Skip to main content

Advertisement

Log in

Spinal Cord Injury: A Systematic Review of Current Treatment Options

  • Symposium: Current Concepts in Cervical Spine Surgery
  • Published:
Clinical Orthopaedics and Related Research®

Abstract

Background

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.

Questions/purposes

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?

Methods

We conducted a systematic review of MEDLINE and EMBASE-cited articles related to SCI to address these questions.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. 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.

    Article  CAS  PubMed  Google Scholar 

  2. Albin MS, White RJ. Epidemiology, physiopathology, and experimental therapeutics of acute spinal cord injury. Crit Care Clin. 1987;3:441–452.

    CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    CAS  PubMed  Google Scholar 

  5. Botel U, Glaser E, Niedeggen A. The surgical treatment of acute spinal paralysed patients. Spinal Cord. 1997;35:420–428.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    CAS  PubMed  Google Scholar 

  8. 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.

    PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  PubMed  Google Scholar 

  14. Chipman JG, Deuser WE, Beilman GJ. Early surgery for thoracolumbar spine injuries decreases complications. J Trauma. 2004;56:52–57.

    Article  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. Croce MA, Bee TK, Pritchard E, Miller PR, Fabian TC. Does optimal timing for spine fracture fixation exist? Ann Surg. 2001;233:851–858.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    CAS  PubMed  Google Scholar 

  21. 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.

    Article  PubMed  Google Scholar 

  22. Dolan EJ, Tator CH, Endrenyi L. The value of decompression for acute experimental spinal cord compression injury. J Neurosurg. 1980;53:749–755.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. Fournier AE, Takizawa BT, Strittmatter SM. Rho kinase inhibition enhances axonal regeneration in the injured CNS. J Neurosci. 2003;23:1416–1423.

    CAS  PubMed  Google Scholar 

  27. Guest J, Eleraky MA, Apostolides PJ, Dickman CA, Sonntag VK. Traumatic central cord syndrome: results of surgical management. J Neurosurg. 2002;97:25–32.

    PubMed  Google Scholar 

  28. 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.

    CAS  PubMed  Google Scholar 

  29. 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.

    CAS  PubMed  Google Scholar 

  30. 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.

    Article  PubMed  Google Scholar 

  31. Kakulas BA. Neuropathology: the foundation for new treatments in spinal cord injury. Spinal Cord. 2004;42:549–563.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  PubMed  Google Scholar 

  33. Kitzman PH. Effectiveness of riluzole in suppressing spasticity in the spinal cord injured rat. Neurosci Lett. 2009;455:150–153.

    Article  CAS  PubMed  Google Scholar 

  34. Kobrine AI, Evans DE, Rizzoli H. Correlation of spinal cord blood flow and function in experimental compression. Surg Neurol. 1978;10:54–59.

    CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    Article  PubMed  Google Scholar 

  39. 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.

    Google Scholar 

  40. 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.

    Article  PubMed  Google Scholar 

  41. McLain RF, Benson DR. Urgent surgical stabilization of spinal fractures in polytrauma patients. Spine. 1999;24:1646–1654.

    Article  CAS  PubMed  Google Scholar 

  42. 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.

  43. 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.

    Article  CAS  PubMed  Google Scholar 

  44. Mu X, Azbill RD, Springer JE. Riluzole improves measures of oxidative stress following traumatic spinal cord injury. Brain Res. 2000;870:66–72.

    Article  CAS  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  Google Scholar 

  46. 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.

    Article  CAS  PubMed  Google Scholar 

  47. Nystrom B, Berglund JE. Spinal cord restitution following compression injuries in rats. Acta Neurol Scand. 1988;78:467–472.

    Article  CAS  PubMed  Google Scholar 

  48. 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.

    Article  PubMed  Google Scholar 

  49. Pollard ME, Apple DF. Factors associated with improved neurologic outcomes in patients with incomplete tetraplegia. Spine. 2003;28:33–39.

    Article  PubMed  Google Scholar 

  50. 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.

    Google Scholar 

  51. Sapkas GS, Papadakis SA. Neurological outcome following early versus delayed lower cervical spine surgery. J Orthop Surg (Hong Kong). 2007;15:183–186.

    CAS  Google Scholar 

  52. 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.

    Google Scholar 

  53. 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.

    CAS  PubMed  Google Scholar 

  54. Sekhon LH, Fehlings MG. Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine (Phila Pa 1976). 2001;26:S2–12.

    Google Scholar 

  55. 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.

    Article  CAS  PubMed  Google Scholar 

  56. 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.

    Article  CAS  PubMed  Google Scholar 

  57. 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.

    Article  CAS  PubMed  Google Scholar 

  58. 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.

    Article  CAS  PubMed  Google Scholar 

  59. 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.

    CAS  PubMed  Google Scholar 

  60. Tator CH, Koyanagi I. Vascular mechanisms in the pathophysiology of human spinal cord injury. J Neurosurg. 1997;86:483–492.

    Article  CAS  PubMed  Google Scholar 

  61. Thienprasit P, Bantli H, Bloedel JR, Chou SN. Effect of delayed local cooling on experimental spinal cord injury. J Neurosurg. 1975;42:150–154.

    Article  CAS  PubMed  Google Scholar 

  62. 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.

    Article  CAS  PubMed  Google Scholar 

  63. 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.

    Article  CAS  PubMed  Google Scholar 

  64. 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.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael G. Fehlings MD, PhD, FRCSC, FACS.

Additional information

One of the authors (MGF) is the principal investigator on clinical trials investigating the use of riluzole and Cethrin in spinal cord injury, which are funded by the Christopher and Dana Reeve Paralysis Foundation and Alseres Pharmaceuticals, respectively; and is also Principal Investigator on the STASCIS trial, which is supported by the Spine Trauma Study Group through grants from Medtronic.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 26 kb)

Supplementary material 2 (DOCX 47 kb)

About this article

Cite this article

Cadotte, D.W., Fehlings, M.G. Spinal Cord Injury: A Systematic Review of Current Treatment Options. Clin Orthop Relat Res 469, 732–741 (2011). https://doi.org/10.1007/s11999-010-1674-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11999-010-1674-0

Keywords

Navigation