Researching traumatic brain injury

Researching traumatic brain injury
One of the most important clinical guides for determining the need for a CT scan is the patient’s initial level of alertness—measured using the Glasgow Coma Scale score (GCS. A new blood test, however, has been able to predict which patients did not have a brain injury visible on CT scan with very high accuracy.

SciTech Europa looks at recent examples of research into different elements of traumatic brain injury (TBI).

Quoting 2012 statistic obtained from Eurostat, in a 2016 article in the journal The Lancet Public Health, Dr Marek Majdan et al described how the year had seen 1,375,974 hospital discharges (data from 24 countries) and 33,415 deaths (25 countries) related to traumatic brain injury (TBI).

‘TBI caused 37% …of all injury-related deaths in the analysed countries,’ the authors add. This goes some way to highlighting the prevalence of this type of injury and, indeed, the burden it has.

Indeed, in a related article in the same edition of the journal, Mark Wilson from Imperial College, London, UK, wrote: ‘The public health consequences of traumatic brain injury (TBI) are currently woefully underappreciated. The burden created is often presented as number of deaths and injuries, with the cost calculated by the expense of ongoing care. However, many patients and their families live with the psychological consequences of minor TBI that have hidden costs such as the inability to hold down work, disinhibited (often aggressive or easily agitated) behaviour, and altered mood states.’

As such, it is important that more research is done so as to add to the already-existing body of knowledge surrounding this area, and this year alone much progress has been made.

Biomarkers

For instance, a team at the Department of Neurosurgery at the David Geffen School of Medicine within The University of California, Los Angeles, USA, has found elevated levels of lysophosphatidic acid in brain areas associated with cell death and axonal injury as well as in blood.

Writing in The American Journal of Pathology earlier this year, the researchers revealed they had found that a brain lipid molecule, lysophosphatidic acid (LPA), was significantly increased after traumatic brain injury (TBI) in a preclinical animal model. They also found that it was elevated in areas associated with cell death and axonal injury, both major hallmarks of moderate and severe TBI. This strengthens the evidence that LPA could be used as a biomarker of TBI through blood testing, potentially providing a prognostic indicator of injury and outcome.

Given the high incidence rate of traumatic brain injury, there is a need for non-invasive biomarkers to indicate the degree of injury and predict functional outcomes – the authors revealed that TBI is characterised by impairments in cognition, emotion, or physical function caused by a violent blow to the head or direct brain penetration by an object. Upon injury, it is often difficult to evaluate the extent of damage or predict how long the impairment will last or whether it will worsen – and advise how long an injured patient must remain away from sports or work before resuming any activity, explained lead investigator Dr Neil Harris.

“LPA may well be a potential marker for that since we found it to be associated with major regions of brain pathology. It is also present in blood in high concentrations after injury,” he added.

Although LPA has been previously suggested as a marker for TBI, this study showed for the first time that levels of LPA change within the area of the injury as well as in regions distant to the injury site and linked these changes to pathological findings in brain cells.

Atrophy of the connections between the cortex and thalamus is a common finding in TBI. When the investigators analysed the thalamus in this animal model, they found intracellular levels of LPA and its precursor phosphatidic acid increased one hour after injury but returned to normal levels three hours after injury. A special stain revealed that cell death was evident after three hours, leading the researchers to suggest that the observed changes in lipid levels are part of the early response of the brain to trauma and act to initiate the later sequence of neurodegenerative changes associated with TBI. The researchers also saw that although LPA levels were elevated in haemorrhagic areas, increases were also seen in brain regions not contaminated with blood.

Blood test

In more recent research – published in The Lancet Neurology – a high sensitivity blood test was developed which could help doctors rule out traumatic intracranial injuries like brain haemorrhage and contusion before resorting to CT scanning.

The large, multicentre observational trial, co-led by Dr Jeffrey Bazarian at the University of Rochester School of Medicine, USA, saw the novel blood test administered within 12 hours of a suspected traumatic brain injury (TBI). The levels of two biomarker proteins which are released into the bloodstream following a brain injury were then measured, with the authors reporting that the test correctly identified 99.6% of patients who did not have a traumatic intracranial injury on head CT scans among over 1,900 adults (mostly with mild TBI) presenting to emergency departments in the USA and Europe.

The blood test investigated in this study was thus able to predict which patients did not have a brain injury visible on CT scan with very high accuracy, even among those with a GCS less than 15. Further research to determine the extent to which the biomarker test complements decision rules, and as well as its impact on health care costs and patient throughput, will be key to understanding the test’s usefulness in clinical practice.

Bazarian said: “Based on the results of this multicentre study, routine use of the new biomarker test in emergency departments could reduce head CT scans by a third in acutely head injured patients thought to be in need of CT scanning, avoiding unnecessary CT-associated costs and radiation exposure, with a very low false-negative rate.”

One of the most important clinical guides for determining the need for a CT scan is the patient’s initial level of alertness—measured using the Glasgow Coma Scale score (GCS)—with some guidelines recommending a head CT for anyone with a less than perfect GCS score of 15.

Bazarian commented: “Our results suggest that patients with mild TBI (initial GCS of 14 or 15) who have no other indication for a CT (such as a focal neurologic deficit), and who have a negative test can safely avoid a CT scan. Those patients with a positive test have a 10% chance of an intracranial lesion and most clinicians would get a CT scan of their head to determine if an intracranial injury exists, and define it further. The extent to which these biomarker results can be applied to patients presenting with more severe injury, that is in those with a GCS less than 14, requires further confirmation.”

According to co-lead author Dr Peter Biberthaler from the Technical University of Munich, Germany: “The majority of patients presenting with mild traumatic brain injuries like concussion do not have visible traumatic intracranial injuries on CT scans. Given the GFAP and UCH-L1 biomarker test’s inherent simplicity, requiring only a blood draw, and its reliability at predicting the absence of intracranial injuries, we are hopeful of its future role in ruling out the need for CT scans in these patients.”

The authors note several limitations, however, including that the study did not evaluate the test’s predictive ability for clinical outcomes such as prolonged post-concussive symptoms, cognitive impairment, and decreased functional status. They also note that it did not attempt to assess the test’s diagnostic accuracy compared with currently used biomarkers (i.e., S100B) and clinical decision rules for triaging CT scanning. Finally, the sensitivity analysis comparing the diagnostic performance of the biomarker test for each of the proteins separately suggested that GFAP alone might perform as well as the two proteins combined, and requires further validation.

Diagnosis

Additionally, researchers from the University of Geneva (UNIGE), Switzerland, in collaboration with the Hospitals of Barcelona, Madrid and Seville, Spain, have developed a small device – Point-of-Care Test (POCT) – that analyses the level of proteins in the blood and allows, using a single drop of blood, to diagnose the possibility of a mild traumatic brain injury. This discovery, described in the journal PLOS One, will not only relieve emergency departments and free patients from often long waits, but will also save on costly medical examinations, the researchers have said.

UNIGE Professor Jean-Charles Sanchez explained: “We wondered if it was possible to isolate certain proteins whose presence in the blood increases in the event of mild traumatic brain injury. Our idea was to find a way to do a quick examination that would allow, during a boxing or American football match for example, to determine whether the athlete can return to the field or if his condition requires hospitalisation. The opposite of the CT Scan, an exam that lasts a long time and cannot be done anywhere.”

It was still necessary to develop a device that could be used everywhere, quickly and simply, and that could be available in pharmacies or sports halls.

Sanchez’s team thus developed a rapid diagnostic test (POCT) called ‘TBIcheck’, which was inspired by the principle of pregnancy testing: by placing a single drop of blood on the well of a small 5cm plastic case, the patient knows within 10 minutes whether there is a risk of mild trauma, namely whether or not his H-FABP level is higher than 2.5 nanograms per millilitre of blood.

Sanchez said: “If a lane appears, the injured person must go to a hospital for a CT scan, if there is nothing, he can go home safely.”

In case of doubt when reading the result, a small reader, the Cube Reader, can be installed on TBIcheck. It will display the word ‘positive’ or ‘negative’ and send the result to the patient’s or caregiver’s smartphone via Bluetooth.

Research into various different facets of TBI is thus taking place, and so perhaps some of the biggest challenges relating to TBI could, in time, come to be tackled.

This article will appear in SciTech Europa Quarterly issue 28, which will be published in September, 2018.

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