Neurology & Neurosurgery

crawling baby

Gene-targeting may help prevent or recover neonatal brain injuries

crawling baby

The findings of a new pre-clinical study published in The Journal of Neuroscience are helping pave the way toward better understanding, prevention and recovery of neonatal brain injuries.

The findings of a new pre-clinical study published in The Journal of Neuroscience are helping pave the way toward better understanding, prevention and recovery of neonatal brain injuries. During pregnancy, the fetus normally grows in low oxygen conditions. When babies are born preterm, there is an abrupt change into a high oxygen environment which may be higher than the baby can tolerate. These preterm babies often need support to breathe because their lungs are immature. If the oxygen they receive is too high, oxygen-free radicals can form and cause cell death.

Premature infants have underdeveloped antioxidant defenses that prevent or delay some types of cell damage under normal conditions. In a high oxygen environment, these underdeveloped defenses cannot fully protect against oxidative stress, damaging different brain regions without available treatments or preventative measures.

“I am thrilled that we identified a defect in a specific cell population in the hippocampus for memory development,” said Vittorio Gallo, Ph.D., interim chief academic officer and interim director of the Children’s National Research Institute, and principal investigator for the District of Columbia Intellectual and Developmental Disabilities Research Center. “I did not think we would be able to do it at a refined level, identifying cell populations sensitive to oxidative stress and its underlying signaling pathway and molecular mechanism.”

Vittorio Gallo

“I am thrilled that we identified a defect in a specific cell population in the hippocampus for memory development,” said Vittorio Gallo, Ph.D.

Children’s National Hospital experts found that oxidative stress over-activates a glucose metabolism enzyme, GSK3β, altering hippocampal interneuron development and impairing learning and memory, according to the pre-clinical study. The researchers also inhibited GSK3β in hippocampal interneurons, reversing these cellular and cognitive deficits.

The role of oxidative stress in the developing hippocampus, as well as GSK3β involvement in oxidative stress-induced neurodevelopmental disorders and cognitive deficits, have both been unexplored until now. Goldstein et al. suggest the study paves the way for the field as a viable approach to maximize functional recovery after neonatal brain injury.

To better understand the mechanisms underlying neonatal brain injury, the researchers mimicked the brain injury by inducing high oxygen levels in a pre-clinical model for a short time. This quest led to unlocking the underpinnings of the cognitive deficits, including the pathophysiology and molecular mechanisms of oxidative damage in the developing hippocampus.

Once they identified what caused cellular damage, the researchers used a gene-targeted approach to reduce GSK3β levels in POMC-expressing cells or Gad2-expressing interneurons. By regulating the levels of GSK3β in interneurons ⁠— but not in POMC-expressing cells — inhibitory neurotransmission was significantly improved and memory deficits due to high oxygen levels were reversed.

caspase molecule

Caspases may link brain cell degeneration and cardiac surgery

caspase molecule

The review summarizes both the known physiological roles of caspases as well as some of the well-characterized neurotoxic effects of anesthetics in pre-clinical models.

A review article in the journal Cell Press: Trends in Neuroscience outlines the wide variety of cellular signaling roles for caspase proteins — a type of cellular enzyme best known for its documented role in the natural process of cell death (apoptosis). The authors, including Nemanja Saric, Ph.D., Kazue Hashimoto-Torii, Ph.D., and Nobuyuki Ishibashi, M.D., all from Children’s National Research Institute, pay particular attention to what the scientific literature shows about caspases’ non-apoptotic roles in the neurons specifically. They also highlight research showing how, when activated during a cardiac surgery with anesthesia and cardiopulmonary bypass, these enzymes may contribute to the degeneration of brain cells seen in young children who undergo heart surgery for critical congenital heart defects (CHDs).

Why it matters

The review summarizes both the known physiological roles of caspases as well as some of the well-characterized neurotoxic effects of anesthetics in pre-clinical models.

The authors propose that these non-apoptotic activities of caspases may be behind some of the adverse effects on the developing brain related to cardiac surgery and anesthesia. Those adverse effects are known to increase risk of behavioral impairments in children with congenital heart disease who underwent cardiac surgery with both anesthesia and cardiopulmonary bypass at a very young age.

This work is the first to propose a possible link between developmental anesthesia neurotoxicity and caspase-dependent cellular responses.

The patient benefit

Better understanding of the time and dose-dependent effects of general anesthetics on the developing brain, particularly in children who have genetic predispositions to conditions such as CHDs, will help researchers understand their role (if any) in behavioral problems often encountered by these patients after surgery.

If found to be a contributing factor, perhaps new therapies to mitigate this caspase activity might be explored to alleviate some of these adverse effects on the developing brain.

What’s next?

The authors hope to stimulate more in-depth research into caspase signaling events, particularly related to how these signaling events change when an anesthetic is introduced. Deeper understanding of how anesthetics impact caspase activation in the developing brain will allow for better assessments of the risk for children who need major surgery early in life.

Children’s National leads the way

Children’s National Hospital leads studies funded by the U.S. Department of Defense to better understand how these other roles of caspases, which until now have not been well-documented, may contribute to brain cell degeneration when activated by prolonged anesthesia and cardiopulmonary bypass during cardiac surgery for congenital heart disease.

pregnant woman by window

Stress during pregnancy may hinder cognitive development

pregnant woman by window

This is the first study to shed light on an important link between altered in-utero fetal brain development and the long-term cognitive development consequences for fetuses exposed to high levels of toxic stress during pregnancy.

Women’s elevated anxiety, depression and stress during pregnancy altered key features of the fetal brain, which subsequently decreased their offspring’s cognitive development at 18 months. These changes also increased internalizing and dysregulation behaviors, according to a new study by Children’s National Hospital published in JAMA Network Open. Researchers followed a cohort of 97 pregnant women and their babies. The findings further suggest that persistent psychological distress after the baby is born may influence the parent-child interaction and infant self-regulation.

This is the first study to shed light on an important link between altered in-utero fetal brain development and the long-term cognitive development consequences for fetuses exposed to high levels of toxic stress during pregnancy. While in the womb, the researchers observed changes in the sulcal depth and left hippocampal volume, which could explain the neurodevelopment issues seen after birth. Once they grow into toddlers, these children may experience persistent social-emotional problems and have difficulty establishing positive relationships with others, including their mothers. To further confirm this, future studies with a larger sample size that reflect more regions and populations are needed.

“By identifying the pregnant women with elevated levels of psychological distress, clinicians could recognize those babies who are at risk for later neurodevelopmental impairment and might benefit from early, targeted interventions,” said Catherine Limperopoulos, Ph.D., chief and director of the Developing Brain Institute at Children’s National and senior author of the study.

Catherine Limperopoulos

“By identifying the pregnant women with elevated levels of psychological distress, clinicians could recognize those babies who are at risk for later neurodevelopmental impairment and might benefit from early, targeted interventions,” said Catherine Limperopoulos, Ph.D., chief and director of the Developing Brain Institute at Children’s National and senior author of the study.

Regardless of their socioeconomic status, about one of every four pregnant women suffers from stress-related symptoms, the most common pregnancy complication. The relationship between altered fetal brain development, prenatal maternal psychological distress and long-term neurodevelopmental outcomes remain unknown. Studying in utero fetal brain development poses challenges due to fetal and maternal movements, imaging technology, signal-to-noise ratio issues and changes in brain growth.

All pregnant participants were healthy, most had some level of education and were employed. To quantify prenatal maternal stress, anxiety and depression, the researchers used validated self-reported questionnaires. Fetal brain volumes and cortical folding were measured from three-dimensional reconstructed images derived from MRI scans. Fetal brain creatine and choline were quantified using proton magnetic resonance spectroscopy. The 18-month child neurodevelopment was measured using validated scales and assessments.

This study builds upon previous work from the Developing Brain Institute led by Limperopoulos, which discovered that anxiety in pregnant women appears to affect the brain development of their babies. Her team also found that maternal mental health, even for women with high socioeconomic status, alters the structure and biochemistry of the developing fetal brain. The growing evidence underscores the importance of mental health support for pregnant women.

“We’re looking at shifting the health care paradigm and adopting these changes more broadly to better support moms,” said Limperopoulos. “What’s clear is early interventions could help moms reduce their stress, which can positively impact their symptoms and thereby their baby long after birth.”

model of the brain

Treating newborns with hemimegalencephaly by inducing strokes

model of the brain

Experts at Children’s National Hospital have pioneered a novel approach using controlled strokes to stop seizures and improve neurodevelopmental outcomes in newborns under three months born with hemimegalencephaly (HME). They now consider it their new standard of care for babies in this age group with HME and refractory epilepsy.

Asking a physician to induce strokes in newborns is asking her to do something contrary to her training. But over the past eight years, experts at Children’s National Hospital have pioneered a novel approach using controlled strokes to stop seizures and improve neurodevelopmental outcomes in newborns under three months born with hemimegalencephaly (HME). They now consider it their new standard of care for babies in this age group with HME and refractory epilepsy.

“We have demonstrated the ability to intervene and stop the intractable seizures during a critical time of neurodevelopment in which no other effective medical or surgical option exists. That is extremely rewarding,” said Monica Pearl, M.D., director of the Neurointerventional Radiology Program at Children’s National. Children’s National is the only center in the world currently offering this treatment. A multi-disciplinary team led by Dr. Pearl; Taeun Chang, M.D., director of the Neonatal Neurology and Neonatal Neurocritical Care Program; neurophysiologist and neonatal neurologist Tammy Tsuchida, M.D., Ph.D.; and other experts has now successfully treated seven patients using this minimally-invasive approach.

“We want patients and providers to understand this is a better alternative to a delayed hemispherectomy, the standard of care currently offered to newborns with HME,” said Dr. Chang.

The best treatment for newborns with hemimegalencephaly

HME, a rare congenital condition occurring in a handful of newborns each year, is characterized by abnormal growth and enlargement of half of the brain which leads to intractable seizures. The seizures often result in severe cognitive delays and hemiparesis. The standard treatment is an anatomic hemispherectomy — surgical removal of the affected half of the brain, allowing the remaining half of the brain to develop and function without constant seizures.

Such a large and complex surgery poses serious risks for infants younger than three months, leaving doctors with the difficult choice to delay surgery until these newborns grow bigger and stronger, even as they are experiencing seizures. These persistent seizures compromise the development of the healthy half of the brain. One study reports as much as a drop of 10 to 20 IQ points with each month’s delay in surgical hemispherectomy.

“I was willing to consider performing these procedures because there is a clear, unmet medical need and these babies are in dire circumstances,” Dr. Pearl said. “Waiting for curative hemispherectomy means more than just lost time; uncontrolled seizures and anti-seizure medications have detrimental effects on the ‘normal,’ unaffected parts of the brain. We needed a better option for these patients.” Dr. Pearl said that complete embolization of the affected hemisphere as both primary and definitive treatment had never been described. They could only find one example in the literature – a paper from 1995 – suggesting embolization as an adjunct to surgery, and nothing suggesting it as a primary modality.

About the care received

Dr. Pearl is one of only a handful of dedicated pediatric neurointerventionalists across the country with neurovascular expertise in people of all ages, in particular neonates and young infants. For these procedures to be performed safely, the neurointerventionalist must be proficient in obtaining femoral arterial access and navigating small caliber cervicocerebral blood vessels that are less than one millimeter in diameter.

Additionally, one needs a neonatal neurocritical care service and NICU that can medically manage large strokes and their potential complications in newborns. Dr. Chang has developed a specialized protocol based on decades of managing strokes and other acute brain injuries in newborns. She created the neonatal neurocritical care service at Children’s National, the only one in the region and the largest in the world.

“Our teams are fortunate in that we each respectively have extensive prior experience in treating and managing neonates and very young infants for various cerebrovascular disorders,” Dr. Pearl said. “We relied on this collective experience to make this hemispheric embolization pathway possible.”

How it happens

To perform the embolizations, Dr. Chang and her team first optimizes control of the seizures using medications. Dr. Pearl places a sheath in the femoral artery using ultrasound guidance – a delicate task in a neonate whose femoral artery diameter is only two to three millimeters. She then navigates a catheter up the aorta and selects the targeted carotid artery using radiographic guidance. What follows is a set of intricate navigations to direct the microcatheter through small blood vessels in the brain, often less than one millimeter.

Using x-ray guidance, Dr. Pearl injects contrast through the microcatheter to visualize the arterial anatomy and advance the microcatheter into position for embolization. She uses glue that hardens when exposed to blood, blocking off the blood supply to the seizure-inducing areas. The process is repeated until the blood supply to the entire affected hemisphere is occluded. Meanwhile, Dr. Chang and her team monitor the brain’s electrical activity using an electroencephalogram (EEG) to watch how the brain responds to each stroke. The surgical epilepsy, neonatal neurocritical care and neonatology teams are all in constant communication throughout the procedure.

Together, they have to contend with the same symptoms patients have immediately following a stroke, most notably brain swelling that can cause bleeding and herniation. The resultant brain swelling is complicated further by the already enlarged hemisphere of the brain. Using neuroprotective strategies learned from treating over a thousand newborns with perinatal brain injury, Dr. Chang and her team and the NICU coordinate to minimize brain swelling and protect the healthy half of the brain by tightly controlling the brain temperature, glucose, sodium levels, and blood pressure. Over the course of a few weeks, Dr. Pearl performs three to four embolization sessions to halt blood supply to the seizing half of the brain.

“The risks of intracranial vasospasm and hemorrhage during embolization are higher in this distinct group of patients compared to other neonates requiring embolization, such as in vein of Galen malformations. These events must be controlled immediately to prevent complications and I know I only have seconds to react,” Dr. Pearl said.

“Here, we have the cultivation of brain-centric neonatal care, a large level IV tertiary NICU with expertise in keeping critically ill babies alive and rare pediatric neurologic subspecialists like Dr. Pearl and myself. All of this is what makes this level of innovation possible,” Dr. Chang said. Now, they wish this minimally invasive approach to be available to all newborns with HME and refractory epilepsy.

“This is not a fluke. This is not a one-time thing. Our team at Children’s National has been perfecting this method for close to a decade,” Dr. Chang said. As for proof, her answer is clear.

Follow our patients: Bella and Trace.

mother and daughter embracing

Understanding end-of-life treatment preferences for adolescents

mother and daughter embracing

FACE-TC effectively increases communication between adolescents with cancer and their families about the patients’ preferences.

Talking about death and dying is taboo. Some families believe it is their role alone to make end-of-life healthcare decisions or they may believe pediatric advance care planning is against their religion.

In a recent trial, Maureen Lyon, Ph.D., a clinical health psychologist at Children’s National Hospital and lead author of the study, analyzed the value of high-quality pediatric advance care planning and how this enabled families to know their adolescents’ end-of-life treatment preferences.

This is the first fully powered randomized controlled trial to focus on adolescents with cancer and their engagement with their families in pediatric advance care planning conversations.

What this means

Some physicians believe it is not their role to discuss the “what ifs.” Others report that they do not have the training or time to do so. As a result, in clinical practice, adolescents living with a serious illness rarely have documented advance care plans. The default is to provide intensive treatments that potentially increase suffering.

“Despite cancer being the leading cause of disease-related death in adolescents, conversations about goals of care and documentation of end-of-life care and treatment preferences for adolescents with cancer are not a routine and standard part of care,” Dr. Lyon said.

Why it matters

Family-centered advance care planning for teens with cancer (FACE-TC) effectively increases communication between adolescents with cancer and their families about the patients’ end-of-life preferences. This meets the first challenge of pediatric advance care planning – knowledge of patient’s preferences.

This low-tech intervention commits to more deeply respecting adolescents with cancer, integrating them into health care decision-making and giving them some control in a low control situation.

The patient and family benefits

“FACE-TC strengthens communication between adolescents with cancer and their families about adolescents’ understanding of their illness, their hopes and fears, their goals of care and their end-of-life treatment preferences,” Dr. Lyon added. “With increased access to palliative care services and pediatric advance care planning, families may better understand that stopping intensive medical interventions when their child is dying is not giving up, but rather choosing how best to spend the final days of one’s life.”

Dr. Lyon and the team at Children’s National have pioneered this effort to give seriously ill adolescents a voice and help families break the ice so they know what their child would want if the worst were to happen. The team also aims to provide an extra level of support for busy clinicians so the first conversation about goals of end-of-life care does not happen in the intensive care unit.

You can read the full trial, An Intervention in Congruence for End-of-Life Treatment Preference: A Randomized Trial, in Pediatrics.

You can also read the last manuscript from this clinical trial, Effect of the Family-Centered Advance Care Planning for Teens with Cancer Intervention on Sustainability of Congruence About End-of-Life Treatment Preferences, in JAMA Network.

girl looking at her phone

TikTok could be causing rising cases of tic-like behaviors

girl looking at her phone

Many teenagers who viewed a high number of Tourette syndrome TikTok videos during the COVID-19 pandemic started portraying similar tic-like behaviors.

The impact of social media on children is once again front and center. During the pandemic, experts noticed the increase in functional tic-like disorders and suggested an association with the rise in popularity of social media videos on TikTok. Many teenagers who viewed a high number of Tourette syndrome (TS) TikTok videos during the COVID-19 pandemic portrayed similar tic-like behaviors.

In a new study published in Pediatric Neurology, experts analyzed the 100 most-viewed videos under #tourettes on the media platform. The authors found the symptoms  portrayed as TS on viewed TikTok videos are an inaccurate representation of TS and are more consistent with functional tic-like behaviors.

“Tourette syndrome symptoms portrayals on highly-viewed TikTok videos are predominantly not representative or typical of Tourette syndrome,” says Alonso Zea Vera, M.D., neurologist at Children’s National Hospital and lead author of the study.

“Although many videos are aimed at increasing Tourette syndrome awareness, I worry that some features of these videos can result in confusion and further stigmatization,” Dr. Zea Vera says. “A common cause of stigmatization in Tourette syndrome is the exaggeration of coprolalia (cursing tics) in the media. We found that many videos portrayed this (often used for a comedic effect) despite being a relatively rare symptom in Tourette syndrome.”

There have been recent discussions about the accuracy of current social media videos of TS. This study highlights the importance of mentioning the source of the medical information and providing guidance. Children’s National has one of the largest movement disorders teams in the U.S. that is trained to differentiate TS from functional tic-like disorders.

“This differentiation can be challenging but important since the treatment is different,” Dr. Zea Vera adds. “Both of these conditions can be very impairing for patients.”

You can read the full study ‘The phenomenology of tics and tic-like behavior in TikTok” here.

binary numbers

New datasets predict surgeon performance during complications

binary numbers

In a new study published in JAMA Network Open, experts at Children’s National and allied institutions created and validated the first dataset to depict hemorrhage control for machine learning applications, the simulated outcomes following carotid artery laceration (SOCAL) video dataset.

Computer algorithms, such as machine learning and computer vision, are increasingly able to discover patterns in visual data, powering exciting new technologies worldwide. At Children’s National Hospital, physician-scientists develop and apply these advanced algorithms to make surgery safer by studying surgical video.

The big picture

In a new study published in JAMA Network Open, experts at Children’s National and allied institutions created and validated the first dataset to depict hemorrhage control for machine learning applications, the simulated outcomes following carotid artery laceration (SOCAL) video dataset.

The authors designed SOCAL to serve as a benchmark for data-science applications, including object detection, performance metric development and outcome prediction. Hemorrhage control is a high-stakes adverse event that can pose unique challenges for video analysis. With SOCAL, the authors aim to solve a valuable use case with algorithms.

“As neurosurgeons, we are often called to perform high-risk and high-impact procedures. No one is more passionate about making surgery safer,” said Daniel Donoho, M.D., neurosurgeon at Children’s National Hospital and senior author of the study. “Our team at Children’s National and the Sheikh Zayed Institute is poised to lead this exciting new field of surgical data science.”

The hold-up in the field

These algorithms require raw data for their development, but the field lacks datasets that depict surgeons managing complications.

By creating automated insights from surgical video, these tools may one day improve patient care by detecting complications before patients are harmed, facilitating surgeon development.

Why it matters

“Until very recently, surgeons have not known what may be possible with large quantities of surgical video captured each day in the operating room,” said Gabriel Zada, M.D., M.S., F.A.A.N.S., F.A.C.S., director of the Brain Tumor Center at the University of Southern California (USC) and co-author of the study. “Our team’s research led by Dr. Donoho shows the feasibility and the potential of computer vision analysis in surgical skill assessment, virtual coaching and simulation training of surgeons.”

The lack of videos of adverse events creates a dataset bias which hampers surgical data science. SOCAL was designed to meet this need. After creating a cadaveric simulator of internal carotid artery injury and training hundreds of surgeons on the model at nationwide courses, the authors then developed computational models to measure and improve performance.

“We are currently comparing our algorithms to experts, including those developed using the SOCAL dataset,” Dr. Donoho said. “Human versus machine, and our patients are ultimately the winners in the competition.”

What’s next

The authors are also building a nationwide collective of surgeons and data scientists to share data and improve algorithm performance through exciting partnerships with USC, California Institute of Technology and other institutions.

You can read the full study “Utility of the Simulated Outcomes Following Carotid Artery Laceration Video Data Set for Machine Learning Applications” in JAMA Network Open.

colorful strands of DNA

Paving the way to activate a single gene in Angelman syndrome

colorful strands of DNA

Angelman syndrome (AS) is a rare disorder that causes neurodevelopmental issues such as intellectual disability, impaired speech and motor skills, epilepsy and sleep disruptions. This single gene disorder is caused by mutations or deletions in the maternal copy of the UBE3A gene.

Angelman syndrome (AS) is a rare disorder that causes neurodevelopmental issues such as intellectual disability, impaired speech and motor skills, epilepsy and sleep disruptions. This single gene disorder is caused by mutations or deletions in the maternal copy of the UBE3A gene. To date, there is no treatment for AS.

It is easier to treat this syndrome when the disrupted gene is present but repressed. If experts can figure out how to activate it in clinical trials, they believe patients could receive a treatment that tackles the root of the problem. Children’s National Hospital experts support this vision and the AS community by helping establish appropriate biomarkers for current and future clinical trials.

While the field is trying to figure out the best scientific method to quantify progress in clinical trials for AS, the Sidorov Laboratory found that overnight sleep testing is not necessary for detecting Angelman syndrome electroencephalography (EEG) biomarkers, according to the study published in Autism Research. The data further suggests that while sleep EEGs do not provide additional benefit for detecting delta EEG rhythms, sleep itself represents a valuable AS biomarker.

What this means

“It is encouraging to see that wake EEGs are sufficient, and perhaps ideal, for detecting delta waves in a clinical trial setting,” said Michael S. Sidorov, Ph.D., principal investigator with the Center for Neuroscience Research at Children’s National. “With this biomarker, researchers can measure how AS severity changes in children over the course of a clinical trial. This enables trials to test the efficacy of exciting new treatments.”

The hold-up in the field

In the past decade, the research community has focused on activating the dormant paternal copy of the UBE3A gene in pre-clinical models. Presently, there are three ongoing phase I clinical trials for AS in the U.S. These trials use antisense oligonucleotides (ASOs), which can modify gene expression to treat genetic disorders, and have been FDA approved for other disorders. These new compounds specifically target the gene activation to unleash the existing copy of UBE3A. However, there is a need for better and more accurate ways to know if the drug is working or not. The field has not reached a consensus yet on the appropriate biomarkers that can correctly measure success.

There are also challenges associated with performing overnight EEG studies in children with AS due to the severe sleeping problems, difficulty in tolerating the process and sample recruitment.

The patient benefit

Elizabeth R. Jalazo, M.D., assistant professor of pediatrics at the University of North Carolina in Chapel Hill, chief medical officer at the Angelman Syndrome Foundation, is also the parent of a child with Angelman syndrome. Dr. Jalazo, who was not part of the study, mentioned that her experience with a daughter with a rare disorder had brought challenges to their family over the last seven years. But, alas, she said the joy Evelyn has brought to their lives far outweighs the day-to-day challenges of special needs parenting.

“As a parent I’m thrilled that we can potentially capture as much meaningful EEG data in a short daytime EEG rather than subjecting our children to overnight EEG studies,” said Dr. Jalazo. “As a clinician this is equally exciting from a clinical trial feasibility standpoint.”

One of the greatest challenges facing Angelman syndrome and other neurodevelopmental disorder therapeutic development is the lack of appropriate endpoints to assess the efficacy of our interventions.

“I worry very much that without objective measures specific to Angelman syndrome, potentially beneficial therapeutics may fail to meet the mark and ultimately not reach the community,” she added.

The scientific community has transitioned from the hope of clinical trials to lessen those day-to-day challenges to witnessing first-in-human trials of potentially transformative therapeutics in just the last few years.

“It is a biomarker work like this that is critical as we delve into the exciting landscape of clinical trial design and advance therapeutics for Angelman syndrome,” said Dr. Jalazo.

You can read the full study “Evaluation of electroencephalography biomarkers for Angelman syndrome during overnight sleep” in Autism Research.

 

zika virus

Researcher to decipher how viruses affect the developing brain with nearly $1M NIH award

zika virus

Zika virus in blood with red blood cells, a virus which causes Zika fever found in Brazil and other tropical countries.

The National Institutes of Health (NIH) awarded Children’s National Hospital nearly $1M of research support toward uncovering the specific cellular response that happens inside a developing brain once it is infected with a virus, including how the neuron gets infected, and how it dies or survives. The research is expected to gather critical information that can inform prenatal neuro-precision therapies to prevent or attenuate the effects of endemic and pandemic viruses in the future.

“We need to use all of the information we have from ongoing and past pandemics to prevent tomorrow’s public health crisis,” said Youssef Kousa, MS, D.O., Ph.D., neonatal critical care neurologist and physician-scientist at Children’s National. “There is still here a whole lot to learn and discover. We could eventually — and this is the vision that’s inspiring us — prevent neurodevelopmental disorders before a baby is born by understanding more about the interaction between the virus, mother, fetus, and environment, among other factors.”

Different viruses, including HIV, CMV, Zika and rubella, injure the developing brain in very similar ways. This line of work was fostered first by the clinical research team led by Adre du Plessis, M.B.Ch.B., and Sarah Mulkey, M.D., supported by Catherine Limperopoulos, Ph.D., chief and director of the Developing Brain Institute at Children’s National.

The clinical research findings then led to the NIH support, which then inspired more basic science research. Fast forward to now, Kousa will study how Zika affects the human brain and extrapolate what is learned and discovered for a broader understanding of neurovirology.

The research program is supported by senior scientists and advisors, including Tarik Haydar, Ph.D., and Eric Vilain, M.D., Ph.D., both at Children’s National and Avindra Nath, M.D., at NIH, as well as other leading researchers at various U.S. centers.

“This is a team effort;” added Kousa, “I’m thankful to have a group of pioneering and seasoned researchers engaged with me throughout this process to provide invaluable guidance.”

Many viruses can harm the developing brain when they replicate in the absence of host defenses, including the gene regulatory networks responsible for the neuronal response. As a result, viral infections can lead to brain injury and neurodevelopmental delays and disorders such as intellectual disability, seizures that are difficult to treat, and vision or hearing loss.

The big picture

Youssef Kousa

Youssef Kousa, MS, D.O., Ph.D., neonatal critical care neurologist and physician-scientist at Children’s National.

The translational research supported by NIH with this award synergistically complements nationally recognized clinical research programs and ongoing prospective cohort studies at Children’s National to identify the full spectrum of neurodevelopmental clinical outcomes after prenatal Zika and other viral infections led by Dr. Mulkey and Roberta DeBiasi, M.D., M.S..

The award also builds upon strengths at the Children’s National Research & Innovation Campus, which is in proximity to federal science agencies. Children’s National experts from the Center for Genetic Medicine Research, known for pediatric genomic and precision medicine, joined forces with the Center of Neuroscience Research and the NIH-NINDS intramural research program to focus on examining prenatal and childhood neurological disorders.

Kousa received this competitive career development award from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number K08NS119882. The research content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The hold-up in the field

Many neurodevelopmental disorders are caused by endemic viruses, such as CMV, and by viral pandemics, including rubella as seen in the 1960s and Zika since 2015. By studying Zika and other prenatal viral infections, Kousa and team hope to gain deeper biological understanding of the viral effects toward developing therapies for anticipating, treating and preventing virally induced prenatal brain injury in the long-term future.

To date, little is known about how viruses affect developing neurons and, as a result, prenatal brain injury is not yet treatable. To bridge the gap towards prenatal neuro-precision therapies, the research explores how genes regulate neuronal developmental and viral clearance by innovatively integrating three systems:

  • Cerebral organoids, which illuminate how a neuron reacts to a viral infection
  • Pre-clinical models that link prenatal brain injury to postnatal neurodevelopmental outcomes
  • Populational genomics to identify human genetic risk or protective factors for prenatal brain injury

Given the scope and complexity of this issue, the international Zika Genetics Consortium, founded in 2015 by Kousa and a team of leading investigators across the world, provides critical samples and resources for the third arm of the research by performing comprehensive genomic analyses using sequencing data collected from diverse human populations throughout Central and South America, which are not as heavily sequenced as Western populations. Through partnerships with the Centers for Disease Control and Prevention and NIH, the consortium’s database and biorepository houses thousands of patient records and biospecimens for research studies to better understand how viruses affect the developing human brain.

“It is inspiring to imagine that, in the longer term, we could recognize early on the level of brain-injury risk faced by a developing fetus and have the tools to mitigate ensuing complications,” said Kousa. “What is driving this research is the vision that one day, brain injury could be prevented from happening before a baby is born.”

Hands holding letters that spell autism

Increasing access to autism spectrum disorder services through enhanced training

Hands holding letters that spell autismMany service providers struggle to keep pace with advances in autism-specific knowledge and tend to refer children to autism specialty clinics when the diagnosis of autism spectrum disorder (ASD) is in question. Unfortunately, it is in these settings where children most often wait for months or, worse, experience barriers to accessing any care at all. This has resulted in an access crisis for children and families with ASD concerns contributing to delays in diagnosis and treatment, particularly for children of color and for under-resourced families. Service disruptions and challenges related to the COVID-19 pandemic have only added to delays. As the need for autism-related services continues to grow, innovative models must be used to enhance competence among frontline medical, behavioral health and community-based providers who currently serve these children and families on a regular basis.

Children’s National Hospital has initiated a number of endeavors focused on increasing access to ASD services through enhanced training experiences, mentorship of allied mental health and frontline professionals and utilization of multidisciplinary approaches. These approaches enhance the skills and knowledge of treatment providers, which allows them to accurately address the needs of autistic patients while they await more comprehensive evaluations and sometimes reduce the need for additional evaluation. The following are efforts currently underway.

Virtual ECHO (Extension Community Healthcare Outcomes) Autism Clinics

The Center for Autism Spectrum Disorders (CASD) is hosting virtual ECHO (Extension Community Healthcare Outcomes) Autism Clinics aimed at building autism knowledge and competencies amongst community providers by creating shared learning forums with a multidisciplinary group of autism specialists for dissemination of knowledge and mentorship.

Clinics run in 6-month sessions on a bimonthly basis and target professionals in medical, community and educational/early intervention settings. There is no requirement for prior autism-related knowledge or training. The emphasis in learning stems from case-based discussions primarily, along with targeted autism specific didactics.

We have found good satisfaction with the program overall, as well as self-report of gains in ASD-specific knowledge and care competencies as a result of participation in ECHO. To date, CASD’s ECHO Autism program has reached 290 professionals and trainees serving autistic children and their families.

Integration of autism evaluations into primary care sites

The Community Mental Health (CMH) CORE (Collaboration, Outreach, Research, Equity) within the Children’s National Hospital Child Health Advocacy Institute (CHAI) has been working collaboratively with several other divisions, including CASD, to integrate autism evaluations into primary care sites for young children with high concern about ASD. We aim to increase capacity and access to autism services by training embedded psychologists in primary care settings in autism diagnostics.

By increasing behavioral health provider capacity and integrating in primary care, this clinic has been able to drastically decrease waits for ASD services by months to years. Families served by the program were predominately Black (81%) or Latinx (10%), and most (87%) had public insurance. Nearly one third (32%) were not primary English speakers. An ASD diagnosis was provided in 68% of all cases.

All referring PCPs surveyed indicated that they were “satisfied” or “very satisfied” with the program, that they “strongly like the integrated clinic model,” and that the program “is increasing equitable access to ASD. Currently, CHAI-supported ASD-focused embedded clinics in primary care have served 94 children and their families.

illustration of brain tumor

International initiative aims to find rare brain tumor treatments

illustration of brain tumor

Rare brain tumors are not as well characterized due to the paucity of biological and clinical data available.

Certain brain tumors can be hard to diagnose. And as such, that makes it complicated to find a treatment.

In an effort to identify and tailor treatments to patients with rare brain tumors, Children’s National is launching a rare brain tumor initiative. The hospital is collaborating with other hospitals in North America, South America and Europe to compile a registry of children diagnosed with rare brain tumors. The registry will collect biospecimens, clinical and radiological data from patients diagnosed with certain rare brain tumors.

The goal is to find a correlation between the molecular findings and the clinical findings to categorize them. This will help doctors get different prognosticators or different treatment approaches.

Here, Adriana Fonseca Sheridan, M.D., pediatric neuro-oncologist at Children’s National Hospital, tells us more about this international initiative.

What’s been the hold-up in the field?

The recent incorporation of molecular features as part of the diagnostic criteria and classification of brain tumors highlighted a high biological and molecular heterogeneity within previously histologically defined entities. The improvement in our diagnostic capabilities have been incredibly useful to stratify patients into different disease-specific risk groups and tailor therapeutic approaches accordingly in the most common brain tumors. In contrast, rare brain tumors are not as well characterized due to the paucity of biological and clinical data available. Additionally, newly molecularly defined entities lack specific clinical and therapeutic data and represent a major challenge to patients and doctors alike.

How does this work move the field forward?

The overarching objective of the international rare brain tumor registry is to deepen our understanding of the biological underpinnings of rare brain tumors. The registry also seeks to create infrastructure that allows for development of rational and personalized treatment strategies for children with rare entities.

What are you hoping to discover?

We hope to characterize the clinicopathological features and identify risk factors for survival and optimal therapeutic approaches of:

  • CNS sarcomas
  • BCOR-ITD tumors
  • Astroblastoma/MN1 altered tumors
  • Histologically ambiguous/unclassifiable brain tumors

How unique is this work?

Children’s National will spearhead the development of this initiative and lead an effort to prospectively collect biological specimens, radiological and clinical data that allow us to better understand the biologic mechanisms and therapeutic susceptibilities of these rare diseases.

We know that the best way to lead the advancement of the field in rare diseases is through collaboration. Therefore, we will synchronize efforts and collaborate with our European colleagues. They will be running a similar initiative. Our goal is to generate meaningful and robust data that will allow us to better understand how to successfully treat patients with these rare brain tumors across the globe.

mitochondria

Grant funds study of two maternally inherited mitochondrial diseases

mitochondria

The National Institutes of Health awarded George Washington University and Children’s National Hospital a grant to study two maternally inherited mitochondrial diseases.

The National Institutes of Health awarded George Washington University and Children’s National Hospital a grant to study two maternally inherited mitochondrial diseases. Andrea Gropman, M.D., division chief of Neurodevelopmental Pediatrics and Neurogenetics at Children’s National, along with her co-investigator, Anne Chiaramello, M.D., from the George Washington University School of Medicine, will lead the study.

The proposed studies focus on two ultra-rare maternally inherited mitochondrial diseases:

  • Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes (MELAS); and
  • Leber’s Hereditary Optic Neuropathy-Plus (LHON-Plus).

Both diseases are among those studied by the Rare Diseases Clinical Research Network.

“We are really pleased to be able to change the landscape for MELAS and LHON, two mitochondrial disorders with relentless progression and no treatment,” Dr. Gropman said. “This grant represents the fruition of an eight-year collaboration with my colleague Dr. Chiaramello and we are fortunate to be able to deliver this at Children’s National and serve our patients and community.”

Because patients currently do not have access to effective therapeutic intervention, this results in significant disability, morbidity and premature death. The UG3 phase of the study will focus on translational MELAS and LHON-Plus studies and submission of an IND protocol to the Food and Drug Administration. The UH3 phase will focus on a basket clinical trial with MELAS and LHON-Plus to:

  • Provide proof-of-concept that the basket design can be applied to divergent ultra-rare diseases.
  • Advance the dataset for safety and pharmacokinetics/pharmacodynamics of our lead compound for a larger number of patients than in a conventional clinical trial setting.
  • Gather outcomes and practical information for optimizing the design of future basket clinical trial.

“Dr. Gropman is dedicated to giving children with MELAS the very best care,” said Elizabeth Wells, M.D., vice president of Neuroscience and Behavioral Medicine Center at Children’s National. “This new research funding is exciting and means more patients can benefit from the expertise she has developed at Children’s National.”

brain network illustration

Changing the surgical evaluation of epilepsy

brain network illustrationThe choice between stereoelectroencephalography (SEEG) and subdural evaluation is not mutually exclusive, according to a new opinion piece published in JAMA Neurology.

In their article, Chima Oluigbo, M.D., pediatric epilepsy neurosurgeon, William D. Gaillard, M.D., division chief of Epilepsy and Neurophysiology and Neurology, both at Children’s National Hospital, and Mohamad Z. Koubeissi, M.D., M.A., from The George Washington University Hospital, discuss how the practicing epileptologist requires a profound understanding of the roles of different technologies. It also looks at how to integrate both traditional and emerging paradigms to optimize seizure control. This issue is particularly relevant to choosing the best method of invasive intracranial electroencephalography monitoring in individual cases.

Noting that despite the dramatic increase in SEEG use in recent years, the authors talk about how many patients still benefit from invasive monitoring using subdural grids. Therefore, it is important to define the considerations that should guide decision-making on the choice of SEEG versus subdural monitoring in each patient. The authors expand on their statement explaining that it is critical to define the roles of SEEG vs subdural grid investigation in each patient as subdural grid evaluations are still indicated in specific circumstances.

Additionally combined hybrid deployment of both techniques may be indicated in specific situations. Accommodation should be made to allow customization of the technique chosen to available technical expertise and equipment as well as patient preference.

2021 neurology infographic

2021 at a glance: Neurology and Neurosurgery at Children’s National

2021 neurology infographic

MRI Room

Children’s National uses HIFU to perform first ever non-invasive brain tumor surgery

MRI Room

Children’s National Hospital successfully performed the first-ever high-intensity focused ultrasound (HIFU) surgery on a pediatric patient with neurofibromatosis (NF). This is the youngest patient to undergo HIFU treatment in the world. Image provided by Insightec.

Children’s National Hospital successfully performed the first-ever high-intensity focused ultrasound (HIFU) surgery on a pediatric patient with neurofibromatosis (NF). This is the youngest patient to undergo HIFU treatment in the world. The advancement of children’s medical devices in the U.S. continues to significantly lag behind adult devices. This is why this milestone marks a significant advance in making pediatric surgery more precise and less invasive.

The hospital is offering this treatment to patients under an ongoing research clinical trial. Children’s National is one of the first pediatric hospitals in the nation to use HIFU for neuro-oncology patients. It’s also the first hospital in the world to use it to treat a pediatric patient with NF. NF is a condition that occurs in approximately 1 in 3,500 births and causes tumors to form in the brain, spinal cord and nerves.

“Using HIFU to treat our pediatric patients is a quantum leap towards non-invasive surgery for kids,” said Robert Keating, M.D., division chief of Neurosurgery and co-director of the HIFU program at Children’s National. “It’s exciting because the future is now here and it’s significantly better for our kids, in terms of non-invasive surgery with lower risk of complications and no exposure to radiation.”

Focused ultrasound (FUS) is a non-invasive therapeutic technology with the potential to transform the treatment of many medical disorders by using ultrasonic thermal energy to specifically target tissue deep in the body. The technology can treat without incisions or the need of radiation.

FUS, which has been used for adult clinical trials for many decades, can be delivered through high- or low-intensity focused ultrasound (LIFU). HIFU uses non-invasive therapy that uses focused ultrasound waves to thermally ablate a focal area of tissue. Children’s National will now use HIFU to treat low-grade type tumors located in difficult locations of the brain, such as hypothalamic hamartomas and pilocytic astrocytoma, as well as for movement disorders and epilepsy.

An alternative approach, LIFU uses lower levels of energy to disrupt the blood-brain barrier. Unlike medications, which often have difficulty crossing the blood-brain barrier, LIFU can transiently open the blood-brain barrier to chemotherapy. This may allow more effective treatment of tumors and offer opportunities to treat, for the first time, the entire extent of a malignant brain tumor.

“Having focused ultrasound technology as a tool and conducting clinical trials will allow our neurologists and oncologists to offer a non-invasive treatment option to many patients who suffer from neurological conditions,” said Hasan Syed, M.D., co-director of the HIFU center at Children’s National. “The milestone of performing this first HIFU procedure will lead the way to better understanding of the effect of this technology and provide patients with more options.”

At Children’s National, the HIFU program is being led by Dr. Keating and a multidisciplinary team, including clinicians and investigators from the Sheik Zayed Institute for Pediatric Innovationradiologyoncologysurgery and orthopedics. In an effort to collaborate with the region’s adult hospitals, Children’s National will also treat adult patients on a selective basis who have movement disorders such as essential tremor and Parkinson’s. There is a scarcity of similar resources in the metro region. Many adult patients face one-year wait periods for treatment of their movement disorders, requiring many to travel out of state for treatment.

The LIFU program is scheduled to be operational in 2022. It will likely be the first in the U.S. to treat high-grade pediatric brain tumors with disruption of the blood-brain barrier and provide more effective routes for chemotherapy as well as potential immunotherapy and molecular approaches.

“The use of LIFU with microbubbles to open up the blood-brain barrier is an exciting, potentially game-changing approach for children with these tumors,” said Roger Packer, M.D., senior vice president of the Center for Neurosciences and Behavioral Medicine at Children’s National. “It should safely allow the blood-brain barrier to open and allow delivery of potentially life-saving personalized therapy to the tumor and spare the rest of the brain. It is the most exciting, new development in brain tumor therapy for these malignant midline tumors in the past 50 years.”

Children’s National continues to be a leader in pediatric HIFU use. In 2015, Children’s National doctors became the first in the U.S. to use MR-HIFU to treat pediatric osteoid osteoma – a benign, but painful bone tumor. Successful clinical trial results led to FDA approval in early 2021 for the use of the technology for this treatment. In 2020, the Focused Ultrasound Foundation also designated Children’s National as the first global pediatric Center of Excellence for using this technology to help patients with specific types of childhood tumors.

boy with headache

Kids’ headaches can be disruptive. We need solutions.

Experts leading the Headache Program at Children’s National Hospital recognize how common these disorders are. They also know how disruptive they can be in the day-to-day of children.

Marc DiSabella, D.O., is the director of the program. He is currently leading five pediatric headache trials. In this Q&A, he tells us about the ongoing trials, offering insight into innovative solutions and how he’s carving a new path to improve the quality of life of his patients.

Q: How has your team advised other neurologists on innovative care for patients with headaches that have been refractory to medicines?

A: We receive referrals from outside institutions when they need additional input for diagnostic and management options. We receive patient consult requests from around the country – and sometimes out of the country – to help improve symptoms. In most instances, these headaches tend to be difficult to control and do not respond to available medications. We really try to take a holistic approach to their care, and use treatments in parallel. For example, diagnostic, lifestyle techniques, medications, pain focused cognitive behavioral therapy and physical therapy. We also use complementary medicine as needed, such as acupuncture, injections and infusions.

Q: It is unusual for neurology divisions to run multiple pediatric trials focused on headaches. You are currently leading five that are open. How does this work move the field forward?

A: The medications we offer through our trials allow us to offer treatments that would otherwise not be available to pediatric patients. We do this in hopes of providing them relief while advancing the field. We are hopeful that these new therapies are as effective in pediatrics as they have shown to be in adults. But it is necessary to complete randomized clinical trials to prove this is the case. Historically, pediatric patients in clinical trials investigating painful conditions like migraines have had a disproportionately high placebo response rate. This means even the patients receiving a benign placebo have a high chance of symptom improvement. The newer medications show much better tolerability to the drugs used historically.

Q: What excites you about this work?

A: Pediatric pain disorders are unbelievably gratifying to treat because we take a mysterious disorder that waxes and wanes with no clear reason and give patients back control of their lives. It is extremely frustrating for a patient and their family to know that their day-to-day life can be abruptly derailed by a pain crisis. We work to provide them with several tools they can use daily to take back their lives.

Q: How is this work unique?

A: Our program was created organically over the years through our experiences with our patients. First, we noticed the disruption to patients’ personal and school performance from having untreated pain and recognized the need for pain psychology. Then, we expanded to have physical therapy to recondition patients and perform desensitization. Finally, we recognized our patients need additional medication options not offered through the standard of care. So, we expanded to open our various clinical trials, including those with pharma and internal protocols. As a result, we incorporated the use of Botox injections, for example, and soon will use a novel remote electro-neuromodulatory device.

girl with down syndrome

Study finds delayed oligodendrocyte progenitor maturation in Down syndrome

girl with down syndrome

People with Down syndrome (DS) can have moderate to severe intellectual disability, which is thought to be associated with changes in early brain development.

People with Down syndrome (DS) can have moderate to severe intellectual disability, which is thought to be associated with changes in early brain development. Children’s National Hospital experts discovered delayed maturation in oligodendrocyte progenitors in DS. Oligodendrocytes produce the white matter which insulates neural pathways and ensures speedy electrical communication in the brain. The researchers identified these delays by measuring gene expression at key steps in cell development, according to a new study published in Frontiers in Cellular Neuroscience.

The findings further suggest that brain and spinal cord oligodendrocytes differ in their developmental trajectories and that “brain-like” oligodendrocyte progenitors were most different from control cells, indicating that oligodendrocytes in the brains of people with DS are not equally affected by the trisomy 21.

“This is one of the critical steps towards identifying the key stages and molecular players in the DS white matter deficits,” said Tarik Haydar, Ph.D., director of the Center for Neuroscience Research. “With this knowledge, and with further work in this direction, we envision future therapies that may improve nerve cell communication in the brains of people with Down syndrome.”

The hold-up in the field

The mechanisms that lead to the reduction of white matter in the brains of people with DS are unknown. To better understand early neural precursors, they used isogenic pluripotent stem cell lines derived from two individuals with Down syndrome to study the brain development and spinal cord oligodendrocytes.

“I was excited that we discovered another example of how important it is not to generalize when studying DS brain development,” said Haydar. “This is one of several papers, from our group and others, that demonstrate how important it is to be very specific about the brain area and the developmental stage when investigating the causes of DS brain dysfunction.”

What’s next

Dysmaturation of oligodendrocyte cells are a relatively new discovery by the Haydar Lab, one of the preeminent labs in DS research. These results isolate specific steps that are affected in human cells with trisomy 21. They are using these results to develop a drug screening platform that may prevent altered generation of oligodendrocytes in the future.

You can read the full study “Sonic Hedgehog Pathway Modulation Normalizes Expression of Olig2 in Rostrally Patterned NPCs With Trisomy 21” in Frontiers in Cellular Neuroscience.

DNA moleucle

Multidisciplinary team seeks to reverse epigenetic changes associated with fetal alcohol syndrome disorder

DNA moleucle

The team hopes to optimize and develop treatments that can reverse epigenetic changes in clinical trials, paving the way to make significant progress in the field — something that is lacking to date.

A clinical team joined forces with a research team at Children’s National Hospital to help advance treatments that can improve a child’s development caused by fetal alcohol syndrome disorder (FASDs), which is a group of conditions that can occur in a person who was exposed to alcohol before birth. This boost in collaboration between the bench and clinical hopes to optimize and develop treatments that can reverse epigenetic changes in clinical trials, paving the way to make significant progress in the field — something that is lacking to date.

So far, Children’s National experts have published various pre-clinical studies that identified epigenetic changes caused by alcohol exposure during pregnancy. These changes observed in the pre-clinical models created neuropsychiatric problems like patients with fetal alcohol syndrome disorder. Now, they want to bring such potential treatments effective in pre-clinical models to the bedside.

“As a first step, we are going to test whether the epigenetic changes that were observed in pre-clinical models of FASD are also true in human patients,” said Kazue Hashimoto-Torii, Ph.D., principal investigator of the Center for Neuroscience Research at Children’s National. “We hope a small amount of blood donated by patients with FASD reveal the changes. Meanwhile, my group has also been optimizing drug candidates that reverse the epigenetic changes toward clinical trials.”

Advances in genetics and genomics have led to discoveries about the timing of exposure and developmental outcomes and genetic and epigenetic signatures that may be protective or harmful in terms of how in utero alcohol exposure affects developmental outcomes.

The hold-up in the field

While the exact number of people with FASDs is unknown, the National Institutes of Health estimates that 1% to 5% of the population have FASDs. FASDs has a spectrum of diagnoses that represent a broad range of effects that can be manifested in an individual whose mother drank alcohol during pregnancy. These conditions can affect everyone in different ways and range from mild to severe. Individuals with mild conditions may go undiagnosed. The more affected individuals have comorbid attention-deficit/hyperactivity disorder (ADHD) and behavioral problems that become the focus of clinical encounters. The individual’s health care provider may not recognize the core features as part of FASD.

“Because there is a stigma associated with drinking while pregnant, many providers fail to get this history, and women may be reluctant to offer this information,” said Andrea Gropman, M.D., division chief of Neurodevelopmental Pediatrics and Neurogenetics at Children’s National. “There are subtle and more obvious facial dysmorphology that may help with suspicion or identification, but many individuals do not have these findings.”

The core features may be nonspecific, such as intellectual disabilities and problems with behavior and learning, difficulties with math, memory, attention, judgment and poor impulse control, which are frequent findings in ADHD, autism, learning disorders and other conditions.

“Unless history is taken and FASD is in the differential diagnosis, the diagnosis may not be made,” said Dr. Gropman. “Individuals with FASD may feel stigmatized and opt not to participate in clinical trials.”

As mentioned by Dr. Gropman, stigma can make a patient family be reluctant to seek treatment, and thus the development of treatment for FASD cannot make significant progress to date, Hashimoto-Torii added.

Children’s National Hospital leads the way in an IRB approved study

Researchers at Children’s National have identified a potential drug candidate that reverse the epigenetic changes and may lead to clinical trials. The team is seeking people to participate in an IRB approved study. The study will involve cognitive testing, filling out surveys about current functioning and cheek swab and blood sample to determine if these changes are seen in patients. To participate, subjects must be

  • Children between the ages 5-12 with prenatal alcohol exposure.
  • Mother of child recruited above.

For participation, please contact Grace Johnson, research coordinator at to screen for eligibility at 202-476-6034 or gjohnson3@childrensnational.org

Meet the multidisciplinary team with different yet complementary skills in different fields, such as basic science, medical, social sciences, neurology and developmental disabilities, and development, who are working tirelessly to address the complex health problem.

Gropman lab:

Andrea Gropman, M.D., received her medical doctorate degree from the University of Massachusetts Medical School and specializes in neurogenetics, with a focus on mitochondrial disorders and Smith Magenis syndrome. Her latest research focuses on atypical patterns of inheritance, childhood mitochondrial disorders and other inborn errors of metabolism presenting with white matter disease.

Meira Meltzer, M.A., M.S., C.G.C., genetic counselor with a demonstrated history of working in the hospital and healthcare industry. Also skilled in molecular biology, clinical research and medical education. Strong healthcare services professional with a M.S. focused on genetic counseling from Brandeis University.

Cathy Scheiner, M.D., developmental behavioral pediatrician with a special interest in attention-deficit / hyperactivity disorder (ADHD), cerebral palsy and premature infant.

Grace Johnson, research assistant.

Hashimoto-Torii Lab:

Kazue Hashimoto-Torii, Ph.D., received her postdoctoral training in the Pasko Rakic laboratory at Yale University. Her research focuses on neurobehavior problems of children that stem from their environment during development, such as prenatal exposure to alcohol, drug and high-level glucose. A few drug candidates that her lab discovered have been patented and her lab is currently working hard to bring those medicines to bedside.

Satoshi Yamashita, M.D., Ph.D., postdoctoral research fellow skilled in developmental neurobiology. He is a pediatrician with Japanese medical license and received his Ph.D. with iPS cell research for STXBP1 encephalopathy in Japan.

Chiho Yamashita, B.N., research assistant passionate about child disease research. She is a nurse with a Japanese nursing license and worked in the pediatric department in Japan.

cancer cells

Advancing immunotherapy for pediatric brain tumors

cancer cells

While immunotherapy has revolutionized cancer treatments, its efficacy remains relatively undefined in pediatric settings for brain tumors.

While immunotherapy has revolutionized cancer treatments, its efficacy remains relatively undefined in pediatric settings for brain tumors. Children’s National Hospital experts and other institutions argue in a review published in Nature Cancer that there is a need for closer collaborations between academia, industry partners, regulatory bodies and funders to progress the field.

Eugene Hwang, M.D., associate division chief of Oncology and neuro-oncologist at Children’s National, led the review that outlines immunotherapeutic hurdles and simultaneously proposes next steps for immunotherapy use in these patients. These considerations will aid pediatric oncologists make better recommendations and advances in this type of treatment.

“The promise of immunotherapy in helping to cure children with brain tumors is exciting,” Dr. Hwang said. “This type of approach has already revolutionized treatments for many different kinds of cancer, and a comprehensive review of this complicated arena, especially by leading voices in the field, can help set the stage for finally moving the needle for these patients.”

The review is especially helpful as children harbor unique elements of immunity and the brain presents distinct obstacles to immune attack that are not present in other cancers. For example, there are challenges in antigen identification, the blood-brain barrier and the tumor microenvironment. For many pediatric cancer doctors as well this novel, complex form of therapy is outside of their historical training.

To overcome these challenges, the authors encourage philanthropic organizations and patient advocacy groups to be part of the process that can help fill funding gaps in patient-focused pre-clinical and clinical research and educate patients and families.

“Multiple stakeholders around pediatric brain cancer immunotherapy must be mobilized in a concerted fashion,” Hawk et al. argue in the piece. “The need for close academic collaboration with industry partners and regulatory bodies is increasingly apparent given the unique pediatric phenotypes and complex outcomes in immunotherapeutic trials, and progress will be made at the interface of the interactions of all these key stakeholders.”

The group of internationally renowned pediatric brain tumor-focused immunotherapy experts comprehensively reviewed the advances in the major modalities of immunotherapy and the landscape of preclinical modeling for these patients to date.

Investigators at Children’s National, for example, are leading several national and international trials involving immunotherapy which have spurred international meetings with a focus in childhood brain tumor immunotherapies.

“The multiple T cell trials led by Children’s National are perfect examples of truly field-leading innovative immunotherapy, as are the other trials that are led by our own investigators,” Dr. Hwang added.

Representative OFF and DIFF spectra

GABA and glutamate in the preterm neonatal brain

Preterm and sick newborns are at high risk of brain injury that can lead to cognitive delays and behavioral disorders including autism and ADHD. Gamma-aminobutyric acid (GABA) and glutamate system disruptions may underlie these neonatal brain injuries and hence it is important to describe their normative profile in the developing neonatal brain.

In a study led by Sudeepta Basu, M.D., neonatologist at Children’s National Hospital and Assistant Professor of Pediatrics at George Washington University School of Medicine and Health Sciences, specialized GABA editing spectroscopy (MEGA-PRESS) was acquired on a 3Tesla MRI scanner. Although MEGA-PRESS has been used in older subjects, there are challenges in the newborn population that have limited investigations with only a few institutions worldwide. Under the leadership of Catherine Limperopoulos, Ph.D., in the Developing Brain Institute (DBI) at Children’s National, a team of scientists (in particular, Dr. Subechhya Pradhan) have diligently overcome the technical challenges to enable use of this cutting-edge technology for research at the institute.

With this unique capability, Dr. Basu’s team prospectively enrolled 58 healthy newborns to describe the normal GABA and glutamate concentrations in different regions of the developing brain. In a recent article published in the American Journal of Neuroradiology, Dr. Basu reports that GABA and glutamate concentrations were highest in the cerebellum, slightly lower in the basal ganglia, but significantly lower in the frontal lobe.

“Our ability to reliably describe the normal metabolic-neurotransmitter milieu of the developing newborn brain is the first step in filling a critical gap in knowledge,” says Dr. Basu. “We hope to identify early bio-markers of brain injury of cognitive delays and autism and ADHD risk which remains a major challenge until clinical symptoms manifest later in childhood.”

Under the direction of Dr. Limperopoulos, advanced multi-modal high precision MRI protocols have been developed for use in research studies at Children’s National that allows the scientists to identify subtle signs of delayed growth and development of the newborn brain. With the optimization of MEGA-PRESS for newborns, Children’s National is one of a few institutions worldwide capable of investigating the newborn brain neurotransmitters in future research studies.

Read the full article in American Journal of Neuroradiology.

Representative OFF and DIFF spectra

Representative OFF and DIFF spectra.