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What Can We Expect Of MUNE in ALS ?

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(1)

Wang FC

Wang FC

CHU de Liège

CHU de Liège

Nice, 2004 Nice, 2004

(2)

Nice, 2004

(3)

1. Estimation of the mean motor unit size

Sample of 10-20 distinct motor unit responses

average S-MUP size

2. Measure of the maximum CMAP size

MUNE = 2 : 1

Nice, 2004

(4)

A. Stimulation MUNE Techniques

1. Incremental stimulation

(McComas et al., 1971)

a. Original technique

(McComas et al., 1971)

b. Multiple Point Stimulation

(Brown and Milner-Brown, 1976)

c. Adapted Multiple Point Stimulation

(Kadrie et al., 1976 ; Wang and Delwaide, 1995)

A. F-response MUNE techinque

(Feasby and Brown, 1974)

B. Intraneural microstimulation

(Arasaki and Tamaki, 1998)

C. Statistical MUNE

(Daube, 1988)

D. MUESA

(Slawnych et al., 1996)

a.

Voluntary MUNE Techniques

1. Spike triggered averaging

(Nandedkar and Barkhaus, 1987 ; Brown et al., 1988 ; Bromberg, 1993)

2. Rectified integrated EMG

(Petajan, 2003)

3. Motor unit number index (MUNIX)

(Nandedkar et al., 2003)

(5)

A. Stimulation MUNE Techniques

1. Incremental stimulation

(McComas et al., 1971)

a. Original technique

(McComas et al., 1971)

b. Multiple Point Stimulation

(Brown and Milner-Brown, 1976)

c. Adapted Multiple Point Stimulation

(Kadrie et al., 1976 ; Wang and Delwaide, 1995)

2. F-response MUNE techinque

(Feasby and Brown, 1974)

3. Intraneural microstimulation

(Arasaki and Tamaki, 1998)

4. Statistical MUNE

(Daube, 1988)

5. MUESA

(Slawnych et al., 1996)

a.

Voluntary MUNE Techniques

1. Spike triggered averaging

(Nandedkar and Barkhaus, 1987 ; Brown et al., 1988 ; Bromberg, 1993)

2. Rectified integrated EMG

(Petajan, 2003)

3. Motor unit number index (MUNIX)

(Nandedkar et al., 2003)

Nice, 2004

(6)

A. Stimulation MUNE Techniques

1. Incremental stimulation

(McComas et al., 1971)

a. Original technique

(McComas et al., 1971)

one stimulation point

ten increments

Nice, 2004

Percutaneous nerve stimulation

Short stimulation duration = 0.05 ms

Weak intensity gradually increased by

increments of 0.1 mA

Individual and sequential

activation of motor axons

(7)

Nice, 2004

Nice, 2004

Five motor units

successively recruited

by incremental

stimulation.

But, six distinct motor

responses

Underestimation of

average S-MUP size

Overestimation of

MUNE

(8)

Nice, 2004

3

mA

(9)

Nice, 2004

Nice, 2004

5

mA

(10)

Nice, 2004

6

mA

(11)

Nice, 2004

Nice, 2004

6 mA

(12)

Nice, 2004

6 mA

(13)

Nice, 2004

Nice, 2004

9

mA

(14)

2 3

4 1

Nice, 2004

A. Stimulation MUNE Techniques

1. Incremental stimulation

(McComas et al., 1971)

a. Original technique

(McComas et al., 1971)

one stimulation point

ten increments

b. Multiple Point Stimulation

(Brown and Milner-Brown, 1976)

ten stimulation points

one increment/site

c. Adapted Multiple Point Stimulation

(Kadrie et al., 1976 ;

Wang and Delwaide, 1995)

3-5 stimulation points

2-3 increments/site

(15)
(16)

• 120-300 stimuli at fixed,

submaximal intensity

• If : - Poisson distribution

of motor evoked

responses

- All MU are assumed to

have the same size

• Variance = Mean

Nice, 2004

Submaximal CMAP

Maximal CMAP

Size distribution of submaximal CMAP

CMAP variance

Single S-MUP size =

mean CMAP-minimum CMAP

Relies on alternation

of axon excitability

(17)

Nice, 2004

Nice, 2004

• Reproducibility of MUNE studies

• Comparison of MUNE

(18)

Technique

Muscle(s)

r

CV (%)

Healthy subjects ALS Healthy subjects ALS Incremental

Brown & Jaatoul, 1974 : Thenar & extensor digitorum brevis

± 15 Spike Triggered Averaging

Bromberg, 1993 : Biceps brachialis 0.07 0.54 45 33 Multiple point stimulation

Felice, 1995 : Thenar 0.85 0.99 17 10

Adapted MPS

Wang & Delwaide, 1995 :

Wang & Delwaide, 1998 : ThenarThenar

0.95 0.97 10 4 Statistical MUNE Olney et al, 2000 :

Lomen-Hoerth & Olnay, 2001 : Hypothenar Hypotheanr 0.84 19 7 Nice, 2004

(19)

Muscle(s)/species

Technique

MUNE

Soleus/rat (Eisen et al, 1974) Anatomical Incremental 30 31 Extensor digitorum brevis/monkey

(Peyronnard & Lamarre, 1977)

Anatomical Incremental 153 120 Medial gastrocnemius/mouse (Arasaki et al, 1997) Anatomical

Multiple point stimulation

103

93 Thenar/man

(Lee et al, 1975)

Anatomical

Spike Triggered Averaging

203

167

Nice, 2004

(20)

• Incremental stimulation technique :

alternation is a major problem

Nice, 2004

• Spike triggered averaging :

alternation is not a problem

invasive

time comsuming

reproducibility of results is not

satisfactory

(21)

Statistical MUNE

MPS/AMPS

•Alternation is not a problem •MPS eliminates alternation

•AMPS minimizes alternation •statistical estimate from a wide spectrum of

motor units motor •Sample of 10 -20 « true » single unit

•Large and small units are not incorporated in

the analysis •No sample bias

•Results are reproducible •Results are reproducible

•Algorithms under continued development and

not always applicable (severe denervation) •Well established methodalways applicable (AMPS)

•120-300 stimuli at high stimulus level •Well tolerated

•Patient cooperation : +++ •Patient cooperation : +

•Fast procedure (< 20’) •Fast procedure (< 20’)

Nice, 2004

(22)

Statistical MUNE

MPS/AMPS

•Alternation is not a problem •MPS eliminates alternation

•AMPS minimizes alternation

•statistical estimate from a wide spectrum of

motor units motor •Sample of 10 -20 « true » single unit

•Large and small units are not incorporated in

the analysis •No sample bias

•Results are reproducible •Results are reproducible

•Algorithms under continued development and

not always applicable (severe denervation) •Well established methodalways applicable (AMPS)

•120-300 stimuli at high stimulus level •Well tolerated

•Patient cooperation : +++ •Patient cooperation : +

•Fast procedure (< 20’) •Fast procedure (< 20’)

(23)

Statistical MUNE

MPS/AMPS

•Alternation is not a problem •MPS eliminates alternation •AMPS minimizes alternation

•statistical estimate from a wide spectrum of

motor units •Smallmotor units sample of 10 -20 « true » single •Very large and small units are not

incorporated in the analysis •No significant sample bias

•Results are reproducible •Results are reproducible

•Algorithms under continued development and

not always applicable (severe denervation) •Well established methodalways applicable (AMPS)

•120-300 stimuli at high stimulus level •Well tolerated

•Patient cooperation : +++ •Patient cooperation : +

•Fast procedure (< 20’) •Fast procedure (< 20’)

Nice, 2004

(24)

Statistical MUNE

MPS/AMPS

•Alternation is not a problem •MPS eliminates alternation •AMPS minimizes alternation •statistical estimate from a wide spectrum of

motor units motor •Sample of 10 -20 « true » single units •Large and small units are not incorporated in

the analysis •No sample bias

•Results are reproducible •Results are reproducible

•Algorithms under continued development and

not always applicable (severe denervation) •Well established methodalways applicable (AMPS)

•120-300 stimuli at high stimulus level •Well tolerated

•Patient cooperation : +++ •Patient cooperation : +

•Fast procedure (< 20’) •Fast procedure (< 20’)

(25)

Statistical MUNE

MPS/AMPS

•Alternation is not a problem •MPS eliminates alternation •AMPS minimizes alternation •statistical estimate from a wide spectrum of

motor units motor •Sample of 10 -20 « true » single units •Large and small units are not incorporated in

the analysis •No sample bias

•Results are reproducible •Results are reproducible

•Algorithms under continued development and

not always applicable (severe denervation) •Well established methodalways applicable (AMPS)

•120-300 stimuli at high stimulus level •Well tolerated

•Patient cooperation : +++ •Patient cooperation : +

•Fast procedure (< 20’) •Fast procedure (< 20’)

Nice, 2004

(26)

Statistical MUNE

MPS/AMPS

•Alternation is not a problem •MPS eliminates alternation •AMPS minimizes alternation •statistical estimate from a wide spectrum of

motor units motor •Sample of 10 -20 « true » single units •Large and small units are not incorporated in

the analysis •No sample bias

•Results are reproducible •Results are reproducible

•Algorithms under continued development and

not always applicable (severe denervation) •Well established methodalways applicable (AMPS)

•120-300 stimuli at high stimulus level •Well tolerated

•Patient cooperation : +++ •Patient cooperation : +

•Fast procedure (< 20’) •Fast procedure (< 20’)

(27)

Statistical MUNE

MPS/AMPS

•Alternation is not a problem •MPS eliminates alternation •AMPS minimizes alternation •statistical estimate from a wide spectrum of

motor units motor •Sample of 10 -20 « true » single units •Large and small units are not incorporated in

the analysis •No sample bias

•Results are reproducible •Results are reproducible

•Algorithms under continued development and

not always applicable (severe denervation) •Well established methodalways applicable (AMPS) •120-300 stimuli at high stimulus level •Well tolerated

•Hands-off technique

Patient cooperation : +++ Patient cooperation•Not hands-off techniques : +

•Fast procedure (< 20’) •Fast procedure (< 20’)

Nice, 2004

(28)

Statistical MUNE

MPS/AMPS

•Alternation is not a problem •MPS eliminates alternation •AMPS minimizes alternation •statistical estimate from a wide spectrum of

motor units motor •Sample of 10 -20 « true » single units •Large and small units are not incorporated in

the analysis •No sample bias

•Results are reproducible •Results are reproducible

•Algorithms under continued development and

not always applicable (severe denervation) •Well established methodalways applicable (AMPS) •120-300 stimuli at high stimulus level •Well tolerated

•Hands-off technique

Patient cooperation : +++ Patient cooperation : +•Not hands-off techniques

•Fast procedure (< 20’) •Fast procedure (< 20’)

(29)

• Extensor digitorum brevis muscle = 154 MU

(mean of 11 studies with 6 distinct methods)

• Median nerve innervated

thenar muscles = 229 UM

(mean of 22 studies with 7 distinct methods)

Nice, 2004

(30)

MUNE

Turnbull et al., 2003

177 thenar muscles

Above 60 years

Below 60 years

Nice, 2004

N

um

be

r

of

m

us

cl

es

Lower

normal

limit

(31)

M U N E Months

Wang et al, 2003

Dantes & McComas, 1991

Nice, 2004Nice, 2004

(32)

Nice, 2004

As measure of progression in ALS,

MUNE seems to be a more sensitive

technique than are strength, CMAP

amplitude, forced vital capacity

and the apple scale.

Felice, 1997

Probably because collateral

sprouting is able to

compensate for the effects

of motor unit loss

(33)

r = - 0.60

r = - 0.60

P <

P <

0.001

0.001

70

70

100

100

1000

1000

3

3

10

10

300

300

Average SMUP size

Average SMUP size

(µV.ms)

(µV.ms)

M

U

N

E

M

U

N

E

100

100

2000

2000

r = - 0

r = - 0

.

.

60

60

p

p

< 0

< 0

.001

.

001

Nice, 2004 Nice, 2004

(34)

X

C

X

0 20 40 60 80 100 120 200

100

200

300

400

MUNE (EDB)

EHB twitches (g)

Nice, 2004 Nice, 2004

McComas

et al., 1971

(35)

SPINAL MOTONEURON LOSS

• is not immediately widespread

• regions more than others

• motoneuron groups more than others

- thenar > hypothenar

- extensor digitorum brevis > plantar

• cells more than others

- some cells are in the degenerescence process

- other cells are healthy and capable of doing

an intense collateral reinnervation

- apparent resilience, to the degenerative

process, of about 10% of cells

Nice, 2004

(36)

COLLATERAL REINNERVATION

• intense at start

• more efficacious when the MU loss is slow

• is able to maintain the CMAP size and the global

muscular twitch tension in the normal range

as long as :

Reinnervation capacity > denervation rate

(37)

TERMINAL PHASE

• reinnervation capacity reduction :

the MU loss is responsible for the decreased

number of MU with overlaping territories

• terminal collapsus of MU

Nice, 2004

(38)

Dantes & McComas, 1991

Reversible

motoneuronal

dysfunction ?

(39)

Sanofi 1 + Ril

0

2-3

5-6

Months

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

1,8

Placebo

Riluzole

Sanofi 1

Sanofi 2

Sanofi 2 + Ril

M

U

N

E/

M

U

N

E

(T

0)

Nice, 2004 Nice, 2004

Gooch, 2002

(40)

Decreased MUNE and

increased average SMUP size

• non-specific data, related to peripheral motor

denervation

• in a suggestive clinical context, a decreased MUNE,

particularly in an asymtomatic territory, is in

favour of the diagnostic hypothesis

• MUNE within the normal range, at several occasions

over time, should induce a doubt about the

diagnostic certainty

(41)

Desease duration (months)

T

he

na

r

M

U

N

E

0 5 10 15 20 25 30 35

2

10

400

100

40 45 50 55 60

r = - 0.69

p < 0.05

r = - 0.42

p < 0.05

> 3 years

< 3 years

Survival

Nice, 2004 Nice, 2004

Wang et al., 2003

(42)

Thenar MUNE

r = 0.71

p < 0.001

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

-50 -40 -30 -20

-10

-0

-60

0

MUNE decline at T4/T0 (%)

M

U

N

E

de

cl

in

e

at

T

12

/T

0

(%

)

Nice, 2004

Wang et al., 2002

(43)

100 80 60 40 20 0 8 16 24 32 40 Nice, 2004 Nice, 2004

Wang (unpublished data)

Longitudinal study in 15 ALS patients

Time (months)

S

ur

vi

va

l

(%

)

MU loss the first

4 months > 30%

MU loss the first

4 months < 30%

(44)

100 80 60 40 20 0 8 16 24 32 40 Nice, 2004

Wang (unpublished data)

Longitudinal study in 11 ALS patients

Time (months)

S

ur

vi

va

l

(%

)

MU loss the first

8 months > 40%

MU loss the first

8 months < 40%

(45)

100 80 60 40 20 0 8 16 24 32 40 Nice, 2004 Nice, 2004

Wang (unpublished data)

Longitudinal study in 10 ALS patients

Time (months)

S

ur

vi

va

l

(%

)

MU loss the first

12 months > 65%

MU loss the first

12 months < 65%

(46)

Nice, 2004

• Sensitive tool

• Reproducible results

• Physiological signification

• Well tolerated, non expansive

• Predictive value

• Able to detect diffrences in the rate of MU loss

MUNE might be valuable in determining the

effectiveness of drugs in slowing the rate of

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