Fatigue leads to gait changes in spinal muscular atrophy

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Mar 15, 2011 - Key words: fatigue, gait, outcome measure, spinal muscular atrophy,. 6-minute walk test .... cal pattern of muscle weakness.14 As such, balance.
FATIGUE LEADS TO GAIT CHANGES IN SPINAL MUSCULAR ATROPHY JACQUELINE MONTES, PT, MA,1 SALLY DUNAWAY, PT, DPT,1 MEGAN J. MONTGOMERY, BS,1 DOUGLAS SPROULE, MD,1 PETRA KAUFMANN, MD,1 DARRYL C. DE VIVO, MD,1 and ASHWINI K. RAO, OTR, EdD2 1

Department of Neurology, Columbia University Medical Center, 180 Ft. Washington Avenue, Fifth Floor, New York, New York 10032, USA 2 Department of Rehabilitation Medicine, Columbia University Medical Center, New York, New York, USA Accepted 13 September 2010 ABSTRACT: Introduction: Impaired mobility and fatigue are common in ambulatory spinal muscular atrophy (SMA) patients. The 6-minute walk test (6MWT) is a reliable measure of fatigue in SMA patients. To further evaluate fatigue, we used quantitative gait analysis during the 6MWT. Methods: Nine subjects with SMA and 9 age- and gender-matched, healthy controls were evaluated. Gait parameters of speed and dynamic balance were correlated with 6MWT distance. Performance during the first and last 25 meters of the 6MWT was compared. Results: Speed-related gait parameters and support base correlated with 6MWT distance. Walking performance was worse for SMA patients. The deterioration in stride length during the 6MWT was greater in SMA patients than in controls. Conclusions: Gait analysis detects fatigue, and the decrement in stride length may reflect selective muscle involvement in SMA. Further understanding of the mechanisms underlying fatigue may suggest additional targets for future therapeutic interventions. Muscle Nerve 43: 485–488, 2011

Spinal muscular atrophy (SMA) is a motor neuron disease manifested by weakness and impaired functional mobility. Although muscle weakness is a common complaint for all SMA phenotypes, reports of fatigue are most prevalent in SMA type 3, the mildest phenotype.1 Ambulatory SMA patients report progressively worsening fatigue and weakness over a 2.5year period despite no discernible change on standard outcome measures.2 This suggests endurance measures may be more meaningful in SMA. Fatigue severity has been evaluated with validated questionnaires3 or measurement of isometric contraction.4 However, questionnaires do not help to elucidate the underlying mechanisms, and measurements of isometric contractions are not functionally meaningful because they are only weakly associated with strength in some muscles.5 The 6-minute walk test (6MWT), a validated measure of functional exercise capacity, is associated with subjective measures of fatigue and disease severity in multiple sclerosis.6 In stroke, there is a decline in walking speed over time during the 6MWT.7 In SMA, the 6MWT is associated with standard function and strength assessments and, similar to other neurological diseases, there is a decline in walking speed Additional Supporting Information may be found in the online version of this article. Abbreviations: 6MWT, 6-minute walk test; SMA, spinal muscular atrophy Key words: fatigue, gait, outcome measure, spinal muscular atrophy, 6-minute walk test Disclosure: This report pertains to Dr. Kaufmann’s work at Columbia University, and should not be understood as the opinion or position of the National Institutes of Health or its affiliates. Correspondence to: J. Montes; e-mail: [email protected] C 2011 Wiley Periodicals, Inc. V

Published online 15 March 2011 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.21917

Fatigue and Gait Changes in SMA

over time.8 In fact, ambulatory SMA patients demonstrated a 17% decrement in performance from the first to the sixth minute during the 6MWT. However, the precise gait changes that underlie the decrement in speed are unknown. Identification of the gait changes associated with fatigue during the 6MWT may provide objective outcomes for clinical trials, elucidate pathophysiological mechanisms, and identify targets for future treatment strategies. METHODS Subjects. Eighteen subjects, 9 with SMA type 3 and 9 age- and gender-matched healthy controls (mean age 22 years, range 4–49 years), were recruited for this cross-sectional study between March 2009 and March 2010. To reduce selection bias, all patients who fulfilled eligibility criteria at the neuromuscular clinic were offered participation. Four of the 9 SMA participants had clinical symptoms before age 3 years, termed type 3a9; 5 SMA participants had clinical symptoms after age 3, termed type 3b. Healthy control subjects had no known neurological or medical conditions. Informed consent or assent for the institutional review board (IRB)-approved study was obtained from all participants. The use of assistive devices such as ankle foot orthoses, crutches, walkers, or canes was not permitted during gait assessments.

All subjects completed the 6MWT and quantitative gait analysis in an uninterrupted fashion.

Procedures.

A 25-meter linear course, marked with a horizontal line at the beginning, the end, and at each intervening meter, was used for the 6MWT. Participants were instructed to walk as fast as possible along the marked course, turn around a marker cone, return to the start, and repeat this loop as often as possible for 6 minutes. Instructions for the 6MWT were given, and the test was performed according to previously described procedures.8 Subjects were instructed to walk on the center of the mat when traversing the course. Falls, if any, were recorded as adverse events. 6MWT.

Quantitative Gait Analysis. The GaitRITE, a 4.6-mlong computerized mat (CIR Systems, Havertown, Pennsylvania), was placed in the middle of the MUSCLE & NERVE

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Table 1. Association of gait parameters with total distance walked during the 6MWT for all subjects (N ¼ 18).

Comparison

Pearson correlation coefficient (r)

P-value

0.966 0.982 0.878 0.905 0.679 0.804 -0.602 -0.631 -0.357

0.000* 0.000* 0.008† 0.000* 0.002† 0.000* 0.008† 0.005 0.145

-0.293

0.238

Velocity first vs. 6MWT distance Velocity last vs. 6MWT distance Stride length first vs. 6MWT distance Stride length last vs. 6MWT distance Cadence first vs. 6MWT distance Cadence last vs. 6MWT distance Support base first vs. 6MWT distance Support base last vs. 6MWT distance Double support % first vs. 6MWT distance Double support % last vs. 6MWT distance *P < 0.001 † P < 0.01

25-m 6MWT course. The GaitRITE contains pressure sensors embedded in the mat, which register location and timing of each footfall, and it computes spatiotemporal measures from customized algorithms. We computed measures of gait speed (velocity, cadence, and stride length) and dynamic balance (support base and percent time spent in double support) for further analysis. Data Analysis. We evaluated early walking performance during the first 25 m and late walking

performance during the last 25 m of the 6MWT on the computerized walkway for patients and controls. We correlated gait variables with 6MWT distance using the Pearson coefficient. Trials were defined as the first and last pass in the first and sixth minutes, respectively, across the gait mat. A group (SMA patients vs. controls) by trial repeatedmeasures analysis of variance for velocity, cadence, stride length, support base, and percent time in double support was performed to assess differences between groups and the effect of trials. Paired samples t-tests were performed on the first and last pass for all gait variables in order to examine in detail the effect of fatigue. Finally, we conducted regression analyses to examine gait variables that were predictive of 6MWT distance in SMA subjects. Statistical analyses were performed using SPSS (version 17.0). P < 0.05 was considered statistically significant. RESULTS

The mean total distance on the 6MWT was 343 m (range 267–449 m) for SMA patients and 601 m (range 490–733 m) for controls. The 6MWT distance was highly correlated with gait velocity, stride length, cadence, and support base at both the first and last pass, but it was not correlated with percent time in double support (Table 1). Repeated-measures analysis of variance demonstrated a significant effect of group (SMA and control) on velocity (P ¼ 0.000), cadence (P ¼ 0.012),

FIGURE 1. Gait parameters at first and last pass during the 6MWT. Comparisons of SMA patients and controls on early walking performance during the first 25 m and late walking performance during the last 25 m of the 6MWT on the computerized walkway. Trials were defined as the first and last pass in the first (First Minute 1) and sixth (Last Minute 6) minutes, respectively, across the gait mat on parameters of (A) velocity, (B) stride length, (C) cadence, and (D) support base. Repeated-measures analysis of variance demonstrated a significant effect of group data (SMA and control) on velocity (P ¼ 0.000), stride length (P ¼ 0.002), cadence (P ¼ 0.012), and support base (P ¼ 0.037). Stride length decreased from the first to the last pass for the SMA subjects, as demonstrated by a significant analysis of data group (SMA and control) for trial (first and last pass during the 6MWT) interaction (P ¼ 0.042). 486

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patients. None of the gait variables were different between the first and last trial in control subjects. Comparisons for each gait parameter of the first and last pass during the 6MWT across groups are summarized in Table S2 (see Supplementary Material). SMA patients and controls were able to complete the test in an uninterrupted fashion, and no falls were observed.

DISCUSSION

FIGURE 2. Quadratic fit of velocity and stride length during the first pass (þ95% confidence interval) with 6MWT distance in SMA subjects. Regression analysis demonstrated that (A) gait velocity (R2 ¼ 0.96, b ¼ 1.72, t ¼ 4.02, P < 0.007) and (B) stride length (R2 ¼ 0.79, b ¼ 2.49, t ¼ 2.45, P < 0.05) for the first minute predicted total 6MWT distance for SMA subjects.

stride length (P ¼ 0.002), and support base (P ¼ 0.037), and no effect of group (SMA and control) on percent time in double support (P ¼ 0.910) (Fig. 1). Stride length decreased from the first to the last pass for SMA subjects, as demonstrated by a significant analysis of data group (SMA and control) for trial (first and last pass during the 6MWT) interaction (P ¼ 0.042). Regression analysis confirmed that gait velocity (R2 ¼ 0.96, F ¼ 78.42, P < 0.0001) and stride length (R2 ¼ 0.79, F ¼ 11.34, P < 0.009) for the first minute predicted total 6MWT distance for SMA subjects, whereas cadence did not (R2 ¼ 0.39, F ¼ 1.93, P ¼ 0.225) (Fig. 2). The mean stride length during the first (1.20 m) and last (1.14 m) pass decreased significantly (P ¼ 0.01) for SMA patients. Similarly, velocity (first pass 1.09 m/s, last pass 0.98 m/s) and cadence (first pass 107.89 steps/min, last pass 101.61 steps/min) demonstrated significant decreases in SMA patients (P ¼ 0.03). However, support base and percent time in double support did not change from the first to the last pass during the 6MWT for SMA Fatigue and Gait Changes in SMA

Gait analysis is a useful complement to the 6MWT and provides a quantitative assessment of fatiguerelated changes in SMA. In addition to providing precise assessments of walking speed, quantitative analysis revealed decrements in SMA gait performance during the 6MWT but not in healthy controls. The changes observed in SMA subjects related more to velocity and stride length than to variables related to dynamic balance. Total 6MWT distance correlated with quantitative gait measures and was able to distinguish between SMA patients and healthy controls. Among the variables related to gait speed, only velocity and stride length for the first and sixth minute were predictive of 6MWT distance. These results highlight the importance of stride length rather than cadence in determining gait speed in SMA subjects. In our sample, velocity decreased 11% on average in SMA patients during the 6MWT, and this decrement in velocity was not observed in healthy controls. The decrease in velocity is consistent with our previous report of 17% decrement in SMA performance, although smaller in magnitude, during the 6MWT.8 The differences between the two studies could either be due to a smaller sample size or a more sensitive measurement of velocity using a computerized walkway in this study. In the previous study, velocity was calculated by averaging the distance walked in the first and last minutes. Quantitative gait analysis using the computerized walkway computes instantaneous velocity during the first and last pass on the 6MWT course. Regardless of the different methods of analysis, the 6MWT is sufficiently sensitive to reveal consistent motor fatigue in SMA. During the 6MWT, SMA patients took shorter steps over time with an average 6% change from first to last pass along the course. Changes in walking speed are a result of adjustments in muscular forces and the resulting stride length.10 Faster speeds require longer strides and greater accelerating and decelerating muscle activity. Although nearly all leg muscles contribute to walking, certain muscles have unique contributions to speed-related gait changes. Forward leg swing largely determines stride length and is generated by iliopsoas and gastrocnemius muscles, whereas forward propulsion is MUSCLE & NERVE

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associated with rectus femoris and soleus muscle activation.11 There were no significant changes in measures of dynamic balance during the 6MWT in SMA patients. Time spent in the double limb support phase of the gait cycle and support base measured as the distance between the feet in stance are measures of stability while walking in the healthy elderly.12 In our study, the support base was on average 5 cm wider in SMA patients than in healthy controls and may represent a strategy to compensate for weakness in proximal leg muscles. However, because support base did not change during the 6MWT, the strategy does not appear to be a specific compensation. In other neurological diseases, impairments of dynamic balance are associated with disease severity reflected by increasing time spent in the double support phase of gait.13 SMA is a lower motor neuron disease without involvement of sensory or extrapyramidal systems. It has a relatively symmetrical pattern of muscle weakness.14 As such, balance impairment is not a common problem in SMA as reflected by the lack of differences in time spent in double support between SMA patients and controls (Table S2). Fatigue-related changes in stride length demonstrated in this study confirm evidence of selective muscle weakness in SMA since the initial description of the disease.15 Leg muscle weakness is most severe in the hip adductors, hip flexors, and quadriceps, and less severe in hamstrings and other pelvic girdle muscles.16 Although the distal musculature is relatively spared, weakness of the gastrocnemius muscle has been reported among ambulatory patients with SMA, with a resultant impact on force production at the ankle and step length.17 The relatively uniform pattern of involvement in SMA is reflected in our observations of fatigue-related changes in performance during the 6MWT. In conclusion, quantitative gait analysis was a useful adjunct to the 6MWT because it enabled detection of specific fatigue-related changes in velocity and stride length in SMA patients. Selective weakness in hip flexors and knee extensors has long been recognized in SMA and is reflected in the changes observed in this study. Understanding the precise relationship of muscle function and fatigue-related changes in SMA patients could help

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direct future rehabilitation treatment strategies. Future preclinical studies may reveal the neurophysiological mechanisms of fatigue in SMA and lead to symptomatic treatment strategies. The 6MWT and quantitative gait analysis provide a functionally meaningful assessment of walking ability in SMA and may serve as a sensitive measure of fatigue. This study was funded by the SMA Foundation. The sponsor had no role in the conduct of this study or the parent SMA natural history study. We gratefully acknowledge the members of the PNCR Network for SMA Clinical Trials Research, the PNCR Network External Advisory Board, and the Muscle Study Group for their guidance and the research participants and their families for their generous gift of time and effort. REFERENCES 1. de Groot IJ, de Witte LP. Physical complaints in ageing persons with spinal muscular atrophy. J Rehabil Med 2005;37:258–262. 2. Piepers S, van den Berg LH, Brugman F, Scheffer H, RuiterkampVersteeg M, van Engelen BG, et al. A natural history study of late onset spinal muscular atrophy types 3b and 4. J Neurol 2008;255: 1400–1404. 3. Kalkman JS, Schillings ML, Zwarts MJ, van Engelen BG, Bleijenberg G. The development of a model of fatigue in neuromuscular disorders: a longitudinal study. J Psychosom Res 2007;62:571–579. 4. Vollestad NK. Measurement of human muscle fatigue. J Neurosci Methods 1997;74:219–227. 5. Sanjak M, Brinkmann J, Belden DS, Roelke K, Waclawik A, Neville HE, et al. Quantitative assessment of motor fatigue in amyotrophic lateral sclerosis. J Neurol Sci 2001;191:55–59. 6. Goldman MD, Marrie RA, Cohen JA. Evaluation of the six-minute walk in multiple sclerosis subjects and healthy controls. Mult Scler 2008;14:383–390. 7. Sibley KM, Tang A, Patterson KK, Brooks D, McIlroy WE. Changes in spatiotemporal gait variables over time during a test of functional capacity after stroke. J Neuroeng Rehabil 2009;6:27. 8. Montes J, McDermott MP, Martens WB, Dunaway S, Glanzman AM, Riley S, et al. Six-minute walk test demonstrates motor fatigue in spinal muscular atrophy. Neurology 2010;74:833–838. 9. Zerres K, Rudnik-Schoneborn S, Forrest E, Lusakowska A, Borkowska J, Hausmanowa-Petrusewicz I. A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients. J Neurol Sci 1997;146:67–72. 10. Murray MP, Mollinger LA, Gardner GM, Sepic SB. Kinematic and EMG patterns during slow, free, and fast walking. J Orthop Res 1984;2:272–280. 11. Neptune RR, Sasaki K, Kautz SA. The effect of walking speed on muscle function and mechanical energetics. Gait Posture 2008;28: 135–143. 12. Maki BE. Gait changes in older adults: predictors of falls or indicators of fear. J Am Geriatr Soc 1997;45:313–320. 13. Rao AK, Muratori L, Louis ED, Moskowitz CB, Marder KS. Spectrum of gait impairments in presymptomatic and symptomatic Huntington’s disease. Mov Disord 2008;23:1100–1107. 14. Crawford TO. Spinal muscular atrophies. In: Jones RH, De Vivo DC, Darras BT, editors. Neuromuscular disorders of infancy, childhood, and adolescence: a clinician’s approach. Philadelphia: ButterworthHeinemann; 2003. p 145–166. 15. Kugelberg E, Welander L. Heredofamilial juvenile muscular atrophy simulating muscular dystrophy. AMA Arch Neurol Psychiatry 1956; 75:500–509. 16. Deymeer F, Serdaroglu P, Parman Y, Poda M. Natural history of SMA IIIB. Neurology 2008;71:664–649. 17. Armand S, Mercier M, Watelain E, Patte K, Pelissier J, Rivier F. A comparison of gait in spinal muscular atrophy, type II and Duchenne muscular dystrophy. Gait Posture 2005;21:369–378.

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