Douglas Nordli Jr., MD, joined the University of Chicago Medicine Comer Children’s Hospital as chief of child neurology in August 2018. He is an internationally recognized epileptologist whose work has been critical to the understanding of the diagnosis, classification and treatment of early onset epilepsies. Nordli has held leadership roles at Columbia Presbyterian Medical Center, Ann & Robert H. Lurie Children’s Hospital of Chicago and Children’s Hospital Los Angeles. In this Q&A, he discusses his research and goals for Comer Children's section of child neurology and his belief that epilepsy can be cured in children.
Ten years ago, we often could not specify a cause for seizures. With modern genetic diagnostic tests like next-generation sequencing, we’ve discovered that many cases of epilepsy are based in genetics. Now that we’ve characterized what’s causing seizures, we hope to customize treatments that get at the root cause of the epilepsy, and even reverse dysfunction and normalize brain function in patients.
We are moving into an era of precision medicine where we can customize a patient’s treatment to their condition. If we don’t get the correct diagnosis, a child’s seizures may persist, causing brain damage and cognitive impairment. We have a saying in neurology that “time is brain.” The more time between a seizure and treatment, the greater the likelihood that the brain will be irreversibly damaged by the seizures.
Brain-wave tracings tell us two important things: when to get high-resolution imaging and when to do next-generation sequencing. Through research, we’ve developed a way of categorizing pediatric epilepsy by interictal EEG into five patterns. This has expanded our understanding of pediatric epilepsy and has led to more accurate diagnoses.
Infants are at the greatest risk of developing epilepsy. Many types of infantile epilepsy are caused by some problem involving the brain, including genetic mutations or brain-structure abnormalities, and if severe, are often expressed very early in life. It is important to point out that the most common reason an infant will have a seizure is because of a febrile illness (febrile seizures). These seizures are not a form of epilepsy and the majority of children with febrile seizures that are short and of the typical type do not go on to develop epilepsy. Through an NIH-supported research study called FEBSTAT, we have learned that children with very prolonged febrile seizures are at risk for later development of epilepsy.
We are establishing a New Onset Seizure Clinic where a pediatric epileptologist and nurse practitioner will see a patient immediately after the onset of symptoms. The goal is that early on every child who has an unprovoked seizure will quickly see a professional team with special expertise in epilepsy. We call it a “reverse referral.” Because of the resources available to us, patients will get an EEG and, many times, a definitive diagnosis on their first visit to the clinic. Depending on the diagnosis, we may direct them back to their primary doctor for continuing care.
One of the compounds many people are interested in is cannabidiol, which has shown promising results in early studies. Interest in the ketogenic diet — a medical diet that incorporates high-fat, moderate-protein and low-carbohydrate foods to induce a metabolic state called ketosis — has literally exploded around the world. We’ve learned so much about how it works, who would benefit from it, and how to make modifications so it is effective for more children. Chalongchai Phitsanuwong, MD, runs our ketogenic diet program. UChicago Medicine Comer Children’s is also one of a select number of centers doing laser ablations in children for epilepsy (see article).
The need to expedite pediatric access to new anti-seizure drugs is particularly urgent because epileptic seizures are the most common neurologic symptom in children. That’s why I am working with PEACE (Pediatric Epilepsy Academic Consortium for Extrapolation) on a strategy to allow drug companies to extrapolate efficacy data from adult trials to secure FDA approval of certain drugs for use in children. Available data show that the pathophysiology of focal seizures and the drug responsiveness of these seizure types for adults and children are quite similar. However, safety, tolerability and pharmacokinetics cannot be extrapolated from adults to children, so we will need to focus our future research on these issues.
Yes, absolutely. With all the genetic information and new techniques like laser ablation at our disposal, we are at a new frontier that will allow us to help more children with epilepsy than ever before. Many children can be cured, and that should be the expectation and our goal.
A minimally invasive procedure called laser interstitial thermal therapy (LITT) is helping the neurosurgical team at the University of Chicago Medicine Comer Children’s Hospital stop seizures in children with drug-resistant focal epilepsy. UChicago Medicine is the only center in Illinois that offers this laser procedure, which destroys seizure-causing lesions with pinpoint accuracy.
During the procedure, Peter Warnke, MD, a specialized fellowship-trained neurosurgeon who has performed over 100 laser ablations, uses magnetic resonance imaging (MRI) in real time to guide a laser fiber through a 3.2 mm hole in the patient’s skull with a 1.6 mm catheter toward the lesion causing the seizures. Once the fiber is in the lesion, the laser heats and destroys the abnormal brain tissue while the patient is continuously monitored in the MRI, leaving the surrounding tissue unharmed. Doing the procedure with real-time MRI imaging allows Warnke to monitor the temperature precisely and assess the extent of lesioning with submillimetric precision.
Warnke works with epileptologists Douglas Nordli Jr., MD, Julia Henry, MD, and Chalongchai Phitsanuwong, MD, to evaluate whether a patient is a candidate for LITT. "The best-suited patients are those whose seizures have a focal onset, from a single or few foci, and may be difficult to access through traditional epilepsy surgery," Phitsanuwong says. The lesion should be seen on an MRI and seizures can be pinpointed based on an EEG.
LITT provides long-term seizure control without the risks associated with open brain surgery.
Julia Henry, MD
For these patients, the advantages of LITT over open resection epilepsy surgery are numerous. The length of stay at the hospital is reduced from 3½ to 1½ days, and patients are back to school and regular activities within days. There is almost zero blood loss, scarring or pain, and no need for radiation.
Henry says that LITT provides long-term seizure control without the risks associated with open brain surgery. LITT also lowers the barriers to entry for epilepsy surgery. “Patients who wouldn’t normally consider surgical treatment agree to laser thermal ablation because of its low-risk/high-benefit ratio.”
Depending on the nature of the epileptic focus, between 78 and 44 percent of the patients who have undergone LITT at UChicago Medicine are seizure-free, while 100 percent have experienced seizure reduction.
“In more complicated patients who may eventually need additional surgeries, we are able to preserve the normal brain tissue, which makes future procedures easier,” Henry said. “One disadvantage of traditional epilepsy surgery, which involves extensive scalp incisions and a large cranial opening, is that it leaves behind scar tissue that may make it difficult to go back in for further treatment.” Also, open surgery is associated with a significantly higher risk of neuropsychological side effects than laser ablations.
UChicago Medicine has two nationally classified Level 4 epilepsy centers — one for adults and one for children — offering continuous care throughout the patient’s life.
Wim van Drongelen, PhD, technical and research director at the University of Chicago Medicine Comer Children’s Hospital Pediatric Epilepsy Center, has devoted his life’s work to understanding the mechanisms that govern different types of epilepsy. “Working in this field is not just an academic exercise to see how epilepsy works,” says van Drongelen. “Ultimately it has real implications for patients with epilepsy.”
The team’s groundwork could lead to the development of a device that successfully stops seizures.
Wim van Drongelen, PhD
Van Drongelen, with UChicago Medicine neurobiology graduate student Tahra Eissa and researchers at Columbia University and the University of Twente in the Netherlands, studied patients with drug-resistant focal epilepsy whose brain activity was being recorded via electrodes in the brain and on its surface in preparation for the removal of the seizure-causing tissue. The team used this data to create a focal epilepsy model that employs local activity patterns to produce realistic global seizures. In a paper published in 2018 in the International Journal of Neural Systems, van Drongelen’s team discusses how this model may help improve treatment for patients who do not respond to medication. "The team’s groundwork could lead to the development of a pace-breaker, a device that successfully stops seizures by disrupting the local unit activity within the seizure focus," van Drongelen says.
In a recent editorial, van Drongelen and his students speculate on how the latest approach in artificial neural network technology, called deep learning, can be used in the field of epilepsy. The deep-learning application, based on artificial neural nets with the neural elements arranged in multiple layers, uses advanced algorithms that detect pathological EEG rhythms quickly and reliably. Deeper layers extract progressively more complex and high-level features, until the deepest layers finally classify inputs using these high-level features.
"Since the review of EEG recordings is a subtle and time-consuming task for physicians, automating this part of the diagnostic process might give doctors more time to focus on high-level aspects of patient care," van Drongelen says.