Biomarkers in spinal cord injury: A highlight on prognostic insights

Introduction

Spinal cord injury (SCI) is a broad term that includes changeable grades of neurological deficits and is still considered an incurable condition. In spite of substantial advances in surgical and medical treatment, just around 1% of SCI patients experience complete healing. Unfortunately, almost 45% of the them suffer from serious neurological loss, which includes incomplete or complete tetraplegia, with or without respiratory compromise ( ). Therefore, SCI usually has devastating vocational, social, and physical implications for patients and caregivers ( ).

The patient’s outcome after initial SCI is still very difficult to predict, because the tools we have today for both evaluating the gravity of spinal cord tissue destruction and better assessing the recovery of SCI patients are still restricted ( ). Imaging examinations of the spinal cord cannot accurately predict the prognosis of the disease. Computed tomography shows only fractures or dislocations, while magnetic resonance imaging is not highly sensitive to edema of the spinal cord, be it related or not to SCI. Furthermore, laboratory tests of blood biochemistry such as lactate dehydrogenase and protein kinase C are not specific for SCI, as other non-neurological damage can also cause changes in blood parameters, having, therefore, no clinical application ( ). There’s no doubt that the sooner we evaluate the extent of the lesion and start treating the patient, the better the outcome is. Nowadays, the best predictive value of neurological assessment of the SCI patient is defined by typical clinical neurological examinations during the patient’s first evaluation ( ). So the identification of biomarkers that can predict lesions is crucial to helping assess damage severity, prognosis, and therapeutic outcomes ( ).

In this chapter, we will highlight the most recent research on the expression of biomarkers in the pathophysiology of the SCI and try to correlate to diagnosis and prognosis.

Pathophysiology of SCI

It is well known that SCI occurs in two mechanisms that progress through three stages. Both mechanisms that lead to acute SCI are now very well characterized and recognized as primary (mechanical) and secondary injuries. The primary injury is caused by the initial mechanical trauma of surrounding tissues, followed by contusion and compression of the spinal cord, which induces damage to nerve cells, blood vessels, and myelin ( ). The secondary lesion is triggered by the primary lesion and is classified in three phases, namely the acute phase, the sub-acute (or intermediate) phase, and the chronic phase, according to the pathomechanism and post-injury time ( ; ).

The acute stage begins with the mechanical injury and extends to the first 48 h after the initial traumatic injury. In this stage, the patient develops some neurological deficits directly associated with the mechanical injury. This is when innumerable pathophysiological processes begin, leading to the initial inflammatory response to the injury and causing patients to develop “spinal shock” ( ; ). It is well established that, at this stage, crucial events are induced by vascular rupture, ischemia, and hemorrhage by the action of inflammatory growth factors which affects neurons and glial cells, including excessive production of free radicals, ionic dysregulation, inflammatory response, and excitotoxicity, inducing pathological changes ( ; ). At this stage, primary care should be provided for the patients, including protection of the airways, maintenance of the respiratory function, and use of hemodynamic support ( ).

It is, however, often difficult to define the baseline severity of the injury, as the patient is often in an unstable clinical condition due to spinal shock ( ). In order to reduce inflammation and neurological deficits, some centers use high-dose corticosteroids in the first 8 h after the injury, following the NASCIS II protocol ( ). Nevertheless, damage to glial cells, neurons and oligodendrocytes caused by the presence of excessive amounts of excitatory neurotransmitters (glutamate, aspartate) cannot be prevented. Furthermore, neurons die during all phases of the injury due to necrosis and astrocytes. Neurons and oligodendrocytes also die due to apoptotic mechanisms ( ).

The secondary or sub-acute stage lasts up to 2 weeks after the damage. At this stage, the patient usually recovers from the initial spine shock. However, neurological loss as well as other potential complications associated with the original trauma continue, as nerve cell dysfunction and blood supply problems derived from the acute stage can get even worse ( ). In this phase, reactive gliosis increases both the content of glial fibrillary-acidic protein (GFAP) and the size of astrocytes to form the glial scar, In this phase, an intense inflammatory response begins, whereby phagocytic cells are recruited ( ; ). The glial scar, with its firmly fused processes, forms an inhibitory agglomerate in the form of a mesh that plays a fundamental role in interrupting axonal regeneration ( ). However, despite limiting regeneration after an injury to the central nervous system (CNS), the uncontrolled proliferation of reactive astrocytes suppresses the formation of aberrant synapses at the injury site and also contributes to both the restoration of the integrity of the blood spinal cord barrier (BSCB) and the reconstruction of microenvironment homeostasis ( ). This mechanism is important for the removal of edemas, in addition to reducing the infiltration of cells of the immune system, helping, thus to limit the spread of the lesion ( ).

The chronic SCI phase, whose characterization requires further investigation, follows the sub-acute SCI phase. At this stage, patients may experience partial neurological recovery, which will depend on the extent of the lesion and the general condition of each patient. In addition, patients may also have maturation of adaptive mechanisms or the onset of more delayed neurological symptoms such as urinary bladder dysfunction, neuropathic pain, lipodystrophy, musculoskeletal atrophy, dysautonomia, and abnormal skeletal postures ( ). This phase may prolong from days to years after the shock, and is characterized by Wallerian degeneration, apoptosis and scarring that cause functional impairment ( ; ). At this stage, it is also normal for patients to develop syringomyelia * due to the formation of the glial scar. Therapeutic strategies generally focus on increasing the regeneration of damaged axons and remyelination through different mechanisms, whether through pharmacological methods or cell therapy ( ).

Biomarkers of SCI

First, it is important to define the word biomarker *. Biomarkers, also known as “biological markers,” are related to a wide sub-category of medical signs which can be measured with precision and reproducibility. Thus, biomarkers are, for purposes of interpretation, quantifiable results of biological mechanisms ( ). A biomarker of tissue injury should ideally be abundant, preferably (or exclusively) produced in the tissue of interest, and to be naturally present in small concentrations in blood and other body fluids ( ; ). It is also important to have good biomarkers that can contribute as a measure of valuable therapeutic responses. They are highly valuable in the decision-making process of seeking additional clinical evaluation of a drug, and in helping to define critical parameters such as the intervention time window, drug dose and monitoring schedule for a clinical trial. It is also important to have good biomarkers that are acutely related to biochemical changes made or sustained during all phases of SCI. It is finally very important to validate all the potential biomarkers candidates.

Currently, there are neither drugs for treatment nor specific laboratory tests for the diagnosis of SCI. Therefore, in order to determine the extent of SCI as soon as possible, it is urgent to further the discovery and use of specific biomarkers for SCI. This could help guide doctors and researchers toward the discovery of a new object of intervention that can help prevent and decrease disability resulting from SCI.