Functional Assessments
in
Spinal Muscular Atrophy
Muscle Study Group Meeting
September 29, 2012
Jacqueline Montes
Department of Neurology, Columbia University
PNCR Network
for SMA
Broad Phenotypic Spectrum of SMA
SMA Type I
SMA Type II
SMA Type III
Severe form
Intermediate form
Mild form
Never sit
Sitting or standing
Walkers at some point
Limited life expectancy
Life expectancy shortened
Respiratory failure
Skeletal deformities
Life expectancy (nearly)
normal
Birth Prevalence 60%
Birth Prevalence 27%
Proximal weakness
prominent
Birth Prevalence 12%
SMA Clinical Outcome Measures
SMA Type I
CHOP INTEND
SMA Type II
SMA Type III
Hammersmith Expanded
6 minute walk test (6MWT)
Hand Held Dynamometry /
Hammersmith Expanded
Forced Vital Capacity
Forced Vital Capacity
Assessments
of Muscle Strength
MMT
Hand Held Dynamometry /
Hand Held
Dynamometry
and
MMT
Upper Limb Module
MMT
• Muscle strength testing is listed as a core data element for
pediatric and adult neuromuscular diseases.
core = elements used by the vast majority of NMD studies
• Functional measures should be related to strength.
• Patterns of weakness can help explain function and
adaptations.
Hammersmith Functional Motor
Scale-Expanded (HFMSE)
• HFMSE adds 13 clinically
relevant items from the GMFM to
include ambulant SMA and
eliminate a ceiling effect
• Detailed manual with operational
definitions and training videos
• Minimal patient burden requiring
only standard equipment and
taking less than 15 minutes on
average
Hammersmith Functional Motor Scale-Expanded (HFMSE)
• HFMSE differentiates
ambulant patients not
captured on the original
scale
(O’Hagen et al. 2007)
• Highly correlated with the
GMFM
Hammersmith Functional Motor Scale-Expanded (HFMSE)
• Discriminates between:
• SMA type
• Walkers and non-walkers
• Respiratory function
(BiPAP use)
• Correlates with SMN2
copy number
(Glanzman et al. 2011)
•
Upper Limb Module (ULM)
Includes activities of daily living not typically included in
measures of gross motor function.
•
9 item scale for children as young as 30 months old
•
Intended to complement standard SMA specific gross motor
function measures such as the HFMSE
The Upper Limb Module (ULM) may help alleviate the floor
effect of the HFMS in weaker patients.
Mazzone et al 2011
Timed Function Tests
Time to rise from floor
Gowers' Maneuver
10 meter walk/run
Time to climb stairs
• Easily administered without equipment
• Correlated with leg strength in SMA patients
(
Merlini L, et al., 2004)
• Sensitive to change in DMD
(
Skura CL, et al., 2008)
• Functional assessments do not necessarily assess
endurance.
• Fatigue is a common symptom and is most commonly
reported in SMA type 3.
de Groot IJ et al, 2005
• Ambulatory SMA patients report increasing fatigue and
weakness over a 2.5 year period despite no discernible
change on standard outcome measures. Piepers S et al, 2008
PNCR Network
for SMA
In SMA no discernible fatigue was identified when
compared to controls using maximum voluntary isometric
contraction (MVIC).
• Cohort of SMA type 2 and 3
patients and controls over 2
years
• Seven muscle groups using
MVIC
• Fatigue was measured as
the percent decline in the
area under the force curve
relative to that of the 100%
MVIC sustained over the
15 seconds.
Six Minute Walk Test (6MWT)
• A test to measure the distance walked around a 25m course.
• Objective, safe and easily administered evaluation of functional
exercise capacity.
• Representative of a person’s ability because the intensity of the test
is self-selected
Solway et al. 2001
• Initially designed for people with
cardiopulmonary disease.
ATS statement. Am J Respir Crit Care Med. 2002
• Used as the primary outcome in a clinical trials
in DMD and other neuromuscular disorders.
• The 6MWT was highly correlated with other
functional measures in SMA and captured
fatigue.
Montes et al. 2010
6MWT with GAITRiteTM
• 4.6 meter long computerized
mat placed in the middle of
the 25 meter course.
• Provides a detailed gait
analysis during the 6MWT.
Endurance demands, such as those required in the 6MWT, may be
necessary to produce measurable fatigue.
P = 0.002
Mean velocity walked during the
1st and 6th minute were
significantly different (p = 0.0003)
Montes, J. et al. Neurology 2010
Stride length deteriorates
during the 6MWT in SMA
patients but not in healthy
individuals (p = 0.002)
Montes, J. et al. Muscle and Nerve 2011
Similar changes during the 6MWT were seen in stroke
patients
Velocity decreased 4% on
average in the last two
minutes of the 6MWT
(p < 0.05)
Fatigue related changes during the 6MWT were also seen in
MS patients and was related to disease severity
• Incorporating EMG assessments during the 6MWT can provide a
real time evaluation of muscle function throughout the duration of
the test.
• Mean frequency of the power spectrum (MPF) and root mean
square amplitude (RMS) are EMG measures of fatigue and have
been shown to be correlated with proportion of muscle fiber type in
healthy adults. Gerdle, et al., 2000
• RMS is directly related to force output where greater forces have
larger RMS of the EMG signal. Bilodeau, et al., 2003
• In healthy individuals, overall decrease after initial increase in the
RMS amplitude of the EMG signal occur with fatigue.
Bilodeau, et al., 2003
6MWT with gait analysis and wireless EMG
recordings of 4 muscle groups
Muscles groups were chosen because of their primary role
in gait and accessibility for recording.
Fatigue can be quantified during the 6MWT using spatiotemporal and
EMG measures.
Variable
Stride Length (m)
Velocity (m/sec)
Root Mean Square
Amplitude (all muscles)
Anterior Tibialis
Gastrocnemius
Biceps Femoris
Rectus Femoris
First Minute
mean (SD)
1.21 (0.39)
Last Minute
Mean (SD)
1.08 (0.38)
F
P
25.365
0.001**
0.99 (0.46)
0.80 (0.42)
45.350
<0.000**
0.20 (0.15)
0.17 (0.13)
4.652
0.038*
0.25 (0.15)
0.28 (0.11)
0.15 (0.18)
0.13 (0.13)
0.20 (0.12)
0.24 (0.16)
0.12 (0.10)
0.12 (0.12)
0.258
0.855
0.275
0.603
0.314
0.815
Mean Power Frequency
140.21 (80.73)
(Hz) (all muscles)
Anterior Tibialis 132.29 (39.93)
Gastrocnemius 99.84 (28.59)
Biceps Femoris 142.93 (65.89)
Rectus Femoris 185.79 (131.49)
146.47 (91.66)
153.51 (93.51)
103.05 (23.00)
153.97 (94.95)
175.33 (122.38)
Knee flexors were stronger
than the knee extensors using
quantitative strength
assessments (HHD).
The centripetal pattern of
weakness in SMA can be
described using clinical
measures (MMT).
t = -4.895; p = 0.001
kg
* = p < 0.05
*** = p < 0.001
Using Pearson’s correlation coefficient, total leg strength was
associated with 6MWT distance indicating the importance of overall
leg muscle strength on function (p = 0.016)
R = 0.733
Fatigue can be quantified by the percent change in stride length,
velocity, or RMS from first to last minute during the 6MWT.
Hip abduction strength, was associated with percent change in
stride length (R = 0.758, p = 0.011).
Knee flexion strength was associated with percent change in
RMS (R = -0.655, p = 0.036).
Ankle plantar flexion strength was not significantly associated
with percent change in stride length (R = 0.626; p = 0.053)
* Pearson’s correlation coefficient was used for all comparisons.
Both the hip abductors and knee flexors are relatively preserved in
ambulatory SMA and may play an important compensatory role in
SMA gait.
Proximal
Distal
A kinematic analysis of SMA patients revealed increased pelvic
rotation initiated by the hip abductors. Armand et al. 2005
Ankle plantar flexors play a critical role in maintaining normal
gait mechanics in the setting of proximal weakness
Goldberg and Neptune 2007
In this study, there was only a moderate association of ankle
plantar flexion strength with fatigue that approached significance
The lack of significant association of plantar flexor strength to
fatigue in this study may be because MMT lacks sensitivity,
particularly in stronger muscle groups Bohannon, 2005
Summary
• Functional measures allow you to assess the
burden of the disease and possible response to
treatment are a necessary component to all clinical
trials.
• Their relationship to strength should be known
because strength might change before function
with an intervention.
• In general ideal functional measures are:
Easily administered
Impose minimal patient burden
Require minimal training and equipment
Disease specific
Acknowledgments
PNCR Network
for SMA
Department of Defense; USAMRAA Grant/Cooperative Award
Columbia University:
Wendy Chung
Darryl De Vivo
Claudia Chiriboga
Douglas Sproule
Sally Dunaway
Nicole Holuba
Jonathan Marra
Brendan Carr
Lianna McLaughlin
Ashwini Rao
Teachers College:
Andrew Gordon
Tara McIsaac
Carol Ewing Garber
PNCR Network /MSG:
Basil Darras
Richard Finkel
Michael McDermott
William Martens
Rabi Tawil
We are grateful for the patients and family members who willingly participate in
these clinical research initiatives.