Spinal cord injury (SCI) is a serious clinical challenge affecting a multitude of bodily systems. Annually, there are an estimated 10,000 new cases which add onto the pre-existing 250,000 North Americans already living with SCI (reference here). Injury to the central nervous system (CNS) is frequently a result of motor vehicle collisions, sporting injuries and falls. Damage to this area is associated with compromised functioning of the cardiovascular, respiratory and neuromuscular systems. Even with treatment, the prognosis for complete recovery from SCI is poor. Paralysis is a reality that the patient faces and is often a direct consequence of SCI. On a neurophysiologic level, ischemic injury (a restriction in blood supply) is believed to be the basal cause of most loss in neural functioning and is a (Talk about difference between primary and secondary injury). Currently, no neuroprotective therapies are available which are capable of providing significant recovery from injury. Owing to this, a plethora of new treatment interventions are being developed. One such strategy involves the use of induced hypothermia. Various degrees of research have examined induced hypothermia as a potential therapeutic modality over the past 50 years in animal and human models. This specific approach was intensively examined in between 1950-60, but due to numerous technical challenges, it fell out of favour for another 40 years. Recent media exposure from Buffalo Bills tight end, Kevin Everett undergoing preoperative systemic hypothermia after an on field incomplete cervical spinal cord injury, and his subsequent neurological recovery, have caused for significant interest upon the topic of therapeutic hypothermia for SCI. Furthermore, increased interest in this modality attributed by recent technological advances in the induction and maintenance of cooling has reshaped the possible values of this treatment (reference here). As such, this treatment now deserves and requires a more accurate evaluation.
Background on Spinal Cord Injury (SCI)
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The core tissue of the spinal cord consists of many nerve cells which are surrounded by branched projections of axons and dendrite fibres. These fibres relay electrical impulses and information between the CNS and PNS. Anatomically, the spinal cord is partitioned into cervical, thoracic, lumbar, and sacral levels. Each of these levels has specific functional spinal nerves. Therefore, types of injuries are dictated by which area is damaged. Depending on the degree of injury, there are varying levels of relayed damage to the neuromuscular, cardiovascular, respiratory, and metabolic systems. The circumference of the spinal cord varies depending on its location. It is larger in the cervical and lumbar areas because these areas supply nerves to the upper body and arms, as well as the lower body and legs, which receive the most sensory signals.
What happens when the spinal cord is injured? ââ‚¬" Introduction to secondary responses
Upon impact, traumatic force to the spine column can fracture or dislocate the vertebrae. This can result in compression of sensitive neural tissue. As this happens, axons may be damaged beyond repair, neural cell membranes break, and blood vessels may rupture, causing haemorrhaging into grey matter of the spinal cord (reference here). The damage of axons, swelling of the cord, and eventual drop in blood pressure marks the initial stages of injury known as primary injury. Over the course of hours to days, the initial physical trauma sets off a cascade of biochemical and cellular events that kills neurons, strips axons of myelin, and triggers an inflammatory immune system response. These subsequent processes are defined as secondary responses to injury.
Excessive release of neurotransmitters
After the injury, an excessive release of neurotransmitters can cause additional damage by overexciting nerve cells. For example, Glutamate is a known excitatory neurotransmitter commonly used by nerve cells to stimulate neuronal activity (reference here). When its NMDA and AMPA receptors are over stimulated, high levels of calcium ions enter into the cell activating degradative enzymes which damage the cell cytoskeleton, membrane, and DNA. This process is known as excitotoxicity and results in neuronal and oligodendrocyte death.
Invasion of immune system cells causes inflammatory response
Normally, there exists a blood-brain barrier between the circulatory and central nervous systems that keeps immune system cells from entering the CNS. This barrier tightly controls the passage of cells and large molecules. However, following trauma, the blood brain barrier can be disrupted; causing immune system components, such as white blood cells, to invade the surrounding tissue and trigger an inflammatory response (reference here). This inflammation is characterized by fluid accumulation and the influx of immune cells - neutrophils, T-cells and macrophages. Neutrophils are the first to enter, within about 12 hours of injury, and they remain for about a day (reference here). Three days after the injury, T-cells infiltrate (reference here). Although their function in the injured spinal cord is not clearly understood, in the healthy spinal cord they kill infected cells and regulate the immune response (reference here). Macrophages enter after T-cells and scavenge cellular debris. The up side of this immune system response is that it helps fight infection and cleans up debris. But the down side is that it sets off the release of cytokines - a group of immune system messenger molecules that exert a negative influence on the activities of nerve cells. For example, microglial cells, which normally function as an on-site immune cell in the spinal cord, begin to respond to signals from these cytokines (reference here). They transform into macrophage-like cells, engulf cell debris, and start to produce their own pro-inflammatory cytokines, which then stimulate and recruit other microglia to respond. Injury also stimulates resting astrocytes to express cytokines (reference here). These "reactive" astrocytes may ultimately participate in the formation of scar tissue within the spinal cord. The protective verses destructive nature of this neuro-immune response is continually speculated.
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Free radicals attack nerve cells
Another consequence of the immune system's entry into the CNS is that inflammation accelerates the production of highly reactive forms of oxygen molecules known as free radicals (reference here). These free radicals are normally produced as by products of cellular metabolic activities. In the healthy spinal cord their numbers are small enough that they cause no harm (reference here). However, with injury to the spinal cord combined with the subsequent wave of inflammation compromising the surrounding tissue, there is a cellular overstimulation producing too many free radicals. Free radicals then attack and disable molecules that are crucial for cell function such as those from cell membranes, ultimately altering their chemical structure. Free radicals can also change how cells respond to natural growth and survival factors, and turn these protective factors into destructive agents (reference here).
Until recently, it was fundamentally thought that all cell death following spinal cord injury was immediate and a direct consequence of primary trauma mechanisms (reference here). However, new experimental findings have shown that cells in the injured spinal cord may also die from programmed apoptosis (i.e cellular death) occurring days to weeks after injury (reference here). Apoptosis is a normal cellular event that occurs in a variety of tissues and cellular systems. It aids in maintenance of the bodily systems by ridding old and unhealthy cells. Research has suggested that apoptosis is regulated by specific promoting and inhibitory molecules (reference here). Current research is examining how SCI specifically initiates apoptosis of neurons and oligodendrocytes. The sudden death of oligodendrocytes is unfortunate and another obstacle in the recovery process as these cells form the myelin covering axons. These coverings increase the conduction speeds of nerve impulses. Apoptosis of oligodendroctyes strips myelin from intact axons in adjacent ascending and descending pathways, which further impairs the spinal cordââ‚¬â„¢s ability to communicate with the brain.
Current Immediate treatments for SCI
It has now been established that SCI produces a biphasic pattern of tissue damage. First, there is an instantaneous, primary injury resulting from the initial trauma. Then, secondary to this, there is progressive tissue loss from the exposure to the cytotoxic influences of hypoxia, and ischemia. This occurs along with the release of oxidative, excitotoxic, and inflammatory molecules. It is this second phase of tissue injury, occurring over hours to weeks following injury that can be potentially targeted for therapeutic intervention.
Up until the last decade, only one neuroprotective therapy was regularly administered to tackle secondary injury: early high dose methylprednisolone. Methylprednisolone was able to provide only modest clinical improvement for spinal cord trauma in humans (reference here). This therapy consisted of implementing the drug following injury into the system which ultimately appeared to reduce neuronal damage and decrease inflammation near the injury site by suppressing immune activity. However, these therapies were limited on many planes. First off, steroid therapy is not without risk. Most patients with acute spinal cord injury are treated in intensive care units, have multiple injuries, have impaired lung capacity and are vulnerable to sepsis. Hyperglycemia and gastrointestinal complications have also been reported following high-dose methylprednisolone treatment (reference here). Therefore, it can be proposed that, without compelling evidence for its efficacy, it is imperative for alternative treatments to be discovered. Here is where the use of therapeutic hypothermia comes into play as a clinically relevant experimental SCI treatment.
What is hypothermia and what is it thought to actually do?
Where it has been employed?
Value in current research ââ‚¬" animal models
Value in current research ââ‚¬" human models
Is it effective in humans?