New tool for craniosynostosis treatment highlights Neuroscience Institute’s push to advance care

For pediatric neurosurgeon, Dr. Suresh Magge and his colleagues in the CHOC Neuroscience Institute, Christmas this year arrived in late June.

That’s when a 3D camera system was installed in the neurosurgery clinic that will significantly advance CHOC’s mission to treat craniosynostosis, says Dr. Magge, PSF neurosurgery division chief for CHOC and co-medical director of the Neuroscience Institute.

Craniosynostosis, which affects 1 in every 2,000 infants, causes an infant’s skull to fuse early, creating an irregular skull shape, and can lead to increased pressure on the brain as a child matures. This can lead to headaches, vision problems, and cognitive issues. 

The 3D motion-capture camera can, in seconds, capture a comprehensive array of images that will allow CHOC neurosurgeons to better analyze and measure in detail a child’s head. This, in turn, will allow them to enhance research in craniosynostosis and design the best possible treatments.

Dr. Suresh Magge, neurosurgery medical director
Dr. Suresh Magge, neurosurgery medical director

“This really makes a difference,” says Dr. Magge, noting that traditional 2D photos and measurements “only go so far.”

“This new camera allows us to get data quickly and safely,” Dr. Magge says.

CHOC recently had its first craniosynostosis patient imaged by the 3D camera.

A push to greatness

The new camera is a critical step in Dr. Magge’s push to advance the path of the Neuroscience Institute in becoming a world-class destination for neurological care.

Dr. Magge was recruited to CHOC last October after an 11-year tenure at Children’s National Hospital in Washington, D.C., where he started the medical center’s neurosurgery fellowship training program and was the director of medical student education in pediatric neurosurgery.

During his time at Children’s National, Dr. Magge started the region’s first minimally invasive craniosynostosis program. He has brought this surgery to CHOC as well.

The neurosurgery division also includes Dr. Michael Muhonen, Dr. William Loudon, and Dr. Joffre Olaya.

For the last several decades, the go-to surgery to treat craniosynostosis has been an open surgical correction called calvarial reconstruction. For this surgery, doctors must wait until the child is 6-12 months of age and perform a large surgery that involves opening the scalp, taking apart the entire skull, then putting it back together.

“It’s a good surgery, and most kids do well, but we have newer techniques that are less invasive,” Dr. Magge says. The open calvarial reconstruction surgery generally takes 4-6 hours and requires a hospital stay of 3-5 days, as well as a blood transfusion during surgery. 

Unlocking the skull

The minimally invasive procedure Dr. Magge learned during his fellowship at Boston Children’s Hospital involves using an endoscope with a camera attached to its tip.

After making one or two small incisions, Dr. Magge goes under the scalp and then under the skull, using the endoscope to separate the skull from the underlying tissue. He then cuts out a piece of bone — 1 to 2 centimeters in width – to “unlock” the skull.

This surgery only takes about an hour, and most children don’t need a blood transfusion and can go home the next day. After surgery, they wear a molding helmet that helps to reshape the skull. This minimally invasive surgery is generally done by 3-4 months of age (earlier than the open surgery).

“The data shows this surgery works very well,” says Dr. Magge, who has given many presentations and written multiple papers about this procedure.

The aesthetic results have been shown to be excellent in many papers, Dr. Magge says. What still needs to be verified by research are the long-term cognitive outcomes of patients after either the open or minimally invasive surgery.

To that end, Dr. Magge launched a study about two years ago involving patients from multiple hospitals that looks at children five years after surgery. Dr. Magge plans to enroll patients from CHOC in the study.

He estimates the study will be completed in about two years. 

Working with plastic surgeon Dr. Raj Vyas, Dr. Magge says CHOC offers comprehensive cranio-facial services. 

Dr. Raj Vyas
Dr. Raj Vyas

“To be comprehensive,” he says, “you have to offer traditional surgery as well as minimally invasive surgery.” 

Part of the funding for the new 3D camera came from a CSO grant established by CHOC Vice President for Research and Chief Scientific Officer Dr. Terence Sanger, a physician, engineer, and computational neuroscientist who also is vice chair of research for pediatrics at the UCI School of Medicine.

Dr. Terence Sanger
Dr. Terence Sanger

The 3D camera arrives as significant infrastructure changes are underway at the Neuroscience Institute: CHOC recently opened its new state-of-the-art outpatient center, establishing a clinical hub for caregivers to serve patients and families in a centralized location. Additionally, plans are underway to expand the hospital’s inpatient neuroscience unit.

“CHOC has been very supportive of the Neuroscience Institute,” Dr. Magge says. “I’m very excited.”

Learn more about the CHOC Neuroscience Institute.

Boy, 9, showing great progress after deep brain stimulation procedure at CHOC

Ryder Montano is the third and youngest CHOC patient with a movement disorder to undergo a procedure called deep brain stimulation (DBS), which is designed to ease involuntary movements by sending electrical currents that jam malfunctioning brain signals. CHOC treated its first DBS patient in late 2020.

Ryder is also among CHOC’s dramatic DBS success stories.

The procedure is being championed by DBS pioneer Dr. Terence Sanger, a physician, engineer, and computational neuroscientist and vice president, chief scientific officer at CHOC, and vice chair of research for pediatrics at the UCI School of Medicine. The DBS team also includes Dr. Joffre E. Olaya, CHOC’s functional restorative neurosurgeon, who implants the electrodes, as well as collaborating partner Dr. Mark Liker, a neurosurgeon at CHLA.

In January 2021, Ryder underwent surgery at CHOC to replace four electrodes in his brain that help ease the severity of a movement disorder, post-pump chorea, that he developed after he had open-heart surgery at age 2 ½. Since those four electrodes were replaced, he has shown remarkable improvement, Ashley says.

“It’s just incredible and mind-blowing that this is happening because of DBS,” she says.

Ashley says Ryder’s clinical team at CHOC had expectations that were lower than what the outcome turned out to be. They thought his condition would worsen before it got better.

But in February 2021, for a post-op appointment, Ryder walked into Dr. Sanger’s office for the first time by himself. He also stood on a scale and sat in a chair without assistance.

Ryder was diagnosed with Williams Syndrome and a heart defect at age 2. After undergoing open-heart surgery, he developed post-pump chorea, which causes involuntary twitching or writhing.

Now, Ryder also can walk independently, feed himself, and sit down and watch a movie. He is limited verbally and uses an AAC (augmentative and alternative communication)device to say simple things. 

“I’m so happy to see how well Ryder is doing,” Dr. Olaya says. “This procedure has tremendously improved his quality of life.”

Answers at age 2

Ryder was born full term on Sept. 29, 2011. He had a heart murmur, but his mother, Ashley, didn’t get a lot of answers from Ryder’s cardiologist until their son was 2. That’s when doctors at another hospital determined that Ryder had been born with supravalvar aortic stenosis (SVAS) and Williams Syndrome.

SVAS, a heart defect that develops before birth, is a narrowing of the large blood vessel that carries blood from the heart to the rest of the body.

Williams Syndrome is a rare genetic condition that affects many parts of the body. It is caused by missing more than 25 genes from a specific area of chromosome 7. Williams Syndrome can cause mild to moderate intellectual disabilities, unique personality traits, distinctive facial features, as well as heart and blood vessel problems.

Ryder’s Williams Syndrome led to him undergoing open-heart surgery at 2 ½, which in turn led to post-pump chorea, which causes involuntary twitching or writhing.

“He was walking and talking and drinking from a cup prior to surgery,” Ashley recalls. “He woke up one day and wasn’t able to sit up or hold his head up or make eye contact. He made weird movements. I first thought it was withdrawal symptoms from the medications he took for the surgery.”

Ryder first saw Dr. Sanger in 2016 at CHLA (Dr. Sanger came to CHOC in March 2020). Ryder’s first DBS surgery was in 2017, the same year he got four permanent electrodes. One of the leads got entwined with a growing bone, which prompted the January 2021 surgery to replace all four electrodes.

The perfect team for Ryder

Ashley and her husband, Al, are determined to provide Ryder with the best quality of life possible. His DBS treatment at CHOC, they say, has made a huge difference.

“Ryder and Dr. Sanger were a perfect match,” Ashley says. “I’m very thankful for DBS and Dr. Sanger. I feel he thinks outside of the box. There are so many other neurologists who think, ‘Oh, let’s just load (the patient) up with medication.’ But Dr. Sanger wants to get at the root of the problem and fix it.”

Ryder loves to go to the beach and on nature walks. At the beach, he will roll into the shallow waters on a stroller with large, fat wheels.

Dr. Olaya stressed the importance of teamwork in treating Ryder and other DBS patients at CHOC.

“We are so fortunate to have the resources and the team here at CHOC to offer DBS treatment to patients with moving disorders,” he says. “Jennifer MacLean, Ryder’s nurse practitioner, is very involved with his care and treating other DBS patients as well. It’s not just one person. It really is the nurses, the OR staff – it’s a lot of people collaborating.”

“I’m so thankful for everybody at CHOC,” Ashley says. “I just feel that without the entire team, none of this would be possible for Ryder or for really anybody. It makes me so happy to know we’ve not only improved Ryder’s life so much, but we’re helping improve other kids’ lives, too. Dr. Sanger goes the extra mile and it’s so amazing to think, yes, that’s our doctor.”

Ashley says Ryder has worked very hard to get to where he is today.

“We’ve all worked hard together to get to this place and give Ryder the validation to show him how much we realize how hard he’s been working,” she says. “I know it’s defeating for a kid who understands but can’t communicate well, but he’s working very hard.”

Learn more about CHOC’s Neuroscience Institute.

First batch of awardees announced for new Chief Scientific Officer small grant program

When Dr. Terence Sanger started at CHOC in January 2020 as its first vice president for research and chief scientific officer, one of his priorities was to “Go Beyond” by making the CHOC Research Institute more robust.

One example of how he’s going about that is a new small grant program he’s funding that is open to all CHOC associates, staff, and faculty with principal investigator (PI) status.

The first batch of awardees in the CSO Small Grant Program, which launched in the third quarter of the current fiscal year, has been announced. Research projects of the winning applicants – 12 of 23 were awarded funding – range from virtual reality training for autism caregivers to racial and ethnic influences in adolescent obesity to the use of artificial intelligence to predict COVID-19 and related diseases.

The amount of all grants totaled $589,365, with recipients receiving up to $75,000 each, says Aprille Tongol, CSO Small Grants Program administrator. In the coming fiscal year, Dr. Sanger, a physician, engineer, and computational neuroscientist who also is vice chair of research for pediatrics at the UCI School of Medicine, will award a total of $1 million in CSO grants, Tongol says.

The CSO Small Grant Program aims to develop promising new research, expand current research activities, and encourage collaboration internally and externally with CHOC research partners. The program promotes and supports CHOC researchers who aspire to leverage research to improve the quality of care, patient outcomes, and well-being for children.

Virtual reality training and autism

Casey Clay, PhD,director of the Behavior Program at the Thompson Autism Center (TAC), was awarded a grant for a project that will examine if a newly developed virtual reality (VR) simulation using behavioral skills training (BST) is effective for training parents of children with autism who exhibit challenging behavior.

Clay says VR simulation is an improvement to typical training because it may increase skills of trainees without exposing them, or individuals with Autism Spectrum Disorder (ASD), to risk such as aggression, property destruction, etc.

Clay’s project builds off previous research he did at the University of Missouri, where he worked before joining CHOC in January 2020. That prior project involved training pre-clinical students to work with kids with autism. Clay’s CHOC project will do the same for parents or caregivers of children with ASD.

“Using the simulation, parents will follow training methods to engage with a virtual avatar and try to say and do the right things and arrange the environment in the right way,” Clay explains. “The idea is to work collaboratively with parents to build their skills at increasing appropriate behavior, and modifying the environment to decrease challenging behavior.”

Clay’s one-year project will begin in August 2021. He plans to sign up 16 teams of parents/children and measure pre- and post-skill levels of the participants, as well as assess parents’ acquired skills with live children during intervention sessions.

“This VR simulation will give parents the opportunity to practice and get immediate feedback from a clinician,” Clay says. “And it’s the practice that makes behavioral intervention effective over time.”

Clay praised the launch of the CSO Small Grants Program.

“It’s a great opportunity to jump start a lot of research,” he says.

Adolescent obesity study

Dr. Uma Rao, director of education and research in psychiatry at CHOC, was awarded a grant to study obesity in adolescents in the African-American, Hispanic/Latina, and Non-Hispanic White female population. The goal of the study is to reduce racial/ethnic health disparities and morbidity and mortality in this population, says Rao, also a professor and vice chair for child and adolescent psychiatry, psychiatry, and human behavior at the UCI School of Medicine.

Adolescence is a critical period for the development and life-long persistence of obesity, a public health epidemic with a range of short- and long-term medical and psychosocial problems and earlier death, Dr. Rao notes.

Her CSO grant is supplemental to a parent grant funded by the National Institutes of Health (NIH). That study, which Rao began in 2018, is assessing biobehavioral processes and social/environmental factors associated with obesity risk from a multi-dimensional perspective in the African-American, Hispanic/Latina, and Non-Hispanic White female population.

The aim of the CSO grant is to identify early stages of liver fibrosis and type 2 diabetes in these samples and assess whether inflammatory biomarkers serve as risk mechanisms for these two obesity-related disease outcomes. 

Knowledge regarding the underlying mechanisms of obesity-related disease burden among high-risk groups will be helpful in early detection and developing effective personalized interventions, thereby reducing racial/ethnic health disparities, morbidity and mortality associated with the obesity epidemic, Dr. Rao says.

Ultimately, she says, the goal is to enroll 300 participants in the study – 100 from each of the three ethnic groups. Participants will range in age from 13 to 17.

“We hope this research ultimately leads to the development of more personalized interventions for these groups to reduce disparities, which cause real havoc,” Dr. Rao says.

List of grant awardees

The second group of awardees of CSO grants was notified on Monday, June 21, 2021.

Here are the 12 recipients of the first round of CSO grants with a brief description of their projects:

Lisa Murdock, RN — Evaluation of a Nurse-Administered Screening Tool to Identify Victims of Child Trafficking in Patients with High-Risk Chief Complaints in a Pediatric Emergency Department

Dr. Autumn Ivy — Identifying Targetable Epigenetic Mechanisms of Early-Life Seizures and Exercise Intervention

Dr. Van Huynh — Utility of Antifungal Prophylaxis to Prevent Invasive Fungal Disease in Pediatric and Adolescent Patients with Hematologic Malignancy

Michelle Fortier, PhD — Opioid Prescribing Patterns in Pediatric and Young Adult Cancer Patients

Dr. Diane Nugent – COVID Antibody Response in Children: Protection and Risk for MIS-C and Late Effects

Dr. Suresh Magge — School-age Outcomes in Patients with Single Suture Craniosynostosis After Endoscopic-assisted Strip Craniectomy and Orthotic Therapy

Dr. Lilibeth Torno — Monitoring of Plasma Cell Free DNA BRAF V600E+ Mutations in Patients with Langerhans Cell Histiocytosis

Casey Clay, PhD — Virtual Reality Training for Autism Caregivers

Alexander Stover, MS — Derivation and Characterization of an NDUFAF5 Mouse Model for the Study of Mitochondrial Complex I Disorders

Louis Ehwerhemuepha, PhD — Artificial Intelligence for Prediction of COVID-19, MIS-C, and Juvenile Dermatomyositis

Dr. Theodore Heyming — Identification of Social and Environmental Determinants of Pediatric Health in an Emergency Setting and Referral Utilization

Dr. Uma Rao — Racial/Ethnic Influences in Adolescent Obesity: Risk Mechanisms for Disease Burden

Study of COVID-19 infection rates among CHOC’s Emergency Department personnel suggests most got virus through community exposure

A team from CHOC has published original research on the prevalence of COVID-19 infection among its Emergency Department workers during the early stages of the pandemic.

A key finding of the study, called PASSOVER (Provider Antibody Serology Study of Virus in the Emergency Room), suggests that most infections were transmitted through community exposure rather than co-workers, although the study stopped short of drawing a definitive conclusion based on the relatively small sample size of workers who agreed to be tested for SARS-CoV-2.

Researchers observed a seroconversion rate of about one new positive case every two days during the period from April 14-May 13, 2020, during which 143 CHOC ED personnel were repeatedly tested for the virus. They included doctors, physician assistants, nurse practitioners, nurses, medical technicians, secretaries, monitor technicians, and additional administrative staff.

“The acquisition of seropositivity in our study group appeared to follow a linear trend, which is not consistent with the exponential rate of growth that would be expected for transmission within a closely interacting group of people,” the study concludes.

The research project, the results of which were electronically published on April 9, 2021 in the Western Journal of Emergency Medicine, was led by Dr. Theodore Heyming, chair of emergency medicine at CHOC, and Dr. Terence Sanger, a physician, engineer, and computational neuroscientist and vice president, chief scientific officer at CHOC, and vice chair of research for pediatrics at the UCI School of Medicine. The other co-authors of the study are John Schomberg, PhD, CHOC’s Department of Nursing; and Aprille Tongol, Kellie Bacon, and Bryan Lara, all of CHOC’s Research Institute.

The study noted that there is limited data that is publicly available on the seroprevalence of SARS-CoV-2 among healthcare workers. Another of the report’s key findings was that rapid antibody testing may be useful for screening for SARS-CoV-2 seropositivity in high-risk populations such as healthcare workers in the ED.

In the CHOC study, blood samples were obtained from asymptomatic ED workers by fingerstick at the start of each shift from April 14-May 13, 2020. Each worker’s blood sample was obtained every four days until the end of the study period. In addition, a nasopharyngeal swab (NPS) was collected from each participant on the date of study entry.

At the time of the study, 35 percent of the participants had known exposure to a COVID-19-positive individuals within the preceding five days.

Depending on the method used for analysis, the seroprevalence of SARS-CoV-2 among CHOC’s pediatric ED workers ranged from 2 percent to 10.5 percent – levels that were slightly higher than those reported for the local general population, the study found.

“This study would benefit from replication at additional sites that draw from larger samples of ED staff,” the report says.

Learn more about CHOC’s COVID-19 vaccine clinic.

Neuroscience leaders discuss innovations and their successes, and the need for much more work to be done

Two of CHOC’s leading pediatric neurosurgeons recently shared their insights on how innovation is helping to close the gap between clinical needs and the availability of pediatric devices, but how there is much more work to be done to get critically ill kids the treatments they need.

The webinar, “From Clinical Insight to Commercialization: Innovations That Can Transform Pediatric Healthcare,” featured Dr. Suresh N. Magge, CHOC CS Neurosurgery Division Chief, and co-director of CHOC’s Neuroscience Institute, and Dr. Michael G. Muhonen, the institute’s previous co-director.

Hosting the “OC LIFe (Lifesciences Innovators Forum)” on April 28, 2021 was Dr. Terence Sanger, a physician, engineer, and computational neuroscientist and vice president, chief scientific officer at CHOC, and vice chair of research for pediatrics at the UCI School of Medicine.

“As innovators, we should never be satisfied,” said Dr. Sanger, who specializes in movement disorders and who helped pioneer deep brain stimulation, which has yielded positive outcomes. “An innovative and collaborative approach is required so that pediatric patients can have access to the fit-for-purpose devices they need.”

Brain tumor treatments

Drs. Magge and Muhonen took turns discussing new neurosurgical technologies and opportunities for interventions.

Dr. Magge focused on new technology that has been used to treat brain tumors, which are a different breed compared to adult brain tumors. More often, Dr. Magge said, pediatric brain tumors are of a lower grade and can be treated.

“Many kids have gone on to live good lives thanks to innovation, research, and applying the technologies we have,” Dr. Magge said.

In one example, he detailed how microsurgical techniques have greatly aided in the removal of a craniopharyngioma, a benign tumor that usually arises in the base of the brain near the pituitary gland that can be dangerous or life threatening if not treated.

“If you can get the tumor out,” Dr. Magge said, “you can cure the patient. But it’s challenging because it’s in a deep part of the brain.” 

During the procedure, the neurosurgeon must locate some of the natural divides of the brain and separate them out to get to the tumor. Microsurgery allows the neurosurgeon to work between very narrow areas.

With a technology known as surgical navigation, neurosurgeons can pinpoint exactly where they are in the brain and get to very specific areas. Another technology is a powerful microscope that magnifies small areas of the brain. In addition, ultrasound and MRI within the operating room can tell you in surgery if there is any tumor left. 

“This is all thanks to innovation and technology that we are incorporating in surgery,” Dr. Magge said.

Dr. Magge then discussed medulloblastomas, one of the most common types of tumors neurosurgeons see in kids. Such large tumors grow in the lower back part of the brain — the cerebellum, which is involved in muscle coordination, balance, and movement.

Thirty years ago, Dr. Magge said, kids with medulloblastomas received high doses of radiation that left a lot of them with severe cognitive and hormonal deficits.

The treatment for medulloblastomas had evolved so that less radiation is used in the treatment. In addition, in the last decade, researchers have discovered that these tumors differ significantly based on their genetic makeup.

“These tumors have multiple genetic subtypes, and we can target them genetically with different types of treatments,” Dr. Magge explained.

He said innovation also has led to advances in the treatment of diffuse intrinsic pontine gliomas (DIGP), highly aggressive and difficult-to-treat brain tumors that grow in an area of the brainstem that controls many of the body’s most vital functions such as breathing, blood pressure, and heart rate.

The prognosis for DIPGs remains very poor because they are considered non-resectable tumors – ones that cannot be removed with surgery. Life expectancy is eight to 12 months after diagnosis.

“This is one of the toughest diagnoses we have to give to families because of the lack of good treatment options,” Dr. Magge said.

For years, biopsies were ruled out because they could cause significant side effects, and neurosurgeons saw no point in performing them since there were no treatments. Without biopsies, the tumor tissue could not be studied in a lab for potentially effective treatments. 

Technology has changed this is the last 10 years, Dr. Magge said, thanks to stereotactically guided needles that allow neurosurgeons to perform DIPG biopsies safely.

“We at CHOC and other pediatric hospitals have shown we can do this safely with minimum morbidity,” said Dr. Magge, who has participated in a large clinical trial regarding DIPG biopsies.

“With this technology, we can get tissue and genetically sequence these tumors and find out if there are certain mutations that are particularly amenable to certain treatments,” Dr. Magge said of this precision-medicine approach. 

“These are small steps along the path,” he added. “We have by no means found all the answers. We have so much farther to go, but I think we’re on the right track.” 

Closing the gap

Dr. Muhonen recalled one of the first patients he saw when he came to Orange County in 1995: a young girl with severe spasms in her legs. She couldn’t walk without assistance.

“We had to do something innovative,” Dr. Muhonen said.

He had injected baclofen, a muscle relaxer and antispasmodic agent, into the spinal column of an adult the year before, but never in a child. After receiving approval to do so, he implanted a device that allowed long-term injection of baclofen in the girl’s spinal cord. Six months later, she was able to walk and even run on her own.

In another example of innovation, Dr. Muhonen worked for five years on helping to develop a wireless sensor to measure pressure in the brain. The FDA approved the device for adults, but has yet to for children.

Most companies get medical devices approved for adults because it’s easier, because there’s a larger patient population, and there’s more money to be made. 

“The bulk of challenges associated with developing and accelerating pediatric medical devices is market-driven,” Dr. Muhonen said. “We want children to get the best possible care available, but the relative market size is small compared to adults, which is one reason some device makers avoid it.”

One of Dr. Muhonen’s chief interests is treating hydrocephalus, the buildup of fluid in the ventricles deep within the brain.

Innovation in this area has been a long time coming, he said, since the invention in the early 1950s of a shunt that drained fluid from the brain into the abdominal cavity. Many problems can occur with the shunt, such as spontaneously twisting up into a knot due to a child’s movement or calcifying and breaking apart after being in the body for a long time. Kids who received a shunt typically face more than 10 surgeries, Dr. Muhonen said.

“The holy grail for pediatric neurosurgeons is, can we create a ‘smart shunt?’” Dr. Muhonen said.

An ideal shunt, he said, could be programmed to drain a specific amount of water and measure pressure.

Dr. Muhonen said a derivative from cone snails is inspiring research into a new generation of painkillers for adults, but has yet to be approved for testing on kids.

Impediments to innovation

Dr. Sanger asked Drs. Magge and Muhonen about impediments to pediatric innovation. Ethically, he posited, shouldn’t new devices and other innovations be tested in adults first? 

“I don’t think there are any easy answers to this,” Dr. Magge said. “It’s difficult. You don’t just do a biopsy on a tumor that might help kids in the future. If you perform surgery on a child, there has to be some potential benefit to that child.”

Dr. Muhonen said children are the most vulnerable of society and thus are the worthiest of innovations in healthcare. 

Dr. Magge said he and others at CHOC have been looking at ways to inject dyes to paint brain tumors to more easily distinguish them from healthy brain tissue.

“Sometimes the tumor is obvious, sometimes it’s more challenging,” he said.  While dye injections have been used in adults, it is less commonly used in children.

Dr. Sanger mentioned “big effect sizes” resulting from innovation in pediatric medicine. 

“We’re used to the idea of statistical research involving a lot of patients,” he said. “But this is a different type of research. You take someone who has never walked before and now they’re running. You take someone who is going to die of a brain tumor and now they’re not. These are very big effect sizes.” 

“There are good reasons for the regulations we have,” Dr. Magge said. “That being said, that doesn’t mean we can’t innovate. And there are mechanisms for us to do that, and to do it safely.

“Our first motto is, ‘Do no harm,’” Dr. Magge continued. “I always tell residents to do the right thing and treat each patient as if they were your own child. Doing the right thing means asking the right questions. ‘How can we do this better?’ You can always learn from everything you do. At the end of every procedure, you critique it. You’re constantly learning. That’s what I always encourage.” 

Dr. Sanger closed the session by noting that clinical evidence should ideally be reflective of the spectrum of pediatric patients and the developmental differences that can impact the use and effectiveness of medical devices.

“This is a collaborative effort,” he added. “CHOC is working closely with the FDA’s new System of Hospitals for Innovation in Pediatrics – Medical Devices (SHIP-MD) Program, our academic partners, industry, entrepreneurs and the investor community to close the gaps. Also, we are now practicing medicine in a world immersed with data. Advances in computing and health information technology have given rise to new sources and types of biomedical data. Clinicians know real-world data will continue to emerge as a source of clinical evidence.”

The Presenting Sponsor of the webinar, “From Clinical Insight to Commercialization: Innovations That Can Transform Pediatric Healthcare,”  was Biocom California, which connects life science organizations to each other so they can collaborate and work smarter together. The CHOC Research Institute co-sponsored the hour-plus session.

The webinar was presented in partnership with SBDC @ UCI Beall Applied Innovation, a resource for any high-technology, high-growth, scalable venture from the community or the UCI ecosystem that needs help with business planning, business development and funding-readiness.

Learn more about CHOC’s Neuroscience Institute.

Three-stage DBS results in better outcomes for secondary dystonia

Due to the complexity of secondary dystonia and the brain’s potentially unpredictable response, deep brain stimulation (DBS) has seldom been used in the treatment of this disorder. However, a CHOC neuroscientist has developed a breakthrough method of DBS to treat secondary dystonia in pediatric patients.

Dr. Terence Sanger, pediatric neurologist and chief scientific officer at CHOC, has pioneered a new surgical approach in DBS for pediatric secondary dystonia. Patients undergo three procedures rather than two, nullifying the need for patients to be awake during DBS surgery. Not only does this save children from the potentially traumatic experience of being awoken during brain surgery, it leads to significantly better outcomes in secondary dystonia treatment, with a current success rate between 85% and 90%.

Dr. Terence Sanger, pediatric neurologist and chief scientific officer at CHOC

Unlike patients receiving DBS for other disorders, where results can be observed during surgery, a child with secondary dystonia may have concerns with movements or actions that can’t be addressed on the operating table. For example, a child with secondary dystonia may have difficulty walking, but the physician cannot test DBS’ effectiveness by waking the child and asking him or her to walk.

To overcome this obstacle, Dr. Sanger and his team first insert test electrodes into the patient’s brain. The initial procedure is followed by a week of surveillance and testing. After selecting which electrodes are most effective at treating the patient’s symptoms, the team places permanent electrodes followed by a third procedure to implant the stimulator. The week between the placement of test electrodes and the placement of permanent electrodes allows Dr. Sanger and his team to observe which electrodes are effective.

“The biggest benefit of the three-procedure method is we know where the wires need to be in the patient’s brain for the most effective treatment,” Dr. Sanger says. “By the time we get to the third surgery, we know exactly what’s going to happen. As an engineer, I’m a big believer in measuring twice and cutting once, and effectively, that’s what these three procedures allow us to do. Every child’s brain is different, so we have to learn about how each brain operates before we can perform a successful surgery.”

In addition to his revolutionary procedure for secondary dystonia, Dr. Sanger believes in the future of neuroscience at CHOC.

“At CHOC, our tagline for research is ‘Go beyond,’ and I’ve never seen that belief more exemplified than in the work I’ve seen at our Neuroscience Institute,” Dr. Sanger says. “We are not going to improve pediatric neurology care by doing what other hospitals do, but better. We are going to improve by doing something different, like we’ve done with DBS for secondary dystonia. It’s very exciting, and I believe we have the opportunity to make a huge difference.”

Our Care and Commitment to Children Has Been Recognized

CHOC Children’s Hospital was named one of the nation’s best children’s hospitals by U.S. News & World Report in its 2020-21 Best Children’s Hospitals rankings and ranked in the neurology/neurosurgery specialty.

USNWR Neurology and Neurosurgery award

Learn how CHOC’s neuroscience expertise, coordinated care, innovative programs and specialized treatments preserve childhood for children in Orange County, Calif., and beyond.

CHOC-UCI origami mask project gets some national attention

Back in the early days of the COVID-19 pandemic, in late March 2020, Jonathan Realmuto, a visiting scientist at CHOC and a postdoctoral researcher at UC Irvine, got a call from his lab leader, Dr. Terence Sanger.

Dr. Sanger, a physician, engineer, and computational neuroscientist who joined CHOC in January 2020 as its vice president of research and first chief scientific officer, was concerned about the possibility of CHOC running out of masks for its frontline healthcare workers.

“Could you please think about this problem and see if you can come up with a solution just in case the supply runs out?” Dr. Sanger asked Realmuto, who has a Ph.D. in mechanical engineering and whose expertise is wearable robotics, which help people regain and strengthen their movements.

Dr. Terence Sanger, chief scientific officer at CHOC

Since September 2017, the two had been working together after Realmuto earned his doctorate degree from the University of Washington.

Thus began the UCI Face Mask Project, a collaboration between Dr. Sanger and Realmuto that grew to a team of five that includes two other UCI professors, aerosol chemist Jim Smith and environmental toxologist Michael Kleinman, and Michael Lawler, an atmospheric chemist and assistant project scientist who works in Smith’s lab.

The work of the UCI Face Mask Project ultimately led to the creation of what experts call a mask for the masses — an inexpensive face covering that takes its cues from origami, the art of paper folding closely associated with Japanese culture.

No sewing is needed to make the origami mask – just a filter material that can be purchased at a craft or hardware store, a stapler, two elastic straps, and a nose clip fashioned from a metal wire such as a twist tie.

Illustrated directions for creating the origami mask

Realmuto was among several origami mask experts recently featured in a National Geographic story that highlights the inexpensive (less than $1 of materials per mask), disposal masks that can be made by anyone after a little practice. The story details how origami pleats and interlocking folds can result in better-fitting, more comfortable, and more stylish face coverings.

Dr. Sanger, who served in an advisory capacity on the UCI Face Mask Project, played a “very critical role” in developing the mask, which has not been mass produced but was designed in case there is a shortage of face coverings such as N95 masks, the gold standard at preventing expelled air leakage during coughing.

“CHOC and UCI were one of the first out of the gate to work on this,” says Realmuto, who with his colleagues has written a paper, “A Sew-Free Origami Mask for Improvised Respiratory Protection,” that details the research that went into the project.

The team put several masks through rigorous testing using a custom-made mannequin head equipped with a breathing tube and mounted inside a chamber.

The team concluded, in the paper they plan to get reviewed by peers and published, that origami masks combine high filtration efficiency with ease of breathing, minimal leakage that can dramatically reduce overall mask performance, and greater comfort compared to some commercial alternatives.

Because of this, origami face coverings are “likely to promote greater mask-wearing tolerance and acceptance,” the researchers concluded in their paper.

Says Realmuto: “Origami presents this really nice solution where you can use the folds as a way to make seams that won’t leak.”

The team produced a how-to video starring Realmuto, who shows how to construct the single-use masks. They tested a variety of materials that have an inner layer of non-woven polypropylene that can be easily and rapidly sourced locally from a hardware or craft store, in addition to a material made by Filti that can be purchased through the manufacturer.

“For a novice without prior experience,” they write, “construction takes approximately 10 minutes. In our experience, practice decreases assembly time to under five minutes.”

Dr. Sanger and Realmuto have collaborated on another unrelated project that earned them accolades. That project involved developing a non-rigid forearm orthosis – a brace to correct alignment or provide support – to help make it easier for people with movement disorders such as cerebral palsy to feed themselves, open doors, and complete other daily tasks. Their work made them finalists in the Best Paper category at the 2019 Institute of Electrical and Electronics Engineers (IEEE) Conference on Soft Robotics.

In July 2021, Realmuto will become a full-time assistant professor in the Department of Mechanical Engineering at UC Riverside. He says he hopes to maintain his collaboration with Dr. Sanger and CHOC on future projects.

“It’s been a great partnership,”Realmuto says.

For more information about the UCI Face Mask Project, click here.

CHOC clinicians pitch ideas for new medical devices to UCI students

In the neonatal intensive care unit (NICU) at CHOC, most pre-term babies are not able to take all their food through a bottle until they’re closer to term. They also must rely on a tube connected to a feeding pump.

In hospitals that have a centralized room where technicians prepare feedings for the nurse, the feeding is often delivered pre-drawn up in a syringe since it is unknown if all of the feeding will be given via the tube or if the baby will be able to take some by mouth.

If the baby is alert enough to eat by mouth, the nurse would need to transfer some of the feeding from the syringe to a bottle. If the baby did not take the full volume in the bottle, the nurse would need to draw any remaining milk back into the syringe to be able to deliver it via a tube.

Because of all these steps, there’s a risk of contamination, misadministration (giving the wrong milk to the wrong baby) and a loss of nutrients caused by milk adhering to the side of the containers.

Wouldn’t it be great to create a device that could solve those concerns and make feeding premature infants safer and more efficient?

That was the concept presented by Michelle Roberts, a registered nurse and lactation consultant, to UCI biomedical engineering graduates at the annual UCI BioENGINE Reverse Project Pitch Night.

Undergraduates students in the BioENGINE Program (Bioengineering Innovation & Entrepreneurship) obtain hands-on experience in the technical and business development aspects of biomedical engineering as they work in teams to further develop med-tech startups into marketable products.

Roberts was among several CHOC associates who gave two-minute presentations at the Fall 2020 Reverse Project Pitch Night, held online because of the COVID-19 pandemic. Kicking off the 90-minute session, which featured some 30 presenters, was Dr. Terence Sanger, a physician, engineer and computational neuroscientist who joined CHOC in January 2020 as its vice president of research and first chief scientific officer.

BioENGINE partners with the UCI School of Medicine, the Henry Samueli School of Engineering, the Donald Bren School of Information and Computer Sciences, the Beckman Laser Institute, UCI Athletics and UCI Applied Innovation. 

At Reverse Project Pitch Night, physicians, scientists, clinicians and industry representatives describe their concepts for new medical devices. Students are matched with projects that interest them and are mentored by the presenters to help develop healthcare solutions.

“Physicians and engineers need to work together,” said Dr. Sanger, a child neurologist who specializes in movement disorders. “The goal is to identify an important problem, marry it to a piece of technology, and create a device in a way that will have an impact. Different knowledges have to be brought together, and personally I find that very inspiring.”

In the final quarter of 2020, the CHOC Research Institute sponsored three pediatric-focused projects that were presented at Reverse Project Pitch Night.

One software project, presented by Sira Medical, involves the use of patient-specific, high fidelity 3D holograms to enable surgeons to better understand complicated anatomy, collaboratively plan an operation, and virtually size medical implants — all before stepping into the operating room.

Another project, presented by Adventure BioFeedback, is designed to deliver speech therapy anywhere, anytime. The company is producing a series of audio linguistic tools that can analyze and learn on-the-fly from the utterances of children performing vocal exercises using a smartphone. 

The third CHOC Research Institute-sponsored project, NeuroDetect, places a patient’s own stem cells on a computer chip to replicate the brain chemistry of the neurological disorder in a laboratory environment and facilitate rapid development of precision-guided therapeutics.  

Roberts offered to serve as a mentor on her project along with Caroline Steele, director of Clinical Nutrition and Lactation Services at CHOC. Edwards Lifesciences is involved in designing the device.

Kaitlin Hipp, another CHOC NICU nurse, introduced her project, Touche, at BioENGINE Reverse Project Pitch Night. It’s a hands-free communications system for nurses and healthcare workers that is especially relevant in the era of COVID-19. The Bluetooth device can communicate with several devices – phones, monitors, etc. — thereby reducing or eliminating the need for nurses to touch the surfaces of items.

“We need to be better about using touchless technology in the healthcare setting,” Hipp said. “Long term, think of this as Alexa for healthcare providers.”

Dr. Timothy Flannery, a pediatric endocrinologist at CHOC, introduced Cervos, a non-invasive device to address cervical incompetence, which affects 1 percent of all pregnancies. The goal is to get Cervos approved for clinical trials at medical schools, Dr. Flannery said.

Dr. Sanger, in his remarks, noted CHOC’s critical mission of ramping up research to better address unmet healthcare needs by marrying engineering with healthcare.

“Medicine is about decision making,” Dr. Sanger said. “Biology is so complicated we can’t hope to ever understand it fully. When you want to make decisions in healthcare, you need to take measurements and design interventions that will respond to those measurements. In medicine, the goal is always to make the next big decision. You don’t even need to know the diagnosis if you can make the right decisions.”

Artificial intelligence seen as critical tool in helping to diagnose rare diseases

Machine learning algorithms could make a dramatic difference when it comes to diagnosing children with rare diseases, two CHOC doctors said in a recent webinar.

Although the use of artificial intelligence (AI) in diagnosing medical conditions is in its infancy stages, the potential is huge, said Dr. Jose Abdenur and Dr. Terence Sanger, speaking on a panel during a two-week summit on rare diseases hosted by Global Genes, an Aliso Viejo-based non-profit that advocates for the rare disease community.

“Human decision making is very, very good,” said Dr. Sanger, vice president for research and chief scientific officer at CHOC. “But we’re not very good at incorporating tens of thousands of pieces of information into making these decisions.”

That’s where machine learning could be of immense value, he and Dr. Abdenur said in the one-hour discussion on Sept. 22, which can be viewed in its entirety here.

Machine learning involves the use of computer algorithms that improve automatically by building mathematical models based on reams of data. This makes AI particularly valuable for improving the rare disease diagnosis process, which remains far from perfect, says Abdenur, chief of the division of metabolic disorders at CHOC and director of CHOC’s metabolic laboratory.

Although great strides are being made in diagnosing rare diseases through such processes as rapid whole genome sequencing, 40 percent of families with sick children still do not have diagnoses, Dr. Abdenur said.

“We’re doing better, but we’re definitely not good enough,” he said. “We hope in the future that artificial intelligence and machine learning will help us (reach diagnoses faster).”

In diagnosing patients, clinicians consider a list of possible conditions or diseases that could be causing symptoms – what’s known as making a differential diagnosis. They consider such things as a patient’s symptoms, his or her medical history, basic lab results, and a physical examination.

With AI, a virtually limitless amount of information beyond that – such as similar symptoms that have occurred in patients around the world, the environment they live in, etc. – could be factored into helping make differential diagnoses.

Dr. Sanger compared the benefits of using AI in diagnosing patients to a standard camera – what’s used now – to a wide-angel lens that can take in much more information, which machine learning would provide.

“If you have an avalanche of information, (physicians) can’t take all of it in themselves,” Dr. Abdenur noted.

But a sophisticated machine-learning program could, he and other panelists said.

An algorithm that gets smarter over time would lead to faster, simpler, accurate, and earlier diagnoses, said panel member Annastasiah Mhaka, co-founder of the Alliance for AI in Healthcare.

“Data is at the heart of (learning more about rare childhood diseases), and AI would help along every step of the way,” said another panelist, Sebastien Lefebvre, an analyst with Alexion Pharmaceuticals.

Both Dr. Abdenur and Dr. Sanger agreed that AI could be used to augment a clinician’s decision, but never replace it.

“(AI) never makes a decision for you,” Sanger said. “It just assists in the decision making.”

Newly emerging technologies such as machine learning in healthcare could lead to lower healthcare costs and better treatment, Mhaka said.

“Diagnosis needs are huge and unmet in the (rare disease) population,” she noted.

Learn more about rare disease research at CHOC.

Wired for hope: deep brain stimulation for dystonia

Every morning when she awakes, Sydney Amato begins her daily battle with her body.

If she’s lucky, the 16-year-old will have gotten a handful of hours of uninterrupted sleep – dreaming, perhaps, of doing what most healthy kids her age take for granted:

Hanging out with friends. Going to school. Learning to drive.

Because of a neurological condition called dystonia, Sydney, who is in excellent cognitive health but speaks and walks with some difficulty, suffers from involuntary and near-constant contraction of muscles in her neck, arms, legs and trunk.

Sydney with her father, Louis

Her mind is unable to control the painful jerking that makes most of her body twist and go rigid, her muscles moving out of normal sequence.

Born a right-hander, she can feed herself with some struggle using her left hand. She wants to dress and put on makeup herself, but those normally simple tasks become lengthy ordeals.

“My body fights me all the time,” says Sydney, trying to distract herself in her hospital bed by watching an old episode of “Keeping Up with the Kardashians.” Listening to her favorite music – Ariana Grande, Lauren Daigle, Drake – can only temporarily transport Sydney away from her debilitating condition.

“She knows what she wants to do,” says her father, Louis. “But her body won’t let her.”

Specialists at CHOC are working hard to change that.

A first for CHOC

On Aug. 14, 2020, a team led by Dr. Terence Sanger, a physician, engineer, and computational neuroscientist who joined CHOC in January 2020 as its first chief scientific officer, and Dr. Joffre E. Olaya, CHOC’s functional restorative neurosurgeon, implanted several temporary electrodes into Sydney’s brain.

Dr. Terence Sanger, a physician, engineer, and computational neuroscientist and CHOC’s chief scientific officer

The surgery marked the first time a patient with a movement disorder at CHOC underwent a procedure called deep brain stimulation (DBS).

Working in perfect harmony as a team, Dr. Sanger and Dr. Olaya performed the first stage of a three-stage surgery on Sydney. As the surgeon, Dr. Olaya placed the leads following advice from Dr. Sanger, the neurologist, where they should go.

In the procedure, millimeter-thick electrodes were precisely positioned into the basal ganglia region of Sydney’s brain – about three inches deep. The surgery involved the use of the ROSA Robot, the same tool that has been used during brain surgery on epilepsy patients at CHOC since 2015.

Dr. Joffre E. Olaya, CHOC pediatric neurosurgeon

Considered one of the most advanced robotized surgical assistants, ROSA includes a computer system and a robotic arm. It’s a minimally invasive surgical tool that improves accuracy and significantly reduces surgery/anesthesia time.

The ROSA Robot helped with implanting and targeting the electrodes, and a portable operating-room CT scanner confirmed their position.

Turning down the volume

DBS is designed to ease Sydney’s condition by sending electrical currents to jam her malfunctioning brain signals.

Think of turning down the volume on your car radio.

“Nobody really understands the cause of dystonia,” Dr. Sanger explains, “but there’s probably too much electrical stimulation going on in the motor areas of the brain. We’re trying to calm down that extra noise.”

Although DBS dates to the 1960s, it wasn’t until the 1980s that the modern era of using it to treat adult patients with tremor and Parkinson’s disease began.

In 2000, Dr. Sanger, working with engineers, data scientists, neurosurgeons, and others, began implanting electrodes in pediatric patients.

Instead of the established method of placing the leads at predetermined sites and hoping they worked, Sanger and his team, just as they did in Sydney’s case, placed temporary leads to best assess where they should go permanently based on patient response.

In 2016, Dr. Sanger began honing DBS to treat children with dystonia. Before the surgery on Sydney, Dr. Sanger had performed DBS on 26 children using the same three-stage technique. He says 80 percent of those children have seen successful results.

Early signs

Sydney began showing symptoms of dystonia – tremors in her hands — when she was 5 ½ years old.

A year later, she was using a wheelchair. She had her first brain surgery at age 7.

Since then, “she’s been all over the U.S.” seeking the right treatment for her condition after several setbacks, says her father.

But her condition was not improving.

Early this year, a neurologist in Kansas City, Mo., recommended that Sydney see Dr. Sanger.

“I asked him, ‘If Sydney was your kid, where would you go?’ Louis Amato recalls. “He said, ‘Hands down, Dr. Sanger.’”

The COVID-19 pandemic pushed Sydney’s surgery to mid-August.

Sydney already had two electrodes in her brain that were only partially working when she came to CHOC in early August for surgery.

After two extensive run-throughs with their team, Dr. Sanger and Dr. Olaya, in a six-hour procedure that at one point had nearly 20 people in the operating room, implanted more electrodes to give her a total of nine.

On Thursday, Aug. 20, six days after Sydney’s surgery, Dr. Sanger stopped by her room at CHOC Hospital. The room was decorated in purple, Sydney’s favorite color.

Dr. Sanger greeted her as CHOC staff members, joined by members of Sanger Lab, which conducts research in pediatric movement disorders, prepared to have Sydney walk back and forth down a hallway while connected to electrical equipment programmed to record signals in her brain and muscles.

A thick coil of multicolored wires snaked from under a large white bandage covering Sydney’s head. Extending about 6 feet, the wires were plugged into specialized recording equipment controlled by Jennifer MacLean, a pediatric nurse practitioner whose job was to manipulate the strength of electrical charges affecting the four points of contact on each electrode.

The goal: determine which charges worked best and on which electrodes.

“It could have turned out that the DBS procedure made no difference,” Dr. Sanger says. “But we’ve seen a very good response in Sydney.”

For example, her once mostly useless right hand was working much better.

“It gives you goosebumps,” Louis Amato says.

After taking a bite of a veggie burger and sipping some water, Sydney started to walk.

Following her were seven CHOC and Sanger Lab specialists.

“Go nice and slowly,” Jennifer told Sydney. “You’re going too fast for us!”

Perhaps Sydney was anxious to get back to riding Tigger, a quarter horse, in her hometown of Carthage, Mo. She has been riding him for six months.

Sydney is eager to get back to riding her favorite horse, Tigger.

“Her balance isn’t bad on the horse,” says Louis Amato.

Sydney also loves to tan by her pool and swim.

What she wants most, however, is to be freed from her body so she can return to school and do what most teens enjoy.

“It’s stressful,” says her mother, Angie. “She has a lot of friends her age, but she can’t do a lot of the things they do. She has her days when she can get really upset.”

Now, however, working with Dr. Sanger, Dr. Olaya and the entire team at CHOC, the Amatos are more optimistic than ever.

“We’re hopeful that this is going to be a big life-changer for her,” Angie Amato says. “That would be the best thing that could ever happen – better than winning the lottery.”

‘The A Team’

After crunching numbers for a week to assess which of the nine electrodes proved to be the most effective based on how Sydney responded to varying degrees of electrical currents, Dr. Sanger and his team settled on four electrodes that were permanently used to treat her condition – three new ones, and one existing one.

The team performed this second surgery on Sydney in late August.

In the third and final surgery, successfully completed in early September, a rechargeable generator that powers the DBS leads was implanted in Sydney’s chest.

“As we get better and better at this,” says Dr. Sanger, “and as the technology progresses, we’ll be able to do this on kids who are less sick than Sydney.”

Dr. Sanger and Dr. Olaya are poised to dramatically improve the lives of many more patients like Sydney at CHOC.

“I’m really excited that we will be doing more of these procedures to help pediatric patients with movement disorders and significantly improve their quality of life,” says Dr. Olaya. “I look forward to continuing to provide this type of personalized care.”

Angie and Louis Amato say Sydney has never gotten this much special attention during her 11-year-plus medical journey.

“Here at CHOC,” Louis Amato says, “we feel like we’re with the A Team.”

Says Sydney: “I’ve never felt this much confidence and this good about treatment before.”

Learn more about deep brain stimulation (DBS) surgery at CHOC.