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Translational Studies In Spinal Cord Injury:

An Update

Translational Studies In Spinal Cord Injury:

An Update

Alexander R. Vaccaro, MD, PhD, FACSProfessor, Vice Chairman

Department of Orthopaedics and NeurosurgeryThomas Jefferson University

and the Rothman InstitutePhiladelphia, PA

DisclosureDisclosure� Grant Support/ Royalties/stock options:

Depuy, Medronics, Stryker, Globus, Stout Medical, Progressive Spinal Technologies, Aesculap, Alphatec, Biomet Spine, Paradigm Spine, Replication Medica, Spinology, Orthofix, Bonovo Spine, Gamma Spine, LBI, SBI, Orthovita, K2M, Cerapedics

• Novel methods to reduce the secondary SCI are of great interest

• Why?

• Regaining even modest control of extremity function can have a dramatic effect on quality of life

Pathophysiology

• Secondary Injury• Ischemia-reperfusion

• Free-radical formation • Calcium influx

• Inflammatory cell recruitment

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Barriers To Regeneration

• Necrosis, Apoptosis• Cystic cavitation

• Glial scar formation

Glial Scar

• Goal: Quantify relationship between glial scar formation and axon regeneration (dog,rat)

• Formation of glial scar defined at 4 weeks

• Electrophysiologic, functional and MRI improvement plateau at 4 weeks

• Glial scar blocked extension of regenerated axons

KDI tripeptide

Antagonists of growth inhibitory signals in CNS •Monoclonal antibodies to Nogo•Phosphodiesterase inhibitors (Rolipram)•Dibutyril cyclic AMP (db cAMP) Inhibitors of Rho signaling (Cethrin)

Scar-preventing substances (chondroitinase ABC, cordaneurin, EphA4 antagonists)

Immune therapy with activated macrophages

Monosialoganglioside GM 1

IGF-1 (insulin-like growth factor)

Neurotrophins—additionally characterized by their pleiotropic effects6

•NGF (nerve growth factor)•NT-3 (neurotrophin-3)•BDNF (brain-derived neurotrophic factor)•GDNF (glial-derived neurotrophic factor)•CNTF (ciliary neurotrophic factor)

Antioxidants •EAAC1 protein•Free radical scavengers: ascorbate, vitamin E, beta-carotene, alpha-tocopherol, penicillamine, superoxide dismutase, Q10 coenzyme•L-cysteine

Apoptosis inhibitors •Protease inhibitors (caspase inhibitors, calpain inhibitors)•PARP (poly (ADP-ribose) polymerase) inhibitors

KDI tripeptide

Antagonists of growth inhibitory signals in CNS •Monoclonal antibodies to Nogo•Phosphodiesterase inhibitors (Rolipram)•Dibutyril cyclic AMP (db cAMP) Inhibitors of Rho signaling (Cethrin)

Scar-preventing substances (chondroitinase ABC, cordaneurin, EphA4 antagonists)

Immune therapy with activated macrophages

Monosialoganglioside GM 1

IGF-1 (insulin-like growth factor)

Neurotrophins—additionally characterized by their pleiotropic effects6

•NGF (nerve growth factor)•NT-3 (neurotrophin-3)•BDNF (brain-derived neurotrophic factor)•GDNF (glial-derived neurotrophic factor)•CNTF (ciliary neurotrophic factor)

Antioxidants •EAAC1 protein•Free radical scavengers: ascorbate, vitamin E, beta-carotene, alpha-tocopherol, penicillamine, superoxide dismutase, Q10 coenzyme•L-cysteine

Apoptosis inhibitors •Protease inhibitors (caspase inhibitors, calpain inhibitors)•PARP (poly (ADP-ribose) polymerase) inhibitors

Cell adhesion molecules (L1-CAM)

DMSO (dimethyl sulfoxide)

Erythropoietin

Melatonin

Inosine (Axosine)

AIT-082 (leteprinim potassium, Neotrofin)

4-aminopyridine (Fampridine)

Riluzole

Fusion technology (polyethylene glycol)

Physical therapy •Low-level LASER (light amplification by stimulated emission of radiation) therapy•Oscillating field stimulator•Functional electrical stimulation•Repetitive transcranial magnetic stimulation

Pharmacological and physiatric stimulation of the spinal central pattern generator (CPG)

Local hypothermia

Hyperbaric oxygen therapy

Combinatory (‘COMBO’) strategies

Cell adhesion molecules (L1-CAM)

DMSO (dimethyl sulfoxide)

Erythropoietin

Melatonin

Inosine (Axosine)

AIT-082 (leteprinim potassium, Neotrofin)

4-aminopyridine (Fampridine)

Riluzole

Fusion technology (polyethylene glycol)

Physical therapy •Low-level LASER (light amplification by stimulated emission of radiation) therapy•Oscillating field stimulator•Functional electrical stimulation•Repetitive transcranial magnetic stimulation

Pharmacological and physiatric stimulation of the spinal central pattern generator (CPG)

Local hypothermia

Hyperbaric oxygen therapy

Combinatory (‘COMBO’) strategies

SCI Translational Studies Therapeutic Approaches Currently In or About to Begin Human Evaluation

TherapyTherapyCommercial

SponsorCommercial

Sponsor Therapeutic ApproachTherapeutic Approach Study DesignStudy Design StatusStatus

Anti-Nogo AntibodiesAnti-Nogo Antibodies

Cethrin®Cethrin®

MinocyclineMinocycline

NovartisNovartis

Aiseres Pharmaceuticles

Aiseres Pharmaceuticles

NoneNone

Inhibit activity of Nogo-A, an inhibatory constituent within CNS myelin that impedes axonal regeneration and/or sprouting

Inhibit activity of Nogo-A, an inhibatory constituent within CNS myelin that impedes axonal regeneration and/or sprouting

Cethrin (BA-210) inhibits rho, a small GTPase that has an important role in mediating axonal growth and neuronal apoptosis.

Cethrin (BA-210) inhibits rho, a small GTPase that has an important role in mediating axonal growth and neuronal apoptosis.

Minocycline attenuates neuro-inflammation and inhibits apoptosis.

Minocycline attenuates neuro-inflammation and inhibits apoptosis.

• ASIA A thoracic and cervical SCI in a multicenter, non-randomized, clinical trial.• Treatment initiated 7-14 days post-injury.• Antibody administered via intrathecal infusion over weeks, or via repeated bolus intrathecal injection

• ASIA A thoracic and cervical SCI in a multicenter, non-randomized, clinical trial.• Treatment initiated 7-14 days post-injury.• Antibody administered via intrathecal infusion over weeks, or via repeated bolus intrathecal injection

• ASIA A thoracic and cervical SCI in a multicenter, non-randomized, clinical trial.• Treatment initiated up to 7 days post-inury.• Cethrin applied to the overlying dura at the time of spinal cord decompression

• ASIA A thoracic and cervical SCI in a multicenter, non-randomized, clinical trial.• Treatment initiated up to 7 days post-inury.• Cethrin applied to the overlying dura at the time of spinal cord decompression

• Complete and incomplete thoracic and cervical SCI in a single center, randomized, clinical trial (Univ of Calgary).• Treatment initiated within 12 hours of injury.• Minocycline intravenously administered twice a day for 1 week.

• Complete and incomplete thoracic and cervical SCI in a single center, randomized, clinical trial (Univ of Calgary).• Treatment initiated within 12 hours of injury.• Minocycline intravenously administered twice a day for 1 week.

Study began in 2006, currently 45 patients enrolled.

Study began in 2006, currently 45 patients enrolled.

Study began in 2005 and completed in 2007, with results in submission. Subsequent prospective randomized study being planned.

Study began in 2005 and completed in 2007, with results in submission. Subsequent prospective randomized study being planned.

Study began in 2004 and has recruited over 50 patients. Preliminary results in submission. Subsequent prospective randomized study being planned.

Study began in 2004 and has recruited over 50 patients. Preliminary results in submission. Subsequent prospective randomized study being planned.

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Continued…

RiluzoleRiluzole

Magnesium (NeuroShield)Magnesium

(NeuroShield)

Human Embryonic Stem

Cell Derived Oligodendrocyte

Progenitors

Human Embryonic Stem

Cell Derived Oligodendrocyte

Progenitors

NoneNone

MedtronicMedtronic

GeronGeron

Riluzole is a sodium channel blocker that is currently FDA approved for the treatment of ALS.

Riluzole is a sodium channel blocker that is currently FDA approved for the treatment of ALS.

Magnesium is a physiologic antagonist to NMDA receptorsMagnesium is a physiologic antagonist to NMDA receptors

hESC-oligodendrocyte progenitors are to re-myelinate demyelinated axons and restore conduction.

hESC-oligodendrocyte progenitors are to re-myelinate demyelinated axons and restore conduction.

• ASIA A, B and C thoracic and cervical SCI in a multicenter, non-randomized, clinical trial.• Treatment initiated up to 12 hours post-inury.• Riluzole to be administered orally twice per day for a week.

• ASIA A, B and C thoracic and cervical SCI in a multicenter, non-randomized, clinical trial.• Treatment initiated up to 12 hours post-inury.• Riluzole to be administered orally twice per day for a week.

• Phase I saftey study in humans complete. ASIA A cervical SCI to be recruited in a multicenter, non-randomized, clinical trial.• Treatment initiated up to 12 hours post-inury.• NeuroShield to be administered intravenously over 24 hours.

• Phase I saftey study in humans complete. ASIA A cervical SCI to be recruited in a multicenter, non-randomized, clinical trial.• Treatment initiated up to 12 hours post-inury.• NeuroShield to be administered intravenously over 24 hours.

• ASIA A thoracic SCI in a multicenter, non-randomized, clinical trial.• Transplantation to occur 7-14 days post-injury. • Cells can be injected into the injured spinal cord.

• ASIA A thoracic SCI in a multicenter, non-randomized, clinical trial.• Transplantation to occur 7-14 days post-injury. • Cells can be injected into the injured spinal cord.

Initiated as a multicenter collaboration through the North American Clinical Trials Network.

Initiated as a multicenter collaboration through the North American Clinical Trials Network.

Phase I safety study in healthy volunteers now completed; SCI study set to begin

Phase I safety study in healthy volunteers now completed; SCI study set to begin

FDA approval granted in January 2009, clinical hold released August 2010

FDA approval granted in January 2009, clinical hold released August 2010

Systemic Hypothermia

Systemic Hypothermia

NoneNone

Hypothermia slows metabolic rate, reduces inflammation and oxidative stress

Hypothermia slows metabolic rate, reduces inflammation and oxidative stress

• Retrospective review of 14 ASIA A cervical SCI in a single center (Univ of Miami)• Treatment initiated within 12 hours of injury in almost all patients• Systemic hypothermia induced to 33°C for 48 hours

• Retrospective review of 14 ASIA A cervical SCI in a single center (Univ of Miami)• Treatment initiated within 12 hours of injury in almost all patients• Systemic hypothermia induced to 33°C for 48 hours

Study initiated in 2006. Review of 14 ASIA A patients suggests that the treatment is safe, and in 6 of 14 improved to ASIA B, C, or D.

Study initiated in 2006. Review of 14 ASIA A patients suggests that the treatment is safe, and in 6 of 14 improved to ASIA B, C, or D.

Hypothermia

• September, 2007• Kevin Everett C3-4 Fx/Dl

• 1970’s

• Performed at several centers after acute SCI

• Poor study designs, few patients, limited outcome measures

• 8 small case series (last in 1984) heterogeneous pop, no control

Hypothermia

• Decreases tissue metabolism and energy requirements Zager J. Neuro 1988

• Decreases swelling of Parenchyma and nerve roots Huang, J. Neuro. Science 1999

• Reduces tissue hemorrhage Albin J. Trauma 1969, Yu, J. Neuro, 2000

• Decreases inflammation, Apoptosis, oxidative stress Ohmuro, Brain Dev. 2005

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Animal Studies25 animal studies in literature� Results are mixed� Most recent with negative results

25 animal studies in literature� Results are mixed� Most recent with negative results

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• 14 pts ASIA A cervical SCI

• Femoral venous catheter

• Cooling rate .5°C/hr to 33°C for 48hrs• 9.1 hrs following injury, 2.1 hrs to cool

Results From Phase I

• 14 pts cooled• 6 of 14 were incomplete at 50 week f/u

• 3 improved to ASIA B, 2 to ASIA C and 1 to ASIA D

• Complications predominately respiratory and infectious

All patients who regained function did so > 2 weeks after injury

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Until even low-quality evidence exists to substantiate the safety and efficacy of hypothermia, physicians should not

be pressured into inducing hypothermia in acute SCI

Steroids

• NASCIS II- High dose MPSS vs Naloxone/Placebo

• Post hoc analysis- Neuroprotection if within 8hrs

• NASCIS III- < 8 hrs, 24 vs 48hrs• Post hoc analysis- Improved function at 6 weeks

and 6 months if administered within 8 hrs

Validity Questioned

• Difficulties in randomization

• Errors in statistical analysis

• Reliability of data collection

• Motor levels poorly defined

• Results not replicated in the US

• 305 surgeons surveyed• 90.5% used steroids

• 24.5% believed in improved outcome• Most common reason for use- Fear of

litigation

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Minocycline

• Commonly used for acne• Neuroprotective in animal models (rat)

• Atenuates secondary injury

• Enhances functional recovery• Yune J Neuroscience, 2007• Ha Eur. Spine J, 2008• Lee J Neurotrauma, 2003

• Mechanism• Inhibition of microglial activiation• Prevents apoptosis

Minocycline

• Phase I/II Clinical trialCompleted 52 patient PRCT (Univ. of Calgary)

• Objectives• Assess feasibility and safety • Assess systemic and CSF absorption characteristics • Assess serial CSF inflammatory mediator concentrations

Cervical SCI(n=29)

∆ =8.7 points P=0.269

∆ =14.97 points

p=0.026

∆ = 20.1 points P=0.024

Minocycline

Placebo

INCOMPLETE (n=9) COMPLETE (n=20)

Riluzole

• Na+/glutamate antagonist• FDA approved in ALS

• Attenuates anterior horn cell degeneration

• Grey/White matter spared • Functional recovery observed• Reduced tissue loss rostral/caudal

• Grey/White matter spared • Functional recovery observed• Reduced tissue loss rostral/caudal

Na+

H O2

VN a +

Activation ofphospholipase

Cytotoxic edemaIncreased Ca

2 +

i

Acidosis

Na+

Ionotropic GlutamateReceptor

ATPNa

+

K+

Excitotoxicity

H+

Na+

Na+

Ca2 +

Glu

Na+

Cl-

Na /HCO+ -

3

DISTANCE from EPICENTER (mm)

RiluzolePHTCNS5546AControl

NO

RM

ALIZ

ED

RE

SID

UA

L T

ISS

UE

AR

EA

EpicenterRostral Caudal-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

*

*

***

**

**

Tissue Preservation with Na Channel Blockers+

Reduced Cavity Area at Injury Epicenter

NO

RM

ALI

ZE

D E

PIC

EN

TE

RC

AV

ITY

AR

EA

RIL PHT CNS CTRL0.0

0.2

0.4

0.6

0.8

1.0

**** *

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Riluzole

• Phase I Clinical trial- currently recruiting• Administered within 12 hours, 14 day course

• C4-T10• ASIA A,B,C

• Safety assessment at 3 months

• Neurologic benefit assessed at 6 months

Targeting Myelin Associated Inhibitors

• Anti-Nogo

• Cethrin

NgR

Myelin AssociatedInhibitors

Myelin AssociatedInhibitors

Rho

ROCK

p75TROYLINGO-1

TNF ReceptorFamilyProterins

Stabilization of ActinCytoskeleton:

Decreased GrowthCone Mobility/Collapse

NogoNogo

MAGMAG

OMgpOMgp

NgR

Myelin AssociatedInhibitors

Myelin AssociatedInhibitors

p75TROYLINGO-1

TNF ReceptorFamilyProterins

IN-1 (Anti-Nogo Antibodies)IN-1 (Anti-Nogo Antibodies)Rho

ROCK

NogoNogo

MAGMAG

OMgpOMgp

Stabilization of ActinCytoskeleton:

Decreased GrowthCone Mobility/Collapse

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NgR

Myelin AssociatedInhibitors

Myelin AssociatedInhibitors

Rho

ROCK

p75TROYLINGO-1

TNF ReceptorFamilyProterins

C3 Transferase(Cethrin®)C3 Transferase(Cethrin®)

NogoNogo

MAGMAG

OMgpOMgp

Stabilization of ActinCytoskeleton:

Decreased GrowthCone Mobility/Collapse

Anti-Nogo

• Anti-Nogo- IN-1 monoclonocal Ab

• Promotes axonal sprouting and functional recovery in animal SCI models

Nature Med 12,2006

Control Ab Hu anti-Nogo-A Ab

Anti-Nogo

• ATI-355• Humanized anti-nogo

• Phase I clinical trial complete• ASIA A C5-T12

• Continuous intrathecal injection 4-14 days post injury

• Neutrapenia earliest complication

Anti-Nogo

• Phase II:51 pts • ASIA A• 6 dosing regimens, infusion/bolus

• Infusion groups- completed

• Bolus groups- on-going

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Anti-Nogo

• Preliminary Results:• No adverse events, no

immunogenicity• Neurologic improvement vs.

spontaneous recovery?• 4 para- ASIA A to B/C

• 2 tetra- ASIA A to B- 1 gained 2 levels

• Preliminary Results:• No adverse events, no

immunogenicity• Neurologic improvement vs.

spontaneous recovery?• 4 para- ASIA A to B/C

• 2 tetra- ASIA A to B- 1 gained 2 levels

C3 mediated Rho inhibition

• C3 transferase from C. botulinum• When activated inhibits Rho.

• Facilitated axonal growth and functional recovery in mouse model

Cethrin ®

• C3-like recombinant Rho inhibitor

• Extra dural delivery via fibrin sealant

• Absorbed by spinal cord

• Rho pathway inhibited

Cethrin ®

• Phase I/II clinical trial complete• 6 month patient data

• 37 patients 10 sites• No adverse events related to treatment• 28% improved 1 ASIA score or better

1 year results show dose dependent response

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Cellular Transplantation Strategies

• Olfactory Ensheathing Cells (OEC)

• Autologous Macrophages

• Schwann Cells

• Embryonic Stem Cell Derived NPC and OPCs

OEC• Specialized glial cells

• Directs olfactory regeneration

• Exceptional plasticity• Allow neurons to cross glial scar and PNS-

CNS boundary

OEC

• Complete SC transection in rat• Motor axon regeneration

distances beyond lesion• Improved locomotion and

sensory-motor reflex

Transplanted Control

Functional RecoveryFunctional Recovery

OEC Clinical Trials

• None in the US

• Portuguese study- uncontrolled• 7 patients, all with ASIA improvement

• Australian study- single blinded• 3 pts, complete SCI within 6 mo to 3 years

� 3 year f/u� No sensory/motor improvement� No adverse events

� No changes on MRI

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OEC Clinical Trials

• China- largest experience• >300 pts• Lack of scientific methodology• Reported neurologic recovery• Outcomes questioned

Activated Macrophages

• Abundant in PNS

• Rapidly clear myelin debris

• Secrete nerve growth factor

Activated Macrophages

• Poor regeneration in CNS thought because of insufficient recruitment

• Schwartz Acta Neurochir Suppl, 2005

Activated Macrophages

• Activated macrophages transplanted into sectioned SC

• Nerve fibers across injury site• Functional recovery

treated

control

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ProCord

• 200 cc blood collection

• Monocyte/skin co-incubation 1 day

• Injected into caudal injury site

ProCord

• Phase I trial• 8 patients

• ASIA A• Within 14 days of

injury

• 3 pts improved from ASIA A to C

• 5 recovered SSEP or MEP activity

• No treatment related complications

First pt treated received partial recovery

• Financial constraints forced permanent discontinuation of trial

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STEM CELLSPluripotent

human embryonic stem cell Differentiation

No longer a multipotent stem cell, but a

“progenitor” cell with a determined fate

hESC-derived oligodendrocyte progenitor cell

☺ ☺ ☺ ☺☺ ☺ ☺ ☺☺

☺ ☺☺

☺ ☺ ☺☺ ☺☺☺

☺☺

hESC-derived OPCs

INTACT axons

DEMYELINATED axons

TRANSECTED axons • High purity OPC’s from human ESCs

• hESC-OPC Transplanted into rats 7 days vs. 10 mo post SCI

• Produces Oligodendrocytes in Vivo• Myelinates denuded axons

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1 week post-injury transplantationremyelination and improved recovery, 8 rats

1 week post-injury transplantationremyelination and improved recovery, 8 rats

10 months post-injury transplantationno recovery

10 months post-injury transplantationno recovery

Geron

• Proposed Phase I/IIA Trial

• 10-12 Thoracic ASIA A, non-penetrating SCI

• Transplant of hESC-derived oligodendrocyte progenitor cells (GRNOPC1) 7-14 days post injury

• Immunosupression x 2 months

• International Society For Stem Cell Research concerned about aggressive marketing of treatments

• some clinics may not have safeguards to ensure safety or likely benefit

• the society launched a website that “offers background information on stem cell research”

Vaccaro, Spine 1997

• Prospective randomized controlled study• 64 patients with cervical spinal cord injury and

radiographically documented cord compression• Randomized to early (<72 hrs) or late (>5 days)

surgery

• 64 pt met inclusion criteria• ASIA A-D; Level C3 to T1

• Early-mean 1.8 d; Late-mean 16.8 d• No significant difference in ICU stay, length of

inpatient rehab, or neurological recovery

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STASCISSurgical Trial in Acute SCI Study

PI: Michael Fehlings (U of T) Alexander Vaccaro (TJU)

• Prospective cohort/randomized study

• Goal to examine role and timing of decompressive surgery after acute SCI

AANS/CNS Section on Neurotrauma and Critical Care

American Spinal Injury Association

Krembil Foundation

• Primary outcome measure of interest-AIS grade

change at 6-months follow-up

STASCISInclusion Criteria Exclusion Criteria1) Male or female 2) Ages 16-703) Initial GCS >134) Initial AIS grade A-D5) Cervical spinal cord compression confirmed by MRI or

CT Myelography6) Patient or Proxy willing to provide consent for

enrollment

1) Cognitive impairment preventing accurate neurologic assessment

2) Penetrating injuries to the neck3) Pregnant females4) Pre-injury major neurologic deficits or disease (i.e.

ischemic stroke, Parkinson’s Disease )5) Life threatening injuries which prevent early

decompression of the spinal cord6) Significant pre-morbid medical illness (including, but

not limited to):1)Myocardial Infarction within 3 months2) Uncompensated Heart Failure3) Active systemic cancer4) AIDS

1) Criminals under indictment or incarceration2) Ankylosing Spondylitis

STASCISSurgical Trial in Acute SCI Study

PI: Michael Fehlings (U of T), Co-PI: Alexander Va ccaro (TJU)

• University of Toronto• Michael Fehlings; Raja Rampersaud; Eric Massicotte; Stephen Lewis

• Thomas Jefferson University• Alexander Vaccaro;James Harrop

• University of Maryland• Bizhan Aarabi

• University of Virginia• Christopher Shaffrey; John Jane

• University of British Columbia (ICORD)• Marcel Dvorak; Charles Fisher

STASCISDefinition of Early Versus Late

Decompression

I. Prospective Cohort Study• Early – within 24 hours

• Late – greater than 24 hours

II. Prospective randomized study• Early-within 12 hours

• Late-greater than 24 hours

III. Prospective nonrandomized study on facet dislocations in setting of neurologic deficit

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Patient Flow470 patients

screened for study entry

325 patients enrolled

187 early surgery cohort

138 late surgery cohort

135 patients at 6 months follow-up

96 patients at 6 months follow-up

Inclusion/exclusion criteria applied

Surgery <24hours Surgery ≥ 24 hours

6 mortalities46 lost to follow-up 4 mortalities

38 lost to follow-up

characteristics Overall (n=313) Early surgery (n=182)Late surgery (n=131) p

Mean age ± SD P=0.002847.40±16.89 44.99±17.20 50.74±15.90

Gender n(%) p>0.05Male 236 (75.40%) 140 (76.92%) 96 (73.28%)Female 77 (24.60%) 42 (23.08%) 35 (26.72%)

Etiology p>0.05Motor Vehicle Accident 119 (38.02%) 76 (41.76%) 43 (32.82%)Fall 121 (38.66%) 64(35.16%) 57 (43.51%)assault – blunt 13 (4.15%) 8 (4.40%) 5 (3.82%)sports 3 (9.58%) 16 (8.79%) 12 (9.16%)other 3 (9.58%) 18 (9.89%) 14 (10.69%)

Baseline AIS P=0.0047A 101(32.27%) 65 (35.71%) 36 (27.48%)B 54 (17.25%) 40 (21.98%) 14 (10.69%)C 66 (21.09%) 32 (17.58%) 34 (25.95%)D 92 (29.39%) 45 (24.73%) 47 (35.88%)

GCS ± SD P>0.0514.90±0.36 14.90±0.35 14.89±0.37

Demographics and Key Covariates

Mean times to decompression

14.2 ±5.4 hrs 48.4 ±29.3 hrs

Hrs

Preoperative AIS scores: Early vs. Late Surgery

0

5

1015

20

25

30

3540

45

50

ASIA A ASIA B ASIA C ASIA D

Early SurgLate Surg

Preoperative AIS scores

Per

cen

tage

of

Pat

ien

ts

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AIS grade improvement at 6 months:Early vs. Late Surgery

0

10

20

30

40

50

60

-1 0 1 2 3

EarlyLate

AIS grade change at 6 months

Per

cen

tage

of

Pat

ien

tsAIS grade improvement at 6 months:

Early vs. Late Surgery

• Two or more grade improvement:

27 patients (20.0%) in the early group and 10 patients (10.4%) in the late group experienced at least a 2 grade improvement (p=0.036) at 6 months.

AIS grade improvement at 6 months:Early vs. Late Surgery

• Final Regression model:• Early vs. Late surgery

• Positive Effect Estimate 0.236 (P=0.006)• Pre-operative AIS grade

• Negative Effect Estimate -0.306 (P<0.0001)• Age

• Not significantly related to AIS grade improvement (p=0.4693)

• Corticosteroids• Not a significant independent effect on AIS

grade outcome

There was a trend for higher complications rates (46%) in the late group compared to the early group (36%)

-main difference: reduction in ventilator associated pneumonia

ComplicationsComplications Prior to Discharge by Time to Decompr ession

53 36.1% 56 45.5% 109 40.4%

94 63.9% 67 54.5% 161 59.6%

147 100.0% 123 100.0% 270 100.0%

Yes

No

Total

Were there anycomplicationsprior to discharge?

Count Column N %Early

Count Column N %Late

Count Column N %Total

Time to Decompression

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Cervical SCI with Fracture/Dislocation

Summary

• Clinical evidence for hypothermia sparse • Methylprednisolone use diminishing• Initial results from current pharmacologic

trials promising• Stem cell clinical trial now beginning • Maintenance of MAP/ Early

decompression most promising

THANK YOU