Skip to main content

Advertisement

SpringerLink
Log in

The Responsiveness of Gait and Balance Outcomes to Disease Progression in Friedreich Ataxia

  • Original Article
  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

To identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA), we administered a battery of potential measures three times over a 12-month period. Sixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, 6 months and 12 months. Outcomes included GAITRite® spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25-Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. SenseWear Armband daily step count had the largest effect size of all the variables over 6 months (SRM = −0.615), while the PST medial–lateral index had the largest effect size (SRM = 0.829) over 12 months. The FARS USS (SRM = 0.824) and BBS (SRM = −0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of −2.59 (95% CI −3.52 to −1.66, p < 0.001, SRM = −1.429). In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

Data not published within this article will be shared after approval by the Friedreich’s Ataxia Research Alliance, USA, and ethics review boards.

References

  1. Bidichandani SI, Delatycki MB. Friedreich Ataxia. In: Adam MP, Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviewsTM. Seattle: University of Washington; 2017.

    Google Scholar 

  2. Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol. 2009;256 Suppl 1:3–8.

    Article  PubMed  Google Scholar 

  3. Blair IA, Farmer J, Hersch S, et al. The current state of biomarker research for Friedreich’s ataxia: a report from the 2018 FARA biomarker meeting. Future Sci OA. 2019;5:FSO398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wilson CL, Fahey MC, Corben LA, et al. Quality of life in Friedreich ataxia: what clinical, social and demographic factors are important? Eur J Neurol. 2007;14:1040–7.

    Article  CAS  PubMed  Google Scholar 

  5. Ejaz R, Chen S, Isaacs CJ, et al. Impact of mobility device use on quality of life in children with Friedreich ataxia. J Child Neurol. 2018;33:397–404.

    Article  PubMed  Google Scholar 

  6. Fahey MC, Corben LA, Collins V, Churchyard AJ, Delatycki MB. The 25-foot walk velocity accurately measures real world ambulation in Friedreich ataxia. Neurology. 2007;68:705–6.

    Article  CAS  PubMed  Google Scholar 

  7. Milne SC, Murphy A, Georgiou-Karistianis N, Yiu EM, Delatycki MB, Corben LA. Psychometric properties of outcome measures evaluating decline in gait in cerebellar ataxia: a systematic review. Gait Posture. 2018;61:149–62.

    Article  PubMed  Google Scholar 

  8. Ilg W, Synofzik M, Brotz D, Burkard S, Giese MA, Schols L. Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology. 2009;73:1823–30.

    Article  CAS  PubMed  Google Scholar 

  9. Ilg W, Schatton C, Schicks J, Giese MA, Schols L, Synofzik M. Video game-based coordinative training improves ataxia in children with degenerative ataxia. Neurology. 2012;79:2056–60.

    Article  PubMed  Google Scholar 

  10. Stephenson J, Zesiewicz T, Gooch C, et al. Gait and balance in adults with Friedreich’s ataxia. Gait Posture. 2015;41:603–7.

    Article  PubMed  Google Scholar 

  11. Zesiewicz TA, Stephenson JB, Kim SH, et al. Longitudinal gait and balance decline in Friedreich’s ataxia: a pilot study. Gait Posture. 2017;55:25–30.

    Article  PubMed  Google Scholar 

  12. Milne SC, Hocking DR, Georgiou-Karistianis N, Murphy A, Delatycki MB, Corben LA. Sensitivity of spatiotemporal gait parameters in measuring disease severity in Friedreich ataxia. Cerebellum. 2014;13:677–88.

    Article  CAS  PubMed  Google Scholar 

  13. Galea CA, Huq A, Lockhart PJ, et al. Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia. Ann Neurol. 2016;79:485–95.

    Article  CAS  PubMed  Google Scholar 

  14. World Health Organization. International classification of functioning, disability and health: ICF. Geneva: World Health Organization; 2001.

    Google Scholar 

  15. Subramony SH, May W, Lynch D, et al. Measuring Friedreich ataxia: interrater reliability of a neurologic rating scale. Neurology. 2005;64:1261–2.

    Article  CAS  PubMed  Google Scholar 

  16. Rummey C, Corben LA, Delatycki MB, et al. Psychometric properties of the Friedreich Ataxia Rating Scale. Neurol Genet. 2019;5:371.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Schmitz-Hubsch T, du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006;66:1717–20.

    Article  CAS  PubMed  Google Scholar 

  18. Delatycki MB. Evaluating the progression of Friedreich ataxia and its treatment. J Neurol. 2009;256 Suppl 1:36–41.

    Article  PubMed  Google Scholar 

  19. Stansfield BW, Hillman SJ, Hazlewood ME, et al. Normalisation of gait data in children. Gait Posture. 2003;17:81–7.

    Article  CAS  PubMed  Google Scholar 

  20. Cachupe WJC, Shifflett B, Kahanov L, Wughalter EH. Reliability of Biodex Balance System measures. Meas Phys Educ Exerc Sci. 2001;5:97–108.

    Article  Google Scholar 

  21. Calabro MA, Lee JM, Saint-Maurice PF, Yoo H, Welk GJ. Validity of physical activity monitors for assessing lower intensity activity in adults. Int J Behav Nutr Phys Act. 2014;11:119.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Marchetti GF, Lin CC, Alghadir A, Whitney SL. Responsiveness and minimal detectable change of the dynamic gait index and functional gait index in persons with balance and vestibular disorders. J Neurol Phys Ther. 2014;38:119–24.

    Article  PubMed  Google Scholar 

  23. Berg K, Wood-Dauphinee S, Williams JI, Gayton D. Measuring balance in the elderly: preliminary development of an instrument. Physiother Canada. 1989;41:304–11.

    Article  Google Scholar 

  24. Fischer JS, Rudick RA, Cutter GR, Reingold SC. The multiple sclerosis functional composite measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force. Mult Scler. 1999;5:244–50.

    Article  CAS  PubMed  Google Scholar 

  25. Whitney S, Wrisley D, Furman J. Concurrent validity of the Berg Balance Scale and the Dynamic Gait Index in people with vestibular dysfunction. Physiother Res Int. 2003;8:178–86.

    Article  PubMed  Google Scholar 

  26. Lynch DR, Farmer JM, Tsou AY, et al. Measuring Friedreich ataxia: complementary features of examination and performance measures. Neurology. 2006;66:1711–6.

    Article  CAS  PubMed  Google Scholar 

  27. Schmitz-Hubsch T, Fimmers R, Rakowicz M, et al. Responsiveness of different rating instruments in spinocerebellar ataxia patients. Neurology. 2010;74:678–84.

    Article  CAS  PubMed  Google Scholar 

  28. Liang MH, Fossel AH, Larson MG. Comparisons of five health status instruments for orthopedic evaluation. Med Care. 1990;28:632–42.

    Article  CAS  PubMed  Google Scholar 

  29. Tomczak M, Tomczak E. The need to report effect size estimates revisited. An overview of some recommended measures of effect size. Trends Sport Sci. 2014;1:19–25.

    Google Scholar 

  30. Bhidayasiri R, Perlman SL, Pulst SM, Geschwind DH. Late-onset Friedreich ataxia: phenotypic analysis, magnetic resonance imaging findings, and review of the literature. Arch Neurol. 2005;62:1865–9.

    Article  PubMed  Google Scholar 

  31. Rummey C, Farmer JM, Lynch DR. Predictors of loss of ambulation in Friedreich’s ataxia. EClinicalMedicine. 2020;18:100213.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Coulter EH, Miller L, McCorkell S, et al. Validity of the activPAL3 activity monitor in people moderately affected by multiple sclerosis. Med Eng Phys. 2017;45:78–82.

    Article  CAS  PubMed  Google Scholar 

  33. Alinia P, Cain C, Fallahzadeh R, Shahrokni A, Cook D, Ghasemzadeh H. How accurate is your activity tracker? A comparative study of step counts in low-intensity physical activities. JMIR mHealth uHealth. 2017;5:e106.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Biau DJ, Kerneis S, Porcher R. Statistics in brief: the importance of sample size in the planning and interpretation of medical research. Clin Orthop Relat Res. 2008;466:2282–8.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ilg W, Seemann J, Giese M, et al. Real-life gait assessment in degenerative cerebellar ataxia: toward ecologically valid biomarkers. Neurology. 2020;95:e1199–210.

    Article  CAS  PubMed  Google Scholar 

  36. Haberkamp M, Moseley J, Athanasiou D, et al. European regulators’ views on a wearable-derived performance measurement of ambulation for Duchenne muscular dystrophy regulatory trials. Neuromuscul Disord. 2019;29:514–6.

    Article  PubMed  Google Scholar 

  37. Alsalaheen B, Haines J, Yorke A, Broglio SP. Reliability and construct validity of limits of stability test in adolescents using a portable force plate system. Arch Phys Med Rehabil. 2015;96:2194–200.

    Article  PubMed  Google Scholar 

  38. Laessoe U, Grarup B, Bangshaab J. The use of cognitive cues for anticipatory strategies in a dynamic postural control task - validation of a novel approach to dual-task testing. PLoS One. 2016;11:e0157421.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Hausdorff JM. Gait variability: methods, modeling and meaning. J Neuroeng Rehabil. 2005;2:19.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Bauby CE, Kuo AD. Active control of lateral balance in human walking. J Biomech. 2000;33:1433–40.

    Article  CAS  PubMed  Google Scholar 

  41. Brach JS, Berlin JE, VanSwearingen JM, Newman AB, Studenski SA. Too much or too little step width variability is associated with a fall history in older persons who walk at or near normal gait speed. J Neuroeng Rehabil. 2005;2:21.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Brach JS, Studenski S, Perera S, VanSwearingen JM, Newman AB. Stance time and step width variability have unique contributing impairments in older persons. Gait Posture. 2008;27:431–9.

    Article  PubMed  Google Scholar 

  43. Wuehr M, Schniepp R, Ilmberger J, Brandt T, Jahn K. Speed-dependent temporospatial gait variability and long-range correlations in cerebellar ataxia. Gait Posture. 2013;37:214–8.

    Article  CAS  PubMed  Google Scholar 

  44. Egerton T, Danoudis M, Huxham F, Iansek R. Central gait control mechanisms and the stride length - cadence relationship. Gait Posture. 2011;34:178–82.

    Article  PubMed  Google Scholar 

  45. Kurz MJ, Heinrichs-Graham E, Becker KM, Wilson TW. The magnitude of the somatosensory cortical activity is related to the mobility and strength impairments seen in children with cerebral palsy. J Neurophysiol. 2015;113:3143–50.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wuehr M, Schniepp R, Schlick C, et al. Sensory loss and walking speed related factors for gait alterations in patients with peripheral neuropathy. Gait Posture. 2014;39:852–8.

    Article  PubMed  Google Scholar 

  47. Gouelle A, Leroux J, Bredin J, Megrot F. Changes in gait variability from first steps to adulthood: normative data for the gait variability index. J Mot Behav. 2016;48:249–55.

    Article  PubMed  Google Scholar 

  48. Roche B, Simon AL, Guilmin-Crepon S, et al. Test-retest reliability of an instrumented electronic walkway system (GAITRite) for the measurement of spatio-temporal gait parameters in young patients with Friedreich’s ataxia. Gait Posture. 2018;66:45–50.

    Article  PubMed  Google Scholar 

  49. Cattaneo D, Jonsdottir J, Repetti S. Reliability of four scales on balance disorders in persons with multiple sclerosis. Disabil Rehabil. 2007;29:1920–5.

    Article  PubMed  Google Scholar 

  50. Kraan CM, Tan AHJ, Cornish KM. The developmental dynamics of gait maturation with a focus on spatiotemporal measures. Gait Posture. 2017;51:208–17.

    Article  CAS  PubMed  Google Scholar 

  51. Schwabova J, Zahalka F, Komarek V, et al. Uses of the postural stability test for differential diagnosis of hereditary ataxias. J Neurol Sci. 2012;316:79–85.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank all the participants who have given their time for this project. The authors would also like to thank the Kingston Centre Physiotherapy Department, Monash Health, Melbourne, and the Clinical Research Center for Movement Disorders and Gait, University of South Florida, Tampa, for their support during the study. We wish to thank Lucretia Campbell and Mary Freeman, University of South Florida Ataxia Research Center, for their assistance with data collection.

Funding

This study was supported by the Friedreich’s Ataxia Research Alliance (USA) (FARA), PTC Therapeutics and Voyager Therapeutics, as a part of FARA's Biomarker Consortium.

Author information

Authors and Affiliations

  1. Bruce Lefroy Centre, Murdoch Children’s Research Institute, Melbourne,, Australia

    Sarah C. Milne, Eppie M. Yiu, Geneieve Tai, Martin B. Delatycki & Louise A. Corben

  2. Physiotherapy Department, Monash Health, Melbourne, Australia

    Sarah C. Milne

  3. Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia

    Sarah C. Milne

  4. Department of Paediatrics, The University of Melbourne, Melbourne, Australia

    Sarah C. Milne, Eppie M. Yiu, Martin B. Delatycki & Louise A. Corben

  5. School of Primary and Allied Health Care, Monash University, Melbourne, Australia

    Sarah C. Milne & Louise A. Corben

  6. University of South Florida, Tampa, FL, USA

    Seok Hun Kim, Ritchie Malapira, Jessica Shaw, Fatemeh Rasouli & Theresa Zesiewicz

  7. MonARC, Monash Health, Melbourne, Australia

    Anna Murphy & Mary Danoudis

  8. School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia

    Anna Murphy & Mary Danoudis

  9. PepGen Inc., Boston, MA, USA

    Jane Larkindale

  10. Friedreich’s Ataxia Research Alliance, Downingtown, PA, USA

    Jennifer Farmer

  11. Los Alamos National Laboratory, Los Alamos, NM, USA

    Tyagi Ramakrishnan

  12. Department of Neurology, The Royal Children’s Hospital Melbourne, Melbourne, Australia

    Eppie M. Yiu

  13. Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, Australia

    Nellie Georgiou-Karistianis

  14. Victorian Clinical Genetics Services, Melbourne, Australia

    Martin B. Delatycki

Authors
  1. Sarah C. Milne
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seok Hun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jane Larkindale
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jennifer Farmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ritchie Malapira
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mary Danoudis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jessica Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tyagi Ramakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fatemeh Rasouli
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Eppie M. Yiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nellie Georgiou-Karistianis
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Geneieve Tai
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Theresa Zesiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Martin B. Delatycki
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Louise A. Corben
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Sarah C Milne, Seok Hun Kim, Anna Murphy, Jane Larkindale, Jennifer Farmer, Eppie Yiu, Nellie Georgiou-Karistianis, Theresa Zesiewicz, Martin B Delatycki and Louise A Corben contributed to the study conception and design. Material preparation and data collection were performed by Sarah C Milne, Seok Hun Kim, Ritchie Malapira, Mary Danoudis, Jessica Shaw, Tyagi Ramakrishnan, Fatemeh Rasouli and Geneieve Tai. Analysis was performed by Sarah C Milne. The first draft of the manuscript was written by Sarah C Milne, and all authors revised the manuscript for intellectual content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sarah C. Milne.

Ethics declarations

Ethics Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Monash Health Human Research Ethics Committee (15035A) and the USF Institutional Review Board (Pro00021414).

Consent to Participate

All participants (or their parents/guardians if aged under 18 years) provided informed consent as per the Declaration of Helsinki.

Conflict of Interest

This study was sponsored by the Friedreich’s Ataxia Research Alliance (USA) (FARA), PTC Therapeutics and Voyager Therapeutics, as a part of FARA’s Biomarker Consortium. S. C. Milne received a National Health and Medical Research Council of Australia Postgraduate Scholarship (APP1093259). E. M. Yiu is a National Health and Medical Research Council Early Career Fellow (APP 1073323). L. A. Corben is a Medical Research Futures Fund Career Development Fellow (APP1143098). J. Larkindale was employed by the Friedreich’s Ataxia Research Alliance. J. Farmer is employed by the Friedreich’s Ataxia Research Alliance. S. H. Kim, A. Murphy, R. Malapira, M. Danoudis, J. Shaw, T. Ramakrishnan, F. Rasouli, N. Georgiou-Karistianis, G. Tai, T. Zesiewicz and M.B. Delatycki declare they have no financial or non-financial interests to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 125 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Milne, S.C., Kim, S.H., Murphy, A. et al. The Responsiveness of Gait and Balance Outcomes to Disease Progression in Friedreich Ataxia. Cerebellum 21, 963–975 (2022). https://doi.org/10.1007/s12311-021-01348-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-021-01348-2

Keywords

Search

Navigation