Spinal Cord InjurySpinal Cord Injury

(A presentation made at the Calgary Animal Referral and (A presentation made at the Calgary Animal Referral and Emergency Centre Rounds, Oct 11, 2007)Emergency Centre Rounds, Oct 11, 2007)

Aubrey A. Webb, DVM, PhDAubrey A. Webb, DVM, PhD

Hotchkiss Brain Institute and Faculty of Veterinary Hotchkiss Brain Institute and Faculty of Veterinary MedicineMedicine

University of CalgaryUniversity of Calgary

GoalsGoalsTo provide basic epidemiology of human and canine SCITo provide basic epidemiology of human and canine SCI

To get you to think about assessment techniques if one To get you to think about assessment techniques if one were to conduct a clinical trialwere to conduct a clinical trial

To get you to question the rigor in which you evaluate To get you to question the rigor in which you evaluate recovery after injury in SCI dogsrecovery after injury in SCI dogs

To provide current thoughts on the use of steroids for To provide current thoughts on the use of steroids for SCISCI

To update you on what is being done in clinical canine To update you on what is being done in clinical canine SCI trialsSCI trials

OutlineOutlineBasic epidemiology of spinal cord injury (SCI)Basic epidemiology of spinal cord injury (SCI)

Methods of evaluating recovery from SCIMethods of evaluating recovery from SCI

Mechanisms of SCI damageMechanisms of SCI damagePrimaryPrimarySecondarySecondary

Lines of SCI researchLines of SCI research

Corticosteroids?Corticosteroids?

Relatively recent, current, and forthcoming research in Relatively recent, current, and forthcoming research in canine SCIcanine SCI

May, 1995

Christopher ReeveSeptember 25, 1952 - October 10, 2004 Mcdonald et al, J Neurosurg, 2002

Rick Hansen – wheeled around world (40 000 km) from 1985-1987

Epidemiology Epidemiology -- HumansHumansTraumatic spinal cord injury (SCI)Traumatic spinal cord injury (SCI)

Approx. 16% of people with Approx. 16% of people with spinal cord injury die prior to spinal cord injury die prior to being admitted to a hospital being admitted to a hospital (Dryden et al, 2003)(Dryden et al, 2003)

Approx. Approx. 80%80% occur in malesoccur in males

Vast majority occurs in Vast majority occurs in individuals under 35 years of ageindividuals under 35 years of age

Motor vehicle accidents # 1 Motor vehicle accidents # 1 causecause

IncidenceIncidence: 35/million people : 35/million people affected annually = affected annually = 1100 1100 CanadiansCanadians affected affected annuallyannually

PrevalencePrevalence = approx. = approx. 36 000 36 000 peoplepeople living with SCI in Canada living with SCI in Canada todaytoday

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

Cervical Thoracic Lumbosacral

From Dryden et al, Can J Neurol Sci, 2003

From http://www.spinalcord.uab.edu/show.asp?durki=21446

Epidemiology Epidemiology -- HumansHumans

Epidemiology Epidemiology -- DogsDogs

Most common cause is Most common cause is prolapsedprolapsedintervertebralintervertebral discdisc

Observed in Observed in 0.02 0.02 -- 2%2% of all clinical cases of all clinical cases admitted to a veterinary hospital admitted to a veterinary hospital ((PriesterPriester, 1976; , 1976; Coates, 2000)Coates, 2000)

Type 1 disc extrusion is seen in Type 1 disc extrusion is seen in chondrodystrophicchondrodystrophic breeds at 3breeds at 3--6 years of 6 years of ageage

Type 2 disc Type 2 disc prolapseprolapse is seen in is seen in nonchondrodystrophicnonchondrodystrophic breeds and occurs breeds and occurs between 6 and 10 years of agebetween 6 and 10 years of age

60%60% of all dog and cat of all dog and cat SCIsSCIs, not resulting , not resulting from IVDD, are the result of from IVDD, are the result of motor vehicle motor vehicle accidentsaccidents (McKee, 1990) (McKee, 1990)

5% of dogs involved in motor vehicle 5% of dogs involved in motor vehicle accidents will have SCI accidents will have SCI ((KolataKolata, 1975), 1975)

From Neurology for the Small Animal Practioner, Chrisman, Mariani, Platt, Clemmons

IntervertebralIntervertebral disc disease disc disease -- dogsdogs

15% occur at cervical level15% occur at cervical level

85% 85% thoracolumbarthoracolumbar levellevelT12T12--T13 T13 –– 26%26%T13T13--L1 L1 –– 25%25%L1L1--L2 L2 –– 13%13%L2L2--L3 L3 –– 8%8%L3L3--L4 L4 –– 7%7%L4L4--L5 L5 –– 6%6%L5L5--L6 L6 –– 2%2%

From Neurology for the Small Animal Practioner, Chrisman, Mariani, Platt, Clemmons

Assessment of RecoveryAssessment of Recovery

Endpoint measuresEndpoint measures

KinematicsKinematics

KineticsKinetics

Physiological measuresPhysiological measures

Assessment of RecoveryAssessment of Recovery

Endpoint MeasuresEndpoint MeasuresQuantitativeQuantitativeSimple to performSimple to performRelatively inexpensiveRelatively inexpensiveRequires little training or experienceRequires little training or experienceIdentifies whether task is performedIdentifies whether task is performedDoes not identify how a task is performedDoes not identify how a task is performed

Endpoint measuresEndpoint measures

Endless listEndless list

Number of pellets of food grasped in XNumber of pellets of food grasped in X--amount of amount of timetimeNumber of footfalls while crossing a ladder, Number of footfalls while crossing a ladder, horizontal beamhorizontal beamTime to swim from one point to anotherTime to swim from one point to anotherLimb use while rearingLimb use while rearingWithdrawal thresholdWithdrawal thresholdEtc, etc, etc.Etc, etc, etc.

Tapered BeamTapered Beam

Withdrawal ThresholdWithdrawal Threshold

Webb et al, Behav Brain Res, 2003

Assessment of RecoveryAssessment of Recovery

KinematicsKinematicsQualitativeQualitativeSemiquantitativeSemiquantitative (ordinal rating scales)(ordinal rating scales)Quantitative Quantitative -- highly objectivehighly objectiveRequires variable amounts of trainingRequires variable amounts of trainingAnswers how a behaviour is performedAnswers how a behaviour is performed

KinematicsKinematics

Movement notation Movement notation

Rating scales (e.g. Canine Rating scales (e.g. Canine locomotorlocomotorrating scale)rating scale)

Quantitative kinematicsQuantitative kinematicsUse of motion analysis system (e.g. Peak Use of motion analysis system (e.g. Peak MotusMotus))

SemiquantitativeSemiquantitative kinematicskinematics

Metz and Whishaw, J Neurosci Methods, 2002

Quantitative KinematicsQuantitative Kinematics

Webb et al, Behav Brain Res, 2003

Assessment of RecoveryAssessment of Recovery

KineticsKineticsQuantitativeQuantitativeHighly objectiveHighly objectiveRequires substantial amount of trainingRequires substantial amount of trainingAnswers how a behaviour is performedAnswers how a behaviour is performed

KineticsKinetics

Use of force measuring devices to Use of force measuring devices to measure:measure:

Strength of graspingStrength of grasping

Ground reaction forcesGround reaction forces

Force to Break Force to Break a Piece of a Piece of

PastaPasta

Ballerman et al, Brain Res Bull, 2001

Ground Ground Reaction Reaction ForcesForces

Webb and Muir, Eur J Neurosci, 2003

Physiological MeasuresPhysiological Measures

Recommendations regarding Recommendations regarding behavioural analysis of SCI dogsbehavioural analysis of SCI dogs

Perform a series of neurological evaluationsPerform a series of neurological evaluations

Use a logical and complimentary battery of testsUse a logical and complimentary battery of testsEnsure tests are appropriate for speciesEnsure tests are appropriate for speciesEnsure tests are appropriate for level of SCIEnsure tests are appropriate for level of SCI

When possible, When possible, examine a variety of neural systemsexamine a variety of neural systems ––sensory (incl. pain), motor, and autonomicsensory (incl. pain), motor, and autonomic

Ensure that behaviour examined will answer your Ensure that behaviour examined will answer your questionquestion

Webb et al, Vet Rec, 2004

Mechanisms of InjuryMechanisms of InjuryPrimary injury mechanismsPrimary injury mechanisms

Secondary injury mechanismsSecondary injury mechanismsIschemiaIschemiaFree radical formationFree radical formationExcitotoxicityExcitotoxicityLocal electrolyte imbalancesLocal electrolyte imbalancesInflammationInflammation

Cell deathCell deathApoptosis and necrosisApoptosis and necrosis

Primary InjuryPrimary Injury

Webb et al, 2006

Secondary InjurySecondary Injury

From Rabchevsky, Arch Neurol, 2001

From www.Wingsforlife.com

Species DifferencesSpecies Differences

Sroga et al, J Comp Neurol, 2003 42 d

RAT

MOUSE

Species DifferencesSpecies DifferencesMouse

Hamster

Rat

1 wk 3 wk 8 wk

Inman and Steward, J Neurotrauma, 2003

Species DifferencesSpecies DifferencesMouse

Hamster

Rat

GFAP around periphery in all species

Inman and Steward, J Neurotrauma, 2003

Lines of SCI researchLines of SCI researchNeuroprotectionNeuroprotection

RegenerationRegeneration

Replacing lost tissueReplacing lost tissue

Promoting neural plasticityPromoting neural plasticity

Combinatorial approachesCombinatorial approaches

Treatment strategiesTreatment strategiesNeuroprotectionNeuroprotection

Methylprednisolone (NASCIS trials)Methylprednisolone (NASCIS trials)MinocyclineMinocyclineAntiAnti--integrinsintegrinsUse of Use of neurotrophinsneurotrophins

RegenerationRegenerationProinhibitoryProinhibitory

MyelinMyelinChondroitinChondroitin, , heparanheparan, and , and keratankeratan sulfate sulfate proteoglycansproteoglycans

Overcoming inhibitionOvercoming inhibitionNOGO antibody (INNOGO antibody (IN--1)1)RolipramRolipramChondroitinaseChondroitinase

Treatment strategiesTreatment strategiesBridging the gap and replacing lost tissueBridging the gap and replacing lost tissue

Schwann cellsSchwann cellsOlfactory Olfactory ensheathingensheathing gliagliaStem/precursor cellsStem/precursor cellsFetal tissueFetal tissue

Promoting neural plasticityPromoting neural plasticityTraining/rehabilitationTraining/rehabilitation

Combinatorial approachesCombinatorial approaches

MethylprednisoloneMethylprednisolone??Human clinical trials under scrutinyHuman clinical trials under scrutiny

No longer a standard of care in many Canadian No longer a standard of care in many Canadian hospitals (e.g. Calgary) hospitals (e.g. Calgary) (Hurlbert and Moulton, Can J (Hurlbert and Moulton, Can J NeurolNeurol SciSci, 2002; Hurlbert, , 2002; Hurlbert, Spine, 2006)Spine, 2006)

No longer a standard of care in veterinary No longer a standard of care in veterinary medicine medicine (Vitale and Coates, Standards of Care Newsletter, 2007)(Vitale and Coates, Standards of Care Newsletter, 2007)

Standard of care recommendations for dogs and Standard of care recommendations for dogs and humans are to:humans are to:

Ensure tissue perfusion/oxygenation and prevent Ensure tissue perfusion/oxygenation and prevent further spinal cord ischemia further spinal cord ischemia (Hurlbert 2006; Vitale and Coates, (Hurlbert 2006; Vitale and Coates, Standards of Care Newsletter, 2007)Standards of Care Newsletter, 2007)

Relatively recent, current and Relatively recent, current and forthcoming research for clinical canine forthcoming research for clinical canine

SCI researchSCI research

44--aminopyridineaminopyridine

Oscillating electrical fieldsOscillating electrical fields

SurfactantsSurfactants

Olfactory Olfactory ensheathingensheathing gliaglia

Questions ?Questions ?

Future lab link:Future lab link:www.webblab.ucalgary.cawww.webblab.ucalgary.ca

AcknowledgementsAcknowledgements

Brendan Kerr; Hisham Assem, Tanya NevilleBrendan Kerr; Hisham Assem, Tanya NevilleNSERCNSERCHBIHBIUCVMUCVMUCUCCheryl Cullen and Brennan WebbCheryl Cullen and Brennan Webb