Se ha denunciado esta presentación.
Utilizamos tu perfil de LinkedIn y tus datos de actividad para personalizar los anuncios y mostrarte publicidad más relevante. Puedes cambiar tus preferencias de publicidad en cualquier momento.

Spinal cord injury 2015

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

  • Inicia sesión para ver los comentarios

Spinal cord injury 2015

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 23. Surgical interventionSurgical intervention
  24. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.

×