Spinal Cord InjurySpinal Cord InjuryA systematic review A systematic review

of current treatment options of current treatment options and and

future medical therapeutic strategies future medical therapeutic strategies for the functional repair for the functional repair

of of spinal cord injuryspinal cord injury

George SapkasGeorge SapkasProfessor at OrthopaedicsProfessor at Orthopaedics

Metropolitan HospitalMetropolitan Hospital

Epidemiology Epidemiology

The incidence of acute SCI has been The incidence of acute SCI has been reported as 15 to 40 in a million in the reported as 15 to 40 in a million in the world.world.Common causes :Common causes :– Motor vehicle accidentsMotor vehicle accidents– Sport injuries Sport injuries – Work related accidentsWork related accidents– Assaults Assaults – Falls Falls

The majority of The majority of patients with SCI are patients with SCI are young and the young and the economic and economic and societal impact is societal impact is enormous, enormous, both to the immediate both to the immediate family and to society family and to society at large.at large.

PathophysiologyPathophysiology

It is now well It is now well recognized recognized that acute SCI that acute SCI involves both involves both – primaryprimary

– and secondary injury and secondary injury mechanisms. mechanisms.

The primary The primary mechanism involves mechanism involves the initial mechanical the initial mechanical injury due to:injury due to:– local deformation and local deformation and – energy transformation energy transformation – that occurs within the that occurs within the

spinal cord at the spinal cord at the moment of injury, moment of injury, which is irreversible.which is irreversible.

Bunge RP et al 1993Kakulas BA et al 1984

In the majority of In the majority of cases, primary SCI cases, primary SCI is caused by:is caused by:– rapid spinal cord rapid spinal cord

compression due to compression due to bone displacement bone displacement from from a fracture dislocation a fracture dislocation or burst fracture.or burst fracture.

Bunge RP et al 1993Kakulas BA et al 1984

Other potential Other potential mechanisms include:mechanisms include:– Acute spinal cord Acute spinal cord

distractiondistraction– Acceleration Acceleration

deceleration with deceleration with shearing shearing

– Laceration from Laceration from penetrating injuriespenetrating injuries

Kraus GF et al, 1975Dolan EG et al 1980

The concept of secondary The concept of secondary mechanisms injury following mechanisms injury following primary SCI was first postulated primary SCI was first postulated by Allen in 1911.by Allen in 1911.

Allen A. et al, 1911

There is now There is now considerable evidence considerable evidence that the primary that the primary mechanical injury initiates mechanical injury initiates a cascade of secondary a cascade of secondary injury mechanisms such injury mechanisms such as:as:– Vascular changesVascular changes– Including ischemiaIncluding ischemia– Loss of autoregulationLoss of autoregulation– Neurogenic shock Neurogenic shock – Hemorrhage Hemorrhage

Cont…

Fehling MG, et al 2000Tator CH, 1991

– Loss of microcirculationLoss of microcirculation– VasospasmVasospasm– ThrombosisThrombosis– Electrolyte Electrolyte

derangementsderangements– Increased intracellular Increased intracellular

calciumcalcium– Increased potassium Increased potassium – Accumulation of Accumulation of

intracellular sodiumintracellular sodium– Accumulation of Accumulation of

neurotransmittersneurotransmitters

Cont…

Fehling MG, et al 2000Tator CH, 1991

– Seretonin catecholaminesSeretonin catecholamines– Extracellular glutamete Extracellular glutamete – ExcitoxicityExcitoxicity– Arachidonic acid release Arachidonic acid release – Production Production

Eicosanoids Eicosanoids Free radicalsFree radicals

– Lipid peroxidationLipid peroxidation– Endogenous opioidsEndogenous opioids– Edema Edema – Inflamation Inflamation

Cont…

Fehling MG, et al 2000Tator CH, 1991Young W et al, 1986

– Loss of energy metabolism Loss of energy metabolism – Including adenosime Including adenosime

thriphosphate dependent thriphosphate dependent cellular processescellular processes

– Apoptosis Apoptosis

Secondary injury is Secondary injury is preventable, and may be preventable, and may be reversiblereversible..

Fehling MG, et al 2000Tator CH, 1991Young W et al, 1986

The increased The increased understanding of the understanding of the pathophysiology of pathophysiology of acute SCI has led to acute SCI has led to clinically relevant clinically relevant neuroprotective neuroprotective therapies to attenuate therapies to attenuate the effects of the the effects of the secondary injury.secondary injury.

Fehlings MG et al, 1994

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

Pharmacological treatmentPharmacological treatment(neuro protecting – neuro regeneration promoting)(neuro protecting – neuro regeneration promoting)

SteroidsSteroidsMethyprednisoloneMethyprednisoloneGanglioside GM-1Ganglioside GM-1Opioid receptor antagonistsOpioid receptor antagonistsThyrotroping releasing hormone and its analogsThyrotroping releasing hormone and its analogsNimodipine Nimodipine Gaciclidine GK11Gaciclidine GK11MagnesiumMagnesium

Cont…

David W. et al Clin. Orthop. 2011Tevfik Y. et al World J. Orthop. 2015

Pharmacological treatmentPharmacological treatment(neuro protecting – neuro regeneration promoting)(neuro protecting – neuro regeneration promoting)

HypothermiaHypothermiaMinocyclineMinocyclineErythropoietinErythropoietinProgesteroneProgesteroneCyclooxygenase inhibitorsCyclooxygenase inhibitorsRiluzoleRiluzoleAtrovastinAtrovastinRho antagonists and other componentsRho antagonists and other components(Cethrin)(Cethrin)

David W. et al Clin. Orthop. 2011Tevfik Y. et al World J. Orthop. 2015

Methylprednisolone Methylprednisolone (neuro protection)(neuro protection)

NASCIS NASCIS (National Acute Spinal Cord Injuries Studies) (National Acute Spinal Cord Injuries Studies)

I.I. NASCIS I for 48 hoursNASCIS I for 48 hoursII.II. NASCIS II for 24 hoursNASCIS II for 24 hoursIII.III. NASCIC III for 72 hoursNASCIC III for 72 hours

• Started within 3 – 8 hours after traumaStarted within 3 – 8 hours after trauma

The National Acute Spinal The National Acute Spinal Injury studies (NASCIS II – Injury studies (NASCIS II – NASCIS III) have reported NASCIS III) have reported a modest beneficial effect a modest beneficial effect of high dose of high dose methylprednisolonemethylprednisolone if given within eight hours if given within eight hours of injury in patients with of injury in patients with SCI, and suggested that SCI, and suggested that treatment within three treatment within three hours may be better than hours may be better than treatment initiated 3 – 8 treatment initiated 3 – 8 hours after trauma.hours after trauma.

Bracken MB et al 1993Bracken MB et al, 1997

RizuloleRizulole

Is a sodium channel blocking agentIs a sodium channel blocking agentIt is reported to have It is reported to have neuro protecting properties neuro protecting properties for blocking voltage-sensitve sodium for blocking voltage-sensitve sodium channels whose persistent activation channels 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

Rho antagonists (Cethrin)Rho antagonists (Cethrin)

Is a protein therapeutic that blocks Is a protein therapeutic that blocks signaling form myelin debris present at the signaling 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 cut Cethrin promotes regeneration of cut axons and remodeling of damaged axons and remodeling of damaged circuits.circuits.Cethrin is delivered topically during Cethrin is delivered topically during decompression surgery.decompression surgery.

Greece (-)

Cellular Transplantation TherapiesCellular Transplantation Therapies

The rationale for cell transplantation The rationale for cell transplantation treatments are to provide the injured tissue treatments are to provide the injured tissue with :with : Growth promoting factorsGrowth promoting factors Cell replacementsCell replacements Structural elementsStructural elements Myelinating unitsMyelinating units

Garcia Alias G, J. Neurosci. Res. 2004

Reconstructive and regenerative experimental Reconstructive 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 varying All of them have been reported with varying degrees of recovery in different models of SCI degrees of recovery in different models of SCI

Garcia Alias G, J. Neurosci. Res. 2004Barakat DJ, et al Cell Transpl. 2005

Surgical interventionSurgical intervention

The role and timing of The role and timing of surgical intervention surgical intervention after an acute spinal after an acute spinal cord injury (SCI) cord injury (SCI) remains one of the remains one of the most controversial most controversial topics pertaining to topics pertaining to spinal surgeryspinal surgery

Studies support the Studies support the concept of targeting concept of targeting secondary secondary mechanisms in acute mechanisms in acute SCI and also SCI and also the the importance of the importance of the timing of interventiontiming of intervention..

There is experimental There is experimental evidence that evidence that persistent compression persistent compression of the spinal cordof the spinal cord is a is a potentially reversible potentially reversible form of secondary form of secondary injury.injury.

Dolan EJ, et al 1980Aki T et al, 1984

The presence and The presence and duration of a duration of a therapeutic windowtherapeutic window during which surgical during which surgical decompression could decompression could mitigate the mitigate the secondary secondary mechanisms of SCI mechanisms of SCI remains unclearremains unclear

This lecture will review the This lecture will review the experimental and clinical evidence experimental and clinical evidence regarding: regarding: – the value of decompressive surgery in the value of decompressive surgery in

treating patients with acute non-treating patients with acute non-penetrating SCI penetrating SCI

AndAnd– the role and timing of early the role and timing of early

decompression for SCIdecompression for SCI

This computerized This computerized literature review literature review yielded a total of 960 yielded a total of 960 studies, which were studies, which were then pared down based then pared down based on relevance to the on relevance to the tissue of SCI tissue of SCI management.management.

M. G. Fehlings , R.G. Perin, Injury, 2005

Study DesignStudy Design Class of Class of evidenceevidence

well designed and well conducted well designed and well conducted randomized controlled trialsrandomized controlled trials II

prospective cohort studies or prospective cohort studies or controlled studies with well controlled studies with well defined comparison groupsdefined comparison groups IIII

case series; retrospective reviews case series; retrospective reviews and expert opinionand expert opinion IIIIII

ResultsResults

A total of 65 articles A total of 65 articles

– 19 experimental studies 19 experimental studies in animal modelsin animal models

– 46 clinical studies 46 clinical studies

were selected for were selected for detailed analysis.detailed analysis.

Of the clinical articles:Of the clinical articles:– 9 dealt with non 9 dealt with non

operative managementoperative management– 31 with the role of early 31 with the role of early

(< 4 weeks) surgical (< 4 weeks) surgical interventionintervention

– 12 with the effect of 12 with the effect of closed reductionclosed reduction

– 7 with the role of 7 with the role of delayed decompressiondelayed decompression

Based on this analysis, Based on this analysis, evidence based evidence based recommendations recommendations regarding the role of regarding the role of acute decompression acute decompression in SCI was suggested.in SCI was suggested.

The severity of SCI in animal models is related The severity of SCI in animal models is related to:to:– The force of compression The force of compression – Duration of compressionDuration of compression– DisplacementDisplacement– ImpulseImpulse– Kinetic energyKinetic energy

Numerous exeprimental studies of Numerous exeprimental studies of decompression after SCI have been performed decompression after SCI have been performed in various animal models including:in various animal models including:– PrimatesPrimates– DogsDogs– CatsCats– Rodents Rodents

These studies have consistently These studies have consistently shown that shown that neurological recovery neurological recovery is enhanced by early is enhanced by early decompressiondecompressionThe most convincing experimental The most convincing experimental evidence that spinal cord evidence that spinal cord decompression after SCI is decompression after SCI is beneficial was provided by Dimar beneficial was provided by Dimar et al 1999. et al 1999.

The effect of The effect of decompression at decompression at 0, 2, 6, 24 and 72 0, 2, 6, 24 and 72 hours after SCI was hours after SCI was then assessed by then assessed by quantitative analysis of:quantitative analysis of:– Locomotor recoveryLocomotor recovery– Lesion volumeLesion volume– Electrophysiology Electrophysiology

Neurological recovery was Neurological recovery was inversely related to the inversely related to the duration of compression with duration of compression with statistically significant statistically significant differences seen in all differences seen in all experimental groups.experimental groups.Functional recovery was Functional recovery was significantly better, and significantly better, and lesion volume was lesion volume was significantly smaller in those significantly smaller in those animals undergoing early animals undergoing early decompressiondecompression

In contrast the prospective In contrast the prospective studies by:studies by:

– Vale et al, 1999 Vale et al, 1999 – Vaccaro et al, 1997 Vaccaro et al, 1997 – Waters et al ,1996Waters et al ,1996

were unable to document were unable to document a beneficial effect of a beneficial effect of surgical decompression.surgical decompression.It is noteworthy, however, that It is noteworthy, however, that all patients underwent delayed all patients underwent delayed operative management.operative management.““Early surgery” was defined as Early surgery” was defined as being within 72 hours after being within 72 hours after SCI.SCI.

Aebi et al undertook a Aebi et al undertook a retrospective review retrospective review of 100 patients with of 100 patients with cervical spine injuries cervical spine injuries and attempted to find and attempted to find an association an association between between neurological recoveryneurological recovery and and the timing of fracture the timing of fracture reductionreduction by closed or open by closed or open techniques.techniques.

Aebi M. et al , 1986

Overall Overall 31% of the 100 patients 31% of the 100 patients recovered recovered and and 75% of the recoveries 75% of the recoveries were in patients were in patients reduced reduced within the within the first six hours.first six hours.

In contrast to the In contrast to the aforementioned studies of aforementioned studies of early decompression. early decompression. Larson et al, Larson et al, advocated operating advocated operating a week or morea week or more after SCI to allow medical after SCI to allow medical and neurological and neurological stabilization of the injured stabilization of the injured patientpatient

Larson et al, 1976

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

Interestingly a number Interestingly a number of authors have of authors have documented recovery of documented recovery of neurological function neurological function after after delayed decompressiondelayed decompression of the spinal cord of the spinal cord (months to years) after (months to years) after the injurythe injury

Larson SJ, et al 1976Anderson PA et al, 1992Bohlman HH et al, 1992

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

Effect of surgery on complications Effect of surgery on complications and length of stay after SCIand length of stay after SCI

The issue of whether The issue of whether surgery, especially surgery, especially early surgery,early surgery, increases the rate of increases the rate of complications in complications in patients with SCI has patients with SCI has been one that has been one that has generated generated considerable considerable controversy and controversy and debate.debate.

Many authors have argued Many authors have argued against surgery, especially against surgery, especially early intervention in these early intervention in these critically ill patients.critically ill patients.Gutman L, 1976Gutman L, 1976Wilmot CB et al., 1986Wilmot CB et al., 1986However, modern However, modern techniques of spine surgery techniques of spine surgery as well as advances in as well as advances in critical care and critical care and neuroanesthesia have neuroanesthesia have allowed these patients to allowed these patients to undergo surgery with undergo surgery with minimal differences in minimal differences in complication rates between complication rates between operative and non operative operative and non operative cases.cases.Benzel EC et al, 1986Benzel EC et al, 1986 Vale FL et al, 1997 Vale FL et al, 1997

Duh showed that those Duh showed that those operated on in the operated on in the first 24 hoursfirst 24 hours had a lower rate of had a lower rate of complications than complications than those undergoing those undergoing operative intervention at operative intervention at a later time.a later time.

Duh et al, 1994

Waters et al in a Waters et al in a prospective study of prospective study of 2.204 cases found that 2.204 cases found that there was no difference there was no difference in the complication rates in the complication rates of cases managed by of cases managed by non operative or non operative or surgical techniques.surgical techniques.

Waters et al, 1999

Accordingly, there is Accordingly, there is Class I evidence to Class I evidence to support the support the safetysafety of of surgery, including surgery, including operative treatment operative treatment within the within the first 24 hours.first 24 hours.

Mirza SK et al, 1999

ConclusionsConclusionsThere is strong There is strong experimental experimental evidence from animal evidence from animal models that models that decompression of the decompression of the spinal cordspinal cord improves improves recovery after SCI.recovery after SCI.It is difficult to It is difficult to determine a time determine a time windowwindow for the for the effective application effective application of decompression in of decompression in the clinical setting the clinical setting from these animal from these animal models.models.

Studies of secondary Studies of secondary injury mechanisms injury mechanisms including: including: – ischemia, ischemia, – free radical mediatedfree radical mediated– lipid peroxidation lipid peroxidation – and calcium mediated and calcium mediated

cytoxicity, cytoxicity,

suggest that suggest that early early interventionintervention within hours within hours of SCI is critical to obtain of SCI is critical to obtain a neuroprotective effect.a neuroprotective effect.

There is Class II There is Class II evidence evidence suggesting that suggesting that early surgical early surgical intervention is safe intervention is safe and effective and and effective and even delayed even delayed decompression decompression may convey a may convey a neurological neurological benefit.benefit.

Clearly, what is Clearly, what is needed to definitely needed to definitely answer the question answer the question regarding the timing of regarding the timing of surgery following SCI surgery following SCI is a well designed is a well designed prospective, prospective, randomized controlled, randomized controlled, multicenter producing multicenter producing Class I evidence data.Class I evidence data.This can often be This can often be done within 24 hours done within 24 hours of admission.of admission.