Clinical Neuropharmacology Vol. 24, No. 5, pp. 254–264 © 2001 Lippincott Williams & Wilkins, Inc., Philadelphia Acute Spinal Cord Injury, Part I: Pathophysiologic Mechanisms *Randall J. Dumont, †David O. Okonkwo, ‡Subodh Verma, ‡R. John Hurlbert, †Paul T. Boulos, †Dilantha B. Ellegala, and †‡Aaron S. Dumont *Faculty of Medicine, University of British Columbia, Vancouver, British Columbia; †Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia, USA; and ‡Division of Neurosurgery and University of Calgary Spine Program, University of Calgary, Calgary, Alberta, Canada Summary: Spinal cord injury (SCI) is a devastating and common neurologic disorder that has profound influences on modern society from physical, psychosocial, and socio- economic perspectives. Accordingly, the present decade has been labeled the Decade of the Spine to emphasize the importance of SCI and other spinal disorders. Spinal cord injury may be divided into both primary and secondary mechanisms of injury. The pri- mary injury, in large part, determines a given patient’s neurologic grade on admission and thereby is the strongest prognostic indicator. However, secondary mechanisms of injury can exacerbate damage and limit restorative processes, and hence, contribute to overall morbidity and mortality. A burgeoning body of evidence has facilitated our un- derstanding of these secondary mechanisms of injury that are amenable to pharmaco- logical interventions, unlike the primary injury itself. Secondary mechanisms of injury encompass an array of perturbances and include neurogenic shock, vascular insults such as hemorrhage and ischemia–reperfusion, excitotoxicity, calcium-mediated secondary injury and fluid–electrolyte disturbances, immunologic injury, apoptosis, disturbances in mitochondrion function, and other miscellaneous processes. Comprehension of sec- ondary mechanisms of injury serves as a basis for the development and application of targeted pharmacological strategies to confer neuroprotection and restoration while mitigating ongoing neural injury. The first article in this series will comprehensively review the pathophysiology of SCI while emphasizing those mechanisms for which pharmacologic therapy has been developed, and the second article reviews the pharma- cologic interventions for SCI. Key Words: Spinal cord injury—Secondary injury— Pathophysiologic mechanisms Spinal cord injury (SCI) may be defined as an injury mechanisms underlying spinal cord injury is of para- resulting from an insult inflicted on the spinal cord that mount importance to facilitate comprehension of phar- compromises, either completely or incompletely, its macological interventions. These pharmacological major functions (motor, sensory, autonomic, and re- strategies are largely targeted at attenuating or elimi- flex). Spinal cord injury remains an important cause of nating the effects of secondary injury mechanisms. Ad- morbidity and mortality in modern society. An esti- ditionally, an appreciation of these pathophysiologic mated 8,000–10,000 people experience traumatic SCI mechanisms in SCI has further relevance, because in the United States each year (1–6). In addition to its many, if not all, of these processes are common to other cost to the individual physically as well as the health insults of the central nervous system such as head care system and society financially, SCI has profound injury, cerebral ischemia, and subarachnoid hemor- psychosocial effects that are devastating for patients, rhage (7–9). families, and friends. The pathophysiology of acute SCI comprises both A basic understanding of the pathophysiological primary and secondary mechanisms of injury. The prognosis for recovery after SCI has been closely ex- amined (10–18). The extent of the primary injury may Address correspondence and reprint requests to Aaron S. Dumont, Department of Neurological Surgery, Box 212, University of Virginia group patients with SCI into severity categories (neu- Health Sciences Center, Charlottesville, VA 22908, USA. rologic grades). A patient’s neurologic grade at admis- 254 PATHOPHYSIOLOGY OF SPINAL CORD INJURY 255 sion to the hospital has proven to be the strongest prog- within the spinal cord develops early, and blood flow nostic indicator. Nonetheless, for a large majority of within the spinal cord is later disrupted after the initial patients with SCI, the extent of secondary injury mechanical injury. Disruption in blood flow results in evokes further damage, limits restorative processes, local infarction caused by hypoxia and ischemia. This and predicts their long-term morbidity. Therefore, a is particularly damaging to the gray matter because of full understanding of secondary injury mechanisms its high metabolic requirement. Neurons that pass in SCI facilitates the development of targeted inter- through the injury site are physically disrupted and ex- ventions. In the following passages, pathophysiologic hibit diminished myelin thickness (22). Nerve trans- mechanisms of spinal cord injury are reviewed, with mission may be further disrupted by microhemorrhages special attention to secondary injuries against which or edema near the injury site (23–25). It is thought that pharmacologic therapies have been postulated and the gray matter is irreversibly damaged within the first applied. hour after injury, whereas the white matter is irrevers- ibly damaged within 72 hours after injury.(26) PRIMARY INJURY SECONDARY INJURY There are four characteristic mechanisms of primary injury: (i) impact plus persistent compression; (ii) im- The primary mechanical injury serves as the nidus pact alone with transient compression; (iii) distraction; from which additional secondary mechanisms of injury and (iv) laceration/transection. The first and most com- extend. These secondary mechanisms include neuro- mon mechanism involves impact plus persistent com- genic shock, vascular insults such as hemorrhage and pression (9,19). This is evident in burst fractures with ischemia–reperfusion, excitotoxicity, calcium-medi- retropulsed bone fragment(s) compressing the cord, ated secondary injury and fluid-electrolyte distur- fracture-dislocations, and acute disc ruptures. The sec- bances, immunologic injury, apoptosis, disturbances in ond mechanism involves impact alone with only tran- mitochondrion function, and other miscellaneous pro- sient compressions as observed with hyperextension cesses (Figs. 1, 2). injuries in individuals with underlying degenerative cervical spine disease. Distraction, forcible stretching of the spinal column in the axial plane, provides a third Neurogenic Shock mechanism and becomes apparent when distractional Spinal cord injury may result in neurogenic shock. forces resulting from flexion, extension, rotation, or Although there are several interpretations of this term, disclocation produce shearing or stretching of the spi- it is defined in this context as inadequate tissue perfu- nal cord and/or its blood supply. This type of injury sion caused by serious paralysis of vasomotor input may underlie SCI without radiological abnormality, es- (thereby producing deleterious disruption of the bal- pecially in children where cartilaginous vertebral bod- ance of vasodilator and vasoconstrictor influences to ies, underdeveloped musculature, and ligament laxity the arterioles and venules). It is characterized by bra- are predisposing factors (20). This type of injury may dycardia and hypotension with decreased peripheral re- also be a causative factor in SCI without radiologic evi- sistance and depressed cardiac output (27). These ef- dence of trauma, which is a syndrome most common in fects have been linked to underlying abnormalities such adults with underlying degenerative spine disease (9). as decreased sympathetic tone, depressed myocardial Laceration and transection comprise the final primary function from increased vagal tone, and possibly sec- mechanism of injury. Laceration of the spinal cord ondary changes in the heart itself (27,28). If untreated, may result from missile injury, sharp bone fragment the systemic effects of neurogenic shock (namely, is- dislocation, or severe distraction. Laceration may oc- chemia of the spinal cord and other organs) may exac- cur to varying degrees, from minor injury to complete erbate neural tissue damage. transection. Thus, primary mechanisms of injury in- clude impact plus persistent compression, impact alone with only transient compression, distraction, and Vascular Insults: Hemorrhage and laceration/transection. Ischemia–Reperfusion The initial mechanical insult tends to damage pri- marily the central gray matter, with relative sparing of As alluded to previously, vascular insult has delete- the white matter, especially peripherally. This in- rious effects on the spinal cord, both initially at the time creased propensity for damage to the gray matter has of injury and subsequent to this. These vascular injuries been speculated to be a result of its softer consistency produce both hemorrhagic and ischemic damage. The and greater vascularity (21). Evidence of hemorrhage microcirculation, especially venules and capillaries, Clin. Neuropharmacol., Vol. 24, No. 5, 2001 256 R. J. DUMONT ET AL. FIG. 1. The mechanisms underlying injury after spinal cord trauma are depicted, emphasizing the central importance of ischemia, increased intracellular calcium, and apoptosis in cell death. Each of these boxes represents potential avenues for pharmacologic intervention. appears to be damaged at the site of injury