CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Amy Carpenter Aquino
April 2023—Traumatic brain injury triage in the emergency department is badly in need of biomarkers—and ones that can change practice.
“If biomarkers don’t change practice, they’re a waste of time,” said W. Frank Peacock IV, MD, professor of emergency medicine, vice chair of research, and research director, Department of Emergency Medicine, Baylor College of Medicine.
“We have no biomarkers now that tell me who has damage to their brain,” he said in an AACC session last year. “We have a couple that say, ‘I don’t need a scan,’ but there are a lot of people with negative CT scans who have subsequent brain injuries. We’re only sorting that out now.”
Dr. Wu
Dr. Peacock painted a bleak picture of the biomarker practice gap in traumatic brain injury. His co-speakers, Alan Wu, PhD, D(ABCC), of Zuckerberg San Francisco General Hospital, and Pradip Datta, PhD, D(ABCC), of Siemens Healthineers, talked about short- and long-term laboratory diagnostics for TBI today and to come. (For Dr. Datta’s rundown, see “Traumatic brain injury biomarkers”. )
If the patient’s TBI is not a clear emergency, and most are not, “I have to decide what to do,” Dr. Peacock said. The American College of Emergency Physicians advises getting a CT scan “in almost every case,” he said. A neurology consult follows a positive scan. If the CT scan is negative, “you go into the black box,” which Dr. Peacock describes as “I don’t have a clue, but I know what to do: I’m going to send you home.” The worry, he said, is post-concussive syndrome. The ACEP’s level A guidelines include a long list of symptoms including headache. “I’ve never seen anybody with a TBI who didn’t have a headache,” Dr. Peacock said, so patients with mild TBI automatically get a head CT scan, “and 95 percent of them are negative.”
ACEP level B guidelines go further, he said. If a patient falls more than three feet, for example—“and most people are taller than three feet”—they get a CT scan.
“You can see where I’m going with this: Everybody’s getting a CT scan.”
The ALERT-TBI study of almost 2,000 patients found a 98 percent sensitivity and high negative predictive value (0.996) for the ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) tests in ruling out the need for a CT scan (Bazarian JJ, et al. Lancet Neurol. 2018;17[9]:782–789). “If it’s negative, I am done,” Dr. Peacock said of the utility of the assay results. The specificity is low: 0.364 for patients with a Glasgow Coma Scale score of nine to 15; 0.367 for GCS 14–15; 0.344 for patients with neurologically manageable lesions. Even so, “I can get rid of a third of CT scans,” he said. If a patient with a TBI has assay results above the cutoff values, “that’s a positive, and you’re off to the CT scanner.” If the results are below the cutoff values, the patient can go home.
“What I’m always interested in are the people whose Glasgow Coma scores are 14 or 15. I could even go down to 13,” Dr. Peacock said. “But below that, you’re getting a CT scan.”
Time from injury to blood draw is important, he said, and in the ALERT-TBI study, it’s 3.2 hours. “So if you show up one hour after your injury, what does it mean? It means I don’t have a clue. You can’t trust these labs, and one of the problems is the literature is sloppy about this,” with some studies saying within one hour of injury “this works,” he said. However, “if you really look into the data, it’s always three hours,” because there is delay in when patients arrive in the ED for most major events, and getting a patient involved in a clinical trial adds another hour. “This is just the realities of studies.”
For patients with a negative CT scan, there are no guidelines for what to tell them to do, Dr. Peacock said. “We’re winging it.” But post-concussive syndrome and its symptoms and aftermath—in some cases job loss—are the problem.
Dr. Peacock said the sensitivity of an ED physician knowing who has a TBI and who does not is eight percent (Korley FK, et al. Acad Emerg Med. 2019;26[12]:1384–1387). “It’s the worst number I’ve ever seen published. . . . It implies emergency docs don’t have a clue, and the reality is we don’t. I cannot tell who has a TBI. In fact, the patients can’t tell—that’s the other reality.” Symptoms sometimes don’t show up for a couple of weeks.
“What we’re really talking about is acute traumatic encephalopathy,” Dr. Peacock said, known more commonly as chronic traumatic encephalopathy. “It’s not a chronic problem with no beginning,” he said of CTE. “The beginning is acute traumatic encephalopathy,” and there is no ability to diagnose it at this time. Before markers, there was no way to detect non-ST-elevation myocardial infarction, but there was subclinical damage, leading to heart failure five years later. “It’s the same thing here,” he said. “Five years later after multiple hits, you’re going to have chronic traumatic encephalopathy.” These are patients who may have post-concussive syndrome symptoms. They’ll have post-traumatic biomarker abnormalities and may have abnormal functional testing.
Dr. Peacock and colleagues evaluated the use of three biomarker proteins in adult patients examined for head injury at two emergency departments within the Johns Hopkins Hospital system and enrolled in the prospective observational HeadSMART study. All had a CT scan and a GCS score of 13 to 15. Two control cohorts were used. They found that neurogranin (NRGN) and neuron-specific enolase (NSE) were elevated and that metallothionein 3 (MT3) decreased in mild TBI patients compared with controls (Peacock WF IV, et al. Front Neurol. Published online Nov. 30, 2017. doi:10.3389/fneur.2017.00641).
“These are three markers that have the characteristics of something that would be useful for ATE,” he said.