Muscle Study Group Meeting September 29, 2012 Jacqueline Montes

1. Functional Assessments • in • Spinal Muscular Atrophy • Muscle Study Group Meeting • September 29, 2012 • Jacqueline Montes • Department of Neurology, Columbia University

2. Broad Phenotypic Spectrum of SMA SMA Type I Severe form Never sit Limited life expectancy Respiratory failure Birth Prevalence 60% SMA Type II Intermediate form Sitting or standing Life expectancy shortened Skeletal deformities Birth Prevalence 27% SMA Type III Mild form Walkers at some point Life expectancy (nearly) normal Proximal weakness prominent Birth Prevalence 12%

3. SMA Clinical Outcome Measures SMA Type I CHOP INTEND SMA Type II Hammersmith Expanded Hand Held Dynamometry / MMT Upper Limb Module Forced Vital Capacity SMA Type III 6 minute walk test (6MWT) Hammersmith Expanded Hand Held Dynamometry / MMT Forced Vital Capacity • Assessments of Muscle Strength • Hand Held Dynamometry and MMT

4. 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.

5. 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

6. 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

7. 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)

8. 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

9. The Upper Limb Module (ULM) may help alleviate the floor effect of the HFMS in weaker patients. Mazzone et al 2011

10. Timed Function Tests Time to rise from floor 10 meter walk/run Time to climb stairs Gowers' Maneuver • 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)

11. 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

12. 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.

13. 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

14. 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.

15. Endurance demands, such as those required in the 6MWT, may be necessary to produce measurable fatigue. • P = 0.002 • Stride length deteriorates during the 6MWT in SMA patients but not in healthy individuals (p = 0.002) • Mean velocity walked during the 1st and 6th minute were significantly different (p = 0.0003) Montes, J. et al. Muscle and Nerve 2011 Montes, J. et al. Neurology 2010

16. 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)

17. Fatigue related changes during the 6MWT were also seen in MS patients and was related to disease severity

18. 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

19. 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.

20. Fatigue can be quantified during the 6MWT using spatiotemporal and EMG measures.

21. 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 • t = -4.895; p = 0.001 • * = p < 0.05 • *** = p < 0.001 • kg • kg

22. 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

23. 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.

24. 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

25. 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

26. 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

27. Acknowledgments • Department of Defense; USAMRAA Grant/Cooperative Award • Columbia University: • Wendy Chung Teachers College: • Darryl De Vivo Andrew Gordon • Claudia Chiriboga Tara McIsaac • Douglas Sproule Carol Ewing Garber • Sally Dunaway • Nicole Holuba PNCR Network /MSG: • Jonathan Marra Basil Darras • Brendan Carr Richard Finkel • Lianna McLaughlin Michael McDermott • Ashwini Rao William Martens • Rabi Tawil • We are grateful for the patients and family members who willingly participate in these clinical research initiatives.