Neurology & Neurosurgery

Digital background depicting innovative technologies in (AI) artificial systems, neural interfaces and internet machine learning technologies

AI algorithm that detects brain abnormalities could help cure epilepsy

Digital background depicting innovative technologies in (AI) artificial systems, neural interfaces and internet machine learning technologies

A new AI algorithm can detect subtle brain abnormalities that cause epileptic seizures.

An artificial intelligence (AI) algorithm that can detect subtle brain abnormalities that cause epileptic seizures has been developed by a UCL-led team of international researchers, including Children’s National Hospital.

To do this, the team quantified features from MRI scans, such as how thick or folded the brain was at nearly 300,000 locations in each case.

They then trained the AI algorithm using examples labelled by expert radiologists as either a healthy brain or one with focal cortical dysplasia (FCD) based on their patterns and features.

The results, published in Brain, showed that in the main cohort of 538 patients, the algorithm was able to detect the FCD in 67% of cases.

“We put an emphasis on creating an AI algorithm that was interpretable and could help doctors make decisions. Showing doctors how the Multicentre Epilepsy Lesion Detection project (MELD) algorithm made its predictions was an essential part of that process,” said Mathilde Ripart, research assistant at UCL and the study’s co-first author.

Around 1% of the population have epilepsy and, of these, 20-30% do not respond to medications.

“We are excited to collaborate with MELD on ways to improve the treatment of pharmacoresistant epilepsy,” said Nathan Cohen, M.D., neurologist at Children’s National Hospital and co-author of the study. “This advanced imaging platform is open source and demonstrates the benefit of team science at the broadest scale.”

In children who have had surgery to control their epilepsy, FCD is the most common cause, and in adults it is the third most common cause.

Additionally, of patients who have epilepsy that have an abnormality in the brain that cannot be found on MRI scans, FCD is the most common cause.

You can read the full UCL press release here.

Tired student studying online on laptop at home

Headache disorders and mental health worsened during pandemic

Tired student studying online on laptop at home

Children’s headaches and mental health worsened during pandemic, new study finds.

Since the beginning of the COVID-19 pandemic, many pediatric patients who suffer from headaches have experienced more frequent headaches and worsening anxiety and mood, and a new study finds links to stress, decreased physical activity and increased screen time.

The findings, published in the Journal of Child Neurology, showed that elevated stress associated with disruptions to daily life, social distancing practices and anxiety about the threat of illness to oneself and others brought on by the pandemic impacted the quality of life for kids with headache disorders.

“These findings are really impactful to me as a physician and a parent. It is important we gain a better understanding about how stress and changes in routine affect children’s wellbeing and mood,” says lead author Marc DiSabella, D.O., director of the Headache Program at Children’s National Hospital. “Things like moving to a virtual environment may have resulted in feelings of isolation and anxiety for kids, and increased screen time may have played a role in more frequent headaches.”

Migraine and other headache disorders are exceedingly common in adolescents and children. For this study, 107 patients completed a questionnaire from summer 2020 to winter 2021 examining changes in headache characteristics and lifestyle factors since the start of the pandemic. The survey found:

  • Pre-pandemic, 60% of patients reported having headaches less than 15 days of the month. After the start of the pandemic, that number dropped to 50%.
  • Patients reporting constant daily headaches went from 22% pre-pandemic to 36% after the start of the pandemic.
  • 49% of patients reported their headaches had worsened since the onset of the pandemic.
  • 54% of patients reported that their physical activity levels decreased because of the pandemic.
  • When asked about screen use during the pandemic, 61% of patients reported using screens for more than six hours a day.

The authors of the study note that whether or not increased screen time worsens headaches has not yet been clearly established; however, patients and families routinely cite screen use as a headache trigger. Lack of physical exercise is also often cited as a migraine trigger.

“Having a headache every day, all the time, with no break in sight, is really frustrating to children and their parents,” Dr. DiSabella adds. “They just want to be a normal child, yet have no control over when the pain increases, and they suddenly are unable to do simple activities like reading a book or seeing friends, which adds to the uncertainty of their future.”

Participants also reported worsened anxiety, mood and workload. According to the authors, this is likely to affect headache patients given their elevated rates of anxiety and depression.

“We already know that patients with headache disorders have disproportionately high rates of mood complaints, including anxious and depressive symptoms,” Dr. DiSabella says. “The fact that our patients reported this worsened during quarantine is an additional stress on their already complex lives, managing pain, school and extra-curricular activities.”

While the study is limited by sample size and observational design, future population-based studies will further explain the impact of this pandemic on kids who suffer from headaches. In the interim, Dr. DiSabella recommends parents talk with their children about how the pandemic has impacted their headaches and mood. He also recommends offering children help, either at home or with a professional trained in child psychology.

William Gaillard

William D. Gaillard, M.D., named as first endowed Professor of Epilepsy and Neurophysiology

William GaillardChildren’s National Hospital named William D. Gaillard, M.D., as the hospital’s first endowed Professor of Epilepsy and Neurophysiology.

Dr. Gaillard serves as Division Chief of Child Neurology, Epilepsy and Neurophysiology, Director of the Comprehensive Pediatric Epilepsy Program and Associate Director of the Center for Neuroscience Research at Children’s National Hospital. He also is Professor of Pediatrics and Neurology at the George Washington University School of Medicine, Professor of Neurology at Georgetown University and Adjunct Professor of Hearing and Speech Sciences at the University of Maryland, College Park.

About the award

Dr. Gaillard joins a distinguished group of 41 Children’s National physicians and scientists who are endowed chairs. Professorships at Children’s National advance groundbreaking work on behalf of children and their families and foster new discoveries and innovations in pediatric medicine. These prestigious appointments carry honor and reflect the recipient’s achievements and donor’s forethought to advance and sustain knowledge.

Dr. Gaillard is an internationally recognized expert in advanced structural and functional imaging, with a focus on examining the effects of epilepsy on brain structure and function. His pioneering work with functional imaging has changed clinical practice for patients with epilepsy, impacted structural and functional imaging methods and provided fundamental insights on brain plasticity. Dr. Gaillard’s research is improving patient outcomes and the lives of children with epilepsy.

Donors Betsy Williams and Tom Moore, through their vision and generosity, will ensure that Dr. Gaillard and future holders of this professorship can launch bold, new initiatives to rapidly advance the field of pediatric epilepsy and neurophysiology, elevate our leadership and improve the lifetimes of children with epilepsy and seizure disorders.

“This Professorship is a great honor and opportunity for our team and for the future of pediatric epilepsy medicine,” says Dr. Gaillard. “Thanks to Betsy, Tom and the Hess Foundation’s generosity, we can continue to invest in people and programs that show promise. We can have the flexibility to respond to the needs of our current patient families and prepare for those that will need us tomorrow. We are forever grateful.”

About the donors

Betsy and Tom are parents, members of the Epilepsy Council at Children’s National and long-time supporters. To acknowledge their gratitude and respect for Dr. Gaillard and the comprehensive team he’s built, the Professorship will be named for Dr. Gaillard in the future.

boy getting vaccinated

Adolescents with ADHD more hesitant to get COVID-19 vaccine

boy getting vaccinatedAdolescents with attention-deficit/hyperactivity disorder (ADHD) report greater hesitancy and less confidence in COVID-19 vaccine safety compared to adolescents without ADHD, a new study finds.

For all adolescents in the study, those who identified as Black or Latino — and came from families with lower income levels — were more likely to be vaccine hesitant and report lower confidence in the safety of COVID-19 vaccines.

Whereas greater COVID-19 concerns, compliance to social distancing guidelines, media use and perceived negative impact of COVID-19 on relationships was associated with greater vaccination willingness.

The study, led by Melissa Dvorsky, Ph.D., director of ADHD & Learning Differences Program at Children’s National Hospital, also highlighted that:

  • Adolescents with ADHD who engage in large gatherings indoors are at greater risk for vaccine hesitancy.
  • Interventions should target social-cognitive processes for adolescent vaccination.

“Adolescents with ADHD being more vaccine hesitant is perhaps in part due to core risk mechanisms associated with ADHD, likely impacting planning, motivation and execution of vaccination, adolescents’ risk appraisal, and perceived susceptibility to COVID-19,” Dr. Dvorsky said. “Our study also found key social mechanisms predicted increased vaccine acceptance and uptake, and these factors should be leveraged in ongoing initiatives addressing vaccine uptake among teens.”

Findings have important implications for health and mental health providers and educational strategies aimed at promoting COVID-19 vaccinations in adolescents.

Earlier this month, Mayor Muriel Bowser and DC Health announced amplified efforts to encourage families to vaccinate youth ahead of the upcoming 2022-2023 school year, sending a message that students must get caught up on vaccinations over the summer. In addition to expanding access to vaccination services, a concerted effort, Dvorsky added, is needed to increase trust, confidence, motivation and social relevance among adolescents. This is especially true for those with ADHD and from lower socio-economic backgrounds.

“As health and mental health care providers, we are uniquely positioned to offer effective communication using strong, presumptive language with all adolescents in our community to address vaccine hesitancy. Adolescents with ADHD, in particular, can benefit from frequent behavioral ‘nudges’ (such as prompts or reminders, automatic appointments) and social/motivational strategies (such as social network interventions, peer-delivered approaches, motivational interviewing) to increase vaccine uptake.”

It’s important to note that research addressing adolescent COVID-19 vaccination willingness and readiness remains scarce.

The study included 196 adolescents (87 male) ages 16-18 from two sites in the Southeastern and Midwestern United States. Participants were high school students in 11th and 12th grade during the 2020-2021 school year. Participants came from a range of socioeconomic backgrounds, with 21% of families falling below the 2019 U.S. median household income ($68,703). Approximately half of the participants were comprehensively diagnosed with ADHD prior to COVID-19.

US News Badges

Children’s National named to U.S. News & World Report’s Best Children’s Hospitals Honor Roll

US News BadgesChildren’s National Hospital in Washington, D.C., was ranked No. 5 nationally in the U.S. News & World Report 2022-23 Best Children’s Hospitals annual rankings. This marks the sixth straight year Children’s National has made the list, which ranks the top 10 children’s hospitals nationwide. In addition, its neonatology program, which provides newborn intensive care, ranked No.1 among all children’s hospitals for the sixth year in a row.

For the twelfth straight year, Children’s National also ranked in all 10 specialty services, with seven specialties ranked in the top 10.

“In any year, it would take an incredible team to earn a number 5 in the nation ranking. This year, our team performed at the very highest levels, all while facing incredible challenges, including the ongoing pandemic, national workforce shortages and enormous stress,” said Kurt Newman, M.D., president and chief executive officer of Children’s National. “I could not be prouder of every member of our organization who maintained a commitment to our mission. Through their resilience, Children’s National continued to provide outstanding care families.”

“Choosing the right hospital for a sick child is a critical decision for many parents,” said Ben Harder, chief of health analysis and managing editor at U.S. News. “The Best Children’s Hospitals rankings spotlight hospitals that excel in specialized care.”

The annual rankings are the most comprehensive source of quality-related information on U.S. pediatric hospitals and recognizes the nation’s top 50 pediatric hospitals based on a scoring system developed by U.S. News.

The bulk of the score for each specialty service is based on quality and outcomes data. The process includes a survey of relevant specialists across the country, who are asked to list hospitals they believe provide the best care for patients with the most complex conditions.

The seven Children’s National specialty services that U.S. News ranked in the top 10 nationally are:

The other three specialties ranked among the top 50 were cardiology and heart surgerygastroenterology and gastro-intestinal surgery, and urology.

illustration of the brain

LIFU successfully delivers targeted therapies past the blood-brain barrier

illustration of the brain

LIFU offers doctors the first opportunity to open the blood-brain barrier and treat the entire malignant brain tumor.

Children’s National Hospital will leverage low-intensity focused ultrasound (LIFU) to deliver therapy directly to a child’s high-grade glioma. The approach offers doctors the first opportunity to open the blood-brain barrier and treat the entire malignant brain tumor.

Children’s National will be the first hospital in the U.S. to treat high-grade pediatric brain tumors with LIFU to disrupt the blood-brain barrier. Crossing it has been a major hurdle for effective therapy. The barrier, a network of blood vessels and tissue, prevents harmful substances from reaching the brain but also stops molecular targeted therapy and immunotherapy from getting into the tumor site and staying there.

“LIFU gives us a way to potentially transiently open up the barrier, so we can deliver novel therapy directly to the tumor and improve the likelihood of survival,” said Roger Packer, M.D., senior vice president of the Center for Neurosciences and Behavioral Medicine at Children’s National. “It is the greatest breakthrough we’ve potentially had in the past 50 years or more for the management of these tumors. We made great strides in our understanding of molecular genetics and the molecular drivers of tumors, but we have not yet translated that knowledge into better therapies; this may be our most effective mechanism to overcome the barrier.”

In 2020, Children’s National was recognized as the first worldwide Center of Excellence by the Focused Ultrasound Foundation.

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.

How it works

Doctors at Children’s National will be using LIFU in two different types of procedures:

  • 5-ALA: Doctors will give the patient 5-aminolevulinic acid (5-ALA) with the LIFU treatment. 5-ALA enters rapidly dividing cells and is activated by the ultrasound to a state where it kills the dividing cells of the tumor. The surrounding normal brain cells around the tumor are not dividing, so they do not take up the 5-ALA and are left unharmed after ultrasound therapy.
  • Microbubbles: While receiving different doses of LIFU over a one- to two-hour period, the patient is given “microbubbles,” which are widely used in medical imaging and as carriers for targeted drug delivery. These microbubbles bounce around against the walls like seltzer, opening the blood vessels and transiently opening that space.

Both studies are the first in the world for pediatric gliomas of the brain stem, allowing experts to treat patients 4-6 weeks after radiotherapy. The patient then receives medication orally or intravenously as it passes through the bloodstream. It does not go at high levels anywhere within the brain except where the blood-brain-barrier was opened, allowing oral medication or immune therapies to rush into the tumor.

The launch of this program comes a few months after the hospital successfully performed the first-ever high-intensity focused ultrasound surgery on a pediatric patient with neurofibromatosis.

Watch this video to learn more.

Dr. Limperopoulos talks to a mom

Pandemic-related stressors in pregnant women affect fetal brain development

Dr. Limperopoulos talks to a mom

Dr. Catherine Limperopoulos walking with a mom.

Prolonged levels of stress and depression during the COVID-19 pandemic contributed to altering key features of fetal brain development — even if the mother was not infected by the virus. This is what a study published in Communications Medicine suggests after following more than 200 pregnant women. The study, led by Children’s National Hospital experts, emphasized the need for more scientific inquiry to shed light on the long-term neurodevelopmental consequences of their findings and COVID-19 exposures on fetal brain development.

“Understanding how contemporary stressors may influence fetal brain development during pregnancy has major implications for basic science and informing public policy initiatives,” said Catherine Limperopoulos, Ph.D., chief and director of the Developing Brain Institute at Children’s National and senior author of the study. “With this work, we are able to show there’s a problem, it’s happening prenatally, and we can use this model to start exploring how we can reduce stress in moms and support unborn babies.”

To better understand the effects of environmental exposures on the fetus during pregnancy, further confirmation of the team’s latest findings is needed by ruling out other possibilities, such as maternal nutrition, financial security and genetic factors.

The psychosocial impact of COVID-19 on fetal brain development remains vastly understudied. The neurologic underpinnings of fetal development that turn into psycho-behavioral disorders later in life, including bipolar disorder, mood disorder or anxiety disorder, remain complex and difficult to explain.

Among the 202 participants from the Washington D.C. metropolitan area, 137 were part of the pre-pandemic cohort and 65 were part of the pandemic cohort.

Through advanced MRI imaging techniques and reconstruction of high-resolution 3D brain models, the researchers found a reduction of fetal white matter, hippocampal and cerebellar volumes and delayed brain gyrification in COVID-19 pandemic-era pregnancies. Validated maternal stress, anxiety and depression scales were also used to compare the scores between the two cohorts.

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 in high socioeconomic status, alters the structure and biochemistry of the developing fetal brain, emphasizing the importance of mental health support for pregnant women.

“We’re looking at modifiable conditions,” said Limperopoulos. “What’s clear is the next frontier is intervening early to see how we can prevent or reduce stress in the mom’s current setting.”

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.