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Gait, balance, and falls in Huntington disease
Handbook of Clinical Neurology, Vol. 159 (3rd series) Balance, Gait, and Falls B.L. Day and S.R. Lord, Editors https://doi.org/10.1016/B978-0-444-63916-5.00016-1 Copyright © 2018 Elsevier B.V. All rights reserved
Chapter 16
Gait, balance, and falls in Huntington disease KENNY VUONG1, COLLEEN G. CANNING2, JASMINE C. MENANT3, AND CLEMENT T. LOY4* 1 St. Joseph’s Hospital, Auburn, Sydney, Australia 2
Faculty of Health Sciences, University of Sydney, Sydney, NSW, Australia 3
Neuroscience Research Australia, Randwick, Sydney, NSW, Australia
4
Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
Abstract Huntington disease (HD) is an autosomal-dominant, progressive, neurodegenerative disorder, characterized by involuntary movements and other motor impairments, cognitive/behavioral symptoms, and psychiatric disorders. Gait and balance impairments and falls greatly impact on the quality of life among people with HD, and being fall-prone is one of the strongest predictors of nursing-home placement. Gait impairment in HD is characterized by bradykinesia, reduced velocity, and increased variability in spatiotemporal features. Detrimental changes in symmetry, step length, stride time, balance measures, gait adaptability (external cues, dual tasking), and hypo/hyperkinesia have also been observed. Balance impairment is characterized by impairments of anticipatory balance without a change in base of support, anticipatory balance with a change in base of support, and reactive balance. In addition to gait and balance impairment, people with HD have a range of intrinsic and extrinsic factors that increase fall risk, including reduced cognitive reserve for dual tasking. Currently there is some evidence to suggest exercise interventions can address some HD-specific gait and balance deficits. However, no intervention studies to date have specifically targeted falls. Large, well-designed, randomized controlled trials are needed to guide future fall prevention interventions in people with HD.
Huntington disease (HD) is an autosomal-dominant, progressive, neurodegenerative disorder, due to abnormal CAG expansion in the chromosome 4 Huntingtin gene (The Huntington’s Disease Collaborative Research Group, 1993). It is one of the most common neurogenetic disorders (MacMillan and Harper, 1991). Typical age of onset is in the 30s–40s, and symptoms include involuntary movements and other motor impairments, cognitive/ behavioral symptoms, and psychiatric disorders (Ross et al., 2014). While symptomatic treatments exist, they do not prolong survival (Walker, 2007). Median survival is 20 years, but for 81% of people with HD, 5 years or more of this 20-year period require 24-hour residential care (McCusker, 2007). HD strikes at a productive period in work and family life, and requires a high level of complex care. In particular, gait, balance impairment, and falls greatly impact quality of life, with falls cited as
one of the strongest predictors of nursing-home placement (Wheelock et al., 2003). HD is a germline adult-onset genetic disorder, i.e., people carry abnormal CAG genetic expansions from birth, but typically do not develop sufficient signs and/or symptoms for clinical diagnosis till mid-adulthood. Whilst there remains some uncertainty over when a clinical diagnosis should be made (Loy and McCusker, 2013), a distinction between the premanifest (before clinical diagnosis) and manifest (after clinical diagnosis) stages remains a helpful one for HD families and in clinical practice. In general, people who are premanifest are able to live unimpaired work life and everyday life, although a range of subclinical changes can be present among premanifest individuals, up to decades prior to clinical diagnosis (Paulsen et al., 2008; Tabrizi et al., 2013).
*Correspondence to: Clement Loy, Edward Ford Building, A27, The University of Sydney, NSW 2006, Australia. Tel: +61-288906793, Fax: +61-2-96356684, E-mail: [email protected]
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GAIT IN HUNTINGTON DISEASE Overall, gait among people with HD is characterized by chorea (abnormal involuntary movements that are brief, unpredictable, and nonstereotyped), as well as spatial and temporal gait variability. In addition, people with HD have compromised ability to control gait under various conditions of distraction, external cueing, and variations of speed. Among premanifest individuals, broadly speaking, bradykinesia, akinesia, gait variability, and impaired dynamic balance are the key detectable features (Rao et al., 2008; Delval et al., 2011). However, gait abnormalities among premanifest individuals are not limited to these (Rao et al., 2008; Delval et al., 2011; Collett et al., 2014). As the disease progresses to the manifest stage, additional gait parameters are also affected (Rao et al., 2008). As each feature presents, they continue to worsen with disease progression (Rao et al., 2008). Most studies are limited by small sample sizes and heterogeneous groups, with few studies stratifying subjects into disease stage. Between-study variability can partly be explained by inconsistent gait measurement methodology. The gait parameters most widely studied are velocity, cadence, and stride length, as well as variability of spatiotemporal features of stride and step (Fig. 16.1). Fewer studies have investigated step symmetry, step length, stride time,
akinesia, hypokinesia, hyperkinesia, and balance measures, while only a handful of studies have investigated the adaptability of gait with external cues, speed modulation, and dual tasking.
Gait features among premanifest CAG expansion carriers Only a few studies have investigated the gait pattern of people in the premanifest HD stage and the definition of the premanifest status has varied. Motor diagnosis confidence level on the motor subscale of the United Huntington Disease Rating Scale (UHDRS) has been used for some studies (Rao et al., 2008; Delval et al., 2011), and the criterion of “a total motor score of 5 or less on the UHDRS” has been used in others (Collett et al., 2014). Nevertheless, the gait pattern is generally found to include bradykinesia, akinesia, increased variability, and impaired dynamic balance (Rao et al., 2008; Delval et al., 2011). People with premanifest HD show slower gait velocity (Rao et al., 2008; Delval et al., 2011) related to shorter stride length (Rao et al., 2008) and time (Delval et al., 2011), together with slower cadence (Delval et al., 2011), but not always (Rao et al., 2008). Increased variability of step/stride length (Rao et al., 2008; Delval et al., 2011), and step time (Rao et al., 2008),
A – Healthy Subject
B – Person 1 with mild to moderate HD, normal walking
C – Person 1 with mild to moderate HD, dual task walking
D -Person 2 with moderate to severe HD, normal walking
E -Person 2 with moderate to severe HD, dual task walking
Fig. 16.1. Gait pattern among people with Huntington disease (HD). Footfall pattern recording from a 6-meter-long electronic pathway of (A) healthy subject, (B) person 1 with mild to moderate HD under normal conditions (walking at self-selected speed), and with (C) a cognitive task, (D) person 2 with moderate to severe HD under normal conditions and with (E) a cognitive task. Note all subjects are walking left to right of page. Cognitive dual task is counting backwards from 100 by 7. Color coding: magenta ¼ right foot, green ¼ left foot, yellow ¼ foot drag. (Source: de-identified data collected from HD-Falls (St Vincent’s Hospital (Sydney) Human Research Ethics Committee approval HREC/13/SVH/378.)
GAIT, BALANCE, AND FALLS IN HUNTINGTON DISEASE swing time (Rao et al., 2011) is also found in most studies. One study, though, which compared highfunctioning premanifest carriers to healthy participants, reported that trunk movement variability during gait was the only parameter that could differentiate the two groups (Collett et al., 2014). Poor dynamic balance control, as indicated by increased double-support and stance time (Rao et al., 2008), as well as akinesia (impaired initiation of movement) during the first step of walking, particularly in self-cued conditions, are also evident in individuals with premanifest HD compared with healthy peers (Delval et al., 2011). Overall, these findings suggest that compensatory strategies to maintain safe and efficient ambulation may be employed prior to the onset of definitive clinical signs (Patla, 2003).
Gait features among people with manifest Huntington disease One of the most distinguishable motor features of people with manifest HD is chorea (Ross et al., 2014). However, people with manifest HD also show abnormalities in a wide range of gait parameters.
VELOCITY Reduced gait velocity is a key feature of the manifest stage (Koller and Trimble, 1985; Thaut et al., 1999; Churchyard et al., 2001; Rao et al., 2005, 2008; Delval et al., 2006, 2008b; Grimbergen et al., 2008; Dalton et al., 2013; Collett et al., 2014), and is highly variable among people with HD (Reynolds et al., 1999; Thaut et al., 1999; Churchyard et al., 2001; Rao et al., 2005; Delval et al., 2006, 2008b). While reduced velocity is evident in the premanifest stage, it continues to worsen throughout the manifest stage (Reynolds et al., 1999; Thaut et al., 1999; Churchyard et al., 2001).
STEP / STRIDE Stride length is significantly reduced in manifest HD (Koller and Trimble, 1985; Churchyard et al., 2001; Bilney et al., 2005; Rao et al., 2005, 2008; Delval et al., 2008b; Grimbergen et al., 2008; Dalton et al., 2013; Collett et al., 2014; Danoudis and Iansek, 2014) and highly variable (Reynolds et al., 1999; Churchyard et al., 2001; Bilney et al., 2005; Delval et al., 2006, 2008b; Grimbergen et al., 2008; Rao et al., 2008; Dalton et al., 2013; Collett et al., 2014). Stride time is also reduced (Koller and Trimble, 1985; Delval et al., 2006) and variable (Hausdorff et al., 1998; Rao et al., 2005; Delval et al., 2006). One study asked people with various stages of HD to walk at self-preferred pace, and found stride-to-stride variability triple that of healthy controls (Hausdorff
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et al., 1998). Similarly, two other studies found this variability to be approximately double that of controls (Churchyard et al., 2001; Bilney et al., 2005). Additionally, these stride-to-stride fluctuations are also more random (Hausdorff et al., 1997). As HD progresses, there is greater variability of the spatiotemporal aspects of stride (Hausdorff et al., 1998; Reynolds et al., 1999) and a further reduction of stride length (Churchyard et al., 2001). In the late stage of HD, variability of stride length is significantly worse compared with earlier stages of the disease (Collett et al., 2014). Similar to stride, step length and time are significantly reduced with increased variability when compared to those without HD (Hausdorff et al., 1998; Bilney et al., 2005; Rao et al., 2008; Dalton et al., 2013; Collett et al., 2014; Andrzejewski et al., 2016). Furthermore, step symmetry (as defined by the ratio of left and right step length) and regularity (similarity of consecutive strides) are also significantly impaired (Dalton et al., 2013; Collett et al., 2014).
TRUNK Truncal movement has been shown to be affected during gait with increased amplitude and velocity of mediolateral sway (Andrzejewski et al., 2016). One study found this characteristic is associated with a history of multiple falls (Grimbergen et al., 2008).
BALANCE Balance impairment worsens from premanifest stage to the manifest stage (Rao et al., 2008), with greater time spent in double-support time and stance. Additionally, a wide base of support appears in the early stage of manifest HD, possibly as a compensatory strategy for poor balance (Patla, 2003). As HD progresses, variability of double-support time also increases (Hausdorff et al., 1998).
AKINESIA/HYPOKINESIA/HYPERKINESIA Akinesia continues to be found in people with early to middle-stage HD (Delval et al., 2007), associated with lower-limb hypokinesia (Delval et al., 2007, 2008b). Interestingly, hyperkinesia can exist simultaneously with hypokinesia in the ankle joint (Delval et al., 2006).
CADENCE Numerous biomechanical studies have found cadence to be significantly reduced (Koller and Trimble, 1985; Churchyard et al., 2001; Bilney et al., 2005; Rao et al., 2005, 2008; Delval et al., 2006, 2008b; Andrzejewski et al., 2016) and with increased variability (Reynolds et al., 1999; Churchyard et al., 2001; Bilney et al., 2005; Rao et al., 2005; Delval et al., 2006, 2008b;
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Collett et al., 2014). Cadence remains reduced even when measured at home as opposed to the clinical setting (Andrzejewski et al., 2016). There is conjecture as to what stage reduced cadence first appears, but it seems to be during the early to middle stages of HD (Delval et al., 2006; Rao et al., 2008). One study did not find reduced cadence, but more than half of the cohort were in early-stage HD (Danoudis and Iansek, 2014). As HD advances, cadence is further reduced. One study noted that cadence was significantly reduced when people in late-stage HD were compared to earlier stages (Collett et al., 2014).
CADENCE–STRIDE RELATIONSHIP In early-stage clinical HD, the relationship between cadence and stride length remains linear (Danoudis and Iansek, 2014). Additionally, for the same cadence, those with HD have a shorter stride length when compared with healthy subjects (Danoudis and Iansek, 2014). Whether this relationship is maintained in later stages remains to be investigated.
walking leads to a deterioration of velocity, cadence (Churchyard et al., 2001; Delval et al., 2008a), and stride length (Delval et al., 2008a). This degree of deterioration is greater than that observed among healthy adults (Churchyard et al., 2001; Delval et al., 2008a; Jacobs et al., 2015). Gait velocity also decreases under both simple and complex cognitive alphabet naming task conditions. As HD progresses, there is reduced walking speed under dual cognitive task conditions (Delval et al., 2008b). Additionally, both gait and cognitive performance deteriorate when HD patients are instructed to prioritize gait over the cognitive task (Fritz et al., 2016). These deleterious effects are likely due to the interference a cognitive task has on gait (Delval et al., 2008a). Interestingly, an upper-limb task had no bearing on walking performance in one study, although the instructions provided were to continue walking despite any mistakes made (Delval et al., 2008a). This suggests that the participants may have focused on gait and not the upper-limb task, thereby not offering interference to the performance.
DYSTONIA Dystonia is another common feature of HD. It is defined as an involuntary muscle co-contraction that, most commonly, produces abnormal posturing (Fahn, 1988). It can present in the upper limbs, trunk, and lower limbs. Abnormal knee posturing can present initially during swing phase and is held for an excessive amount of time into early stance phase (Louis et al., 1999). Though its impact on gait has not yet been investigated in HD, one can extrapolate many potential detrimental effects of excessive knee flexion throughout the gait cycle. A knee held in flexion instead of extension at late swing would limit stride length. Additionally, during stance phase, a knee already flexed has an impaired ability to absorb shock in yield phase. It could also lead to a lowering of the center of mass, thus a greater than expected perturbation to balance. If we conceptualize gait to be a repetitive sequence of movements, an unexpected dystonic posture would interrupt the flow of movement and momentum, rendering gait to become potentially energy-inefficient, unpredictable, and unsteady.
GAIT ADAPTABILITY A handful of studies have investigated the effects of dual tasking, change in selected walking speed, and external cueing on gait characteristics. Dual tasking People with HD have difficulty walking and performing cognitive tasks simultaneously. In comparison to simple walking, counting backwards whilst
Fast and slow walking When attempting to walk faster or slower than their preferred pace, people with HD are able to modulate their velocity (Thaut et al., 1999; Churchyard et al., 2001) but still remain significantly slower when compared to healthy subjects (Churchyard et al., 2001). There is conjecture as to the effect of fast and slow walking on cadence. Two studies found reduced cadence when compared to healthy adults (Bilney et al., 2005; Thaut et al., 1999), In contrast, two other studies found no difference (Churchyard et al., 2001; Danoudis and Iansek, 2014), though in one of these studies, more than half of the subjects were in the early stages of HD (Danoudis and Iansek, 2014). There is agreement, however, that stride length is significantly reduced at varied speeds in people with manifest HD (Churchyard et al., 2001; Bilney et al., 2005; Danoudis and Iansek, 2014). At self-selected walking speeds, cadence is reduced to a greater extent than stride length, and at faster speeds this remains the case. Therefore stride length is relied upon more than cadence to generate velocity at both normal and fast speeds (Thaut et al., 1999; Bilney et al., 2005). In contrast, people with early-stage HD modulate cadence and stride length when changing speed in the same ratio as healthy subjects (Danoudis and Iansek, 2014). Increased variability of velocity (Churchyard et al., 2001), cadence, and stride length (Churchyard et al., 2001; Bilney et al., 2005) occurs with speed changes, with one study finding stride length variability was twice that of controls (Bilney et al., 2005).
GAIT, BALANCE, AND FALLS IN HUNTINGTON DISEASE External cueing Delval et al. (2008a) found an audible metronome intended to cue cadence did not improve the gait pattern of people with HD. In fact, a deleterious effect on gait pattern occurred. Two studies asked subjects to walk to the pace of a metronome and found stride length shortened (Churchyard et al., 2001; Bilney et al., 2005) and cadence decreased. Variability of velocity as well as stride length increased (Churchyard et al., 2001; Bilney et al., 2005) and cadence was three times more variable than controls at 80 beats/min, increasing to six times more variable at 120 beats/min (Bilney et al., 2005). In another study, the metronome was set at a moderately faster or slower rate than preferred self-paced walk. It was found that velocity could be modulated to the rhythm. However, when music was applied, velocity could not be modulated (Thaut et al., 1999). This may be due to the greater cognitive demands of attending to the beat of music rather than a metronome. People with HD have difficulty synchronizing their steps to an external cue (Thaut et al., 1999; Churchyard et al., 2001; Bilney et al., 2005) at fast or slow frequencies (Churchyard et al., 2001). They underestimate the cadence at fast beats, and overestimate the cadence at slow beats, leading to a reduced cadence range (Bilney et al., 2005). As HD progresses, there is diminished ability to modulate cadence to external cues (Thaut et al., 1999). There are however potential benefits of external cueing. Akinesia has been shown to improve when an external cue triggers stepping, in both people with premanifest and manifest HD (Delval et al., 2007, 2011).
BALANCE IN HUNTINGTON DISEASE Balance impairment among people with HD begins in the premanifest stage and worsens in the manifest stages. Current evidence for balance impairment in HD can be categorized into three broad areas: anticipatory balance without a change in base of support, anticipatory balance with a change in base of support, and reactive balance. There are relatively few studies investigating balance in people with HD. All studies are biomechanical in nature and have relatively small sample sizes. Additionally, there is very little information on specific balance deficits at each disease stage. Furthermore, there are only a handful of studies that include people in the premanifest stage. It is therefore difficult to determine how balance deficits evolve throughout the disease stages.
Balance features among premanifest CAG expansion carriers Premanifest expansion carriers perform as well as healthy subjects during eyes-open quiet standing
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(Salomonczyk et al., 2010). However, they display increased postural sway when their sensory inputs and/ or base of support are manipulated: standing with eyes closed with either a normal or narrowed base of support (Dalton et al., 2013), standing in maximum leaning positions (Blanchet et al., 2014), and /or when vision is eliminated and proprioception attenuated (Salomonczyk et al., 2010; Blanchet et al., 2014). People with premanifest HD also show limited anticipatory postural adjustments at gait initiation, as shown by a decreased backward shift in the center of pressure in that phase (Delval et al., 2011). To date, standardized clinical tests of balance such as tandem walking, retropulsion, and the Functional Reach Test have not shown to be sensitive to changes among people in the premanifest stage (Rao et al., 2009a).
Balance features among people with manifest Huntington disease ANTICIPATORY BALANCE WITHOUT A CHANGE IN BASE OF SUPPORT
Standing in a normal base of support People with manifest HD exhibit greater sway than those without HD during eyes-open standing with a normal base of support (Huttunen and Homberg, 1990; Tian et al., 1992; Salomonczyk et al., 2010; Reilmann et al., 2012; Dalton et al., 2013). Additionally, the center of mass has been shown to move greater distances and at faster speeds in this condition (Reilmann et al., 2012). Given the balance impairment when standing with a normal base of support, it is unsurprising that a narrow base of support creates further postural instability (Goldberg et al., 2010; Jacobs et al., 2015). Sensory manipulation Compared with people with premanifest HD, those in the manifest stage require less sensory challenge to become unstable (Salomonczyk et al., 2010) and when similarly challenged display greater sway (Salomonczyk et al., 2010; Dalton et al., 2013). Eyes-closed standing with a narrow base of support leads to significantly greater sway than for those with premanifest HD (Dalton et al., 2013), and healthy subjects (Reilmann et al., 2012; Dalton et al., 2013). During the Sensory Organization Test, people with manifest HD display significantly greater sway compared to healthy subjects when either vision or proprioception is reduced, and the greatest deterioration of performance occurs, when the vestibular system is predominantly relied upon (Tian et al., 1992; Salomonczyk et al., 2010; Jacobs et al.). The attenuation of proprioception produces approximately twice the amount of sway to when only vision is eliminated (Tian et al., 1992). People with HD also
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have more falls when sensory input is challenged (Salomonczyk et al., 2010). Compensatory strategies to maintain standing balance under sensory manipulation have not been thoroughly investigated. However one study infers that a hip strategy is more often used by those with HD to maintain balance (Tian et al., 1992), whereas healthy adults tend to use an ankle strategy. Extremes of posture Instability in extreme leaning postures worsens in the manifest stage. The range of center-of-pressure displacement is significantly decreased as soon as the leaning position is attained, whereas people in premanifest stage need to sustain this position over time before showing a similar effect (Blanchet et al., 2014). This displacement also occurs along both the axis of the direction of lean and the axis perpendicular to the direction of lean, compared to premanifest participants who only exhibit displacements along the axis of direction of lean. Sensory manipulation in maximum leaning has shown similar results to quiet standing. People in manifest stage are affected in all conditions, earlier in time and to a greater extent, compared to premanifest participants. When standing at the limits of stability, people with manifest HD are also affected to a greater extent.
ANTICIPATORY BALANCE WITH A CHANGE IN BASE OF SUPPORT
People with manifest HD have instability of posture control in a range of functional and balance tasks where a change in the base of support occurs (Goldberg et al., 2010; Panzera et al., 2011; Blanchet et al., 2014; Jacobs et al., 2015). This is evident in a number of areas, as discussed below. Bradykinesia Bradykinesia has been shown to occur in many types of dynamic functional tasks. Greater time is taken to complete tasks such as step up and over an obstacle, step and turn, and weight transfer during sit to stand (Panzera et al., 2011). Cued and self-triggered step response times in people with HD are also slower than in healthy people (Delval et al., 2007; Goldberg et al., 2010). The center of mass movement exhibits bradykinesia during anticipatory postural adjustments prior to taking a step from quiet standing (Delval et al., 2007). Sway People with manifest HD have greater sway velocity of the center of gravity during functional tasks. This is indicative of poor stability control (Panzera et al., 2011). This
increased sway velocity increases the risk that the center of mass moves beyond the limits of the base support, increasing fall risk. Anticipatory postural adjustments People with manifest HD have impaired anticipatory postural adjustments that is not limited to bradykinesia. When taking a self-initiated step, anticipatory postural adjustment is also of significantly shorter duration. The trajectory of the center of mass tends to deviate from the consistent path taken by healthy subjects. Additionally, the center of mass shows less displacement as the foot disengages from the ground (Delval et al., 2007). Slower, shorter, and smaller movements of the center of mass define anticipatory postural adjustments in HD. Whether this is part of a compensatory strategy developed to mitigate postural instability or a direct consequence of HD remains to be investigated. Internal cueing Internal cueing for postural changes seems to be impaired in people with HD. If external cueing is applied to a step response task, the duration of the anticipatory postural adjustment is not significantly different to that of healthy controls. In contrast, under self-triggered conditions, there is a marked deterioration of performance. Additionally, there is greater deterioration of step response time when movement is self-triggered, compared to when externally cued (Delval et al., 2007).
REACTIVE BALANCE In response to a sudden toe-up tilt, electromyography of tibialis anterior shows delayed reaction and longer duration of the long-latency reflex (Huttunen and Homberg, 1990). Similarly, there is delayed and prolonged lowerlimb muscle activation when a force plate is suddenly translated forwards or backwards (Tian et al., 1992). During rotational movements of a force plate, people with HD had significantly more falls (Tian et al., 1992). The MiniBESTest incorporates tests of anticipatory balance, with and without a change in base of support and reactive balance (Jacobs et al., 2015). When tested with the MiniBESTest, people with HD had poorer recovery of balance after an externally applied pressure is released during the compensatory stepping correction item. People with HD also perform poorly on the retropulsion pull test item of the motor subscale of the UHDRS (Goldberg et al., 2010).
CONFIDENCE People with clinically manifest HD have reduced balance confidence. This has been found on the
GAIT, BALANCE, AND FALLS IN HUNTINGTON DISEASE Activities-Specific Balance Confidence Scale (Powell and Myers, 1995), a self-rated scale of balance confidence during various day-to-day functional activities (Goldberg et al., 2010; Jacobs et al., 2015). However, this measure may not be a reliable measure of confidence in people with HD (Kloos et al., 2014). Reduced confidence can have potentially deleterious effects on function and thus quality of life, and may also be a fall risk factor. On the other hand, reduced balance confidence may have a protective function prompting judicious use of stable supports (e.g., use of hand rails on steps) in individuals with severe balance impairments.
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when fall diaries were returned immediately after each fall, the adherence rate was 89% (40 out of 45) (Grimbergen et al., 2008). In future, technologic advances may enable real-time falls data collection. There are limited data on injurious falls. Among people with early to mid-stage HD, 73% suffered only minor injury, mainly bruises and abrasions, with no serious injuries recorded (Grimbergen et al., 2008). In mid-stage HD, 50% reported injury with all recalled falls but the seriousness was not reported (Brozova et al., 2011). Among nursing-home residents with HD, minor injury occurred in 14% and serious injury in 9% of falls, although the injury categorization was not well defined (Zarowitz et al., 2014).
Fall and fall injury incidence Retrospective studies find high rates of falls among people with early to mid-stage HD. For the preceding 6 months, 22% (Kloos et al., 2010) to 38% (Kloos et al., 2012) of participants reported a single fall, and a further 36% reported multiple falls (Kloos et al., 2012). For the preceding 12 months, single fall rates range from 21% to 75% and multiple falls range from 58% to 60% (Grimbergen et al., 2008; Busse et al., 2009). Not surprisingly, 65–85% of people reported falls over the course of disease (Koller and Trimble, 1985; Brozova et al., 2011). In a group of North American nursing homes, almost half of residents (162 out of 339) with HD fell over in an 18-month period (Zarowitz et al., 2014). Only one study has published findings for a 3-month follow-up using a standardized falls calendar, with 40% falling once and 20% falling two or more times (Grimbergen et al., 2008). Excluding nursing-home residents, published fall rates are for people who present to healthcare professionals or researchers. Therefore, an accurate estimate of falls incidence in the community is not known. Methodologically, it is difficult to obtain accurate falls data from people with HD. Recall bias, cognitive deficits, and behavioral issues may impact on the accuracy of retrospective data. Unsurprisingly, one small study found carers to be more reliable reporters of falls than people with HD (Brozova et al., 2011). Compounding this issue is the heterogeneity of falls data collection methods across studies. Only two studies have used a validated interview and questionnaire to collect retrospective falls data (Grimbergen et al., 2008; Busse et al., 2009) and most other studies have not specified the timeframe for reporting or method of interview. Response rates for prospective falls diaries are also variable. When instructed to return diaries at the completion of the follow-up, response rates were between 59% and 66% (Fritz et al., 2016; Quinn et al., 2016). However
Factors associated with falls Studies of gait-related fall risk in people with HD have focused on recurrent fallers rather than single fallers. Recurrent fallers display decreased gait velocity (Grimbergen et al., 2008; Busse et al., 2009), decreased stride length, mediolateral trunk sway, and increased variability of stride length (Grimbergen et al., 2008). Bradykinesia and chorea scores on the motor subscale of the UHDRS, as well as disability levels, are also significantly worse in recurrent fallers (Grimbergen et al., 2008; Busse et al., 2009). In studies of balance in people with HD, externally applied perturbations were more likely to induce falls in the manifest stage than the premanifest stage or healthy controls (Tian et al., 1992; Salomonczyk et al., 2010), with most falls during the first few external perturbation repetitions and subsequent improvements in balance, indicating an element of trainability (Tian et al., 1992). A few studies have found the Timed Up and Go (Podsiadlo and Richardson, 1991; Busse et al., 2012) and Berg Balance Scale (Berg et al., 1992; Quinn et al., 2013) performance scores are associated with a history of falls (Rao et al., 2009b). For example, a cutoff score of equal or greater than 14 seconds on the Timed Up and Go and 40 seconds or less on the Berg Balance Scale is associated with increased fall risk in HD (Busse et al., 2009). A Tinetti Mobility Test (Tinetti, 1986; Quinn et al., 2013) score of 21 or less identified fallers with 74% sensitivity and 60% specificity (Kloos et al., 2010). This demonstrates that simple physical outcome measures cannot accurately predict falls, and other intrinsic and extrinsic factors should be considered. A tool that accounts for multifactorial fall risk factors would assist clinicians, people with HD, and their families to predict falls and implement strategies to decrease fall risk. Cognition and aggression have been found to significantly increase fall risk, after adjusting for chorea,
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bradykinesia, disability, and balance (Grimbergen et al., 2008). Falls have also been associated with impaired performance in the walking while talking test (Fritz et al., 2016) and self-reports of multitasking leading up to fall (Grimbergen et al., 2008). There is no indication that exercise participation increases fall risk (Khalil et al., 2013; Quinn et al., 2014, 2016). However, during supervised balancechallenging exercise, some participants with more severe impairments required assistance to recover balance (Kloos et al., 2013). Therapists, therefore, should be aware that exercises that challenge balance may increase the risk of falls in the short term, necessitating consideration of appropriate levels of supervision. When analyzing 40 falls Grimbergen et al. (2008) reported floor obstacles were involved in 25% of recurrent falls, 20% were during stair use, and 18% occurred on uneven or slippery floors. Notably, 93% of falls were in a familiar environment and 58% were indoors. The type of walking aid may also play a role in falls. One study recorded falls when using a standard walker, three-wheeled walker, or no aid at all, during figure-of-eight walking. This contrasts with no falls when using a four-wheeled walker instead (Kloos et al., 2012).
Confidence and fear Despite limited reliability in HD (Kloos et al., 2014), it has been found that recurrent fallers report lower balance confidence as measured by the Activities-specific Balance Confidence scale (Powell and Myers, 1995) than single fallers (Grimbergen et al., 2008; Busse et al., 2009). Interestingly, in one study, fallers reported less balance confidence but not an increased fear of falls (Grimbergen et al., 2008). This may be due to the specificity of questioning in the Activities-specific Balance Confidence scale and limited insight.
CONCLUSIONS There is an emerging understanding of gait and balance impairments among people with HD. Falls are common and impact greatly on quality of life among people with HD. Evidence from randomized controlled trials of exercise interventions and rehabilitation shows that these interventions are safe, feasible, and acceptable for addressing HD-specific gait and balance deficits with some positive effects (Busse et al., 2013; Khalil et al., 2013; Kloos et al., 2013; Thompson et al., 2013; Quinn et al., 2014, 2016). However, the small heterogeneous samples, along with variability in exercise type, dose, and supervision, limit the conclusions that can be drawn currently. Furthermore, no interventions have
specifically targeted fall risk factors among people with HD. Large, well-designed, randomized controlled trials are needed to guide future exercise and rehabilitation interventions among people with HD.
ACKNOWLEDGMENTS CTL is supported by an Australian National Health and Medical Research Council Australian Research Council Dementia Research Development Fellowship (APP1107657).
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GAIT, BALANCE, AND FALLS IN HUNTINGTON DISEASE Delval A, Krystkowiak P, Blatt JL et al. (2007). A biomechanical study of gait initiation in Huntington’s disease. Gait Posture 25: 279–288. Delval A, Krystkowiak P, Delliaux M et al. (2008a). Effect of external cueing on gait in Huntington’s disease. Mov Disord 23: 1446–1452. Delval A, Krystkowiak P, Delliaux M et al. (2008b). Role of attentional resources on gait performance in Huntington’s disease. Mov Disord 23: 684–689. Delval A, Bleuse S, Simonin C et al. (2011). Are gait initiation parameters early markers of Huntington’s disease in premanifest mutation carriers? Gait Posture 34: 202–207. Fahn S (1988). Concept and classification of dystonia. Adv Neurol 50: 1–8. Fritz NE, Hamana K, Kelson M et al. (2016). Motor-cognitive dual-task deficits in individuals with early-mid stage Huntington disease. Gait Posture 49: 283–289. Goldberg A, Schepens SL, Feely SM et al. (2010). Deficits in stepping response time are associated with impairments in balance and mobility in people with Huntington disease. J Neurol Sci 298: 91–95. Grimbergen YA, Knol MJ, Bloem BR et al. (2008). Falls and gait disturbances in Huntington’s disease. Mov Disord 23: 970–976. Hausdorff JM, Mitchell SL, Firtion R et al. (1997). Altered fractal dynamics of gait: reduced stride-interval correlations with aging and Huntington’s disease. J Appl Physiol 82: 262–269. Hausdorff JM, Cudkowicz ME, Firtion R et al. (1998). Gait variability and basal ganglia disorders: stride-to-stride variations of gait cycle timing in Parkinson’s disease and Huntington’s disease [erratum appears in Mov Disord 1998 Jul;13(4):757]. Mov Disord 13: 428–437. Huntington’s Disease Collaborative Research Group (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72: 971–983. Huttunen J, Homberg V (1990). EMG responses in leg muscles to postural perturbations in Huntington’s disease. J Neurol Neurosurg Psychiatry 53: 55–62. Jacobs JV, Boyd JT, Hogarth P et al. (2015). Domains and correlates of clinical balance impairment associated with Huntington’s disease. Gait Posture 41: 867–870. Khalil H, Quinn L, van Deursen R et al. (2013). What effect does a structured home-based exercise programme have on people with Huntington’s disease? A randomized, controlled pilot study. Clin Rehabil 27: 646–658. Kloos AD, Kegelmeyer DA, Young GS et al. (2010). Fall risk assessment using the Tinetti mobility test in individuals with Huntington’s disease. Mov Disord 25: 2838–2844. Kloos AD, Kegelmeyer DA, White SE et al. (2012). The impact of different types of assistive devices on gait measures and safety in Huntington’s disease. PLoS One 7. Kloos AD, Fritz NE, Kostyk SK et al. (2013). Video game play (Dance Dance Revolution) as a potential exercise therapy in Huntington’s disease: a controlled clinical trial. Clin Rehabil 27: 972–982.
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Kloos AD, Fritz NE, Kostyk SK et al. (2014). Clinimetric properties of the Tinetti Mobility Test, Four Square Step Test, Activities-specific Balance Confidence Scale, and spatiotemporal gait measures in individuals with Huntington’s disease. Gait Posture 40: 647–651. Koller WC, Trimble J (1985). The gait abnormality of Huntington’s disease. Neurology 35: 1450–1454. Louis ED, Lee P, Quinn L et al. (1999). Dystonia in Huntington’s disease: prevalence and clinical characteristics. Mov Disord 14: 95–101. Loy CT, McCusker EA (2013). Is a motor criterion essential for the diagnosis of clinical huntington disease? PLoS Curr 5. MacMillan JC, Harper PS (1991). Single-gene neurological disorders in South Wales: an epidemiological study. Ann Neurol 30: 411–414. McCusker EL (2007). Huntington disease: outcomes in advanced disease. In: American Academy of Neurology 59th Annual Meeting. Boston. Panzera R, Salomonczyk D, Pirogovosky E et al. (2011). Postural deficits in Huntington’s disease when performing motor skills involved in daily living. Gait Posture 33: 457–461. Patla AE (2003). Strategies for dynamic stability during adaptive human locomotion. IEEE Eng Med Biol Mag 22: 48–52. Paulsen JS, Langbehn DR, Stout JC et al. (2008). Detection of Huntington’s disease decades before diagnosis: the Predict-HD study. J Neurol Neurosurg Psychiatry 79: 874–880. Podsiadlo D, Richardson S (1991). The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 39: 142–148. Powell LE, Myers AM (1995). The Activities-specific Balance Confidence (ABC) scale. J Gerontol A Biol Sci Med Sci 50A: M28–M34. Quinn L, Khalil H, Dawes H et al. (2013). Reliability and minimal detectable change of physical performance measures in individuals with pre-manifest and manifest Huntington disease. Phys Ther 93: 942–956. Quinn L, Debono K, Dawes H et al. (2014). Task-specific training in Huntington disease: a randomized controlled feasibility trial. Phys Ther 94: 1555–1568. Quinn L, Hamana K, Kelson M et al. (2016). A randomized, controlled trial of a multi-modal exercise intervention in Huntington’s disease. Parkinsonism Relat Disord 31: 46–52. Rao AK, Quinn L, Marder KS (2005). Reliability of spatiotemporal gait outcome measures in Huntington’s disease. Mov Disord 20: 1033–1037. Rao AK, Muratori L, Louis ED et al. (2008). Spectrum of gait impairments in presymptomatic and symptomatic Huntington’s disease. Mov Disord 23: 1100–1107. Rao AK, Louis ED, Marder KS (2009a). Clinical assessment of mobility and balance impairments in pre-symptomatic Huntington’s disease. Gait Posture 30: 391–393. Rao AK, Muratori L, Louis ED et al. (2009b). Clinical measurement of mobility and balance impairments in
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Thaut MH, Miltner R, Lange HW et al. (1999). Velocity modulation and rhythmic synchronization of gait in Huntington’s disease. Mov Disord 14: 808–819. Thompson JA, Cruickshank TM, Penailillo LE et al. (2013). The effects of multidisciplinary rehabilitation in patients with early-to-middle-stage Huntington’s disease: a pilot study. Eur J Neurol 20: 1325–1329. Tian J, Herdman SJ, Zee DS et al. (1992). Postural stability in patients with Huntington’s disease. Neurology 42: 1232–1238. Tinetti ME (1986). Performance-oriented assessment of mobility problems in elderly patients. J Am Geriatr Soc 34: 119–126. Walker FO (2007). Huntington’s disease. Lancet 369: 218–228. Wheelock VL, Tempkin T, Marder K et al. (2003). Predictors of nursing home placement in Huntington disease. Neurology 60: 998–1001. Zarowitz BJ, O’Shea T, Nance M (2014). Clinical, demographic, and pharmacologic features of nursing home residents with Huntington’s disease. J Am Med Dir Assoc 15: 423–428.
Chapter 16
Gait, balance, and falls in Huntington disease KENNY VUONG1, COLLEEN G. CANNING2, JASMINE C. MENANT3, AND CLEMENT T. LOY4* 1 St. Joseph’s Hospital, Auburn, Sydney, Australia 2
Faculty of Health Sciences, University of Sydney, Sydney, NSW, Australia 3
Neuroscience Research Australia, Randwick, Sydney, NSW, Australia
4
Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
Abstract Huntington disease (HD) is an autosomal-dominant, progressive, neurodegenerative disorder, characterized by involuntary movements and other motor impairments, cognitive/behavioral symptoms, and psychiatric disorders. Gait and balance impairments and falls greatly impact on the quality of life among people with HD, and being fall-prone is one of the strongest predictors of nursing-home placement. Gait impairment in HD is characterized by bradykinesia, reduced velocity, and increased variability in spatiotemporal features. Detrimental changes in symmetry, step length, stride time, balance measures, gait adaptability (external cues, dual tasking), and hypo/hyperkinesia have also been observed. Balance impairment is characterized by impairments of anticipatory balance without a change in base of support, anticipatory balance with a change in base of support, and reactive balance. In addition to gait and balance impairment, people with HD have a range of intrinsic and extrinsic factors that increase fall risk, including reduced cognitive reserve for dual tasking. Currently there is some evidence to suggest exercise interventions can address some HD-specific gait and balance deficits. However, no intervention studies to date have specifically targeted falls. Large, well-designed, randomized controlled trials are needed to guide future fall prevention interventions in people with HD.
Huntington disease (HD) is an autosomal-dominant, progressive, neurodegenerative disorder, due to abnormal CAG expansion in the chromosome 4 Huntingtin gene (The Huntington’s Disease Collaborative Research Group, 1993). It is one of the most common neurogenetic disorders (MacMillan and Harper, 1991). Typical age of onset is in the 30s–40s, and symptoms include involuntary movements and other motor impairments, cognitive/ behavioral symptoms, and psychiatric disorders (Ross et al., 2014). While symptomatic treatments exist, they do not prolong survival (Walker, 2007). Median survival is 20 years, but for 81% of people with HD, 5 years or more of this 20-year period require 24-hour residential care (McCusker, 2007). HD strikes at a productive period in work and family life, and requires a high level of complex care. In particular, gait, balance impairment, and falls greatly impact quality of life, with falls cited as
one of the strongest predictors of nursing-home placement (Wheelock et al., 2003). HD is a germline adult-onset genetic disorder, i.e., people carry abnormal CAG genetic expansions from birth, but typically do not develop sufficient signs and/or symptoms for clinical diagnosis till mid-adulthood. Whilst there remains some uncertainty over when a clinical diagnosis should be made (Loy and McCusker, 2013), a distinction between the premanifest (before clinical diagnosis) and manifest (after clinical diagnosis) stages remains a helpful one for HD families and in clinical practice. In general, people who are premanifest are able to live unimpaired work life and everyday life, although a range of subclinical changes can be present among premanifest individuals, up to decades prior to clinical diagnosis (Paulsen et al., 2008; Tabrizi et al., 2013).
*Correspondence to: Clement Loy, Edward Ford Building, A27, The University of Sydney, NSW 2006, Australia. Tel: +61-288906793, Fax: +61-2-96356684, E-mail: [email protected]
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GAIT IN HUNTINGTON DISEASE Overall, gait among people with HD is characterized by chorea (abnormal involuntary movements that are brief, unpredictable, and nonstereotyped), as well as spatial and temporal gait variability. In addition, people with HD have compromised ability to control gait under various conditions of distraction, external cueing, and variations of speed. Among premanifest individuals, broadly speaking, bradykinesia, akinesia, gait variability, and impaired dynamic balance are the key detectable features (Rao et al., 2008; Delval et al., 2011). However, gait abnormalities among premanifest individuals are not limited to these (Rao et al., 2008; Delval et al., 2011; Collett et al., 2014). As the disease progresses to the manifest stage, additional gait parameters are also affected (Rao et al., 2008). As each feature presents, they continue to worsen with disease progression (Rao et al., 2008). Most studies are limited by small sample sizes and heterogeneous groups, with few studies stratifying subjects into disease stage. Between-study variability can partly be explained by inconsistent gait measurement methodology. The gait parameters most widely studied are velocity, cadence, and stride length, as well as variability of spatiotemporal features of stride and step (Fig. 16.1). Fewer studies have investigated step symmetry, step length, stride time,
akinesia, hypokinesia, hyperkinesia, and balance measures, while only a handful of studies have investigated the adaptability of gait with external cues, speed modulation, and dual tasking.
Gait features among premanifest CAG expansion carriers Only a few studies have investigated the gait pattern of people in the premanifest HD stage and the definition of the premanifest status has varied. Motor diagnosis confidence level on the motor subscale of the United Huntington Disease Rating Scale (UHDRS) has been used for some studies (Rao et al., 2008; Delval et al., 2011), and the criterion of “a total motor score of 5 or less on the UHDRS” has been used in others (Collett et al., 2014). Nevertheless, the gait pattern is generally found to include bradykinesia, akinesia, increased variability, and impaired dynamic balance (Rao et al., 2008; Delval et al., 2011). People with premanifest HD show slower gait velocity (Rao et al., 2008; Delval et al., 2011) related to shorter stride length (Rao et al., 2008) and time (Delval et al., 2011), together with slower cadence (Delval et al., 2011), but not always (Rao et al., 2008). Increased variability of step/stride length (Rao et al., 2008; Delval et al., 2011), and step time (Rao et al., 2008),
A – Healthy Subject
B – Person 1 with mild to moderate HD, normal walking
C – Person 1 with mild to moderate HD, dual task walking
D -Person 2 with moderate to severe HD, normal walking
E -Person 2 with moderate to severe HD, dual task walking
Fig. 16.1. Gait pattern among people with Huntington disease (HD). Footfall pattern recording from a 6-meter-long electronic pathway of (A) healthy subject, (B) person 1 with mild to moderate HD under normal conditions (walking at self-selected speed), and with (C) a cognitive task, (D) person 2 with moderate to severe HD under normal conditions and with (E) a cognitive task. Note all subjects are walking left to right of page. Cognitive dual task is counting backwards from 100 by 7. Color coding: magenta ¼ right foot, green ¼ left foot, yellow ¼ foot drag. (Source: de-identified data collected from HD-Falls (St Vincent’s Hospital (Sydney) Human Research Ethics Committee approval HREC/13/SVH/378.)
GAIT, BALANCE, AND FALLS IN HUNTINGTON DISEASE swing time (Rao et al., 2011) is also found in most studies. One study, though, which compared highfunctioning premanifest carriers to healthy participants, reported that trunk movement variability during gait was the only parameter that could differentiate the two groups (Collett et al., 2014). Poor dynamic balance control, as indicated by increased double-support and stance time (Rao et al., 2008), as well as akinesia (impaired initiation of movement) during the first step of walking, particularly in self-cued conditions, are also evident in individuals with premanifest HD compared with healthy peers (Delval et al., 2011). Overall, these findings suggest that compensatory strategies to maintain safe and efficient ambulation may be employed prior to the onset of definitive clinical signs (Patla, 2003).
Gait features among people with manifest Huntington disease One of the most distinguishable motor features of people with manifest HD is chorea (Ross et al., 2014). However, people with manifest HD also show abnormalities in a wide range of gait parameters.
VELOCITY Reduced gait velocity is a key feature of the manifest stage (Koller and Trimble, 1985; Thaut et al., 1999; Churchyard et al., 2001; Rao et al., 2005, 2008; Delval et al., 2006, 2008b; Grimbergen et al., 2008; Dalton et al., 2013; Collett et al., 2014), and is highly variable among people with HD (Reynolds et al., 1999; Thaut et al., 1999; Churchyard et al., 2001; Rao et al., 2005; Delval et al., 2006, 2008b). While reduced velocity is evident in the premanifest stage, it continues to worsen throughout the manifest stage (Reynolds et al., 1999; Thaut et al., 1999; Churchyard et al., 2001).
STEP / STRIDE Stride length is significantly reduced in manifest HD (Koller and Trimble, 1985; Churchyard et al., 2001; Bilney et al., 2005; Rao et al., 2005, 2008; Delval et al., 2008b; Grimbergen et al., 2008; Dalton et al., 2013; Collett et al., 2014; Danoudis and Iansek, 2014) and highly variable (Reynolds et al., 1999; Churchyard et al., 2001; Bilney et al., 2005; Delval et al., 2006, 2008b; Grimbergen et al., 2008; Rao et al., 2008; Dalton et al., 2013; Collett et al., 2014). Stride time is also reduced (Koller and Trimble, 1985; Delval et al., 2006) and variable (Hausdorff et al., 1998; Rao et al., 2005; Delval et al., 2006). One study asked people with various stages of HD to walk at self-preferred pace, and found stride-to-stride variability triple that of healthy controls (Hausdorff
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et al., 1998). Similarly, two other studies found this variability to be approximately double that of controls (Churchyard et al., 2001; Bilney et al., 2005). Additionally, these stride-to-stride fluctuations are also more random (Hausdorff et al., 1997). As HD progresses, there is greater variability of the spatiotemporal aspects of stride (Hausdorff et al., 1998; Reynolds et al., 1999) and a further reduction of stride length (Churchyard et al., 2001). In the late stage of HD, variability of stride length is significantly worse compared with earlier stages of the disease (Collett et al., 2014). Similar to stride, step length and time are significantly reduced with increased variability when compared to those without HD (Hausdorff et al., 1998; Bilney et al., 2005; Rao et al., 2008; Dalton et al., 2013; Collett et al., 2014; Andrzejewski et al., 2016). Furthermore, step symmetry (as defined by the ratio of left and right step length) and regularity (similarity of consecutive strides) are also significantly impaired (Dalton et al., 2013; Collett et al., 2014).
TRUNK Truncal movement has been shown to be affected during gait with increased amplitude and velocity of mediolateral sway (Andrzejewski et al., 2016). One study found this characteristic is associated with a history of multiple falls (Grimbergen et al., 2008).
BALANCE Balance impairment worsens from premanifest stage to the manifest stage (Rao et al., 2008), with greater time spent in double-support time and stance. Additionally, a wide base of support appears in the early stage of manifest HD, possibly as a compensatory strategy for poor balance (Patla, 2003). As HD progresses, variability of double-support time also increases (Hausdorff et al., 1998).
AKINESIA/HYPOKINESIA/HYPERKINESIA Akinesia continues to be found in people with early to middle-stage HD (Delval et al., 2007), associated with lower-limb hypokinesia (Delval et al., 2007, 2008b). Interestingly, hyperkinesia can exist simultaneously with hypokinesia in the ankle joint (Delval et al., 2006).
CADENCE Numerous biomechanical studies have found cadence to be significantly reduced (Koller and Trimble, 1985; Churchyard et al., 2001; Bilney et al., 2005; Rao et al., 2005, 2008; Delval et al., 2006, 2008b; Andrzejewski et al., 2016) and with increased variability (Reynolds et al., 1999; Churchyard et al., 2001; Bilney et al., 2005; Rao et al., 2005; Delval et al., 2006, 2008b;
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Collett et al., 2014). Cadence remains reduced even when measured at home as opposed to the clinical setting (Andrzejewski et al., 2016). There is conjecture as to what stage reduced cadence first appears, but it seems to be during the early to middle stages of HD (Delval et al., 2006; Rao et al., 2008). One study did not find reduced cadence, but more than half of the cohort were in early-stage HD (Danoudis and Iansek, 2014). As HD advances, cadence is further reduced. One study noted that cadence was significantly reduced when people in late-stage HD were compared to earlier stages (Collett et al., 2014).
CADENCE–STRIDE RELATIONSHIP In early-stage clinical HD, the relationship between cadence and stride length remains linear (Danoudis and Iansek, 2014). Additionally, for the same cadence, those with HD have a shorter stride length when compared with healthy subjects (Danoudis and Iansek, 2014). Whether this relationship is maintained in later stages remains to be investigated.
walking leads to a deterioration of velocity, cadence (Churchyard et al., 2001; Delval et al., 2008a), and stride length (Delval et al., 2008a). This degree of deterioration is greater than that observed among healthy adults (Churchyard et al., 2001; Delval et al., 2008a; Jacobs et al., 2015). Gait velocity also decreases under both simple and complex cognitive alphabet naming task conditions. As HD progresses, there is reduced walking speed under dual cognitive task conditions (Delval et al., 2008b). Additionally, both gait and cognitive performance deteriorate when HD patients are instructed to prioritize gait over the cognitive task (Fritz et al., 2016). These deleterious effects are likely due to the interference a cognitive task has on gait (Delval et al., 2008a). Interestingly, an upper-limb task had no bearing on walking performance in one study, although the instructions provided were to continue walking despite any mistakes made (Delval et al., 2008a). This suggests that the participants may have focused on gait and not the upper-limb task, thereby not offering interference to the performance.
DYSTONIA Dystonia is another common feature of HD. It is defined as an involuntary muscle co-contraction that, most commonly, produces abnormal posturing (Fahn, 1988). It can present in the upper limbs, trunk, and lower limbs. Abnormal knee posturing can present initially during swing phase and is held for an excessive amount of time into early stance phase (Louis et al., 1999). Though its impact on gait has not yet been investigated in HD, one can extrapolate many potential detrimental effects of excessive knee flexion throughout the gait cycle. A knee held in flexion instead of extension at late swing would limit stride length. Additionally, during stance phase, a knee already flexed has an impaired ability to absorb shock in yield phase. It could also lead to a lowering of the center of mass, thus a greater than expected perturbation to balance. If we conceptualize gait to be a repetitive sequence of movements, an unexpected dystonic posture would interrupt the flow of movement and momentum, rendering gait to become potentially energy-inefficient, unpredictable, and unsteady.
GAIT ADAPTABILITY A handful of studies have investigated the effects of dual tasking, change in selected walking speed, and external cueing on gait characteristics. Dual tasking People with HD have difficulty walking and performing cognitive tasks simultaneously. In comparison to simple walking, counting backwards whilst
Fast and slow walking When attempting to walk faster or slower than their preferred pace, people with HD are able to modulate their velocity (Thaut et al., 1999; Churchyard et al., 2001) but still remain significantly slower when compared to healthy subjects (Churchyard et al., 2001). There is conjecture as to the effect of fast and slow walking on cadence. Two studies found reduced cadence when compared to healthy adults (Bilney et al., 2005; Thaut et al., 1999), In contrast, two other studies found no difference (Churchyard et al., 2001; Danoudis and Iansek, 2014), though in one of these studies, more than half of the subjects were in the early stages of HD (Danoudis and Iansek, 2014). There is agreement, however, that stride length is significantly reduced at varied speeds in people with manifest HD (Churchyard et al., 2001; Bilney et al., 2005; Danoudis and Iansek, 2014). At self-selected walking speeds, cadence is reduced to a greater extent than stride length, and at faster speeds this remains the case. Therefore stride length is relied upon more than cadence to generate velocity at both normal and fast speeds (Thaut et al., 1999; Bilney et al., 2005). In contrast, people with early-stage HD modulate cadence and stride length when changing speed in the same ratio as healthy subjects (Danoudis and Iansek, 2014). Increased variability of velocity (Churchyard et al., 2001), cadence, and stride length (Churchyard et al., 2001; Bilney et al., 2005) occurs with speed changes, with one study finding stride length variability was twice that of controls (Bilney et al., 2005).
GAIT, BALANCE, AND FALLS IN HUNTINGTON DISEASE External cueing Delval et al. (2008a) found an audible metronome intended to cue cadence did not improve the gait pattern of people with HD. In fact, a deleterious effect on gait pattern occurred. Two studies asked subjects to walk to the pace of a metronome and found stride length shortened (Churchyard et al., 2001; Bilney et al., 2005) and cadence decreased. Variability of velocity as well as stride length increased (Churchyard et al., 2001; Bilney et al., 2005) and cadence was three times more variable than controls at 80 beats/min, increasing to six times more variable at 120 beats/min (Bilney et al., 2005). In another study, the metronome was set at a moderately faster or slower rate than preferred self-paced walk. It was found that velocity could be modulated to the rhythm. However, when music was applied, velocity could not be modulated (Thaut et al., 1999). This may be due to the greater cognitive demands of attending to the beat of music rather than a metronome. People with HD have difficulty synchronizing their steps to an external cue (Thaut et al., 1999; Churchyard et al., 2001; Bilney et al., 2005) at fast or slow frequencies (Churchyard et al., 2001). They underestimate the cadence at fast beats, and overestimate the cadence at slow beats, leading to a reduced cadence range (Bilney et al., 2005). As HD progresses, there is diminished ability to modulate cadence to external cues (Thaut et al., 1999). There are however potential benefits of external cueing. Akinesia has been shown to improve when an external cue triggers stepping, in both people with premanifest and manifest HD (Delval et al., 2007, 2011).
BALANCE IN HUNTINGTON DISEASE Balance impairment among people with HD begins in the premanifest stage and worsens in the manifest stages. Current evidence for balance impairment in HD can be categorized into three broad areas: anticipatory balance without a change in base of support, anticipatory balance with a change in base of support, and reactive balance. There are relatively few studies investigating balance in people with HD. All studies are biomechanical in nature and have relatively small sample sizes. Additionally, there is very little information on specific balance deficits at each disease stage. Furthermore, there are only a handful of studies that include people in the premanifest stage. It is therefore difficult to determine how balance deficits evolve throughout the disease stages.
Balance features among premanifest CAG expansion carriers Premanifest expansion carriers perform as well as healthy subjects during eyes-open quiet standing
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(Salomonczyk et al., 2010). However, they display increased postural sway when their sensory inputs and/ or base of support are manipulated: standing with eyes closed with either a normal or narrowed base of support (Dalton et al., 2013), standing in maximum leaning positions (Blanchet et al., 2014), and /or when vision is eliminated and proprioception attenuated (Salomonczyk et al., 2010; Blanchet et al., 2014). People with premanifest HD also show limited anticipatory postural adjustments at gait initiation, as shown by a decreased backward shift in the center of pressure in that phase (Delval et al., 2011). To date, standardized clinical tests of balance such as tandem walking, retropulsion, and the Functional Reach Test have not shown to be sensitive to changes among people in the premanifest stage (Rao et al., 2009a).
Balance features among people with manifest Huntington disease ANTICIPATORY BALANCE WITHOUT A CHANGE IN BASE OF SUPPORT
Standing in a normal base of support People with manifest HD exhibit greater sway than those without HD during eyes-open standing with a normal base of support (Huttunen and Homberg, 1990; Tian et al., 1992; Salomonczyk et al., 2010; Reilmann et al., 2012; Dalton et al., 2013). Additionally, the center of mass has been shown to move greater distances and at faster speeds in this condition (Reilmann et al., 2012). Given the balance impairment when standing with a normal base of support, it is unsurprising that a narrow base of support creates further postural instability (Goldberg et al., 2010; Jacobs et al., 2015). Sensory manipulation Compared with people with premanifest HD, those in the manifest stage require less sensory challenge to become unstable (Salomonczyk et al., 2010) and when similarly challenged display greater sway (Salomonczyk et al., 2010; Dalton et al., 2013). Eyes-closed standing with a narrow base of support leads to significantly greater sway than for those with premanifest HD (Dalton et al., 2013), and healthy subjects (Reilmann et al., 2012; Dalton et al., 2013). During the Sensory Organization Test, people with manifest HD display significantly greater sway compared to healthy subjects when either vision or proprioception is reduced, and the greatest deterioration of performance occurs, when the vestibular system is predominantly relied upon (Tian et al., 1992; Salomonczyk et al., 2010; Jacobs et al.). The attenuation of proprioception produces approximately twice the amount of sway to when only vision is eliminated (Tian et al., 1992). People with HD also
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have more falls when sensory input is challenged (Salomonczyk et al., 2010). Compensatory strategies to maintain standing balance under sensory manipulation have not been thoroughly investigated. However one study infers that a hip strategy is more often used by those with HD to maintain balance (Tian et al., 1992), whereas healthy adults tend to use an ankle strategy. Extremes of posture Instability in extreme leaning postures worsens in the manifest stage. The range of center-of-pressure displacement is significantly decreased as soon as the leaning position is attained, whereas people in premanifest stage need to sustain this position over time before showing a similar effect (Blanchet et al., 2014). This displacement also occurs along both the axis of the direction of lean and the axis perpendicular to the direction of lean, compared to premanifest participants who only exhibit displacements along the axis of direction of lean. Sensory manipulation in maximum leaning has shown similar results to quiet standing. People in manifest stage are affected in all conditions, earlier in time and to a greater extent, compared to premanifest participants. When standing at the limits of stability, people with manifest HD are also affected to a greater extent.
ANTICIPATORY BALANCE WITH A CHANGE IN BASE OF SUPPORT
People with manifest HD have instability of posture control in a range of functional and balance tasks where a change in the base of support occurs (Goldberg et al., 2010; Panzera et al., 2011; Blanchet et al., 2014; Jacobs et al., 2015). This is evident in a number of areas, as discussed below. Bradykinesia Bradykinesia has been shown to occur in many types of dynamic functional tasks. Greater time is taken to complete tasks such as step up and over an obstacle, step and turn, and weight transfer during sit to stand (Panzera et al., 2011). Cued and self-triggered step response times in people with HD are also slower than in healthy people (Delval et al., 2007; Goldberg et al., 2010). The center of mass movement exhibits bradykinesia during anticipatory postural adjustments prior to taking a step from quiet standing (Delval et al., 2007). Sway People with manifest HD have greater sway velocity of the center of gravity during functional tasks. This is indicative of poor stability control (Panzera et al., 2011). This
increased sway velocity increases the risk that the center of mass moves beyond the limits of the base support, increasing fall risk. Anticipatory postural adjustments People with manifest HD have impaired anticipatory postural adjustments that is not limited to bradykinesia. When taking a self-initiated step, anticipatory postural adjustment is also of significantly shorter duration. The trajectory of the center of mass tends to deviate from the consistent path taken by healthy subjects. Additionally, the center of mass shows less displacement as the foot disengages from the ground (Delval et al., 2007). Slower, shorter, and smaller movements of the center of mass define anticipatory postural adjustments in HD. Whether this is part of a compensatory strategy developed to mitigate postural instability or a direct consequence of HD remains to be investigated. Internal cueing Internal cueing for postural changes seems to be impaired in people with HD. If external cueing is applied to a step response task, the duration of the anticipatory postural adjustment is not significantly different to that of healthy controls. In contrast, under self-triggered conditions, there is a marked deterioration of performance. Additionally, there is greater deterioration of step response time when movement is self-triggered, compared to when externally cued (Delval et al., 2007).
REACTIVE BALANCE In response to a sudden toe-up tilt, electromyography of tibialis anterior shows delayed reaction and longer duration of the long-latency reflex (Huttunen and Homberg, 1990). Similarly, there is delayed and prolonged lowerlimb muscle activation when a force plate is suddenly translated forwards or backwards (Tian et al., 1992). During rotational movements of a force plate, people with HD had significantly more falls (Tian et al., 1992). The MiniBESTest incorporates tests of anticipatory balance, with and without a change in base of support and reactive balance (Jacobs et al., 2015). When tested with the MiniBESTest, people with HD had poorer recovery of balance after an externally applied pressure is released during the compensatory stepping correction item. People with HD also perform poorly on the retropulsion pull test item of the motor subscale of the UHDRS (Goldberg et al., 2010).
CONFIDENCE People with clinically manifest HD have reduced balance confidence. This has been found on the
GAIT, BALANCE, AND FALLS IN HUNTINGTON DISEASE Activities-Specific Balance Confidence Scale (Powell and Myers, 1995), a self-rated scale of balance confidence during various day-to-day functional activities (Goldberg et al., 2010; Jacobs et al., 2015). However, this measure may not be a reliable measure of confidence in people with HD (Kloos et al., 2014). Reduced confidence can have potentially deleterious effects on function and thus quality of life, and may also be a fall risk factor. On the other hand, reduced balance confidence may have a protective function prompting judicious use of stable supports (e.g., use of hand rails on steps) in individuals with severe balance impairments.
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when fall diaries were returned immediately after each fall, the adherence rate was 89% (40 out of 45) (Grimbergen et al., 2008). In future, technologic advances may enable real-time falls data collection. There are limited data on injurious falls. Among people with early to mid-stage HD, 73% suffered only minor injury, mainly bruises and abrasions, with no serious injuries recorded (Grimbergen et al., 2008). In mid-stage HD, 50% reported injury with all recalled falls but the seriousness was not reported (Brozova et al., 2011). Among nursing-home residents with HD, minor injury occurred in 14% and serious injury in 9% of falls, although the injury categorization was not well defined (Zarowitz et al., 2014).
Fall and fall injury incidence Retrospective studies find high rates of falls among people with early to mid-stage HD. For the preceding 6 months, 22% (Kloos et al., 2010) to 38% (Kloos et al., 2012) of participants reported a single fall, and a further 36% reported multiple falls (Kloos et al., 2012). For the preceding 12 months, single fall rates range from 21% to 75% and multiple falls range from 58% to 60% (Grimbergen et al., 2008; Busse et al., 2009). Not surprisingly, 65–85% of people reported falls over the course of disease (Koller and Trimble, 1985; Brozova et al., 2011). In a group of North American nursing homes, almost half of residents (162 out of 339) with HD fell over in an 18-month period (Zarowitz et al., 2014). Only one study has published findings for a 3-month follow-up using a standardized falls calendar, with 40% falling once and 20% falling two or more times (Grimbergen et al., 2008). Excluding nursing-home residents, published fall rates are for people who present to healthcare professionals or researchers. Therefore, an accurate estimate of falls incidence in the community is not known. Methodologically, it is difficult to obtain accurate falls data from people with HD. Recall bias, cognitive deficits, and behavioral issues may impact on the accuracy of retrospective data. Unsurprisingly, one small study found carers to be more reliable reporters of falls than people with HD (Brozova et al., 2011). Compounding this issue is the heterogeneity of falls data collection methods across studies. Only two studies have used a validated interview and questionnaire to collect retrospective falls data (Grimbergen et al., 2008; Busse et al., 2009) and most other studies have not specified the timeframe for reporting or method of interview. Response rates for prospective falls diaries are also variable. When instructed to return diaries at the completion of the follow-up, response rates were between 59% and 66% (Fritz et al., 2016; Quinn et al., 2016). However
Factors associated with falls Studies of gait-related fall risk in people with HD have focused on recurrent fallers rather than single fallers. Recurrent fallers display decreased gait velocity (Grimbergen et al., 2008; Busse et al., 2009), decreased stride length, mediolateral trunk sway, and increased variability of stride length (Grimbergen et al., 2008). Bradykinesia and chorea scores on the motor subscale of the UHDRS, as well as disability levels, are also significantly worse in recurrent fallers (Grimbergen et al., 2008; Busse et al., 2009). In studies of balance in people with HD, externally applied perturbations were more likely to induce falls in the manifest stage than the premanifest stage or healthy controls (Tian et al., 1992; Salomonczyk et al., 2010), with most falls during the first few external perturbation repetitions and subsequent improvements in balance, indicating an element of trainability (Tian et al., 1992). A few studies have found the Timed Up and Go (Podsiadlo and Richardson, 1991; Busse et al., 2012) and Berg Balance Scale (Berg et al., 1992; Quinn et al., 2013) performance scores are associated with a history of falls (Rao et al., 2009b). For example, a cutoff score of equal or greater than 14 seconds on the Timed Up and Go and 40 seconds or less on the Berg Balance Scale is associated with increased fall risk in HD (Busse et al., 2009). A Tinetti Mobility Test (Tinetti, 1986; Quinn et al., 2013) score of 21 or less identified fallers with 74% sensitivity and 60% specificity (Kloos et al., 2010). This demonstrates that simple physical outcome measures cannot accurately predict falls, and other intrinsic and extrinsic factors should be considered. A tool that accounts for multifactorial fall risk factors would assist clinicians, people with HD, and their families to predict falls and implement strategies to decrease fall risk. Cognition and aggression have been found to significantly increase fall risk, after adjusting for chorea,
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bradykinesia, disability, and balance (Grimbergen et al., 2008). Falls have also been associated with impaired performance in the walking while talking test (Fritz et al., 2016) and self-reports of multitasking leading up to fall (Grimbergen et al., 2008). There is no indication that exercise participation increases fall risk (Khalil et al., 2013; Quinn et al., 2014, 2016). However, during supervised balancechallenging exercise, some participants with more severe impairments required assistance to recover balance (Kloos et al., 2013). Therapists, therefore, should be aware that exercises that challenge balance may increase the risk of falls in the short term, necessitating consideration of appropriate levels of supervision. When analyzing 40 falls Grimbergen et al. (2008) reported floor obstacles were involved in 25% of recurrent falls, 20% were during stair use, and 18% occurred on uneven or slippery floors. Notably, 93% of falls were in a familiar environment and 58% were indoors. The type of walking aid may also play a role in falls. One study recorded falls when using a standard walker, three-wheeled walker, or no aid at all, during figure-of-eight walking. This contrasts with no falls when using a four-wheeled walker instead (Kloos et al., 2012).
Confidence and fear Despite limited reliability in HD (Kloos et al., 2014), it has been found that recurrent fallers report lower balance confidence as measured by the Activities-specific Balance Confidence scale (Powell and Myers, 1995) than single fallers (Grimbergen et al., 2008; Busse et al., 2009). Interestingly, in one study, fallers reported less balance confidence but not an increased fear of falls (Grimbergen et al., 2008). This may be due to the specificity of questioning in the Activities-specific Balance Confidence scale and limited insight.
CONCLUSIONS There is an emerging understanding of gait and balance impairments among people with HD. Falls are common and impact greatly on quality of life among people with HD. Evidence from randomized controlled trials of exercise interventions and rehabilitation shows that these interventions are safe, feasible, and acceptable for addressing HD-specific gait and balance deficits with some positive effects (Busse et al., 2013; Khalil et al., 2013; Kloos et al., 2013; Thompson et al., 2013; Quinn et al., 2014, 2016). However, the small heterogeneous samples, along with variability in exercise type, dose, and supervision, limit the conclusions that can be drawn currently. Furthermore, no interventions have
specifically targeted fall risk factors among people with HD. Large, well-designed, randomized controlled trials are needed to guide future exercise and rehabilitation interventions among people with HD.
ACKNOWLEDGMENTS CTL is supported by an Australian National Health and Medical Research Council Australian Research Council Dementia Research Development Fellowship (APP1107657).
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