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Neurotrauma

and
Spinal Cord Injury
A. Curt, MD FRCPC
Spinal Cord Injury Center, University of Zuerich
University Hospital Balgrist

Neurotrauma

Neurotrauma
Brain

Spinal cord

CNS

PNS

Spinal Cord Injury


a neurological problem

Rehabilitation research starts here!

Rehabilitation research starts here!

The challenge
informed clinical trials in human SCI
appraisal of pre-clinical studies in SCI
proof of mechanisms in human SCI

Principles in SCI rehabilitation

Sir Ludwig Guttmann


Stoke Mandeville 1944
Spinal cord injuries:
comprehensive management
and research
(1976)

Dr. Huang, Bejing China


OEC transplantation in SCI
2007 StemCellsChina.com
Visitors: 466.754

Appraisal of pre-clinical studies in SCI


effectiveness and clinical relevance in humans

Species specific differences in:


Rubro reticulo vestibulo spinal descending motor projections
proprio spinal pathways and influence of CPG on locomotor output
requirements of body function to achieve ADL relevant outcomes

Proof of mechanism in human SCI


from bench to bedside in SCI
neuro- plasticity / regeneration / repair / protection

European Multicenter study group in Spinal Cord Injury


EM-SCI
EM-SCI Centers
22
20
18
16
14
12
10
8
6
4
2
0
2001

2002

2003

2004

2005

2006

2007

2008

2009

Publications based on EMSCI data


30
25

Scientific output
International recognition

20

First European Spinal Cord Injury


network
Lead: Uniklinik Balgrist, Zrich

15
10
5
0
2004

2005

2006

2007

2008

2009

Informed clinical trials in human SCI

Pedestrians 6 m onths post iSCI


(% )

outcome measures and thresholds

100
80
60
40
20
0
ASIA B

ASIA C

ASIA D

ASIA category 2 months post iSCI

Fawcett J et al (2007) Spinal Cord

Dobkin B et al (2006) Neurology

Informed clinical trials in human SCI


outcome measures and thresholds

70
60

40

30
20
10

C07

C07

C06

C06

C06

C06

C05

C05

C05

C05

C05

C04

C04

C04

C04

C03

0
C01

delta motor score

50

Level of Injury

Sygen control data (n=195 tetraplegic patients)

Motor Level Changes

Functional recovery independent of


changes in motor deficit
thoracic

80

80

80

60

40

ASIA motor

100

60
40

20

20

60

40
20

0
0

30

60

90

120

150

180

210

240

270

300

330

360

30

60

90

120 150

180

210 240

270

300 330

360

100

100

SCIM in %

60
40
20

SCIM

80

SCIM

60

40

30

60

90

120 150 180

210 240 270 300 330 360

90

120

150

180

210

240

270

300

330

360

80
60

SCIM

40

0
0

60

20

20

30

100

SCIM in %

80

SCIM in %

conus/cauda

100

ASIA motor

ASIA motor

Complete tetra
100

30

60

90

120 150 180 210 240

270 300 330 360

30

60

90

120

150

180

210

240

270

300

330

Curt A, Hedel vH et al.. Recovery from a spinal cord injury: Significance of compensation, neural plasticity and repair. J Neurotrauma 2008
Wirth B, et al.. Changes in activity after a complete spinal cord injury as measured by the Spinal Cord Independence Measure II (SCIM II).
Neurorehabil Neural Repair 2007

360

SCIM recovery after delayed rehabilitation


SCIM score of matched EMSCI patients compared to a patient
with delayed onset of rehabilitation
100

level of lesion: th9

90
80

77

SCIM score

70

69

68

60

56

55
50
40
30

26
20

20

14
10
0
0

30

60

90

120

150

180

210

days after SCI

240

270

300

330

360

Objectives of talk
Is there spinal cord repair in clinical recovery?
Sensitive assessment of longitudinal spinal and segmental
pathways?
Spinal cord plasticity and proof of mechanism / concept of
interventional trials?

Is there repair of damaged pathways?

lesion

Functional recovery in
incomplete spinal cord injury

3 weeks after injury

12 weeks after injury

Outcome measures:
high clinical value

!
!
s
m
s
i
10-m walk test
n
a
h
6-minute walk test
c
e
m
Timed up and go test
f
o
s
n
LEMS (manual muscle testing)
a
e
m
SCIM III (walking items)
o
n
t
WISCI
II
u
b
Modified Ashworth Test

e
Robotic SCI rehab devices
l
b

a
t
u
b
i
r s!!
t
t
a
m
s
s
e ni
g
n
a
a
h
c
h
c
e
d
m
e
e
c
l
u
p
i
t
d
l
n
u
I
m
to
Gait Trainer

Armeo

AutoAmbulator

ReoTM

Lokomat

InMotion

Erigo

ARMin

Neuro-imaging spinal cord


acute spinal cord damage
chronic spinal cord damage
post traumatic complication
spinal cord plasticity

Neuro-imaging spinal cord


Post traumatic cystic deformation

Neuro-imaging spinal cord

acute
acute

chronic

acute
acute

chronic
chronic

Neuro-imaging spinal cord


Male 36 yrs
snowboard acc
mild central cord
neuropathic pain
works as a
surgeon again!

Clinical Neurophysiology of
Spinal Cord Function

Spinal pathway

Method

Acceptance

Clinical
correlate

cortico-spinal1

MEP

routine

central
paresis

dorsal column2

SSEP
dSSEP

routine

proprioception

sympa-thetic3

SSR

routine

cardiovascular
control

spino-thalamic4

EP
(CHEPs)

routine

pain/temp
perception

vestibulo-spinal5

GVS

investigational

postural
instability

peripheral system6

NCS / Reflex
EMG

routine

peripheral
paresis

1
3
4

6
1
5

Dietz V, Curt A. Neurological aspects of spinal cord repair: promises and challenges. Lancet Neurology 2006

Paresis in iSCI

MMV remains unchanged with frequency, ROM becomes reduced with frequency and
but is reduced in iSCI

is lower in iSCI

Dexterity in iSCI

Range of motion

ROM

Accuracy

iSCI patient
control

Time

Wirth et al, J Neurol 2008

Dexterity in iSCI

Accuracy

Dexterity in iSCI

Accuracy

Dexterity in iSCI

Dexterity in iSCI
 accuracy in simple activation
Swing phase

timing of activation
releasing the antagonist

 dorsiflexion in ambulation

initiation of swing phase

 visually controlled tracking task

accuracy of tonic and phasic


activation

Wirth B, van Hedel H, Curt A. Foot control in incomplete SCI: distinction between paresis and dexterity. Neurological Res 2007

Motor evoked potentials


EMG recordings
MEP silent period
Torque performance

TMS trigger

Cumulus sum

Diehl P, Kliesch U, Dietz V, Curt A. Impaired facilitation of motor evoked potentials in incomplete spinal cord injury. J Neurology 2006

CST conductivity and motor


function
Dependent
variable
Measures of
muscle strength

Dynamic MEP latency

Dynamic MEP amplitude

Standardized
regression
coefficient

p-value

Standardized
regression
coefficient

p-value

R2adj.

Max Movement
Velocity 0.8 Hz

-0.435

0.046

0.542

0.016

Max Movement
Velocity 1.6 Hz

-0.571

0.013

0.367

0.091

0.350

Max Movement
Velocity 2.4 Hz

-0.606

0.002

0.589

0.002

0.616

Max Ankle
Torque

-0.505

0.039

excluded

0.205

excluded

0.000

Manual Muscle
Testing

excluded

0.371

Hedel vH, Murer C, Dietz V, Curt A. The amplitude of lower leg motor evoked potentials is a reliable measure when controlled for torque and motor task.
J Neurol 2007

CST conductivity during recovery


P<0.001
p=0.002
P<0.001

Follow up study in acute iSCI


Wirth B, Hedel vH, Curt A. Changes in corticospinal function and ankle motor control during recovery from incomplete SCI. J Neurotrauma 2008

SSEP recordings

normal

reduced
reduced
slowed
suspected
abolished

Follow-up SSEP in ASIA C/D


P = 40.5 ms

P = 44 ms

P = 53 ms

1. mth

3. mths

6. mths
Iseli E, Cavigelli A, Dietz V, Curt A. Prognosis and recovery in ischemic and traumatic SCI: Clinical and electrophysiological evaluation.
J Neurol Neurosurg Psychiatry 1999

Message I
No obvious spinal cord repair in respect of
remyelination of longitudinal spinal pathways!

Neural plasticity is fundamental for recovery!

Segmental Sensory Recovery

Dermatomal SSEP
Electrical Perception Threshold (EPT)

Kramer J, et al.. D-SSEP and EPT for the assessment of posterior cord function in SCI.
J Neurotrauma 2008

Pre-surgical MRI

Dermatomal SSEP
C4

C5

C6/7

C6

C7

Male 41yrs, fall injury


C6 ASIA A

C8

Kramer J, et al.. D-SSEP and EPT for the assessment of posterior cord function in SCI. J Neurotrauma 2008

dSSEP of the trunk


from schematic drawing to reality
the T2 - 4 7 (50% equidistance) 10 schema

Complete paraplegia ASIA A


male 37 years, T5/6 dislocation fracture
T2

T4

T7

T 10

Spinothalamic pathways
a-Delta / C-fiber stimulation (CHEPs)
C4

C5

Characteristic, reliable late evoked potentials


C6

C8

C4
Non-affected

C5

Pathological

C6

Abolished

Segmental CHEPs

Pat FN, 40 yrs

Pat RB, 51 yrs

Ulnar SSEP

Tibial SSEP

Pat RB, 51 yrs

Message II
Limited recovery of segmental pathways
close to the epicenter of lesion!

Spinal cord plasticity


WS 46 yrs
tingling sensation left hand

syringo - hydromyelia of the


cervical cord up to brain stem

Spinal cord plasticity


GRASSP hand function
graded redefined assessment of

Strength
49/50
Sensibility
21/24
Prehension
42/42

98%
88%
100%

right upper limb with almost regular


hand arm function

Spinal cord plasticity


ulnar
right

ADM
right

median
right
C6
right

C6
right

MNCS
MEP/TMS

SSEP

CHEP
dSSEP

Spinal cord plasticity


PH 47 yrs
LBP and fatigue during walking

T7

T 7/8 disc protrusion with severe


(>80%) spinal canal encroachment

Spinal cord plasticity


SSEP
regular

Cz
[V]

15

10

CHEPs

T7

-5

regular

-10

-15

100

200

300

400

500

600

700

800

900

[ms]

MEP
latency

Message III
There is a huge spinal cord plasticity dependent
on the pathophysiological background!
Do we underestimate potential approaches to
induce slowly evolving recovery?

Road map for assessment in SCI


for the proof of concept
functional
impairment

neuronal
deficit

neuronal
structure

Neurotrauma
In human SCI:
CORTICOL CONTROL

SPINAL CONDUCTION

Brain control
Preservation - Reorganization
No effective remyelination
Propriospinal pathways ?

Plasticity of neural circuits


SPINAL CIRCUITS

Adaptation of motoneurones
and muscle properties

SPINAL SEGMENTS
Dexterity
Weakness
MOTOR OUTPUTS

Thank you for your attention!