ARTICLE IN BRIEF
Experts said TBI research could benefit from better animal models, and well-designed trials on brain pharmacokinetics, biomarkers, and surrogate endpoints.
A RLINGTON, VA—In an era when mission-motivated military service personnel and driven, competitive athletes are suffering from traumatic brain injury (TBI), it is critical to fund research to understand the course of TBI, especially mild TBI, in order to develop more effective therapies, said speakers at a joint meeting here in March of the American Society of Experimental NeuroTherapeutics (ASENT) and the International Society for CNS Clinical Trials and Methodology.
“Historically TBI has not received the research attention it deserves,” said ASENT immediate past president Alan I. Faden, MD, professor in the department of neuroscience at Georgetown University Medical Center. In part, said Dr. Faden, who co-chaired a session on methodological issues in TBI research, this neglect has been due to the fact that 70- to 80-percent of TBIs were considered mild — and their impact was not fully appreciated.
But, said Dr. Faden, “The attitudes toward TBI have changed quite dramatically in the last few years,” mostly because of the high numbers of military personnel who have experienced TBIs in combat in Iraq or Afghanistan. “Mild TBI is not so mild,” said Dr. Faden, noting that the symptoms of a mild TBI “can go on and on.”
Citing the use of tPA to dissolve clots in stroke, Ross Bullock, MD, PhD, clinical director of the Neurotrauma Program in the department of neurological surgery of the University of Miami Leonard M. Miller School of Medicine, said the field of TBI research needs better animal models — there is no consensus on those most useful in developing therapies — as well as well-designed studies on brain pharmacokinetics, biomarkers, and surrogate endpoints.
OBSTACLES TO OVERCOME
Col. Michael M. Jaffee, MD, national director of the Defense & Veterans Brain Injury Center at Walter Reed Army Medical Center in Washington, DC, who is a neurologist and a psychiatrist, said there are many obstacles in TBI research in the military that must be overcome to obtain useful clinical trial results. There are the obvious challenges of trying to study TBI in a combat situation. Not only is there imminent danger, but personnel may be suffering from sleep deprivation, may be in a state of hyper-arousal, or may have other injuries or psychiatric co-morbidities.
Second, he noted, service personnel may downplay their symptoms because their mission supersedes everything else. “These are highly motivated young men and women who don't want to be taken out of the fight,” he said.
Third, he said, “there are a lot of restrictions on DoD (Department of Defense) computer systems,” for fear that such systems could be exploited by an enemy. Thus using computerized systems for TBI research is an issue.
In addition, Dr. Jaffee noted, studying the beneficial effects of drugs for TBI in the military is difficult because “many medication side effects acceptable in civilian studies [such as drowsiness and a slowed reaction time] could be dangerous in a combat environment.”
In the civilian population, the Centers for Disease Control and Prevention (CDC) estimates that there are 1.6 million to 3.8 million sports-related mild TBIs in the United States each year. About 1 million children sustain a TBI every year, and TBI accounts for about 10 percent of pediatric emergency department evaluations annually — many from sports-related injuries, said Mark R. Lovell, PhD, professor in the departments of orthopedics and neurological surgery and director of the Sports Medicine Concussion Program at the University of Pittsburgh Medical Center.
Dr. Lovell noted that many times young athletes will downplay their symptoms because they want to get back onto the field of competition. Nonetheless, he said that sports is a good research laboratory for mild TBI, because pre-injury baseline information is available on many athletes and researchers have access to large groups of individuals who have a relatively high likelihood of injury.
Currently, said Dr. Lovell, he is doing follow-up research on patients who have had a sports-related mild TBI, using functional MRI. “With athletes we're always worrying about putting them back on the field too soon; the brain is more vulnerable post-concussion,” said Dr. Lovell.
As for testing neuroprotective drugs for mild TBI in young athletes, Dr. Lovell said, “It's hard to get an IRB to give approval to give kids for anything.”
One issue that surfaced during this session at the meeting was the crucial need to better understand the impact of multiple mild TBI exposures on a patient's course of recovery and cognition.
“People are coming back reporting 10 or 15 blast injuries,” said Karen A. Schwab, PhD, chief of epidemiology and statistics at the DVBIC. In terms of return to active duty after multiple TBIs, “How many is too many?” asked Dr. Jaffee. And what about patients who have had multiple mild TBIs and also suffer from post-traumatic stress syndrome (PTSD) — since the two often go hand in hand? As for athletes, “Past studies have suggested that repetitive trauma in athletes is associated with a poorer outcome,” said Dr. Lovell. Thus an athlete with three or more mild TBIs is three times more likely to have an additional injury, he said.
In summary, “We need well-controlled studies, including randomized controlled trials, in TBI rehabilitation,” said Dr. Schwab. “We should not wait for total information before we begin,” she urged. “We need trials on pharmaceutical management, other rehabilitation strategies and prevention approaches. One trial will probably not provide definitive evidence; replication and studies of different treatments, different populations and with different research methodologies, are required.”