Biomarker Panel Accurately Predicts Intracranial Pathology in Mild TBI

Deborah Brauser

September 04, 2009

September 4, 2009 — A combination of 3 biomarkers (D-Dimer, BNP, and S100B) is significantly accurate in predicting the probability of intracranial pathology in mild traumatic brain injury (TBI), according to results reported at the Military Health Research Forum (MHRM) 2009.

"A rapid diagnostic point-of-care test with high negative predictive value would be a beneficial tool for physicians in emergency departments and for medics in the field, both civilian and military, when determining appropriate care for patients who have had a mild TBI, said co–lead investigator Gerald A. Grant, MD, associate professor of neurosurgery and director of neuro-trauma at Duke University Medical Center in Durham, North Carolina. Dr. Grant is also a former Air Force Lieutenant Colonel and military neurosurgeon deployed during Operation Iraqi Freedom.

"In this study, we demonstrated that a panel of biomarkers can be used to assess the potential risk of intracranial pathology with a high negative predictive value and a high sensitivity rate in patients presenting with an acute mild TBI," said Dr. Grant.

In addition, both D-Dimer and BNP were independently found to be significant predictors of abnormal computed tomography (CT) scans, and S100B, which has been a focus of recent TBI biomarker research, demonstrated the least predictive value of the 3 biomarkers.

However, "We really don't think the Holy Grail is 1 specific biomarker," said Dr. Grant. "A panel of markers in unison can represent time frames and different pathologies, leading to more predictive outcomes."

Difficult to Diagnose

Patients with mild TBI are generally difficult to diagnose clinically, as they often do not have any apparent focal symptoms. More than 8% of these patients have intracranial abnormalities that will later lead to the need for hospitalized care, reported other co–lead author Daniel Laskowitz, MD, associate professor of neurology and neurobiology and director of the neurovascular laboratories at Duke.

"The vast majority of patients with mild TBI will have no problems and can be sent home with impunity," he explained. "However, a small number, as was the case with the actress Natasha Richardson, may have minimal symptoms that if you miss [them], the results can be catastrophic."

Although the role of biomarkers in TBI research has been the focus of multiple studies, no single marker to date has been able to reliably predict intracranial pathology.

Dr. Grant explained that his interest in biomarkers came out of his military experience. "In Iraq, it's very difficult to get a patient rushed over to a center for a CAT scan. From a civilian's point of view, this is also important in sports or car accidents or other occurrances that can cause a concussion.

"We need ways to quickly access and triage these patients to help us decide: Are they at risk and need further treatment? Or can we send these folks right back to play or back on the field? The absence of a widely available and sensitive diagnostic test really limits the management of patients with acute mild TBI," said Dr. Grant.

In this study, the investigators explored whether an exploratory panel of brain injury biomarkers could be identified that would have a high negative predictive value and sensitivity rate to reliably determine which mild TBI patients were at risk for potential intracranial pathology after their injury.

Rate of Pathology Higher Than Average

The investigators drew blood samples from a total of 119 patients (median age, 60 years; 56% men; 57% white) presenting with mild TBI (defined as Glasgow Coma Scale score, 14 – 15) at Duke University Medical Center from June 2006 to September 2007.

The primary outcome was the clinical diagnosis of intracranial pathology, defined by noncontrast CT scans. A simple logistic regression was then performed for each biomarker, and the most predictive were entered into a multiple logistic regression model. A final 3-variable logistic model was generated to predict abnormal CT. In addition, biomarker plasma levels related to brain injury were measured by immunoassay.

At the end of the study, noncontrast CT evaluation revealed that 28% of the enrolled patients had some form of intracranial pathology.

"Our percentage of patients with positive CT findings was higher than those found in other studies and may be potentially due in part to the study having been performed at a level 1 trauma hospital," reported Dr. Grant.

In univariate analysis, both BNP (chi square < 0.02) and D-Dimer values (chi square < 0.04) were significantly predictive of CT abnormality, whereas S100B values were not.

"This is probably a timing issue," explained Dr. Grant. "The timing from injury is extremely critical with the S100B, which really starts to lose its sensitivity window after 3 hours. Rarely are patients getting blood drawn within 3 hours of injury." There was a mean time of 8 hours, 14 minutes from time of injury to time of enrollment for the study patients.

Larger Studies Needed

A logistic model incorporating all 3 biomarkers was found to be predictive of intracranial pathology, with an area under the receiver operating characteristic curve of 0.73. In addition, this model had a sensitivity of 92% and corresponding specificity of 32%. The negative predictive value of this model test was 92%.

"This exploratory study demonstrated the feasibility of using a panel of biomarkers to aid in the initial triage and management decisions of patients with mild TBI," concluded Dr. Grant. "A diagnostic approach using this panel may have clinical utility in identifying which of these patients are especially at risk for intracranial pathology, while also aiding in the reduction of unnecessary imaging testing."

However, he advised caution when using the panel in patients with comorbidities such as congestive heart failure, renal insufficiency, or increased age, as they are factors known to increase BNP levels.

The investigators report that further studies, rigorously timed and with larger patient numbers, will be needed to validate this approach of using a point-of-care platform in both civilian and military settings.

An Excellent Process

In an interview with Medscape Psychiatry, Dr. Barbara Terry-Koroma, PhD, program manager of the Psychological Health and Traumatic Brain Injury Research Program at the Congressionally Directed Medical Research Program, said that this study was well organized and had an "excellent process." Dr. Terry-Koroma was not associated with the study.

"It would be very important to have a test that you could easily use, whether you're a medic in the field related to deployment or in the field with a car accident, to be able to determine whether that patient needs to be monitored further," said Dr. Terry-Koroma.

"Now in this case it means you've got to draw some blood to do it," she added. "So from that perspective it's not as early a detector as we might like. But it certainly is beneficial, and I applaud [the investigators]."

Dr. Terry-Koroma added that this type of ongoing research has the potential to lead to the development of a useful diagnostic tool to aid health care providers in the diagnosis of such injuries.

This study was supported in part by the Roche Biomarker Program and Biosyte, Inc. Dr. Grant, Dr. Laskowitz, and Dr. Terry-Koroma have reported no relevant financial relationships.

Military Health Research Forum (MHRF) 2009: Abstract P23-17. Presented September 3, 2009.

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