- Scar is a second major inhibitory element within the CNS. Its importance in inhibiting regeneration was recognized prior to the discovery of myelin and ECM inhibitors, but scarring has posed a greater therapeutic challenge. The reasons are that scar is both a physical and a chemical barrier, is heterogenous in composition, and has both beneficial and harmful characteristics.
- At a minimum scarring in the CNS must be thought of in terms of its glial and fibrous components. Glial scarring results when hypertrophied astrocytes form a physical barrier at the periphery of the lesion, walling off injured tissue from healthy tissue. These reactive astrocytes elaborate large cytoplasmic processes that interweave to form a barrier. The astrocytes of the scar also form a chemical barrier by secreting a number of growth inhibitory CSPGs, including neurocan, versican, aggecan, brevican, phosphacan, and neural/glial antigen 2 (NG2). Glial scarring is of additional clinical significance because it has been associated with neuropathic pain. The fibrous component of scar has a more potent inhibitory effect on neurite outgrowth than the glial component. The fibrous scar is located at the lesion core. It is associated with fibroblast infiltration and the deposition of inhibitory ECM molecules. These molecules function as chemical barriers to axonal regeneration in the same fashion as myelin inhibitors.
- Scarring after SCI has a number of beneficial qualities. Reactive astrocytes reestablish both ionic homeostasis and the integrity of the blood-brain barrier (BBB), steps important for resolving edema and limiting the infiltration of immune cells. Although much of the glial scar contains inhibitory CSPGs, there are regions that are instead rich in growth-promoting ECM molecules such as laminin and fibronectin. Indeed, astroglial scar remote from the lesion has been shown to support axonal growth. Astrocytes are also thought to supply neurons with energy and to elaborate growth factors and beneficial cytokines. Moreover, reactive astrocytes are believed to sequester excess glutamate and potassium, which can be harmful after injury.
- The most convincing evidence demonstrating the importance of the glial scar comes from a classic experiment performed by Faulkner and colleagues. In their study, transgenic mice expressing a glial fibrillary acidic protein (GFAP)–herpes simplex virus—thymidine kinase transgene were given ganciclovir following SCI. The result was ablation of reactive, transgene-expressing astrocytes, which led to exacerbated tissue disruption as well as neuronal and oligodendrocyte death. The investigators also noted failure of wound contraction and severe persisting motor deficits.
- It is thus easy to see why astrogliosis is a challenging target following injury—it will be difficult to preserve the beneficial effects of astrocytes while preventing those that inhibit regeneration. Appropriate timing may be key to therapeutic strategies targeting the glial scar. Employed strategies to date include irradiation, photoablation, and surgical resection; however, little success has been seen with any of these approaches as yet.
- A long-held belief—once again dating back to Cajal—viewed the mature CNS as incapable of neurogenesis. This entrenched idea was refuted when contemporary research proved the existence of adult neurogenesis and its importance in avian song learning. Subsequent research localized regions of intense neurogenesis to the subependymal region and the subgranular cell layer of the hippocampus. Moreover, neurogenesis has been demonstrated in the brains of rodents and mammals, providing further evidence that the adult CNS has a greater capacity for repair than was previously recognized. The ependymal region of the spinal cord appears to function in a capacity similar to that of the subependymal region of the brain but is less well characterized as yet. Unfortunately native adult neurogenesis is insufficient for robust neural repair.
- The discovery of adult neurogenesis was coincident with the birth of stem cell science, which has recognized the presence of multipotent cells in adult tissues capable of differentiating into the various mature cell types of their resident organs. Evidence has also emerged to support the notion of tumor stem cells that drive the growth of tumors. The prospect of augmenting the function of native stem cells or transplanting them to assist tissue repair has spawned the field of regenerative medicine. Hopes for regenerative medicine have been very high in neurotrauma, given the severe deficits that accompany injury as well as the limited endogenous repair inherent to the CNS.
- Classification systems are intimately linked to the diagnosis and treatment of medical conditions. They facilitate research and assist with outcome prediction, and their sophistication tends to mimic our understanding of the condition they characterize. Developing a sensitive scale that precisely, accurately, and reliably captures the innumerable functions of the spinal cord has been a great challenge. Considerable advances have occurred in the development of valid, objective assessment techniques to measure changes in spinal cord function in the setting of injury or disease.
- The first widely accepted classification scheme to assess neurological function following SCI was not described until 1967, when Frankel published his classic work. Frankel described a simple and convenient five-grade scale that classified SCI as Complete (A), Sensory Only (B), Motor Useless (C), Motor Useful (D), or Recovery (E). This work has had considerable influence in that it provides an easy scheme for classifying patients on the basis of obvious and easily assessed aspects of neurological function. Its general framework lives on in more modern classification schemes. A major shortcoming of this scale, however, is the subjectivity inherent in judging what constitutes “useful.” This scale also fails to recognize laterality and the independence with which motor and sensory functions can be lost. Furthermore, the grades C and D have a ceiling effect or discontinuity, whereby disproportionately few patients improve beyond them.
- The American Spinal Injury Association scale, alternatively known as the International Standard for Neurological Classification of Spinal Cord Injury (ISNCSCI), was first published in 1982 and now forms the international standard for post-injury evaluation of neurological function. The scale is endorsed by the International Medical Society of Paraplegia (IMSOP) and has undergone numerous revisions over the years. The ASIA scale tests five key muscles in each extremity, each scored up to 5 points, thus totaling 100. It also allows for optional testing of the diaphragm, deltoids, abdominals, medial hamstrings, and hip adductors. Sensory testing results are graded as normal (2 points), decreased (1 point), or absent (0) for pinprick and light touch in the C2 through S5 dermatomes, allowing the generation of scores for each up to a total of 112 points. Testing of position sense and awareness of deep pressure/pain is considered. The result is a sensitive score useful for clinical research that can be presented in simplified form via the ASIA Impairment Scale, which is essentially a modernization of the Frankel scale. In this scale, grade A remains a complete injury and grade E remains normal neurological function. Intervening scores have been made more objective, with a muscle power grade of 3 used to discriminate among them. Unfortunately the complexity of the ASIA scale makes it time-consuming to perform, and special training is required for personnel who employ it. As well, it neglects bowel, bladder, and other autonomic functions and lacks sensitivity related to hand function and thoracic injuries. Moreover, it does not assess pain or other aspects of quality of life.
- Given the importance of quality of life measures in modern medical research, scales that assess it are frequently employed alongside the ASIA scale in SCI studies. The Functional Independence Measure (FIM) has been perhaps most widely used in the SCI literature despite the fact that it was designed for widespread application to all rehabilitation recipients. It evaluates areas of self-care, sphincter control, mobility, locomotion, and communication because it was largely designed to determine burden of care. It grossly scores patients as independent or dependent .
- In 2001 Catz and associates published the Spinal Cord Independence Measure (SCIM) as a means of better assessing patients with SCI. The SCIM assesses self-care, respiration, sphincter management, and mobility. The SCIM has demonstrated more sensitivity to functional changes in patients with SCI than the FIM, and it has been revised to increase interobserver reliability with respect to bathing, dressing, bowel management, and mobility in bed.
- Also emerging are scales that assess walking after SCI. The Walking Index for Spinal Cord Injury (WISCI) was published in 2000 and revised a year later. Other walking tests include the Timed Up and Go (TUG), the 10 Meter Walk test, and the 6 Minute Walk Test, all three of which have been compared in the same cohort of patients and found to be valid and reliable.
- Clinical management of acute SCI is largely aimed at preventing further injury and optimizing the provision of nutrients to the injured tissue. A detailed discussion of the management of acute SCI is found elsewhere in this textbook; however, there is value to reviewing clinical management principles as they relate to the scientific perspective.
- Secondary insults are distinct from secondary injury. They occur at the level of the organism and lead to deficient provision of nutrients to injured CNS tissue. Hypotension and hypoxia, two secondary insults commonly seen after SCI, are believed to exacerbate secondary injury processes and worsen neurological injury. There is strong evidence that secondary insults markedly worsen outcome from TBI. Data supporting ill effects from secondary insults in SCI are fewer, but avoiding such additional insults is central to the clinical management of acute SCI. Ideally such insults are prevented; next best is recognizing harmful clinical events rapidly and treating them expediently.
- The top priority in managing acute SCI is assessment and stabilization of vital signs, with strict adherence to Advanced Trauma Life Support (ATLS) protocol and managing the ABCs ( a irway, b reathing, and c irculation) in that order or priority. Securing the airway and protecting the cervical spine share top priority. The next priority is breathing, which deserves special attention in patients with cervical spinal cord injuries, in whom compromise of the diaphragm and intercostal musculature can markedly impair respiratory effort. Paralysis of intercostal musculature is associated with an approximate 70% decrease in forced vital capacity and maximal inspiratory force because inspiration causes chest wall collapse until the onset of spasticity. Patients whose bodies compensate initially can rapidly fatigue, and indeed, a third of patients with cervical injuries require intubation in the first 24 hours. It is thus useful to monitor vital capacity in such patients; intubation should be considered in patients whose vital capacity is less than 1L, particularly if there is evidence of fatigue.
- Hypotension is an additional secondary insult that is critical to avoid after SCI. Two causes deserve special consideration in the context of SCI. First, neurogenic shock refers to hypotension and bradycardia due to interruption of the descending sympathetic tracts after severe CNS damage (brain or cervical or high thoracic [T6 or above] SCI). Neurogenic shock is typified by preserved urine output and warm extremities. Care must be taken to ensure that hypotension from other causes is excluded, in particular occult hemorrhage, which can be challenging to detect in patients with sensorimotor deficits. Fluid administration is generally considered first-line therapy in this situation, although restricted heart rate makes patients with neurogenic shock susceptible to fluid overload. Early consideration of vasoactive agents is thus recommended. In the Clinical Practice Guidelines of the Consortium for Spinal Cord Medicine, this approach is recommended to maintain systolic blood pressure above 90mmHg, with at least level II evidence supporting this recommendation. Largely on the basis of a study by Vale and colleagues, SCI guidelines currently recommend efforts to optimize spinal cord perfusion by maintaining mean arterial pressures higher than 85mmHg for the first 7 days after injury.
- Spinal shock, which is not to be confused with neurogenic shock, is characterized by the loss of reflexes, bladder function, and muscle tone below the level of injury. Spinal shock usually lasts for days or weeks after SCI, the average duration being 4 to 12 weeks. The identification of clinical signs that define the duration of spinal shock is controversial. Different writers have defined the termination of spinal shock as the appearance of the bulbocavernosus reflex, the recovery of deep tendon reflexes, or the return of reflex detrusor functions. In 2004, Ditunno and colleagues proposed a four-phase model for spinal shock: areflexia or hyporeflexia (0 to 24 hours), initial reflex return (1 to 3 days), early hyperreflexia (4 days to 1 month), and spasticity (1 to 12 months).
- Spinal cord compression is frequently seen after spinal injuries and can impair blood flow, causing spinal ischemia. Given the exquisite sensitivity of the CNS to ischemia, it seems logical that efforts to mitigate this compression and ischemia as quickly as possible should reduce secondary SCI and improve outcome. A significant body of animal research has indeed demonstrated neurological benefit to early decompression of the injured spinal cord; however, such benefit is less clear in the human, particularly in patients with polytrauma, who are often medically unstable in the acute postinjury phase. Despite the fact that early spine surgery appears safe in patients with polytrauma, the question whether early decompression for acute human SCI is beneficial has been viewed as incompletely answered.
- The Surgical Treatment of Acute Spinal Cord Injury Study (STASCIS) was initiated in 2003 to investigate the putative efficacy of early decompression. This trial was designed to be randomized, but resistance to randomly assigning patients to intentionally delayed decompression led to the trial's restructuring as a prospective observational study. The results of the study were published in 2012. A total of 313 patients were enrolled, of whom underwent early surgery, defined as within 24 hours of SCI; underwent late decompressive surgery. Univariate analysis showed that patients who had early decompression were 2.6 times more likely to have a two-grade improvement in ASIA Impairment Score by 6 months after injury (95% confidence interval [CI], 1.11-5.97). In multivariate analysis, the odds of two-grade improvement in ASIA Impairment Score increased to 2.8 with early decompression (95% CI, 1.10-7.28). Early surgery was associated with a nonsignificant decrease in the risk of complications.
- Central cord syndrome is uniquely challenging with respect to determining the optimal timing of intervention, given that most patients present without spinal instability and experience substantial spontaneous neurological improvement. Also, a historic and influential publication from Schneider and colleagues in 1954, which first described central cord syndrome, reported several poor outcomes arising from early decompression. The result was a recommendation to consider central cord syndrome a unique clinical entity and to avoid early procedures because of perceived risk to the spinal cord. Despite the tenuous evidence supporting it, this recommendation has persisted in the literature, although later evidence challenges this conclusion.
- It is our opinion that unless compelling evidence to the contrary arises in the future, central cord syndrome should be treated in the same fashion as other spinal cord injuries.
- Numerous putative neuroprotective drugs targeting secondary injury processes have been tested in large multicenter prospective randomized controlled trials for human SCI. Tested agents include methylprednisolone sodium succinate (MPSS), tirilazad mesylate, GM-1 ganglioside, thyrotropin-releasing hormone (TRH), gacyclidine, naloxone, and nimodipine. GM-1 ganglioside, also known as Sygen, is a complex glycolipid abundant in the membranes of nervous tissue that demonstrated inconsistent results in human clinical trials. Thyrotropin-releasing hormone demonstrated statistically significant benefit in patients with incomplete SCI, but this finding may represent type I error, given the attrition seen in the study. Gacyclidine, or GK-11, is a glutamate antagonist that failed to show a sustained benefit in a phase 2 human trial, although this finding may represent type II error. Nimodipine was tested in a French human trial in 1996 but did not show benefit. The opioid antagonist naloxone was tested in two human clinical trials but also did not demonstrate convincing benefit.
- Methylprednisolone sodium succinate, (Solu-Medrol, Pfizer, Inc., New York) is the only agent from completed clinical trials that has entered clinical use for SCI, but this use is controversial. MPSS is a corticosteroid. Corticosteroids have been employed in neurotrauma for decades but have only lately been subject to intensive scientific scrutiny. Their described neuroprotective effects include antioxidant properties, enhancement of spinal cord blood flow, reduced cellular calcium influx, reduced axonal dieback, and attenuated lipid peroxidation. Following the accumulation of preclinical data that were generally supportive of a neuroprotective role in animal models of acute SCI, MPSS was studied in five prospective human acute SCI trials, making it the most extensively studied drug for acute SCI.
- The landmark National Acute Spinal Cord Injury Study (NASCIS) and its two later versions examined the use of MPSS for acute SCI. The first study, published in 1984, compared high-dose with low-dose MPSS ; the use of placebo was judged unethical because benefit from steroids was presumed. Neurological improvement was not significantly different in the two treatment groups, although a statistically significant higher rate of wound infection was noted in the high-dose group as well as higher rates of gastrointestinal hemorrhage, sepsis, pulmonary embolism, delayed wound healing, and death.
- Animal studies completed subsequent to the first NASCIS suggested that higher MPSS doses may be required for neuroprotection. NASCIS II was thus designed to compare a higher dose of MPSS with placebo and with the opioid antagonist naloxone given within 24 hours of injury. In the overall analysis there was no neurological benefit in the MPSS-treated group; however, a post hoc analysis performed as part of the original plan found that patients receiving the drug within 8 hours of injury benefited neurologically—including those with complete injuries. As in NASCIS I, MPSS administration was associated with higher rates of wound infection and pulmonary embolism.
- NASCIS III was designed and powered to explore the beneficial effects of administration of MPSS within 8 hours of injury, as reported in NASCIS II. This was the only NASCIS to assess functional outcome, employing the FIM. NASCIS III compared the 24-hour MPSS infusion used in NASCIS II with a 48-hour MPSS infusion and with tirilazad mesylate, a 21-aminosteroid with antioxidant but not glucocorticoid effects. Overall this trial demonstrated no sustained benefit to MPSS administration. A post hoc analysis noted that patients receiving MPSS 3 to 8 hours after injury demonstrated improved neurological function at 6 weeks and 6 months but not at 1 year, when administered MPSS for 48 hours rather than 24 hours. This finding led to the recommendation that if MPSS were given within 3 hours of injury, the 24-hour infusion would suffice, but if treatment was initiated between 3 and 8 hours after injury, a 48-hour MPSS regimen was better than the 24-hour regimen. The 48-hour regimen represents the highest dose of MPSS prescribed for any clinical condition and was associated with a two-times-higher rate of severe pneumonia, a four-times-higher rate of severe sepsis, and a six-times-higher incidence of death in comparison with the 24-hour regimen.
- Two other prospective human SCI trials involving corticosteroids have been published. Although Otani and colleagues reported benefit from MPSS administration, Pointillart and associates reported none. Nonetheless, both studies were small and plagued by methodologic problems that limit the interpretation of their results as either positive or negative.
- Later evidence further informs the use of MPSS for SCI. A 2012 Cochrane meta-analysis and review concluded that the benefit of MPSS for acute SCI is not associated with a significant increase in the risk of complications or mortality although a trend is apparent. As well, the STASCIS noted a benefit to MPSS administration and the researchers had to control for this effect in their analysis.
- Two predominant concerns regarding the use of MPSS for acute SCI have arisen. First, the benefits noted have been modest and have come from secondary analyses for which the studies were not designed or powered. Second, high rates of adverse events were consistently associated with MPSS administration. The latest version of the acute SCI guidelines now provide a level I recommendation against the administration of MPSS, a marked change from the previous version despite little change in the evidence considered. Our personal view is that given the severity of SCI deficits and current lack of alternatives, administration of MPSS (NASCIS II protocol) remains justified for selected patients with acute SCI if begun within 8 hours of injury.