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%.
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.
CHOC’s Blueprint for Achieving Successful Outcomes for Bone Marrow Transplant Patients Long-term survivorship and improved quality of life among pediatric cancer patients undergoing bone marrow transplants is routinely threatened by three ...
The state of California has awarded CHOC, in partnership with UC Irvine and Chapman University, a $2.3-million grant to screen patients for adverse childhood experiences (ACEs) and childhood unpredictability to assess how such high-stress events affect the brain and put kids at increased risk of later developing physical and mental illnesses.
In a novel aspect of the study, researchers also will determine if there are epigenetic markers on the DNA that predict whether any given child will be more adversely affected than another.
The team is among four awardees statewide that have been given a total of $9 million to assess which children are most vulnerable to the effects of ACEs and unpredictability in the home environment, and to design medical care to improve the outcomes for this particular group of patients – a model known as “precision medicine,” which eschews a one-therapy-fits-all approach to healthcare.
“The whole concept here is that kids who grow up in environments with frequent exposures to toxic levels of stress can have all kinds of internal things happen in their bodies related to prolonged or extensive stress hormone response – their brains can develop differently, and when they become adults, research has shown that they have a higher risk of developing medical conditions such as heart disease, asthma and cancer, among other physical diseases, as well as mental disorders,” says Dr. Charles Golden, a co-investigator on the study and executive medical director of the CHOC Primary Care Network (PCN).
The California Governor’s Office of Planning & Research, in partnership with the Office of the California Surgeon General, awarded the three-year research project as part of the California Initiative to Advance Precision Medicine (CIAPM). The other three recipients were Children’s Hospital Los Angeles, University of California, San Francisco, and Loma Linda University.
The CHOC-UCI-Chapman research project begins in July 2021, with screening expected to start in CHOC PCN clinics by November 2021. Lead principal investigator on the project is Dr. Tallie Baram, Bren Distinguished Professor and director of the Conte Center at UCI. The National Institute of Mental Health-funded Conte Center also addresses how early-life experiences influence the brain and contribute to mental illnesses.
Results of the study are expected by the end of 2024, says Laura Glynn, PhD, a Professor of Psychology and Associate Dean for Research at Chapman University and one of the principal investigators on the study.
CHOC’s PCN has been screening its Medi-Cal patient population for ACEs since February 2020, and expanded such screening – using a tool called PEARLS, for Pediatric ACEs and Related Life Events Screener – to all patients in November 2020, Dr. Golden says.
The 17-question PEARLS tool screens for such experiences as a parent being jailed, the prevalence of alcohol or drug abuse in the household, and whether the child has been a victim of violence in his or her neighborhood, in the community at large, or at school.
“This existing infrastructure at CHOC was a very important part of the application for this grant,” Glynn says.
The CHOC-UCI-Chapman study, “Using Precision Medicine to Tackle Impacts of Adverse and Unpredictable Experiences on Children’s Neurodevelopment,” will dig deeper than standard PEARLS screening.
The children will be asked an additional five questions to assess exposure to unpredictability in the social, emotional, and physical domains. Such questions are an attempt by researchers to develop an instrument that will predict this population of kids’ resilience to, or risk of developing, physical or mental illnesses. Children from low socioeconomic and racial/ethnic minority communities are at greater risk of exposure to ACEs.
“This study will involve looking at whether routine, or lack of routine, in a child’s life contribute as an ACE,” Dr. Golden explains. “In other words, do they eat dinner every night at 6 p.m., do they have a routine bedtime, do they have a stable household versus a family with no routine or little structure.”
Such factors of unpredictability potentially are amenable to intervention, Glynn notes.
Emerging evidence from experiments with rodents show that fragmented or unpredictable maternal signals influence the maturation of systems governing emotional and cognitive function in the developing brain. In preclinical work led by Dr. Baram, the group has shown that rats exhibited diminished memory function when exposed to unpredictable maternal signals early in life, as well as anhedonia (reduced ability to experience pleasure) beginning in adolescence.
Also, as part of the study, DNA swabs will be performed on a cohort of 120 children who experience high levels of ACEs to determine if genetic expression patterns indicate a vulnerability to chaos and unpredictability in their lives. The team also will be examining whether epigenetics – the process of how genes may be altered based on environmental events – may play a role in the development of ACE-related medical conditions.
“We think potentially we can look at these epigenetic profiles to predict neurodevelopmental outcomes,” Glynn says.
Dr. Michael Weiss, vice president of population health at CHOC and a primary investigator on the study, says such information may make it easier for doctors to identify a child who has a genetic predisposition to experiencing a bad outcome from being exposed to ACEs – thus leading to targeted interventions to kids who need them the most.
“This project is a great demonstration of a collaboration between CHOC and UCI and Chapman University involving primary care research,” Dr. Weiss says.
Other CHOC researchers who will participate in the research project are Dr. Dan Cooper, who treats kids with lung conditions at CHOC and who serves as director of UC Irvine’s Institute for Clinical & Translational Science; Dr. Candice Taylor Lucas, co-director of LEAD-ABC (Leadership Education to Advance Diversity–African, Black and Caribbean) at UCI/CHOC; Louis Ehwerhemuepa, PhD, a senior data scientist; and Dr. Mary Zupanc, co-medical director of the Neuroscience Institute.
In the only known hospital research project of its kind in the United States, CHOC’s Emergency Department is leading a study on how food and housing insecurity impacts children’s health and environment.
The project, being conducted in collaboration with departments at UC Irvine and Chapman University, involves surveying 7,000 CHOC ED patients by September 2021, with results expected by the end of the year, says Dr. Theodore Heyming, medical director of emergency medicine at CHOC and chief architect of the effort.
The study, which to date already has enrolled some 2,500 CHOC patients, will assess ACEs, also known as adverse childhood experiences. Most ACEs studies conducted to date by other hospitals have been limited to the primary care setting. Since July 2020, CHOC’s ED has been screening for ACEs with particular attention to the following three areas: abuse, neglect, and/or household challenges.
“To my knowledge, we’re the only pediatric hospital that has this kind of health research project implemented in an emergency department,” Dr. Heyming says. And that makes sense, he adds.
“People don’t usually think of an emergency room as a primary care setting,” Dr. Heyming says. “However, the opposite actually is true. A lot of patients use the ER as their primary care. EDs also have the ability to potentially intervene on patients even to a greater extent than in the primary care setting, given the availability of experienced social workers.”
The potential benefits of the study, which involves questioning patients in more depth than standard ACEs screenings, are numerous, as detailed in an abstract that Dr. Heyming and his collaborators have submitted to the American Public Health Association (APHA), a Washington, D.C.-based organization for public health professionals.
For example, ED-based research has yet to investigate the extent to which neighborhood-level factors such as fast-food accessibility and a lack of healthy food options contribute to poor pediatric health outcomes.
The CHOC-led study aims to identify such neighborhood-level factors and generate valuable information that could be leveraged for public policy and advocacy efforts to improve pediatric health. That, in turn, could lead to a reduction of ED overutilization and associated healthcare costs.
Disadvantaged kids hit hardest
Food and housing insecurity disproportionately impact children in disadvantaged communities, studies show.
And children living in so-called “food swamps” — areas with an abundance of fast-food restaurants, pharmacies and discount stores that sell cheap but unhealthy food — as well as “food deserts,” areas that lack affordable food that is fresh and nutritious, are more at risk of obesity, diabetes and other adverse health conditions, as well as mental and behavioral issues and trauma, the paper explains.
The study of 7,000 CHOC ED patients comes on the heels of a smaller CHOC ED study on the prevalence of ACEs in patients that was conducted between July 2020 and February 2021. Twenty-four CHOC ED doctors were certified in state-run ACEs modules and 1,861 patients participated – the biggest cross-sectional survey that CHOC has done to date, according to Dr. Heyming.
About 20 percent of respondents in that smaller-scale survey reported at least one ACE or more — a percentage consistent with national numbers, Dr. Heyming says. In addition, the survey found that the prevalence of food insecurity among CHOC patients is about 15 percent.
Now, in partnering with Chapman University and UCI, CHOC is digging deeper into the prevalence of food and housing insecurity with its study of 7,000 patients — and the potential neighborhood-level factors that contribute to such insecurity.
Dr. Jason Douglas, an assistant professor of public health at Chapman University, specializes in investigating social and environmental determinants of public health disparities that disproportionately impact the Black and Latinx communities.
Dr. Douglas, who has extensive experience connecting social and environmental factors to public health disparities in Los Angeles County as well as Northern California, New York and Jamaica, will use data from the 7,000 survey respondents to analyze neighborhood-level factors that contribute to poor pediatric health.
“The goal is to identify factors that are affecting community health and well-being and inform public policies to improve health in underserved communities,” Dr. Douglas says. “To be able to identify adverse childhood experiences and food and housing security within the clinical context and use that data to garner a better understanding of how social and environmental factors may be exacerbating health disparities will allow us to develop a more holistic understanding of the deleterious impacts of these challenges on children’s lives.”
At UCI, Dr. Victor Cisneros, an emergency medicine clinical instructor and current research fellow in population health and social emergency medicine, will lead a team of investigators who will participate in follow-up phone calls with the CHOC ED survey respondents. The follow-up interviews will be conducted three and six weeks after respondents complete the survey.
“These follow-up interviews are important to assess if interventions given in the ED are effective, and if not, what barriers our patients are facing,” Dr. Cisneros says.
All CHOC ED patients up to 18 years of age and their parents or guardians qualify as potential participants in the survey, which is available in English and Spanish. The survey includes 16 questions that take about 5 to 10 minutes to complete on iPads provided by CHOC.
Patients identified as experiencing food and/or housing insecurity are directed to passive food and housing resource materials in the form of informational pamphlets and flyers.
“We’re going to potentially be able to leverage this data to help cities and the county to make informed policy changes,” Dr. Heyming says.
“Obtaining this information will not only be great for Orange County,” he adds. “I think we’ll be able to point to the fact that pediatric EDs are a great place to conduct these screenings because there’s a high incidence of either adverse childhood experiences or food or housing insecurity.”
Dr. Heyming says pediatric EDs in the future would be able to provide patients more active resources such as gift and food cards.
Dr. Douglas says the study ideally will serve as a model for pediatric and other emergency departments across the country.
The bottom line, Dr. Cisneros says, is getting people resources they need – for example, food that restaurants now dispose of that can be “recycled.”
The ED, he says, is a perfect microcosm of the community.
“One of the beauties of this study,” Dr. Cisneros says, “is we’ll be able to identify people with housing and food insecurity and be able to refer these people to the appropriate tailored resources. In addition, we will be able to further quantify what obstacles our patients face both at the individual and community level.”
CHOC Hospital has been verified by the American College of Surgeons as a Level II pediatric trauma center. This achievement recognizes CHOC’s commitment to providing the highest quality trauma care ...
In the yard of his home just outside Boise, Idaho, Ely Bowman loves to toss balls and play with Bobo, the family Goldendoodle. He also loves the trampoline.
“If you were to come over and just watch him,” says his mother, Bekah, “you would not believe me if I told you he was blind.”
Ely, who turns 8 in July, lost his sight when he was 6 due to the rare neurological disorder CLN2 disease, one of the most common forms of a group of inherited disorders known as Batten disease.
Kids with CLN2 disease are missing an enzyme that chews up waste products in the brain. This lack of a cellular “Pac Man” to gobble up the bad stuff eventually leads to the destruction of neurons, resulting in blindness, loss of ability to speak or move, dementia, and death – usually by the teens.
There is no cure for CLN2 disease. But thanks to genetic scientists, neurosurgeons and nurses at CHOC, there is hope for delaying progression of the disease – one that claimed the life of Ely’s older brother, Titus, at age 6 in September 2016 before a cutting-edge therapy became available at CHOC six months later.
The therapy, Brineura, is a medication that treats the brain via a port under the scalp with a synthetic form of the missing enzyme. CLN2 patients come to CHOC every two weeks for the four-hour infusion to keep the drug working effectively.
Largest infusion center in country
CHOC since has grown into the largest Brineura infusion center in the country and the second largest in the world. Kids from all over the United States have come to CHOC for Brineura treatment since it first was offered in March 2017 following a three-year effort by Dr. Raymond Wang to get the green light for CHOC to become the second infusion site in the U.S.
“When a family has a child with a rare disease,” Dr. Wang says, “and if the South Pole were the only place that was offering treatment, the family would find a way to get there. Those are the lengths that a rare disease family would go to help their child.”
CHOC now has treated 13 Brineura patients, the latest being 3-year-old Max Burnham, whose parents having been making the trek to Orange every two weeks from their home in the Bay Area since Max’s first infusion on Feb. 8, 2021.
CHOC’s Brineura program underscores its growing reputation as a destination for kids with rare diseases.
Recently, CHOC specialists started treating a 3-month-old with Hurler syndrome, another serious and neurodegenerative condition. The family drove across the country because CHOC is the only site in the world that has a clinical trial of gene therapy for their son’s condition.
Because the family will be staying at CHOC for at least through April 2021, a team of three study coordinators — Nina Movsesyan, Harriet Chang, and Ingrid Channa – helped the family get settled in at an Airbnb in Irvine.
Dr. Wang says CHOC became an active site for the RGX-111 gene therapy after treating a child from a family in Indio in 2019. Another 14-year-old girl from West Virginia has received the same treatment.
“All of these cases wouldn’t be possible without the awesome teamwork from team members, who all are dedicated to the mission of CHOC,” says Dr. Wang. “I think it’s pretty remarkable that people from all over the country are coming here for clinical care and research studies because of our expertise and what we offer them: hope for their beloved children.”
Susan See is nurse manager of CHOC Hospital’s neuroscience unit, where the patients receive their infusion and stay for care afterward.
“We quickly put together a comprehensive program that really treats the patient and family not just medically, but also from an emotional support standpoint,” she says.
Batten disease especially is terribly cruel because its symptoms typically hit just as parents are starting to enjoy their child reaching several developmental and cognitive milestones such as walking and talking.
Untreated, the disease eventually takes all that away.
“What makes them who they are gets rapidly erased,” says Dr. Wang. “As a practitioner, it’s hard. I’m trying to imagine being in the shoes of a parent knowing this is going to happen to their child.”
For Bekah Bowman and her husband, Daniel, the diagnosis for Titus and, two months later, Ely, was like being on a high diving board and being shoved off and belly flopping into the water.
“We had to learn what little control we have in life,” Bekah says.
The Bowmans worked closely with Dr. Wang to get the Brineura clinical trial launched at CHOC.
“When we met Dr. Wang,” Bekah says, “he told us: ‘We don’t have the answers for you right now, but I want you to know we’re going to keep fighting and we’re not going to give up.’”
Brineura families form tight bonds with their team at CHOC, which includes eight nurses who have been trained to care for them: Allison Cubacub, Genevieve Romano-Valera, Anh Nguyen, Melissa Rodriguez, Kendall Galbraith, Annsue Truong, Monica Hernandez and Trisha Stockton.
Some families, including the Bowmans, have moved on from the program at CHOC when Brineura infusions became available near their hometowns. The Bowmans returned to their native Idaho outside Boise in October 2018. Leaving CHOC was difficult.
“That was one of the hardest goodbyes we had to say,” Bekah says.
All Brineura patients receive the transfusions on the same day – something unique to CHOC, See says.
“We learn what is unique about each patient and we become very close to them,” she adds. “It really reminds us why we said yes to nursing. What we thrive on is being able to care for families.”
Quick to action
Laura Millener, the mother of Max, CHOC’s latest Brineura patient, says she selected CHOC for Max’s condition, diagnosed in January 2021, because he needed to be treated right away. She first spoke to Dr. Wang on Jan. 11, and Max got his first infusion less than a month later.
“You could just tell how much he cares about his patients,” Laura says of Dr. Wang.
Says Dr. Wang, who has three children ages 10 to 18: “I count [my patients and my families] as my extended family, and I want the best for all of them.”
Laura and her husband, Matthew, a C-5 pilot in the U.S. Air Force, will be relocating to Quantico Marine Base in Virginia this summer from Pleasantville, Calif. Max, who has a 6-year-old sister, Ella, will continue his Brineura infusions at Children’s National Hospital in Washington, D.C.
“I don’t want to leave CHOC,” Laura says. “CHOC has done such an amazing job of making this easier on us. I am so grateful for the team.”
Dr. Wang says the Brineura infusions have made it possible for the patients to maintain meaningful interactions with their parents and siblings – despite having such conditions as, in Ely’s case, blindness.
Ultimately, the goal is for CHOC to be considered for a gene therapy clinical trial aimed at giving brain cells the ability to produce the missing enzyme by itself so Batten disease patients wouldn’t have to receive infusions every two weeks. Dr. Wang says such a trial could happen this fall.
“If there’s anything in my power I can do to help these families,” says Dr. Wang, “I’m going to try to make it happen.”
While there is less data about pediatric patients, emerging evidence shows that people infected with COVID-19 are at increased risk for myocarditis. Because of this, it is important that pediatricians appropriately evaluate patients before they are cleared to return to play as sports resume after a prolonged COVID-prompted off season.
Patients should be seen in the provider’s office for an in-person, formal evaluation and physical exam to determine clearance, recommend Drs. Kornswiet and Koutures. The following decision tree can aid in triaging patients, as well as providing consistent patient care. This decision tree is applicable to middle and high school athletes, as well as to those who compete in high-exertion activities and to other patients on an individual basis.
The California Interscholastic Federation recommends that if a patient’s infection was over three months ago, they had an asymptomatic, mild or moderate illness, and the patient has regained fitness or is back to full activity without symptoms, then they can return to sports as long as they have an active/recent preparticipation physical exam.
Once an athlete is cleared for a return to sports, Drs. Kornswiet and Koutures recommended that they go through a gradual and step-wise return to play. This is similar to the return-to-play protocol for concussions, and should be performed under the supervision of a physician and athletic trainer, if possible.
Each phase should last at least 24 to 48 hours and should not cause return of symptoms. If the athlete/student experiences a return of symptoms or develops unexpected fatigue, dizziness, difficulty breathing, chest pain/pressure, decreased exercise tolerance, or fainting, then they should stop their return progression and return to their physician for further evaluation.
These protocols are not substitutes for medical judgment, and additional queries should be directed to pediatric cardiologists or sports medicine specialists.
Following are more general return-to-sports guidance for parents and coaches: