Wang FC
Wang FC
CHU de Liège
CHU de Liège
Nice, 2004 Nice, 2004Nice, 2004
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
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)
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
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
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
Nice, 2004
3
mA
Nice, 2004
Nice, 2004
5
mA
Nice, 2004
6
mA
Nice, 2004
Nice, 2004
6 mA
Nice, 2004
6 mA
Nice, 2004
Nice, 2004
9
mA
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
• 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
Nice, 2004
Nice, 2004
• Reproducibility of MUNE studies
• Comparison of MUNE
Technique
Muscle(s)
r
CV (%)
Healthy subjects ALS Healthy subjects ALS IncrementalBrown & 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
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
• 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
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
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’)
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
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’)
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
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’)
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
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’)
• 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
MUNE
Turnbull et al., 2003
177 thenar muscles
Above 60 years
Below 60 years
Nice, 2004N
um
be
r
of
m
us
cl
es
Lower
normal
limit
M U N E Months
Wang et al, 2003
Dantes & McComas, 1991
Nice, 2004Nice, 2004Nice, 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
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, 2004X
CX
0 20 40 60 80 100 120 200
100
200
300
400
MUNE (EDB)
EHB twitches (g)
Nice, 2004 Nice, 2004McComas
et al., 1971
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
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
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
Dantes & McComas, 1991
Reversible
motoneuronal
dysfunction ?
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, 2004Gooch, 2002
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
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, 2004Wang et al., 2003
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, 2004Wang et al., 2002
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%
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%
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%
Nice, 2004