Cerebellum DOI 10.1007/s12311-014-0583-2
ORIGINAL PAPER
Sensitivity of Spatiotemporal Gait Parameters in Measuring Disease Severity in Friedreich Ataxia Sarah C. Milne & Darren R. Hocking & Nellie Georgiou-Karistianis & Anna Murphy & Martin B. Delatycki & Louise A. Corben
# Springer Science+Business Media New York 2014
Abstract Friedreich ataxia (FRDA) is an autosomal recessive disease with gait ataxia being the main source of morbidity. Mobility progressively declines, from initial symptom onset at approximately 10–15 years of age to being unable to ambulate 10–15 years later. Here, we sought to investigate the relationship between spatiotemporal gait parameters and clinical markers of disease severity. Thirteen people with FRDA walked along an 8.3-m GAITRite® mat six times each at their preferred fast and slow speeds. Relationships between spatiotemporal gait parameters and a range of clinical and disease characteristics were examined. Significant correlations were found between spatiotemporal gait characteristics at each of the walking speeds and Friedreich Ataxia Rating Scale (FARS) score and disease duration. During the fast-walking condition, gait speed and cadence decreased with an increase in disease duration and the FARS score. GAA1 repeat
expansion negatively correlated with double-support percentage of the gait cycle in all speed conditions demonstrating a relationship between the genetic mutation and compensatory strategies for impaired dynamic balance. In all speed conditions, there were correlations between a range of spatiotemporal gait characteristics and the timed 25-ft walk test, a wellestablished measure of gait mobility. These findings suggest that spatiotemporal gait parameters are a sensitive measure of gait decline in individuals with FRDA and should be considered for inclusion in intervention studies whilst participants are still ambulant.
Keywords Friedreich ataxia . Gait analysis . Cerebellum . Spatiotemporal . Neurodegenerative diseases . Outcome measure
Sarah C. Milne and Darren R. Hocking are joint first authors Electronic supplementary material The online version of this article (doi:10.1007/s12311-014-0583-2) contains supplementary material, which is available to authorized users. S. C. Milne Physiotherapy Department, Kingston Centre, Monash Health, Cheltenham, VIC, Australia
D. R. Hocking Olga Tennison Autism Research Centre, School of Psychological Science, La Trobe University, Bundoora, VIC, Australia
S. C. Milne : N. Georgiou-Karistianis : M. B. Delatycki : L. A. Corben School of Psychological Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
A. Murphy MONARC, Faculty of Medicine, Nursing and Health Sciences, Monash University, Cheltenham, VIC, Australia
S. C. Milne : M. B. Delatycki : L. A. Corben (*) Bruce Lefroy Centre, Murdoch Childrens Research Institute, Flemington Road, Parkville, VIC 3052, Australia e-mail:
[email protected] S. C. Milne Community Rehabilitation Program, Peter James Centre, Eastern Health, Burwood East, VIC, Australia
A. Murphy Clinical Research Centre for Movement Disorders and Gait, Kingston Centre, Monash Health, Cheltenham, VIC, Australia M. B. Delatycki Clinical Genetics, Austin Health, Heidelberg, VIC, Australia L. A. Corben Monash Medical Centre, Monash Health, Clayton, VIC, Australia
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Background Friedreich ataxia (FRDA) is an autosomal recessive condition affecting approximately 1 in 30,000 Caucasian individuals [1]. In around 93 % of people, FRDA is caused by homozygous GAA trinucleotide expansions in intron 1 of FXN, whilst the remaining 7 % have an expanded GAA repeat on one allele and a point mutation or deletion on the other [2]. The length on the smaller GAA repeat (GAA1) is predictive of disease severity and age of onset [3]. The initial symptoms of FRDA are usually ‘clumsiness’ and gait ataxia with average symptom onset between 10 and 15 years [4]. Clinical features of FRDA include gait ataxia, upper and lower limb dysmetria, atrophy and weakness of the distal extremities, spasticity, loss of joint and vibratory sense, foot deformity, scoliosis, dysarthria, diabetes mellitus and cardiomyopathy [4]. Mobility progressively declines, and people with FRDA are typically non-ambulant 10 to 15 years after disease onset [5]. The progressive decline in gait is thought to be largely related to spinocerebellar degeneration, peripheral sensory neuropathy and cerebellar and vestibular pathology [6]. However, the direct contribution of these functional neurological systems to gait deterioration has not yet been clearly defined. Declining and eventual loss of physical function, particularly the capacity to walk, have a significant impact on quality of life in FRDA [7, 8]. A more comprehensive understanding of the specific components of gait dysfunction associated with FRDA may offer new treatment opportunities for improving or ameliorating gait impairment. The Timed 25-ft Walk Test (25FWT) is the most widely used mobility test in FRDA [9] and is established as an accurate reflection of real-life ambulation in people with this condition [10]. Although validity has been established [7, 10], there are a number of limitations with using the 25FWT as a measure of gait in individuals with FRDA. Timed walk tests measure ambulation in day-to-day function; however, they are unable to measure effort and the severity of deficiency in specific functional neurological systems [11]. Floor effects may be present for those with mild symptoms [12]. Further, with the ‘goal’ of walking at maximal speed, gait patterns may differ from those at ‘preferred’ speeds [13]. Additional methods of evaluating gait are available in validated and reliable clinical rating scales that measure a range of FRDArelated symptoms including gait ataxia [14–16]. For example, in the Friedreich Ataxia Rating Scale (FARS), there are two items within the upright stability subscale, tandem walking and walking with a turn [14]. Both of these items rely on the assessor to provide a score based on observation of the quality of gait. This process is subjective and lacks sensitivity to early gait changes that precede more severe clinical symptoms in individuals with FRDA. Gait analysis, as an objective measure of gait quality, provides information on spatiotemporal characteristics of gait
[17], alongside compensatory mechanisms for deconditioning and impaired balance, and therefore may be sensitive to early identification of specific pathologies [11]. Gait analysis can also identify clinically subtle changes in gait [11] and consequently may be a more sensitive tool to influence clinical decision-making in pharmacological interventions and rehabilitation. In addition, gait analysis is an inexpensive and portable means of measuring gait in the clinical setting [18]. To date, there are only three publications that have investigated gait characteristics and gait deterioration utilising gait analysis in people with FRDA. All studies included a component that compared the performance of spatiotemporal parameters in individuals with FRDA to control participants or existing normative gait data [19–21]. Not surprisingly, there were several significant differences in spatiotemporal gait characteristics in individuals with FRDA, including an increased double-support duration, shorter step length, greater step width and reduced speed [21]. These gait changes are suggestive of strategies used to compensate for the wide oscillation of centre of mass (COM) indicative of impairments in dynamic balance or postural stability [19]. In addition, increased gait variability as measured by the Gait Variability Index, capturing the magnitude of fluctuation in nine spatiotemporal gait parameters, has been shown to significantly correlate with reduced 25FWT scores and posture/gait disturbance on the International Cooperative Ataxia Rating Scale (ICARS) [20]. The FARS has also been shown to correlate with mean spatiotemporal gait parameters of velocity, stride length and cadence and is able to predict independent ambulation approximately 73 % of the time [21]. Together, these studies have highlighted the specific components of gait that may contribute to the loss of physical function associated with disease progression. However, due to the choice of methodology, the utilisation of footswitches to measure spatiotemporal parameters and the use of an index capturing multiple gait parameters, an exploration of the unique and multiple neural circuits involved in FRDA has not yet occurred. These studies failed to sensitively examine the specific relationship between spatiotemporal gait characteristics and other important clinical and disease parameters of FRDA such as GAA repeat length, the age at disease onset and disease duration. Identification of the relationship between changes in spatiotemporal gait parameters, intra-individual variability and disease severity and known genetic markers will help us develop a more comprehensive understanding of the impact of disease on gait dysfunction in people with FRDA. Comprehensive analysis will distinguish core features of gait in FRDA that may signify the contribution of cerebellar and somatosensory loss to gait decline and will subsequently provide a better basis for the development of specific and targeted physical rehabilitation strategies for people with FRDA. This will provide further examination, at a finer grained level, of specific gait characteristics that could provide an important avenue for examining
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the efficacy of therapeutic intervention, particularly early in the disease process [7]. The primary aim of the current study was to examine the interrelationships between spatiotemporal gait characteristics at different walking speeds and a range of clinical and disease characteristics in individuals with FRDA. Gait patterns and variability were examined to determine which specific gait characteristics are selectively associated with the underlying markers of disease and clinical decline in FRDA. We hypothesised that a range of gait parameters would be associated with clinical parameters of disease severity in FRDA. It was expected that greater postural instability as indicated by reduced speed, stride length and swing percentage of the gait cycle, and increased base of support and double-support percentage of the gait cycle, would be associated with earlier age of onset and longer GAA1 in individuals with FRDA. This information will be crucial in identifying surrogate markers of the disease which are associated with greater postural instability suggestive of increased clinical risk [22] as well as indicating mechanisms of gait adaptation more amenable to physical therapies [23].
Methods Participants Participants were recruited from the Friedreich ataxia clinical research database located at the Murdoch Childrens Research Institute. Participants were included if they were homozygous for a GAA trinucleotide expansion in intron 1 of FXN, were able to walk independently without a gait aid and were over the age of 12 years. Participants were excluded if they reported other neurological, musculoskeletal or medical conditions likely to impact their gait. This study received approval from the Southern Health Human Research Ethics Committee (HREC number 02114A). All participants (or their parents/ guardians if aged under 18 years) provided written informed consent as per the Declaration of Helsinki. Clinical details including height, weight, age at the time of testing, age at disease onset and disease duration were collected. Neurological and Functional Rating Scales All participants were assessed using the FARS and the 25FWT according to established protocols previously described [14]. The FARS comprises a functional ataxiastaging score, activities of daily living subscale and a neurological exam comprising five subscales [24]. The lower limb coordination, upright stability and peripheral nervous system subscales were investigated in this study in order to determine if these subscales were associated with gait function or if the domains measured by these subscales were related to the
decline in gait. A higher score on the FARS corresponds to greater disability. The 25FWT measures the fastest possible speed (s) at which the person is able to walk 25 ft in a straight line [25]. Gait Analysis Spatiotemporal parameters of gait were assessed using the GAITRite® instrumented walkway (CIR Systems Inc., Clifton, NJ, USA). The GAITRite® is an 830 cm long, 89 cm wide computerised walking mat, with 1.27-cm pressure sensors arranged in a horizontal grid to identify footfall contacts [26]. The GAITRite® is a valid tool for measuring both averaged and individual step parameters of gait [26] and has excellent test-retest reliability [27] and temporal accuracy of one sample (240 Hz ~4.17 ms). Procedure Participants walked along the GAITRite® mat at three different self-selected speeds: preferred, fast and slow. These speeds were selected as they reflect most aspects of daily walking. Participants started walking 80 cm prior to the mat and were instructed to maintain the same pace when walking on and off the mat. Participants completed six trials, with the last five trials used in the analysis. Preferred speed was conducted first to provide a basis for participants to adjust their walking speed in the fast and slow conditions and to prevent influences from the slow and fast speeds. Fast and slow speeds followed and were randomised using a computer software programme [28]. Analysis The GAITRite® computer software extrapolates data by calculating spatial and temporal parameters in response to sensory activation as a person walks across the walkway. Four of the five domains of gait performance were measured for each walk accounting for approximately 80 % of variation in gait in a healthy population [29]. Partial footfalls were removed from the analysis. Variables measured from the rhythm domain included gait speed (cm/s) and cadence (step/min), the pace domain included gait speed (cm/s) and stride length (cm), the gait cycle phase domain included percentage of gait cycle in swing (%) and in double support (%), and the base of support domain included the heel-to-heel base of support (cm) for each walk. The measurement of intra-individual variability was calculated by standard deviation (SD). Normal distribution of the spatiotemporal parameters were analysed using the Shapiro-Wilk test for normality. All mean values of spatiotemporal gait were normally distributed except for stride length in the fast-speed condition. Hence, we used Pearson product-moment correlation coefficients (r) or, where violations of normality occurred, the Spearman’s rank correlation
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coefficients (rho), to examine the relationship between spatiotemporal parameters of gait and disease and clinical characteristics. These included age at disease onset, disease duration, GAA1 repeat size, 25 FWT and FARS subscale scores including upright stability, lower limb coordination and peripheral nervous system scores being subscales of the FARS particularly targeting gait and lower limb function. A paired sample t test was conducted to evaluate the participants’ ability to vary their speed and to ensure that there was a true self-selected preferred, slow and fast condition. Significance was recorded as p
