More than a decade ago, spinal-cord injury meant confinement to a wheelchair and a lifetime of medical comorbidity. The physician’s armamentarium of treatments was very limited, and provision of care for individuals with spinal-cord injury was usually met with frustration. Advances in neuroscience have drawn attention to research into spinal-cord injury. Nowadays, advanced interventions provide high hope for regeneration and functional restoration. As scientific advances become more frequent, scepticism is giving way to the ideas that spinal-cord injury will eventually be repairable and that strategies to restore function are within our grasp.

To understand the rationale of the recent therapeutic advances, it is first necessary to review the pathophysiology of spinal cord injury (SCI). There are four general types of SCI [1]. The first is a cord maceration, in which the morphology of the cord is severely distorted. The second type is a cord laceration (gunshot or knife wounds). The third potential type is a contusion injury, in which damaged blood vessels leak into surrounding areas. Lastly, the fourth class is a solid cord injury, in which there is no central focus of hemorrhaging or an overt disruption in morphology. In the first two injuries, the surface of the cord is lacerated and a prominent connective tissue response is invoked, whereas in the latter two the spinal cord surface is not breached and the connective tissue component is minimal. Of these four injury types, the contusion injury represents from 25 to 40% of the cases and is a progressive injury that enlarges over time [2]. The most commonly used animal model in SCI research is patterned after the contusion injury. Within these four injury types, degree of completeness must be considered, as incomplete lesions will benefit more dramatically from experimental interventions than complete lesions in terms of degree of recovery that can be obtained. It is important to note that the clinical presentation of SCI is most often characterized as an anatomically incomplete lesion, irrespective of initial neurological presentation [3].

There are three phases of SCI response that occur after injury: the acute, secondary, and chronic injury processes [4]. When the spinal cord is lacerated or macerated by a sharp penetrating force, contused or compressed by a blunt force, or infarcted by a vascular insult, it begins a neurological damage in the spinal cord that is normally called “primary injury”. This initial mechanical injury leads to a cascade of biological events, described as “secondary injury”, which occurs over the time course of minutes to weeks and leads to further neurological damage. Finally, there is the onset of a chronic phase, which can occur days to years after the injury, leading to neurological impairments [5].

Understanding the biochemical and cellular events that compose the secondary phase is of utmost importance, since it could provide significant information that might lead to promising therapies that would minimize the extension of the lesion and improve the regeneration. In 1911, it was suggested, for the first time, that secondary events happen after spinal cord injury when a neurologist named Dr. Allen removed inflammatory fluid from an injured dog’s spine and noticed improvements in the animal’s neurological dependent functions [6]. Subsequently, Dr. Allen theorized that it was a noxious agent present in the hemorrhagic fluid that might be causing further damage to the spinal cord. Following him, several authors postulated numerous biochemical mechanisms that elucidate the progressive post-traumatic damage of spinal cord tissue. These secondary events consist of: vascular changes, free radical formation, lipid peroxidation, disruption of ionic balance, glutamate excitotoxicity, apoptosis, and inflammatory response [7].

Vascular changes include hemorrhaging, narrowing of the arteries, thrombosis (blood clotting), loss of autoregulation of blood flow, breakdown of blood brain barrier and the infiltration of inflammatory cells into the region [8]. This leads to fluid collection in cavities, cell death in the tissue, and lack of blood flow to the tissue [9]. Free radical formation and lipid peroxidation cause death in spinal cord neurons and reduce the spinal cord blood flow leading again to edema (fluid build-up) and inflammatory response. Free radicals react with the polyunsaturated fatty acid of the cellular membrane leading to the disruption of the normal phospholipid architecture of cellular and subcellular organelle membranes. Moreover, lipid peroxidation leads to the formation of aldehyde biological products that impair the function of key metabolic enzymes. This enzyme activity is critical for the maintenance of neuronal excitability, and its failure leads to loss of neuronal function and may ultimately lead to tissue dissolution [10]. Disruption of the ionic balance, triggers the release of ions from channels and leads to cell death. Glutamate excitotoxicity occurs after SCI when there is an increased release of extracellular amino acids, namely glutamate, that induce excessive activation of glutamate receptors leading to further neuronal cell death [10]. Apoptosis is a form of programmed cell death seen in a variety of developmental and disease states, including traumatic injuries [7]. There is strong morphological and biochemical evidence demonstrating the presence of apoptosis after SCI. Apoptosis occurs in populations of neurons, oligodendrocytes, microglia, and, perhaps, astrocytes; these are all cells that support the spinal cord and nervous system functioning [8]. The death of oligodendrocytes in white matter tracts continues for many weeks after injury and may contribute to post-injury demyelination (which slows down the ability of a neuron to transmit a signal). Lastly, the inflammatory response following trauma in the initial stages can lead to further tissue death in the afflicted region of the central nervous system [7]

Chronic spinal cord injury refers to a permanent and/or progressive interruption in the conduction of impulses across the neurons and tracts of the spinal cord. It is usually due to physical distortion or vascular ischemia (lack of blood flow) of the spinal cord arising from trauma, tumor, infection, or other space-occupying lesions [10]. Commensurate neurologic deficits commonly occur that may be stable or progressive; these often lead to disability with spasticity, joint contractures, sensory changes, and sphincter and locomotion abnormalities [7]. Acute and long-term secondary medical complications are common in patients with SCI; however, chronic complications especially further negatively impact patients’ functional independence and quality of life. Therefore, prevention, early diagnosis and treatment of chronic secondary complications in patients with SCI is critical for limiting these chronic complications, improving survival, community participation and health-related quality of life.The most common chronic complications of SCI include: respiratory complications, cardiovascular complications, urinary and bowel complications, spasticity, chronic pain, and bone fractures [11].

SCI often leads to respiratory dysfunction, including insufficiency of respiratory muscles, reduction in vital capacity, ineffective cough, reduction in lung and chest wall compliance and excess oxygen cost of breathing [12]. Individuals with SCI have a high risk of cardiovascular complications and their long-term effects such as thromboembolism (blood clot obstruction) and autonomic dysreflexia (excessively high blood pressure). One of the most important complications following SCI is the loss of genitourinary and gastrointestinal function, due to the fact that bladder control is heavily dependent on the central nervous system in order to both fill and empty the bladder [13]. Neurogenic bowel (NB) is also a major problem in terms of physical and psychological aspects for people with SCI; aq neurogenic bowel occurs when there is a dysfunction of the colon due to lack of nervous control, causing stool to be retained since the sphincter, which allows fecal release, remains tight [13]. Spasticity is a common secondary impairment after SCI characterized by increased intermittent or sustained involuntary somatic reflexes (hyperreflexia), clonus (involuntary muscle contractions) and painful muscle spasms [14]. Chronic pain is one of the frequent secondary complications for individuals with SCI. This is caused by damage, irritation, or distention of internal organs; this can result in burning, aching or stinging [15]. Osteoporosis, a condition characterized by low bone mass and deterioration of the skeletal microarchitecture, is a well-known complication of SCI; a significant decrease in bone mineral density has been reported in chronic SCI patients [11]

The acute primary, secondary, and chronic stages of SCI are complex. The mechanisms of SCI have recently become better understood through research on the underlying mechanisms of pathogenesis, but this understanding is also further complicated by the psychosocial impact of the nature of injury. Treatment and management therapies do not work holistically in isolation and need to be combined with pharmacological methods, physical therapy, and psychological input in specialist centers. However, in order to begin this it is important to elucidate the biological mechanisms of each stage, and the progression of pathogenesis to the chronic condition. The failure to undertake a comprehensive diagnostic approach when evaluating patients with SCI can lead to mismanagement and further chronicity, since the proper causes and hazards are not identified. The spine is directly connected to a wide range of possible injuries, with a wide range of causative diagnoses, making SCI a prolific and significant avenue of therapeutic research.


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