Neonatology

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.

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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.

vaccination

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

newborn

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.

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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.

Neonatal Baby

Treating the smallest opioid epidemic victims

Neonatal Baby

The Virginia Commissioner of Health recently declared the opioid epidemic a public health crisis. A little-known facet of the ongoing crisis is the effects it can have on babies born to opioid-addicted mothers. In fact, according to the New England Journal of Medicine, substance-exposed babies make up as many as 27 out of every 1,000 deliveries across the country.

Neonatal Abstinence Syndrome (NAS) is a condition that affects infants who are born to mothers who are chronic users of some form of opiate during pregnancy. While heroin certainly falls into this category, in recent years the dramatic increase in prescriptions of other opioids as a therapy for chronic pain has led to a correlated increase in the number of infants who withdraw from substances like OxyContin, Percocet, and Morphine.

Infants with NAS can experience tremors, sleep problems, excessive high-pitched crying (often inconsolable), irritability, difficulty feeding and seizures. Unfortunately, these symptoms may present while the infant is in the care of parents who are withdrawing from an opioid addiction themselves, and tragically, cases of non-accidental trauma have been recorded.

In an effort to draw increased attention to this troubling aspect of the ongoing opioid crisis in Virginia and across the country, and with hopes of breaking down barriers to effective treatment for newborns, Children’s National neonatologists and pediatricians are working with lawmakers in Virginia to standardize a streamlined protocol for all newborns born to opioid-addicted mothers in the Commonwealth based on best practices.

In each of the three hospitals in Virginia where Children’s National physicians operate, the established NAS protocol has been implemented to identify at-risk infants, monitor their treatment and attempt to reduce length of stay and rate of readmission. The goals are to standardize the protocol and have it put into practice in all newborn units in Virginia and eventually extend it throughout the region. The protocol includes the following:

  • Universal risk assessment of newborns
  • Appropriate observation period
  • NAS scoring to assess severity of condition
  • Prioritize non-pharmacologic interventions vs. pharmacologic therapy
  • Discharge criteria

Children’s National staff based in Mary Washington Hospital in Fredericksburg, Va., first brought to light the importance of the issue and pointed out that better coordination and government involvement could work together to significantly improve care for these infants. Since then, leaders from the Division of Neonatology at Children’s National have been working closely with Virginia legislation to develop and pass several bills that as a package help address the issue in the following ways:

  • Adding NAS to the list of diseases which must be reported to the state Department of Health
  • Directing the Department of Health and Human Resources to look at NAS in collaboration with other related stakeholders to study the issue at large and specifically collect pertinent information to help address it
  • Removing language that states for the purposes of defining a substance-affected infant that the substance must be illicit

This protocol and these bills are important steps forward in both providing the effective treatment needed for and the collection of data related to NAS cases, but they are only a first step. Children’s National and state leaders continue to work together to bring Virginia’s hospitals together in an attempt to foster a collaborative approach to addressing NAS. By sharing expertise and techniques, Virginia’s health care providers can ensure that the tiniest victims of the opioid crisis do not go untreated.

Cas9-mediated correction of metabolic liver disease

AAV.CRISPR-SaCas9

In vivo gene correction of the OTC locus in the mouse liver by AAV.CRISPR-SaCas9. Source: Nature Publishing Group copyright 2016.

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What’s known

A deficiency of the enzyme ornithine transcarbamylase (OTC) in humans causes life-threatening hyperammonemic crises.  The OTC gene enables the body to make an enzyme that is a critical player in the urea cycle, a process that ensures excess nitrogen is excreted by the kidneys. Left unchecked, accumulating nitrogen becomes a toxic form of ammonia. Infants with OTC deficiency can suffer their first metabolic crisis as newborns. Up to 50 percent die or sustain severe brain injury, and survivors typically need a liver transplant by age 1. Gene therapy could cure OTC deficiency, but currently used viruses, such as adeno-associated virus (AAV), are not optimal in the neonatal setting.

What’s new

A research team led by Children’s National Health System and the University of Pennsylvania reasoned that the newborn liver may be an ideal setting for AAV-mediated gene correction using CRISPR-Cas9 gene editing. They intravenously infused two AAVs into two-day-old mice with partial OTC deficiency. One AAV expressed Cas9 and the other expressed a guide RNA and a donor OTC DNA. This resulted in correction of the mutation in 10 percent of liver cells and increased survival in mice challenged with a high-protein diet, which normally exacerbates disease. After consuming a high-protein diet for one week, the treated newborns had a 40 percent reduction in ammonia compared with the untreated group. The correction appears to last long term. The study “provides evidence for efficacy of gene editing in neonatal onset OTC deficiency,” says Mark L. Batshaw, M.D., Physician-In-Chief and Chief Academic Officer at Children’s National, and a study co-author. “This study provides convincing evidence for efficacy of in vivo genome editing in an authentic animal model of a lethal human metabolic disease,” the research team concludes.

Questions for future research

Q: More than 400 mutations can cause OTC deficiency, and each would require a separate gene-editing approach. Is it possible instead to insert the OTC genome using CRISPR-Cas9 to correct the disorder irrespective of the mutation?
Q: Will such gene editing also work in adult animal models of the OTC disorder?
Q: Do these encouraging results in animals translate to efficacy in infants?

Source: Yang, Y., L. Wang, P. Bell, D. McMenamin, Z. He, J. White, H. Yu, C. Xu, H. Morizono, K. Musunuru, M.L. Batshaw and J.M. Wilson. “A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice.” Published Feb. 1, 2016 by Nature Biotechnology.

Sarah B. Mulkey

Researchers tackle Zika’s unanswered questions

Youssef A. Kousa

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

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.

Chinwe Unegbu

PDE-5 inhibitors for pediatric hypertension

Chinwe Unegbu

A study led by Chinwe Unegbu, M.D., indicates the benefits of PDE-5 inhibitors to treat pediatric pulmonary hypertension far outweigh potential harmful side effects.

Pulmonary hypertension (PH), when pressure in the blood vessels leading from the heart to the lungs is too high, is primarily a disease of adults: Patient registries suggest that the mean age of diagnosis is around age 50. However, more and more children are developing this condition, says Chinwe Unegbu, M.D., an assistant professor in the Division of Anesthesiology, Pain and Perioperative Medicine at Children’s National Health System.

Although adults with PH have several different effective treatments, Dr. Unegbu adds, children have few options. One of these is a class of medications known as phosphodiesterase type 5 (PDE-5) inhibitors, which act on molecular pathways that can open up constricted blood vessels. However, some studies have raised questions about the safety of this class of medications, particularly with long-term use of high dosages.

In a new study, Dr. Unegbu and colleagues performed a systematic review of available literature on this class of drugs evaluating their effectiveness and safety for pediatric patients. The review showed that like all medications, PDE-5 inhibitors have some risks. However, Dr. Unegbu says, the review showed that their benefits, including improved echocardiography measurements, cardiac catheterization parameters and oxygenation, far outweigh potential harmful side effects.

“Pediatricians across the nation view the rise in pediatric PH cases with growing concern because the disease can worsen, leading to right ventricular failure and death,” says Dr. Unegbu, lead author of the study. “PH can occur in newborns, infants and children who have a number of health conditions, including congenital heart disease, the most common birth defect among newborns. There are few available treatments for the growing population of children affected by this condition, so it is heartening that the evidence supports PDE-5 inhibitors for patients with PH.”

Patients with PH experience increased pressure in the pulmonary arteries, which carry blood from the heart to the lungs where it picks up oxygen that is ferried throughout the body. According to the National Institutes of Health, this leads patients to suffer from shortness of breath while doing routine tasks, chest pain and a racing heartbeat. Changes to the arteries make it progressively harder for the heart to pump blood to the lungs, which forces the heart to work even harder. Despite the heart muscle compensating by growing larger, less blood ultimately flows from the right to the left side of the heart which can compromise the kidney, liver and other organs, Dr. Unegbu says.

The study team included four researchers from Johns Hopkins University: Corina Noje, M.D., John D. Coulson, M.D., Jodi B. Segal, M.D., M.P.H., and study senior author Lewis Romer, M.D. The researchers scoured Medline, Embase, SCOPUS and the Cochrane Central Register of Controlled Trials, looking for studies that examined PDE-5 inhibitor use by pediatric patients with primary and secondary PH. Their goals included describing the nature and scale of the pediatric PH, assessing available pharmacologic therapies and conducting the systematic review of clinical studies of PDE-5 inhibitors, a mainstay of PH therapy.

They identified 1,270 studies. Twenty-one met the criteria to be included in the comprehensive review, including eight randomized controlled trials – the gold standard. The remaining 13 were  observational studies in children ranging in age from extremely preterm to adolescence.

“Although there is some risk associated with PDE-5 inhibitor use by pediatric patients with PH, overwhelmingly the data indicate the benefits of using this class of drugs far outweigh the risks. When we looked at specific clinical outcomes, we see definite improvement in a number of measures including oxygenation, hemodynamics and better clinical outcomes: The patients are doing better, feeling better and their exercise capacity rises,” Dr. Unegbu says.

Because of lingering concerns about increased mortality, they also looked at toxicity data associated with this class of drugs. “With the exception of a single trial, the remaining trials included in our review did not demonstrate increased mortality in patients placed on this class of medicines, which was reassuring to us,” she says. Side effects ranged from mild to moderate, such as flushing and headaches. “We can say with a good degree of confidence that providers should feel fairly comfortable prescribing PDE-5 inhibitors.”

Ideally, researchers would like to have access to patient-specific measures that are a good fit for neonates and infants. Unlike adults, infants’ exercise capacity cannot be measured by their ability to climb stairs or use a treadmill. Another limitation, the study authors note, is the dearth of adequately powered clinical trials conducted in kids.

“Most of the studies have been conducted in adults. However, this disease unfolds in a much different fashion in children compared with adults,” Dr. Unegbu says. “We are desperately in need of high-quality studies in the form of randomized controlled trials in pediatric patients and studies that examine the full range of formulations of this class of drugs.”

Sarah B. Mulkey

Puzzling symptoms lead to collaboration

Sarah B. Mulkey, explaining the research

Sarah B. Mulkey, M.D., Ph.D., is lead author of a study that describes a brand-new syndrome that stems from mutations to KCNQ2, a genetic discovery that began with one patient’s unusual symptoms.

Unraveling one of the greatest mysteries of Sarah B. Mulkey’s research career started with a single child.

At the time, Mulkey, M.D., Ph.D., a fetal-neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National Health System, was working at the University of Arkansas for Medical Sciences. Rounding one morning at the neonatal intensive care unit (NICU), she met a new patient: A newborn girl with an unusual set of symptoms. The baby was difficult to wake and rarely opened her eyes. Results from her electroencephalogram (EEG), a test of brain waves, showed a pattern typical of a severe brain disorder. She had an extreme startle response, jumping and twitching any time she was disturbed or touched, that was not related to seizures. She also had trouble breathing and required respiratory support.

Dr. Mulkey did not know what to make of her new patient: She was unlike any baby she had ever cared for before. “She didn’t fit anything I knew,” Dr. Mulkey remembers, “so I had to get to the bottom of what made this one child so different.”

Suspecting that her young patient’s symptoms stemmed from a genetic abnormality, Dr. Mulkey ran a targeted gene panel, a blood test that looks for known genetic mutations that might cause seizures or abnormal movements. The test had a hit: One of the baby’s genes, called KCNQ2, had a glitch. But the finding deepened the mystery even further. Other babies with a mutation in this specific gene have a distinctly different set of symptoms, including characteristic seizures that many patients eventually outgrow.

Dr. Mulkey knew that she needed to dig deeper, but she also knew that she could not do it alone. So, she reached out first to Boston Children’s Hospital Neurologist Philip Pearl, M.D., an expert on rare neurometabolic diseases, who in turn put her in touch with Maria Roberto Cilio, M.D., Ph.D., of the University of California, San Francisco and Edward Cooper, M.D., Ph.D., of Baylor College of Medicine. Drs. Cilio, Cooper and Pearl study KCNQ2 gene variants, which are responsible for causing seizures in newborns.

Typically, mutations in this gene cause a “loss of function,” causing the potassium channel to remain too closed to do its essential job properly. But the exact mutation that affected KCNQ2 in Dr. Mulkey’s patient was distinct from others reported in the literature. It must be doing something different, the doctors reasoned.

Indeed, a research colleague of Drs. Cooper, Cilio and Pearl in Italy — Maurizio Taglialatela, M.D., Ph.D., of the University of Naples Federico II and the University of Molise — had recently discovered in cell-based work that this particular mutation appeared to cause a “gain of function,” leaving the potassium channel in the brain too open.

Wondering whether other patients with this same type of mutation had the same unusual constellation of symptoms as hers, Dr. Mulkey and colleagues took advantage of a database that Dr. Cooper had started years earlier in which doctors who cared for patients with KCNQ2 mutations could record information about symptoms, lab tests and other clinical findings. They selected only those patients with the rare genetic mutation shared by her patient and a second rare KCNQ2 mutation also found to cause gain of function — a total of 10 patients out of the hundreds entered into the database. The researchers began contacting the doctors who had cared for these patients and, in some cases, the patients’ parents. They were scattered across the world, including Europe, Australia and the Middle East.

Dr. Mulkey and colleagues sent the doctors and families surveys, asking whether these patients had similar symptoms to her patient when they were newborns: What were their EEG results? How was their respiratory function? Did they have the same unusual startle response?

She is lead author of the study, published online Jan. 31, 2017 in Epilepsia, that revealed a brand-new syndrome that stems from specific mutations to KCNQ2. Unlike the vast majority of others with mutations in this gene, Dr. Mulkey and her international collaborators say, these gain-of-function mutations cause a distinctly different set of problems for patients.

Dr. Mulkey notes that with a growing focus on precision medicine, scientists and doctors are becoming increasingly aware that knowing about the specific mutation matters as much as identifying the defective gene. With the ability to test for more and more mutations, she says, researchers likely will discover more cases like this one: Symptoms that differ from those that usually strike when a gene is mutated because the particular mutation differs from the norm.

Such cases offer important opportunities for researchers to come together to share their collective expertise, she adds. “With such a rare diagnosis,” Dr. Mulkey says, “it’s important for physicians to reach out to others with knowledge in these areas around the world. We can learn much more collectively than by ourselves.”

Dr. Keating and Abigail

Multidisciplinary approach to hydrocephalus care

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.”

Congenital heart disease and cortical growth

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.

This is the consequential malfunction of the brain during congenital heart defects.

Congenital heart disease and white matter injury

This is the consequential malfunction of the brain during congenital heart defects.

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.