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Advances in the Management ofSpinal Cord Injury

Abstract

Historically, clinical outcomes following spinal cord injury have beendismal. Over the past 20 years, the survival rate and long-termoutcome of patients with spinal cord injury have improved withadvances in both medical and surgical treatment. However, theefficacy and timing of these adjuvant treatments remaincontroversial. There has been a tremendous increase in thenumber 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 newpharmacotherapy and cellular transplantation strategies. It isunlikely that a single approach can uniformly address all of theissues associated with spinal cord injury. Thus, a multidisciplinaryapproach will be needed.

Every year, an estimated 12,000Americans sustain and survive a

spinal cord injury (SCI).1 Approxi-mately 259,000 Americans currentlylive with an SCI.1 SCI was tradition-ally thought of as a condition affect-ing primarily young males, but theage of spinal cord–injured patients isincreasing,2 with an average ageof 40.2 years.1 Of the injuries re-ported since the year 2005, mosthave occurred in males and Cauca-sians (80.9% and 66.1%, respec-tively).1 SCIs can occur in severalways, but motor vehicle crashesare the most common cause.1 Incom-plete quadriplegia is the most fre-quent neurologic category of SCI(30.1%), followed by complete para-plegia (25.6%), complete quadriple-gia (20.4%), and incomplete para-plegia (18.5%).1

In the 1990s, the refinement of spi-nal stabilization led to changes in themanagement of acute spinal trauma.Research efforts in the search for apharmacologic intervention to limit sec-

ondary injury are ongoing. Results fromthe National Acute Spinal Cord InjuryStudy (NASCIS) trials were initiallyviewed as promising, and the adminis-tration of methylprednisolone sodiumsuccinate (MPSS) was often considereda standard of care in the acute SCI set-ting. However, more recent studies havebeen highly critical of the interpretationof these trials, particularly the statisti-cal analysis.3 Although analysis ofNASCIS II revealed that the small sam-ple of patients treated with MPSSwithin the first 8 hours of injury showedsignificantly improved motor and sen-sory function,4 clinical improvementsremain modest, and the efficacy ofthe drug is controversial.

Patients with SCI face significantneurologic dysfunction and disabil-ity. In the past few years, several po-tential advancements, including stemcell transplantation, have come tothe forefront of SCI research. Wesummarize the pathophysiology andacute management of SCI as well asrecent advances in acute therapy that

Ranjan Gupta, MD

Mary E. Bathen, BS

Jeremy S. Smith, MD

Allan D. Levi, MD, PhD, FACS

Nitin N. Bhatia, MD

Oswald Steward, PhD

From the Department ofOrthopaedic Surgery, University ofCalifornia, Irvine, Irvine, CA(Dr. Gupta, Dr. Smith, Dr. Bhatia,and Dr. Steward), the University ofCalifornia, San Diego School ofMedicine, San Diego, CA(Ms. Bathen), and the Department ofNeurological Surgery, University ofMiami School of Medicine, Miami,FL (Dr. Levi).

J Am Acad Orthop Surg 2010;18:210-222

Copyright 2010 by the AmericanAcademy of Orthopaedic Surgeons.

Review Article

210 Journal of the American Academy of Orthopaedic Surgeons

are important to the treating ortho-paedic surgeon and neurosurgeon.

Pathophysiology

The neurologic deficits related to SCIdevelop as a result of primary andsecondary injury processes.5 As theinjury cascade continues, the like-lihood of functional recovery de-clines. Thus, therapeutic interventionshould not be delayed; in most cases,the window for therapeutic interven-tion is believed to be 6 to 24 hourspostinjury. The primary mechanismsare those resulting from the initialinjury and include energy transferto the spinal cord, spinal cord de-formation, and persistent postinjurycord compression. These mecha-nisms, which occur within seconds tominutes after injury, lead to immedi-ate cell death, axonal disruption, andvascular and metabolic changes,which have ongoing effects.

The secondary injury process,which begins within minutes of in-jury and lasts for weeks to months,involves a complex cascade of bio-chemical interactions, cellular reac-tions, and fiber tract disturbances, allof which are only partially under-stood. It is clear, however, that in-creased production of free radicalsand endogenous opioids, excessiverelease of excitatory neurotransmit-ters, and inflammatory reactions allplay a significant role. Furthermore,mRNA profiles have identified nu-merous gene expression changes af-ter SCI, and these changes are beingpinpointed as possible therapeutictargets.6

Several theories have been proposedto explain the pathophysiology of sec-ondary injury.4 The free-radical the-ory maintains that, because of rapiddepletion of antioxidants, oxygenfree radicals accumulate in injuredcentral nervous system (CNS) tissueand attack membrane lipids, pro-teins, and nucleic acids. This resultsin the production of lipid peroxides,which cause failure of cell mem-branes. The calcium theory suggeststhat the propagation of secondary in-jury relies on the influx of extracellu-lar calcium ions into nerve cells. Cal-cium ions activate phospholipases,proteases, and phosphatases—the ac-tivation of which results in the inter-ruption of mitochondrial activityand disruption of the cell membrane.The opiate receptor theory proposesthat endogenous opioids may be in-volved in the propagation of SCI andthat opiate antagonists (eg, nalox-one) may improve neurologic recov-ery. The inflammatory theory isbased on the hypothesis that inflam-matory substances (ie, prostaglan-dins, leukotrienes, platelet-activatingfactor, serotonin) accumulate inacutely injured spinal cord tissue andare mediators of secondary tissuedamage.4 Since the 1990s, extraordi-nary scientific advances have beenmade in understanding the immunesystem and its interactions with thenervous system.4

Following SCI, the primary modes ofcell death are necrosis and apoptosis.Although the predominant mode of celldeath immediately following the pri-mary injury is necrosis, apoptotic pro-grammed cell death has significant ef-

fects on the subacute secondary injury.Apoptosis-induced oligodendrocyte celldeath results in demyelination and ax-onal degeneration at and adjacent to theinjury site. It has also been implicatedin the initiation of wallerian degener-ation in both ascending and descend-ing white matter tracts surrounding theinjury. The mechanisms and signalingcascades involved in SCI-induced ap-optosis continue to be defined and of-fer potential points of intervention fornovel treatment methods to delay andprevent secondary injury.

The secondary injury process cul-minates with the formation of theglial scar, which is arguably the cen-tral barrier to axonal regenerationwithin the CNS. Glial scar formationis a reactive process involving an in-crease in the number of astrocytes(ie, astrogliosis).7 Following necrosisof central cord gray matter and cys-tic degeneration, scar tissue developsand extends into the axonal longtracts. The pattern of scar formationand inflammatory cell infiltration isinfluenced by the type of spinal cordlesion and may have an impact onthe potential for overcoming thisneuroregenerative barrier (Figure 1).There are three types of lesion: mi-crolesion, contusive, and large stab.

In the microlesion, the blood-brainbarrier is minimally disrupted, astro-cytes maintain normal alignment butproduce chondroitin sulfate proteogly-cans (CSPGs) and keratan sulfate pro-teoglycans (KSPGs) along the injurytract, and macrophages invade the le-sion site. Axons are unable to regener-ate beyond the lesion. In the contusivelesion, 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 apaid consultant to or is an employee of Alphatec Spine, Biomet, and Seaspine; and has received research or institutional supportfrom Alphatec Spine, Biomet, Arthrex, NIH (NIAMS and NICHD), and Spinewave. Dr. Steward or an immediate family member hasreceived research or institutional support from NIH-NINDS. None of the following authors or any immediate family member hasreceived anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject ofthis article: Ms. Bathen, Dr. Smith, and Dr. Levi.

Ranjan Gupta, MD, et al

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rupted, but the meninges remain intact.Cavitation occurs at the epicenter of thelesion. Astrocyte alignment is altered atthe lesion site. Astrocytes produceCSPGs and KSPGs in a gradient in-creasing from the penumbra toward thecenter of the lesion. There is no fibro-blast invasion of the lesion core, and,thus, no fibroblast-expressed inhibitors

are present. Macrophages invade the le-sion and its core, and dystrophic axonsapproach the lesion before growthceases. In the large stab lesion, theblood-brain barrier is disrupted, andcavitation occurs at the lesion center.Astrocyte alignment is altered at the le-sion site, and astrocytes produce CSPGsand KSPGs in a gradient increasing to-

ward the lesion. Transforming growthfactor, ephrin-B2, and Slit protein ex-pression increases in reactive astrocytesadjacent to the fibroblasts. Fibroblastsinvade the lesion and express class 3semaphorin and the ephrin-B2 recep-tor. Macrophages invade the lesion andrelease inflammatory cytokines. Dystro-phic neurons are highly repelled by the

Schematic representations of three stereotypical lesions of the central nervous system: microlesion (A), contusivelesion (B), and large stab lesion (C). In all types, macrophages invade the lesion, and both chondroitin sulfateproteoglycans (CSPGs) and keratan sulfate proteoglycans (KSPGs) are upregulated. A, Astrocyte alignment is notaltered by the injury process, but axons are unable to regenerate past the lesion site. B, The meninges are notdisrupted, but cavitation at the epicenter of the lesion and proteoglycan deposition are produced. Axons are unable toregenerate beyond the lesion, but spared axons can be found distal to the injury site. C, Stab lesion that penetratesthe meninges and allows fibroblast and macrophage invasion. Axons are highly repulsed by the increasing gradient ofCSPGs and KSPGs. Several other inhibitory molecules are also made in this type of injury and are especiallyprevalent 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;5:146-156.)

Figure 1

Advances in the Management of Spinal Cord Injury


lesion core and express neutrophil 1.The glial scar has important nega-

tive consequences to neuroregenera-tion, as many cells within the scar se-crete neurodevelopmental inhibitormolecules. As such, methods to limitscar formation following SCI mayprove useful in improving function.

Acute Management

The acute management of SCI requiresa multidisciplinary and multisystem ap-proach. Appropriate treatment beginsin the field, with immobilization of thespine by emergency response personnel.Spinal precautions, including externalimmobilization and log rolling, are thenused to prevent further SCI, especiallyin the unstable spine. The initial hos-pital evaluation of the spinal cord–in-jured patient should include diagnosisand treatment of the spinal pathologyas well as any other acute or life-threatening injury.

Medical management is of utmostimportance during the acute postin-jury period. Traumatic injury de-creases the ability of the spinal cordto autoregulate local blood flow,which leaves the spinal cord vulnera-ble to systemic changes in bloodflow. Few management techniqueshave been directly studied prospec-tively in the spinal cord–injured pa-tient; however, inferences from nu-merous studies of human traumaticbrain injury (TBI) have been shownto be valid. Hypotension (systolicblood pressure <90 mm Hg) and hy-poxia (Pao2 ≤60 mm Hg) have beenshown to be independently associ-ated with significantly increasedmorbidity and mortality followingTBI.8 Thus, maintenance of systemicblood flow and oxygenation is cen-tral to the acute medical manage-ment of the spinal cord–injured pa-tient. Strategies include bloodpressure support, avoidance of acuteanemia, and ventilatory support.

Several SCI case series have con-firmed that maintenance of systemicmean arterial pressure >90 mm Hgcan improve neurologic outcomes,and that diagnostic and treatment in-terventions used to accomplish thisgoal are safe.9 Invasive hemodynamicmonitoring of the patient in an inten-sive care unit is recommended in theacute postinjury period.

It can be challenging to maintain nor-mal blood pressure in spinal cord–in-jured patients. These patients frequentlyhave multiple injuries, and hypotension,hypoxemia, and anemia can be inducedby varied and numerous causes. Hy-potension in the multisystem traumapatient is frequently caused by hypo-volemia resulting from hemorrhage ordehydration. Although these causes ofhypotension should be pursued, de-creased blood pressure in the spinalcord–injured patient may occur evenwith normal blood volume because ofdecreased sympathetic outflow. Thisform of hypotension is known as neu-rogenic shock. Neurogenic shock canbe distinguished from hypovolemic hy-potension by the lack of appropriatecardiac response to the decreased bloodpressure and resultant relative brady-cardia. No one algorithm for mainte-nance of blood pressure is widely ac-cepted, but several aspects of treatmentare generally agreed on, including in-vasive blood pressure monitoring withSwan-Ganz catheters or arterial lines;the use of crystalloid, colloid, or bloodto optimize fluid volume; and the useof vasopressors in patients with optimalvolume status but with ongoing neuro-genic hypotension. Based on the TBIstudies, blood pressure monitoring andsupport is generally continued for 7days postinjury,8 although studies inspinal cord–injured patients have notconfirmed this length of time.

The timing of decompression remainscontroversial, even though the issue hasbeen explored in several experimentaland clinical studies. Although there isno level I evidence to support early sur-

gery, most physicians would agree thatemergent surgical decompression isindicated in patients with acute andprogressive neurologic deficit in thepresence of persistent spinal cord com-pression (Figure 2). Similarly, althoughthere is little support in the literature,there is growing enthusiasm regardingemergent decompression, even in pa-tients who present with neurologicallycomplete injuries10 (Table 1). TheSurgical Treatment of Acute SpinalCord Injury Study (STASCIS) is cur-rently underway.21 It is being done inan effort to apply quality, evidence-based scientific method to the debateregarding surgical timing.

On September 9, 2007, Kevin Ever-ett, a tight end in the National FootballLeague, sustained an American SpinalInjury Association (ASIA) grade B cer-vical SCI resulting from a C3-C4fracture-dislocation.22,23 Shortly after theinjury, an attempt at systemic hypo-thermia was initiated. Although Ever-ett received 2 L of iced saline in the am-bulance, he was normothermic onadmission to the hospital (37.2°C).Subsequently, Everett underwent de-compression and stabilization of his sur-gical fracture-dislocation.22,23 Hypo-thermia was also induced via anindwelling vascular catheter duringhospitalization. When Everett beganto show early signs of recovery withvoluntary movement just 2 days afterinjury, there was a resurgence of in-terest in the neuroprotective effectsof hypothermia. Research into thetherapeutic potential of hypothermiaemerged in the 1950s, but enthu-siasm dwindled because adversecomplications (eg, atelectasis, pneu-monia, acute respiratory distress syn-drome) could not be overcome.22,23

Hypothermia is a condition in whichan organism’s temperature drops belowthat required for normal metabolism.From a neuroprotective standpoint, hy-pothermia reduces swelling and hem-orrhage, potentially slowing the second-ary injury cascade.22,23 Although


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some recent basic science studieshave demonstrated the benefit ofmodest hypothermia following SCI,24

the evidence to date is not compel-ling. Moreover, higher quality clini-cal trials do not exist. One recentstudy assessed hypothermia treat-ment of acute SCI with intravascularcooling techniques in a series of 14patients.25 Although this study mayprovide baseline data, larger multi-center, randomized studies are re-quired before this modality gainswidespread acceptance. Hypother-mia remains an experimental ther-apy.

PharmacologicInterventions

Optimal medical management ofacute SCI remains the subject ofmuch debate and controversy. Medi-cal therapy is done with the goal ofminimizing damage caused by theprimary and secondary mediators of

SCI. US FDA approval requires suc-cessful clinical trials (Tables 2 and3), which often depend on successfulanimal studies. Many clinical trialshave been completed, and severalmore are in the initial trial stages.Numerous therapies are currently be-ing tested in animal models. Becauseof the multidimensional nature ofthe pathophysiology of SCI, effectivetherapies will certainly require com-bined approaches.

Methylprednisolone SodiumSuccinateMPSS is a glucocorticoid that hasbeen shown to reduce the neurotox-icity of excitatory amino acid, inhibitlipid peroxidation, increase bloodperfusion in the spinal tissue, andslow traumatic ion shifts. In thisway, MPSS has the potential to in-hibit inflammatory damage to thespinal cord.

The effectiveness of MPSS in acuteSCI has been tested in three indepen-

dent trials (NASCIS).11-13,42-45 Pub-lished in 1984, the NASCIS I trialcompared high- versus low-doseMPSS treatment.11,42 Patients who re-ceived high doses of MPSS werefound to have statistically significantincreases in wound infection rates(relative risk, 3.55; 95% CI, 1.20-10.59) as well as a higher incidenceof sepsis, gastrointestinal hemor-rhage, pulmonary embolism, anddeath.11 No significant neuroprotec-tive benefit was found with eithertreatment.11,42

The NASCIS II trial was subse-quently designed to compare high-dose MPSS (administered <24 h)with placebo and naloxone.12,43 Nosignificant neurologic benefit wasfound with MPSS. However, posthoc analysis revealed neuroprotec-tive potential when MPSS was re-ceived within 8 hours of injury.There were increases in the rate ofwound complications and pulmo-nary embolism in this trial, as well.

Images of a 15-year-old girl who was struck by a motor vehicle. She sustained a C4 teardrop fracture with resultantspinal cord injury—clinically complete C4 American Spinal Injury Association (ASIA) grade A. A, Sagittal T2-weightedmagnetic resonance image demonstrating spinal cord edema and swelling with some ventral spinal cord compressionfrom the kyphosis and retropulsed bone fragments. B, Lateral radiograph demonstrating improved alignment and someimmediate decompression of the spinal canal following the use of cervical traction. C, Postoperative lateral radiographdemonstrating repair of the fracture via C4 corpectomy and fibular allograft reconstruction with an anterior platespanning C3 to C5 and supplemented by a posterior lateral mass rod-and-screw reconstruction.

Figure 2



The NASCIS III trial was designedto determine the beneficial effects ofMPSS when administered <8 hoursafter acute SCI.13,44 The study comparedinfusion for 24 hours versus 48 hoursafter injury. In addition, functional re-covery was included for the first timeas an outcome measure. As with theNASCIS II trial, no significant im-provement in neurologic recovery wasnoted. Post hoc analysis found im-proved functional recovery at 6 weeksand 6 months following injury in pa-tients in whom treatment was initiated

3 to 8 hours after SCI when the dosewas continued for 48 hours. Significantrates of sepsis, pneumonia, and deathwere also noted in the group receiv-ing the 48-hour dose. As a result ofthese trials, a 24-hour dose was recom-mended when administered within3 hours of injury, and a 48-hour dosewas recommended when adminis-tered between 3 and 8 hours after in-jury.

Intense controversy persists sur-rounding the efficacy of MPSS in pa-tients with acute SCI. Scrutiny of the

design of the NASCIS trials andanalysis of data have raised seriousquestions about the neuroprotectivepotential of MPSS and have raisedconcerns about the possibility of ad-verse side effects following its admin-istration. Because of an increasedcomplication rate with steroid treat-ment and the lack of evidence cor-roborating the NASCIS results, treat-ment with MPSS has become largelya clinical decision to be made by thetreating physician based on each in-dividual case. Many physicians con-

Table 1

Completed Prospective Randomized Controlled Trials of Pharmacologic Approaches to the Management ofAcute Spinal Cord Injury

Trial Treatment Arms Conclusions

MPSSNASCIS I11 MPSS (100 mg for 10 d), MPSS (1,000

mg for 10 d)No difference

NASCIS II12 MPSS,a naloxone,b placebo Significantly improved neurologic recovery withearly (<8 h of SCI) MPSS treatment (P = 0.03)

Japan MPSS16 MPSS,a MPSS (100 mg for 7 d) Improved neurologic and sensory recovery withearly treatment (<8 h of SCI)

NASCIS III13 MPSS,a MPSS,c MPSS (30 mg/kg bolus+ TMd)

Improved neurologic recovery with MPSStreatment

GM1 gangliosideMaryland GM1

14 GM1e vs placebo Improved neurologic recovery with GM1 treatment

Sygen GM1 (Fidia Pharmaceutical,Washington, DC)17

MPSSa + low-dose GM1,f MPSSa + high-dose GM1,g MPSSa + placebo

Negative primary outcomes, trend for enhancedsecondary outcomes

TRH15 TRHh vs placebo Improved neurologic recovery with TRHtreatment

Calcium channel blocker (nimodipine)Petitjean et al18 MPSS,a nimodipine,i nimodipine +

MPSS,a placeboNo difference. Study likely was too underpow-

ered to detect a difference.Pointillart et al19 MPSS,a nimodipine, nimodipine +

MPSS,a placeboNo difference. Increased infection in MPSS

groups.Gacyclidine (GK-11)20 Gacyclidine (0.005, 0.01, or 0.02 mg/kg;

two doses) vs placeboTrend for increased motor recovery in cervical

incomplete SCI patient strata

a MPSS, MPSS 30 mg/kg bolus + 5.4 mg/kg/h over 24 hb 5.4 mg/kg bolus + 4.0 mg/kg/h over 24 hc MPSS, MPSS 30 mg/kg bolus + 5.4 mg/kg/h for 48 hd 2.5 mg/kg bolus every 6 h over 48 he 100 mg/d for 18-32 df 300 mg loading dose followed by 100 mg/d for 56 dg 600 mg loading dose followed by 200 mg/d for 56 dh 0.2 mg/kg bolus + 0.2 mg/kg/h infusion over 6 hi 0.015 mg/kg/h over 2 h followed by 0.03 mg/kg/h for 7 dGM1 = monosialotetrahexosylganglioside (100 mg/d for 18-32 d), MPSS = methylprednisolone sodium succinate, NASCIS = National AcuteSpinal Cord Injury Study, SCI = spinal cord injury, TM = tirilazad mesylate, TRH = thyrotropin-releasing hormoneAdapted with permission from Baptiste DC, Fehlings MG: Pharmacological approaches to repair the injured spinal cord. J Neurotrauma2006;23:318-334.


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tinue to administer MPSS in thesetting of acute SCI, although the ra-tionale for its use appears to havechanged. A survey published in 2006concluded that prescribing physi-cians indicate a fear of litigationrather than clinical efficacy as theprimary motivating factor for admin-istering the drug.46

Opiate BlockersRelease of opioid peptides, which arenatural pain relievers, increases in re-sponse to traumatic SCI. Althoughpain relief is necessary, evidence ex-ists that opioid peptides (eg, dynor-phin A) can induce edema, hyper-algesia, and allodynia and mayindirectly contribute to neurodegen-eration.47 In addition, sustained ex-posure to a high level of opioids isneurotoxic.47 Naloxone, a nonselec-tive opioid receptor antagonist, hasbeen shown to improve spinal cord

conduction and reduce allodynia andedema.12 However, naloxone failedto provide therapeutic effects whenadministered for the NASCIS II tri-al.12 It remains unclear whethernaloxone could be an effective treat-ment option with refinement in dos-age in timing.

GM1 GangliosideGM1 ganglioside has shown modestbut significant potential in the man-agement of SCI. These sialic acid–containing glycosphingolipids arefound in great concentrations in theouter membranes of nervous tissue.GM1 is potentially a better optionthan MPSS because it has beenshown to have no effect on gray mat-ter at the level of trauma and has alonger therapeutic window.14 In an ini-tial prospective randomized study of 37patients, GM1 showed a statistically sig-nificant improvement in ASIA motor

scores up to 48 hours after injury (P =0.047).14 This prompted the SygenMulti-Center Acute Spinal CordStudy, the largest prospective ran-domized clinical trial in acute SCI todate.17 In this study of more than750 patients over 5 years, GM1 gan-glioside failed to show significant im-provement in motor recovery usingthe modified Benzel walking scale,although a trend of improved boweland bladder function and sacral sen-sation and a more rapid return ofneurologic function were observed.The study has since been criticizedfor having unrealistic primary out-come measures (ie, a two point im-provement in the Benzel walkingscale) considering the large numberof complete (ASIA grade A) patientsenrolled. GM1 has not been approvedfor general use in the setting of acuteSCI, and no clinical trials are cur-rently underway.48

Table 2

Clinical Studies That Oppose Early Surgical Decompression

Study No. of Patients (level) Study Design Conclusions

Aito et al26 82 patients with traumatic cen-tral cord syndrome: 45%treated surgically, 55%treated conservatively

Retrospective case series No difference in outcome was found as aresult of spine surgery

Pollard andApple30

412 (cervical) incompleteinjuries

Retrospective case series Baseline neurologic assessment not availablein 51% of cases. Early surgery (<24 h) notassociated with improved recovery.

McKinley et al27 779 (all): 603 decompressed,176 nonsurgical

Retrospective case series No significant differences in neurologic recov-ery between early surgery (<24 h), late sur-gery (>72 h), and nonsurgical management

Vaccaro et al31 62 (cervical): early 34, late 28 Prospective, randomized No difference in neurologic recovery or lengthof hospital stay between early (<72 h) andlate (>5 d) surgery groups

Bötel et al28 255 (all): 178 decompressed(51.4% early [<24 h], 10.5%late [>2 wk])

Retrospective case series No neurologic recovery in patients with com-plete SCI. No association between neuro-logic recovery and timing of decompression.

Marshall et al29 283 (all): 12 showed decline inneurologic function associ-ated with specific manage-ment

Prospective comparative study Early surgery on the cervical spine when cordinjury is present appears to be hazardous;each of the three patients with a cervicalcord injury who deteriorated was operatedon within the first 5 days

SCI = spinal cord injuryAdapted with permission from Fehlings MG, Perrin RG: The timing of surgical intervention in the treatment of spinal cord injury: A systematicreview of recent clinical evidence. Spine (Phila Pa 1976) 2006;31(11 suppl):S28-S35.



Thyrotropin-releasingHormoneThyrotropin-releasing hormone(TRH) is a tripeptide with numerousphysiologic and biochemical actions,including a role in stimulating the re-lease of thyroid-stimulating hormoneand prolactin by the anterior pitu-itary. In animal models it has beenshown that TRH and TRH analogsmay reduce or prevent the biochemi-cal events of secondary SCI by antag-onizing the effects of endogenousopioids, platelet-activating factor,peptido-leukotrienes, and excitatoryamino acids.49 TRH has also beenshown to improve neurologic func-tion in rats with SCI in a dose-

dependent manner.49 Equipped withpromising results from animal stud-ies, Pitts et al15 performed a clinicaltrial of TRH involving 20 patients.Four months after TRH treatment,statistically significant improvementswere seen in neurologic and sensoryfunction for patients with incompleteSCI (P = 0.043 and P = 0.031, re-spectively). Trials on a larger scaleand of longer duration are needed totest the reliability of these results andthe long-term effects of TRH ther-apy.

ErythropoietinErythropoietin (EPO) is a hematopoi-etic growth factor normally produced

in the kidney, bone marrow, and devel-oping human brain and spinal cord. Inaddition to its hematopoietic effects,EPO appears to have neuroprotectiveabilities, as demonstrated by animalmodels of Parkinson disease, multiplesclerosis, diabetic neuropathy, andstroke.50 In SCI animal models, EPOhas demonstrated neuroprotective ef-fects by inhibiting trauma-inducedlipid peroxidation, preventing neu-ronal apoptosis, and promoting neu-roregeneration with resultant im-proved functional recovery. Becauseof its already widely accepted use inthe treatment of anemia, its ability tocross the blood-brain barrier to exertits neuroprotective action, and the

Table 3

Clinical Studies That Support Early Surgical Decompression

Study No. of Patients (level) Study Design Conclusions

La Rosa et al32 1,683 (all): 793 decompressed,890 nonsurgical

Systematic literature review ofyears 1966-2000

Early decompression (<24 h) improves neuro-logic recovery in patients with incompleteneurologic deficits

Papadopouloset al33

91 (cervical): 66 decom-pressed, 25 nonsurgical

Prospective, nonrandomized Early decompression (<10 h) is feasible, mayimprove neurologic recovery, and reduceshospital stay

Waters et al34 2,204 (all): 88% admitted <72 hof injury

Prospective, nonrandomized Surgery does not increase complication ratesof patients with SCI

Tator et al35 585 (all): 23.5% underwentearly decompression (<24 h)

Retrospective case series 65% of patients in North America with SCIundergo surgery. No consensus on timing ofintervention.

Mirza et al36 30 (cervical): 15 <72 h,15 >72 h

Retrospective case series Early (<72 h) decompression improves neuro-logic recovery and does not increase com-plication rates

Ng et al37 26 (cervical): 7 decompressed<12 h

Prospective, nonrandomized Surgical decompression within 8 h of injurywas feasible in 8% and was not associatedwith increased complication rates

Chen et al38 37 (cervical): 16 decompressed<2 wk, 21 managed nonsurgi-cally

Prospective, nonrandomized Surgery associated with improved neurologicrecovery, shorter hospital stay, and fewercomplications

Vale et al39 77 (all): 58 decompressed Prospective, nonrandomized No clear relationship between neurologic re-covery and timing of surgery, but aggressivemedical treatment enhanced any potentialbenefit provided by surgery

Waters et al40 269 (all): 127 decompressed,142 nonsurgical

Prospective, nonrandomized Surgery of no benefit; however, all patientsunderwent delayed surgery

Petitjean et al41 49 (thoracic): early avg 12 h,late avg 9 d

Retrospective case series Decompression of no benefit in completethoracic paraplegia

SCI = spinal cord injuryAdapted with permission from Fehlings MG, Perrin RG: The timing of surgical intervention in the treatment of spinal cord injury: A systematicreview of recent clinical evidence. Spine (Phila Pa 1976) 2006;31(11 suppl):S28-S35.


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relative lack of a host-mounted im-mune response, EPO is an optimalcandidate for clinical trial. A recentphase II clinical trial demonstrateddecreased infarct size and improvedclinical outcome in stroke patients.51

Although there are ongoing phase IIclinical trials of EPO in the treatmentof patients with malignant spinalcord compression, its efficacy in thetreatment of acute SCI has not yetbeen evaluated.

Cellular Transplantation

In hopes of overcoming roadblocksto neurorestoration, in the past de-cade experimental therapies havegone beyond traditional pharmaco-logic solutions to explore the realmof cellular-based therapy. In cellular-based approaches, neural and non-neural tissue elements are trans-planted into the injured spinal cordwith the aim of regenerating whitematter long tracts and/or replacinglost cellular components. Some ther-apies of this kind have already beentranslated into the clinical arena, andothers show the potential to do so.The ideal cellular transplant shouldsupport axonal elongation and re-growth through the adult CNS, re-store myelin, coexist with astrocytes,and fully integrate with the lesionmicroenvironment. The cellulartransplants actively being tested cur-rently include peripheral nerve mi-crografts, activated autologous mac-rophages, and stem cell therapies.

Peripheral NerveMicrografts

Peripheral nerve micrografts haveproved to be effective in experimentalstudies and have significant bench-to-bedside potential. Peripheral nerve tis-sue has long been the subject of researchbecause it contains Schwann cell glialelements that can stimulate fiber re-growth and remyelination.

Schwann cells are glial cells thatprovide myelin insulation to axons inthe peripheral nervous system (PNS).Experimental models have shownthat Schwann cells produce manyneurotrophic factors, synthesize ex-tracellular matrix, and express a va-riety of cell adhesion molecules topromote axonal regeneration in thePNS. Furthermore, grafting of pe-ripheral nerves with varying combi-nations of growth factors in spinalcord–injured rats has resulted in ax-onal and functional recovery.52 How-ever, the ability of Schwann cells tofoster regeneration varies markedlyand depends on the physiologic stateand phenotype. Because of inhibitionby astrocytes, transplantation of pu-rified Schwann cells will result inonly marginal axonal regeneration.53

Keirstead et al54 revealed the preciseneurotrophic factors that constitute aproregenerative Schwann cell pheno-type and the mechanisms that lead totheir expression. Notably, proregener-ative Schwann cells of injured periph-eral nerves upregulate the expression ofspecific cell adhesion molecules (ie,N-CAM, N-cadherin, L1), extracellu-lar matrix molecules, and trophic fac-tors (ie, nerve growth factor, brain-derived neurotrophic factor [BDNF],neurotrophin-3 [NT-3]). This knowl-edge helped direct a recent study of theMiami Project to Cure Paralysis.55 Inthis study, the injured spinal cordwas implanted with Schwann cellstransduced ex vivo with lentiviralvectors encoding a bifunctional neu-rotrophin molecule (D15A), whichmimics actions of both NT-3 andBDNF. Increased neurotrophin se-cretion by the implanted D15ASchwann cells led to the presence ofa significantly increased number ofaxons in the contusion site on post-mortem analysis.

Preconditioning peripheral nervegrafts with mechanical stimulationwas tested in 2006 as a means to ac-tivate Schwann cells.56 This study and

others like it were based on the discov-ery that sustained mechanical stimula-tion of peripheral nerves induces a mas-sive proliferation of Schwann cells in thecompressed segments.52,57,58 The prolif-erative response is accompanied bysprouting of undamaged axons, whichsuggests that Schwann cells are acti-vated in a way that promotes axonalgrowth.52,57,58 The promising resultsindicating that functional recoveryimproved in rats transplanted withpreconditioned peripheral nerveswarrant further investigation for po-tential clinical application.

The potential of cells of the pri-mary olfactory system to promoteneural regeneration has also been ex-plored. The primary olfactory systemsupports neurogenesis throughoutlife, and newly generated olfactoryneurons can grow into the inhibitoryCNS environment of the olfactorybulb tissue and reform synapses.This unique regenerative property isbelieved to depend on the presenceof olfactory ensheathing cells(OECs). OECs are distinct glial cellsthat wrap olfactory axons and directtheir regeneration from the nasalmucosa to synapses of second-orderneurons in the CNS. In contrast toSchwann cells, OECs have beenshown to intimately interact withhost astrocytes and other CNS ele-ments. Furthermore, OECs havebeen reported to have exceptionalplasticity, and they allow neurons tocross the glial scar as well as thePNS-CNS boundary.59 In animalmodels, it has been demonstratedthat OECs have the ability to sur-vive, migrate, and remyelinate axonsas Schwann cells do, and even to re-generate axons across the injurysite.60

Clinical explorations with OECsare underway in China, Portugal,Russia, England, and Australia. Onecontroversial study obtains OECsfrom aborted fetuses and transplantsthem into injured spinal cords via in-



jection.61 More than 300 Chinese pa-tients with SCI have received thistreatment. However, the effectivenessof this treatment cannot be easily de-fined nor seriously considered. Pub-lished results in 171 patients de-scribed improved scores on the ASIAscale for motor recovery, light touch,and pinprick sensation ranging from2 to 8 weeks after transplantation.61

Although these results may seem tobe promising, the study design didnot meet the basic qualifications of acontrolled clinical trial based on cur-rently accepted international stan-dards. Moreover, these trials can ap-peal to spinal cord–injured patientswith misleading marketing regardingthe regaining of function. It is imper-ative that patients with SCI be edu-cated about the high risks, marginalto no benefit, and tremendous finan-cial costs of these interventions.

Activated AutologousMacrophagesResearch has shown that, following asciatic nerve lesion, peripheral mac-rophages synthesize nerve growth fac-tor, a neurotrophic agent that promotesaxonal regeneration. In addition, theseactivated macrophages phagocytosemyelin, which contains numerous pro-teins known to inhibit neural re-growth.62 Thus, macrophages holdthe potential to promote neuropro-tection and neuroregeneration withinthe environment of the injured spinalcord.

Early preclinical research of acti-vated autologous macrophages hasdemonstrated that the relative reluc-tance of the CNS to regenerate maybe explained by insufficient recruit-ment of macrophages.63 Moreover,sciatic nerve or skin-coincubatedmacrophages injected into the con-tused spinal cord of rats has resultedin enhanced synthesis of neuropro-tective trophic factors interleukin(IL)-1β and BDNF as well as de-

creased synthesis of neurotoxic tu-mor necrosis factor (TNF)-α.64 Thisresulted in significant recovery ofmotor function and reduction of spi-nal cystic cavitation.

Use of activated autologous mac-rophages in the treatment of SCI inhumans is being evaluated by clinicaltrials of ProCord (Proneuron Bio-technologies, New York, NY).65 Pro-Cord is composed of macrophagesisolated from the patient’s ownblood, activated through the compa-ny’s proprietary process, and injecteddirectly into the epicenter of the in-jured spinal cord. Initial outcomesfrom phase I of this clinical trialwere promising, demonstrating func-tional improvement in spinal cord–injured patients from ASIA grade A(complete functional loss) to grade C(recovery of clinically significantneurologic motor and sensory func-tion) in three of the eight patients.65

These encouraging results led to theinternational multicenter phase IIProCord trial for the treatment ofcomplete SCI. However, financialconstraints forced the permanent dis-continuation of the trial.

Stem Cell TherapyStem cell–based therapies have thepotential to replace damaged or dis-eased cells, provide cell-based electri-cal relay between neurons above andbelow the injury, and ameliorateclinical deterioration and/or facilitateregeneration by providing neuropro-tective or growth factors, as well asto play other indirect roles.66 Thereare two broad categories of stemcells: embryonic stem cells (ESCs)and progenitor stem cells. ESCsshow the greatest potential for thewidest range of cell replacement ther-apies, largely because they are pluri-potent, that is, they can differentiateinto all types of cells.67 By executiveorder, the Bush administration lim-ited federal funding for research to

preexisting human ESC lines createdbefore August 9, 2001.68 Largely as aresult of such federal restrictions onESC use, research on progenitor celllines grew significantly during theBush administration.

Neural stem cells (NSCs) are onetype of progenitor stem cell with thepotential to treat SCI. EndogenousNSCs exist within the CNS of higherorder mammals and have recentlybeen isolated from regions of the de-veloping and adult brain, spinalcord, and optic nerve. NSCs are ofparticular interest to SCI repair be-cause they are already committed toa neural fate. As noted by Enzmannet al,67 approximately 35 to 40 re-ports have described NSC treatmentsof SCI, most of which used brain-derived NSCs, and many of whichshowed that transplanted NSCs gen-erate astrocytes and oligodendro-cytes very effectively. These studiessuggest that the SCI environment isconducive for NSC differentiationinto glial cell lines but not for NSCdifferentiation into neuronal celllines. Thus, proof at this time thatendogenous NSC can replace lostneuronal cells after SCI is poor.

Mesenchymal stem cells (MSCs)may be used as an alternative. MSCsare a group of progenitor cells thatinclude multipotent bone marrowmononuclear cells and multipotentcells derived from umbilical cordblood. MSCs and bone marrow–de-rived cells have many practical ad-vantages: they are easily obtainable,autologous transplantation is possi-ble, they may be immunoprivileged,and they have the ability to migrateto areas of damage and inflam-mation.66 Although most studies re-port improved function as a resultof MSC implantation,69,70 decreasedfunction has also been reported.71

Despite the lack of a basic under-standing of the underlying mechan-ism by which MSCs may improvefunctional outcomes following SCI,


April 2010, Vol 18, No 4 219

clinical trials for SCI treatments withMSCs are beginning.72

Although progenitor cells showsignificant promise in the manage-ment of SCI, they are limited in thenumber of cell types they can differ-entiate into, and they react to thehost environment in a variable man-ner. In contrast, the pluripotent po-tential of ESCs allows them to differ-entiate into all cell types, therebyoffering greater promise for neurore-generation in SCI. On March 9,2009, President Obama ended the re-strictions on federal funding for ESCresearch, overturning the Bush ad-ministration policy.73 This changewill allow federally funded research-ers to work with ESCs from severalsources, explore new therapeuticstrategies, and potentially offer cell-based treatments of several debilitat-ing conditions, including SCI.

Summary

Despite the existence of numerouslaboratory studies and clinical trials,no reliable effective treatment of SCIhas yet been developed. Althoughadvances in clinical managementover the past 15 years have led toimprovement in survival and long-term outcome of spinal cord–injuredpatients, there is still no clinically rel-evant therapeutic intervention. Thetremendous increase in the numberof basic science and clinical investi-gations has resulted in the develop-ment of numerous techniques withthe potential to become novel treat-ment strategies. In addition, ad-vances in surgical management ofacute SCI continue to affect the tim-ing of decompression and methodsof stabilization. It is hoped that re-sults from ongoing clinical trials,such as STASCIS,21 will create amore standardized surgical treatmentalgorithm for patients with acuteSCI.

A sense of urgency from the SCI com-munity and patient advocacy groupscontinue to fuel research efforts and willlikely expedite the initiation of clinicaltrials involving recent pharmacologicand cellular transplantation strategies.Although it is unlikely that any singleintervention will result in a cure, com-bination therapies involving molecularand cellular advances will likely limitsecondary injury, possibly resulting insome enhanced functional recovery fol-lowing SCI. A multidisciplinary ap-proach involving these new strategieswill require the integral involvement ofthe treating orthopaedic surgeon.

References

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