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Basic Science

Epidemiology, Demographics, and Pathophysiology of Acute Spinal Cord Injury

Sekhon, Lali H.S. MB, BS, PhD, FRACS*; Fehlings, Michael G. MD, PhD, FRCS(C)

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Spinal cord injury (SCI) occurs in various countries throughout the world with an annual incidence of 15 to 40 cases per million, with the causes of these injuries ranging from motor vehicle accidents and community violence to recreational activities and workplace-related injuries. 136 Of the estimated 12,000 new cases of paraplegia and quadriplegia that occur in the United States each year, 4000 die before reaching the hospital and 1000 die during their hospitalization. 3,30,95,121 Despite much research, the only pharmacologic treatment to date known to ameliorate neurologic dysfunction that occurs at or below the level of neurologic injury has been methylprednisolone. 20–27 Despite this, much research over the past 30 to 40 years has focused on elucidating the complex pathophysiologic processes involved in SCI. In addition to an understanding of the biomolecular changes that occur after SCI, an understanding of the epidemiology of an acute SCI is essential for all those involved in the care of patients undergoing SCI. The social and economic impact of SCI extends to involve, not just the patient and the immediate family, but the community and society at large. Much of what we know about the epidemiology of SCI has evolved over the past 2 decades, and this, as well as the current pathophysio-logy, is now examined in more detail.

Epidemiology and Demographics


The annual incidence of SCI in developed countries varies from 11.5 to 53.4 per million population. 19,98 Olmsted County, Minnesota data from 1975 to 1981 suggested an age- and sex-adjusted incidence rate of 71 injuries per million, and these may reflect a more accurate figure as immediate deaths before reaching the hospital were counted. The incidence rate (based on those patients who reached the hospital alive) was 50 per million population per year. 65–67,96,97,100,111 Typically, only one in 40 patients admitted to a major trauma center suffers an acute SCI. 29 An accurate incidence rate requires enumeration of all injured individuals as well as a valid count of the population at risk. Most published reports on SCI count only those persons who are admitted to the hospital. Deaths of persons before admission to the hospital are not usually counted. The mortality of these injuries, despite their relatively low incidence, is between 48.3% and 79% either at the time of the accident or on arrival to the hospital. 97 Deaths after admission for acute SCI range from 4.4% to 16.7%. 96 Case fatality rates (the proportion of those with SCI that die because of the injury) for patients admitted to a hospital with SCI in recent studies are variable, probably because length of follow-up varies greatly. Coupled with this, there are epidemiologic problems, in terms of case definition and classification. In Olmsted County, Minnesota, 11% of all SCI die within the first hospitalization. The 1-year case fatality rate for all patients was 46%, with a case fatality rate of 13% for those who reached the hospital alive. 97 Mortality aside, the relative morbidity associated with acute SCI is also high, with many survivors requiring prolonged or repeated admissions to hospitals for complications after the injury. 84

When looking at the trends in incidence over time, some interesting observations have been made. Again, looking at the Olmsted County, Minnesota data, the average annual age- and sex-adjusted incidence rate of SCI increased steadily from 22 per million in 1935–1944 to 67 per million in 1965–1974 and 71 per million in 1975–1981 (age- and sex-adjusted to the 1970 U.S. white population). Age-adjusted mortality peaked in the 1965–1974 period at 36 per million, declining to 32 per million for 1975–1981. 66 The incidence rate of those reaching the hospital alive increased from 17 (1935–1944) to 50 in the 1975–1981 period. 67 It seems probable that over the past 20 years the incidence has not decreased but survival has continued to improve.

Looking at the data from the state of New York from 1982 to 1988, the unadjusted incidence of SCI was 43 per million residents. 98 During this time there was a statistically significant decrease in the rate of women, particularly over the age of 65, suffering an acute SCI. 139


Prevalence in acute SCI is defined as all persons with an SCI in a specified population at a particular point in time. Evaluation of the prevalence of SCI is difficult for several reasons, including the lack of a standard definition of a prevalent case, whereby lifelong SCI patients may be counted in this measure. Similarly, those with milder injuries may not be counted. Looking at the Olmsted County, Minnesota data, the prevalence of mild (residua requiring no additional follow-up or care), moderate (mild residua involving some disability, continuing therapy, or follow-up), and serious (all others), in 1980 was 583 per million population. 66 Various other studies have quoted prevalence rates between 130 and 1124 per million. 10,42,52,81 Prevalence data indicate that the median age of persons with SCI is approximately 27 years, with a white/black ratio of 8:1. 98 Recent data from the National Cord Injury Database in the United States ( indicate that the prevalence of SCI is between 721 and 906 per million population, or 183,000 to 230,000 persons.

Prognostic Factors for Survival After Spinal Cord Injury

As demonstrated by our group, the most important premorbid factors for survival after acute SCI are age, level of injury, and neurologic grade. 32 Patients with lesions at C1–C3 have a 6.6 times higher mortality than the mortality rate for those with paraplegia. Similarly, the relative risks for those lesions at C4 or C5 and C6–C8 were 2.5 and 1.5 times higher, respectively, than the mortality rate for those with paraplegia. 45


Quite apart from the emotional, physical, and social costs of acute SCI, the actual monetary costs of acute SCI to the community are enormous. In 1990, it was estimated that the cost of management of all SCI in the United States was $4 billion annually. 131 Harvey et al 82 have shown that more recently injured SCI persons (i.e., those injured since 1970) spent an average of 171 days in a hospital over the first 2 years postinjury. Initial hospital expenses will average $95,203. Home modification costs in excess of $8000 can also be expected. After recovery and rehabilitation, a person with SCI will pay, on average, $2958 per year in hospital expenses and $4908 per year for other medical services, supplies, and adaptive equipment. Personal assistance costs and costs of institutional care will average $6269 per year. The unmeasured costs of loss of income and loss of productivity must also be considered.


The causes of acute SCI are summarized in Table 1. Most available epidemiologic figures focus on SCI in developed nations. Clearly, the causes of injury vary between countries, as they do between regions within a country and urban versus rural locations. 137 On a global level traffic accidents involving motor vehicles, bicycles, or pedestrians account for the greatest number of SCIs, typically 50% of all injuries. Some comments on recent trends can be made. Sports and recreational causes have increased and work-related accidents have decreased in some countries, as work safe practices have improved. The logging, mining, and construction industries are safer now than ever before. Conversely, recreational activities, such as parachuting, hang gliding, surfing, abseiling, and rock climbing, by virtue of the major forces transmitted to the spinal column in potentially uncontrolled situations, have increased the frequency of sports and recreational injuries, which in some countries are more common than work-related injuries. Falls, tending to affect the older population, may exceed even traffic accidents as a cause of SCI in the population more than 65 years of age. These falls occur especially at home. Younger victims are subject to differing physiologic stresses at the time of injury because of increasingly elastic vertebral ligaments and underdeveloped spinal musculature. They have a greater preponderance of injuries in high velocity/high impact pursuits, such as motor sports and diving, and are usually subjected to greater forces of injury than older victims. 137 Violence, which comprises the forth category, has shown alarming increases most obviously in developing nations, where communal violence is rife. 29,132 Many of these injuries are penetrating in nature. 34 Prevalence data indicate that 45% of SCI injuries in the United States are caused by motor vehicle accidents, with 16% caused by falls and recreational injuries. 98,140

Table 1:
Etiology of Adult SCI

Neurologic Level

The stratification of SCI by level is shown in Table 2. Approximately 55% of acute SCI occurs in the cervical region, with approximately 15% occurring in every other region. The relatively increased mobility seen in the cervical spinal cord combined with the smaller vertebrae with reduced strength of stabilizing osseous/liga-mentous/muscular structures makes this region in the vertebral column more exposed to the injurious forces. Some injuries, in particular diving injuries, have a preponderance for the cervical spine, whereas others, such as those seen in mining, logging, or recreational activities (e.g., parachuting), have a greater tendency to occur in the thoracolumbar spine. There is some variation in the distribution of anatomic location of incidence versus prevalence cases of SCI. Whereas 52% of all newly diagnosed cases of SCI are in the cervical region, only 40% of prevalent cases have lesions in this region, indicative of the high mortality associated with acute spinal cord trauma to the neck. 98

Table 2:
Level of Injury in Adult SCI

Severity of Neurologic Deficit After Spinal Cord Injury

Forty years ago approximately two thirds of SCIs were complete, whereas in more recent times approximately 45% are complete (Table 3). 138 This changing trend in the relative incidence of complete versus incomplete injuries has been observed in several series in various countries. 72,80,109 The reasons for this change are multiple and include improved initial care and retrieval systems, greater awareness of the importance of immobilization after injury, use of restraints and air bags in motor vehicles, and hospital maneuvers to limit secondary injury. These latter would include aggressive avoidance of systemic hypotension, improved moving and nursing of patients, and avoidance of hypoxia. When the level of injury is correlated to severity of neurologic deficit, it is generally recognized that thoracic injuries more often produce complete SCIs than cervical or lumbar spine injuries. 134 When complete injuries do occur, the greatest neurologic recovery occurs in the more rostral injuries; conversely, those with more caudal injuries showed the least recovery. Consequently, cervical injuries show the greatest recovery after an initial complete injury, followed by thoracic and then thoracolumbar injuries. The cervical and thoracic groups show equal recovery, with a lower recovery in thoracolumbar injuries. Regardless of the level of injury, in patients with incomplete injuries, recovery is related to the severity of initial neurologic deficit, with those with greater neurologic deficit at injury showing the worst neurologic recovery. 134

Table 3:
Severity of Neurologic Deficit in Adult SCI

Age and Sex

Table 4 shows the age distribution for SCI. Typically, young male patients comprise the majority of victims, peaking in the third and forth decade in most countries. Of these, 80% to 85% are male. Males are also consistently at greater risk of morbidity and mortality from SCI across all age groups. The ratio of men to women is typically 3 to 4:1. 66,97,130 A higher incidence of injuries in recreational and work-related injuries is similarly demonstrable in young adult males. 137

Table 4:
Age Distribution for Acute SCI

When looking at age, two thirds of new SCI injuries occur in individuals less than 30 years of age. 130 According to recent data from the National Spinal Cord Injury Database in the United States (, there has been an increase in the mean age of SCI since 1973. Indeed, since 1990, the mean age of an individual with SCI has increased to 35.3 years. Moreover, the proportion of patients more than 60 years has increased to 10% from a level of 4.7% in the 1970s.

Associated Vertebral Column Injury

The types of vertebral column injuries associated with SCI are shown in Table 5. Computed tomographic scanning with the ability to reformat images using thin slices and magnetic resonance imaging have significantly improved the ability to evaluate the bony lesions associated with SCI. 61 The incidence of spinal cord injury without obvious radiologic abnormality has been reduced, although it still prevails in children in whom magnetic resonance imaging is able to show ligamentous strains and disruptions. Computed tomographic scanning has also allowed for the reclassification of some simple crush fractures (which would typically be single column injuries) to burst fractures when posterior vertebral cortex disruption is visualized on computed tomographic imaging with bony contents in the spinal canal. Computed tomographic and magnetic resonance imaging have also allowed for patients with spinal cord injuries without radiologic evidence of trauma to reveal underlying cervical spondylosis or congenital anomalies. 50 Correlation between osseous injuries and neurologic deficits shows that anterior dislocations and fracture dislocations are more likely to be complete SCI than burst or compression fractures. 137

Table 5:
Vertebral Column Injuries in Adult SCI

Alcohol and Substance Abuse

Alcohol appears to play a major role in acute adult SCI, particularly given the predisposition for injuries in young males and traffic accidents. In approximately 25% of patients with acute SCI alcohol played a major factor in their injury, with a much smaller percentage in which other drugs were associated with their injuries. 138

Associated Spinal Conditions

Cervical spondylosis is the most common pre-existing abnormality of the spinal column in SCI patients, with a prevalence as high as 10% in some series. 138 Spinal cord trauma may be superimposed on and exacerbated by the presence of congenital abnormalities, such as atlantoaxial instability, congenital fusions, or tethered cord, and may also occur in the presence of acquired disorders such as metastatic disease, spinal arthropathies such as ankylosing spondylitis, or rheumatoid arthritis. Typically, injuries are worsened or occur with a greater frequency in the face of these associated conditions and, in some cases, would not have occurred had the associated anomaly not been present.

Systemic Injuries

Twenty to 57% of persons with SCI have significant other injuries such as traumatic brain injury or major chest injuries. 53,79,107,108 Typically, these multisystem traumas occur in motor vehicle accidents. Isolated SCI is said to occur in only 20% of cases. 29 Five to 10% of head-injured patients have an associated SCI. Conversely, 25% to 50% of patients with acute SCI have an associated head injury. 137 The significance of multiple injuries in the face of an acute SCI is severalfold. First, the additional injuries more commonly precipitate hypoxia and hypotension, both of which may cause additional secondary injuries to the spinal cord. It has been suggested that there is reduced neurologic recovery and increased mortality in patients with SCI and other systemic injuries. 107 Whether it is the secondary injuries or whether or not these patients suffer more severe acute SCI remains to be seen. The other important consideration in this group is that the challenges to the assessing and treating physician are greater in the face of an SCI. Establishment of an adequate airway is fraught with difficulty; respiratory failure is more common, particularly with high cervical injuries; hypotension may be exacerbated by neurogenic shock; and intra-abdominal pathology is more difficult to diagnose in the presence of an SCI. These factors have a cumulative effect of worsening the outcome from the SCI, both in terms of mortality and morbidity.

Clinical Causes of Death After Spinal Cord Injury

There are relatively little data on the cause of death after acute SCI. Assuming survival from the initial injury and hospitalization, it was originally thought that renal failure and other urinary tract infections were the leading causes of death in patients who had had an SCI. More recent studies suggest that respiratory complications are the leading cause of death. 43 Aside from pneumonia, the leading causes of death include nonischemic heart disease, septicemia, pulmonary emboli, ischemic heart disease, suicide, and unintentional injuries. Urologic complications do not appear to be a prominent cause, as previously perceived. 43

Length of Stay After Spinal Cord Injury

Examining the Olmsted County, Minnesota data, the length of stay (LOS) of 85 patients (discharged alive) ranged from 4 to 1000 days, with a median of 67 days (including inpatient rehabilitation). Of this group, 16 patients were discharged in less than 2 weeks, whereas 6 were hospitalized for more than 1 year. 67 Other studies have found LOS from 117.2 to 126.6 days, measured in the late 1980s. 28,44 Recent data from the 24 Model SCI Care Systems in the United States (http://www.spinalcord. indicate that the LOS in the acute care unit until discharge to rehabilitation has decreased from 26 days in 1974 to 16 days in 1999.

Rehospitalization After Spinal Cord Injury

Patients suffering SCI are often readmitted for complications well after the initial injury has been dealt with. Rehospitalization is both a frequent and expensive occurrence. 36 This group suggested that previous studies of rehospitalization for these patients were cross-sectional with respect to time since injury (in years) and did not allow for comparison of patients with equal exposure to the risk of medical complications once they re-entered the community. They reviewed records of 88 consecutive, acute SCI patients who completed initial rehabilitation at a regional model SCI care system. Thirty-four patients (39%) were readmitted at least once by day 365. There was a total of 47 readmissions, mean LOS was 11.9 days per admission, and mean hospital charge per admission was $9683. Univariate comparisons between the characteristics of patients who were readmitted versus those who were not indicated that the readmitted group was less educated (11.8 ± 2.1 years vs. 12.9 ± 0.3 years, P < 0.05) and had a substantially longer initial rehabilitation LOS (88.9 ± 6.6 days vs. 72.9 ± 5.1 days, P < 0.05).

Complications After Spinal Cord Injury

Relatively little has been reported in the published literature about complications after acute SCI. The leading reported secondary complications are typically pressure sores, chills, and fevers secondary to urinary sepsis, atelectasis, pneumonia, and deep vein thrombosis. 106 Patients admitted to SCI centers had a lower risk of developing contractures, heterotopic calcification, atelectasis, cardiac arrest, abnormal renal function, and pressure sores, when compared with patients with a delayed admission (2–60 days postinjury), although the ranking of the leading complications was similar. There may be a degree of selection bias to these data, depending on referral patterns for more severe injuries. When comparing tetraplegics and paraplegics, an increased incidence of urinary tract infections and pressure sores is seen in the former. 146


Concepts of Primary and Secondary Mechanisms

As reviewed by the Dr. Fehlings, it is now generally accepted that acute SCI is a two-step process involving primary and secondary mechanisms. 62,140 The primary mechanism involves the initial mechanical injury due to local deformation and energy transformation, whereas the secondary mechanism encompasses a cascade of biochemical and cellular processes that are initiated by the primary process and may cause ongoing cellular damage and even cell death (Table 6). 34,122,140 This concept of a secondary mechanism to acute SCI was first postulated by Allen in 1911 where he found that there was an improvement in neurologic function after the removal of post-traumatic hematomyelia in dogs who underwent experimental acute SCI. 4 Three years later Allen speculated that there was a putative “biochemical factor” that was present in the hemorrhagic necrotic material at the lesion epicenter and that may be instigating ongoing damage. 5 This concept of primary and secondary mechanisms and their duality in acute SCI has since also been embraced in the understanding of the pathophysiology of subarachnoid hemorrhage, cerebral and spinal ischemia, and head trauma.

Table 6:
Primary and Secondary Mechanisms of Acute Spinal Cord Injury
Primary Mechanisms.

Primary SCI is most commonly a combination of the initial impact as well as subsequent persisting compression (Table 6). This will typically occur with fracture dislocation, burst fractures, missile injuries, and acutely ruptured discs. Clinical scenarios where impact alone occurs without ongoing compression may include severe ligamentous injuries in which the spinal column dislocates and then spontaneously reduces. Similarly, spinal cord laceration from sharp bone fragments or missile injuries can produce a mixture of spinal cord laceration, contusion, and compression or concussion. 136

Secondary Mechanisms.

The various theories of secondary mechanisms of SCI have undergone a process of maturation in the past 3 decades (Table 6). In the 1970s, the free radical hypothesis, as advocated by Demopoulos et al, 39 was thought to be crucial to the injury process. Ten years later the focus shifted onto the role of calcium, opiate receptors, and lipid peroxidation. As we enter the new millennium, modern research is implicating apoptosis, intracellular protein synthesis inhibition, and glutaminergic mechanisms, among a myriad of pathophysiologic pathways that mediate secondary injury mechanisms. There is considerable evidence that the primary mechanical injury initiates a cascade of secondary injury mechanisms, including the following: 1) vascular changes, including ischemia, impaired autoregulation, neurogenic shock, hemorrhage, microcirculatory derangements, vasospasm, and thrombosis 135,140,141; 2) ionic derangements, including increased intracellular calcium, increased extracellular potassium, and increased sodium permeability 1,150; 3) neurotransmitter accumulation, including serotonin or catecholamines 115 and extracellular glutamate, 2 the latter causing excitotoxic cell injury 57; 4) arachidonic acid release and free radical production, 38 eicosanoid production, and lipid peroxidation 78,88; 5) endogenous opioids 55,56; 6) edema 142; 7) inflammation; 8) loss of adenosine triphosphate-dependent cellular processes 8; and 9) programmed cell death or apoptosis. 31,37,103 These theories of secondary injury have been the subject of several recent reviews. 6,34,49,62,140,150 The complexity and inter-relationship of these secondary mechanisms are now being embraced.

The improved understanding of the pathophysiology of acute SCI has led to novel pharmacologic strategies to attenuate the effects of the secondary injury. The NASCIS II study demonstrated a modest beneficial effect of high-dose methylprednisolone if given within 8 hours of injury in patients with complete and incomplete spinal cord injuries, 23 which emphasizes the importance of the timing of treatment. Furthermore, the NASCIS III study gave some evidence that treatment within 3 hours may have been superior to treatment begun 3 to 8 hours after injury. 26 These studies provide validity to the concept of attenuating secondary SCI mechanisms in the clinical setting. It is unclear, however, whether the “time window” for methylprednisolone is directly applicable to surgical decompression. Nevertheless, these pharmacologic and surgical interventions would not be possible without a definite understanding of the pathophysiologic processes following an acute SCI.

Common Causes of Secondary Injury.

Although there are many mediators of secondary injury that include inflammation, calcium-mediated mechanisms, sodium, and glutamatergic pathways, 62 vascular mechanisms and free radicals have received much attention. More recently, apoptosis has also been shown to occur in the spinal cord, and it is these last three mediators that will now be discussed in more detail.

Free Radicals.

Free radicals are highly reactive molecules that possess an extra electron in the outer orbit. There is good evidence for the early occurrence and pathophysiologic importance of oxygen free radical formation with cell membrane lipid peroxidation in central nervous system injury. 38 Free radicals most commonly form from molecular oxygen. Superoxide (O2) is formed by incomplete electron transport in mitochondria. Superoxide is converted to H2O2 by superoxide dismutase and this in turn to H2O and O2 by catalase. In the presence of free iron, released from hemoglobin, transferrin, or ferritin by either lowered pH or oxygen radicals, H2O2 forms highly reactive hydroxyl radicals (HO). These, if unchecked, can cause geometrically progressive lipid peroxidation, spreading over the cellular surface and causing impairment of phospholipid-dependent enzymes, disruption of ionic gradients, and if severe enough, membrane lysis. This process also forms more lipid peroxides and consequently more free radicals. 75

Much work has been done on the role of free radicals in SCI. After experimental contusive or compressive injuries, there is an increase in polyunsaturated fatty acid oxidation products, such as malonyldialdehyde, 73,99,110 with a decrease in tissue cholesterol and the appearance of cholesterol oxidation products, 9,40 radical and lipid peroxidase-sensitive activation of guanylate cyclase and consequent increase in cGMP, 73 early inhibition of the Na+/K+ ATPase, which is lipid peroxidase-sensitive, and a decrease in tissue antioxidant levels (e.g., α-tocopherol). 117,123 These are all markers of early oxygen radical reactions. Lipid peroxidation may also play a role in post-traumatic hypoperfusion after SCI. 76

High-dose steroids may improve spinal cord blood flow (SCBF) and microvascular perfusion 7,77,149 as well as clinical neurologic recovery after experimental SCI. 9 They may also provide some cytoprotection through the inhibition of lipid peroxidation, facilitate spinal cord impulse generation, and inhibit prostaglandin-induced vasoconstriction. 74 Because lipid peroxidation begins within the first 5 minutes after an acute SCI, administration of high-dose steroid should occur as close to the time of injury as possible for maximal efficacy. In the clinical situation, high-dose methylprednisolone improves neurologic function if given within 8 hours of an acute SCI 23,26; however, the improvements noted have been modest with some methodologic problems with the study. Nevertheless, the clinical crossover of methylprednisolone therapy from the laboratory to the bedside demonstrates that with a clearer understanding of secondary mechanisms, therapeutic interventions are possible.

Vascular Mechanisms.

Changes in SCBF and the perturbations that follow are an important part of the changes induced by acute SCI. The changes that occur in SCBF after an acute SCI can be divided into systemic and local. Immediately after SCI, a major reduction in blood flow at the lesion occurs. 18,63,68,90,124,140 This ischemia becomes progressively worse over the first few hours if left untreated. 63 Experimentally, it may persist for at least 24 hours after major SCI in rats 120 or monkeys. 122 The precise mechanisms behind this ischemia are unclear. Vasospasm secondary to mechanical damage or a vasoactive amine may be partially responsible. 140 Endothelial swelling or damage may be occurring. 46 Hemorrhages may promote ischemia, 143 or thrombosis may occur via platelet aggregation. 37,113 Finally, excitatory amino acids, particularly, glutamate, may be involved. Ischemia may play a role in the formation of local cord edema, although whether edema formation is injurious in itself or an epiphenomenon is still unclear.

Because of differences in relative vascularity, the central gray matter, along with adjacent white matter, is more severely affected by acute SCI than peripheral white matter. 145 In the normal situation gray matter to white matter blood flow is maintained at a 3:1 ratio. 83 Studies on in vivo SCBF have confirmed this dichotomy between central gray matter and surrounding white matter. 14,58 White matter perfusion typically decreases within 5 minutes of an acute SCI and begins to return to normal within 15 minutes. It remains thereafter near normal preinjury values during the first 24 hours. In contradistinction, in central gray matter numerous hemorrhages typically occur, as early as 5 minutes after an acute SCI. Perfusion is relatively absent 1 hour after an injury, and this state remains so for at least the first 24 hours. It has been suggested that the peripheral changes in SCBF that are seen are due to initial vasospasm, but it seems unlikely that this alone causes the central phenomenon. This vascular standstill has been confirmed using microangiography, 64,140 fluorescent tracer studies, 47 and the operating microscope 12 and plays a major role in the devastating outcomes from acute SCI.

The contribution of vascular mechanisms in the pathophysiology of human SCI is well reviewed by Tator and Koyanagi. 141 Using silicon rubber microangiography, the authors shed light on the role of the sulcal arterial system and pial arteries in the spinal cord. The centrifugal sulcal arterial system supplies the anterior gray matter, the anterior half of the posterior gray matter, the inner half of the anterior and lateral white columns, and the anterior half of the posterior white columns. Traumatized spinal cords show severe hemorrhages predominantly in gray matter, and it may be obstruction of these anterior sulcal arteries that leads to the hemorrhagic necrosis and subsequent central myelomalacia seen at the site of injury.

Alterations in endothelial cell function causing an increase in vascular permeability and edema formation have been well documented. 69,87,129 Endothelial damage occurs early, with the formation of craters, adherence of noncellular debris, over-riding of endothelial cell junctions, and microglobular formations occurring 1 to 2 hours after acute SCI. 41

Histopathologically, early and often progressive hemorrhages develop in the central region of the spinal cord (especially in the gray matter). It is very likely that these occur because of the forces imparted by the primary injury, with direct mechanical disruption of the capillaries and venules occurring. 46 Angiographic studies in both the human scenario and experimentally confirm that the large arteries remain patent but that a major change occurs in the local microcirculation (mainly capillaries and venules) in the vicinity of the injury, spreading for a considerable distance peripherally. 92,93 The anterior spinal artery is rarely thrombosed. 145

Autoregulation is also impaired after acute SCI. 91,125,147 Systemic hypotension can cause further decreases in SCBF with induced hypertension not necessarily reversing the ischemia, but rather causing marked hyperemia at adjacent sites. 71,140 Experimentally, it has been shown in animal studies that autoregulation is intact during the initial 60 to 90 minutes after SCI but is then lost coincident with the onset of ischemia. It has been suggested that the ischemic response to SCI is mediated both by the loss of autoregulation and by relative constriction of the resistance vessels. 125

Disturbances of venous drainage may play a role in the secondary damage that occurs after acute SCI, particularly in terms of exacerbating ischemia of the posterior columns. 93,94,126 This hypothesis gains weight by studies that show that venous occlusion in various pathologic conditions causes white matter lesions. 89,114,118 It may be that peculiarities of the venous drainage of the spinal cord make it more susceptible to damage. 94

After an acute SCI an immediate but transient increase in mean arterial blood pressure may occur followed by profound hypotension. 48,54,77,133,144,149 The reason for this transient hypertension is unknown but may be mediated by both the thoracic sympathetic ganglions and the adrenal glands. 148 Acute SCI is one of the causes of neurogenic shock, 13 typically being related to the magnitude and severity of the cord injury. Decreased sympathetic tone, unopposed cardiac vagal tone, and other cardiac changes are all contributory. 70 At its extreme, systemic effects including hypotension and bradycardia may be profound. These changes may persist for an extended period of time, sometimes months. In concert with these changes, total peripheral resistance and cardiac output may also remain depressed for a prolonged period of time.

Of all purported mechanisms of secondary injury, the vascular hypothesis has considerable weight, with biochemical, angiographic, histopathologic, and clinical support for its key role in damage after acute SCI. Proven effects include loss of the microcirculation, direct disruption of small vessels and hemorrhage, failure of autoregulation, and glutamate-mediated excitotoxicity. Ischemia is a direct linear dose–response association, with the severity of the injury becoming progressively worse a few hours after the injury and persisting for ≥24 hours. 140 Like so many secondary mechanisms of acute SCI, the precise mechanisms are still unclear.


Cell death occurs either via necrosis or apoptosis. Apoptosis is a form of programmed cell death that occurs in a wide variety of disease states in eukaryotic cells. Unlike necrosis, apoptosis is an active process that is characterized by cell shrinkage, chromatin aggregation, and nuclear pyknosis. 86 The cells die and are engulfed by phagocytes, without initiating an inflammatory response or without discharging their cellular contents into the extracellular environment. This is initiated by physiologic stimuli, either internal or external. 103 Apoptosis is a tightly regulated process with a sequence of activation steps that require energy and specific macromolecular synthesis as de novo gene transcription. 86 Necrosis, however, is characterized by more passive cellular swelling, with mitochondrial damage and disruption of internal homeostasis, leading to membrane lysis, release of intracellular contents, and provocation of an intense inflammatory response. 33,105 It arises from nonphysiologic disturbances. 103 Necrosis has no energy requirements because there is no de novo gene transcription; thus, no new protein or nucleic acid synthesis occurs. 15,31 Apoptosis is recognized as occurring in utero as a form of neuronal cell death during embryonic development 85 and is also now thought to play a role in many postdevelopmental disorders of the central nervous system, including ischemia, trauma, inflammation, and neurodegenerative states. 11,17,112,116,119

A family of cysteine proteins, the caspases, are thought to play an important role in apoptosis. Caspase-3 cleaves several essential downstream substrates involved in the apoptosis pathway, including PAK2, fodrin, and gelsolin. Caspase-3 activation in vitro can be triggered by upstream events, leading to the release of cytochrome c from the mitochondria and the subsequent transactivation of procaspase-9 by Apaf-1. These upstream and downstream components of the caspase-3 apoptotic pathway are activated after traumatic SCI in rats and may occur early in neurons in the injury site and hours to days later in oligodendroglia adjacent to and distant from the injury site. 128

In the spinal cord apoptosis was first identified in 1995 as occurring in rats 35 and, more recently, in the human spinal cord. 51 It is thought that oligodendrocytes are the major cell type in compressive SCI that undergo apoptosis, 34,101 seen in areas of wallerian degeneration and detectable between 24 hours and 3 weeks postinjury. 35 The mechanism behind this is unclear, but it may occur either as a result of adverse changes in the cellular environment resulting in axonal demyelination or as a result of wallerian degeneration, or by a combination of both of these processes. 16,49 It has also been suggested that this death of oligodendrocytes may be as a consequence of microglial activation and peaks at 8 days postinjury. 127 This latter hypothesis is suggested by Shuman et al by their observations of activated microglia in the same regions undergoing apoptosis, with apparent contact between some of the microglial processes and apoptotic oligodendrocytes. 127 Moreover, recent work from Dr. Fehlings’ laboratory has suggested a role for the FAS and p75 death receptors in mediating post-traumatic apoptosis of oligodendrocytes, thus contributing to axonal degeneration. 31

Apoptosis occurs around the lesion epicenter as well as within areas of wallerian degeneration in both ascending and descending white matter tracts. 51 It may be that, in time, targeting the upstream events of the caspase cascade to protect neurons and oligodendrocytes from undergoing apoptotic death may have therapeutic potential in the treatment of acute SCI. Already, agents such as the oncogene Bcl2 have been shown to limit the degree of histologic injury in acute experimental SCI in rats, possibly by regulating an antioxidant pathway that limits free radical generation. 104 Similarly, cycloheximide treatment can improve outcome after contusion trauma in the spinal cords of rats. 102


Epidemiologic analysis of SCI has only really been an area of interest for the past 20 years. Young men, alcohol, and motor vehicles still play a prominent role. Older victims typically have falls leading to their injuries. Cervical spine injuries are still the predominant injury. With an explosion in spinal instrumentation and stabilization techniques as well as improved management and prevention of complications, the management of SCI is undergoing a renaissance. 59,60 Previous conservative, noninterventional approaches are being questioned, and a more aggressive evidence-based approach is evolving. Concurrently, the understanding of the pathophysiology of SCI is improving and the precise roles of pharmacologic interventions and the role of surgical intervention and its timing are being currently examined. Areas of future research and assessment include further pharmacologic therapy for acute SCI, measures of outcome, and an increasing emphasis on prevention because falls and motor vehicle accidents still play a prominent role in the etiology of SCI. Analysis of the demographics of SCI as well as further understanding of its pathophysiology in the next 10 years will shed further light on the successes and failures of these interventions.

Key Points

  • Spinal cord injury occurs with an annual incidence of 15–40 cases per million.
  • Deaths after admission for acute SCI range between 4.4% and 16.7%.
  • Persons with SCI (i.e., those injured since 1970) spent an average of 171 days in a hospital over the first 2 years postinjury. Initial hospital expenses will average $95,203. Lifetime medical expenses vary from $500,000 for a motor incomplete SCI to >$2 million for a high cervical tetraplegia.
  • The pathophysiology of SCI is divisible into primary and secondary injury.
  • Mediators of secondary injury include vascular mechanisms, excitatory amino acids, calcium, sodium, free radicals, inflammation, and apoptosis.


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epidemiology; methylprednisolone; pathophysiology; spinal cord injury; surgery]Spine 2001;26:S2–S12

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