Serum Biomarkers for Classifying Injury Severity and Predicting Outcome After Acute Spinal Cord Injury

When someone suffers an acute spinal cord injury (SCI) and is brought to the hospital emergency room, the clinicians perform a standardized evaluation of muscle strength and skin sensation according to the International Standards for Neurologic Classification of Spinal Cord Injury, otherwise known as the ISNCSCI (pronounced 'in-ski') examination. The severity of the SCI is then classified with an 'AIS Grade' of A, B, C, or D and the extent of remaining muscle function (the 'motor score') is documented. The ISNCSCI is then repeated to determine how much spinal cord function has recovered over time, as reflected by improvements in AIS grade and/or motor score. For decades, the SCI field has relied heavily upon this type of neurologic examination to characterize the degree of initial injury and the extent of subsequent recovery. Also, researchers depend upon the ISNCSCI when conducting clinical trials of new therapies to establish how severe an injury is at the outset, and then determine how much recovery may have occurred as the result of the treatment being tested.

While the ISNCSCI is very helpful for the field, it has significant limitations. It is a subjective and time- consuming assessment, even for the most skilled, experienced clinicians. In acutely injured patients, it is often impossible to even do, given that they may be unconscious or have other injuries that preclude any examination. And even when the ISNCSCI exam can be done and an AIS Grade and motor score assigned, it does not allow one to precisely predict how much recovery will occur. This makes it difficult for clinicians to provide accurate prognostic information to patients. It also makes it extremely difficult for researchers to test new therapies, because they must then enroll large numbers of patients in their clinical trials to be sure that the recovery from the treatment in question is truly better than what would have been achieved spontaneously.

What is required to move the field beyond its singular dependence on the ISNCSCI exam are biomarkers of acute SCI – biological parameters that are objective measures of SCI. We have, for many years, investigated biomarkers within the cerebrospinal fluid (CSF) of acute SCI patients and have identified a number of promising candidates. But CSF can only be obtained through a lumbar puncture (a 'spinal tap'), and a much more practical approach would be to identify biomarkers that can be measured in blood samples. We have recently found that two particular proteins measured in blood samples – neurofilament-light chain (NF-L) and glial fibrillary acidic protein (GFAP) – can accurately classify baseline AIS grade, and also predict the extent of neurologic recovery. This is very exciting, as it opens up the possibility that a simple blood test could overcome many of the limitations of the ISNCSCI. A blood-based biomarker could give clinicians information about how severely the cord is injured, even in patients who are unconscious and unable to be assessed. Such biomarkers could help clinicians provide accurate prognostic information to patients. And such biomarkers could help researchers more rapidly test new treatments by more precisely predicting how much neurologic recovery is expected.

How then do we translate these promising research findings forward so that NF-L and GFAP can become useful biomarker tools for clinicians and researchers? Here, we propose two important steps for moving these blood biomarkers towards clinical implementation. Firstly, we will validate the accuracy with which they can classify injury severity and predict outcome, by recruiting a completely independent group of acute SCI patients to test the performance of NF-L and GFAP as biomarkers. This 'external validation' is an important 'real world' assessment of these biomarkers. Then, while we have traditionally measured NF-L and GFAP in serum samples that are taken to the lab and then evaluated on a highly sophisticated measurement device (a process that can take an entire day), we will evaluate a 'point-of-care' device that can measure blood biomarkers within minutes, right at the patient's bedside. Such point-of-care devices are already in development for measuring blood biomarkers in patients with traumatic brain injury. The advantage of using an already available point-of-care technology is that if its accuracy is confirmed, it could potentially be implemented right away by clinicians and researchers.

The establishment of blood biomarkers would represent a paradigm shift for the SCI field. It would indeed help clinicians in making their diagnosis and estimating the prognosis of acute SCI, fulfilling the need for providing patients with accurate information about their injury. And it would improve how clinical trials in acute SCI are performed, allowing researchers to potentially recruit fewer patients and thus accelerate the pace with which novel treatments can be evaluated. Almost every such novel treatment that has been tested in an acute SCI clinical trial in the last 20 years has failed to make it to enrolment completion and has been terminated prematurely. It is therefore imperative that we develop different strategies for testing new treatments, or we will simply be failing in the same way for the next 20 years. A blood-based biomarker that can be rapidly assessed right at the bedside will be extremely useful for clinicians, researchers, and ultimately patients. The ability to quickly extract this diagnostic and prognostic information from blood samples also makes this approach very applicable to the austere military healthcare setting, where a simple and rapid assessment of spinal cord injury would be very useful.