Simple blood test identifies concussions absent on CT scans

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BloodMany patients with concussion have normal CT scans and are discharged from the hospital without follow-up. But a blood test that is currently under development and costs a fraction of the price of a brain scan may flag concussion in these CT-negative patients, enabling them to be evaluated for long-term complications.

In a study led by University of California – San Francisco (UCSF), researchers tracked 450 patients with suspected traumatic brain injury (TBI) – which includes concussion or mild TBI – who had been admitted to one of 18 level 1 trauma centres throughout the nation. The patients, whose injuries were mainly attributed to traffic accidents or falls, all had normal CT scans, according to the study.

Within 24 hours of their accidents, the patients had their blood drawn to measure for glial fibrillary acidic protein, a marker correlating to TBI. The study used a device by Abbott Laboratories called i-STAT Alinity, a handheld portable blood analyser, currently unavailable in the US, that produces test results in minutes.

The researchers later confirmed the blood test results against MRI, a more sensitive and expensive scan that is not as widely available as CT but offers a more definitive diagnosis of TBI. They found that 120 of these 450 patients (27%) had an MRI that was positive for TBI.

“Our earlier research has shown that even in the best trauma centres, patients with TBI are not getting the care they need,” said Dr Geoffrey Manley, senior author of the study, professor of neurosurgery at UCSF and a member of the Weill Institutes for Neurosciences. “Now we know that many of these patients with TBI are not even getting a diagnosis.”

Manley is also the principal investigator of TRACK TBI, which has analysed clinical data on more than 3,300 patients and comparison participants, and previously has linked concussion with major depression, post-traumatic stress disorder and cognitive deficits. Work by other UCSF faculty has found correlations between TBI and Parkinson’s disease and TBI and dementia.

To assess the accuracy of the blood test, researchers compared the results of the patients whose CT-negative TBIs were confirmed by MRI, with a group of healthy participants as well as a cohort of patients with orthopaedic injuries. They found that the average protein value of the blood samples of patients with positive MRIs was 31.6 times higher than those with orthopaedic injuries and nearly 52 times that of the healthy participants. The protein was elevated even in the patients with normal MRIs, suggesting that the test may be sensitive to injury undetectable by MRI, the researchers noted.

In the future, the blood test may help clinicians decide who can safely avoid a CT scan, with the advantage of not exposing patients to radiation from a CT, said first author Dr John Yue, of the UCSF department of neurological surgery. Additionally, the blood test may be a useful tool for those patients in trauma centres and emergency departments, whose symptoms may be altered by substance use, he said. “Patients with concussion may present as confused and disoriented, and may repeat themselves – symptoms that are similar in people with intoxication. With the blood test, we may be able to discern whether their symptoms are primarily due to brain injury and treat accordingly.”

The blood test may also clarify diagnosis in patients with co-existing conditions or those who take medications that may impact speech and behaviour, said Yue.

“These blood-based biomarkers are the next step in the evolution of diagnosing and treating TBI,” said Manley. “We are finding that not only are they more sensitive than CT in identifying TBI, but they may be more accurate than the current standard of MRI.”

The study follows an earlier TRACK-TBI pilot study that found approximately 30% of concussion patients with negative CTs and positive MRIs had disability three months post-injury.

Abstract
Background: After traumatic brain injury (TBI), plasma concentration of glial fibrillary acidic protein (GFAP) correlates with intracranial injury visible on CT scan. Some patients with suspected TBI with normal CT findings show pathology on MRI. We assessed the discriminative ability of GFAP to identify MRI abnormalities in patients with normal CT findings.
Methods: TRACK-TBI is a prospective cohort study that enrolled patients with TBI who had a clinically indicated head CT scan within 24 h of injury at 18 level 1 trauma centres in the USA. For this analysis, we included patients with normal CT findings (Glasgow Coma Scale score 13–15) who consented to venepuncture within 24 h post injury and who had an MRI scan 7–18 days post injury. We compared MRI findings in these patients with those of orthopaedic trauma controls and healthy controls recruited from the study sites. Plasma GFAP concentrations (pg/mL) were measured using a prototype assay on a point-of-care platform. We used receiver operating characteristic (ROC) analysis to evaluate the discriminative ability of GFAP for positive MRI scans in patients with negative CT scans over 24 h (time between injury and venepuncture). The primary outcome was the area under the ROC curve (AUC) for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings within 24 h of injury. The Dunn Kruskal–Wallis test was used to compare GFAP concentrations between MRI lesion types with Benjamini–Hochberg correction for multiple comparisons. This study is registered with ClinicalTrials.gov, numberNCT02119182.
Findings: Between Feb 26, 2014, and June 15, 2018, we recruited 450 patients with normal head CT scans (of whom 330 had negative MRI scans and 120 had positive MRI scans), 122 orthopaedic trauma controls, and 209 healthy controls. AUC for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings was 0·777 (95% CI 0·726–0·829) over 24 h. Median plasma GFAP concentration was highest in patients with CT-negative and MRI-positive findings (414·4 pg/mL, 25–75th percentile 139·3–813·4), followed by patients with CT-negative and MRI-negative findings (74·0 pg/mL, 17·5–214·4), orthopaedic trauma controls (13·1 pg/mL, 6·9–20·0), and healthy controls (8·0 pg/mL, 3·0–14·0; all comparisons between patients with CT-negative MRI-positive findings and other groups p<0·0001).
Interpretation: Analysis of blood GFAP concentrations using prototype assays on a point-of-care platform within 24 h of injury might improve detection of TBI and identify patients who might need subsequent MRI and follow-up.
Funding: National Institute of Neurological Disorders and Stroke and US Department of Defence.

Authors
John K Yue, Esther L Yuh, Frederick K Korley, Ethan A Winkler, Xiaoying Sun, Ross C Puffer, Hansen Deng, Winward Choy, Ankush Chandra, Sabrina R Taylor, Adam R Ferguson, J Russell Huie, Miri Rabinowitz, Ava M Puccio, Pratik Mukherjee, Mary J Vassar, Kevin K W Wang, Ramon Diaz-Arrastia, David O Okonkwo, Sonia Jain, Geoffrey T Manley, Opeolu M Adeoye, Neeraj Badjatia, Kim Boase, Yelena G Bodien, Malcom R Bullock, Randall M Chesnut, John D Corrigan, Karen Crawford, Sureyya S Dikmen, Ann-Christine Duhaime, Richard G Ellenbogen, Venkata Feeser, Brandon Foreman, Raquel C Gardner, Etienne Gaudette, Joseph T Giacino, Dana P Goldman, Luis Gonzalez, Shankar Gopinath, Rao Gullapalli, J C Hemphill, Gillian Hotz, Joel H Kramer, Natalie P Kreitzer, Harvey S Levin, Christopher J Lindsell, Joan Machamer, Christopher J Madden, Alastair J Martin, Thomas W McAllister, Michael McCrea, Randall Merchant, Lindsay D Nelson, Florence Noel, Eva M Palacios, Daniel P Perl, Ava M Puccio, Miri Rabinowitz, Claudia S Robertson, Jonathan Rosand, Angelle M Sander, Gabriela G Satris, David M Schnyer, Seth A Seabury, Mark Sherer, Murray B Stein, Nancy R Temkin, Arthur W Toga, Alex B Valadka, Mary J Vassar, Paul M Vespa, Esther L Yuh, Ross Zafonte

University of California – San Francisco material
The Lancet Neurology abstract


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