Finding Answers Through Collaboration

When it comes to the connection between hypoglycemia and epilepsy, one thing is certain: “Low blood sugar is bad for the brain,” say Elizabeth Rosenfeld, MD, MSCE, a pediatric endocrinologist at Children’s Hospital of Philadelphia (CHOP).

A collaborative group of physician-researchers at CHOP are working to refine the connection and uncover the best way to reduce seizure activity in individuals with a specific type of hypoglycemia, congenital hyperinsulinism, and even more specifically in those with hyperinsulinism/hyperammonemia (HI/HA).

HI/HA, the second most common type of hyperinsulinism, is caused by activating mutations in the GLUD-1 gene. In children with GLUD-1 mutations, excess insulin secretion causes low blood glucose with fasting or when the child eats protein. They may not have classic manifestations of the disease early in life, which presents a diagnostic challenge. Beyond blood sugar control, individuals with HI/HA have an elevated risk have having seizures.

Two programs at CHOP, the Congenital Hyperinsulinism Center (HI Center) and the Epilepsy Neurogenetics Initiative (ENGIN), have developed special expertise in creating individualized care plans for patients whose GLUD-1 HI/HA may be driving their seizures. They also take advantage of the large number of HI/HA patients seen at CHOP to research the best treatments and to create new ways to treat these complicated patients.

The HI Center treats more children with HI than any center in the world and has been at the forefront of discoveries in diagnosing and treating hyperinsulinism for decades. In fact, it was Charles Stanley, MD, founder of the HI Center, who discovered the GLUD-1 gene’s relationship to HI/HA. ENGIN’s overall focus is the diagnosis and treatment of children with difficult-to-treat or unexplained epilepsies and providing expert care for children with genetic epilepsy syndromes, with an emphasis on discovering how genetic variants cause seizures. Both have been designated as Frontier Programs at CHOP, giving them access to additional support for visionary research that translates to cutting-edge clinical care. Since the ENGIN collaboration began in 2019, they have seen eight patients with HI/HA and GLUD-1 mutations.

“Hypoglycemia in HI/HA responds well to treatment with diazoxide and dietary management — not eating protein without carbohydrate,” Rosenfeld says. “Because the hypoglycemia management is often not as complex as for patients with diazoxide-unresponsive forms of HI, patients may be more likely to be managed locally. They may not have access to specialized neurological care like we offer through this collaboration.”

The challenge in the HI/HA population is the neurological spectrum of presentation.

Some HI/HA patients have seizures, some do not. Some had seizures when they were younger, then they stopped. Those with seizures may have absence seizures, the most common type, while others may have generalized tonic-clonic or myoclonic seizures. Some have more than one type. How high the plasma ammonia level is does not appear to impact seizure activity.

It’s difficult to know if the cause of seizure activity is the GLUD-1 mutation itself, early-life hypoglycemia-induced seizures that caused brain injury — or even some combination of those factors.

“We are only beginning to understand what role the GLUD-1 gene plays in brain electrical control, and how variants in this gene lead to epilepsy.” says ENGIN epileptologist Mark Fitzgerald, MD, PhD, who sees the patients with GLUD-1 mutations along with genetic counselor Sarah McKeown Ruggiero, MS, LCGC. “The seizures are probably related to the specific disease-causing variant in GLUD-1 and how that variant interacts with all the other genetic variation in that patient.”

Atypical EEG patterns

Because of its subtle signs, absence seizure activity may go unnoticed initially as the child’s staring blankly and twitching of eyes or mouth is often mistaken for inattention or daydreaming.

“From an EEG standpoint, absence seizures show a generalized electrical discharge that has a very specific frequency- a rhythmic 3 hertz spike-and-wave pattern all across the brain,” Fitzgerald says. “This type of electrical pattern shouldn’t happen when you have a focal brain injury from hypoglycemia. That type of injury would become the seizure focus and the patient would develop, or be at risk for, focal epilepsy. The fact that many GLUD-1 patients have generalized epilepsies suggests that the GLUD-1 gene is important for brain electrical control on its own.”

Generalized seizure patterns, like those in absence seizures, were the first recognized in patients with GLUD-1 mutations. More observation showed that those patients also might have focal seizures, potentially triggered by hypoglycemic brain injury.

“It’s made us realize that there’s something about this GLUD-1 gene that’s important in the brain separate from ways it’s important to the pancreas,” Fitzgerald says. “Together, our programs will help figure out the how and why.”

Comprehensive care includes Endocrinology and Neurology

Comprehensive care for HI/HA patients includes determining their neurological phenotype in addition to their endocrine phenotype. At CHOP, patients have been followed by Neurology as well as the HI Center for many years. The formalized collaboration with ENGIN expands HI/HA patients’ access to studies that aim to better understand the neurological side of the condition. For example, each patient receives an EEG before seeing Fitzgerald so he can review their brain patterns.

In the course of day-to-day care, the ENGIN program collects data in the electronic medical record on types, frequency and severity of seizures, prescribed antiseizure medication and its effectiveness and side effects, and genetic mutations in a way that facilitates compiling information later on.

“We can quickly review how these kids do over time from a neurological standpoint,” Fitzgerald says. “Once we know the natural history of the process, we can start to recommend treatment strategies that the data shows can alter that natural history to improve things for those kids.”

The near-term goal is to use the collective data to learn what current medications have a high probability of effectiveness for epilepsy patients with GLUD-1 mutations; the longer-term goal is to develop precision therapies.

Those without seizures also welcome

HI/HA patients who do not have known seizure activity are also encouraged to go to the ENGIN clinic. While roughly half have seizures, a higher percentage (potentially as high as 70% in some studies) of GLUD-1 patients have developmental delays, intellectual disability or different types of learning problems such as ADHD.

“Those visits give us the opportunity to offer anticipatory guidance to the families, some who may have a fresh genetic diagnosis of GLUD-1 and might not know that seizures can be an issue,” Fitzgerald says. “We delve into what is possible and what they should watch out for in the future, whether it’s absence seizures or learning differences. It gives them a chance to get ahead of it and get their child any help they need sooner rather than later.”

The ENGIN program will also evaluate children with neurological differences who experienced early life recurrent hypoglycemia outside of an HI diagnosis and those with other types of hyperinsulinism to find the underlying genetic etiology of their epilepsy.

After an initial appointment, patients from beyond of the Philadelphia region are most often managed by their local neurologist and endocrinologist in partnership with ENGIN and the HI Center.

“Recognition of the neurological manifestations of this disorder by people who are trained and knowledgeable about the presentations unique to HI/HA is really important for families,” Rosenfeld says. “Through our collaboration, families receive counseling and surveillance and, if needed, also expertly tailored treatment.”