Neonatology

mitochondria

Mitochondria key for repairing cell damage in DMD

mitochondria

A research team led by Jyoti K. Jaiswal, M.S.C., Ph.D., found that dysfunctional mitochondria prevent repair of muscle cells in Duchenne muscular dystrophy.

What’s known

Duchenne muscular dystrophy (DMD), one of the most severe forms of muscular dystrophy, is caused by a defect in the dystrophin gene. The protein that this gene encodes is responsible for anchoring muscle cells’ inner frameworks, or cytoskeletons, to proteins and other molecules outside these cells, the extracellular matrix. Without functional dystrophin protein, the cell membranes of muscle cells become damaged, and the cells eventually die. This cell death leads to the progressive muscle loss that characterizes this disease. Why these cells are unable to repair this progressive damage has been unknown.

What’s new

A research team led by Jyoti K. Jaiswal, M.S.C., Ph.D., a principal investigator in the Center for Genetic Medicine Research at Children’s National Health System, investigated this question in two experimental models of DMD that carry different mutations of the dystrophin gene. The researchers monitored the effects of the lack of functional dystrophin protein in these preclinical models on the level and function of muscle cell. They found that mitochondria – organelles that act as powerhouses to supply the chemical energy to drive cellular activities – are among the first to be affected. They found that the decline in mitochondrial level and activity over time in these experimental models preceded the onset of symptoms. The research team also looked at the ability of the experimental models’ muscle cells to repair damage. As the muscle cell mitochondria lost function, the cells’ ability to repair damage also declined. Efforts to increase mitochondrial activity after these organelles became dysfunctional did not improve muscle repair. This suggests that poor muscle repair may not be caused by a deficit in energy production by mitochondria.

Questions for future research

Q: Does similar mitochondrial dysfunction occur in human patients with DMD?
Q: How can the mitochondrial dysfunction be prevented?
Q: Is there a way to reverse mitochondrial dysfunction to better preserve the ability of muscle cells to repair from DMD-related damage?

Source: “Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy.” Vila, M.C., S. Rayavarapu, M.W. Hogarth, J.H. Van der Meulen, A. Horn, A. Defour, S. Takeda, K.J. Brown, Y. Hathout, K. Nagaraju and J.K. Jaiswal. Published by Cell Death and Differentiation February 2017.

LCModel output from 32 GA baby

Understanding the long-term consequences of prematurity

LCModel output from 32 GA baby

Children’s National Health System researchers processed H1-MRS data using LCModel software to calculate absolute metabolite concentrations for N-acetyl-aspartate (NAA), choline (Cho) and creatine (Cr). Preterm infants had significantly lower cerebellar NAA (p=<0.025) and higher Cho (p=<0.001) when compared with healthy term-equivalent infants. The area of the brain within the red box is the cerebellum, the region of interest for this study.

Premature birth, a condition that affects approximately 10 percent of births in the United States, often is accompanied by health problems ranging from difficulties breathing and eating to long-term neurocognitive delays and disabilities. However, the reasons for these problems have been unclear.

In a study published online Aug. 15, 2017 in Scientific Reports, a team of Children’s National Health System clinician-researchers reports that prematurity is associated with altered metabolite profiles in the infants’ cerebellum, the part of the brain that controls coordination and balance. Pre-term infants in the study had significantly lower levels of a chemical marker of nerve cell integrity and significantly higher concentrations of a chemical marker of cellular membrane turnover.

“These data suggest that interrupting the developing fetal brain’s usual growth plan during gestation – which can occur through early birth, infection or experiencing brain damage – might trigger a compensatory mechanism. The infant’s brain tries to make up for lost time or heal injured tissue by producing a certain type of cells more quickly than it normally would,” says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National and senior study author. “The more sensitive imaging technique that we used also revealed nerve cell damage from brain injuries extends beyond the site of injury, a finding that contrasts with what is found through conventional magnetic resonance imaging (MRI).”

It has long been clear that prematurity – birth before 37 weeks gestation – is accompanied by a number of immediate and long-term complications, from potential problems breathing and feeding at birth to impairments in hearing and sight that can last throughout an individual’s life.

Neurocognitive developmental delays often accompany pre-term birth, many of which can have long-lasting consequences. Studies have shown that children born prematurely are more likely to struggle in school, have documented learning disabilities and experience significant delays in developing gross and fine motor skills compared with children born at full-term.

Several studies have investigated the root cause of these issues in the cerebrum, the structure that takes up the majority of the brain and is responsible for functions including learning and memory, language and communication, sensory processing and movement. However, the cerebellum – a part of the brain that plays an important role in motor control – has not received as much research attention.

In the new study, Limperopoulos and colleagues used a specialized MRI technique that allowed them to parse out differences in which molecules are present in the cerebellum of full-term infants compared with premature infants. Their findings show a variety of differences that could offer clues to explain developmental differences between these two populations – and potentially identify ways to intervene to improve outcomes.

The researchers recruited 59 premature infants, born at 32 or fewer weeks’ gestation, and 61 healthy, full-term infants. Each baby received a special type of MRI known as proton magnetic resonance spectroscopy, or H1-MRS, that measures the concentrations of particular molecules in the brain. The full-term infants had these MRIs shortly after birth; the pre-term infants had them at 39 to 41 weeks gestational age, or around the time that they would have been born had the pregnancy continued to term.

Looking specifically at the cerebellum, the researchers found that the pre-term infants overall had significantly lower concentrations of N-acetyl-aspartate (NAA), a marker of the integrity of nerve cells. They also had significantly higher concentrations of choline, a marker of cell membrane integrity and membrane turnover.

Concentrations of creatine, a marker of stores of cellular energy, were about the same overall between the two groups. However, the researchers found that brain injuries, which affected 35 of the pre-term infants but none of the full-term infants, were associated with significantly lower concentrations of NAA, choline and creatine. Having a neonatal infection, which affected 21 of the pre-term infants but none of the full-term ones, was associated with lower NAA and creatine.

The findings could offer insight into exactly what’s happening in the brain when infants are born pre-term and when these vulnerable babies develop infections or their brains become injured – conditions that convey dramatically higher risks for babies born too early, Limperopoulos says. The differences between the full-term babies and the pre-term ones reflect disturbances these cells are experiencing at a biochemical level, she explains.

Limperopoulos and colleagues note that more research will be necessary to connect these findings to what is already known about developmental problems in pre-term infants. Eventually, she says, scientists might be able to use this knowledge to develop treatments that might be able to change the course of brain development in babies born too early, getting them on track with infants born at term.

“We know that the bodies of pre-term infants demonstrate a remarkable ability to catch up with peers who were born at full-term, in terms of weight and height. Our challenge is to ensure that preemies’ brains also have an opportunity to develop as normally as possible to ensure optimal long-term outcomes,” Limperopoulos says.

Patricio Ray

Toward a better definition for AKI in newborns

Patricio Ray

The National Institute of Diabetes and Digestive and Kidney Diseases convened a meeting of expert neonatologists and pediatric nephrologists, including Dr. Patricio Ray, to review state-of –the-art knowledge about acute kidney injury in neonates and to evaluate the best method to assess these patients’ kidney function.

Each year, thousands of infants in the United States end up in neonatal intensive care units (NICUs) with acute kidney injury (AKI), a condition in which the kidneys falter in performing the critical role of filtering waste products and excess fluid from the blood to produce urine. Being able to identify neonates during the early stages of AKI is critical to doctors and clinician-scientists who treat and study this condition, explains Patricio Ray, M.D., a nephrologist at Children’s National Health System.

Without an accurate definition and early identification of newborns with AKI, it is difficult for doctors to limit the use of antibiotics or other medications that can be harmful to the kidneys. Neonates who have AKI should not receive large volumes of fluids, a treatment that can cause severe complications when the kidneys do not properly function.

Until recently, there was no standard definition for AKI, leaving doctors and researchers to develop their own guidelines. Lacking set criteria led to confusion, Dr. Ray says. For example, different studies estimating the percentage of infants in NICUs with AKI ranged from 8 percent to 40 percent, depending on which definition was used. In 2012, a group known as the Kidney Disease Improved Global Outcome (KDIGO) issued practice guidelines for AKI that provide a standard for doctors and researchers to follow. They focus largely on measuring the relative levels of serum creatinine, a protein produced by muscles that is filtered by the kidneys, and the amount of urine output, which typically declines in adults and older children with failing kidneys.

The problem with these guidelines, Dr. Ray explains, is they are not sensitive enough to identify newborns experiencing the early stages of AKI during the first week of life. Newborns can have high serum creatinine levels during the first week of life due to residual levels transferred from mothers through the placenta. Also, because their kidneys are immature, failure often can mean higher – not diminished – urine production.

In 2013, the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, convened a meeting of leading neonatologists and pediatric nephrologists – including Dr. Ray – to review state-of-the-art knowledge about AKI in neonates and to evaluate the best manner to assess kidney function in these patients. They published a summary of their discussion online June 12, 2017 in Pediatric Research.

Among other findings, the group concluded that the current definition of AKI lacks the sensitivity needed to identify the early stages of AKI in neonates’ first week of life. They also said that more research was needed to fill this gap.

That’s where Dr. Ray’s current research comes in. Working with fellow Children’s Nephrologist Charu Gupta, M.D., and Children’s Neonatologist An Massaro, M.D., the three clinician-scientists reviewed the medical records of 106 infants born at term with a condition known as hypoxic ischemic encephalopathy (HIE), in which the brain doesn’t receive enough oxygen. Not only does this often lead to brain injury, but it also greatly increases the risk of AKI.

Because these babies had been followed closely in the NICU to assess the possibility of AKI, their serum creatinine had been checked frequently. The researchers found that about 69 percent of the infants with HIE followed at Children’s National never developed signs of kidney failure during their first week of life. These babies’ serum creatinine concentrations dropped by 50 percent or more by the time they were 1 week old, about the same as reported previously in healthy neonates. Another 12 percent of the infants with HIE developed AKI according to the definition established by the KDIGO group in 2012. These infants:

  • Required more days of mechanical ventilation and medications to increase their blood pressure
  • Had higher levels of antibiotics in their bloodstreams
  • Retained more fluid
  • Had lower urinary levels of a molecule that their kidneys should have been cleared and
  • Had to stay in the hospital longer

A third group of the infants with HIE, about 19 percent, did not meet the standard criteria for AKI. However, these babies had a rate of decline of serum creatinine that was significantly slower than the normal newborns and the infants with HIE who had excellent outcomes. Rather, their outcomes matched those of infants with established AKI.

Dr. Ray notes that by following the rate of serum creatinine decline during the first week of life physicians could identify neonates with impaired kidney function. This approach provides a more sensitive method to identify the early stages of AKI in neonates. “By looking at how fast babies were clearing their serum creatinine compared with the day they were born, we could predict how well their kidneys were working,” he says. Dr. Ray and colleagues published these findings July 2016 in Pediatric Nephrology.

He adds that further studies will be necessary to confirm the utility of this new approach to assess the renal function of term newborns with other diseases and preterm neonates. Eventually, he hopes this new approach will become uniform clinical practice.

Catherine Limperopoulos

A closer look at the placenta to predict FGR

Catherine Limperopoulos

Using three-dimensional magnetic resonance imaging, a Children’s National research team that included Catherine Limperopoulos, Ph.D., characterized the shape, volume, morphometry and texture of placentas during pregnancy and, using a novel framework, predicted with high accuracy which pregnancies would be complicated by fetal growth restriction.

Early in development, cells from the fertilized egg form the placenta, a temporary organ that serves as an interface between the mother and her growing offspring. When things go right, as occurs in the vast majority of pregnancies, the placenta properly delivers nutrients from the mother’s diet and oxygen from the air she breathes to the developing fetus while siphoning away its waste products. This organ also plays important immune-modulating and endocrine roles.

However, in a number of pregnancies, the placenta does not do an adequate job. Unable to effectively serve the fetus, a variety of adverse conditions can develop, including preeclampsia, fetal growth restriction (FGR), preterm birth and even fetal death.

Despite the key role that the placenta plays in fetal health, researchers have few non-invasive ways to assess how well it works during pregnancy. In fact, placental disease might not be suspected until very late.

In a new study, a team of Children’s National Health System research scientists is beginning to provide insights into the poorly understood placenta.

Using three-dimensional (3D) magnetic resonance imaging (MRI), the research team characterized the shape, volume, morphometry and texture of placentas during pregnancy and, using a novel framework, predicted with high accuracy which pregnancies would be complicated by FGR.

“When the placenta fails to carry out its essential duties, both the health of the mother and fetus can suffer and, in extreme cases, the fetus can die. Because there are few non-invasive tools that reliably assess the health of the placenta during pregnancy, unfortunately, placental disease may not be discovered until too late – after impaired fetal growth already has occurred,” says Catherine Limperopoulos, Ph.D., co-director of research in the Division of Neonatology at Children’s National Health System and senior author of the study published online July 22 in Journal of Magnetic Resonance Imaging. “Identifying early biomarkers of placental disease that may impair fetal growth and well-being open up brand-new opportunities to intervene to protect vulnerable fetuses.”

The Children’s research team acquired 124 fetal scans from 80 pregnancies beginning at the 18th gestational week and continuing through the 39th gestational week. Forty-six women had normal pregnancies and healthy fetuses while 34 women’s pregnancies were complicated by FGR, defined by estimated fetal weight that fell below the 10th percentile for gestational age. The placenta was described by a combination of shape and textural features. Its shape was characterized by three distinct 3D features: Volume, thickness and elongation. Its texture was evaluated by three different sets of textural features computed on the entire placenta.

“The proposed machine learning-based framework distinguished healthy pregnancies from FGR pregnancies with 86 percent accuracy and 87 percent specificity. And it estimated the birth weight in both healthy and high-risk fetuses throughout the second half of gestation reasonably well,” says the paper’s lead author, Sonia Dahdouh, Ph.D., a research fellow in Children’s Developing Brain Research Laboratory.

“We are helping to pioneer a very new frontier in fetal medicine,” Limperopoulos adds. “Other studies have developed prediction tools based on fetal brain features in utero. To our knowledge, this would be the first proposed framework for semi-automated diagnosis of FGR and estimation of birth weight using structural MRI images of the placental architecture in vivo. This has the potential to address a sizable clinical gap since we lack methods that are both sufficiently sensitive and specific to reliably detect FGR in utero.”

The research team writes that its findings underscore the importance of future studies on a larger group of patients to expand knowledge about underlying placenta mechanisms responsible for disturbed fetal growth, as well as to more completely characterize other potential predictors of fetal/placental development in high-risk pregnancies, such as genetics, physiology and nutrition.

Zhe Han, PhD

Lab led by Zhe Han, Ph.D., receives $1.75 million from NIH

Zhe Han, PhD

A new four-year NIH grant will enable Zhe Han, Ph.D., to carry out the latest stage in the detective work to determine how histone-modifying genes regulate heart development and the molecular mechanisms of congenital heart disease caused by these genetic mutations.

The National Institutes of Health (NIH) has awarded $1.75 million to a research lab led by Zhe Han, Ph.D., principal investigator and associate professor in the Center for Genetic Medicine Research, in order to build models of congenital heart disease (CHD) that are tailored to the unique genetic sequences of individual patients.

Han was the first researcher to create a Drosophila melanogaster model to efficiently study genes involved in CHD, the No.1 birth defect experienced by newborns, based on sequencing data from patients with the heart condition. While surgery can fix more than 90 percent of such heart defects, an ongoing challenge is how to contend with the remaining cases since mutations of a vast array of genes could trigger any individual CHD case.

In a landmark paper published in 2013 in the journal Nature, five different institutions sequenced the genomes of more than 300 patients with CHD and their families, identifying 200 mutated genes of interest.

“Even though mutations of these genes were identified from patients with CHD, these genes cannot be called ‘CHD genes’ since we had no in vivo evidence to demonstrate these genes are involved in heart development,” Han says. “A key question to be answered: How do we efficiently test a large number of candidate disease genes in an experimental model system?”

In early 2017, Han published a paper in Elife providing the answer to that lingering question. By silencing genes in a fly model of human CHD, the research team confirmed which genes play important roles in development. The largest group of genes that were validated in Han’s study were histone-modifying genes. (DNA winds around the histone protein, like thread wrapped around a spool, to become packed into a higher-level structure.)

The new four-year NIH grant will enable Han to carry out the next stage of the detective work to determine precisely how histone-modifying genes regulate heart development. In order to do so, his group will silence the function of histone-modifying genes one by one, to study their function in the fly heart development and to identify the key histone-modifying genes for heart development. And because patients with CHD can have more than one mutated gene, he will silence multiple genes simultaneously to determine how those genes work in partnership to cause heart development to go awry.

By the end of the four-year research project, Han hopes to be able to identify all of the histone-modified genes that play pivotal roles in development of the heart in order to use those genes to tailor make personalized fly models corresponding to individual patient’s genetic makeup.

Parents with mutations linked to CHD are likely to pass heart disease risk to the next generation. One day, those parents could have an opportunity to sequence their genes to learn the degree of CHD risk their offspring face.

“Funding this type of basic research enables us to understand which genes are important for heart development and how. With this knowledge, in the near future we could predict the chances of a baby being born with CHD, and cure it by using gene-editing approaches to prevent passing disease to the next generation,” Han says.

Panel: Significant Zika risks linger for pregnant women and developing fetuses in US

Roberta DeBiasi

The threat from Zika “is not over. It is just beginning for the families who are affected by this,” 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 Health System.

The Zika virus epidemic may have fallen off the radar for many media outlets, but significant risks continue to linger for pregnant women and developing fetuses, a panel of experts told staff working for U.S. Congressional leaders.

“The threat of this virus is real, and the threat continues,” Margaret Honein, Ph.D., M.P.H., of the Centers for Disease Control and Prevention’s (CDC) pregnancy and birth defects task force, said during the July 13 briefing held in the Russell Senate Office Building.

Dr. Honein told about 100 attendees that more than 200 Zika-affected babies have been born in the United States suffering from serious birth defects, such as rigid joints, inconsolable distress that causes them to cry continuously and difficulties swallowing. Some of these infants experience seizures that cause further brain damage.

Predicting what Zika will do next in the United States is very difficult, Dr. Honein said, adding that local outbreaks could occur “at any time.” A map she displayed showed Zika’s impact in shades of blue, with Zika infections documented in nearly every state and the highest number of infections – and deepest shade of blue­ – for California, Florida and Texas.

The threat from Zika “is not over. It is just beginning for the families who are affected by this,” agreed 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 Health System.

Since Children’s National launched its Zika program in May 2016, the multidisciplinary team has consulted on 65 mother-fetus/infant pairs, Dr. DeBiasi said. Because in utero Zika infection can result in a wide range of side effects, the Children’s team includes pediatric infectious diseases experts, fetal/neonatal neurologists to consult on seizures, audiologists to assess hearing, physical therapists and orthopaedists to contend with limb contractures, pulmonologists to relieve breathing problems and ophthalmologists to diagnose and treat vision disorders – among other specialists.

“You really need a program that has all of these areas of expertise available for a family,” Dr. DeBiasi told attendees. “It is not possible for a family to organize 27 different appointments if you have a child with these needs.”

Children’s Zika experts also collaborate with researchers in Colombia to gauge the ability of magnetic resonance imaging to produce earlier Zika diagnoses, to assess the role of viral load as biomarkers and to document Zika’s long-term impact on children’s neurodevelopment. The Colombia study has enrolled an additional 85 women/infant pairs.

In one presentation slide, Dr. DeBiasi showed sharp magnetic resonance imaging scans from their research study of a fetal brain at 18 and 22 weeks gestation that indicated clear abnormalities, including abnormal cortical folding. Ultrasound images taken at the exact same time points did not detect these abnormalities, she said.

Asked for advice by an attendee whose clinic treats women who regularly travel between California and Mexico, Dr. DeBiasi underscored the fact that Zika infection poses a risk to developing fetuses even if the pregnant woman has no symptoms of infection. “Whether or not they’re symptomatic, the risk is the same. It’s hard for people to understand that. That is No. 1,” she said.

Another challenge is for women who scrupulously follow the CDC’s guidance on lowering their infection risk while traveling. Upon return, those women may be unaware that they could still be exposed to Zika through unprotected sex with their partner who also has travelled, for as long as six months after travel.

US News Honor Roll 2017-18

Children’s National is #1 in Neonatology and Top 10 overall in U.S. News & World Report Survey

US News Honor Roll 2017-18Children’s National is proud to be named #1 in Neonatology in the U.S. News & World Report 2017-18 Best Children’s Hospitals survey. Also, Children’s National was once again named to the coveted Honor Roll, placing them among the Top 10 children’s hospitals in the country.

Being the #1 ranked Neonatology program reflects the quality of care throughout Children’s National because it requires the support and partnership of many other specialties, including cardiology, neurology and surgery. In addition to this honor, Children’s National ranked in the Top 10 in four additional services: Cancer (#7), Neurology and Neurosurgery (#9), Orthopedics (#9) and Nephrology (#10).  For the seventh year in a row, Children’s National has ranked in all ten services, a testament to the pediatric care experts across the organization and their commitment to children and families.

“This recognition is a great achievement for Children’s National, affirming our place as a premier destination for pediatric care, and the commitment of our people, partners and supporters to helping every child grow up stronger,” said Kurt Newman, M.D., President and CEO of Children’s National. “I’m particularly proud of our #1 ranking in Neonatology as, in many ways it reflects the quality of care across our hospital. Treating these tiny patients often encompasses many other specialties, including our Fetal Medicine Institute.”

Children’s National is dedicated to improving the lives of children through innovative research, expert care and advocacy on behalf of children’s needs. In addition to being recognized among the “best of the best” by U.S. News & World Report, Children’s National is a Magnet® designated hospital for excellence in nursing and is a Leapfrog Group Top Hospital. As a top NIH-funded pediatric health system, Children’s National marries cutting-edge research with the highest quality care, to deliver the best possible outcomes for children today and in the future.

Oluigbo and Myseros neurosurgery

Working miracles to quiet seizures and preserve brain power in newborns

Oluigbo and Myseros neurosurgery

In the spring of 2017, a multidisciplinary team applied an innovative approach to help preserve function in the working right hemisphere of a baby who experienced her first seizure hours after birth.

When orderly fetal brain development is disturbed, infants can be born with hemimegalencephaly – a rare occurrence – that results in one of the brain’s two hemispheres being oversized, heavy and malformed. Children with hemimegalencephaly can develop horrible seizures within the first few moments of life. According to published research, every month these infants experience uncontrolled seizures correlates to a steep decline in IQ.

Because these types of seizures do not respond to multiple seizure medications – and anticonvulsant medicines cause worrisome side effects of their own – care teams attempt to schedule surgery as soon as feasible to neutralize the hemisphere triggering the damaging seizures. They either remove it, or they sever nerve fibers and that hemisphere’s blood supply in order to leave it in place.

“The ‘bad’ brain does not sustain any function and it interferes with the ‘good’ brain doing what it needs to do,” says William D. Gaillard, M.D., chief of Children’s National Division of Epilepsy and Neurophysiology and chief of Neurology.

Hemispherectomy is intricate surgery on an organ that is softer than normal and crisscrossed with a tangle of blood vessels that supply the damaged hemisphere with blood. Because of the risks of life-threatening blood loss in very young infants, the dramatic surgery usually does not occur until babies are at least 3 months old and weigh at least 10 pounds.

The challenge: The vulnerable babies who most need relief, infants who have been seizing since delivery, are too young for the operation.

Children’s Pediatric Neurosurgeon Chima Oluigbo, M.D., F.R.C.S.C., had pioneered an innovative approach to clamp off the carotid artery to reduce blood loss during the surgery. Dr. Gaillard says that inspired approach got the team thinking: What if we use embolization – blocking blood supply to targeted locations in the brain – to achieve the same effect?

“It was eye-opening for us to think about actually inflicting brain injury as a way of treating something in the brain that was causing seizures. That is really novel in itself: We’re thinking out of the box in applying existing techniques in a different age group. The conventional thinking with newborns is to let them be; their seizures don’t look that bad,” says Taeun Chang, M.D., director of Children’s Neonatal Neurology and Neonatal Neurocritical Care Program.

“We have evidence to suggest this is a safe and effective way of avoiding recurrent seizures and minimizing the need to give these infants toxic medications so early in life. Ultimately, this helps a select group of  kids who need the surgery to get to the point of being old enough to have it – all the while sparing the healthy part of their brain,” Dr. Gaillard adds.

In the spring of 2017, the multidisciplinary team applied the innovative approach to help preserve function in the working right hemisphere of a baby named Darcy Murphy. Darcy experienced her first seizure hours after she was born, and when she arrived at Children’s National had been in and out of two different emergency rooms in another state for the first few weeks of her life.

Darcy hemimegalencephaly

Once the embolization ended Darcy’s most severe seizures, the little girl could make eye contact, started smiling, and then graduated from smiling to full laughs. In weekly physical therapy, the infant works on tummy time, head control and ensuring her eyes track.

The team explained to the Murphy family that Darcy was on multiple medications but her seizures continued unabated. The options included inducing a coma, sending Darcy home despite ongoing seizures or minimally invasive embolization.

“We would not have even posed this if we were not confident in our ability to do the procedure and deal with potential complications,” Dr. Chang says.

“Oh my gosh, as a parent you know what you’re doing is permanent,” says Rachel Murphy, 29, Darcy’s mom said of the decisions that she and husband Ryan, 33, faced for the youngest of their three children. “What if it’s not the right decision? What if in a week they come out with a new procedure you could have done? We were horrified all the time. The nice part with this procedure is the reward is apparent very quickly, and it just gets better. You don’t have to wait two years to know you made the right decision. You can see half a brain is better than the whole thing for this specific child.”

Once the embolization ended Darcy’s most severe seizures, the little girl could make eye contact, started smiling, and then graduated from smiling to full laughs. In weekly physical therapy, the infant works on tummy time, head control and ensuring her eyes track.

“With hemispherectomy, the kids will lose half of their vision in both eyes. It’s not that they’re blind. Their eyes work fine. When images are sent back to brain to be reflected, there is nothing on the left side reflecting back,” Rachel adds.

Children’s multidisciplinary care team includes experts in newborn intensive care (neonatologists) to aggressively manage seizures in the traditional fashion as they occur and to monitor vital signs; a neonatal neurologist/neurointensivist at the bedside and in the Angio suite monitoring Darcy’s brain activity; a neonatal epileptologist; a surgical epilepsy team; an interventional neuroradiologist from Johns Hopkins; neurosurgeons to perform the delicate functional hemispherectomy; and physical therapists working to help Darcy achieve maximum function after surgery.

“We were just like one unit in the sense of being able to provide coherent, comprehensive care. It’s about blood pressure management, breathing, electrolytes, making sure everything is right for going to the operating room,” Dr. Chang explains. “Darcy’s case highlights the ways in which Children’s National is different and offers personalized care that is superior to other centers.”

The team, which has already published a case report of two previous serial embolizations followed by hemispherectomy, plans follow-up papers describing EEG manifestations during an acute stroke in a newborn, advice to the field on best practices for the embolization and using cooling to minimize brain herniation.

Related resources

Chima Oluigbo

A novel way to treat intractable epilepsy caused by hemimegalencephaly

Chima Oluigbo

A multidisciplinary team led by Chima Oluigbo, M.D., F.R.C.S.C., pioneered a novel technique to preserve newborns’ healthy brain tissue, buying time until the infants became old enough to undergo a hemispherectomy.

What’s known

Hemimegalencephaly is an extremely rare birth defect in which one side of the brain grows larger than the other. This anomaly typically leads to severe, recurrent seizures that can be difficult to control solely with medications. While the seizures themselves are detrimental to the developing brain, the amount of medications used to reduce seizure frequency often come with significant side effects and have the potential to hamper brain growth. Hemispherectomy, a radical surgery in which one half of the brain is removed, is often the most successful way to treat severe and intractable epilepsy. However, this surgery can be challenging to perform successfully in very young babies.

What’s new

In this case report, the Children’s National Health System Epilepsy Team led by Chima Oluigbo, M.D., F.R.C.S.C., a pediatric neurosurgeon; Tammy N. Tsuchida, M.D., PhD., a pediatric surgical epileptologist; Monica Pearl, M.D., a pediatric interventional neuroradiologist; Taeun Chang, M.D., a neonatal neurointensivist; and the neonatal intensive care team explored the possibility of using minimally invasive surgery to cut off the blood supply to the brain hemisphere responsible for generating seizures in newborns with hemimegalencephaly. This procedure, they reasoned, could buy time for babies to mature and become more resilient to withstand the future hemispherectomy while also lessening the damage caused by uncontrolled, recurrent seizures. The case report focused on the first two patients with hemimegalencephaly who had sequential procedures to gradually restrict blood flow to the affected brain hemisphere within their first few weeks of life, followed by hemispherectomies at a few months of age. This novel approach significantly lessened their seizures until hemispherectomy, allowing these children to continue to grow and develop seizure-free.

Questions for future research

Q: Which patients are best suited for this surgical procedure?
Q: How can surgeons reduce the risk of excessive blood loss during hemispherectomy caused by the growth of additional blood vessels after flow through the brain’s major vessels has been blocked?
Q: What are the long-term outcomes for infants who undergo these procedures?

Source: “ ‘Endovascular embolic hemispherectomy’: A strategy for the initial management of catastrophic holohemispheric epilepsy in the neonate.” Oluigbo, C., M.S. Pearl, T.N. Tsuchida, T. Chang, C.-Y. Ho and W. D. Gaillard. Published by Child’s Nervous System October 29, 2016.

Children’s National earns five awards at the 2017 SPR Annual Meeting

Radiology PULSE Suite

Several technologists, fellows and faculty in the Division of Diagnostic Imaging and Radiology at Children’s National Health System were recognized at the 2017 Society of Pediatric Radiology (SPR) Annual Meeting in Vancouver, Canada, May 16-20. Each year, the international conference recognizes society members for outstanding research and education in pediatric care on the topics of imaging and image-guided care. Out of 15 major awards, Children’s National staff earned five, including two Caffey Awards – SPR’s most prestigious awards for academic excellence.

The awards received are as follows:

The Society of Pediatric Radiology Caffey Award for Best Clinical Research Paper went to attending radiologist, Dorothy Bulas, M.D., for her clinical research paper titled, “CXR Reduction Protocol in the Neonatal Intensive Care Unit (NICU) – Lessons Learned,” which highlighted collaboration with the NICU team to reduce the reliance on x-rays to monitor neonates. This method decreases the radiation dose with no risk to the patient.

The Society of Pediatric Radiology Caffey Award for Educational Exhibit was given to Benjamin Smith, M.D., a pediatric radiology fellow, for his educational poster “Sonographic Evaluation of Diaphragmatic Motion: A Practical Guide to Performance and Interpretation.” The exhibit displayed a unique technique for examining the motion of the diaphragm using ultrasound to make an accurate diagnosis of diaphragm paralysis or motion. Dr. Smith’s exhibit was also recognized by The American Academy of Pediatrics and was given the Outstanding Clinical Education Poster Award along with radiologist Hansel Otero, M.D.; sonographer Tara K. Cielma, R.D.M.S, R.D.C.S, R.V.T.; and faculty member Anjum N. Bandarkar, M.D.

The Society of Pediatric Radiology Radiographer Best Poster Award was given to Dr. Bandarkar for her poster titled, “Infantile Hypertrophic Pyloric Stenosis: Value of measurement technique to avoid equivocal exam.” The World Federation of Pediatric Imaging also awarded Dr. Bandarkar, Adebunmi O. Adeyiga, M.D. and Tara Cielma the 2017 Outstanding Radiographer Educational Poster Award for their collaborative poster on, “A Sonographic Walk‐Through: Infantile Hypertrophic Pyloric Stenosis.”

Division Chief of Diagnostic Imaging and Radiology, Raymond Sze, M.D., remarked, “This is a major win not only for the department but also for the entire hospital. The support and collaboration of our Children’s National colleagues across many departments allowed us to advance the field of pediatric imaging and earn national recognition for the high-quality and impactful research and education that’s happening at our institution.”

zika virus

Will the Zika epidemic re-emerge in 2017?

Anthony Fauci

Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, discussed the possibility of a reemergence of Zika virus at Children’s National Research and Education Week.

Temperatures are rising, swelling the population of Aedes mosquitoes that transmit the Zika virus and prompting an anxious question: Will the Zika epidemic re-emerge in 2017?

Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH), sketched out contrasting scenarios. Last year in Puerto Rico, at least 13 percent of residents were infected with Zika, “a huge percentage of the population to get infected in any one outbreak,” Dr. Fauci says. But he quickly adds: “That means that 87 percent of the population” did not get infected. When the chikungunya virus swept through the Caribbean during an earlier outbreak, it did so in multiple waves. “We are bracing for a return of Zika, but we shall see what happens.” Dr. Fauci says.

When it comes to the continental United States, however, previous dengue and chikungunya outbreaks were limited to southern Florida and Texas towns straddling the Mexican border. Domestic Zika transmission last year behaved in much the same fashion.

“Do we think we’re going to get an outbreak [of Zika] that is disseminated throughout the country? The answer is no,” Dr. Fauci adds. “We’re not going to see a major Puerto Rico-type outbreak in the continental United States.”

Dr. Fauci’s remarks were delivered April 24 to a standing-room-only auditorium as part of Research and Education Week, an annual celebration of the cutting-edge research and innovation happening every day at Children’s National. He offered a sweeping, fact-filled summary of Zika’s march across the globe: The virus was first isolated from a primate placed in a treehouse within Uganda’s Zika forest to intentionally become infected; Zika lurked under the radar for the first few decades, causing non-descript febrile illness; it bounced from country to country, causing isolated outbreaks; then, it transformed into an infectious disease of international concern when congenital Zika infection was linked to severe neural consequences for babies born in Brazil.

zika virus

Zika virus lurked under the radar for several decades, causing non-descript febrile illness; it bounced from country to country, resulting in isolated outbreaks; then, it transformed into an infectious disease of international concern.

“I refer to Brazil and Zika as the perfect storm,” Dr. Fauci told attendees. “You have a country that is a large country with a lot of people, some pockets of poverty and economic depression –  such as in the northeastern states –  without good health care there, plenty of Aedes aegypti mosquitoes and, importantly, a totally immunologically naive population. They had never seen Zika before. The right mosquitoes. The right climate. The right people. The right immunological status. And then, you have the explosion in Brazil.”

In Brazil, 139 to 175 babies were born each year with microcephaly – a condition characterized by a smaller than normal skull – from 2010 to 2014. From 2015 through 2016, that sobering statistic soared to 5,549 microcephaly cases, 2,366 of them lab-confirmed as caused by Zika.

Microcephaly “was the showstopper that changed everything,” says Dr. Fauci. “All of a sudden, [Zika] went from a relatively trivial disease to a disease that had dire consequences if a mother was infected, particularly during the first trimester.”

As Zika infections soared, ultimately affecting more than 60 countries, the virus surprised researchers and clinicians a number of times, by:

  • Being spread via sex
  • Being transmitted via blood transfusion, a finding from Brazil that prompted the Food and Drug Administration to recommend testing for all U.S. donated blood and blood products
  • Decimating developing babies’ neural stem cells and causing a constellation of congenital abnormalities, including vision problems and contractions to surviving infants’ arms and legs
  • Causing Guillain-Barré syndrome
  • Triggering transient hearing loss
  • Causing myocarditis, heart failure and arrhythmias

When it comes to the U.S. national response, Dr. Fauci says one of the most crucial variables is how quickly a vaccine becomes available to respond to the emerging outbreak. For Zika, the research community was able to sequence the virus and launch a Phase I trial in about three months, “the quickest time frame from identification to trial in the history of all vaccinology,” he adds.

Zika is a single-stranded, enveloped RNA virus that is closely related to dengue, West Nile, Japanese encephalitis and Yellow fever viruses, which gives the NIH and others racing to produce a Zika vaccine a leg up. The Yellow fever vaccine, at 99 percent effectiveness, is one of the world’s most effective vaccines.

“I think we will wind up with an effective vaccine. I don’t want to be over confident,” Dr. Fauci  says. “The reason I say I believe that we will is because [Zika is] a flavivirus, and we have been able to develop effective flavivirus vaccines. Remember, Yellow fever is not too different from Zika.”

Sarah Mulkey Columbia Zika Study

Damage may lurk in “normal” Zika-exposed brains

Sarah Mulkey Columbia Zika Study

An international study that includes Sarah B. Mulkey, M.D., Ph.D., aims to answer one of the most vexing questions about Zika: If babies’ brains appear “normal” at birth, have they survived Zika exposure in the womb with few neurological repercussions? Dr. Mulkey presented preliminary findings at PAS2017.

It has been well established by researchers, including scientists at Children’s National Health System, that the Zika virus is responsible for a slew of birth defects – such as microcephaly, other brain malformations and retinal damage – in babies of infected mothers. But how the virus causes these often devastating effects, and who exactly is affected, has not been explained fully.

Also unknown is whether exposed babies that appear normal at birth are truly unaffected by the virus or have hidden problems that might surface later. The majority of babies born to Zika-infected mothers in the United States appear to have no evidence of Zika-caused birth defects, but that’s no guarantee that the virus has not caused lingering damage.

Recently, Sarah B. Mulkey, M.D., Ph.D., made a trip to Colombia, where Children’s National researchers are collaborating on a clinical study. There, she tested Zika-affected babies’ motor skills as they sat, stood and lay facing upward and downward. The international study aims to answer one of the most vexing questions about Zika: If babies’ brains appear “normal” at birth, have they survived Zika exposure in the womb with few neurological repercussions?

“We don’t know the long-term neurological consequences of having Zika if your brain looks normal,” says Dr. Mulkey, a fetal-neonatal neurologist who is a member of Children’s Congenital Zika Virus Program. “That is what’s so scary, the uncertainty about long-term outcomes.”

According to the Centers for Disease Control and Prevention (CDC), one in 10 pregnancies across the United States with laboratory-confirmed Zika virus infection results in birth defects in the fetus or infant. For the lion’s share of Zika-affected pregnancies, then, babies’ long-term prospects remain a mystery.

“This is a huge number of children to be impacted and the impact, as we understand, has the potential to be pretty significant,” Dr. Mulkey adds.

Dr. Mulkey, the lead author, presented the research group’s preliminary findings during the 2017 annual meeting of the Pediatric Academic Societies (PAS). The presentation was one of several that focused on the Zika virus. Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases at Children’s National, organized two invited symposia devoted to the topic of Zika: Clinical perspectives and knowledge gaps; and the science of Zika, including experimental models of disease and vaccines. Dr. DeBiasi’s presentation included an overview of the 68 Zika-exposed or infected women and infants seen thus far by Children’s multidisciplinary Congenital Zika Virus Program.

“As the world’s largest pediatric research meeting, PAS2017 is an ideal setting for panelists to provide comprehensive epidemiologic and clinical updates about the emergence of Congenital Zika Syndrome and to review the pathogenesis of infection as it relates to the fetal brain,” Dr. DeBiasi says. “With temperatures already rising to levels that support spread of the Aedes mosquito, it is imperative for pediatricians around the world to share the latest research findings to identify the most effective interventions.”

As one example, Dr. Mulkey’s research sought to evaluate the utility of using magnetic resonance imaging (MRI) to evaluate fetal brain abnormalities in 48 babies whose mothers had confirmed Zika infection during pregnancy. Forty-six of the women/infant pairs enrolled in the prospective study are Colombian, and two are Washington, D.C. women who were exposed during travel to a Zika hot zone.

The women were infected with Zika during all three trimesters and experienced symptoms at a mean gestational age of 8.4 weeks. The first fetal MRIs were performed as early as 18 weeks’ gestation. Depending upon the gestational age when they were enrolled in the study, the participants had at least one fetal MRI as well as serial ultrasounds. Thirty-six fetuses had a second fetal MRI at about 31.1 gestational weeks. An experienced pediatric neuroradiologist evaluated the images.

Among the 48 study participants, 45 had “normal” fetal MRIs.

Three fetuses exposed to Zika in the first or second trimester had abnormal fetal MRIs:

  • One had heterotopia and an early, abnormal fold on the surface of the brain, indications that neurons did not migrate to their anticipated destination during brain development. This pregnancy was terminated at 23.9 gestational weeks.
  • One had parietal encephalocele, a rare birth defect that results in a sac-like protrusion of the brain through an opening in the skull. According to the CDC, this defect affects one in 12,200 births, or 340 babies, per year. It is not known if this rare finding is related to Zika infection.
  • One had a thin corpus callosum, dysplastic brainstem, heterotopias, significant ventriculomegaly and generalized cerebral/cerebellar atrophy.

“Fetal brain MRI detected early structural brain changes in fetuses exposed to the Zika virus in the first and second trimester,” Dr. Mulkey says. “The vast majority of fetuses exposed to Zika in our study had normal fetal MRI, however. Our ongoing study, underwritten by the Thrasher Research Fund, will evaluate their long-term neurodevelopment.”

Adré J. du Plessis, MB.Ch.B., M.P.H., director of the Fetal Medicine Institute and senior author of the paper, notes that this group “is a very important cohort to follow as long as Dr. Mulkey’s funding permits. We know that microcephaly is among the more devastating side effects caused by Zika exposure in utero. Unanswered questions remain about Zika’s impact on hearing, vision and cognition for a larger group of infants. Definitive answers only will come with long-term follow-up.”

Many of the Colombian families live in Sabanalarga, a relatively rural, impoverished area with frequent rain, leaving pockets of fresh water puddles that the mosquito that spreads Zika prefers, Dr. Mulkey adds. Families rode buses for hours for access to fetal MRI technology, which is not common in Colombia.

“The mothers are worried about their babies. They want to know if their babies are doing OK,” she says.

Breastfeeding Mom

Breast milk helps white matter in preemies

Breastfeeding Mom

Critical white matter structures in the brains of babies born prematurely at low birth weight develop more robustly when their mothers breast-feed them, compared with preemies fed formula.

Breast-feeding offers a slew of benefits to infants, including protection against common childhood infections and potentially reducing the risk of chronic health conditions such as asthma, obesity and type 2 diabetes. These benefits are especially important for infants born prematurely, or before 37 weeks gestation – a condition that affects 1 in 10 babies born in the United States, according to the Centers for Disease Control and Prevention. Prematurely born infants are particularly vulnerable to infections and other health problems.

Along with the challenges premature infants face, there is a heightened risk for neurodevelopmental disabilities that often do not fully emerge until the children enter school. A new study by Children’s National Health System researchers shows that breast-feeding might help with this problem. The findings, presented at the 2017 annual meeting of the Pediatric Academic Societies, show that critical white matter structures in the brains of babies born so early that they weigh less than 1,500 grams develop more robustly when their mothers breast-feed them, compared with preemie peers who are fed formula.

The Children’s National research team used sophisticated imaging tools to examine brain development in very low birth weight preemies, who weighed about 3 pounds at birth.

They enrolled 37 babies who were no more than 32 weeks gestational age at birth and were admitted to Children’s neonatal intensive care unit within the first 48 hours of life. Twenty-two of the preemies received formula specifically designed to meet the nutritional needs of infants born preterm, while 15 infants were fed breast milk. The researchers leveraged diffusion tensor imaging – which measures organization of the developing white matter of the brain – and 3-D volumetric magnetic resonance imaging (MRI) to calculate brain volume by region, structure and tissue type, such as cortical gray matter, white matter, deep gray matter and cerebellum.

“We did not find significant differences in the global and regional brain volumes when we conducted MRIs at 40 weeks gestation in both groups of prematurely born infants,” says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory and senior author of the paper. “There are striking differences in white matter microstructural organization, however, with greater fractional anisotropy in the left posterior limb of internal capsule and middle cerebellar peduncle, and lower mean diffusivity in the superior cerebellar peduncle.”

White matter lies under the gray matter cortex, makes up about half of the brain’s volume, and is a critical player in human development as well as in neurological disorders. The increased white matter microstructural organization in the cerebral and cerebellar white matter suggests more robust fiber tracts and microarchitecture of the developing white matter which may predict better neurologic outcomes in preterm infants. These critical structures that begin to form in the womb are used for the rest of the person’s life when, for instance, they attempt to master a new skill.

“Previous research has linked early breast milk feeding with increased volumetric brain growth and improved cognitive and behavioral outcomes,” she says. “These very vulnerable preemies already experience a high incidence rate of neurocognitive dysfunction – even if they do not have detectable structural brain injury. Providing them with breast milk early in life holds the potential to lessen those risks.”

The American Academy of Pediatrics endorses breast-feeding because it lowers infants’ chances of suffering from ear infections and diarrhea in the near term and decreases their risks of being obese as children. Limperopoulos says additional studies are needed in a larger group of patients as well as longer-term follow up as growing infants babble, scamper and color to gauge whether there are differences in motor skills, cognition and writing ability between the two groups.

Research and Education Week 2017 recap: The immunization battle

Boris D. Lushniak

Boris D. Lushniak, M.D., M.P.H., Dean of University of Maryland School of Public Health and former deputy surgeon general speaks at Research and Education Week 2017 at Children’s National.

Children’s National Health System recently held its 7th Annual Research and Education Week, inviting many keynote and special lecturers to share insights on the most recent research and education findings. Boris D. Lushniak, M.D., M.P.H., dean of the School of Public Health at the University of Maryland and former deputy surgeon general, was just one of many renowned keynote speakers to grace the stage.

In his presentation, “The immunization battle: Perspectives from a public health guy,” Dr. Lushniak described public health as the “science and art of preventing disease, prolonging health and preventing disease through the organized efforts and informed choices of all.” He discussed immunizations across the years, highlighting past achievements in the public health world, the current state of childhood immunizations, and how to improve the view and impact of immunizations and vaccinations in the future.

Since the 1900s, there have been great achievements in the public health world from vaccinations and child immunizations to the recognition of tobacco as a health hazard. Statistics have revealed how child immunizations are the most cost-effective clinical preventive service with a high return on investment. According to Healthy People 20/20, birth cohorts vaccinated according to the childhood immunization schedule provided by the Center for Disease Control saved 33,000 lives, prevented 14 million cases of disease, reduced direct health care costs by $9.9 billion and saved $33.4 billion in indirect health care costs.

Although the statistics have value to medical professionals, Dr. Lushniak explained how the personal views of patients and families create barriers for advancement. The March 2016 Journal of American Medical Association reported that 300 children in the United States die from vaccine-preventable diseases each year; each case representing a failed opportunity to prevent disease due to vaccine refusal and a decrease in community  immunity.

Based on the views of the Journal of Health Management & Practice¸ Dr. Lushniak recommends following these tips to increase vaccine rates:

  • Creating or supporting effective interventions (client reminder, recall systems, provider assessment/feedback/reminder)
  • Generating and evaluating public health response to outbreaks
  • Facilitating vaccine management and accountability
  • Determining client vaccination status or decisions made by clinicians, health departments, schools
  • Aiding surveillance and investigations on vaccination rates, missed opportunities, invalid doses and disparities in coverage

Dr. Lushniak concluded his presentation by encouraging the audience to keep working towards the advancement of immunization, despite any perceptions against getting children vaccinated.

Sarah Mulkey receives NIH career development grant

Sarah Mulkey

Sarah B. Mulkey, M.D., Ph.D., a fetal-neonatal neurologist in the Division of Fetal and Translational Medicine at Children’s National Health System, has received a KL2 award from the Clinical and Translational Science Institute at Children’s National, which is funded through the National Institutes of Health. This grant, totaling $135,000 over two years, will allow Dr. Mulkey to reserve dedicated research time — apart from her clinical duties — to pursue a research project studying the autonomic nervous system in newborns.

Dr. Mulkey’s project will focus on developing a better understanding of this part of the nervous system — responsible for unconscious control of basic bodily functions, such as heart rate and breathing — in healthy, full-term babies, and how this system integrates with other brain regions responsible for mood and stress responses. Dr. Mulkey and colleagues then will compare these findings to those from babies whose autonomic nervous systems might have abnormal development, such as infants born pre-term or those with congenital heart defects or intrauterine growth restriction. The findings could help researchers develop new interventions to optimize autonomic nervous system development in vulnerable patients and improve long-term neurologic and psychological health in children.

“This award is an incredible opportunity for a young investigator since it provides protected time both for research and career development,” Dr. Mulkey says. “We need more clinicians in pediatric research to improve medical care and outcomes for children. This award makes it possible for me to devote significant time to research in order to contribute to new knowledge about babies throughout my career.”

To that end, NIH’s National Center for Advancing Translational Sciences has created a new LinkedIn page to highlight the innovative work of KL2 scholars.

Drs. DeBiasi and du Plessis

Zika virus, one year later

Drs. DeBiasi and du Plessis

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.”

Children’s sponsors medical and health app development workshop

Hackathon Winners

Team 10, also known as “The BabyDaddies,” won the hackathon for their presentation on BabyData: A medical app for neonatal care providers. Team members, from left to right, are Jessica Castillo, Mohammed Abu-Rub, Saud Aljuhani and Jessica Herstek.

The Clinical and Translational Science Institute at Children’s National (CTSI-CN) recently sponsored a Medical and Health App Development Workshop in collaboration with The George Washington University (GW). Kevin Cleary, Ph.D., technical director of the Bioengineering Initiative at Children’s National Health System, and Sean Cleary, Ph.D., M.P.H., associate professor in epidemiology and biostatistics at GW, created this event to provide an interactive learning experience for those interested in developing medical and health software applications.

Not your average workshop, attendees had the opportunity to network, gain expert knowledge and participate in a group contest for a chance to win up to $10,000 in funding toward prototype development. To kick off events, attendees heard from presenters on the following topics:

  • Human factors: Shelly Heller, Ph.D., professor of the computer science department at GW
  • User interface prototyping: Tim Wood, Ph.D., assistant professor of the computer science department at GW
  • Regulatory environment: Linda Ricci, associate director for digital health within the Office of Device Evaluation, The Food and Drug Administration

Ahead of the workshop, the Children’s National and GW communities submitted ideas for consideration. Judges selected ten ideas for development at the workshop and organized teams of participants around each idea. Teams were judged on their overall presentation, durability of the application, and potential impact in the medical and health world. After careful deliberation, Team 10, also known as “The BabyDaddies,” won for their presentation on BabyData: A medical app for neonatal care providers. The newborn care mobile application aims to calculate the most commonly used values to promote efficient and evidence-based care for newborns in their first hours, days and weeks of life.

“Although some calculations are simple, a lot of time could be saved when you multiply those calculations by seeing 20 to 40 newborns a day,” says Jessica Herstek, M.D., Children’s National project lead and idea originator. “I wanted to create something easy that could help care providers on a day-to-day basis.”

Dr. Herstek is now working with CTSI-CN to bring the application to life. BabyData will feature calculators for measurements, weight assessments, risk evaluations, gestational and chronological age, nutrition, hydration, Group B Streptococcal prophylaxis and glucose infusion rate, all things currently being assessed manually. Medical providers who care for newborns in inpatient, emergency and outpatient settings will have all the resources they need consolidated into one field-specific calculator application.

test tubes

2016: A banner year for innovation

test tubes

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.

How to talk with parents who are vaccine hesitant

vaccination

The single most important factor in parents deciding to accept vaccines is one-on-one contact with an informed, caring and concerned pediatrician.

When facing vaccine-hesitant parents, the key for me is to be collaborative and not to dismiss their questions or concerns.  That’s why the American Academy of Pediatrics advises pediatricians to talk with parents to determine their individual concerns so we can address them. The decision whether to immunize a child ultimately rests with the parents. It’s understandable for parents to be worried – but it also critical that they get the facts.

The conversation can begin simply.

Here’s what I say to vaccine-hesitant parents: You work hard to protect your child every day. Vaccines are as important as feeding your child healthy foods, using a car seat or seat belt and installing a smoke detector.

Here’s what I ask vaccine-hesitant parents: What information can I provide to help you make an informed decision, or to help you feel comfortable with vaccinating your child?  As with most of what we pediatricians do, my goal is to partner with the parent so that we help their child to attain optimal health as a team.

I am a parent. Although my husband and I did not hesitate in vaccinating our daughter, I understand why parents want to feel comfortable about the choices they make for their children.

I also am a pediatrician. I have seen children die from the flu or develop a life-threatening brain infection from chickenpox.  Thanks to the herd immunity that results from decades of vaccination, many of these diseases are now rare in the United States, but there are still episodic outbreaks throughout the country that remind us why we vaccinate children.

Vaccinating is the norm.  Only about 1 percent of children in the United States receive no vaccinations. Most parents who are hesitant about vaccines are not opposed to immunizing their children; they are unsure or have unanswered questions. Fortunately, most vaccine-hesitant parents are responsive to receiving information about vaccines, consider vaccinating their children and do not oppose all vaccines.

When it comes to vaccine-hesitant parents, one-on-one counseling is effective. The single most important factor in parents deciding to accept vaccines is one-on-one contact with an informed, caring and concerned pediatrician.

About the Author

Lanre Omojokun FalusiLanre Omojokun Falusi, M.D., F.A.A.P.
General pediatrician and Associate Medical Director for Municipal and Regional Affairs at Child Health Advocacy Institute

A sirtuin might help repair a common neonatal brain injury

Sirtuin could repair common neonatal brain injury

A sirtuin might help repair a common neonatal brain injury

A team of researchers  investigated the molecular mechanisms behind oligodendrocyte progenitor cell proliferation in neonatal hypoxia.

What’s known

Hypoxia, or a lack of oxygen, is a major cause of diffuse white matter injury (DWMI). This condition leads to permanent developmental disabilities in prematurely born infants. The long-term abnormalities of the brain’s white matter that characterize DWMI are caused by the loss of a specific type of cells known as oligodendrocytes, which support nerve cells and produce myelin, a lipid and protein sheath that electrically insulates nerve cells. Oligodendrocytes are produced by a population of immature cells known as oligodendrocyte progenitor cells (OPCs). Previous research has shown that hypoxia can trigger OPCs to proliferate and presumably produce new oligodendrocytes. The molecular pathways that hypoxia triggers to make new OPCs remain unclear.

What’s new

A team of researchers led by Vittorio Gallo, Ph.D., director of the Center for Neuroscience Research and the Intellectual and Developmental Disabilities Research Center at Children’s National Health System, investigated the molecular mechanisms behind what prompts OPCs to proliferate in a preclinical model of neonatal hypoxia. The researchers found that a molecule known as Sirt1 acts as a major regulator of OPC proliferation and regeneration. Sirt1 is a sirtuin, a class of molecules that has attracted interest over the past several years for its role in stem cells, aging and inflammation. Hypoxia appears to induce Sirt1 formation. When the researchers prevented brain tissues in petri dishes from making Sirt1 or removed this molecule in preclinical models, these actions prevented OPC proliferation. What’s more, preventing Sirt1 production also inhibited OPCs from making oligodendrocytes. These findings suggest that Sirt1 is essential for replacing oligodendrocytes to repair DWMI after hypoxia. Additionally, finding ways to enhance Sirt1 activity eventually could provide a novel way to help infants recover after hypoxia and prevent DWMI.

Questions for future research

Q: How can Sirt1 activity be enhanced in preclinical models and humans?
Q: Can deficits triggered by diffuse white matter injury be prevented or reversed with Sirt1?
Q: Which other treatments might be useful for diffuse white matter injury?

Source: Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury.” Jablonska, M., M. Gierdalski, L. Chew, T. Hawley, M. Catron, A. Lichauco, J. Cabrera-Luque, T. Yuen, D. Rowitch and V. Gallo. Published by Nature Communications on Dec. 19, 2016.