Pursuing concussion’s cure

Veronica Carrillo, 17, and her mother, Paula, waited in the emergency department at University Hospital for the doctor’s diagnosis. The avid soccer midfielder had gone up to head the ball in a game when, in midair, the side of her head collided with the forehead of another player. Skulls are hard; no ball could make that kind of impact.

“I felt dizzy but kept going,” Veronica said. “I didn’t stop until I tried to head the ball again; I headed it wrong, with the top of my head, and I had a period of time when I didn’t know what was going on. They told me I blacked out.

“I thought I was going to get better, so I just went home and stayed there. I started getting really bad headaches, but I’m hardheaded and went and played again a couple of days later. After that game, I felt really bad. I had headaches and started throwing up. I’ve been throwing up since then [for three days].”

Concussions happen every day, everywhere, to anyone, and they happen in so many ways:

Your toddler, who’s interested in everything, reaches for the unanchored TV set, which falls and slams into her head. You’re filled with fear as you agonize about her developing brain.

Your son, the high school football jock, takes a helmet-to-helmet hit. The players climb off the pile, and you realize that the one who lies limp and immobile on the field is your son. The world stops as you see him carried off the field.

Your mother, 85, who still insists on doing things for herself, falls on loose floor tiles. You see closed eyes and a trickle of blood, and you realize she has hit her head. You frantically call 911, wondering what this will mean for the weeks and months ahead.

“I see head injuries every day in the emergency department, and the age range varies from small infants to 90-year-old people who trip and fall,” said Christopher Gelabert, M.D., assistant professor in the Department of Emergency Medicine and physician with UT Health San Antonio. “The most common is probably a slip and fall from a standing height.”

A concussion is a type of brain injury that temporarily stops the brain’s functions. It is commonly described as “getting your bell rung” and “seeing stars.” These casual terms may make the condition sound minor, but concussions are serious. Symptoms can range from a nagging headache to seizures, bleeding in and around the brain, and death.

“What we’ve done in sports medicine is to try to separate the word ‘mild’ from ‘severe’ in a concussion diagnosis,” said Rudy R. Navarro, M.D., assistant professor in the Department of Family and Community Medicine and family physician with UT Medicine. “This is because all concussions are treated the same way, currently, and secondly we don’t have a way to really determine what’s mild or severe or chronic until after the fact.”

Unlike cuts, there is no way to treat a concussion with a Band-Aid. The injury is within the skull, and it isn’t healed readily. Rest and observation are the recommended ways to treat a concussion today, but with an injury like this, they may not be enough.

“Any concussion has the potential to be a serious concussion,” Dr. Navarro said. “A person can develop myriad symptoms, including headaches, dizziness, fatigue, lightheadedness and loss of balance, as well as cognitive issues such as short-term memory impairment, increased time to learn new concepts, and difficulty retaining information. These effects may be developed over days, weeks and even months.”

Over the long term, repeated injuries could be associated with the early onset of degenerative brain diseases, as the public is learning through stories of former National Football League players such as Hall of Fame running back Tony Dorsett of the Dallas Cowboys, who was diagnosed with chronic traumatic encephalopathy. The disease is associated with memory loss and confusion, as well as problems with impulse control, aggression and depression. Eventually, it leads to dementia.

“During football season, we see more head injuries in young people,” Dr. Gelabert said. “Parents are very concerned, with all the things you see on TV with the NFL.”

A potential answer

But what if the brain, the seat of reasoning, memory and emotion, could be stimulated to heal itself? Researchers in the School of Medicine have discovered a possible avenue to do just that, and it lies—appropriately—within the brain’s so-called “caretaker” cells, called astrocytes.

The skull is a confined space, and the brain rests inside it in a bath of cerebrospinal fluid. When a concussion occurs, the brain is temporarily and violently shifted. Swelling from fluid retained in the brain tissues, called edema, creates pressure in the confined area. This can lead to the death of neurons—cells that signal nerves throughout the central nervous system to do all of life’s functions.

The research centers on a class of compounds called purinergic receptor agonists.

James D. Lechleiter, Ph.D., professor in the Department of Cellular and Structural Biology, has found that treating the astrocytes with the agonist compounds can stimulate the caretaker cells to be more active—essentially giving them a kick-start to minimize the swelling.

Illustration by Sam Newman, Creative Media Services

The effects are significant. In the brains of live mice, treatment of the astrocytes with the compounds consistently and dramatically reduced neuron death. The results also held true in the first trial on human brain tissue, obtained from patients who underwent surgery for epilepsy.

“We hope to limit and even reverse the effects of concussions,” Dr. Lechleiter said. “Essentially, we think we can enhance the brain’s ability to heal itself.”

Dr. Lechleiter received a U.S. patent for the discovery of the compounds’ benefits at the close of 2013.

He endured a lengthy process—seven years—replete with rejections and arguments. The UT Health Science Center technology commercialization team helped him in this effort.

“You get three strikes and you’re supposed to be out,” he said. “In this case we had at least four strikes but prevailed. When you’re developing something, you have to believe in it. We’re very excited about the clinical impact of our findings and hope this success leads to new drug therapies for people with multiple types of brain injuries.”

According to the Centers for Disease Control and Prevention, an estimated 1.7 million people sustain a traumatic brain injury annually. About 75 percent of these are concussions or other milder forms of brain injury. Children 4 and younger, adolescents 15 to 19, and adults 65 and older are at greatest risk, CDC statistics show. Head injuries result in more than 1 million emergency department visits per year.

“A concussion can happen at any age,” Dr. Navarro said. “The symptoms can be very subtle and can be masked by other disease processes. Also, if a patient has a significant traumatic injury or fracture and is on pain medicine, what may be completely missed, not even considered, is that the patient had a concussion.”

In toddlers and older developing children under the age of 12, the symptoms can be subtle and unusual, and are commonly missed. These symptoms can include irritability, excessive crying, a change in eating or sleeping patterns, loss of balance and appearing dazed or listless.

“That is a difficult group in which to make the diagnosis, because their symptoms are very different from what we see in teenagers and adults,” Dr. Navarro said. An added complication is younger children often can’t articulate what they’re feeling.

The elderly are susceptible to falls and, by extension, concussions.

“We worry in this group about hemorrhages, stroke, fracture and vitamin D deficiency, but sometimes we forget. We don’t step back and say this might be a concussion,” Dr. Navarro said. “There are so many confounding factors that it is difficult to treat.”

Medical science has miles to go in learning how to treat concussions. Rest is usually advised, along with ceasing sports and other activities that increase the risk of a second injury and refraining from activities such as schoolwork and computer use that require thinking and concentration.

In each age group, when a concussion is suspected, a medication based on stimulation of the caretaker astrocyte cells could be a true breakthrough, Dr. Navarro said.

“A treatment that could help prevent immediate or long-term complications, especially the cognitive issues, would be tremendous,” Dr. Navarro said. “We would have to show it makes a significant difference in patients’ lives, more than what we are doing now. We need to truly define the effects of concussion down the road. If we find that these injuries cause dementia or psychiatric issues long term, then any kind of treatment that is an adjunct to current care would absolutely be novel and groundbreaking.”

Promising beginning

The earliest preclinical testing of the therapy is complete, and Dr. Lechleiter, the Health Science Center and his new start-up company, Astrocyte Pharmaceuticals Inc., seek to move the program into different animal models, and ultimately to Food and Drug Administration trials in humans.

“We are at a stage where we know we have a molecule that works,” Dr. Lechleiter said. “The plan is to make small modifications to see what works the best. Once we have the molecule we want, we will enter a subcontract to test it in small animals.”

It is difficult to predict how many years it might be before this therapy could be widely available to the public.

“Right now the delivery method is uncertain,” Dr. Lechleiter said. “Clinical trials may test intravenous injections. It could later be sublingual, and melt in your mouth. We don’t know at this time.”

Animal studies and then human clinical research must show that the benefits of receiving an astrocyte stimulator for a concussion greatly outweigh any possible risks.

Things often move slowly in drug development. But if it takes 10 years or 20 years, it will be worth it, Dr. Lechleiter said, because the applications are enormous—from a toddler’s accident to the battlefield in Iraq.

And, of course, to the sports field.

The day of Veronica Carrillo’s visit to the hospital, nothing was more important than learning the extent of her head injury and what could be done. It was a minor concussion; rest and cessation of activities were prescribed. But what if a safe, effective infusion of astrocyte therapy had been available for a nurse or physician to administer?

“I feel like if I had taken a pill or something, it would have healed me sooner, and I could have played again sooner,” she said a week later.

Her future rides on her getting back on the field. The South San Antonio High School graduate has a scholarship to play for the Larks women’s soccer team at Hesston College, located about 35 miles north of Wichita, Kansas.

Will she do headers during games? “Oh yes,” she said without hesitation. “I am going to play like I’ve always played—strong—I’m still going to do headers and everything.”

She could be just one game away from her next concussion, but that’s a risk she’s willing to take, she said.

In the future, if Dr. Lechleiter’s astrocyte therapy proves successful and is available to emergency responders, someone at such a game could call 911, and the player could either receive the medication at the field or after arriving at a local hospital.

This is the future of medicine Dr. Lechleiter envisions.

“We don’t want to get ahead of where we are with the science,” he said, “but no other options are available to treat concussions at the moment, so any novel effective therapy is going to be a blockbuster. It would be used in emergency rooms and ambulances, in primary care and in any place with trained medical personnel. With professional supervision of this very powerful medicine, we could relieve not only the immediate effects of concussions but prevent many of the long-term effects, too.”