As co-founder of a government-funded national consortium to research new treatments for neurofibromatosis (NF), James H. Tonsgard, MD, is involved in numerous studies that could bring relief to patients suffering from this disorder affecting the skin and nervous system.
The University of Chicago Medicine is one of 13 sites participating in a new study of INFUSE bone graft (recombinant human bone morphogenetic protein 2/absorbable collagen sponge) in the treatment of patients between the ages of two and 18 who have NF1 tibial pseudarthrosis. This research will help determine if use of an osteogenic agent (rhBMP-2) at the time of surgical treatment results in improved bone healing. NF1 is the most common type of NF, occurring in one of every 3,000 babies born.
Tonsgard also is involved in new trials evaluating the use of MEK inhibitors in NF1 patients. A phase II trial of PD-0325901 will evaluate whether the medication shrinks tumors as noted by radiographic response in children and adults with NF1-associated plexiform neurofibromas. Another phase II study will determine the responsiveness of children and adults with NF1 and inoperable plexiform neurofibromas to the MEK inhibitor binimetinib.
Tonsgard is also co-investigator on a study evaluating the drug everolimus to shrink or slow the growth of low-grade gliomas in children with NF1 who have not responded to other therapies.
As a member of the international collaboration, Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS), Tonsgard contributed to important recommendations for the assessment of patient-reported outcomes of pain and physical functioning in NF clinical trials.
“We are very committed to improving the lives of our patients by finding new drug therapies and uncovering the genetic causes of NF,” Tonsgard says. He directs the largest clinic for NF in the country, having seen around 2,000 patients, as well as a large clinic for tuberous sclerosis.
More than 20 anti-seizure drugs are available today, yet one out of three patients with epilepsy still does not respond to medication.
To improve treatment for these unresponsive patients, Professor Wim van Drongelen, PhD, technical director and research director of the Comer Children’s Pediatric Epilepsy Center, focuses his research on understanding the mechanisms that govern different types of epilepsy.
A recent paper co-authored by van Drongelen provides a more detailed look at how epileptic seizures are sustained and how, in turn, physicians might learn to stop them. Published in the Proceedings of the National Academy of Sciences (PNAS 2017 114:10761), the paper examines brain activity during seizures and reveals how a network of only a few neurons can impose widespread effects on the large network dynamics of millions of neurons. The researchers obtained their results from a quantitative analysis of eight spontaneous seizures from four patients with epilepsy.
The team measured seizure activity in greater detail by going beyond the common method of electroencephalography (EEG). Using electrocorticography, or ECoG, data was collected directly from the brain’s cortical surface. Then the team dove deeper still, placing arrays of microelectrodes inside the brain’s cortex. If aimed correctly, these microelectrode arrays, called MEAs, can pick up the activity of small groups of nerve cells inside the core of the seizure. Subsequently they showed that activities of relatively few neurons relate to the ECoG signals across the much larger surrounding cortical area.
Our results were a big surprise to us.
~ Wim van Drongelen, PhD
“Our results were a big surprise to us,” says van Drongelen. “The seizure core is a tiny area with huge effects across larger cortical areas. And this finding may have important consequences for evaluation prior to surgery and treatment of patients with epilepsy.”
In addition, the combined analysis and modeling of the clinical data set revealed a dual role for the neural inhibition function that normally constrains cortical activation. During the seizure, the inhibitory constraint fails inside the small core, but the same inhibitory function plays an important role in the larger area of the cortex that participates in the seizure activity. The neural inhibition function contributes to the typical seizure oscillations seen in the ECoG as well as the EEG, and, more importantly, it creates a distinct dynamical path for the seizure to stop.
Van Drongelen is currently involved with a follow-up study on specific actions, such as electrical stimulation, that might be taken to stop the seizure before it leaves the core and disturbs the larger area.
For nine years, William Allan Sterling rode a roller coaster of epileptic seizures that left him confined to a wheelchair and barely able to walk or talk. Six weeks after starting a ketogenic medical diet prescribed by Chalongchai Phitsanuwong, MD, William was seizure-free.
Born prematurely at 26 weeks with cerebral palsy, William’s seizures started when he was three months old, gradually increasing until they occurred constantly day and night. The multiple anti-seizure medications he tried weren’t effective. Resective surgery was not an option because the boy’s seizures were not localized to a particular area of his brain.
William was referred to Phitsanuwong, a pediatric neurologist and epileptologist trained in ketogenic diets. William stayed at Comer Children’s for five days under the care of Phitsanuwong, as well as a ketogenic dietitian, pediatric neurology nurses, a social worker and a case manager. His seizures were reduced by 50 percent by the end of the week and disappeared completely after six weeks on the diet.
We believe ketogenic diets may have multiple mechanisms that strengthen the nervous system to fight off seizures.
~ Chalongchai Phitsanuwong, MD
Comer Children’s is one of only two health care systems in Illinois offering ketogenic diets to children. The diet consists of a high percentage of calories from fat, with an adequate amount of protein and a low percentage of carbohydrate intake, and is customized to each child’s calorie requirement and nutritional status.
Experts do not fully understand how ketogenic diets control seizures. “We do know the diet’s high-fat, low-carbohydrate content causes the production of ketone bodies and induces the body to become ketotic, which has an anti-seizure effect,” Phitsanuwong says. “We believe ketogenic diets may have multiple mechanisms that strengthen the nervous system to fight off seizures.”
Phitsanuwong reports that of his 35 patients who have attempted ketogenic diets over the last two years, 24 have responded with more than a 50 percent reduction in seizure frequency, and many of them have become seizure-free. Despite the effectiveness and a relatively low occurrence of serious side effects, Phitsanuwong cautions that children not start the medical diet without the specific recommendation and supervision of a neurologist or dietitian.