FATIGUE LEADS TO GAIT CHANGES IN SPINAL MUSCULAR ATROPHYJACQUELINE 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

1Department of Neurology, Columbia University Medical Center, 180 Ft. Washington Avenue, Fifth Floor,New York, New York 10032, USA

2Department of Rehabilitation Medicine, Columbia University Medical Center, New York, New York, USA

Accepted 13 September 2010

ABSTRACT: Introduction: Impaired mobility and fatigue arecommon in ambulatory spinal muscular atrophy (SMA) patients.The 6-minute walk test (6MWT) is a reliable measure of fatiguein SMA patients. To further evaluate fatigue, we used quantita-tive gait analysis during the 6MWT. Methods: Nine subjects withSMA and 9 age- and gender-matched, healthy controls wereevaluated. Gait parameters of speed and dynamic balancewere correlated with 6MWT distance. Performance during thefirst and last 25 meters of the 6MWT was compared. Results:Speed-related gait parameters and support base correlatedwith 6MWT distance. Walking performance was worse for SMApatients. The deterioration in stride length during the 6MWTwas greater in SMA patients than in controls. Conclusions: Gaitanalysis detects fatigue, and the decrement in stride lengthmay reflect selective muscle involvement in SMA. Furtherunderstanding of the mechanisms underlying fatigue may sug-gest additional targets for future therapeutic interventions.

Muscle Nerve 43: 485–488, 2011

Spinal muscular atrophy (SMA) is a motor neurondisease manifested by weakness and impaired func-tional mobility. Although muscle weakness isa common complaint for all SMA phenotypes, reportsof fatigue are most prevalent in SMA type 3, the mild-est phenotype.1 Ambulatory SMA patients report pro-gressively worsening fatigue and weakness over a 2.5-year period despite no discernible change on standardoutcome measures.2 This suggests endurance meas-ures may be more meaningful in SMA. Fatigue severityhas been evaluated with validated questionnaires3 ormeasurement of isometric contraction.4 However,questionnaires do not help to elucidate the underlyingmechanisms, and measurements of isometric contrac-tions are not functionally meaningful because they areonly weakly associated with strength in some muscles.5

The 6-minute walk test (6MWT), a validated mea-sure of functional exercise capacity, is associated withsubjective measures of fatigue and disease severity inmultiple sclerosis.6 In stroke, there is a decline inwalking speed over time during the 6MWT.7 InSMA, the 6MWT is associated with standard functionand strength assessments and, similar to other neuro-logical diseases, there is a decline in walking speed

over time.8 In fact, ambulatory SMA patients demon-strated a 17% decrement in performance from thefirst to the sixth minute during the 6MWT. However,the precise gait changes that underlie the decrementin speed are unknown. Identification of the gaitchanges associated with fatigue during the 6MWTmay provide objective outcomes for clinical trials,elucidate pathophysiological mechanisms, and iden-tify targets for future treatment strategies.

METHODS

Subjects. Eighteen subjects, 9 with SMA type 3and 9 age- and gender-matched healthy controls(mean age 22 years, range 4–49 years), wererecruited for this cross-sectional study betweenMarch 2009 and March 2010. To reduce selectionbias, all patients who fulfilled eligibility criteria atthe neuromuscular clinic were offered participa-tion. Four of the 9 SMA participants had clinicalsymptoms before age 3 years, termed type 3a9; 5SMA participants had clinical symptoms after age3, termed type 3b. Healthy control subjects hadno known neurological or medical conditions.Informed consent or assent for the institutionalreview board (IRB)-approved study was obtainedfrom all participants. The use of assistive devicessuch as ankle foot orthoses, crutches, walkers, orcanes was not permitted during gait assessments.

Procedures. All subjects completed the 6MWTand quantitative gait analysis in an uninterruptedfashion.

6MWT. A 25-meter linear course, marked with ahorizontal line at the beginning, the end, and ateach intervening meter, was used for the 6MWT.Participants were instructed to walk as fast as possi-ble along the marked course, turn around amarker cone, return to the start, and repeat thisloop as often as possible for 6 minutes. Instruc-tions for the 6MWT were given, and the test wasperformed according to previously described pro-cedures.8 Subjects were instructed to walk on thecenter of the mat when traversing the course. Falls,if any, were recorded as adverse events.

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

Additional Supporting Information may be found in the online version ofthis article.Abbreviations: 6MWT, 6-minute walk test; SMA, spinal muscular atrophy

Disclosure: This report pertains to Dr. Kaufmann’s work at ColumbiaUniversity, and should not be understood as the opinion or position of theNational Institutes of Health or its affiliates.Correspondence to: J. Montes; e-mail: jm598@columbia.edu

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

Key words: fatigue, gait, outcome measure, spinal muscular atrophy,6-minute walk test

Fatigue and Gait Changes in SMA MUSCLE & NERVE April 2011 485

25-m 6MWT course. The GaitRITE contains pres-sure sensors embedded in the mat, which registerlocation and timing of each footfall, and it com-putes spatiotemporal measures from customizedalgorithms. We computed measures of gait speed(velocity, cadence, and stride length) and dynamicbalance (support base and percent time spent indouble support) for further analysis.

Data Analysis. We evaluated early walking per-formance during the first 25 m and late walking

performance during the last 25 m of the 6MWTon the computerized walkway for patients and con-trols. We correlated gait variables with 6MWT dis-tance using the Pearson coefficient. Trials weredefined as the first and last pass in the first andsixth minutes, respectively, across the gait mat. Agroup (SMA patients vs. controls) by trial repeated-measures analysis of variance for velocity, cadence,stride length, support base, and percent time in dou-ble support was performed to assess differencesbetween groups and the effect of trials. Paired sam-ples t-tests were performed on the first and last passfor all gait variables in order to examine in detailthe effect of fatigue. Finally, we conducted regres-sion analyses to examine gait variables that were pre-dictive of 6MWT distance in SMA subjects. Statisticalanalyses 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 dis-tance was highly correlated with gait velocity, stridelength, cadence, and support base at both the firstand last pass, but it was not correlated with percenttime in double support (Table 1).

Repeated-measures analysis of variance demon-strated a significant effect of group (SMA and con-trol) on velocity (P ¼ 0.000), cadence (P ¼ 0.012),

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

Comparison

Pearsoncorrelationcoefficient (r) P-value

Velocity first vs. 6MWT distance 0.966 0.000*Velocity last vs. 6MWT distance 0.982 0.000*Stride length first vs. 6MWT distance 0.878 0.008†

Stride length last vs. 6MWT distance 0.905 0.000*Cadence first vs. 6MWT distance 0.679 0.002†

Cadence last vs. 6MWT distance 0.804 0.000*Support base first vs. 6MWT distance -0.602 0.008†

Support base last vs. 6MWT distance -0.631 0.005Double support % first vs.

6MWT distance-0.357 0.145

Double support % last vs.6MWT distance

-0.293 0.238

*P < 0.001†P < 0.01

FIGURE 1. Gait parameters at first and last pass during the 6MWT. Comparisons of SMA patients and controls on early walking per-

formance 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 demon-

strated 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 sig-

nificant analysis of data group (SMA and control) for trial (first and last pass during the 6MWT) interaction (P ¼ 0.042).

486 Fatigue and Gait Changes in SMA MUSCLE & NERVE April 2011

stride length (P ¼ 0.002), and support base (P ¼0.037), 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 tothe last pass for SMA subjects, as demonstrated by asignificant analysis of data group (SMA and control)for trial (first and last pass during the 6MWT) inter-action (P ¼ 0.042). Regression analysis confirmedthat 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 distancefor SMA subjects, whereas cadence did not (R2 ¼0.39, 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 ¼0.01) for SMA patients. Similarly, velocity (first pass1.09 m/s, last pass 0.98 m/s) and cadence (firstpass 107.89 steps/min, last pass 101.61 steps/min)demonstrated significant decreases in SMA patients(P ¼ 0.03). However, support base and percenttime in double support did not change fromthe first to the last pass during the 6MWT for SMA

patients. None of the gait variables were differentbetween the first and last trial in control subjects.Comparisons for each gait parameter of the firstand last pass during the 6MWT across groups aresummarized in Table S2 (see Supplementary Mate-rial). SMA patients and controls were able to com-plete the test in an uninterrupted fashion, and nofalls were observed.

DISCUSSION

Gait analysis is a useful complement to the 6MWTand provides a quantitative assessment of fatigue-related changes in SMA. In addition to providingprecise assessments of walking speed, quantitativeanalysis revealed decrements in SMA gait perform-ance during the 6MWT but not in healthy con-trols. The changes observed in SMA subjectsrelated more to velocity and stride length than tovariables related to dynamic balance. Total 6MWTdistance correlated with quantitative gait measuresand was able to distinguish between SMA patientsand healthy controls. Among the variables relatedto gait speed, only velocity and stride length forthe first and sixth minute were predictive of6MWT distance. These results highlight the impor-tance of stride length rather than cadence indetermining gait speed in SMA subjects.

In our sample, velocity decreased 11% on aver-age in SMA patients during the 6MWT, and thisdecrement in velocity was not observed in healthycontrols. The decrease in velocity is consistent withour previous report of 17% decrement in SMA per-formance, although smaller in magnitude, duringthe 6MWT.8 The differences between the two studiescould either be due to a smaller sample size or amore sensitive measurement of velocity using a com-puterized walkway in this study. In the previousstudy, velocity was calculated by averaging the dis-tance walked in the first and last minutes. Quantita-tive gait analysis using the computerized walkwaycomputes instantaneous velocity during the first andlast pass on the 6MWT course. Regardless of the dif-ferent methods of analysis, the 6MWT is sufficientlysensitive to reveal consistent motor fatigue in SMA.

During the 6MWT, SMA patients took shortersteps over time with an average 6% change fromfirst to last pass along the course. Changes in walk-ing speed are a result of adjustments in muscularforces and the resulting stride length.10 Fasterspeeds require longer strides and greater accelerat-ing and decelerating muscle activity. Althoughnearly all leg muscles contribute to walking, certainmuscles have unique contributions to speed-relatedgait changes. Forward leg swing largely determinesstride length and is generated by iliopsoas and gas-trocnemius muscles, whereas forward propulsion is

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.

Fatigue and Gait Changes in SMA MUSCLE & NERVE April 2011 487

associated with rectus femoris and soleus muscleactivation.11

There were no significant changes in measuresof dynamic balance during the 6MWT in SMApatients. Time spent in the double limb supportphase of the gait cycle and support base measuredas the distance between the feet in stance aremeasures of stability while walking in the healthyelderly.12 In our study, the support base was on av-erage 5 cm wider in SMA patients than in healthycontrols and may represent a strategy to compen-sate for weakness in proximal leg muscles. How-ever, because support base did not change duringthe 6MWT, the strategy does not appear to be aspecific compensation.

In other neurological diseases, impairments ofdynamic balance are associated with disease sever-ity reflected by increasing time spent in the doublesupport phase of gait.13 SMA is a lower motor neu-ron disease without involvement of sensory orextrapyramidal systems. It has a relatively symmetri-cal pattern of muscle weakness.14 As such, balanceimpairment is not a common problem in SMA asreflected by the lack of differences in time spentin double support between SMA patients and con-trols (Table S2).

Fatigue-related changes in stride length demon-strated in this study confirm evidence of selectivemuscle weakness in SMA since the initial descrip-tion of the disease.15 Leg muscle weakness is mostsevere in the hip adductors, hip flexors, and quadri-ceps, and less severe in hamstrings and other pelvicgirdle muscles.16 Although the distal musculature isrelatively spared, weakness of the gastrocnemiusmuscle has been reported among ambulatorypatients with SMA, with a resultant impact on forceproduction at the ankle and step length.17 The rela-tively uniform pattern of involvement in SMA isreflected in our observations of fatigue-relatedchanges in performance during the 6MWT.

In conclusion, quantitative gait analysis was auseful adjunct to the 6MWT because it enableddetection of specific fatigue-related changes in ve-locity and stride length in SMA patients. Selectiveweakness in hip flexors and knee extensors haslong been recognized in SMA and is reflected inthe changes observed in this study. Understandingthe precise relationship of muscle function and fa-tigue-related changes in SMA patients could help

direct future rehabilitation treatment strategies.Future preclinical studies may reveal the neurophys-iological mechanisms of fatigue in SMA and lead tosymptomatic treatment strategies. The 6MWT andquantitative gait analysis provide a functionallymeaningful assessment of walking ability in SMAand may serve as a sensitive measure of fatigue.

This study was funded by the SMA Foundation. The sponsor hadno role in the conduct of this study or the parent SMA natural his-tory study. We gratefully acknowledge the members of the PNCRNetwork for SMA Clinical Trials Research, the PNCR NetworkExternal Advisory Board, and the Muscle Study Group for theirguidance and the research participants and their families for theirgenerous gift of time and effort.

REFERENCES

1. de Groot IJ, de Witte LP. Physical complaints in ageing persons withspinal muscular atrophy. J Rehabil Med 2005;37:258–262.

2. Piepers S, van den Berg LH, Brugman F, Scheffer H, Ruiterkamp-Versteeg M, van Engelen BG, et al. A natural history study of lateonset spinal muscular atrophy types 3b and 4. J Neurol 2008;255:1400–1404.

3. Kalkman JS, Schillings ML, Zwarts MJ, van Engelen BG, BleijenbergG. The development of a model of fatigue in neuromuscular disor-ders: a longitudinal study. J Psychosom Res 2007;62:571–579.

4. Vollestad NK. Measurement of human muscle fatigue. J NeurosciMethods 1997;74:219–227.

5. Sanjak M, Brinkmann J, Belden DS, Roelke K, Waclawik A, NevilleHE, et al. Quantitative assessment of motor fatigue in amyotrophiclateral sclerosis. J Neurol Sci 2001;191:55–59.

6. Goldman MD, Marrie RA, Cohen JA. Evaluation of the six-minutewalk in multiple sclerosis subjects and healthy controls. Mult Scler2008;14:383–390.

7. Sibley KM, Tang A, Patterson KK, Brooks D, McIlroy WE. Changes inspatiotemporal gait variables over time during a test of functionalcapacity 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 spi-nal muscular atrophy. Neurology 2010;74:833–838.

9. Zerres K, Rudnik-Schoneborn S, Forrest E, Lusakowska A, BorkowskaJ, Hausmanowa-Petrusewicz I. A collaborative study on the natural his-tory 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 andEMG patterns during slow, free, and fast walking. J Orthop Res1984;2:272–280.

11. Neptune RR, Sasaki K, Kautz SA. The effect of walking speed onmuscle function and mechanical energetics. Gait Posture 2008;28:135–143.

12. Maki BE. Gait changes in older adults: predictors of falls or indica-tors of fear. J Am Geriatr Soc 1997;45:313–320.

13. Rao AK, Muratori L, Louis ED, Moskowitz CB, Marder KS. Spectrumof gait impairments in presymptomatic and symptomatic Hunting-ton’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: Butterworth-Heinemann; 2003. p 145–166.

15. Kugelberg E, Welander L. Heredofamilial juvenile muscular atrophysimulating muscular dystrophy. AMA Arch Neurol Psychiatry 1956;75:500–509.

16. Deymeer F, Serdaroglu P, Parman Y, Poda M. Natural history ofSMA IIIB. Neurology 2008;71:664–649.

17. Armand S, Mercier M, Watelain E, Patte K, Pelissier J, Rivier F. Acomparison of gait in spinal muscular atrophy, type II and Duch-enne muscular dystrophy. Gait Posture 2005;21:369–378.

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