Neurology and Neurosurgery

Neonatal baby

Thrasher to fund Children’s project

Neonatal baby

The Thrasher Research Fund will fund a Children’s National Health System project, “Defining a new parameter for post-hemorrhagic ventricular dilation in premature infants,” as part of its Early Career Award Program, an initiative designed to support the successful training and mentoring of the next generation of pediatric researchers.

The proposal was submitted by Rawad Obeid, M.D., a neonatal neurology clinical research fellow at Children’s National who will serve as the project’s principal investigator. The competition for one-year Thrasher Research Fund awards is highly competitive with just two dozen granted across the nation. Research clinicians at Children’s National received two awards this funding cycle, with another awarded to support a neurologic outcomes study about Zika-affected pregnancies led by Fetal-Neonatal Neurologist Sarah B. Mulkey, M.D., Ph.D.

“Preterm infants born earlier than the 29th gestational week are at high risk for developing cerebral palsy and other brain injuries,” Dr. Obeid says. “Infants with intraventricular hemorrhage (IVH) followed by hydrocephalus (post-hemorrhagic hydrocephalus) face the highest risks of such brain injuries.”

Dr. Obeid hypothesizes that measuring distinct frontal and temporal horn ratio trajectories in extremely premature infants with and without IVH will help to definitively characterize post-hemorrhagic ventricular dilation (PHVD). Right now, experts disagree about the degree of PHVD that should trigger treatment to avoid life-long impairment.

He will be mentored by Anna A. Penn, M.D., Ph.D., Director, Translational Research for Hospital-Based Services & Board of Visitors Cerebral Palsy Prevention Program; Taeun Chang, M.D., Director of the Neonatal Neurology Program within the Division of Neurophysiology, Epilepsy & Critical Care; and Dorothy Bulas, M.D., F.A.C.R., F.A.I.U.M., F.S.R.U., Vice Chief of Academic Affairs.

In the award nomination letter, Dr. Penn noted that in “clinical settings and in the laboratory, I have supervised many trainees, but a trainee like Dr. Obeid is rare. He has pursued his research interests with great commitment. Before coming to Children’s National, he already had multiple job offers, but chose further training to enhance his research skills. While I have worked with many accomplished students, residents and fellows, Dr. Obeid stands out not only for his strong clinical skills, but also for his eagerness to learn and his dedication to both his patients and his research.”

 

pregnancy

New Children’s National and Inova collaboration

pregnancy

A new research collaboration will streamline completion of retrospective and prospective research studies, shedding light on myriad conditions that complicate pregnancies.

A new three-year, multi-million dollar research and education collaboration in maternal, fetal and neonatal medicine aims to improve the health of pregnant women and their children. The partnership between Children’s National Health System and Inova will yield a major, nationally competitive research and academic program in these areas that will leverage the strengths of both health care facilities and enhance the quality of care available for these vulnerable populations.

The collaboration will streamline completion of retrospective and prospective research studies, shedding light on a number of conditions that complicate pregnancies. It is one of several alliances between the two institutions aimed at improving the health and well-being of children in Northern Virginia and throughout the region.

“The Washington/Northern Virginia region has long had the capability to support a major, nationally competitive research and academic program in maternal and fetal medicine,” says Adre du Plessis, M.B.Ch.B., Director of the Fetal Medicine Institute at Children’s National and a co-Principal Investigator for this partnership. “The Children’s National/Inova maternal-fetal-neonatal research education program will fill this critical void.

“This new partnership will help to establish a closer joint education program between the two centers, working with the OB/Gyn residents at Inova and ensuring their involvement in Children’s National educational programs and weekly fetal case review meetings,” Dr. du Plessis adds.

Larry Maxwell, M.D., Chairman of Obstetrics and Gynecology at Inova Fairfax Medical Campus and a co-Principal Investigator for the collaboration, further emphasizes that “Inova’s experience in caring for women and children — combined with genomics- and proteomics-based research — will synergize with Children National’s leadership in neonatal pediatrics, placental biology and fetal magnetic resonance imaging (MRI) to create an unprecedented research consortium. This will set the stage for developing clinically actionable interventions for mothers and babies in metropolitan District of Columbia.”

Children’s National, ranked No. 3 nationally in neonatology, has expertise in pediatric neurology, fetal and neonatal neurology, fetal and pediatric cardiology, infectious diseases, genetics, neurodevelopment and dozens of additional pediatric medical subspecialties. Its clinicians are national leaders in next-generation imaging techniques, such as MRI. Eighteen specialties and 50 consultants evaluate more than 700 cases per year through its Fetal Medicine Institute. In mid-2016, Children’s National created a Congenital Zika Virus Program to serve as a dedicated resource for referring clinicians and pregnant women. The hospital performs deliveries in very high-risk, complex situations, but does not offer a routine labor and delivery program.

Inova Fairfax Medical Campus is home to both Inova Women’s Hospital and Inova Children’s Hospital. Inova Women’s Hospital is the region’s most comprehensive and highest-volume women’s hospital — delivering more than 10,000 babies in 2016. Inova Children’s Hospital serves as Northern Virginia’s children’s hospital —providing expert care in pediatric and fetal cardiology, cardiac surgery, genetics, complex general surgery, neurology, neurosurgery and other medical and surgical specialties. Its 108-bed Level IV neonatal intensive care unit is one of the largest and most comprehensive in the nation. Inova’s Translational Medicine Institute includes a genomics lab, as well as a research Institute focused on studies designed to build genetic models that help answer questions about individual disease. Each of these specialties is integrated into the Inova Fetal Care Center — which serves as a connection point between Inova Women’s and Children’s Hospitals. The Inova Fetal Care Center provides complex care coordination for women expecting infants with congenital anomalies or with other fetal concerns. Because Inova Women’s Hospital and Inova Children’s Hospital are co-located, women are able to deliver their babies in the same building where their children will receive care.

The research collaboration will support research assistants; tissue technicians; a placental biologist; as well as support for biomedical engineering, fetal-neonatal imaging, telemedicine, regulatory affairs and database management. The joint research projects that will take place under its auspices include:

  • Fetal growth restriction (FGR), which occurs when the failing placenta cannot support the developing fetus adequately. FGR is a major cause of stillbirth and death, and newborns who survive face numerous risks for multiple types of ailments throughout their lives. A planned study will use quantitative MRI to identify signs of abnormal brain development in pregnancies complicated by FGR.
  • Placental abnormalities, including placenta accreta. A planned study will combine quantitative MRI studies on the placenta during the third trimester and other points in time with formal histopathology to identify MRI signals of placenta health and disease.
  • Microcephaly, a condition that is characterized by babies having a much smaller head size than expected due to such factors as interrupted brain development or brain damage during pregnancy. While the global Zika virus epidemic has heightened awareness of severe microcephaly cases, dozens of pregnancies in the region in recent years have been complicated by the birth defect for reasons other than Zika infection. A planned study will examine the interplay between MRI within the womb and head circumference and weight at birth to examine whether brain volume at birth correlates with the baby’s developmental outcomes.

Using fMRI for assessment prior to neurosurgery

For more than 20 years, Children’s National has explored the use of non-invasive fMRI as an alternative to more invasive testing to assess children’s language and memory.

A new Practice Guideline Summary published in Neurology, the journal of the American Academy of Neurology, contains the first complete, objective assessment of available data on the efficacy of functional magnetic resonance imaging (fMRI) to assess baseline language and memory, brain hemisphere dominance and to predict postsurgical impacts prior to surgery in patients with epilepsy.

According to contributing author William D. Gaillard, M.D., chief of Child Neurology, Epilepsy and Neurophysiology, and director of the Comprehensive Pediatric Epilepsy Program at Children’s National Health System, the report outlines several cases in which fMRI presents an effective alternative to the current standard of care, intracarotid amobarbital procedure (IAP). In IAP, medication is injected through the carotid artery to isolate one hemisphere of the brain at a time, followed by the patient performing memory or language tasks. The approach requires catheterization via a major artery. While minimally invasive, the procedure still carries the standard risks of vascular catheter procedures and requires recovery time.

“This publication took six years to complete,” Dr. Gaillard notes, “but we are happy to finally have the practice parameters that will make the case for the use of fMRI in an evidence-based way.”

Though the Practice Guidelines focus on adults, the evidence assessment included all available pediatric data as well, says Dr. Gaillard. A great deal of that data were contributed by Children’s National faculty, who lead the nation in clinical applications of fMRI. More than 20 years ago, Dr. Gaillard and his team began studying fMRI as a viable alternative to IAP to collect accurate language assessments in children, particularly those with epilepsy. Today, Children’s National is at the forefront of clinical application of fMRI, having performed about 1,000 pediatric assessments in the last two decades — more than nearly every other institution.

An 11-member panel of international experts conducted the analyses for the Practice Guidelines. Overall, the report indicates:

  • fMRI is a viable option for measuring lateralized language functions in place of IAP in medial temporal lobe epilepsy, temporal epilepsy in general or extratemporal epilepsy.
  • Evidence was insufficient to recommend fMRI over IAP for patients with temporal neocortical epilepsy or temporal tumors.
  • Pre-surgical fMRI can serve as an adequate alternative to IAP memory testing for predicting verbal memory outcome.

In closing, the authors also explicitly recommend that clinicians carefully advise every patient of the risks and benefits of both fMRI and IAP before recommending either approach.

Related resources: Use of fMRI in the presurgical evaluation of patients with epilepsy

Vittorio Gallo

Vittorio Gallo named Chief Research Officer

Vittorio Gallo

As chief research officer, Vittorio Gallo, Ph.D., will be instrumental in developing and realizing Children’s Research Institute’s long-term strategic vision.

Children’s National Health System has appointed the longtime director of its Center for Neuroscience Research, Vittorio Gallo, Ph.D., as Chief Research Officer. Gallo’s appointment comes at a pivotal time for the institution’s research strategic plan, as significant growth and expansion will occur in the next few years. Gallo is a neuroscientist who studies white matter disorders, with particular focus on white matter growth and repair. He is also the Wolf-Pack Chair in Neuroscience at Children’s Research Institute, the academic arm of Children’s National.

As Chief Research Officer, Gallo will be instrumental in developing and realizing Children’s Research Institute’s long-term strategic vision, which includes building out the nearly 12-acre property once occupied by Walter Reed National Military Medical Center to serve as a regional innovation hub and to support Children’s scientists conducting world-class pediatric research in neuroscience, genetics, clinical and translational science, cancer and immunology. He succeeds Mendel Tuchman, M.D., who has had a long and distinguished career as Children’s Chief Research Officer for the past 12 years and who will remain for one year in an emeritus role, continuing federally funded research projects and mentoring junior researchers.

“I am tremendously pleased that Vittorio has agreed to become Chief Research Officer as of July 1, 2017, at such a pivotal time in Children’s history,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “Since Mendel announced plans to retire last summer, I spent a great deal of time talking to Children’s Research Institute investigators and leaders and also asking colleagues around the nation about the type of person and unique skill sets needed to serve as Mendel’s successor. With each conversation, it became increasingly clear that the most outstanding candidate for the Chief Research Officer position already works within Children’s walls,” Dr. Batshaw adds.

“I am deeply honored by being selected as Children’s next Chief Research Officer and am excited about being able to play a leadership role in defining the major areas of research that will be based at the Walter Reed space. The project represents an incredible opportunity to maintain the core nucleus of our research strengths – genetics, immunology, neurodevelopmental disorders and disabilities – and to expand into new, exciting areas of research. What’s more, we have an unprecedented opportunity to form new partnerships with peers in academia and private industry, and forge new community partnerships,” Gallo says. “I am already referring to this as Walter Reed ‘Now,’ so that we are not waiting for construction to begin to establish these important partnerships.”

Gallo’s research focus has been on white matter development and injury, myelin and glial cells – which are involved in the brain’s response to injury. His past and current focus is also on neural stem cells. His work in developmental neuroscience has been seminal in deepening understanding of cerebral palsy and multiple sclerosis. He came to Children’s National from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) intramural program. His intimate knowledge of the workings of the National Institutes of Health (NIH) has helped him to establish meaningful collaborations between both institutions. During his tenure, he has transformed the Center for Neuroscience Research into one of the nation’s premier programs. The Center is home to the prestigious NIH/NICHD-funded District of Columbia Intellectual and Developmental Disabilities Research Center, which Gallo directs.

Children’s research scientists working under the auspices of Children’s Research Institute conduct and promote highly collaborative and multidisciplinary research within the hospital that aims to better understand, treat and, ultimately, prevent pediatric disease. As Chief Research Officer, Gallo will continue to establish and enhance collaborations between research and clinical programs. Such cross-cutting projects will be essential in defining new mechanisms that underlie pediatric disease. “We know, for instance, that various mechanisms contribute to many genetic and neurological pediatric diseases, and that co-morbidities add another layer of complexity. Tapping expertise across disciplines has the potential to unravel current mysteries, as well as to better characterize unknown and rare diseases,” he says.

“Children’s National is among the nation’s top seven pediatric hospitals in NIH research funding, and the extraordinary innovations that have been produced by our clinicians and scientists have been put into practice here and in hospitals around the world,” Dr. Batshaw adds. “Children’s leadership aspires to nudge the organization higher, to rank among the nation’s top five pediatric hospitals in NIH research funding.”

Gallo says the opportunity for Children’s research to expand beyond the existing buildings and the concurrent expansion into new areas of research will trigger more hiring. “We plan to grow our research enterprise through strategic hires and by attracting even more visiting investigators from around the world. By expanding our community of investigators, we aim to strengthen our status as one of the nation’s leading pediatric hospitals,” he says.

Harnessing progenitor cells in neonatal white matter repair

The sirtuin protein Sirt1 plays a crucial role in the proliferation and regeneration of glial cells from an existing pool of progenitor cells — a process that rebuilds vital white matter following neonatal hypoxic brain injury. Although scientists do not fully understand Sirt1’s role in controlling cellular proliferation, this pre-clinical model of neonatal brain injury outlines for the first time how Sirt1 contributes to development of additional progenitor cells and maturation of fully functional oligodendrocytes.

The findings, published December 19 in Nature Communications, suggest that modulation of this protein could enhance progenitor cell regeneration, spurring additional white matter growth and repair following neonatal brain injury.

“It is not a cure. But, in order to regenerate the white matter that is lost or damaged, the first steps are to identify endogenous cells capable of regenerating lost cells and then to expand their pool. The glial progenitor cells represent 4 to 5 percent of total brain cells,” says Vittorio Gallo, Ph.D., Director of the Center for Neuroscience Research at Children’s National, and senior author of the study. “It’s a sizable pool, considering that the brain is made up of billions of cells. The advantage is that these progenitor cells are already there, with no requirement to slip them through the blood-brain barrier. Eventually they will differentiate into oligodendrocyte cells in white matter, mature glia, and that’s exactly what we want them to do.”

The study team identified Sirt1 as a novel, major regulator of basal oligodendrocyte progenitor cell (OPC) proliferation and regeneration in response to hypoxia in neonatal white matter, Gallo and co-authors write. “We demonstrate that Sirt1 deacetylates and activates Cdk2, a kinase which controls OPC expansion. We also elucidate the mechanism by which Sirt1 targets other individual members of the Cdk2 signaling pathway, by regulating their deacetylation, complex formation and E2F1 release, molecular events which drive Cdk2-mediated OPC proliferation,” says Li-Jin Chew, Ph.D., research associate professor at Children’s Center for Neuroscience Research and a study co-author.

Hypoxia-induced brain injury in neonates initiates spontaneous amplification of progenitor cells but also causes a deficiency of mature oligodendrocytes. Inhibiting Sirt1 expression in vitro and in vivo showed that loss of its deacetylase activity prevents OPC proliferation in hypoxia while promoting oligodendrocyte maturation – which underscores the importance of Sirt1 activity in maintaining the delicate balance between these two processes.

The tantalizing findings – the result of four years of research work in mouse models of neonatal hypoxia – hint at the prospect of lessening the severity of developmental delays experienced by the majority of preemies, Gallo adds. About 1 in 10 infants born in the United States are delivered preterm, prior to the 37th gestational week of pregnancy, according to the Centers for Disease Control and Prevention.  Brain injury associated with preterm birth – including white matter injury – can have long-term cognitive and behavioral consequences, with more than 50 percent of infants who survive prematurity needing special education, behavioral intervention and pharmacological treatment, Gallo says.

Time is of the essence, since Sirt1 plays a beneficial role at a certain place (white matter) and at a specific time (while the immature brain continues to develop). “We see maximal Sirt1 expression and activity within the first week after neonatal brain injury. There is a very narrow window in which to harness the stimulus that amplifies the progenitor cell population and target this particular molecule for repair,” he says.

Sirt1, a nicotinamide adenine dinucleotide-dependent class III histone deacetylase, is known to be involved in normal cell development, aging, inflammatory responses, energy metabolism and calorie restriction, the study team reports. Its activity can be modulated by sirtinol, an off-the-shelf drug that inhibits sirtuin proteins. The finding points to the potential for therapeutic interventions for diffuse white matter injury in neonates.

Next, the research team aims to study these processes in a large animal model whose brains are structurally, anatomically and metabolically similar to the human brain.

“Ideally, we want to be able to promote the timely regeneration of cells that are lost by designing strategies for interventions that synchronize these cellular events to a common and successful end,” Gallo says.

Thrasher Research Fund supports Zika virus neurologic outcomes study

The Thrasher Research Fund will fund a Children’s National project, “Neurologic Outcomes of Apparently Normal Newborns From Zika Virus-Positive Pregnancies,” as part of its Early Career Award Program, an initiative designed to support the successful training and mentoring of the next generation of pediatric researchers.

The project was submitted by Sarah B. Mulkey, M.D., Ph.D., a fetal-neonatal neurologist who is a member of the Congenital Zika Virus Program at Children’s National. During the award period, Dr. Mulkey will be mentored by Adre du Plessis, M.B.Ch.B., director of the Fetal Medicine Institute, and Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases. Drs. du Plessis and DeBiasi co-direct the multidisciplinary Zika program, one of the nation’s first.

In the award letter, the fund mentioned Children’s institutional support for Dr. Mulkey, as demonstrated by the mentors’ letter of support, as “an important consideration throughout the funding process.”

Doctors working together to find treatments for autoimmune encephalitis

Shining light on autoimmune encephalitis

Doctors working together to find treatments for autoimmune encephalitis

Experts at Children’s National Health System brought together over 40 specialists from around the world to talk about autoimmune encephalitis (AE) and how the present institutions can better align their research priorities with the goal of finding more effective treatment for children with AE.

About autoimmune encephalitis

AE is a serious and rare medical condition in which the immune system attacks the brain, significantly impairing function and causing the loss of the ability to perform basic actions such as walking, talking or eating. If diagnosed quickly and treated appropriately, many patients recover most or all functions within a few years. However, not all patients will fully recover, or even survive, if the condition is not diagnosed early. AE is mainly seen in female young adults, but is increasingly being seen more in males and females of all ages.

The condition is often difficult to diagnose. Symptoms can vary and include psychosis, tremors, multiple seizures, and uncontrollable bodily movements. Once diagnosed, AE is treated by steroids and neuro-immunology treatments such as plasmapheresis, the removal and exchange of infected plasma with healthy plasma.

The Neuro-Immunology Clinic at Children’s National treats infants, children, and adolescents with several neurologic autoimmune conditions including AE. The multidisciplinary team consists of neurologists, neuropsychologists, physical and rehabilitation medicine experts, and complex care physicians.

A look at the pediatric autoimmune encephalitis treatment consensus meeting

Children’s National, along with Autoimmune Encephalitis Alliance and the Childhood Arthritis and Rheumatology Research Alliance, hosted the first International Pediatric Autoimmune Encephalitis Treatment Consensus Meeting at the Carnegie Endowment for International Peace in Washington, DC, this month. Several leading children’s hospitals and health institutions including Duke University Medical Center, Texas Children’s Hospital, and Alberta Children’s Hospital also co-hosted the event with Children’s National.

“This meeting gathered experts from around the world to discuss our current efforts to standardize approaches to diagnosis, treatment, and research for pediatric autoimmune encephalitis with the common goal of discovering new ways to provide more effective care to children and adolescents with AE,” says Elizabeth Wells, MD, director of the Neuro-Immunology Clinic at Children’s National.

The following were the three main objectives of the meeting:

  • Beginning the formation of treatment roadmaps for initial treatment and maintenance therapy for pediatric AE
  • Discussing current work to standardize approaches to diagnosis, initial treatment, maintenance immunotherapy, disease surveillance, biomarker discovery, supportive care, and multidisciplinary coordination
  • Aligning research priorities and planning future collaborative work

Three families who have children with AE also shared their stories of diagnosis and journeys to recovery, putting the need for more research into perspective for the experts in the room.

“We are very hopeful for the future of autoimmune encephalitis research and are proud to be at the forefront of it so we are able to provide the best possible care to our patients,” says Dr. Wells.

Children’s National spin-off ReveraGen announces agreement with actelion for Duchenne Muscular Dystrophy treatment

Earlier this month, ReveraGen BioPharma announced an exclusive option agreement with Actelion Ltd for lead compound vamorolone, a non-hormonal steroid modulator that is primarily used for the treatment of Duchenne Muscular Dystrophy (DMD). ReveraGen, the first Children’s National private spin-off company, is engaged in the discovery and development of proprietary therapeutic products for neuromuscular and inflammatory diseases.

Under the terms of the license agreement, Actelion and ReveraGen will partner to research and co-develop the novel compound vamorolone, which holds the potential to preserve muscle function and prolong ambulation in DMD patients, without some of the side effects that are commonly associated with glucocorticoid therapy. Those commonly associated include growth stunting and immune suppression, which can pose significant challenges for very young patients.

ReveraGen completed Phase I clinical trials for vamorolone in late 2015, and a Phase IIa program is currently underway to investigate the safety and efficiency of vamorolone in male DMD patients between four and seven years of age who have not taken deflazacort or prednisone. A Phase IIb program is also in early planning stages.

ReveraGen Co-Founder and CEO Eric Hoffman, PhD, has worked on DMD since the late 1980’s and has led his own research group for nearly 20 years at Children’s National. He co-founded ReveraGen back in 2008 with John McCall, PhD and Kanneboyina Nagaraju, PhD, DVM, before being named CEO in 2014. Children’s National maintains a 38 percent stake in ReveraGen.

Brain tumor expert from Children’s National speaks at Society for Neuro-Oncology’s scientific meeting and Education Day

Roger Packer

Roger Packer, M.D., Senior Vice President for the Center of Neuroscience and Behavioral Medicine and Director of the Brain Tumor Institute at Children’s National Health System, will be speaking at the 21st Annual Meeting and Education Day of the Society for Neuro-Oncology. From November 17-20, 2016, the conference will gather neuro-oncologists, medical oncologists, adult and pediatric neurosurgeons, pediatric neuro-oncologists, neuroradiologists, neuropathologists, radiation oncologists, neuropsychologists, and epidemiologists from across the country to discuss the future of neuro-oncology. Dr. Packer will be sharing his expertise in treating neurofibromatosis and pediatric brain tumors. He also will be part of a working group to discuss guidelines for response assessment in PDCT-13 medulloblastoma and other leptomeningeal seeding tumors.

2016 Neurobiology of Disease in Children Symposium: neurofibromatosis features Children’s National expert

Roger Packer, M.D., Senior Vice President for the Center of Neuroscience and Behavioral Medicine and Director of the Gilbert Neurofibromatosis Institute at Children’s National Health System, was an invited speaker at the 2016 Neurobiology of Disease in Children Symposium: Neurofibromatosis (NF). This conference brought together experts from around the world to discuss the newest developments in the understanding and treatment of children with NF. While at the conference, which was held on October 26, 2016, Dr. Packer gave an update of the Department of Defense-sponsored Neurofibromatosis Clinical Trial Consortium. The Neurofibromatosis Clinical Trials Consortium, of which Dr. Packer is the group chair, was established by the Department of Defense Neurofibromatosis Research Program to develop and perform clinical trials for the treatment of NF complications in children and adults.

Read more about the symposium.

Brain Tumor Institute Director Speaks at Coalition against Childhood Cancer Meeting

Roger Packer, MD, Senior Vice President for the Center of Neuroscience and Behavioral Medicine and Director of the Brain Tumor Institute at Children’s National Health System, was an invited speaker at the Coalition Against Childhood Cancer meeting at Cold Springs Harbor Laboratory on October 31 and November 1, 2016. This international conference was a unique collaborative effort between multiple foundations, the National Cancer Institute, and industry experts to develop a new path forward for the treatment of childhood cancer. Dr. Packer spoke on “Pediatric Brain Tumors: Where Are We Now” and shared his expertise in treating pediatric brain tumors and what he hopes the future of pediatric brain tumor research will look like. Pediatric brain tumors recently surpassed leukemia as the most deadly form of childhood cancer.

Read more about the conference here.

How technology can predict vision loss in neurofibromatosis patients

Roger Packer and patient

For the first time, scientists have been able to definitively connect tumor volume and vision loss for children with neurofibromatosis type 1 (NF1). The first study to use quantitative imaging technology to accurately assess the total volume of individual optic nerve glioma (OPG) in NF1 was published in the November 4, 2016 issue of Neurology.

NF1 is a genetic condition that occurs in one in 3,500 births. Children with NF1 develop tumors in multiple locations across the nervous system. About 20 percent of children with NF1 will develop optic pathway gliomas, or tumors that occur in the visual system. Half of those with OPG will have irreversible vision loss, which occurs at a very young age, usually before age 3.

“Neuroradiologists typically assess these tumors through a measurement of the tumor’s radii using magnetic resonance images (MRI) of the patient,” said Marius George Linguraru, D.Phil., M.A., M.S., Principal Investigator in the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System, who is senior author on the study.

“These measurements aren’t detailed enough to serve as a good indicator of whether an OPG will cause vision loss for a child. Through automated computerized analysis, however, we’ve taken the MRI data and systematically analyzed the size and shape, as well as documented changes over time, all in 3-D, to pinpoint the volume of each tumor.”

A look inside the study

The study included children with NF1-related OPGs who are currently cared for at the Gilbert Family Neurofibromatosis Institute at Children’s National. Investigators compared the MRI analysis to the patients’ retinal nerve fiber layer (RNFL), a measure of the health of the visual system. The analysis showed a quantifiable negative relationship between increasing tumor volume within the structures of the anterior visual pathway (the optic nerve, chiasm, and tract) and decreasing thickness of the RNFL, indicating damage to the visual system and vision loss.

“Measuring the tumors in a precise, systematic manner, along with knowing how they grow, is the first step in recognizing which children are at highest risk for vision loss and to potentially identifying them before they suffer any visual symptoms,” added Dr. Linguraru. “If we know which children will probably lose vision, we can treat earlier, and perhaps improve how patients respond to treatment.”

A multicenter collaborative study to validate the findings will begin in 2017.

Every day fetuses remain in utero critical to preserving normal brain development

preemieimage

If it does not jeopardize the health of the pregnant mother or her fetus, pregnancies should be carried as close to full term as possible to avoid vulnerable preemies experiencing a delay in brain development, study results published October 28 in Pediatrics indicate.

Some 15 million infants around the world – and 1 in 10 American babies – are born prematurely. While researchers have known that preemies’ brain growth is disturbed when compared with infants born at full term, it remained unclear when preemies’ brain development begins to veer off course and how that impairment evolves over time, says Catherine Limperopoulos, Ph.D., Director of the Developing Brain Research Laboratory at Children’s National Health System and senior study author.

A look at the research

In order to shine a spotlight on this critical phase of fetal brain development, Limperopoulos and colleagues studied 75 preterm infants born prior to the 32th gestational week who weighed less than 1,500 grams who had no evidence of structural brain injury. These preemies were matched with 130 fetuses between 27 to 39 weeks gestational age.

The healthy fetal counterparts are part of a growing database that the Children’s National Developing Brain Research Laboratory has assembled. The research lab uses three-dimensional magnetic resonance imaging to carefully record week-by-week development of the normal in utero fetal brains as well as week-by-week characterizations of specific regions of the fetal brain.

The availability of time-lapsed images of normally developing brains offers a chance to reframe research questions in order to identify approaches to prevent injuries to the fetal brain, Limperopoulos says.

“Up until now, we have been focused on examining what is it about being born too early? What is it about those first few hours of life that leaves preemies more vulnerable to brain injury?” she says. “What is really unique about these study results is for the very first time we have an opportunity to better understand the ways in which we care for preemies throughout their hospitalization that optimize brain development and place more emphasis those activities.”

When the research team compared third-trimester brain volumes, preemies showed lower volumes in the cerebrum, cerebellum, brainstem, and intracranial cavity. The cerebrum is the largest part of the brain and controls speech, thoughts, emotions, learning, as well as muscle function. The cerebellum plays a role in learning and social-behavioral functions as well as complex motor functions; it also controls the balance needed to stand up and to walk. The brainstem is like a router, ferrying information between the brain, the cerebellum, and the spinal cord.

“What this study shows us is that every day and every week of in utero development is critical. If at all possible, we need to keep fetuses in utero to protect them from the hazards that can occur in the extra uterine environment,” she says.

Transgender adolescents on the autism spectrum, and the first clinical guidelines for care

Evidence indicates a link between transgenderism and autism spectrum disorders (ASD). John Strang, Psy.D., a neuropsychologist in the Center for Autism Spectrum Disorders at Children’s National Health System, has dedicated his career to learning more about this co-occurrence and led a group of experts who recently released the first clinical guidelines for the care of transgender adolescents with ASD.

Through a comprehensive international search procedure, the research team, led by Dr. Strang, identified 22 experts in the care of transgender youth with autism. The expert group from around the world worked together for one year to create guidelines, putting processes in place to avoid interpersonal influence or bias.

The findings, published in the Journal of Clinical Child and Adolescent Psychology, outline the first initial clinical guidelines for treating transgender adolescents with ASD.

With overall 89.6 percent consensus achieved among the identified experts, key recommendations include the importance of assessing for ASD among transgender youth, and assessing for gender concerns among youth on the autism spectrum.

More study findings and recommendations

The study also indicates that gender-related medical treatments, including cross-sex hormone therapy, are appropriate for some youth with ASD, but emphasizes the importance of providing more extended time and supports in many cases to allow an adolescent with autism to explore a range of options regarding gender.

The guidelines emphasize that for many transgender youth with autism, parents must play a more active role. “Teens on the autism spectrum often struggle understanding how others perceive them,” Dr. Strang said. “Our study found that many transgender youth on the autism spectrum require specific coaching and supports in how to achieve their gender-related needs regarding gender presentation.”

Several risks for transgender adolescents with autism were emphasized in the study, including around physical safety and obtaining employment. “Trans youth are at increased risk for bullying, persecution, and violence in the community, and those on the autism spectrum are at even higher risk, as they often struggle to read social cues and recognize potentially dangerous social situations,” Dr. Strang said.

The importance of this study

The study group did not achieve consensus around specific guidelines for when an adolescent is appropriate for commencing medical gender treatments (e.g., cross-sex hormones). A majority (about 90 percent) of the expert participants elected to identify themselves as co-authors of the study, including many well-known clinicians across the United States as well as clinicians from The Netherlands.

“Until now, care for individuals with autism and gender concerns has been a matter of individual clinician judgment. This study has allowed for dialogue and discernment between the world’s experts in this field to establish the first recommendations for care,” Dr. Strang said.

Dr. Strang is currently working on a follow-up study to more directly capture the voices and experiences of youth with this co-occurrence, as key stakeholders and collaborators in the research.

hands on simulation training at AAP

At AAP: hands-on simulation training with life-saving technology

aap_nshah_techdependentinfants_atmospheric

Recent medical breakthroughs have enabled very premature infants and children with rare genetic and neurological diseases to survive what had once been considered to be fatal conditions. This has resulted in a growing number of children with medically complex conditions whose very survival depends on ongoing use of technology to help their brains function, their lungs take in oxygen, and their bodies remain nourished.

“Many pediatricians care for technology-dependent children with special health needs,” says Neha Shah, M.D., M.P.H., an associate professor of pediatrics in the Division of Hospitalist Medicine at Children’s National Health System. “These kids have unique risks – some of which may be associated with that life-saving device malfunctioning.” Because there is no standard residency training for these devices, many clinicians may feel ill-equipped to address their patients’ device-related issues. To bridge that training gap, Dr. Shah and co-presenters, Priti Bhansali, M.D., M.Ed., and Anjna Melwani, M.D., will lead hands-on simulation training during the American Academy of Pediatrics 2016 National Conference.

“Inevitably, these things happen at 3 in the morning,” Dr. Shah adds. “Individual clinicians’ skill level and comfort with the devices varies. We should all have the same core competency.”

How the training works

During the simulation, the audience is given a specific case. They have eight minutes to troubleshoot and resolve the issue, using mannequins specially fitted with devices, such as trach tubes and feeding tubes, in need of urgent attention. Depending on their actions, the mannequin may decompensate with worsened breathing and racing heartbeats. The high-stakes, hands-on demo is followed by a 12-minute debrief, a safe environment to review lessons learned. Once they complete one simulation, attendees move to the next in the series of four real-life scenarios.

“We’ve done this a few times and my heart rate still goes up,” Dr. Shah admits. After giving similar training sessions at other academic meetings, participants said that having a chance to touch and feel the devices and become familiar with them in a calm environment is a benefit.

Dr. Shah came up with the concept for the hands-on training by speaking with a small group of peers, asking about how comfortable they felt managing kids with medical complex cases. The vast majority favored additional education about common devices, such as gastronomy tubes, tracheostomy tubes, and ventriculoperitoneal shunts.  In addition to the in-person training, the team has created a web-based curriculum discussing dysautonomia, spasticity, gastroesophageal reflux disease, enteric feeding tubes, venous thromboembolism, and palliative care, which they described in an article published in the Fall 2015 edition of the Journal of Continuing Education in the Health Professions.

“Most times, clinicians know what they need to do and the steps they need to follow. They just haven’t done it themselves,” Dr. Bhansali adds. “The simulation forces people to put their hands on these devices and use them.”

AAP 2016 presentations:
Saturday, October 22, 2016

  • W1059- “Emergencies in the Technology-Dependent Child: What Every Pediatrician Should Know” 8:30 a.m. to 10 a.m. (SOLD OUT)
  • W1131-  “Emergencies in the Technology-Dependent Child: What Every Pediatrician Should Know” (Encore) 2 p.m. to 3:30PM
Chima Oluigbo

The benefits of deep brain stimulation for pediatric patients

Chima Oluigbo

There was no effective treatment for uncontrolled, difficult, and sometime painful movements associated with movement disorders. That is, before the development of deep brain stimulation (DBS) techniques.

Children’s National Health System is one of only two children’s hospitals with fully integrated DBS programs. Chima Oluigbo, M.D., who leads the pioneering Deep Brain Stimulation Program within Children’s Division of Neurosurgery, is one of few pediatric deep brain stimulation experts in North America and cross-trained in pediatric and functional neurosurgery.

Dr. Oluigbo says the effects of DBS are often dramatic: 90 percent of children with primary dystonia show up to 90 percent symptom improvement.

A 6-year-old boy with dystonia so severe that his body curved like a “C” was one of the first patients to undergo the procedure at Children’s National. Six weeks later, he gained the ability to sit straight and to control his hands and legs. He also was able to smile, an improvement that brought particular joy to his parents.

Inside the brain with movement disorders

Patients with movement disorders experience difficulties due to neurological dysfunction that impact the speed, fluency, quality, and ease in which they move. In these cases, neurons in the brain’s motor circuits misfire. Through the use of DBS, neurosurgeons can synchronize neuronal firing and accomplish the previously impossible: restoring muscle control to patients with these disorders.

Movement disorders are common in children. “It’s not just numbers, it’s also about impact. Think about the potential of a child who is very intelligent and can contribute to society. When that child is not able to contribute because he or she is disabled by a movement disorder, the lost potential is very significant. It has an impact,” Dr. Oluigbo says.

What is deep brain stimulation?

DBS uses an implantable device to send continuous, low-level electrical impulses to areas deep within the brain. The impulses prevent the brain from firing abnormal signals that are linked to movement disorders and seizures. When a child is considered to be a candidate for the technique, here’s what happens next:

  1. Imaging: Magnetic resonance imaging (MRI) helps pinpoint the area of brain tissue responsible for movement disorders and informs the treatment plans.
  2. Neurotransmitter implant procedure: Using minimally invasive neurosurgery techniques, doctors access the brain through a tiny incision in the child’s skull and place thin, insulated wires (leads) in the area of brain tissue responsible for the condition.
  3. Pulse generator implant procedure: The pulse generator (neurostimulator) is a battery-operated device that sends low-level electrical impulses to the leads. During a separate procedure, the pulse generator is implanted near the child’s collarbone. Leads are threaded under the child’s skin to connect with the pulse generator.
  4. Stimulation treatments: Once the leads and pulse generator are connected, the child receives a continuous stream of electrical impulses. Impulses are generated by the neurostimulator, travel through the leads, and end up in the deep tissue of the brain. Here, they block abnormal signals that are linked to the child’s movement disorder.
  5. Follow-up care: The child will likely need deep brain stimulation throughout his or her lifetime to make sure the device is working correctly and to adjust the neurotransmitter settings to meet his or her changing needs.

Deep brain stimulation at Children’s National

Children’s National is currently conducting clinical trials seeking to expand the use of this procedure to patients with cerebral palsy, one of the most common dystonias. The effective use of deep brain stimulation requires ongoing attention from a multidisciplinary team (from neuropsychology to rehabilitation medicine), giving seamless care under one roof.

There is evidence to suggest that this technique could be used to aid people with memory disorders, patients in minimally conscious states, and patients with incurable epilepsies.

Dr. Roger Packer

New brain tumor research collaborative taps Children’s for scientific director

Dr. Roger Packer

This year, more than 4,600 children and adolescents (0-19 years) will be diagnosed with a pediatric brain tumor. Brain tumors have now passed leukemia as the leading cause of pediatric cancer-related deaths. Despite this, there has never been a drug developed specifically to treat pediatric brain tumors and for many pediatric brain tumor-types, no standards of care or effective treatment options exist. In particular, pediatric high-grade gliomas have no standard of care and a very low survival rate.

To combat this, the National Brain Tumor Society (NBTS), the largest nonprofit dedicated to the brain tumor community in the United States, with its partner, the St. Baldrick’s Foundation, the largest private funder of childhood cancer research grants, as well as several world-renowned experts in the field of pediatric neuro-oncology, announced a new awareness and fundraising campaign to support a major translational research and drug discovery program. The campaign, called “Project Impact: A Campaign to Defeat Pediatric Brain Tumors,” was unveiled at the National Press Club in Washington, DC, on Sept. 12. Watch the live streaming replay.

Children’s National brain tumor expert leads the way
The collaborative hopes to improve clinical outcomes for pediatric brain tumor patients and inform the development of the first standard of care for treating pediatric high-grade gliomas, including DIPG – the deadliest of pediatric cancers.

Roger J. Packer, M.D., Senior Vice President of the Center for Neuroscience and Behavioral Medicine and Director of Brain Tumor Institute at Children’s National Health System, serves as the Scientific Director of the Defeat Pediatric Brain Tumors Research Collaborative.

“Treatment of pediatric high-grade gliomas has been extremely frustrating with little progress made over the past quarter century,” said Dr. Packer. “New molecular insights provide hope that therapies will be dramatically more effective in the very near future. In the last two years alone we have had great breakthroughs, primarily identifying genes which are critical in development of new pediatric treatments. But we need to maintain forward momentum from discovering the molecular and genetic underpinnings of these tumors, to understanding how these changes drive these tumors, and to ultimately developing effective, biologically precise therapies. This is a major opportunity for the field, patients, and their families.”

Pediatric high-grade gliomas make up to 20 percent of all pediatric brain tumors with roughly 500-1,000 new diagnoses every year. These tumors are WHO Grade III and Grade IV gliomas, including: pediatric glioblastoma (GMB); glioma malignant, NOS; pediatric anaplastic astrocytoma; anaplastic oilgodendroglioma; giant cell glioblastoma; gliosarcoma; and diffuse intrinsic pontine gliomas (DIPG).

David Arons, CEO of the National Brain Tumor Society said, “Researching and developing new treatments for pediatric brain tumors is a particularly challenging task, which faces multiple – but interrelated – barriers that span the research and development spectrum from small patient populations, lack of effective preclinical models, to complex basic biology, regulatory hurdles and economic disincentives. To overcome these complex challenges, and get better treatments to patients, we needed to create an equally sophisticated intervention. We believe that having groups with complementary skills work together in a coordinated effort, sharing data and expertise, and tackling the problem from multiple angles as one team is the starting point for greater and faster progress.”

How the collaborative is set up
The model for the collaborative consists of scientists and researchers who will each lead interrelated “Cores” to work on critical areas of research simultaneously and in concert with one another, encouraging sharing of findings real time. This design allows new findings to quickly move onto the next stage of research without barriers or other typical delays, significantly speeding up the research process.

Dr. Packer said the goal of this research collaboration is to work with pediatric brain tumor researchers from around the world to discover new treatments for children in the next two to three years, instead of the next decade.

Javad Nazarian

Surviving pediatric diffuse intrinsic pontine glioma

Mutations in histone-encoding genes are associated with the vast majority of pediatric DIPG cases.

For more than four decades, clinicians around the nation have been giving the parents of pediatric patients diagnosed with diffuse intrinsic pontine glioma (DIPG) the same grim prognosis. In the past five years, there has been an explosion of innovative research at Children’s National Health System and elsewhere that promises to change that narrative. That’s because the black box that is DIPG is beginning to divulge its genetic secrets. The new-found research knowledge comes as a direct result of parents donating specimens, judicious shepherding of these scarce resources by researchers, development of pre-clinical models, and financing from small foundations.

From just 12 samples six years ago, Children’s National has amassed one of the nation’s largest tumor bio banks – 3,000 specimens donated by more than 900 patients with all types of pediatric brain tumors, including DIPG.

Such donated specimens have led to the identification of H3K27M mutations, a groundbreaking finding that has been described as the single-most important discovery in DIPG. Mutations in histone-encoding genes are associated with the vast majority of pediatric DIPG cases.

Histone mutations (also referred to as oncohistones) are sustained in the tumor throughout its molecular evolution, found a research team led by Javad Nazarian, Ph.D. Not only were H3K27M mutations nearly ubiquitous in all samples studied, the driver mutation maintained partnerships with other secondary mutations as DIPG tumor cells spread throughout the developing brain. Children’s National researchers have identified tumor driver mutations and obligate partner mutations in DIPG. They are examining what happens downstream from the histone mutation – changes in the genome that indicate locations they can target in their path toward personalized medicine. The value of that genomic knowledge is akin to emergency responders being told the specific house where their help is needed, rather than a ZIP code or city name, Dr. Nazarian says. While there is currently no effective treatment for DIPG, new research has identified a growing number of genomic targets for future therapeutics.“That changed the dynamic,” says Dr. Nazarian. “In DIPG clinical research, nothing had changed for 45 years. Now we know some of the genomic mutations, how the tumor was evolving – gaining new mutations, losing mutations. With precision medicine, we can target those mutations.”

Another study led by neuro-oncologist Eugene Hwang, M.D., reported the most comprehensive phenotypic analyses comparing multiple sites in a young girl’s primary and metastatic tumors. This study showed that despite being uniform, small molecules (mRNA) could be used to distinguish an evolved tumor from its primary original tumor mass.Key to this multidisciplinary work is collaboration across divisions and departments. Within the research lab, knowledge about DIPG is expanding.

Each member of the DIPG team – neurosurgery, neuro-oncology, immunology, genomics, proteomics – feeds insight back to the rest of the team, accelerating the pace of research discoveries being translated into clinical care. Among the challenges that the team will address in the coming months is outmaneuvering tumors that outsmart T-cells (immune cells).

“What is happening in the checkpoint inhibitor field is exciting,” says Catherine M. Bollard, MBChB, MD, Chief of Allergy and Immunology and Director of the Program for Cell Enhancement of Technologies for Immunotherapy. “The inhibitors work by reversing the ‘off’ switch – releasing the brake that has been placed on the T-cells so they can again attack multiple tumor proteins. The next exciting step, and novel to Children’s National, will be to combine this approach with T-cell therapies specifically designed to attack the DIPG tumors. Unlike the use of combination chemotherapy, which has had a limited impact, we hope that the novel combination of immunotherapeutic approaches will offer the hope of a potential cure.”

Dr. Hwang, another member of the multidisciplinary team, adds: “When you’re looking at the landscape – for me, at least – it starts and ends with how my patients are doing. There are kids for whom we have had great successes in improving survival rates in some cancers, like leukemia, and some where the needle has moved nowhere, like DIPG. We’re still trying to figure out the whole picture of who responds. The immune system is present in all kids. Its ability to attack is present in all kids.”

Children’s National is one of the few hospitals in the nation that conducts brainstem biopsies for DIPG and does so with very little chance of complications. The pons is like a superhighway through which nerves pass, making it instrumental in smooth operation of such vital functions as breathing, heart rate, sleeping, and consciousness. The ability of neurosurgeon Suresh Magge, MD, to perform such sensitive biopsies upends conventional wisdom that these procedures were inherently too dangerous. Within two weeks of diagnosis, genomics analyses are run to better understand the biology of that specific tumor. Within the following weeks, the tumor board occurs, and patients with DIPG are placed on therapy that best targets their tumor’s mutations.

The black box that is diffuse intrinsic pontine glioma is beginning to divulge its genetic secrets.

Despite an increasing number of experimental therapies tested via clinical trials, more than 95 percent of children with DIPG die within two years of diagnoses. Biomarkers that point to DIPG – like the copies of DNA that tumors shed and leave behind in the bloodstream – could enable creation of liquid biopsies, compared with today’s surgical approach.

Children’s also is making a concerted effort to create preclinical models of DIPG. Preclinical models will be used to winnow the field of potential therapeutics to the candidates most likely to help children survive DIPG. The preclinical tumor cells will be labeled with luciferase – enzymes that, like photoproteins, produce bioluminescence – permitting the researcher to visually see the formation, progression, and response of DIPG tumors to treatment in preclinical settings.

These preclinical models could be used to test multiple drug combinations in conjunction with radiation therapy. Molecular signatures and response to treatment could then be assessed to learn how the tumor resists therapy. Due to the obligate partnerships between driver mutations and secondary mutations, the research team already knows that effective DIPG medicines will need more than one target. If there were a single mutation, that would be like having a single master key to open many locks. Multiple mutations imply that more than one key will be needed. Thus, the search for cures for DIPG will necessitate taking a multi-pronged approach.

Combined drug regimens, including those created with proprietary technology, with or without radiation, will be keys to targeting myriad mutations in order to kill tumors where they are. Those drug combinations that demonstrate they can do their jobs – slowing tumor growth, increasing chances of survival, taming toxicity – will be selected for clinical application.

Immunotherapy leverages T-cells, the immune system’s most able fighters, to help in the overall goal of extending patients’ survival. One of the most challenging aspects of pediatric brain tumors is the body does a very good job of shielding the brain from potential pathogens. Precise drug delivery means finding innovative ways for therapeutics to cross the blood-brain barrier in order to reach the tumor. The team has identified one such potential target, the protein NG2, which may represent a good target for immune therapy. The protein is expressed in primitive cells that have not become specialized – meaning there may be an opportunity to intervene before it is driven to become a tumor cell.

Related resources
Research at a Glance: Clinicopathology of diffuse intrinsic pontine glioma and its redefined genomic and epigenomic landscape
Research at a Glance: The role of NG2 proteoglycan in glioma
Research at a Glance: Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma
Research at a Glance: Histological and molecular analysis of a progressive diffuse intrinsic pontine glioma: a case report

Neurology and neurosurgery update: whole exome sequencing, Sesame Workshop

May 9, 2016 WES yields clinical diagnoses for 42 percent, ending ‘diagnostic odyssey’.
Whole exome sequencing (WES), a method to look at all the genes in the genome at once, yielded clinical diagnoses for 42 percent of patients whose white matter abnormalities had been unresolved an average of eight years, ending families’ “prolonged diagnostic odyssey.”  White matter disorders, which affect 1 in 7,000 children born each year, are progressive and involve age-related weakness in the region of the nerves that connect various parts of the brain to each other and to the spinal cord. Nine of 28 named authors of the study, published online May 9, 2016 in Annals of Neurology, are affiliated with Children’s National Health System.

April 6, 2016 Georgetown, Children’s National researchers to evaluate Sesame Workshop’s Autism Initiative.
Sesame Workshop, the nonprofit educational organization behind Sesame Street, has selected Georgetown University Medical Center and Children’s National Health System researchers to lead an evaluation of  “Sesame Street and Autism: See Amazing in All Children,” an initiative developed to reduce stigma and build understanding about autism spectrum disorder. Sesame Workshop launched a new phase of its autism initiative in early April. Last year, Sesame Street introduced Julia, an autistic preschool digital Muppet, and accompanying resources, such as an app, videos, storybooks, and daily routine cards as part of the Sesame Street and Autism: See Amazing in All Children initiative. Now ready for evaluation, Sesame Workshop awarded a grant for real-world testing of the materials to Bruno Anthony, PhD, deputy director of the Georgetown Center for Child and Human Development in collaboration with his wife and research collaborator Laura Anthony, PhD, at the Center for Autism Spectrum Disorder at Children’s National.

In Brief- Fetal Medicine

Cognitive training exercises at home help kids with sickle cell boost visuospatial working memory

A team led by Children’s National Health System clinicians and research scientists attempted to identify novel approaches to boost working memory in children who suffer from sickle cell disease.

A team led by Children’s National Health System clinicians and research scientists attempted to identify novel approaches to boost working memory in children who suffer from sickle cell disease.

Youths with sickle cell disease who used hand-held computers to play game-like exercises that get harder as a user’s skill level rises improved their visuospatial working memory (WM). Children with sickle cell disease, however, completed fewer training sessions during an initial study compared with children with other disease-related WM deficits.

A team led by Children’s National Health System clinicians and research scientists attempted to identify novel approaches to boost WM in children who suffer from sickle cell disease. Kids who have this red blood cell disorder inherit abnormal hemoglobin genes from each parent. Rather than slipping through large and small vessels to ferry oxygen throughout the body, their stiff, sickle-shaped red blood cells stick to vessel walls, impeding blood supply and triggering sudden pain. Children with sickle cell disease have more difficulty completing tasks that place demands on one’s WM, the brain function responsible for temporarily remembering information and manipulating that information to facilitate learning and reasoning. As a result, they’re more likely to repeat a grade, require special academic services, and to have difficulty maintaining employment as adults.

Because computerized cognitive training programs have been used with success to boost WM for children with other health conditions, such as childhood cancer, the research team sought to examine the feasibility of using the technique for kids with sickle cell disease. “This small study highlights the challenges and opportunities of implementing a home-based cognitive training intervention with youths who have sickle cell disease,” says Steven J. Hardy, PhD, a pediatric psychologist in the Divisions of Hematology, Oncology, and Blood and Marrow Transplantation at Children’s National. “While a larger, randomized controlled clinical trial is needed to better characterize efficacy, our initial work indicates that Cogmed is acceptable and moderately feasible in this population.”

Children’s National is home to the Sickle Cell Disease (SCD) Program, one of the nation’s largest, most comprehensive pediatric programs that cares for 1,350 patients younger than 21 annually. Over 15 months, the team recruited youths aged 7 to 16 participating in the program who had an intelligence quotient of at least 70 and an absolute or relative memory deficit. Those who lacked access to a tablet computer were loaned an iPad Mini 2 loaded with Cogmed RM, an interactive audiovisual cognitive training program that consists of exercises that get progressively more challenging. A clinical psychologist provided coaching and moral support through weekly telephone calls to review progress and challenges, and to offer tips on how to optimize the youths’ progress.

Six of 12 eligible participants – all girls – completed by finishing at least 20 sessions of the program. The mean number of sessions completed was 15.83, and the kids spent a median of 725 minutes working actively on Cogmed exercises. “Participants who completed Cogmed indicated that they perceived greater levels of social support from teachers,” Hardy and colleagues write in the study, published by Pediatric Blood & Cancer. “[T]here was not a statistical difference in perceived parent support.”

Among those children who completed Cogmed, standard scores increased an average of 5.05 on a measure of visuospatial short-term memory, 19.72 on a measure of verbal WM, 27.53 on a measure of visuospatial short-term memory, and 23.82 on a measure of visuospatial WM. The researchers also observed a normalizing of memory functioning for those who finished Cogmed, as a significant portion of participants scored below the average range before using Cogmed and most scored in the average range or higher on memory tests after finishing the program.

“In this initial feasibility trial, adherence to Cogmed was lower than expected (50 percent completion) compared to adherence rates of other samples of children with medical histories, including patients with symptomatic epilepsy and youth treated for cancer,” Hardy and co-authors write. “Thus, additional modifications may be needed to achieve consistent delivery of the intervention to youth with SCD.”

Related Resources: Research at a Glance