A systematic review of current treatment options and future medical therapeutic strategies for the functional repair of spinal cord injury

1. Spinal Cord InjurySpinal Cord Injury
A systematic reviewA systematic review
of current treatment optionsof current treatment options
andand
future medical therapeutic strategiesfuture medical therapeutic strategies
for the functional repairfor the functional repair
ofof
spinal cord injuryspinal cord injury
George SapkasGeorge Sapkas
Professor at OrthopaedicsProfessor at Orthopaedics
Metropolitan HospitalMetropolitan Hospital

2. EpidemiologyEpidemiology
The incidence of acute SCI has beenThe incidence of acute SCI has been
reported as 15 to 40 in a million in thereported as 15 to 40 in a million in the
world.world.
Common causes :Common causes :
– Motor vehicle accidentsMotor vehicle accidents
– Sport injuriesSport injuries
– Work related accidentsWork related accidents
– AssaultsAssaults
– FallsFalls

3. The majority ofThe majority of
patients with SCI arepatients with SCI are
young and theyoung and the
economic andeconomic and
societal impact issocietal impact is
enormous,enormous,
both to the immediateboth to the immediate
family and to societyfamily and to society
at large.at large.

4. PathophysiologyPathophysiology
It is now wellIt is now well
recognizedrecognized
that acute SCIthat acute SCI
involves bothinvolves both
– primaryprimary
– and secondary injuryand secondary injury
mechanisms.mechanisms.

5. The primaryThe primary
mechanism involvesmechanism involves
the initial mechanicalthe initial mechanical
injury due to:injury due to:
– local deformation andlocal deformation and
– energy transformationenergy transformation
– that occurs within thethat occurs within the
spinal cord at thespinal cord at the
moment of injury,moment of injury,
which is irreversible.which is irreversible.
Bunge RP et al 1993
Kakulas BA et al 1984

6. In the majority ofIn the majority of
cases, primary SCIcases, primary SCI
is caused by:is caused by:
– rapid spinal cordrapid spinal cord
compression due tocompression due to
bone displacementbone displacement
fromfrom
a fracture dislocationa fracture dislocation
or burst fracture.or burst fracture.
Bunge RP et al 1993
Kakulas BA et al 1984

7. Other potentialOther potential
mechanisms include:mechanisms include:
– Acute spinal cordAcute spinal cord
distractiondistraction
– AccelerationAcceleration
deceleration withdeceleration with
shearingshearing
– Laceration fromLaceration from
penetrating injuriespenetrating injuries
Kraus GF et al, 1975
Dolan EG et al 1980

8. The concept of secondaryThe concept of secondary
mechanisms injury followingmechanisms injury following
primary SCI was first postulatedprimary SCI was first postulated
by Allen in 1911.by Allen in 1911.
Allen A. et al, 1911

9. There is nowThere is now
considerable evidenceconsiderable evidence
that the primarythat the primary
mechanical injury initiatesmechanical injury initiates
a cascade of secondarya cascade of secondary
injury mechanisms suchinjury mechanisms such
as:as:
– Vascular changesVascular changes
– Including ischemiaIncluding ischemia
– Loss of autoregulationLoss of autoregulation
– Neurogenic shockNeurogenic shock
– HemorrhageHemorrhage
Cont…
Fehling MG, et al 2000
Tator CH, 1991

10. – Loss of microcirculationLoss of microcirculation
– VasospasmVasospasm
– ThrombosisThrombosis
– ElectrolyteElectrolyte
derangementsderangements
– Increased intracellularIncreased intracellular
calciumcalcium
– Increased potassiumIncreased potassium
– Accumulation ofAccumulation of
intracellular sodiumintracellular sodium
– Accumulation ofAccumulation of
neurotransmittersneurotransmitters
Cont…
Fehling MG, et al 2000
Tator CH, 1991

11. – Seretonin catecholaminesSeretonin catecholamines
– Extracellular glutameteExtracellular glutamete
– ExcitoxicityExcitoxicity
– Arachidonic acid releaseArachidonic acid release
– ProductionProduction
EicosanoidsEicosanoids
Free radicalsFree radicals
– Lipid peroxidationLipid peroxidation
– Endogenous opioidsEndogenous opioids
– EdemaEdema
– InflamationInflamation
Cont…
Fehling MG, et al 2000
Tator CH, 1991
Young W et al, 1986

12. – Loss of energyLoss of energy
metabolismmetabolism
– Including adenosimeIncluding adenosime
thriphosphatethriphosphate
dependent cellulardependent cellular
processesprocesses
– ApoptosisApoptosis
Secondary injury isSecondary injury is
preventable, and maypreventable, and may
be reversiblebe reversible..
Fehling MG, et al 2000
Tator CH, 1991
Young W et al, 1986

13. The increasedThe increased
understanding of theunderstanding of the
pathophysiology ofpathophysiology of
acute SCI has led toacute SCI has led to
clinically relevantclinically relevant
neuroprotectiveneuroprotective
therapies to attenuatetherapies to attenuate
the effects of thethe effects of the
secondary injury.secondary injury.
Fehlings MG et al, 1994

14. Currently the management of patientsCurrently the management of patients
with acute spinal cord injury (SCI)with acute spinal cord injury (SCI)
includes :includes :
I.I. Pharmacological agentsPharmacological agents
II.II. Cellular therapiesCellular therapies
III.III. Surgical interventionSurgical intervention

15. Pharmacological treatmentPharmacological treatment
(neuro protecting – neuro regeneration promoting)(neuro protecting – neuro regeneration promoting)
SteroidsSteroids
MethyprednisoloneMethyprednisolone
Ganglioside GM-1Ganglioside GM-1
Opioid receptor antagonistsOpioid receptor antagonists
Thyrotroping releasing hormone and its analogsThyrotroping releasing hormone and its analogs
NimodipineNimodipine
Gaciclidine GK11Gaciclidine GK11
MagnesiumMagnesium
Cont…
David W. et al Clin. Orthop. 2011
Tevfik Y. et al World J. Orthop. 2015

16. Pharmacological treatmentPharmacological treatment
(neuro protecting – neuro regeneration promoting)(neuro protecting – neuro regeneration promoting)
HypothermiaHypothermia
MinocyclineMinocycline
ErythropoietinErythropoietin
ProgesteroneProgesterone
Cyclooxygenase inhibitorsCyclooxygenase inhibitors
RiluzoleRiluzole
AtrovastinAtrovastin
Rho antagonists and other componentsRho antagonists and other components
(Cethrin)(Cethrin)
David W. et al Clin. Orthop. 2011
Tevfik Y. et al World J. Orthop. 2015

17. MethylprednisoloneMethylprednisolone
(neuro protection)(neuro protection)
NASCISNASCIS
(National Acute Spinal Cord Injuries Studies)(National Acute Spinal Cord Injuries Studies)
I.I. NASCIS I for 48 hoursNASCIS I for 48 hours
II.II. NASCIS II for 24 hoursNASCIS II for 24 hours
III.III. NASCIC III for 72 hoursNASCIC III for 72 hours
• Started within 3 – 8 hours after traumaStarted within 3 – 8 hours after trauma

18. The National Acute SpinalThe National Acute Spinal
Injury studies (NASCIS II –Injury studies (NASCIS II –
NASCIS III) have reportedNASCIS III) have reported
a modest beneficial effecta modest beneficial effect
of high doseof high dose
methylprednisolonemethylprednisolone
if given within eight hoursif given within eight hours
of injury in patients withof injury in patients with
SCI, and suggested thatSCI, and suggested that
treatment within threetreatment within three
hours may be better thanhours may be better than
treatment initiated 3 – 8treatment initiated 3 – 8
hours after trauma.hours after trauma.
Bracken MB et al 1993
Bracken MB et al, 1997

19. RizuloleRizulole
Is a sodium channel blocking agentIs a sodium channel blocking agent
It is reported to haveIt is reported to have
neuro protecting propertiesneuro protecting properties
for blocking voltage-sensitve sodiumfor blocking voltage-sensitve sodium
channels whose persistent activationchannels whose persistent activation
(excitotoxicity) has been demonstrated to(excitotoxicity) has been demonstrated to
have deleterious effects on neural tissue.have deleterious effects on neural tissue.
RILUTEK - Greece

20. Rho antagonists (Cethrin)Rho antagonists (Cethrin)
Is a protein therapeutic that blocksIs a protein therapeutic that blocks
signaling form myelin debris present at thesignaling form myelin debris present at the
site of injury in the injured spinal cord.site of injury in the injured spinal cord.
Cethrin promotes regeneration of cutCethrin promotes regeneration of cut
axons and remodeling of damagedaxons and remodeling of damaged
circuits.circuits.
Cethrin is delivered topically duringCethrin is delivered topically during
decompression surgery.decompression surgery.
Greece (-)

21. Cellular Transplantation TherapiesCellular Transplantation Therapies
The rationale for cell transplantationThe rationale for cell transplantation
treatments are to provide the injuredtreatments are to provide the injured
tissue with :tissue with :
 Growth promoting factorsGrowth promoting factors
 Cell replacementsCell replacements
 Structural elementsStructural elements
 Myelinating unitsMyelinating units
Garcia Alias G, J. Neurosci. Res. 2004

22. Reconstructive and regenerative experimentalReconstructive and regenerative experimental
cellular strategies containing:cellular strategies containing:
– Embryonic or adult stem cells or tissueEmbryonic or adult stem cells or tissue
– Genetically modified fibroplastsGenetically modified fibroplasts
– Olfactory ensheathing cellsOlfactory ensheathing cells
– Bone marrow stromal cellsBone marrow stromal cells
– Neural stem cellsNeural stem cells
– Activated macrophagesActivated macrophages
All of them have been reported with varyingAll of them have been reported with varying
degrees of recovery in different models of SCIdegrees of recovery in different models of SCI
Garcia Alias G, J. Neurosci. Res. 2004
Barakat DJ, et al Cell Transpl. 2005

23. Surgical interventionSurgical intervention

24. The role and timing ofThe role and timing of
surgical interventionsurgical intervention
after an acute spinalafter an acute spinal
cord injury (SCI)cord injury (SCI)
remains one of theremains one of the
most controversialmost controversial
topics pertaining totopics pertaining to
spinal surgeryspinal surgery

25. Studies support theStudies support the
concept of targetingconcept of targeting
secondarysecondary
mechanisms in acutemechanisms in acute
SCI and alsoSCI and also thethe
importance of theimportance of the
timing of interventiontiming of intervention..

26. There is experimentalThere is experimental
evidence thatevidence that
persistent compressionpersistent compression
of the spinal cordof the spinal cord is ais a
potentially reversiblepotentially reversible
form of secondaryform of secondary
injury.injury.
Dolan EJ, et al 1980
Aki T et al, 1984

27. The presence andThe presence and
duration of aduration of a
therapeutic windowtherapeutic window
during which surgicalduring which surgical
decompression coulddecompression could
mitigate themitigate the
secondarysecondary
mechanisms of SCImechanisms of SCI
remains unclearremains unclear

28. This lecture will review theThis lecture will review the
experimental and clinical evidenceexperimental and clinical evidence
regarding:regarding:
– the value of decompressive surgery inthe value of decompressive surgery in
treating patients with acute non-treating patients with acute non-
penetrating SCIpenetrating SCI
AndAnd
– the role and timing of earlythe role and timing of early
decompression for SCIdecompression for SCI

29. This computerizedThis computerized
literature reviewliterature review
yielded a total of 960yielded a total of 960
studies, which werestudies, which were
then pared down basedthen pared down based
on relevance to theon relevance to the
tissue of SCItissue of SCI
management.management.
M. G. Fehlings , R.G. Perin, Injury, 2005

30. Study DesignStudy Design
Class ofClass of
evidenceevidence
well designed and well conductedwell designed and well conducted
randomized controlled trialsrandomized controlled trials II
prospective cohort studies orprospective cohort studies or
controlled studies with wellcontrolled studies with well
defined comparison groupsdefined comparison groups IIII
case series; retrospective reviewscase series; retrospective reviews
and expert opinionand expert opinion IIIIII

31. ResultsResults
A total of 65 articlesA total of 65 articles
– 19 experimental studies19 experimental studies
in animal modelsin animal models
– 46 clinical studies46 clinical studies
were selected forwere selected for
detailed analysis.detailed analysis.

32. Of the clinical articles:Of the clinical articles:
– 9 dealt with non9 dealt with non
operative managementoperative management
– 31 with the role of early31 with the role of early
(< 4 weeks) surgical(< 4 weeks) surgical
interventionintervention
– 12 with the effect of12 with the effect of
closed reductionclosed reduction
– 7 with the role of7 with the role of
delayed decompressiondelayed decompression

33. Based on this analysis,Based on this analysis,
evidence basedevidence based
recommendationsrecommendations
regarding the role ofregarding the role of
acute decompressionacute decompression
in SCI was suggested.in SCI was suggested.

34. The severity of SCI in animal models is relatedThe severity of SCI in animal models is related
to:to:
– The force of compressionThe force of compression
– Duration of compressionDuration of compression
– DisplacementDisplacement
– ImpulseImpulse
– Kinetic energyKinetic energy
Numerous exeprimental studies ofNumerous exeprimental studies of
decompression after SCI have been performeddecompression after SCI have been performed
in various animal models including:in various animal models including:
– PrimatesPrimates
– DogsDogs
– CatsCats
– RodentsRodents

35. These studies have consistentlyThese studies have consistently
shown thatshown that neurological recoveryneurological recovery
is enhanced by earlyis enhanced by early
decompressiondecompression
The most convincing experimentalThe most convincing experimental
evidence that spinal cordevidence that spinal cord
decompression after SCI isdecompression after SCI is
beneficial was provided by Dimarbeneficial was provided by Dimar
et al 1999.et al 1999.

36. The effect ofThe effect of
decompression atdecompression at
0, 2, 6, 24 and 720, 2, 6, 24 and 72
hours after SCI washours after SCI was
then assessed bythen assessed by
quantitative analysis of:quantitative analysis of:
– Locomotor recoveryLocomotor recovery
– Lesion volumeLesion volume
– ElectrophysiologyElectrophysiology

37. Neurological recovery wasNeurological recovery was
inversely related to theinversely related to the
duration of compression withduration of compression with
statistically significantstatistically significant
differences seen in alldifferences seen in all
experimental groups.experimental groups.
Functional recovery wasFunctional recovery was
significantly better, andsignificantly better, and
lesion volume waslesion volume was
significantly smaller in thosesignificantly smaller in those
animals undergoing earlyanimals undergoing early
decompressiondecompression

38. In contrast the prospectiveIn contrast the prospective
studies by:studies by:
– Vale et al, 1999Vale et al, 1999
– Vaccaro et al, 1997Vaccaro et al, 1997
– Waters et al ,1996Waters et al ,1996
were unable to documentwere unable to document
a beneficial effect ofa beneficial effect of
surgical decompression.surgical decompression.
It is noteworthy, however, thatIt is noteworthy, however, that
all patients underwent delayedall patients underwent delayed
operative management.operative management.
““Early surgery” was defined asEarly surgery” was defined as
being within 72 hours afterbeing within 72 hours after
SCI.SCI.

39. Aebi et al undertook aAebi et al undertook a
retrospective reviewretrospective review
of 100 patients withof 100 patients with
cervical spine injuriescervical spine injuries
and attempted to findand attempted to find
an associationan association
betweenbetween
neurological recoveryneurological recovery
andand
the timing of fracturethe timing of fracture
reductionreduction
by closed or openby closed or open
techniques.techniques.
Aebi M. et al , 1986

40. OverallOverall
31% of the 100 patients31% of the 100 patients
recoveredrecovered
andand
75% of the recoveries75% of the recoveries
were in patientswere in patients
reducedreduced
within thewithin the
first six hours.first six hours.

41. In contrast to theIn contrast to the
aforementioned studies ofaforementioned studies of
early decompression.early decompression.
Larson et al,Larson et al,
advocated operatingadvocated operating
a week or morea week or more
after SCI to allow medicalafter SCI to allow medical
and neurologicaland neurological
stabilization of the injuredstabilization of the injured
patientpatient
Larson et al, 1976

42. This approach remains theThis approach remains the
practice in many institutions,practice in many institutions,
particularly in light of earlyparticularly in light of early
reports suggesting anreports suggesting an
increased rate of medicalincreased rate of medical
complications with earlycomplications with early
surgery (< 5 days after SCI)surgery (< 5 days after SCI)

43. Interestingly a numberInterestingly a number
of authors haveof authors have
documented recovery ofdocumented recovery of
neurological functionneurological function
afterafter
delayed decompressiondelayed decompression
of the spinal cordof the spinal cord
(months to years) after(months to years) after
the injurythe injury
Larson SJ, et al 1976
Anderson PA et al, 1992
Bohlman HH et al, 1992

44. Although these studies areAlthough these studies are
retrospective in design (Classretrospective in design (Class
III evidence)III evidence)
the improvement inthe improvement in
neurological function withneurological function with
delayed decompressiondelayed decompression
in patients with cervical orin patients with cervical or
thoracolumbar SCI who havethoracolumbar SCI who have
plateaud in their recovery isplateaud in their recovery is
noteworthy and suggests thatnoteworthy and suggests that
compression of the cord is ancompression of the cord is an
important contributing causeimportant contributing cause
of neurological dysfunction.of neurological dysfunction.

45. Effect of surgery on complicationsEffect of surgery on complications
and length of stay after SCIand length of stay after SCI
The issue of whetherThe issue of whether
surgery, especiallysurgery, especially
early surgery,early surgery,
increases the rate ofincreases the rate of
complications incomplications in
patients with SCI haspatients with SCI has
been one that hasbeen one that has
generatedgenerated
considerableconsiderable
controversy andcontroversy and
debate.debate.

46. Many authors have arguedMany authors have argued
against surgery, especiallyagainst surgery, especially
early intervention in theseearly intervention in these
critically ill patients.critically ill patients.
Gutman L, 1976Gutman L, 1976
Wilmot CB et al., 1986Wilmot CB et al., 1986
However, modernHowever, modern
techniques of spine surgerytechniques of spine surgery
as well as advances inas well as advances in
critical care andcritical care and
neuroanesthesia haveneuroanesthesia have
allowed these patients toallowed these patients to
undergo surgery withundergo surgery with
minimal differences inminimal differences in
complication rates betweencomplication rates between
operative and non operativeoperative and non operative
cases.cases.
Benzel EC et al, 1986Benzel EC et al, 1986
Vale FL et al, 1997Vale FL et al, 1997

47. Duh showed that thoseDuh showed that those
operated on in theoperated on in the
first 24 hoursfirst 24 hours
had a lower rate ofhad a lower rate of
complications thancomplications than
those undergoingthose undergoing
operative intervention atoperative intervention at
a later time.a later time.
Duh et al, 1994

48. Waters et al in aWaters et al in a
prospective study ofprospective study of
2.204 cases found that2.204 cases found that
there was no differencethere was no difference
in the complication ratesin the complication rates
of cases managed byof cases managed by
non operative ornon operative or
surgical techniques.surgical techniques.
Waters et al, 1999

49. Accordingly, there isAccordingly, there is
Class I evidence toClass I evidence to
support thesupport the safetysafety ofof
surgery, includingsurgery, including
operative treatmentoperative treatment
within thewithin the
first 24 hours.first 24 hours.
Mirza SK et al, 1999

50. ConclusionsConclusions
There is strongThere is strong
experimentalexperimental
evidence from animalevidence from animal
models thatmodels that
decompression of thedecompression of the
spinal cordspinal cord improvesimproves
recovery after SCI.recovery after SCI.
It is difficult toIt is difficult to
determine a timedetermine a time
windowwindow for thefor the
effective applicationeffective application
of decompression inof decompression in
the clinical settingthe clinical setting
from these animalfrom these animal
models.models.

51. Studies of secondaryStudies of secondary
injury mechanismsinjury mechanisms
including:including:
– ischemia,ischemia,
– free radical mediatedfree radical mediated
– lipid peroxidationlipid peroxidation
– and calcium mediatedand calcium mediated
cytoxicity,cytoxicity,
suggest thatsuggest that earlyearly
interventionintervention within hourswithin hours
of SCI is critical to obtainof SCI is critical to obtain
a neuroprotective effect.a neuroprotective effect.

52. There is Class IIThere is Class II
evidenceevidence
suggesting thatsuggesting that
early surgicalearly surgical
intervention is safeintervention is safe
and effective andand effective and
even delayedeven delayed
decompressiondecompression
may convey amay convey a
neurologicalneurological
benefit.benefit.

53. Clearly, what isClearly, what is
needed to definitelyneeded to definitely
answer the questionanswer the question
regarding the timing ofregarding the timing of
surgery following SCIsurgery following SCI
is a well designedis a well designed
prospective,prospective,
randomized controlled,randomized controlled,
multicenter producingmulticenter producing
Class I evidence data.Class I evidence data.
This can often beThis can often be
done within 24 hoursdone within 24 hours
of admission.of admission.