Spinal Cord Injury: A Systematic Review of Current Treatment Options
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Spinal cord injury (SCI) is a devastating event often resulting in permanent neurologic deficit. Research has revealed an understanding of mechanisms that occur after the primary injury and contribute to functional loss. By targeting these secondary mechanisms of injury, clinicians may be able to offer improved recovery after SCI.
In this review, we highlight advances in the field of SCI by framing three questions: (1) What is the preclinical evidence for the neuroprotective agent riluzole that has allowed this agent to move into clinical trials? (2) What is the preclinical evidence for Rho antagonists that have allowed this group of compounds to move into clinical trials? (3) What is the evidence for early surgical decompression after SCI?
We conducted a systematic review of MEDLINE and EMBASE-cited articles related to SCI to address these questions.
As a result of an improved understanding of the secondary mechanisms of SCI, specific clinical strategies have been established. We highlight three strategies that have made their way from bench to bedside: the sodium-glutamate antagonist riluzole, the Rho inhibitor Cethrin, and early surgical decompression. Each of these modalities is under clinical investigation. We highlight the fundamental science that led to this development.
As our understanding of the fundamental mechanisms of SCI improves, we must keep abreast of these discoveries to translate them into therapies that will hopefully benefit patients. We summarize this process of bench to bedside with regard to SCI.
- Aki T, Toya S. Experimental study on changes of the spinal-evoked potential and circulatory dynamics following spinal cord compression and decompression. Spine. 1984;9:800–809. CrossRef
- Albin MS, White RJ. Epidemiology, physiopathology, and experimental therapeutics of acute spinal cord injury. Crit Care Clin. 1987;3:441–452.
- Ates O, Cayli SR, Gurses I, Turkoz Y, Tarim O, Cakir CO, Kocak A. Comparative neuroprotective effect of sodium channel blockers after experimental spinal cord injury. J Clin Neurosci. 2007;14:658–665. CrossRef
- Bohlman HH, Bahniuk E, Raskulinecz G, Field G. Mechanical factors affecting recovery from incomplete cervical spinal cord injury: a preliminary report. Johns Hopkins Med J. 1979;145:115–125.
- Botel U, Glaser E, Niedeggen A. The surgical treatment of acute spinal paralysed patients. Spinal Cord. 1997;35:420–428. CrossRef
- Brodkey JS, Richards DE, Blasingame JP, Nulsen FE. Reversible spinal cord trauma in cats. Additive effects of direct pressure and ischemia. J Neurosurg. 1972;37:591–593. CrossRef
- Campagnolo DI, Esquieres RE, Kopacz KJ. Effect of timing of stabilization on length of stay and medical complications following spinal cord injury. J Spinal Cord Med. 1997;20:331–334.
- Carlson GD, Gorden CD, Oliff HS, Pillai JJ, LaManna JC. Sustained spinal cord compression: part I: time-dependent effect on long-term pathophysiology. J Bone Joint Surg Am. 2003;85:86–94.
- Carlson GD, Minato Y, Okada A, Gorden CD, Warden KE, Barbeau JM, Biro CL, Bahnuik E, Bohlman HH, Lamanna JC. Early time-dependent decompression for spinal cord injury: vascular mechanisms of recovery. J Neurotrauma. 1997;14:951–962. CrossRef
- Carlson GD, Warden KE, Barbeau JM, Bahniuk E, Kutina-Nelson KL, Biro CL, Bohlman HH, LaManna JC. Viscoelastic relaxation and regional blood flow response to spinal cord compression and decompression. Spine. 1997;22:1285–1291. CrossRef
- Cengiz SL, Kalkan E, Bayir A, Ilik K, Basefer A. Timing of thoracolomber spine stabilization in trauma patients; impact on neurological outcome and clinical course. A real prospective (rct) randomized controlled study. Arch Orthop Trauma Surg. 2008;128:959–966. CrossRef
- Chan CC, Khodarahmi K, Liu J, Sutherland D, Oschipok LW, Steeves JD, Tetzlaff W. Dose-dependent beneficial and detrimental effects of ROCK inhibitor Y27632 on axonal sprouting and functional recovery after rat spinal cord injury. Exp Neurol. 2005;196:352–364. CrossRef
- Chen L, Yang H, Yang T, Xu Y, Bao Z, Tang T. Effectiveness of surgical treatment for traumatic central cord syndrome. J Neurosurg Spine. 2009;10:3–8. CrossRef
- Chipman JG, Deuser WE, Beilman GJ. Early surgery for thoracolumbar spine injuries decreases complications. J Trauma. 2004;56:52–57. CrossRef
- Clohisy JC, Akbarnia BA, Bucholz RD, Burkus JK, Backer RJ. Neurologic recovery associated with anterior decompression of spine fractures at the thoracolumbar junction (T12-L1). Spine. 1992;17:S325–330. CrossRef
- Croce MA, Bee TK, Pritchard E, Miller PR, Fabian TC. Does optimal timing for spine fracture fixation exist? Ann Surg. 2001;233:851–858. CrossRef
- Croft TJ, Brodkey JS, Nulsen FE. Reversible spinal cord trauma: a model for electrical monitoring of spinal cord function. J Neurosurg. 1972;36:402–406. CrossRef
- Delamarter RB, Sherman J, Carr JB. Pathophysiology of spinal cord injury. Recovery after immediate and delayed decompression. J Bone Joint Surg Am. 1995;77:1042–1049.
- Delamarter RB, Sherman JE, Carr JB. 1991 Volvo Award in experimental studies. Cauda equina syndrome: neurologic recovery following immediate, early, or late decompression. Spine. 1991;16:1022–1029. CrossRef
- Dergham P, Ellezam B, Essagian C, Avedissian H, Lubell WD, McKerracher L. Rho signaling pathway targeted to promote spinal cord repair. J Neurosci. 2002;22:6570–6577.
- Dimar JR 2nd, Glassman SD, Raque GH, Zhang YP, Shields CB. The influence of spinal canal narrowing and timing of decompression on neurologic recovery after spinal cord contusion in a rat model. Spine. 1999;24:1623–1633. CrossRef
- Dolan EJ, Tator CH, Endrenyi L. The value of decompression for acute experimental spinal cord compression injury. J Neurosurg. 1980;53:749–755. CrossRef
- Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52:377–384. CrossRef
- Dubreuil CI, Winton MJ, McKerracher L. Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system. J Cell Biol. 2003;162:233–243. CrossRef
- Duh MS, Shepard MJ, Wilberger JE, Bracken MB. The effectiveness of surgery on the treatment of acute spinal cord injury and its relation to pharmacological treatment. Neurosurgery. 1994;35:240–248; discussion 248–249. CrossRef
- Fournier AE, Takizawa BT, Strittmatter SM. Rho kinase inhibition enhances axonal regeneration in the injured CNS. J Neurosci. 2003;23:1416–1423.
- Guest J, Eleraky MA, Apostolides PJ, Dickman CA, Sonntag VK. Traumatic central cord syndrome: results of surgical management. J Neurosurg. 2002;97:25–32.
- Guha A, Tator CH, Endrenyi L, Piper I. Decompression of the spinal cord improves recovery after acute experimental spinal cord compression injury. Paraplegia. 1987;25:324–339.
- Harvey C, Wilson SE, Greene CG, Berkowitz M, Stripling TE. New estimates of the direct costs of traumatic spinal cord injuries: results of a nationwide survey. Paraplegia. 1992;30:834–850.
- Hejcl A, Urdzikova L, Sedy J, Lesny P, Pradny M, Michalek J, Burian M, Hajek M, Zamecnik J, Jendelova P, Sykova E. Acute and delayed implantation of positively charged 2-hydroxyethyl methacrylate scaffolds in spinal cord injury in the rat. J Neurosurg Spine. 2008;8:67–73. CrossRef
- Kakulas BA. Neuropathology: the foundation for new treatments in spinal cord injury. Spinal Cord. 2004;42:549–563. CrossRef
- Kerwin AJ, Frykberg ER, Schinco MA, Griffen MM, Murphy T, Tepas JJ. The effect of early spine fixation on non-neurologic outcome. J Trauma. 2005;58:15–21. CrossRef
- Kitzman PH. Effectiveness of riluzole in suppressing spasticity in the spinal cord injured rat. Neurosci Lett. 2009;455:150–153. CrossRef
- Kobrine AI, Evans DE, Rizzoli H. Correlation of spinal cord blood flow and function in experimental compression. Surg Neurol. 1978;10:54–59.
- Kobrine AI, Evans DE, Rizzoli HV. Experimental acute balloon compression of the spinal cord. Factors affecting disappearance and return of the spinal evoked response. J Neurosurg. 1979;51:841–845. CrossRef
- Krengel WF 3rd, Anderson PA, Henley MB. Early stabilization and decompression for incomplete paraplegia due to a thoracic-level spinal cord injury. Spine. 1993;18:2080–2087. CrossRef
- Levi L, Wolf A, Rigamonti D, Ragheb J, Mirvis S, Robinson WL. Anterior decompression in cervical spine trauma: does the timing of surgery affect the outcome? Neurosurgery. 1991;29:216–222. CrossRef
- Lord-Fontaine S, Yang F, Diep Q, Dergham P, Munzer S, Tremblay P, McKerracher L. Local inhibition of Rho signaling by cell-permeable recombinant protein BA-210 prevents secondary damage and promotes functional recovery following acute spinal cord injury. J Neurotrauma. 2008;25:1309–1322. CrossRef
- McAdoo DJ, Hughes MG, Nie L, Shah B, Clifton C, Fullwood S, Hulsebosch CE. The effect of glutamate receptor blockers on glutamate release following spinal cord injury. Lack of evidence for an ongoing feedback cascade of damage – > glutamate release – > damage – > glutamate release – > etc. Brain Res. 2005;1038:92–99.
- McKinley W, Meade MA, Kirshblum S, Barnard B. Outcomes of early surgical management versus late or no surgical intervention after acute spinal cord injury. Arch Phys Med Rehabil. 2004;85:1818–1825. CrossRef
- McLain RF, Benson DR. Urgent surgical stabilization of spinal fractures in polytrauma patients. Spine. 1999;24:1646–1654. CrossRef
- Mirza SK, Krengel WF 3rd, Chapman JR, Anderson PA, Bailey JC, Grady MS, Yuan HA. Early versus delayed surgery for acute cervical spinal cord injury. Clin Orthop Relat Res. 1999;104–114.
- Mu X, Azbill RD, Springer JE. Riluzole and methylprednisolone combined treatment improves functional recovery in traumatic spinal cord injury. J Neurotrauma. 2000;17:773–780. CrossRef
- Mu X, Azbill RD, Springer JE. Riluzole improves measures of oxidative stress following traumatic spinal cord injury. Brain Res. 2000;870:66–72. CrossRef
- Ng WP, Fehlings MG, Cuddy B, Dickman C, Fazl M, Green B, Hitchon P, Northrup B, Sonntag V, Wagner F, Tator CH. Surgical treatment for acute spinal cord injury study pilot study #2: evaluation of protocol for decompressive surgery within 8 hours of injury. Neurosurg Focus. 1999;6:e3. CrossRef
- Nishio Y, Koda M, Kitajo K, Seto M, Hata K, Taniguchi J, Moriya H, Fujitani M, Kubo T, Yamashita T. Delayed treatment with Rho-kinase inhibitor does not enhance axonal regeneration or functional recovery after spinal cord injury in rats. Exp Neurol. 2006;200:392–397. CrossRef
- Nystrom B, Berglund JE. Spinal cord restitution following compression injuries in rats. Acta Neurol Scand. 1988;78:467–472. CrossRef
- Papadopoulos SM, Selden NR, Quint DJ, Patel N, Gillespie B, Grube S. Immediate spinal cord decompression for cervical spinal cord injury: feasibility and outcome. J Trauma. 2002;52:323–332. CrossRef
- Pollard ME, Apple DF. Factors associated with improved neurologic outcomes in patients with incomplete tetraplegia. Spine. 2003;28:33–39. CrossRef
- Rabinowitz RS, Eck JC, Harper CM Jr, Larson DR, Jimenez MA, Parisi JE, Friedman JA, Yaszemski MJ, Currier BL. Urgent surgical decompression compared to methylprednisolone for the treatment of acute spinal cord injury: a randomized prospective study in beagle dogs. Spine (Phila Pa 1976). 2008;33:2260–2268.
- Sapkas GS, Papadakis SA. Neurological outcome following early versus delayed lower cervical spine surgery. J Orthop Surg (Hong Kong). 2007;15:183–186.
- Schinkel C, Frangen TM, Kmetic A, Andress HJ, Muhr G. Timing of thoracic spine stabilization in trauma patients: impact on clinical course and outcome. J Trauma. 2006;61:156–160; discussion 160.
- Schwartz G, Fehlings MG. Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzole. J Neurosurg. 2001;94:245–256.
- Sekhon LH, Fehlings MG. Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine (Phila Pa 1976). 2001;26:S2–12.
- Springer JE, Azbill RD, Kennedy SE, George J, Geddes JW. Rapid calpain I activation and cytoskeletal protein degradation following traumatic spinal cord injury: attenuation with riluzole pretreatment. J Neurochem. 1997;69:1592–1600. CrossRef
- Stutzmann JM, Pratt J, Boraud T, Gross C. The effect of riluzole on post-traumatic spinal cord injury in the rat. Neuroreport. 1996;7:387–392. CrossRef
- Sung JK, Miao L, Calvert JW, Huang L, Louis Harkey H, Zhang JH. A possible role of RhoA/Rho-kinase in experimental spinal cord injury in rat. Brain Res. 2003;959:29–38. CrossRef
- Tanaka H, Yamashita T, Yachi K, Fujiwara T, Yoshikawa H, Tohyama M. Cytoplasmic p21(Cip1/WAF1) enhances axonal regeneration and functional recovery after spinal cord injury in rats. Neuroscience. 2004;127:155–164. CrossRef
- Tator CH, Fehlings MG, Thorpe K, Taylor W. Current use and timing of spinal surgery for management of acute spinal surgery for management of acute spinal cord injury in North America: results of a retrospective multicenter study. J Neurosurg. 1999;91:12–18.
- Tator CH, Koyanagi I. Vascular mechanisms in the pathophysiology of human spinal cord injury. J Neurosurg. 1997;86:483–492. CrossRef
- Thienprasit P, Bantli H, Bloedel JR, Chou SN. Effect of delayed local cooling on experimental spinal cord injury. J Neurosurg. 1975;42:150–154. CrossRef
- Vaccaro AR, Daugherty RJ, Sheehan TP, Dante SJ, Cotler JM, Balderston RA, Herbison GJ, Northrup BE. Neurologic outcome of early versus late surgery for cervical spinal cord injury. Spine. 1997;22:2609–2613. CrossRef
- Yamagishi S, Fujitani M, Hata K, Kitajo K, Mimura F, Abe H, Yamashita T. Wallerian degeneration involves Rho/Rho-kinase signaling. J Biol Chem. 2005;280:20384–20388. CrossRef
- Zhang Y, Hillered L, Olsson Y, Holtz A. Time course of energy perturbation after compression trauma to the spinal cord: an experimental study in the rat using microdialysis. Surg Neurol. 1993;39:297–304. CrossRef
- Spinal Cord Injury: A Systematic Review of Current Treatment Options
Clinical Orthopaedics and Related Research®
Volume 469, Issue 3 , pp 732-741
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- 1. Division of Neurosurgery, University of Toronto, Toronto, ON, Canada
- 2. Neural Repair and Regeneration, Spinal Program, University Health Network, Toronto Western Hospital, McLaughlin Pavilion, 12th Floor, Room 407, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada