on the new, more detailed information provided by fetal MRI, including three in which a complete diagnosis could not be made due to poor visualization by ultrasound. Five of the 19 cases attributed of heterotaxy were reassigned to different subgroups within this disorder or were given a different diagnosis completely after fetal MRI.

In eight of these 12 diagnoses that changed after fetal MRI, doctors were able to confirm these findings postnatally. Other cases were either lost to follow-up, pregnancy termination, or fetal demise.

The research team led by Dr. Donofrio published these results in the August 2016 issue of Prenatal Diagnosis.

Overall, she says the findings demonstrated the benefits of using fetal MRI as an adjunct to obstetrical ultrasound and fetal echocardiography. MRI offers advantages over ultrasound, she explains, including better spatial resolution, a wider field of view, and a way to see through or around maternal body fat, overlying fetal bone, or a fetus whose position is not optimal.

“Determining the etiology of cardiac malposition remains a challenging diagnosis, and the value of accurate prenatal diagnosis has been long recognized,” Donofrio and colleagues write in the study. “Ultimately, fetal MRI can assist with identifying the etiology of cardiac malposition for informative prenatal counseling and multidisciplinary planning.”

Exploration of the developing brain

August 8, 2016

Common, lifelong health conditions like diabetes and hypertension have footprints that can be traced back to the womb. With advanced fetal MRI we seek to understand as much as possible about brain development during the time in utero. Non-invasive imaging technology helps us to identify signs of abnormal fetal development that may facilitate earlier diagnoses of chronic conditions and intervention.

We’re exploiting both the power and safety of MRI to develop ways to pick up early signs and signals in fetuses whose brain development may be veering off in the wrong direction. Using this advanced technology we can begin to detect varying signals or other signs of distress. These signs of distress may appear in the form of a brain chemical imbalance or a structural brain abnormality that is too subtle to be seen by an ultrasound or other scan. We now have the ability to leverage magnetic resonance imaging to examine the brain in utero for even the most subtle derailments that can lead to lifelong consequences.

The first nine months of life, when a fetus is in the womb, is a time of unparalleled growth and a critical time for fetal brain development. As we examine the maturation of the fetal brain, we know that each and every cortical fold represents future function lost or gained and lays the fundamental background or platform from which critical functions will emerge such as language and social and behavioral development.

We are developing technology that can quickly and reliably pick up early signals of a fetal brain that’s going off route to provide the ability to access therapeutic windows that are currently inaccessible. Earlier identification and intervention can improve the quality of life for children and potentially could even reverse the abnormality.

Early identification of fetal distress is critical. To be able to provide an intervention you must first be able to know that a fetus is getting into trouble, and you must be able to identify the problem early enough, in order to intervene before it has already caused injury to the fetus.

About the Author

Catherine Limperopoulos, Ph.D.
Director, MRI Research of the Developing Brain; Director, Diagnostic Imaging and Radiology/Fetal and Transitional Medicine
Research interests: Fetal neonatal brain injury

Sharp images key to spotting the earliest signs of compromised pregnancies

July 11, 2016

Fetuses wiggle. They waggle. Some pirouette within the womb, amniotic fluid easing their spins. Pregnant mothers’ meals and beverages from hours earlier wend their way through their digestive systems. On top of that, mother and offspring may breathe out of sync and their hearts may beat in time to different drummers.

In short, there’s a whole lot of movement going on in the womb.

As anyone trying to capture a photograph with a digital camera knows, sudden movements are the enemy of a sharp image. The challenge is the same for fetal researchers aiming to capture crisp functional magnetic resonance imaging (fMRI) of the developing brains of fetuses who are always on the move.

Over two years, a Children’s National Health System research team led by Wonsang You, a research associate in the Developing Brain Research Laboratory, worked out complex mathematical algorithms to account for independent fetal and placental motions, to erase those noise artifacts, and to validate the accuracy of the technique.

“[M]otion correction is optimized to the experimental paradigm, and it is performed separately in each phase as well as in each region of interest (ROI), recognizing that each phase and organ experiences different types of motion. To obtain the averaged [blood oxygen level-dependent] BOLD signals for each ROI, both misaligned volumes and noisy voxels are automatically detected and excluded, and the missing data are then imputed by statistical estimation based on local polynomial smoothing,” You and colleagues wrote in a technical article published recently by the Journal of Medical Imaging and spotlighted on the journal’s website as a featured article.

To underscore the work’s clinical utility, they analyzed differences in fetal motion by acquiring BOLD fMRI data from eight pregnant women with healthy fetuses and comparing them with eight women whose fetuses had been diagnosed with congenital heart disease (CHD) between 25 to 40 weeks of gestational age. The team focused on changes in oxygenation of the fetal brain and placenta during maternal hyperoxia, an oxygen challenge test during which both groups of pregnant women received 100 percent oxygen via face mask for four to six minutes. Measurements were then taken to determine whether there were differences in how the fetuses and the placentas responded to the oxygen challenge test.

Recognizing compromised fetuses in utero – and understanding the subtle but important ways they deviate from the trajectory of normal fetuses – opens a critical window of opportunity to intervene through nutritional, pharmaceutical, or surgical means – before brain injury is consolidated, says Catherine Limperopoulos, PhD, Director, MRI Research of the Developing Brain at Children’s National, and the paper’s senior author.“

Our goal is to exploit the power of MRI, a non-invasive imaging technique, to detect the earliest signs of the fetus getting into trouble before it runs into serious problems,” Limperopoulos says. “We needed the technical development described in this foundational work to allow us to reliably measure the fMRI BOLD response in the fetal brain and placenta.”

The BOLD signal can be degraded by the independent and collective movements of the mother and fetus. Traditional motion correction makes assumptions, such as treating all moving objects like the fetal brain, which is solid, rigid, and has a high range of motion. The traditional approach also fails to account for such subtleties as the placenta’s low range of motion and its flexing in response to maternal and fetal movements.

The research team employed four-step pre-processing – which included correcting bias magnetic field, correcting for global and local motion, and rejecting outliers – and followed with data imputation, an alphabet soup of letters and Latin symbols that mathematically accounts for objects (placenta and fetal brain) that move independently.“

We showed that the proposed preprocessing pipeline can be effectively employed to characterize fetal motion in healthy controls and CHD fetuses. Our preliminary data suggest that the degree of fetal motion tends to increase during hyperoxia in CHD fetuses (but not significantly). In addition, the motion of the fetal brain in CHD cases showed higher variance during hyperoxia compare[d] to controls,” You and colleagues write. “These observations suggest that the CHD fetus may be more responsive to maternal hyperoxia. However, these pilot data need to be validated on a larger cohort of healthy and high-risk CHD fetuses.”

Related resources: Research at a Glance