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Innovation Report 2020
Genetic Mapping in Cerebral Palsy
Laser Ablation &
Neurotrauma & TBI Research
Resting-State Functional MRI (rs-fMRI)
Resting-state Functional MRI (rsfMRI)
Barrow Neurological Institute at Phoenix Children's is the largest pediatric neuroscience center in the Southwest, offering the most comprehensive inpatient and outpatient neurological care and services
to infants, children and teens with neurological, behavioral and mental health diseases and disorders.
We are proud to be one of the few hospitals to offer pediatric neurosurgery, neurology, psychology, psychiatry, developmental pediatrics and rehabilitation in one central location. Cutting-edge technology, pediatric patient rooms and pediatric neuro specialists — in addition to our family-centered focus – make us uniquely qualified to treat the most complex neurological disorders in pediatric patients.
“We heal children with neurological, mental and behavioral health diseases and disorders so they can lead happy and healthy quality of lives.” — P. David Adelson, MD, FACS, FAAP | Director, Barrow Neurological Institute at Phoenix Children's
More Treatment Opportunities for Children with Medically Intractable Epilepsy
The Barrow Neurological Institute at Phoenix Children’s was the first hospital in the United States to use the Medtronic Stealth Autoguide™ robotic guidance system for pediatric neurosurgery. Barrow at Phoenix Children’s is also the first and only pediatric hospital in Arizona and the Southwest to use the Stealth Autoguide for laser ablation surgery to treat pediatric epilepsy and brain tumors.
Using laser ablation surgery and the Stealth Autoguide, Phoenix Children’s is on the forefront of nonpharmacologic treatment for children with medically intractable epilepsy and other seizure disorders.
"Although we currently have over 35 different medications to treat epilepsy, as well as three new drugs just approved in 2020, they have not significantly decreased the number of people that have uncontrolled seizures. We know that medications work only about 60% to 70% of the time, so we're not making progress in controlling more people with newer drugs," says Angus A. Wilfong, MD, division chief of Neurology and associate director of Barrow at Phoenix Children's.
Experts at Phoenix Children’s say the answer isn’t more drugs but harnessing the proven efficacy of nonpharmacologic therapies. These include brain surgery or neuromodulation, which can often offer relief from seizures or even a potential cure. Yet, these procedures are underutilized across the country, in part because parents or caregivers and children may be apprehensive about having any type of brain surgery. Physicians play an important role in reversing this trend.
Approximately 1.2% of the U.S. population has epilepsy – some 470,000 children and 3 million adults. Of these, about one in three people has medically intractable epilepsy that cannot be controlled with medications.
First hospital in the United States to use the Medtronic Stealth Autoguide
Bridging the Gap in Epilepsy Treatment with Laser Ablation and Stealth Autoguide™
"While continuing to have seizures is more dangerous than having surgery, there's still this constant fear about epilepsy surgery, even amongst other physicians. There is resistance to referring a patient for surgery or resistance on the patient side to undergo surgery. Despite the fact that delays lead to long-term worse outcomes. Being able to offer a more minimally invasive, low morbidity option for the right child, like laser ablation surgery, is very important for children with medically intractable epilepsy because it may be a cure," says P. David Adelson, MD, division chief of Neurosurgery and director of Barrow at Phoenix Children’s.
There is a lot to be gained by taking advantage of the technology. In the United States, more people die from epilepsy (50,000 people) than breast cancer (40,000 people) every year. The risk of mortality is higher for patients with medically intractable epilepsy because uncontrolled seizures increase the chances of sudden unexpected death in epilepsy (SUDEP). Epilepsy surgery offers the highest chance of reducing or eliminating SUDEP risk. When this population is not given the option of a surgical evaluation, they also miss the opportunity for a cure.
Combining Our Neurosurgeons' Expertise With Technology
Our neurosurgeons use the Stealth Autoguide for laser ablation surgery to provide real-time visualization, stereotactic positioning and trajectory guidance that results in extremely accurate alignment for surgery.
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Stereotactic positioning creates coordinates within the brain on the x, y and z axis. Combining stereotactic positioning with imaging allows neurosurgeons to place electrodes, laser probes or biopsy needles accurately in very sensitive locations of the brain. The robotic guidance system helps find a trajectory that creates the least potential for morbidity.
Robotic assistance improves efficiency because it helps neurosurgeons reach the target in the brain quicker than doing it manually. The robot is also more accurate, which makes it possible to reach the focus, lesion or brain tumor target within
0.1 mm to 0.3 mm
Laser ablation under direct
MRI guidance allows for visualization of the level and time of heating and the system calculates an accurate cell death response.
Children who receive laser ablation surgery using the Stealth Autoguide have incisions that are only 2 mm to 3 mm and are usually able to go home the next day. The robotic-guided surgery has fewer risks and complications. Children also spend less time in the operating room and need less anesthesia.
"One of the ways that we've been able to decrease morbidity is through improved imaging that allows us to see a lot more of the brain anatomy. It helps us see where we want to go, but also what we want to avoid. Our image guidance system is a kind of brain GPS. We can target specific areas of the brain with submillimeter accuracy," says Dr. Adelson.
Only Program to Treat Hypothalamic Hamartomas
In addition to treating medically intractable epilepsy, Barrow at Phoenix Children’s has the only program for evaluating and treating pediatric patients with hypothalamic hamartomas in the Southwest.
We treat patients with hypothalamic hamartomas using the Stealth Autoguide for laser ablation surgery.
"These new technologies provide opportunities for children to get treatment that they in the past may not have been able to get,"
says Dr. Adelson.
As one of the leading hospitals in the world for hypothalamic hamartoma research, our staff continues to work on the development
of innovative surgical therapies for this rare disorder.
Barrow at Phoenix Children’s continuously looks to improve its results and outcomes for children with epilepsy. Whether adding new treatment regimens with new technologies like laser ablation or to improve outcomes, with the addition, more recently, of the Stealth Autoguide to improve accuracy, their outcomes have been excellent with low risk of temporary morbidity and 0% mortality.
As a Level 4 Epilepsy Center recognized by the National Association of Epilepsy Centers, our center provides the highest level of care to children who have epilepsy and other seizure disorders. Patients from across the nation and the world come to Barrow at Phoenix Children’s for laser ablation surgery using the Stealth Autoguide.
One such patient, Katherine, was 15 years old when she had laser ablation surgery at Barrow at Phoenix Children’s for medically intractable epilepsy caused by a brain malformation. Katherine became seizure-free after the procedure and was later able to discontinue medications.
"Katherine was recognized as a good candidate for standard epilepsy surgery many years ago, but the family was concerned about her having a craniotomy and had refused surgery. It wasn't until they learned about laser ablation surgery that they were willing to have their daughter undergo surgery. Today, Katherine is considered cured, has received a driver's license and attends college," says Dr. Wilfong.
Katherine's story is just one example of how nonpharmacologic treatments for otherwise intractable seizure disorders can change and save lives by curing or at least improving their epilepsy. Experts at Barrow at Phoenix Children’s hope her story and others like hers will encourage healthcare providers to help close the epilepsy care gap by taking advantage of the opportunities afforded by minimally invasive treatment options like robotic laser ablation surgery.
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At the Phoenix Children's Neurogenetics Laboratory, researchers are studying the genetic basis of cerebral palsy (CP) and other movement disorders. Michael Kruer, MD, has received a $3 million National Institutes of Health grant, which is the first federally funded grant to investigate the link between genetics and CP.
Dr. Kruer is a pediatric neurologist and director of the Cerebral Palsy and Pediatric Movement Disorders Programs at the Barrow Neurological Institute at Phoenix Children’s and principal investigator at the Phoenix Children's Neurogenetics Laboratory. A study he led has provided the first conclusive statistical evidence that there is a strong genetic basis for cerebral palsy in many affected individuals.
Discovering the Genetic Basis for Cerebral Palsy
Finding the Genetic Basis of Cerebral Palsy
Cerebral palsy affects an estimated 1 in 345 children in the United States, but the causes of this pediatric movement disorder are not always clear. Premature birth, low birth weight, brain injury, in utero infections and a lack of oxygen during delivery are common risk factors, yet about a third of the children with CP do not experience these environmental problems.
Although scientists and medical professionals have suspected that genes may play a role in CP, until now, there has not been clear evidence that genetic mutations lead to CP in some people.
Dr. Kruer's laboratory is using animal models, such as fruit flies, to model what's happening in cerebral palsy and to test treatments that are designed to directly address some of the brain wiring problems. By introducing mutations of the same genes seen in children with CP into the fruit flies, the insects showed movement difficulties that were similar to those seen in cerebral palsy. The flies could not walk or move easily, which is comparable to what patients with CP experience.
The mutated genes do not appear to be randomly distributed throughout the genome, and the research team is finding many genes converge within common pathways. The animal models are helping them learn more about these pathways and potential therapies.
Co-occurring developmental disabilities are common for children with CP. About 42% of children with CP also have epilepsy and 7.5% have autism spectrum disorder (ASD). The study also showed an overlap between CP and neurodevelopmental disorders.
The mutated genes that were picked up by the CP study had previously been implicated in autism, intellectual disability and epilepsy. In the study, Dr. Kruer's team saw that sometimes individuals that had a mutation in this type of gene would have both CP and epilepsy or autism, but other times they would have a mutation in one of these genes and just have CP. Although there appear to be combined neurodevelopmental factors, how they show up can still vary from person to person.
As a multidisciplinary center, Barrow Neurological Institute at Phoenix Children’s specializes in care and research for cerebral palsy, epilepsy, autism and other neurodevelopmental disorders. Not only does this ease the burden on patients by creating a single place for them to receive care, but it also gives patients greater access to resources and improves health outcomes.
Links to Other Neurodevelopmental Disorders
The results of the study show the first firm evidence that there is a strong genetic basis for many cases of cerebral palsy. About 14% of CP cases were linked to mutations in specific brain-wiring genes.
According to the study, CP can be caused by both mutations inherited from carrier parents and spontaneous mutations. "Changes in the DNA code disrupt the protein coding portions of the genes in a significant way. So, the children with CP had an excessive number of these DNA changes, and the changes hit crucial genes that do not tolerate changes to their genetic code very well," says Dr. Kruer.
Dr. Kruer and the rest of the research team are interested in determining how mutations disrupt early brain development and lead to CP and are planning to continue the research. The mutations are usually not in a single gene but appear to be in one of hundreds of different genes. However, certain genes seem more likely to have mutations that affect brain development in children.
Their analysis found that mutations in two genes, FBXO31 and RHOB, can cause cerebral palsy on their own. RHOB has never before been implicated in human disease. RHOB is important for early brain development, and FBXO31 controls the level of other proteins. These mutations altered early brain connections in children with CP.
Dr. Kruer recently shared his research in a MyCP webinar that highlighted the link between genetics and cerebral palsy.
First Conclusive Statistical Evidence
$3 million National Institutes of Health grant, which is the first federally funded grant to investigate the link between genetics and CP.
Cerebral palsy affects an estimated 1 in 345 children in the United States
While research is ongoing, Dr. Kruer led an international collaborative study, published in Nature Genetics, that focused on the genetic basis of cerebral palsy to see if there is a link that may explain why some children have the condition without other risk factors. Dr. Kruer's position as one of the founders and the current chair of the International Cerebral Palsy Genomics Consortium (ICPGC), a collaborative network, helped bring together other researchers for the study.
The study enrolled 250 families with children who have CP from the United States, Australia and China to investigate if mutated genes can cause the condition. To date, this was the largest genetic study of cerebral palsy in the world.
The team sequenced the entire protein-coding portion of the genomes in both the healthy parents and children with CP.
"In the families, most of the children had CP for unclear reasons. We adopted an approach where we compared the genetic code of the healthy mothers and fathers to that of their child with CP. This allowed us to detect mutations that led to CP," says Dr. Kruer.
The results of the study show the first firm evidence that there is a strong genetic basis for many cases of cerebral palsy. About 14% of CP cases were linked to mutations in specific brain-wiring genes.
The mutated genes that were picked up by the CP study had previously been implicated in autism, intellectual disability and epilepsy.
Better Diagnosis and Treatments
By understanding the genetic basis of CP, the potential for new therapies increases. The results of the study have already helped change the treatments for three children with cerebral palsy. In the future, the study may also help improve the diagnosis process for CP and help children start receiving treatment faster.
Determining the genetic basis of CP also creates the opportunity for parents to receive genetic counseling and determine their chances of another child having this condition.
Beyond the neurological consequences of traumatic brain injury (TBI) in children, our Phoenix Children's Translational Neurotrauma Research Program investigates the potential impact of pediatric TBI on the endocrine system. In adults and veterans, damage to the pituitary and hypothalamus from the mechanical forces of TBI disrupts hormone regulation and leads to endocrine disorders. For children, research studies have reported the existence and potential for long-term hypothalamic-pituitary disorders induced by TBI. Continued research is needed to quantify the incidence and justify clinical decisions. Our cross-disciplinary, physician and scientist research team recently completed the first statewide study that showed pediatric patients with TBIs are at a higher risk of being diagnosed with a central endocrinopathy — endocrine and hormone disorder — than the general public.
The Risk of Developing a Hypothalamic-Pituitary Disorder After a Pediatric Traumatic Brain Injury
TBIs usually result from a violent blow or jolt to the head or body. In children, TBIs account for more than 812,000 emergency department visits every year and are a leading cause of childhood mortality and morbidity in the U.S. Of primary concern for children with TBI is the identification of neurological symptoms from among normal developmental processes. In our youngest patients, the ability to transition through developmental milestones can be delayed or advanced by hormone dysregulation. In adolescent patients, any post-concussion symptoms may be concurrent with growth phases or even puberty. How can parents distinguish injury-related aggression from expected puberty-related disdain for one’s parents? Without evidence, clinical decisions cannot be made or justified.
The Translational Neurotrauma Research Program at Barrow Neurological Institute at Phoenix Children's Hospital is a joint venture with the University of Arizona College of Medicine – Phoenix and the Phoenix VA Health Care System. They analyzed the risk of developing a hypothalamic-pituitary disorder after a TBI in the pediatric population in the state of Arizona. The study was led by J. Bryce Ortiz, PhD, a postdoctoral researcher at the College of Medicine – Phoenix, and Alona Sukhina, MD, a pediatrics resident at Phoenix Children’s Hospital. Together, our junior physician-scientist team secured statewide billing data from the Arizona Health Care Cost Containment System (AHCCCS; the equivalent of children’s Medicare)” for all participants under 18 years old, with no pre-existing endocrine condition, who had a TBI and subsequent central endocrine disorder.
TBIs account for more than 812,000 emergency department visits every year and are a leading cause of childhood mortality and morbidity in the U.S.
“Our hormones are regulated, in part, in our brains, and a TBI can potentially cause damage to those areas,” says Jonathan Lifshitz, PhD, senior author of the study and director of the Translational Neurotrauma Research Program. “Damage to these brain regions can disturb critical developmental periods in children. As children grow from babies to toddlers, to adolescents and finally to adults, they rely on complex relationships among their hormones to regulate their bodies' growth and metabolism. Most notably, hormones govern growth and pubertal development.”
Those who survive pediatric TBIs can have persistent post-traumatic symptoms. Many children do not have the experience or the vocabulary to describe their symptoms or communicate their challenges. With the potential for a TBI-related endocrine disorder to divert growth stages and puberty, the risk for lifelong adversities necessitated the investigation into the incidence, prevalence and risk to children with TBI. Over a five-year period, 498 children were identified to have had a TBI and subsequent, new-onset endocrine condition. The range of diagnosis for the endocrine disorder after the TBI was days to years. Pediatric AHCCCS patients with a central endocrine diagnosis had 3.2-fold higher odds of a history of a TBI diagnosis than those without an endocrine diagnosis. Furthermore, female subjects were more likely to present with a central endocrine diagnosis after a TBI diagnosis compared to male subjects. Research showed that for every 151 children diagnosed with a TBI, at least one would develop a hypothalamic-pituitary disorder.
“Damage to these brain regions can disturb critical developmental periods in children. As children grow from babies to toddlers, to adolescents and finally to adults, they rely on complex relationships among their hormones to regulate their bodies' growth and metabolism. Most notably, hormones govern growth and pubertal development.”
Jonathan Lifshitz, PhD
Director of the Translational Neurotrauma Research Program
“The impact of our findings lies with the fact that endocrine disorders are treatable. For the one child of 151, our endocrinology colleagues have diagnostic tools and intervention strategies to intervene,” says Dr. Sukhina. Dr. Sukhina was responsible for building a relationship between Barrow at Phoenix Children's and the endocrinology service to better deliver comprehensive care to patients.
“This work represents multiple facets of our institute. First, our clinical practice is based on best evidence. Second, our clinical care considers the impact of disease or diagnosis on all systems and the relevant clinical service. And third, we work towards our research programs being a destination for training, as evidenced by Dr. Ortiz and Dr. Sukhina,” says P. David Adelson, MD, division chief of Neurosurgery and director of Barrow at Phoenix Children’s.
The population data query and analysis were made possible by a Valley Research Partnership grant. Academic medical institutions in the Phoenix Valley allocate funds for training and collaboration to advance translational research. The resultant epidemiology demonstrated that children in Arizona had endocrine disorders subsequent to TBI, and yet no systematic approach exists to monitor or diagnose these outcomes.
With this finding, the evidence-based recommendation is to screen children with TBI for endocrine disorders within six months of the injury, as it may affect many aspects of their life. Additionally, parents, grandparents and loved ones should be aware that TBI can not only affect a child’s concentration and mood, but also can affect the hormone system of the body, and call attention to these changes when bringing them to the doctor.
To extend these results, the research team has secured a Phoenix Children’s Leadership Circle grant, selected by membership vote to allocate pooled philanthropic funds. The grant will support a retrospective chart review with prospective data collection. Phoenix Children’s patients treated for TBI will be contacted for a research nursing visit to evaluate growth trajectory and endocrine system function. Annually, Phoenix Children’s treats hundreds of TBIs from catastrophic to minor, where each patient may endure neurological symptoms. Our published results indicate that some symptoms may be endocrine in nature and benefit from treatment. When prior TBI patients are identified with endocrine concerns, a referral to endocrinology will be made. The team is focused on eliminating the downstream effects that can include dysregulation of blood sugar, body weight or blood pressure, preventing them from fully concentrating and learning in school, reaching their potential height and even delaying puberty.
Future studies will be proactive prospective trials to treat endocrine disorders before or as they occur. To establish the foundation for this work, Rachel Rowe, PhD, leads her Barrow at Phoenix Children's research laboratory, along with Dr. Ortiz, to test treatment strategies in experimental diffuse TBI in the pre-pubertal and pubertal rat. Her laboratory is among the few with expertise in pediatric experimental TBI, with a focus on developmental milestones, endocrine system evaluation, and neurological function assessment, with recent funding from the Valley Research Partnership. “Translational research permits a more rapid evaluation of hypotheses to guide clinical investigations and observations. We are the information source to improve the health and welfare of children with neurological conditions,” says Dr. Rowe.
How Resting-State Functional MRI (rs-fMRI) and SearchLight Are Changing Epilepsy Surgery
The Neurocritical Care Program at the Barrow Neurological Institute at Phoenix Children’s is the only one in the Southwest and one of only a handful of programs across the nation. Our program brings together experts from clinical neurophysiology, neurosonology, multimodality monitoring, advanced neuroimaging, neonatal neurology and pediatric stroke. Research and innovation are an important part of the Neurocritical Care Program as we work to better understand the brain and improve treatments for children.
How rs-fMRI Works
Resting-state functional magnetic resonance imaging is done in a regular MRI machine. MRI is a safe, noninvasive and advanced brain-imaging machine. The rs-fMRI takes about 20 minutes of scanner time. The patient lies awake or lightly sedated in the scanner. They must lie still during the procedure, or motion may corrupt the images. Most children cannot lie perfectly still this long and Phoenix Children’s is accustomed to administering light sedation to help. Afterward, the child goes home. Dr. Boerwinkle analyzes the results, which are typically available within a week, though expedited analysis is available, if indicated.
rs-fMRI has been around for about 25 years and shows all of the major brain networks. Brain networks are areas of the brain that perform a function, such as moving the hand, processing visual information or speaking. Each brain network uses oxygen in a coordinated manner. This oxygen use is detectable by the MRI scanner because the oxygen is associated with iron (a metal in blood that carries the oxygen to the brain). The MRI magnet detects the changes of iron in the blood as the network uses the oxygen.
Normal brain networks use the oxygen in a predictable slow oscillating pattern, whereas atypical areas of the brain may use excess oxygen at an irregular pace. Thus, abnormally functioning brain areas, even if they are anatomically normal, are detectable by rs-fMRI.
This helps in understanding what capacities the child may develop over time. It also helps neurosurgeons see where major brain networks are located to avoid them if possible during surgery, reducing the chances of lost capacities.
Advantages of Using rs-fMRI
• Localization of serious brain pathology, such as where seizures occur.
• Identification of the major brain networks. This helps in understanding what capacities the child may develop over time. Also helps neurosurgeons see where major brain networks are to avoid them if possible during surgery, reducing the chances of lost capacities.
• Helps doctors understand in those with reduced consciousness, such as coma, the capacity to recover consciousness. Some children appear to be unconscious but are actually awake or may have seizures not seen by EEG. rs-fMRI has unique findings in these conditions to help doctors treat patients.
Varina Boerwinkle, MD, is spearheading brain network discovery in children through resting-state functional magnetic resonance imaging (rs-fMRI). Dr. Boerwinkle, who is the medical director of the Neurocritical Care Program and the Functional Neuroimaging and Neuroscience Laboratory at Phoenix Children’s, began analyzing rs-fMRI in children with all types of drug-resistant epilepsy in 2010. She has since interpreted more than 2,000 individual studies and created computer programs, such as Salience and SearchLight, speeding brain network analysis and sorting rs-fMRI signals.
In a paper published in Brain Connectivity in 2017, Dr. Boerwinkle demonstrated that rs-fMRI surgical targets have high correlation with those confirmed by depth electrodes and surgical outcomes at one year in those children with many types of drug-resistant epilepsy.
In another paper published in the American Epilepsy Society’s most prestigious peer-reviewed scientific journal, Epilepsia, in September 2018, Dr. Boerwinkle and her team showed that better targeting from rs-fMRI and Searchlight improved freedom from seizures by 45% compared to conventional ablation regardless of hamartoma size.
Recently, rs-fMRI was shown to help locate the seizure onset zone in a meta-analysis, which reviewed many authors' work, and was published in Epilepsia in August 2020, strengthening the evidence for this innovative approach.
"We improved our analysis technique to study the brain on what we call a voxel by voxel basis of areas that we think are the most likely seizure candidates from our initial assessment. Then, we reduced that area in children who have seizures coming from hypothalamic hamartoma. We were more accurate in which area was targeted during surgery, and we actually improved the cure rate from the operation," says Dr. Boerwinkle.
At Barrow at Phoenix Children’s, children who have hypothalamic hamartoma (HH) are benefiting from rs-fMRI technology that improves seizure localization. Surgery for epilepsy can target the subcentimeter-sized epileptogenic onset zone (EZ) in HH.
Resting-state functional MRI is a good alternative for children who cannot do task-based fMRI and serves to provide a roadmap for neurosurgeons preparing for an operation. rs-fMRI is a noninvasive method that helps show functional brain connectivity. Since surgical intervention presents the possibility of a cure for epilepsy through the destruction of the EZ in the brain, finding accurate targets through rs-fMRI improves the chances of success.
After finding the targets through rs-fMRI, stereotactic laser ablation can eliminate them. First, a 2 mm skull burr hole has to be drilled to insert a 2 mm diameter tube to reach the EZ target. A laser goes through the tube, and thermal tissue destruction occurs at the EZ target, which has a maximum size of 20 mm in diameter.
By having a smaller and more accurate target for the laser, the risk of surgical morbidity goes down and the possibility of using less invasive techniques exists.
"I had a 15-year-old with hypothalamic hamartoma where rs-fMRI worked well because it assisted with surgical strategy, allowing the planning team to see where within the HH the seizures were coming from, and importantly, avoid the critical nearby memory structures," says Dr. Boerwinkle.
Hypothalamic Hamartoma and rs-fMRI
SearchLight of the HH shows that the location with the red dot in the top row of images is connected to the rest of the brain in the pattern shown in the bottom row of images. This area was ablated, and the patient became seizure-free.
The SearchLight program automates the process of determining functional correlation between all voxels within an HH and the rest of the brain to find which voxels are the likely EZ. The program gives each voxel a coordinate and creates preoperative and remote postoperative images that a neurosurgeon can check before and after an operation.
One of the benefits of checking every voxel within a surgical candidate region is that it can identify an EZ regardless of its location within the HH. This expands the possibilities of finding a more accurate target area within the HH instead of limiting it to the border zone. Limiting the surgical target to the border zone between the HH and the rest of the brain may well disconnect the HH. However, the brain structures in this region are compactly located together, making targeting of the border zone higher risk to these brain regions, which are critical for memory, life-sustaining salt balance, appetite control, emotional regulation and motor strength – the primary reported morbidities of this surgical strategy.
SearchLight and rs-fMRI
Child with drug-resistant epilepsy secondary to HH. Each row of images is a set showing an example voxel on the left (red dot within the HH in the axial, sagittal and coronal views) and that voxel’s connectivity to the rest of the brain in the images to the right. Note in the first row, there are preoperative images showing a voxel with abnormal connectivity to the rest of the brain shown in yellow-red over the right temporal lobe and deep gray matter (radiological orientation of images – right side of image is left side of brain). The other sampled voxels were not abnormal in comparison.
Now six months after surgery, this child is seizure-free and rs-fMRI now shows no abnormal connectivity from residual HH to the rest of the brain.
Dr. Boerwinkle and her team showed rs-fMRI is a tool that can positively impact surgical decisions in a study published in the Journal of Neurosurgery in March 2020.
"In one of our most recent papers, our group wanted to know how this tool impacts surgical decision-making for a team. We presented all of the information except for the rs-fMRI data to the team and asked them to make a surgical plan. Then, we presented the rs-fMRI information and asked them to make a plan. We compared the plans and found that 26% more children had surgery based on the rs-fMRI data. So that's a big difference in surgical candidacy because of employing this tool," says Dr. Boerwinkle.
In a teenage child with drug-resistant epilepsy due to Rasmussen's encephalitis, which is a progressive neurodegenerative disease that most typically slowly attacks one side of the brain, rs-fMRI demonstrated that the language networks relocated to the other side of the brain, making it safer to proceed with surgery, so that she could still speak intelligently.
Positive Impact on Surgical Decisions
"We compared the plans and found that 26% more children had surgery based on the rs-fMRI data."
Additional research focuses on further developing rs-fMRI analysis, making it more reproducible so that other centers can use it without having to accrue as much expertise. For example, artificial intelligence may one day help make analytical determinations and predict or help direct where deep brain stimulation devices should be implanted to improve the outcome of movement disorder surgery.
The possibility of expanding rs-fMRI and SearchLight to treat other types of epilepsy and disorders exists. The program and technology may be especially applicable to broader intractable epilepsy cases.
Digital Health: Catching Up to Technology
It was the collision of a flock of birds with a turboprop jet, after it took off from Boston’s Logan airport in 1962, that would indirectly lead to the emergence of telemedicine at this site in the late 1960s. Massachusetts General's internist Kenneth Bird, who led the small clinic established at Logan in the aftermath of the crash, found an innovative way to communicate remotely with airport clinic patients using audiovisual technology.
Despite its earnest beginnings in the 1960s, telemedicine had limited adoption by healthcare over the ensuing 50 years until the current COVID-19 crisis. Utilization of telemedicine has dramatically increased from 11% in 2019 to 46% based on recent estimates, with providers seeing 50 to 175 times the number of patients via telehealth now than pre-COVID-19. It is further estimated that annual revenues using telehealth could increase from approximately $3 billion pre-COVID-19 to a possible $250 billion a year – or 20% of all Medicare, Medicaid and commercial outpatient, office and home healthcare visits.
As healthcare organizations continue to respond to the pandemic and position themselves to recover and succeed in its aftermath, there will be a need to confront the possibility of melding short-terms goals in the time of crisis with long-range strategic priorities, such as wider digital health transformation, so vital for the future of healthcare in a rapidly changing world.
The convergence of the consumer technology revolution of the past few decades with the current COVID-19 crisis has ensured the permanent disruption of healthcare as we know it and has exposed the extraordinary opportunities – as well as the urgent need for broader adoption – of digital technologies in our healthcare systems. Consumer technology is pervasive and has disrupted almost all industries; consider music streaming, social media platforms, e-commerce, etc.
The Emergence of Digital Health
In healthcare, ongoing transformation will require hospitals to create a solid digital foundation that can be adaptable, interoperable and scalable in a changing environment. This, in turn, can drive innovation, reduce costs and improve the efficacy of healthcare, and the lives of consumers and providers. Increasingly, healthcare will be focused and organized around consumer needs rather than healthcare organization needs.
Future care models, especially with the increasing burden of chronic disease, will be facilitated by newly emerging digital technology that allows for quality care to be provided in people’s homes or communities. For example, there is an emerging market of telemedicine peripherals for home use, enabling immediate access to care via smartphone web-based applications, such as TytoCare™, a small handheld device with a camera that measures body temperature and heart rate, and has a Food and Drug Administration-approved stethoscope, otoscope and tongue depressor.
Future Care Models
Despite the increasing use of digital technology in healthcare, we are still only seeing the tip of the iceberg. The current digital technology transformation in healthcare was partly driven by the adoption of the electronic medical record. Today, analytic tools and artificial intelligence (AI) are increasingly informing healthcare decisions, imaging and diagnosis, precision medicine, genomics and drug discovery. AI has the potential to further enhance quality and accuracy of the decision-making process, drive safety and improve efficiency by automating essential tasks. It is also starting to impact surgery, particularly pre-operative imaging and planning, and intra-operative navigation and guidance with robotic-assisted surgery.
New machine learning applications are in the nascent stage in medicine but have the potential to transform healthcare for the future, increasing our ability to improve quality and safety and reduce costs. Natural Language Processing (NLP), a subcategory of AI that involves the automatic processing of human natural language, is a powerful tool used not only to understand human speech, but also to extract patterns from data that can then be used for decision support and analytics.
As such, NLP has the ability to augment and automate human behaviors and skills. This technology is already used in our everyday lives – consider spellcheck and internet search engines. In the healthcare arena, sophisticated NLP applications have tremendous potential to organize electronic healthcare data and reduce the amount of time providers spend organizing and retrieving information from the electronic health record.
Artificial Intelligence in Healthcare
There are many challenges to integrating NLP technology into healthcare. There has been a flood of data in the healthcare space from the electronic healthcare record, medical literature and insurance providers. Much of the data captured by information technology is unstructured and narrative. Many physicians still prefer free texting health information into the electronic medical record, and the increasing use of shortcuts and templates all provide a challenge for harnessing the potential of NLP. Ambiguity occurs in abbreviations frequently adopted in free text; for example, “ASD” could denote autism spectrum disorder or atrial septal defect. This is further exacerbated by the fact that medical text is ungrammatical, often written in bullet-point style, or uses telegraphic phrases.
Areas where NLP has already made an impact on healthcare with a good return of investment include application of speech recognition software, improvement in documentation, computer-assisted coding and automated registry reporting. Emerging uses span clinical decision-making support, clinical trial matching and risk adjustment. Future opportunities will include ambient virtual scribe, computational phenotyping, biomarker discovery, and population health management and analytics, all of which have the potential to simplify or automate time-consuming tasks that can detract from quality patient care.
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By: Neil Friedman, MBChB, Pediatric Neurologist at Phoenix Children's
There has been an explosion of digital health technology on the consumer side, including the adoption of wearable medical data-capturing devices and mobile health applications. This has given rise to the Internet of Medical Things (IoMT), which is the interconnection of computing devices embedded in everyday objects, enabling them to send and receive data such as patients’ vitals, sleep patterns and electrocardiograms. For example, smart aerosol inhalers that connect with a mobile application allow healthcare providers to monitor medication schedules, impending respiratory crises and dosage reminders.
While it has been estimated that 4.5 billion digital health devices existed in 2015, accounting for 30.3% of all IoMT devices globally, the number is expected to grow to 20-30 billion devices by 2020. Mobile health is currently one of the most popular subsections of digital health, with an increasing capability for combining clinical support with real-time information.
Clearly, the technology is developing faster than our ability to adapt, and obstacles to the further adoption of digital technology remain – arising from interoperable data and digital platforms, regulation and compliance, reimbursement, digital literacy, ethical considerations and physician resistance.
However, as healthcare providers, we will have to learn new skills to adapt to the evolving, technology-enabled healthcare environment, understanding that digital health, coupled with cutting-edge technologies such as cloud computing, AI, NLP and the emerging 5G network, has the potential to make healthcare delivery more personal, convenient, affordable and secure, and will continue to shape the healthcare landscape in the foreseeable future. As Dr. Eric Topol, a leading proponent of AI, notes, rather than replacing physicians, future technology will allow providers to spend more time providing quality care to patients.
Prior to the COVID-19 pandemic, Phoenix Children’s Hospital was conducting very limited telemedicine virtual visits with very few providers trained in the technology. Additionally, we had no formal telemedicine platform at the onset of the crisis in mid-March 2020.
Within a week or two, the Information Technology Department undertook the enormous task of integrating the unique Phoenix Children’s outpatient dashboard functionality, using Microsoft’s Power BI, to build out its virtual-care capabilities using the Zoom platform. At the same time, over 300 providers in more than 35 specialties were trained in the use of the Zoom platform to conduct telehealth consultations, legal and documentation regulatory requirements, and specialty-specific methodology for conducting virtual visits.
Consequently, within a few weeks after telehealth virtual visits were formally launched in mid-March 2020, over two-thirds of the nearly 9,000 in-person ambulatory clinic visits were conducted using the telemedicine Zoom platform. Barrow Neurological Institute at Phoenix Children’s was able to convert as many as 70-80% of our visits to telemedicine, with outpatient volumes exceeding (and maintaining) pre-COVID-19 visits by the end of March. The use of telehealth also reduced “no-show” rates by more than 50%.
Embracing Digital Health at Phoenix Children's