Functional Assessments in Spinal Muscular Atrophy Muscle Study

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

Broad Phenotypic Spectrum of 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 III Hammersmith Expanded 6 minute walk test (6 MWT) Hand Held Dynamometry / Hammersmith Expanded 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 (Bi. PAP use) • Correlates with SMN 2 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

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 (6 MWT) • A test to measure the distance walked around a 25 m 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 6 MWT was highly correlated with other functional measures in SMA and captured fatigue. Montes et al. 2010

6 MWT with GAITRite. TM • 4. 6 meter long computerized mat placed in the middle of the 25 meter course. • Provides a detailed gait analysis during the 6 MWT.

Endurance demands, such as those required in the 6 MWT, may be necessary to produce measurable fatigue. P = 0. 002 Mean velocity walked during the 1 st and 6 th minute were significantly different (p = 0. 0003) Montes, J. et al. Neurology 2010 Stride length deteriorates during the 6 MWT in SMA patients but not in healthy individuals (p = 0. 002) Montes, J. et al. Muscle and Nerve 2011

Similar changes during the 6 MWT were seen in stroke patients Velocity decreased 4% on average in the last two minutes of the 6 MWT (p < 0. 05)

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

• Incorporating EMG assessments during the 6 MWT 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

6 MWT 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 6 MWT 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 Mean Power Frequency (Hz) (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) 140. 21 (80. 73) 0. 20 (0. 12) 0. 24 (0. 16) 0. 12 (0. 10) 0. 12 (0. 12) 146. 47 (91. 66) 0. 258 0. 275 0. 855 0. 603 132. 29 (39. 93) 99. 84 (28. 59) 142. 93 (65. 89) 185. 79 (131. 49) 153. 51 (93. 51) 103. 05 (23. 00) 153. 97 (94. 95) 175. 33 (122. 38) 0. 314 0. 815

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 6 MWT 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 6 MWT. 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 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 Mc. Laughlin Ashwini Rao Teachers College: Andrew Gordon Tara Mc. Isaac Carol Ewing Garber PNCR Network /MSG: Basil Darras Richard Finkel Michael Mc. Dermott William Martens Rabi Tawil We are grateful for the patients and family members who willingly participate in these clinical research initiatives.