Every year, an estimated 12,000

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1 Review Article Advances in the Management of Spinal Cord Injury Ranjan Gupta, MD Mary E. Bathen, BS Jeremy S. Smith, MD Allan D. Levi, MD, PhD, FACS Nitin N. Bhatia, MD Oswald Steward, PhD Abstract Historically, clinical outcomes following spinal cord injury have been dismal. Over the past 20 years, the survival rate and long-term outcome of patients with spinal cord injury have improved with advances in both medical and surgical treatment. However, the efficacy and timing of these adjuvant treatments remain controversial. There has been a tremendous increase in the number of basic science and clinical studies on spinal cord injury. Current areas of investigation include early acute management, including early surgical intervention, as well as new pharmacotherapy and cellular transplantation strategies. It is unlikely that a single approach can uniformly address all of the issues associated with spinal cord injury. Thus, a multidisciplinary approach will be needed. From the Department of Orthopaedic Surgery, University of California, Irvine, Irvine, CA (Dr. Gupta, Dr. Smith, Dr. Bhatia, and Dr. Steward), the University of California, San Diego School of Medicine, San Diego, CA (Ms. Bathen), and the Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL (Dr. Levi). J Am Acad Orthop Surg 2010;18: Copyright 2010 by the American Academy of Orthopaedic Surgeons. Every year, an estimated 12,000 Americans sustain and survive a spinal cord injury (SCI). 1 Approximately 259,000 Americans currently live with an SCI. 1 SCI was traditionally thought of as a condition affecting primarily young males, but the age of spinal cord injured patients is increasing, 2 with an average age of 40.2 years. 1 Of the injuries reported since the year 2005, most have occurred in males and Caucasians (80.9% and 66.1%, respectively). 1 SCIs can occur in several ways, but motor vehicle crashes are the most common cause. 1 Incomplete quadriplegia is the most frequent neurologic category of SCI (30.1%), followed by complete paraplegia (25.6%), complete quadriplegia (20.4%), and incomplete paraplegia (18.5%). 1 In the 1990s, the refinement of spinal stabilization led to changes in the management of acute spinal trauma. Research efforts in the search for a pharmacologic intervention to limit secondary injury are ongoing. Results from the National Acute Spinal Cord Injury Study (NASCIS) trials were initially viewed as promising, and the administration of methylprednisolone sodium succinate (MPSS) was often considered a standard of care in the acute SCI setting. However, more recent studies have been highly critical of the interpretation of these trials, particularly the statistical analysis. 3 Although analysis of NASCIS II revealed that the small sample of patients treated with MPSS within the first 8 hours of injury showed significantly improved motor and sensory function, 4 clinical improvements remain modest, and the efficacy of the drug is controversial. Patients with SCI face significant neurologic dysfunction and disability. In the past few years, several potential advancements, including stem cell transplantation, have come to the forefront of SCI research. We summarize the pathophysiology and acute management of SCI as well as recent advances in acute therapy that 210 Journal of the American Academy of Orthopaedic Surgeons

2 Ranjan Gupta, MD, et al are important to the treating orthopaedic surgeon and neurosurgeon. Pathophysiology The neurologic deficits related to SCI develop as a result of primary and secondary injury processes. 5 As the injury cascade continues, the likelihood of functional recovery declines. Thus, therapeutic intervention should not be delayed; in most cases, the window for therapeutic intervention is believed to be 6 to 24 hours postinjury. The primary mechanisms are those resulting from the initial injury and include energy transfer to the spinal cord, spinal cord deformation, and persistent postinjury cord compression. These mechanisms, which occur within seconds to minutes after injury, lead to immediate cell death, axonal disruption, and vascular and metabolic changes, which have ongoing effects. The secondary injury process, which begins within minutes of injury and lasts for weeks to months, involves a complex cascade of biochemical interactions, cellular reactions, and fiber tract disturbances, all of which are only partially understood. It is clear, however, that increased production of free radicals and endogenous opioids, excessive release of excitatory neurotransmitters, and inflammatory reactions all play a significant role. Furthermore, mrna profiles have identified numerous gene expression changes after SCI, and these changes are being pinpointed as possible therapeutic targets. 6 Several theories have been proposed to explain the pathophysiology of secondary injury. 4 The free-radical theory maintains that, because of rapid depletion of antioxidants, oxygen free radicals accumulate in injured central nervous system (CNS) tissue and attack membrane lipids, proteins, and nucleic acids. This results in the production of lipid peroxides, which cause failure of cell membranes. The calcium theory suggests that the propagation of secondary injury relies on the influx of extracellular calcium ions into nerve cells. Calcium ions activate phospholipases, proteases, and phosphatases the activation of which results in the interruption of mitochondrial activity and disruption of the cell membrane. The opiate receptor theory proposes that endogenous opioids may be involved in the propagation of SCI and that opiate antagonists (eg, naloxone) may improve neurologic recovery. The inflammatory theory is based on the hypothesis that inflammatory substances (ie, prostaglandins, leukotrienes, platelet-activating factor, serotonin) accumulate in acutely injured spinal cord tissue and are mediators of secondary tissue damage. 4 Since the 1990s, extraordinary scientific advances have been made in understanding the immune system and its interactions with the nervous system. 4 Following SCI, the primary modes of cell death are necrosis and apoptosis. Although the predominant mode of cell death immediately following the primary injury is necrosis, apoptotic programmed cell death has significant effects on the subacute secondary injury. Apoptosis-induced oligodendrocyte cell death results in demyelination and axonal degeneration at and adjacent to the injury site. It has also been implicated in the initiation of wallerian degeneration in both ascending and descending white matter tracts surrounding the injury. The mechanisms and signaling cascades involved in SCI-induced apoptosis continue to be defined and offer potential points of intervention for novel treatment methods to delay and prevent secondary injury. The secondary injury process culminates with the formation of the glial scar, which is arguably the central barrier to axonal regeneration within the CNS. Glial scar formation is a reactive process involving an increase in the number of astrocytes (ie, astrogliosis). 7 Following necrosis of central cord gray matter and cystic degeneration, scar tissue develops and extends into the axonal long tracts. The pattern of scar formation and inflammatory cell infiltration is influenced by the type of spinal cord lesion and may have an impact on the potential for overcoming this neuroregenerative barrier (Figure 1). There are three types of lesion: microlesion, contusive, and large stab. In the microlesion, the blood-brain barrier is minimally disrupted, astrocytes maintain normal alignment but produce chondroitin sulfate proteoglycans (CSPGs) and keratan sulfate proteoglycans (KSPGs) along the injury tract, and macrophages invade the lesion site. Axons are unable to regenerate beyond the lesion. In the contusive lesion, the blood-brain barrier is dis- Dr. Gupta or an immediate family member has received research or institutional support from Arthrex and National Institutes of Health (NIH)-NINDS. Dr. Bhatia or an immediate family member has received royalties from Alphatec Spine; is a member of a speakers bureau or has made paid presentations on behalf of Biomet, Stryker, Alphatec Spine, Seaspine, and Globus Medical; serves as a paid consultant to or is an employee of Alphatec Spine, Biomet, and Seaspine; and has received research or institutional support from Alphatec Spine, Biomet, Arthrex, NIH (NIAMS and NICHD), and Spinewave. Dr. Steward or an immediate family member has received research or institutional support from NIH-NINDS. None of the following authors or any immediate family member has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Ms. Bathen, Dr. Smith, and Dr. Levi. April 2010, Vol 18, No 4 211

3 Advances in the Management of Spinal Cord Injury Figure 1 Schematic representations of three stereotypical lesions of the central nervous system: microlesion (A), contusive lesion (B), and large stab lesion (C). In all types, macrophages invade the lesion, and both chondroitin sulfate proteoglycans (CSPGs) and keratan sulfate proteoglycans (KSPGs) are upregulated. A, Astrocyte alignment is not altered by the injury process, but axons are unable to regenerate past the lesion site. B, The meninges are not disrupted, but cavitation at the epicenter of the lesion and proteoglycan deposition are produced. Axons are unable to regenerate beyond the lesion, but spared axons can be found distal to the injury site. C, Stab lesion that penetrates the meninges and allows fibroblast and macrophage invasion. Axons are highly repulsed by the increasing gradient of CSPGs and KSPGs. Several other inhibitory molecules are also made in this type of injury and are especially prevalent in the core of the lesion. ECM = extracellular matrix. (Redrawn with permission from Silver J, Miller JH: Regeneration beyond the glial scar. Nat Rev Neurosci 2004;5: ) rupted, but the meninges remain intact. Cavitation occurs at the epicenter of the lesion. Astrocyte alignment is altered at the lesion site. Astrocytes produce CSPGs and KSPGs in a gradient increasing from the penumbra toward the center of the lesion. There is no fibroblast invasion of the lesion core, and, thus, no fibroblast-expressed inhibitors are present. Macrophages invade the lesion and its core, and dystrophic axons approach the lesion before growth ceases. In the large stab lesion, the blood-brain barrier is disrupted, and cavitation occurs at the lesion center. Astrocyte alignment is altered at the lesion site, and astrocytes produce CSPGs and KSPGs in a gradient increasing toward the lesion. Transforming growth factor, ephrin-b2, and Slit protein expression increases in reactive astrocytes adjacent to the fibroblasts. Fibroblasts invade the lesion and express class 3 semaphorin and the ephrin-b2 receptor. Macrophages invade the lesion and release inflammatory cytokines. Dystrophic neurons are highly repelled by the 212 Journal of the American Academy of Orthopaedic Surgeons

4 Ranjan Gupta, MD, et al lesion core and express neutrophil 1. The glial scar has important negative consequences to neuroregeneration, as many cells within the scar secrete neurodevelopmental inhibitor molecules. As such, methods to limit scar formation following SCI may prove useful in improving function. Acute Management The acute management of SCI requires a multidisciplinary and multisystem approach. Appropriate treatment begins in the field, with immobilization of the spine by emergency response personnel. Spinal precautions, including external immobilization and log rolling, are then used to prevent further SCI, especially in the unstable spine. The initial hospital evaluation of the spinal cord injured patient should include diagnosis and treatment of the spinal pathology as well as any other acute or lifethreatening injury. Medical management is of utmost importance during the acute postinjury period. Traumatic injury decreases the ability of the spinal cord to autoregulate local blood flow, which leaves the spinal cord vulnerable to systemic changes in blood flow. Few management techniques have been directly studied prospectively in the spinal cord injured patient; however, inferences from numerous studies of human traumatic brain injury (TBI) have been shown to be valid. Hypotension (systolic blood pressure <90 mm Hg) and hypoxia (Pao 2 60 mm Hg) have been shown to be independently associated with significantly increased morbidity and mortality following TBI. 8 Thus, maintenance of systemic blood flow and oxygenation is central to the acute medical management of the spinal cord injured patient. Strategies include blood pressure support, avoidance of acute anemia, and ventilatory support. Several SCI case series have confirmed that maintenance of systemic mean arterial pressure >90 mm Hg can improve neurologic outcomes, and that diagnostic and treatment interventions used to accomplish this goal are safe. 9 Invasive hemodynamic monitoring of the patient in an intensive care unit is recommended in the acute postinjury period. It can be challenging to maintain normal blood pressure in spinal cord injured patients. These patients frequently have multiple injuries, and hypotension, hypoxemia, and anemia can be induced by varied and numerous causes. Hypotension in the multisystem trauma patient is frequently caused by hypovolemia resulting from hemorrhage or dehydration. Although these causes of hypotension should be pursued, decreased blood pressure in the spinal cord injured patient may occur even with normal blood volume because of decreased sympathetic outflow. This form of hypotension is known as neurogenic shock. Neurogenic shock can be distinguished from hypovolemic hypotension by the lack of appropriate cardiac response to the decreased blood pressure and resultant relative bradycardia. No one algorithm for maintenance of blood pressure is widely accepted, but several aspects of treatment are generally agreed on, including invasive blood pressure monitoring with Swan-Ganz catheters or arterial lines; the use of crystalloid, colloid, or blood to optimize fluid volume; and the use of vasopressors in patients with optimal volume status but with ongoing neurogenic hypotension. Based on the TBI studies, blood pressure monitoring and support is generally continued for 7 days postinjury, 8 although studies in spinal cord injured patients have not confirmed this length of time. The timing of decompression remains controversial, even though the issue has been explored in several experimental and clinical studies. Although there is no level I evidence to support early surgery, most physicians would agree that emergent surgical decompression is indicated in patients with acute and progressive neurologic deficit in the presence of persistent spinal cord compression (Figure 2). Similarly, although there is little support in the literature, there is growing enthusiasm regarding emergent decompression, even in patients who present with neurologically complete injuries 10 (Table 1). The Surgical Treatment of Acute Spinal Cord Injury Study (STASCIS) is currently underway. 21 It is being done in an effort to apply quality, evidencebased scientific method to the debate regarding surgical timing. On September 9, 2007, Kevin Everett, a tight end in the National Football League, sustained an American Spinal Injury Association (ASIA) grade B cervical SCI resulting from a C3-C4 fracture-dislocation. 22,23 Shortly after the injury, an attempt at systemic hypothermia was initiated. Although Everett received 2Loficed saline in the ambulance, he was normothermic on admission to the hospital (37.2 C). Subsequently, Everett underwent decompression and stabilization of his surgical fracture-dislocation. 22,23 Hypothermia was also induced via an indwelling vascular catheter during hospitalization. When Everett began to show early signs of recovery with voluntary movement just 2 days after injury, there was a resurgence of interest in the neuroprotective effects of hypothermia. Research into the therapeutic potential of hypothermia emerged in the 1950s, but enthusiasm dwindled because adverse complications (eg, atelectasis, pneumonia, acute respiratory distress syndrome) could not be overcome. 22,23 Hypothermia is a condition in which an organism s temperature drops below that required for normal metabolism. From a neuroprotective standpoint, hypothermia reduces swelling and hemorrhage, potentially slowing the secondary injury cascade. 22,23 Although April 2010, Vol 18, No 4 213

5 Advances in the Management of Spinal Cord Injury Figure 2 Images of a 15-year-old girl who was struck by a motor vehicle. She sustained a C4 teardrop fracture with resultant spinal cord injury clinically complete C4 American Spinal Injury Association (ASIA) grade A. A, Sagittal T2-weighted magnetic resonance image demonstrating spinal cord edema and swelling with some ventral spinal cord compression from the kyphosis and retropulsed bone fragments. B, Lateral radiograph demonstrating improved alignment and some immediate decompression of the spinal canal following the use of cervical traction. C, Postoperative lateral radiograph demonstrating repair of the fracture via C4 corpectomy and fibular allograft reconstruction with an anterior plate spanning C3 to C5 and supplemented by a posterior lateral mass rod-and-screw reconstruction. some recent basic science studies have demonstrated the benefit of modest hypothermia following SCI, 24 the evidence to date is not compelling. Moreover, higher quality clinical trials do not exist. One recent study assessed hypothermia treatment of acute SCI with intravascular cooling techniques in a series of 14 patients. 25 Although this study may provide baseline data, larger multicenter, randomized studies are required before this modality gains widespread acceptance. Hypothermia remains an experimental therapy. Pharmacologic Interventions Optimal medical management of acute SCI remains the subject of much debate and controversy. Medical therapy is done with the goal of minimizing damage caused by the primary and secondary mediators of SCI. US FDA approval requires successful clinical trials (Tables 2 and 3), which often depend on successful animal studies. Many clinical trials have been completed, and several more are in the initial trial stages. Numerous therapies are currently being tested in animal models. Because of the multidimensional nature of the pathophysiology of SCI, effective therapies will certainly require combined approaches. Methylprednisolone Sodium Succinate MPSS is a glucocorticoid that has been shown to reduce the neurotoxicity of excitatory amino acid, inhibit lipid peroxidation, increase blood perfusion in the spinal tissue, and slow traumatic ion shifts. In this way, MPSS has the potential to inhibit inflammatory damage to the spinal cord. The effectiveness of MPSS in acute SCI has been tested in three independent trials (NASCIS) ,42-45 Published in 1984, the NASCIS I trial compared high- versus low-dose MPSS treatment. 11,42 Patients who received high doses of MPSS were found to have statistically significant increases in wound infection rates (relative risk, 3.55; 95% CI, ) as well as a higher incidence of sepsis, gastrointestinal hemorrhage, pulmonary embolism, and death. 11 No significant neuroprotective benefit was found with either treatment. 11,42 The NASCIS II trial was subsequently designed to compare highdose MPSS (administered <24 h) with placebo and naloxone. 12,43 No significant neurologic benefit was found with MPSS. However, post hoc analysis revealed neuroprotective potential when MPSS was received within 8 hours of injury. There were increases in the rate of wound complications and pulmonary embolism in this trial, as well. 214 Journal of the American Academy of Orthopaedic Surgeons

6 Ranjan Gupta, MD, et al Table 1 Completed Prospective Randomized Controlled Trials of Pharmacologic Approaches to the Management of Acute Spinal Cord Injury Trial Treatment Arms Conclusions MPSS NASCIS I 11 MPSS (100 mg for 10 d), MPSS (1,000 No difference mgfor10d) NASCIS II 12 MPSS, a naloxone, b placebo Significantly improved neurologic recovery with early (<8 h of SCI) MPSS treatment (P = 0.03) Japan MPSS 16 MPSS, a MPSS (100 mg for 7 d) Improved neurologic and sensory recovery with early treatment (<8 h of SCI) NASCIS III 13 G M1 ganglioside 14 Maryland G M1 Sygen G M1 (Fidia Pharmaceutical, Washington, DC) 17 MPSS, a MPSS, c MPSS (30 mg/kg bolus +TM d ) G e M1 vs placebo MPSS a + low-dose G M1, f MPSS a + highdose G M1, g MPSS a + placebo Improved neurologic recovery with MPSS treatment Improved neurologic recovery with G M1 treatment Negative primary outcomes, trend for enhanced secondary outcomes TRH 15 TRH h vs placebo Improved neurologic recovery with TRH treatment Calcium channel blocker (nimodipine) Petitjean et al 18 MPSS, a nimodipine, i nimodipine + MPSS, a placebo Pointillart et al 19 MPSS, a nimodipine, nimodipine + MPSS, a placebo Gacyclidine (GK-11) 20 Gacyclidine (0.005, 0.01, or 0.02 mg/kg; two doses) vs placebo No difference. Study likely was too underpowered to detect a difference. No difference. Increased infection in MPSS groups. Trend for increased motor recovery in cervical incomplete SCI patient strata a MPSS, MPSS 30 mg/kg bolus mg/kg/h over 24 h b 5.4 mg/kg bolus mg/kg/h over 24 h c MPSS, MPSS 30 mg/kg bolus mg/kg/h for 48 h d 2.5 mg/kg bolus every 6 h over 48 h e 100 mg/d for d f 300 mg loading dose followed by 100 mg/d for 56 d g 600 mg loading dose followed by 200 mg/d for 56 d h 0.2 mg/kg bolus mg/kg/h infusion over 6 h i mg/kg/h over 2 h followed by 0.03 mg/kg/h for 7 d G M1 = monosialotetrahexosylganglioside (100 mg/d for d), MPSS = methylprednisolone sodium succinate, NASCIS = National Acute Spinal Cord Injury Study, SCI = spinal cord injury, TM = tirilazad mesylate, TRH = thyrotropin-releasing hormone Adapted with permission from Baptiste DC, Fehlings MG: Pharmacological approaches to repair the injured spinal cord. J Neurotrauma 2006;23: The NASCIS III trial was designed to determine the beneficial effects of MPSS when administered <8 hours after acute SCI. 13,44 The study compared infusion for 24 hours versus 48 hours after injury. In addition, functional recovery was included for the first time as an outcome measure. As with the NASCIS II trial, no significant improvement in neurologic recovery was noted. Post hoc analysis found improved functional recovery at 6 weeks and 6 months following injury in patients in whom treatment was initiated 3 to 8 hours after SCI when the dose was continued for 48 hours. Significant rates of sepsis, pneumonia, and death were also noted in the group receiving the 48-hour dose. As a result of these trials, a 24-hour dose was recommended when administered within 3 hours of injury, and a 48-hour dose was recommended when administered between 3 and 8 hours after injury. Intense controversy persists surrounding the efficacy of MPSS in patients with acute SCI. Scrutiny of the design of the NASCIS trials and analysis of data have raised serious questions about the neuroprotective potential of MPSS and have raised concerns about the possibility of adverse side effects following its administration. Because of an increased complication rate with steroid treatment and the lack of evidence corroborating the NASCIS results, treatment with MPSS has become largely a clinical decision to be made by the treating physician based on each individual case. Many physicians con- April 2010, Vol 18, No 4 215

7 Advances in the Management of Spinal Cord Injury Table 2 Clinical Studies That Oppose Early Surgical Decompression Study No. of Patients (level) Study Design Conclusions Aito et al 26 Pollard and Apple 30 McKinley et al patients with traumatic central cord syndrome: 45% treated surgically, 55% treated conservatively 412 (cervical) incomplete injuries 779 (all): 603 decompressed, 176 nonsurgical No difference in outcome was found as a result of spine surgery Baseline neurologic assessment not available in 51% of cases. Early surgery (<24 h) not associated with improved recovery. No significant differences in neurologic recovery between early surgery (<24 h), late surgery (>72 h), and nonsurgical management Vaccaro et al (cervical): early 34, late 28 Prospective, randomized No difference in neurologic recovery or length of hospital stay between early (<72 h) and late (>5 d) surgery groups Bötel et al 28 Marshall et al (all): 178 decompressed (51.4% early [<24 h], 10.5% late [>2 wk]) 283 (all): 12 showed decline in neurologic function associated with specific management Prospective comparative study No neurologic recovery in patients with complete SCI. No association between neurologic recovery and timing of decompression. Early surgery on the cervical spine when cord injury is present appears to be hazardous; each of the three patients with a cervical cord injury who deteriorated was operated on within the first 5 days SCI = spinal cord injury Adapted with permission from Fehlings MG, Perrin RG: The timing of surgical intervention in the treatment of spinal cord injury: A systematic review of recent clinical evidence. Spine (Phila Pa 1976) 2006;31(11 suppl):s28-s35. tinue to administer MPSS in the setting of acute SCI, although the rationale for its use appears to have changed. A survey published in 2006 concluded that prescribing physicians indicate a fear of litigation rather than clinical efficacy as the primary motivating factor for administering the drug. 46 Opiate Blockers Release of opioid peptides, which are natural pain relievers, increases in response to traumatic SCI. Although pain relief is necessary, evidence exists that opioid peptides (eg, dynorphin A) can induce edema, hyperalgesia, and allodynia and may indirectly contribute to neurodegeneration. 47 In addition, sustained exposure to a high level of opioids is neurotoxic. 47 Naloxone, a nonselective opioid receptor antagonist, has been shown to improve spinal cord conduction and reduce allodynia and edema. 12 However, naloxone failed to provide therapeutic effects when administered for the NASCIS II trial. 12 It remains unclear whether naloxone could be an effective treatment option with refinement in dosage in timing. G M1 Ganglioside G M1 ganglioside has shown modest but significant potential in the management of SCI. These sialic acid containing glycosphingolipids are found in great concentrations in the outer membranes of nervous tissue. G M1 is potentially a better option than MPSS because it has been shown to have no effect on gray matter at the level of trauma and has a longer therapeutic window. 14 In an initial prospective randomized study of 37 patients, G M1 showed a statistically significant improvement in ASIA motor scores up to 48 hours after injury (P = 0.047). 14 This prompted the Sygen Multi-Center Acute Spinal Cord Study, the largest prospective randomized clinical trial in acute SCI to date. 17 In this study of more than 750 patients over 5 years, G M1 ganglioside failed to show significant improvement in motor recovery using the modified Benzel walking scale, although a trend of improved bowel and bladder function and sacral sensation and a more rapid return of neurologic function were observed. The study has since been criticized for having unrealistic primary outcome measures (ie, a two point improvement in the Benzel walking scale) considering the large number of complete (ASIA grade A) patients enrolled. G M1 has not been approved for general use in the setting of acute SCI, and no clinical trials are currently underway Journal of the American Academy of Orthopaedic Surgeons

8 Ranjan Gupta, MD, et al Table 3 Clinical Studies That Support Early Surgical Decompression Study No. of Patients (level) Study Design Conclusions La Rosa et al 32 Papadopoulos et al 33 Waters et al 34 Tatoretal 35 1,683 (all): 793 decompressed, 890 nonsurgical 91 (cervical): 66 decompressed, 25 nonsurgical 2,204 (all): 88% admitted <72 h of injury 585 (all): 23.5% underwent early decompression (<24 h) Mirza et al (cervical): 15 <72 h, 15 >72 h Ng et al 37 Chen et al (cervical): 7 decompressed <12 h 37 (cervical): 16 decompressed <2 wk, 21 managed nonsurgically Systematic literature review of years Prospective, nonrandomized Prospective, nonrandomized Prospective, nonrandomized Prospective, nonrandomized Early decompression (<24 h) improves neurologic recovery in patients with incomplete neurologic deficits Early decompression (<10 h) is feasible, may improve neurologic recovery, and reduces hospital stay Surgery does not increase complication rates of patients with SCI 65% of patients in North America with SCI undergo surgery. No consensus on timing of intervention. Early (<72 h) decompression improves neurologic recovery and does not increase complication rates Surgical decompression within 8hofinjury was feasible in 8% and was not associated with increased complication rates Surgery associated with improved neurologic recovery, shorter hospital stay, and fewer complications Vale et al (all): 58 decompressed Prospective, nonrandomized No clear relationship between neurologic recovery and timing of surgery, but aggressive medical treatment enhanced any potential benefit provided by surgery Waters et al (all): 127 decompressed, 142 nonsurgical Petitjean et al (thoracic): early avg 12 h, late avg 9 d Prospective, nonrandomized Surgery of no benefit; however, all patients underwent delayed surgery Decompression of no benefit in complete thoracic paraplegia SCI = spinal cord injury Adapted with permission from Fehlings MG, Perrin RG: The timing of surgical intervention in the treatment of spinal cord injury: A systematic review of recent clinical evidence. Spine (Phila Pa 1976) 2006;31(11 suppl):s28-s35. Thyrotropin-releasing Hormone Thyrotropin-releasing hormone (TRH) is a tripeptide with numerous physiologic and biochemical actions, including a role in stimulating the release of thyroid-stimulating hormone and prolactin by the anterior pituitary. In animal models it has been shown that TRH and TRH analogs may reduce or prevent the biochemical events of secondary SCI by antagonizing the effects of endogenous opioids, platelet-activating factor, peptido-leukotrienes, and excitatory amino acids. 49 TRH has also been shown to improve neurologic function in rats with SCI in a dosedependent manner. 49 Equipped with promising results from animal studies, Pitts et al 15 performed a clinical trial of TRH involving 20 patients. Four months after TRH treatment, statistically significant improvements were seen in neurologic and sensory function for patients with incomplete SCI (P = and P = 0.031, respectively). Trials on a larger scale and of longer duration are needed to test the reliability of these results and the long-term effects of TRH therapy. Erythropoietin Erythropoietin (EPO) is a hematopoietic growth factor normally produced in the kidney, bone marrow, and developing human brain and spinal cord. In addition to its hematopoietic effects, EPO appears to have neuroprotective abilities, as demonstrated by animal models of Parkinson disease, multiple sclerosis, diabetic neuropathy, and stroke. 50 In SCI animal models, EPO has demonstrated neuroprotective effects by inhibiting trauma-induced lipid peroxidation, preventing neuronal apoptosis, and promoting neuroregeneration with resultant improved functional recovery. Because of its already widely accepted use in the treatment of anemia, its ability to cross the blood-brain barrier to exert its neuroprotective action, and the April 2010, Vol 18, No 4 217

9 Advances in the Management of Spinal Cord Injury relative lack of a host-mounted immune response, EPO is an optimal candidate for clinical trial. A recent phase II clinical trial demonstrated decreased infarct size and improved clinical outcome in stroke patients. 51 Although there are ongoing phase II clinical trials of EPO in the treatment of patients with malignant spinal cord compression, its efficacy in the treatment of acute SCI has not yet been evaluated. Cellular Transplantation In hopes of overcoming roadblocks to neurorestoration, in the past decade experimental therapies have gone beyond traditional pharmacologic solutions to explore the realm of cellular-based therapy. In cellularbased approaches, neural and nonneural tissue elements are transplanted into the injured spinal cord with the aim of regenerating white matter long tracts and/or replacing lost cellular components. Some therapies of this kind have already been translated into the clinical arena, and others show the potential to do so. The ideal cellular transplant should support axonal elongation and regrowth through the adult CNS, restore myelin, coexist with astrocytes, and fully integrate with the lesion microenvironment. The cellular transplants actively being tested currently include peripheral nerve micrografts, activated autologous macrophages, and stem cell therapies. Peripheral Nerve Micrografts Peripheral nerve micrografts have proved to be effective in experimental studies and have significant bench-tobedside potential. Peripheral nerve tissue has long been the subject of research because it contains Schwann cell glial elements that can stimulate fiber regrowth and remyelination. Schwann cells are glial cells that provide myelin insulation to axons in the peripheral nervous system (PNS). Experimental models have shown that Schwann cells produce many neurotrophic factors, synthesize extracellular matrix, and express a variety of cell adhesion molecules to promote axonal regeneration in the PNS. Furthermore, grafting of peripheral nerves with varying combinations of growth factors in spinal cord injured rats has resulted in axonal and functional recovery. 52 However, the ability of Schwann cells to foster regeneration varies markedly and depends on the physiologic state and phenotype. Because of inhibition by astrocytes, transplantation of purified Schwann cells will result in only marginal axonal regeneration. 53 Keirstead et al 54 revealed the precise neurotrophic factors that constitute a proregenerative Schwann cell phenotype and the mechanisms that lead to their expression. Notably, proregenerative Schwann cells of injured peripheral nerves upregulate the expression of specific cell adhesion molecules (ie, N-CAM, N-cadherin, L1), extracellular matrix molecules, and trophic factors (ie, nerve growth factor, brainderived neurotrophic factor [BDNF], neurotrophin-3 [NT-3]). This knowledge helped direct a recent study of the Miami Project to Cure Paralysis. 55 In this study, the injured spinal cord was implanted with Schwann cells transduced ex vivo with lentiviral vectors encoding a bifunctional neurotrophin molecule (D15A), which mimics actions of both NT-3 and BDNF. Increased neurotrophin secretion by the implanted D15A Schwann cells led to the presence of a significantly increased number of axons in the contusion site on postmortem analysis. Preconditioning peripheral nerve grafts with mechanical stimulation was tested in 2006 as a means to activate Schwann cells. 56 This study and others like it were based on the discovery that sustained mechanical stimulation of peripheral nerves induces a massive proliferation of Schwann cells in the compressed segments. 52,57,58 The proliferative response is accompanied by sprouting of undamaged axons, which suggests that Schwann cells are activated in a way that promotes axonal growth. 52,57,58 The promising results indicating that functional recovery improved in rats transplanted with preconditioned peripheral nerves warrant further investigation for potential clinical application. The potential of cells of the primary olfactory system to promote neural regeneration has also been explored. The primary olfactory system supports neurogenesis throughout life, and newly generated olfactory neurons can grow into the inhibitory CNS environment of the olfactory bulb tissue and reform synapses. This unique regenerative property is believed to depend on the presence of olfactory ensheathing cells (OECs). OECs are distinct glial cells that wrap olfactory axons and direct their regeneration from the nasal mucosa to synapses of second-order neurons in the CNS. In contrast to Schwann cells, OECs have been shown to intimately interact with host astrocytes and other CNS elements. Furthermore, OECs have been reported to have exceptional plasticity, and they allow neurons to cross the glial scar as well as the PNS-CNS boundary. 59 In animal models, it has been demonstrated that OECs have the ability to survive, migrate, and remyelinate axons as Schwann cells do, and even to regenerate axons across the injury site. 60 Clinical explorations with OECs are underway in China, Portugal, Russia, England, and Australia. One controversial study obtains OECs from aborted fetuses and transplants them into injured spinal cords via in- 218 Journal of the American Academy of Orthopaedic Surgeons

10 Ranjan Gupta, MD, et al jection. 61 More than 300 Chinese patients with SCI have received this treatment. However, the effectiveness of this treatment cannot be easily defined nor seriously considered. Published results in 171 patients described improved scores on the ASIA scale for motor recovery, light touch, and pinprick sensation ranging from 2 to 8 weeks after transplantation. 61 Although these results may seem to be promising, the study design did not meet the basic qualifications of a controlled clinical trial based on currently accepted international standards. Moreover, these trials can appeal to spinal cord injured patients with misleading marketing regarding the regaining of function. It is imperative that patients with SCI be educated about the high risks, marginal to no benefit, and tremendous financial costs of these interventions. Activated Autologous Macrophages Research has shown that, following a sciatic nerve lesion, peripheral macrophages synthesize nerve growth factor, a neurotrophic agent that promotes axonal regeneration. In addition, these activated macrophages phagocytose myelin, which contains numerous proteins known to inhibit neural regrowth. 62 Thus, macrophages hold the potential to promote neuroprotection and neuroregeneration within the environment of the injured spinal cord. Early preclinical research of activated autologous macrophages has demonstrated that the relative reluctance of the CNS to regenerate may be explained by insufficient recruitment of macrophages. 63 Moreover, sciatic nerve or skin-coincubated macrophages injected into the contused spinal cord of rats has resulted in enhanced synthesis of neuroprotective trophic factors interleukin (IL)-1β and BDNF as well as decreased synthesis of neurotoxic tumor necrosis factor (TNF)-α. 64 This resulted in significant recovery of motor function and reduction of spinal cystic cavitation. Use of activated autologous macrophages in the treatment of SCI in humans is being evaluated by clinical trials of ProCord (Proneuron Biotechnologies, New York, NY). 65 Pro- Cord is composed of macrophages isolated from the patient s own blood, activated through the company s proprietary process, and injected directly into the epicenter of the injured spinal cord. Initial outcomes from phase I of this clinical trial were promising, demonstrating functional improvement in spinal cord injured patients from ASIA grade A (complete functional loss) to grade C (recovery of clinically significant neurologic motor and sensory function) in three of the eight patients. 65 These encouraging results led to the international multicenter phase II ProCord trial for the treatment of complete SCI. However, financial constraints forced the permanent discontinuation of the trial. Stem Cell Therapy Stem cell based therapies have the potential to replace damaged or diseased cells, provide cell-based electrical relay between neurons above and below the injury, and ameliorate clinical deterioration and/or facilitate regeneration by providing neuroprotective or growth factors, as well as to play other indirect roles. 66 There are two broad categories of stem cells: embryonic stem cells (ESCs) and progenitor stem cells. ESCs show the greatest potential for the widest range of cell replacement therapies, largely because they are pluripotent, that is, they can differentiate into all types of cells. 67 By executive order, the Bush administration limited federal funding for research to preexisting human ESC lines created before August 9, Largely as a result of such federal restrictions on ESC use, research on progenitor cell lines grew significantly during the Bush administration. Neural stem cells (NSCs) are one type of progenitor stem cell with the potential to treat SCI. Endogenous NSCs exist within the CNS of higher order mammals and have recently been isolated from regions of the developing and adult brain, spinal cord, and optic nerve. NSCs are of particular interest to SCI repair because they are already committed to a neural fate. As noted by Enzmann et al, 67 approximately 35 to 40 reports have described NSC treatments of SCI, most of which used brainderived NSCs, and many of which showed that transplanted NSCs generate astrocytes and oligodendrocytes very effectively. These studies suggest that the SCI environment is conducive for NSC differentiation into glial cell lines but not for NSC differentiation into neuronal cell lines. Thus, proof at this time that endogenous NSC can replace lost neuronal cells after SCI is poor. Mesenchymal stem cells (MSCs) may be used as an alternative. MSCs are a group of progenitor cells that include multipotent bone marrow mononuclear cells and multipotent cells derived from umbilical cord blood. MSCs and bone marrow derived cells have many practical advantages: they are easily obtainable, autologous transplantation is possible, they may be immunoprivileged, and they have the ability to migrate to areas of damage and inflammation. 66 Although most studies report improved function as a result of MSC implantation, 69,70 decreased function has also been reported. 71 Despite the lack of a basic understanding of the underlying mechanism by which MSCs may improve functional outcomes following SCI, April 2010, Vol 18, No 4 219

11 Advances in the Management of Spinal Cord Injury clinical trials for SCI treatments with MSCs are beginning. 72 Although progenitor cells show significant promise in the management of SCI, they are limited in the number of cell types they can differentiate into, and they react to the host environment in a variable manner. In contrast, the pluripotent potential of ESCs allows them to differentiate into all cell types, thereby offering greater promise for neuroregeneration in SCI. On March 9, 2009, President Obama ended the restrictions on federal funding for ESC research, overturning the Bush administration policy. 73 This change will allow federally funded researchers to work with ESCs from several sources, explore new therapeutic strategies, and potentially offer cellbased treatments of several debilitating conditions, including SCI. Summary Despite the existence of numerous laboratory studies and clinical trials, no reliable effective treatment of SCI has yet been developed. Although advances in clinical management over the past 15 years have led to improvement in survival and longterm outcome of spinal cord injured patients, there is still no clinically relevant therapeutic intervention. The tremendous increase in the number of basic science and clinical investigations has resulted in the development of numerous techniques with the potential to become novel treatment strategies. In addition, advances in surgical management of acute SCI continue to affect the timing of decompression and methods of stabilization. It is hoped that results from ongoing clinical trials, such as STASCIS, 21 will create a more standardized surgical treatment algorithm for patients with acute SCI. A sense of urgency from the SCI community and patient advocacy groups continue to fuel research efforts and will likely expedite the initiation of clinical trials involving recent pharmacologic and cellular transplantation strategies. Although it is unlikely that any single intervention will result in a cure, combination therapies involving molecular and cellular advances will likely limit secondary injury, possibly resulting in some enhanced functional recovery following SCI. A multidisciplinary approach involving these new strategies will require the integral involvement of the treating orthopaedic surgeon. References Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, references 11-14, 17-20, and are level I studies. References 1, 8, 15, 16, 29, 31-34, 37, 39, 40, 65, and 72 are level II studies. References 2, 9, 21, 26-28, 30, 35, 36, 41, and 61 are level III studies. Reference 25 is a level IV study. The remaining references are review articles and level V expert opinion. Citation numbers printed in bold type indicate references published within the past 5 years. 1. National Spinal Cord Injury Statistical Center: Spinal Cord Injury Facts and Figures at a Glance. 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