Neurology and Neurosurgery Research

New robotic therapies for cerebral palsy

February 27, 2018

The hippobot is a mechanical horseback riding simulator that provides hippotherapy for children.

Cerebral palsy is the most common type of movement disorder in children, affecting 1 in 500 babies born each year. For these infants, learning to sit up, stand and walk can be a big challenge which often requires years of physical therapy to stretch and strengthen their muscles. A team led by Kevin Cleary, Ph.D., technical director of the Bioengineering Initiative at Children’s National Health System, and Sally Evans, M.D., director of Pediatric Rehabilitation Medicine at Children’s National, has created two new types of robotic therapy that they hope will make physical therapy more enjoyable and accessible for children.

Hippobot equine therapy simulator

One of the most effective types of therapy for children with cerebral palsy is hippotherapy, which uses horseback riding to rehabilitate children with neurological and musculoskeletal disabilities. The movement of horses helps riders with cerebral palsy improve endurance, balance and core strength, which in turns helps them gain the ability to sit without support. If a child with cerebral palsy does not master independent sitting early in life, he or she may never gain the ability to stand or walk. Unfortunately, many children never have the chance to experience hippotherapy due to geographical constraints and cost issues.

To increase patient access to hippotherapy, the bioengineering team (Reza Monfaredi, Ph.D.; Hadi Fooladi Talari, M.S.; Pooneh Roshani Tabrizi, Ph.D.; and Tyler Salvador, B.S.) developed the hippobot — a mechanical horseback riding simulator that provides hippotherapy for children ages 4 to 10 in the office setting. To create the hippobot, the researchers mounted a carousel horse on a six-degree of freedom commercial motion platform (the platform moves in the x, y and z directions and rotates about roll, pitch and yaw axes). They then programmed the platform to simulate a horse walking, trotting and cantering.

“Several experienced horse riders have tried the motion platform and commented that it gives a realistic feel,” says Dr. Cleary.

The team then incorporated optical tracking of the hippobot rider’s spine and pelvis to monitor their posture and created a virtual reality video display that simulates a horse moving down a pier. As other animals come towards the horse, the rider must lean right or left to avoid them. The trackers on their back show which way they are leaning and feed that information into the gaming system.

“We wanted to see how the patient’s spine reacts as the horse moves through different patterns, and if the patients get better at maintaining their posture over several sessions,” says Dr. Cleary.

To date the system has been used with several children with cerebral palsy under an IRB-approved study. All of the participants enjoyed riding the horse and came back for multiple sessions.

The hippobot system was developed in close collaboration with the Physical Medicine and Rehabilitation Division at Children’s National, including Olga Morozova, M.D., Justin Burton, M.D., and Justine Belschner, P.T.

Pedbot ankle rehabilitation system

Patients use pedbot as an input device to pilot an airplane through a series of hoops. The level of the difficulty of the game can be easily adjusted based on the patient’s capability and physical condition.

More than half of children with cerebral palsy also have gait impairment as a result of excessive plantar flexion and foot inversion/eversion, or equinovarus/equinovalgus at their ankle and foot. To help these patients, Dr. Cleary’s team developed the pedbot — a small robot platform that enables better strengthening, motor control and range of motion in the ankle joint.

“Children with cerebral palsy have difficulty walking in part because they have trouble controlling their feet,” explains Dr. Evans. “Use of pedbot as part of therapy can help to give them increased control of their feet.”

Most ankle rehabilitation robots are limited in their movements, and have only one or two degrees of freedom, focusing on ankle dorsiflexion/plantarflexion and sometimes inversion/eversion. Pedbot is unique in that it has three degrees of freedom with a remote center of motion in the ankle joint area that allows it to move in ways other devices can’t.

The pedbot platform can move in three translational directions (x, y and z) and also rotate about three axes (the x, y and z axes). As an analogy, this is similar to the movement of a flight simulator. The system also includes motors and encoders at each axis and can be used in passive and active modes.

In both modes, the patient sits on a therapy chair with their foot strapped to the robotic device. In the passive mode, the therapist assists the patient in training motions along each axis. The robot can then repeat the motion under therapist supervision while incrementally increasing the range of motion as desired by the therapist.

For the active mode or “gaming” mode, the team developed a video game based on an airplane motif. Patients use pedbot as an input device to pilot an airplane through a series of hoops. The level of the difficulty of the game can be easily adjusted based on the patient’s capability and physical condition.

To date, four patients have participated in an IRB-approved clinical trial for the pedbot. All of the patients enjoyed the game and they were willing to continue to participate as suggested by a physiotherapist.

The pedbot team, in addition to the engineers mentioned above, includes Catherine Coley, P.T.; Stacey Kovelman, P.T.; and Sara Alyamani, B.A. In future work, they plan to expand the system to include electromyography measurements with Paola Pergami, M.D.,Ph.D. They also are planning to develop a low cost, 3D printed version for the home market so children can do Pedbot therapy every day.

Sounding the alarm on fluorescent calcium dyes

February 9, 2018

“This study serves as a warning to other neuroscientists,” says Nathan A. Smith, Ph.D., a new principal investigator in the Center for Neuroscience Research at Children’s National Health System and first author of the study.

Scientists using chemical based fluorescent dyes to study the calcium dynamics of the cells within the central nervous system suspected that something external was disrupting normal cell function in their studies.

Neuroscientists at the University of Rochester Medical Center and Children’s National Health System have confirmed their suspicions by capturing data that shows, for the first time, how these fluorescent calcium dyes are causing cell damage when loaded over an extended period of time. Their findings appeared in Science Signaling.

“This study serves as a warning to other neuroscientists,” says Nathan A. Smith, Ph.D., a new principal investigator in the Center for Neuroscience Research at Children’s National Health System and first author of the study. “As many of my colleagues have noted, we’ve known that something was going on, but now, we have evidence that the longer these dyes stay in cells, or the longer time it takes to load them into cells, the more problems we see with normal cell function.”

The study comparatively analyzed the effects of chemical and genetically encoded calcium ion indicators on cellular functions, which had not been previously performed. The outcomes showed that all of the fluorescent calcium dyes, including Fluo-4, Rhod-2, and FURA-2, had negative consequences for a number of cellular functions. For example, the dyes inhibited the sodium potassium pump (Na,K-ATPase), a membrane protein essential for many cellular membrane functions including the exchange between intracellular sodium ions (Na⁺) and extracellular potassium ions (K⁺). Inhibiting the Na,K-ATPase process results in the buildup of K⁺ ions in the synapses, leading to errant neural firing that has been linked to a number of disorders, including epilepsy. Additional observed impacts of exposure to the dyes included reduced cell viability, decreased glucose uptake, increased lactate release and cell swelling.

“Now, our field needs to take a step back and reevaluate findings that may have been influenced by these chemical trackers, to make sure that our observations were driven by our intended manipulations and not this additional factor,” Dr. Smith continues.

Non-chemical alternatives

Tracking calcium ions and their dynamics within the central nervous system through fluorescent calcium indicators is the primary method of measuring glial activity and glial interactions with other cell types. Unlike neurons, glial cells are electrically non-excitable; therefore electrical-based recording methods used to measure neuronal activity are ineffective.

In recent years, neuroscientists have developed additional methods to track calcium ions: genetically encoded calcium indicators (GECIs), which have grown in use since 2008. These GECIs have evolved over the years to have higher signal to noise ratios, target specific cell types and sub-compartments, and remain stable over time.*

Dr. Smith’s lab uses GECIs exclusively to monitor the calcium dynamics of glial brain cells called astrocytes as well as their interactions with other cells such as neurons. His work now seeks to understand how those interactions influence neural networks and how they operate differently in neurodevelopmental disorders, including attention-deficit hyperactivity disorder (ADHD), epilepsy and others.

“Our field has continued using these traditional calcium indicator dyes in labs because they are familiar and affordable,” Dr. Smith notes. “Our findings are a clear call to action that it’s time to revisit some of those approaches in favor of new technology.”

Children’s National submissions make hackathon finals

February 8, 2018

This April, the Clinical and Translational Science Institute at Children’s National (CTSI-CN) and The George Washington University (GW) will hold their 2nd Annual Medical and Health App Development Workshop. Of the 10 application (app) ideas selected for further development at the hackathon workshop, five were submitted by clinicians and researchers from Children’s National.

The purpose of the half-day hackathon is to develop the requirements and prototype user interface for 10 medical software applications that were selected from ideas submitted late in 2017. While idea submissions were not restricted, the sponsors suggested that they lead to useful medical software applications.

The following five app ideas from Children’s National were selected for the workshop:

A patient/parent decision tool that could use a series of questions to determine if the patient should go to the Emergency Department or to their primary care provider; submitted by Sephora Morrison, M.D., and Ankoor Shah, M.D., M.P.H.
The Online Treatment Recovery Assistance for Concussion in Kids (OnTRACK) smartphone application could guide children/adolescents and their families in the treatment of their concussion in concert with their health care provider; submitted by Gerard Gioia, Ph.D.
A genetic counseling app that would provide a reputable, easily accessible bank of counseling videos for a variety of topics, from genetic testing to rare disorders; submitted by Debra Regier, M.D.
An app that would allow the Children’s National Childhood and Adolescent Diabetes Program team to communicate securely and efficiently with diabetes patients; submitted by Cynthia Medford, R.N., and Kannan Kasturi, M.D.
An app that would provide specific evidence-based guidance for medical providers considering PrEP (pre-exposure prophylaxis) for HIV prevention; submitted by Kyzwana Caves, M.D.

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 the hackathon to provide an interactive learning experience for people interested in developing medical and health software applications.

The workshop, which will be held on April 13, 2018, will start with short talks from experts on human factors engineering and the regulatory environment for medical and health apps. Attendees will then divide into small groups to brainstorm requirements and user interfaces for the 10 app ideas. After each group presents their concepts to all the participants, the judges will pick the winning app/group. The idea originator will receive up to $10,000 of voucher funding for their prototype development.

Tracking oxygen saturation with vital signs to identify vulnerable preemies

February 7, 2018

Khodayar-Rais-Bahrami

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What’s known

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

What’s new

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

Questions for future research

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

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

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

MRI opens new understanding of fetal growth restriction

February 6, 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Children’s receives NIH grant to study use of stem cells in healing CHD brain damage

February 2, 2018

“Bone marrow stem cells are used widely for stroke patients, for heart attack patients and for those with developmental diseases,” explains Nobuyuki Ishibashi, M.D. “But they’ve never been used to treat the brains of infants with congenital heart disease. That’s why we are trying to understand how well this system might work for our patient population.”

The National Institutes of Health (NIH) awarded researchers at Children’s National Health System $2.6 million to expand their studies into whether human stem cells could someday treat and even reverse neurological damage in infants born with congenital heart disease (CHD).

Researchers estimate that 1.3 million infants are born each year with CHD, making it the most common major birth defect. Over the past 30 years, advances in medical technology and surgical practices have dramatically decreased the percentage of infants who die from CHD – from a staggering rate of nearly 100 percent just a few decades ago to the current mortality rate of less than 10 percent.

The increased survival rate comes with new challenges: Children with complex CHD are increasingly diagnosed with significant neurodevelopmental delay or impairment. Clinical studies demonstrate that CHD can reduce oxygen delivery to the brain, a condition known as hypoxia, which can severely impair brain development in fetuses and newborns whose brains are developing rapidly.

Nobuyuki Ishibashi, M.D., the study’s lead investigator with the Center for Neuroscience Research and director of the Cardiac Surgery Research Laboratory at Children’s National, proposes transfusing human stem cells in experimental models through the cardio-pulmonary bypass machine used during cardiac surgery.

“These cells can then identify the injury sites,” says Dr. Ishibashi. “Once these cells arrive at the injury site, they communicate with endogenous tissues, taking on the abilities of the damaged neurons or glia cells they are replacing.”

“Bone marrow stem cells are used widely for stroke patients, for heart attack patients and for those with developmental diseases,” adds Dr. Ishibashi. “But they’ve never been used to treat the brains of infants with congenital heart disease. That’s why we are trying to understand how well this system might work for our patient population.”

Dr. Ishibashi says the research team will focus on three areas during their four-year study – whether the stem cells:

Reduce neurological inflammation,
Reverse or halt injury to the brain’s white matter and
Help promote neurogenesis in the subventricular zone, the largest niche in the brain for creating the neural stem/progenitor cells leading to cortical growth in the developing brain.

At the conclusion of the research study, Dr. Ishibashi says the hope is to develop robust data so that someday an effective treatment will be available and lasting neurological damage in infants with congenital heart disease will become a thing of the past.

Multidisciplinary experts help CDC’s Zika research

January 30, 2018

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

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

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

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

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

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

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

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

Children’s National to host 28th Annual Pediatric Neurology Update

January 19, 2018

The Children’s National Health System Center for Neuroscience and Behavioral Medicine is proud to host the 28th Annual Pediatric Neurology Update course.

This year’s course will be focused on new understandings, molecular pathogenesis, novel treatment and outcomes of infections which affect the central nervous system; as well as the often indistinct boundaries between CNS infections and neuro immunologic diseases of the nervous system.

We invite you to join us for presentations from renowned experts in the field in this full-day, CME accredited event on May 3, 2018 at the Children’s National main campus in Washington, D.C.

For more information and to register, visit ChildrensNational.org/NeurologyUpdate.

Researchers discover new gene variant for inherited amino acid-elevating disease

December 29, 2017

Carlos Ferreira Lopez

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What’s known

Hypermethioninemia is a rare condition that causes elevated levels of methionine, an essential amino acid in humans. This condition stems from genetic variations inherited from one or both parents. Some forms of hypermethioninemia are recessive, meaning that two copies of defective genes are necessary to cause this disease. Other forms are dominant, meaning that only one copy can cause hypermethioninemia. Recessive forms of the disease tend to have more serious consequences, causing elevated methionine levels throughout life and leading to changes in the brain’s white matter visible on magnetic resonance imaging that can cause neurological problems. The dominant forms are generally thought to be largely benign and require minimal follow-up.

What’s new

A research team led by Carlos Ferreira Lopez, M.D., a medical geneticist at Children’s National Health System, discovered a new gene variant that had not been associated with hypermethioinemia previously when an infant who had tested positive for elevated methionine on newborn blood-spot screening came in for a follow-up evaluation. While the majority of dominant hypermethioninemia are caused by a genetic mutation known as MAT1A p.Arg264His, the child didn’t have this or any of the common recessive hypermethioninemia mutations. Genetic testing showed that she carried a different mutation to the MAT1A gene known as p.Ala259Val, of which she carried only a single copy. The child fit the typical profile of having the dominant form of the disease, with methionine levels gradually declining over time. Testing of her mother showed that she carried the same gene variant, with few consequences other than a hepatitis-like illness as a child. Because liver disease can accompany dominant hypermethioninemia, the infant’s doctors will continue periodic follow-up to ensure she remains healthy.

Questions for future research

Q: Besides the potential for harmful liver effects, does dominant hypermethioninemia have other negative consequences?

Q: How common is this gene variant, and are certain people at more risk for carrying it?

Source: “Confirmation that MAT1A p.Ala259Val mutation causes autosomal dominant hypermethioninemia.” Muriello, M.J., S. Viall, T. Bottiglieri, K. Cusmano-Ozog and C. R. Ferreira. Published by Molecular Genetics and Metabolism Reports December 2017.

Putting childhood epilepsy in the spotlight at American Epilepsy Society Meeting

December 21, 2017

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

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

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

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

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

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

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

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

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

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

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

The effects of cardiopulmonary bypass on white matter development

December 12, 2017

Nobuyuki Ishibashi, M.D., and a team of researchers looked the effects of cardiopulmonary bypass surgery on the white matter of an animal model.

Mortality rates for infants born with congenital heart disease (CHD) have dramatically decreased over the past two decades, with more and more children reaching adulthood. However, many survivors are at risk for neurodevelopmental abnormalities associated with cardiopulmonary bypass surgery (CPB), including long-term injuries to the brain’s white matter and neural connectivity impairments that can lead to neurological dysfunction.

“Clinical studies have found a connection between abnormal neurological outcomes and surgery, but we don’t know what’s happening at the cellular level,” explains Nobuyuki Ishibashi, M.D., Director of the Cardiac Surgery Research Laboratory at Children’s National. To help shed light on this matter, Ishibashi and a team of researchers looked at the effects of CPB on the white matter of an animal model.

The research team randomly assigned models to receive one of three CPB-induced insults: a sham surgery (control group); full-flow bypass for 60 minutes; and 25°C circulatory arrest for 60 minutes. The team then used fractional anisotropy — a technique that measures the directionality of axon mylenation — to determine white matter organization in the models’ brains. They also used immunohistology techniques to assess the integrity of white matter oligodendrocytes, astrocytes and microglia.

The results, published in the Journal of the American Heart Association, show that white matter experiences region-specific vulnerability to insults associated with CPB, with fibers within the frontal cortex appearing the most susceptible. The team also found that fractional anisotropy changes after CPB were insult dependent and that regions most resilient to CPB-induced fractional anisotropy reduction were those that maintained mature oligodendrocytes.

From these findings, Ishibashi and his co-authors conclude that reducing alterations of oligodendrocyte development in the frontal cortex can be both a metric and a goal to improve neurodevelopmental impairment in the congenital heart disease population. “Because we are seeing cellular damage in these regions, we can target them for future therapies,” explains Ishibashi.

The study also demonstrates the dynamic relationship between fractional anisotropy and cellular events after pediatric cardiac surgery, and indicates that the technique is a clinically relevant biomarker in white matter injury after cardiac surgery.

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

Tracking preemies’ blood flow to monitor brain maturation

December 11, 2017

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

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

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

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

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

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

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

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

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

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

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

William D. Gaillard, M.D., elected Second Vice President of the American Epilepsy Society

December 8, 2017

William Davis Gaillard, M.D., has been elected second vice president of the American Epilepsy Society (AES), a medical and scientific society with 4,000 members. Dr. Gaillard’s term started at the end of the society’s annual meeting, December 1-5, in Washington, D.C.

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

Dr. Gaillard, an internationally recognized expert in pediatric epilepsy and imaging, is chief of Neurology, Epilepsy and Neurophysiology at Children’s National. He is also the associate director of the DC-IDDC and director of the of the Intellectual and Developmental Disabilities Research Center (DC-IDDRC) imaging core and associate director of the Center for Neuroscience Research, Children’s Research Institute. His academic appointments include professor of Pediatrics and Neurology at George Washington University and professor of Neurology at Georgetown University.

As division chief of Child Neurology, Epilepsy and Neurophysiology, Dr. Gaillard directs a team of pediatric specialists who see thousands of patients each year. Dr. Gaillard has worked throughout his career to care for children and young adults with epilepsy from the onset of seizures through novel therapeutic interventions, medication trials and, when appropriate, surgery. Treatment at Children’s National addresses the full range of the condition, including problems of difficult-to-control epilepsy. Additionally, treatment includes the concurrent social, educational and emotional issues faced by children with the condition and their families.

An active participant in AES activities, Dr. Gaillard has served as treasurer and as chair of the Clinical Investigator Workshop and Pediatric Content Committees. He also serves as an associate editor for the journal Epilepsy Research, and as a regular reviewer on AES and Epilepsy Foundation study sections. Dr. Gaillard will service as first vice president in 2019 and accede to the presidency of AES in 2020.

Kids’ resilience pushes neurologist to seek better therapies

December 5, 2017

“I get strength from kids and families, strength like that shown by Nick and his family,” answered Roger Packer, M.D., when Quicken Loans owner Dan Gilbert asked how he copes with the stress of seeing children struggling with brain tumors and other neurological problems every day.

Dr. Packer, senior vice president of the Center for Neuroscience and Behavioral Medicine at Children’s National Health System, joined Mr. Gilbert and his son, Nick, who was treated for neurofibromatosis at Children’s National, for a panel discussion at the recent Crain’s Health Care Heroes event. The discussion focused on Nick Gilbert, now a college student, and how he has stayed positive while undergoing intense treatments for neurofibromatosis since he was 15 months old.

Dr. Packer met Nick at age 10, when he first came to Children’s National for its world-renowned expertise in neurofibromatosis research and care. After their experiences, the Gilberts generously supported the creation of the Gilbert Family Neurofibromatosis Institute at Children’s National Health System to continue research into new and innovative treatments for the disorder.

Mr. Gilbert credits Dr. Packer with taking on difficult cases and having a positive impact on both Nick and himself. “When other doctors give up on patients, he intervenes with magic and saves lives.”

The reason, according to Dr. Packer, is that kids like Nick “don’t want to give up.” Thankfully, he notes, better tools to treat diseases like cancer and neurofibromatosis have finally arrived. “There are remarkable advances that were not possible five years ago,” he said.

The full session at the Health Care Heroes event was featured in Crain’s Detroit Business.

Working to reduce brain injury in newborns

November 9, 2017

A new study from Children’s National Health System and Drexel University College of Medicine has identified a promising treatment to reduce or prevent brain injury in newborns who have suffered hypoxia-ischemia.

Research-clinicians at Children’s National Health System and Drexel University College of Medicine led the first study to identify a promising treatment to reduce or prevent brain injury in newborns who have suffered hypoxia-ischemia, a serious complication in which restricted blood flow deprives the brain of oxygen.

Consequences of brain injury resulting from oxygen deprivation affect the entire lifespan and range from mild (learning disabilities) to severe (inability to breathe, walk, talk or see). This complication can occur during or before birth due to maternal/placental problems, such as placental abruption or cord prolapse, or due to fetal/newborn issues, such as asphyxia due to labor difficulties, infection, fetal-maternal bleeding or twin-to-twin transfusion.

Published in Neonatology on Oct. 13, 2017, the study evaluated newborn experimental models exposed to hypoxia-ischemia. The experimental models were given standard cooling therapy (therapeutic hypothermia) alone and in combination with a selective Src kinase inhibitor, PP2, that blocks a regulatory enzyme of apoptosis (cell death), which intensifies as a result of hypoxia-ischemia. The Food and Drug Administration has approved a Src kinase inhibitor as an oncology treatment. This study is the first to test the benefits of blocking this enzyme in reducing the neurological damage caused by brain hypoxia-ischemia.

“In hypoxia-ischemia, CaM kinase is over-activated, but hypothermia has been shown to decrease this enzyme’s activation. We theorized that a Src kinase inhibitor, in addition to hypothermia, would further attenuate the activation of CaM kinase IV and that the result might be less brain damage,” explains Panagiotis Kratimenos, M.D., Ph.D., the study’s lead author, and a specialist in neonatology and neonatal neurocritical care at Children’s National. “From this study, we were pleased that this seems to be the case.”

The research team assessed neuropathology, adenosine triphosphate and phosphocreatine concentrations as well as CaM kinase IV activity. The CaM kinase IV activity in cerebral tissue was 2,002 (plus or minus 729) with normal oxygen levels and in normal temperatures, 4,104 (plus or minus 542) in hypoxia with hypothermia treatment, and 2,165 (plus or minus 415) in hypoxia with hypothermia treatment combined with PP2 administration.

The authors conclude that hypothermia alone attenuated the over-activation of CaM kinase IV and improved neuropathology after hypoxia. However, the combination of hypothermia with Src kinase inhibition following hypoxia further attenuated the increased activation of CaM kinase IV, compared with hypothermia alone in the newborn experimental model brain.

Currently, the only treatment for hypoxia-ischemia is therapeutic hypothermia. Starting in the first six hours of life, doctors in the neonatal intensive care unit lower a baby’s temperature by about 3 degrees Celsius for three days. This therapy is proven to reduce neural defects by up to 30 percent, yet many infants still have poor outcomes even after the therapeutic cooling treatment.

“In oxygen deprivation of the brain, the pathways leading to cell death are over-activated, including the nuclear enzyme CaM kinase IV. We sought to intervene in this pathway to reduce the heightened cell death, which leads to brain damage,” explains Dr. Kratimenos, an assistant professor of pediatrics at The George Washington University School of Medicine and Health Sciences whose research focus is neonatal encephalopathy and therapeutic hypothermia.

To continue preclinical research into this approach, Dr. Kratimenos envisions studying the effect of other types of small molecule inhibitors to target the apoptotic cascade, perhaps in multiple doses, eliminating the potential side effects, and determining the best dose and duration of treatment.

“If confirmed by further studies, this approach─in combination with cooling─may help to further attenuate neurological damage that babies suffer after experiencing hypoxia-ischemia,” says Dr. Kratimenos.

The study co-authors include Ioannis Koutroulis, M.D., Ph.D., a faculty member in Children’s Division of Emergency Medicine; and Amit Jain, M.D.; Shadi Malaeb, M.D.; and the world-renowned neonatologist and pioneer in bioenergetics of the brain, Maria Delivoria-Papadopoulos, M.D., all of the Drexel University College of Medicine.

Imaging captures obesity’s impact on the adolescent brain

November 3, 2017

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

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

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

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

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

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

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

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

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

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

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

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

Continuous EEG monitoring better predicts HIE outcomes

November 2, 2017

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

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

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

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

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

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

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

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

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

Related Resources

Avery’s Story: Hypoxic-ischemic Encephalopathy (HIE)

Children’s National experts contribute to new Zika guidelines

October 23, 2017

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

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

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

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

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

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

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

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

Roger Packer, M.D., elected Pediatric Co-Chair by the National Cancer Institute’s Brain Malignancies Steering Committee

October 23, 2017

Roger Packer, MD

Roger J. Packer, M.D., Senior Vice President, Center for Neuroscience & Behavioral Health at Children’s National Health System, has been elected by the National Cancer Institute’s Brain Malignancies Steering Committee (BMSC) as the committee’s new Pediatric Co-Chair.

One of 16 steering committees formed in response to the recommendations of the Clinical Trials Working Group mandated by the National Cancer Advisory Board (NCAB), the BMSC’s goal is to promote the best clinical and translational research for patients with brain cancer by critically reviewing Phase 2 and Phase 3 clinical trial concepts.

Dr. Packer also directs the Brain Tumor Institute and is principal investigator for the Pediatric Brain Tumor Consortium (PBTC), formed under the auspices of the National Cancer Institute (NCI). He has worked closely with the NCI and the National Institute of Neurological Disorders and Stroke (NINDS), and has served on multiple committees setting the directions for neurologic clinical and basic science research for the future. Much of Dr. Packer’s clinical research has been translational in nature. He has been part of studies evaluating the molecular genetics of childhood and adult neurologic diseases, and has also coordinated the first gene therapy study for children with malignant brain tumors in the U.S.

Fetal MRI plus ultrasound assess Zika-related brain changes

October 18, 2017

Magnetic resonance imaging and ultrasound provide complementary data needed to assess ongoing changes to the brains of fetuses exposed to Zika in utero, says Sarah B. Mulkey, M.D., Ph.D.

For Zika-affected pregnancies, fetal magnetic resonance imaging (MRI) used in addition to standard ultrasound (US) imaging can better assess potential brain abnormalities in utero, according to research presented by Children’s National Health System during IDWeek 2017. In cases of abnormal brain structure, fetal MRI can reveal more extensive areas of damage to the developing brain than is seen with US.

“MRI and US provide complementary data needed to assess ongoing changes to the brains of fetuses exposed to Zika in utero,” says Sarah B. Mulkey, M.D., Ph.D., a fetal/neonatal neurologist at Children’s National Health System and lead author of the research paper. “In addition, our study found that relying on ultrasound alone would have given one mother the false assurance that her fetus’ brain was developing normally while the sharper MRI clearly pointed to brain abnormalities.”

As of Sept. 13, the Centers for Disease Control and Prevention (CDC) reported that 1,901 U.S. women were exposed to Zika at some point during their pregnancies but their infants appeared normal at birth. Another 98 U.S. women, however, gave birth to infants with Zika-related birth defects. And eight more women had pregnancy losses with Zika-related birth defects, according to CDC registries.

The longitudinal neuroimaging study led by Children’s National enrolled 48 pregnant women exposed to the Zika virus in the first or second trimester whose infection was confirmed by reverse transcription polymerase chain reaction, which detects Zika viral fragments shortly after exposure, and/or Immunoglobulin M testing, which reveals antibodies the body produces to neutralize the virus. Forty-six of the study volunteers live in Barranquilla, Colombia, where Zika infection is endemic. Two women live in the Washington region and were exposed to Zika during travel elsewhere.

All of the women underwent at least one diagnostic imaging session while pregnant, receiving an initial MRI or US at 25.1 weeks’ gestational age. Thirty-six women underwent a second MRI/US imaging pair at roughly 31 weeks’ gestation. Children’s National radiologists read every image.

Three of 48 pregnancies, or 6 percent, were marked by abnormal fetal MRIs:

One fetus had heterotopias (clumps of grey matter located at the wrong place) and abnormal cortical indent (a deformation at the outer layer of the cerebrum, a brain region involved in consciousness). The US taken at the same gestational age for this fetus showed its brain was developing normally.
Another fetus had parietal encephalocele (an uncommon skull defect) and Chiari malformation Type II (a life-threatening structural defect at the base of the skull and the cerebellum, the part of the brain that controls balance). The US for this fetus also detected these brain abnormalities.
The third fetus had a thin corpus callosum (bundle of nerves that connects the brain’s left and right hemispheres), an abnormally developed brain stem, temporal cysts, subependymal heterotopias and general cerebral/cerebellar atrophy. This fetal US showed significant ventriculomegaly (fluid-filled structures in the brain that are too large) and a fetal head circumference that decreased sharply from the 32nd to 36th gestational week, a hallmark of microcephaly.

After they were born, infants underwent a follow-up MRI without sedation and US. For nine infants, these ultrasounds revealed cysts in the choroid plexus (cells that produce cerebrospinal fluid) or germinal matrix (the source for neurons and glial cells that migrate during brain development). And one infant’s US after birth showed lenticulostriate vasculopathy (brain lesions).

“Because a number of factors can trigger brain abnormalities, further studies are needed to determine whether the cystic changes to these infants’ brains are attributable to Zika exposure in the womb or whether some other insult caused these troubling results,” Dr. Mulkey says.