Impact of tetrabenazine on gait and functional mobility in individuals

Journal of the Neurological Sciences 347 (2014) 219–223

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Impact of tetrabenazine on gait and functional mobility in individuals with Huntington's disease Deb A. Kegelmeyer a,d,⁎, Anne D. Kloos a,d, Nora E. Fritz b, Marianne M. Fiumedora a, Susan E. White c, Sandra K. Kostyk a,d a

The Ohio State University, School of Health and Rehabilitation Sciences, Division of Physical Therapy, United States Johns Hopkins University, Kennedy Krieger Institute, United States The Ohio State University, School of Health and Rehabilitation Sciences, Division of Health Informatics, United States d The Ohio State University, College of Medicine, Neurology Department, Movement Disorders Division, United States b c

a r t i c l e

i n f o

Article history: Received 4 July 2014 Received in revised form 3 September 2014 Accepted 30 September 2014 Available online 7 October 2014 Keywords: Gait Function Mobility Huntington's disease Chorea Balance

a b s t r a c t Chorea may contribute to balance problems and walking difficulties that lead to higher fall rates in individuals with Huntington's disease (HD). Few studies have examined the effects of tetrabenazine (TBZ), an anti-choreic drug, on function and mobility in HD. The purpose of this study was to compare: 1) gait measures in forward walking, 2) balance and mobility measures, and 3) hand and forearm function measures on and off TBZ. We hypothesized that use of TBZ would improve gait, transfers and hand and forearm function. Eleven individuals with HD on stable doses of TBZ were evaluated while off medication and again following resumption of medication. Significant improvements were found on the Unified Huntington's Disease Rating Scale (UHDRS) motor scores, Tinetti Mobility Test (TMT) total (t = 4.20, p = 0.002) and balance subscale (t = −4.61, p = 0.001) scores, and the Five Times Sit-to-Stand test (5TSST, t = 3.20, p = .009) when on-TBZ compared to off-TBZ. Spatiotemporal gait measures, the Six Condition Romberg test, and UHDRS hand and forearm function items were not changed by TBZ use. Improved TMT and 5TSST performance when on drug indicates that TBZ use may improve balance and functional mobility in individuals with HD. © 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction Chorea is a prominent and troublesome motor symptom of Huntington's disease (HD). Frequent, large amplitude choreic movements contribute to impairments in balance, walking, and daily activities, such as getting up and down from a chair, and may increase fall rates [1]. Symptomatic treatment of chorea has the potential to improve motor function, safety, and quality of life. Tetrabenazine (TBZ) is a vesicular monoamine transporter 2 (VMAT-2) inhibitor that causes a depletion of monoamines, particularly dopamine, in the brain and has been used to treat involuntary movements in a variety of movement disorders. Since the FDA approved the use of TBZ specifically for treatment of chorea in HD with orphan drug status in 2007, the use of this medication in individuals with HD has increased in the United States. Though its effect on dampening chorea is now well established, few studies of its effect on other motor and functional parameters have been undertaken. Several neuroleptics and TBZ have been shown to decrease chorea but there are only limited studies of their effects on other motor ⁎ Corresponding author at: The Ohio State University, 453 W. 10th Ave., 516 Atwell Hall, Columbus, OH 43210, United States. Tel.: +1 614 292 0610; fax: +1 614 292 5922. E-mail address: [email protected] (D.A. Kegelmeyer).

functions in HD. The administration of the neuroleptic haloperidol to individuals affected by HD reduced chorea but showed no effects on spatial or temporal measures of gait [2,3]. Studies in a small number of individuals with HD on high doses of some atypical neuroleptics (i.e., olanzapine, zotepine) have documented improvements in chorea as well as fine motor tasks, oral functions, and some gait measures [4,5]. Following administration of TBZ for 80 weeks in 75 individuals with HD, improvements in chorea scores and in Global Improvement rating without improvement in total motor and functional measures from the Unified Huntington's Disease Rating Scale (UHDRS) were reported [6]. Gait and mobility measures were not studied in detail. However, a study of 11 individuals with HD found an association between TBZ and improved lifting of large, light objects [7] and another reported improvements in both chorea and functional measures of balance and gait (i.e., Berg Balance Scale, Dynamic Gait Index) in 10 individuals on TBZ [8]. These observations suggest that there is a need for more detailed investigations into the specific effects of TBZ administration on upper extremity function, gait and functional mobility in individuals with HD. Previous studies evaluating TBZ in HD lacked assessment of a range of balance measures, functional tasks and quantitative changes in gait other than velocity. Therefore the purpose of this study was to compare

http://dx.doi.org/10.1016/j.jns.2014.09.053 0022-510X/© 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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D.A. Kegelmeyer et al. / Journal of the Neurological Sciences 347 (2014) 219–223

performance of objective measures of mobility and function on- and offTBZ in individuals with HD. It was hypothesized that the use of TBZ, either by improving chorea or possibly by modulating other neurological pathways, would improve 1) spatiotemporal gait parameters as measured by the GAITRite, 2) balance and/or mobility as measured by the Tinetti Mobility Test (TMT), Five Times Sit-to-Stand Test (5TSST), and Six Condition Romberg tests, and 3) function of the hand and forearm as measured by finger tapping, hand pronation/supination, and Luria (fist-hand-palm) tests (items 6–8) on the UHDRS motor scale in individuals on stable doses of TBZ. Results of this prospective open-label study will contribute to our understanding of the impact of TBZ on functional activities in the HD population. 2. Subjects and methods Ambulatory individuals with a genetically confirmed diagnosis of HD, who had been maintained on a stable dose of TBZ for at least 30 days, were recruited for this study from The Ohio State University HDSA Center of Excellence. Exclusion criteria included presence of another neurologic disorder (i.e., CVA, TBI), presence of an orthopedic condition that impeded the ability to walk, pregnancy, or inability to consent to the study. Written informed consent, approved by the Institutional Review Board, was obtained from all subjects prior to enrollment. 2.1. Procedures Subjects were instructed to stop TBZ on the day before testing and all subjects were off TBZ for at least 18 h prior to undergoing study tests. This ensured a period of at least 2 half-lives for metabolism of the active metabolite, alpha-dihydrotetrabenazine. Subjects arrived at the Center off-TBZ. After obtaining demographic information, the subjects were tested on the following measures: 1. The UHDRS motor scale was used to quantify motor symptoms. Items are rated on a 0–4 scale with higher scores indicating greater disability. Total motor scores (range 0–124), total chorea scores (item 7, range 0–28), and total forearm and hand function scores (items 6–8, range 0–12) [9] were calculated for each participant. The UHDRS is a commonly used outcome measure for HD clinical trials and has established reliability and validity [10]. 2. Spatiotemporal parameters of walking (i.e., velocity, step and stride length and duration, percent of gait cycle in stance, swing, and double support, heel-to-heel base of support) were measured by a 16′ long GAITRite system (CIR Systems, Inc, Haverton, PA). GAITRite calculates swing percent and double support percent for each leg rather than across the entire cycle. Subjects began walking 2 m before and stopped 2 m beyond the edges of the walkway to allow for acceleration and deceleration phases. All subjects completed four separate passes across the GAITRite walking at their comfortable selfselected speed. The walks were averaged for analysis using the GAITRite software program. GAITRite measures are reliable and valid in individuals with HD [11]. 3. The TMT is reliable and valid in individuals with HD and was used to measure balance, functional mobility, and fall risk [12,13]. The maximum possible score is 28 (balance subscale = 16, gait subscale = 12), with higher scores indicating better performance. 4. The FTSST assessed the subjects' abilities to balance while standing up and sitting down five times as quickly as possible from a standard armless chair. The FTSST has been shown to be a reliable and valid measure in older adults and other patient populations [14]. 5. The Six Condition Romberg test was used to measure static balance. Subjects were asked to stand with arms crossed over the chest and hold each of the following stances and conditions for 30 s: 1) feet together, 2) feet together and eyes closed, 3) feet aligned in a tandem heel-to-toe position, 4) tandem position and eyes closed, 5) tandem position while counting backwards by 3's from 100, and 6) tandem

position while counting backwards by 3's from 100 with eyes closed [15]. If the participant could not hold a stance for the full 30 s, the Romberg test ended at that point. After the initial testing, the subjects were instructed to take their usual dose of TBZ. The same tests were then administered following a 2–3 hour resting period. Kenney et al. [16] documented that chorea scores begin to improve within an hour of administration of TBZ, with a mean duration of effect on chorea lasting 5.4 ± 1.3 h [16]. The majority of subjects had maximal benefit (physician rating) within 2 h of administration [16]. A neurologist with the European Huntington's Disease Network UHDRS motor rater certification administered the UHDRS motor scale. All other tests were administered by one of three physical therapist researchers who had considerable experience with test administration. Each subject was evaluated by the same tester for offand on-TBZ tests. All subjects had practice trials of each test prior to the recorded testing to ensure understanding and to eliminate learning effects. During all gait and functional tests, subjects were guarded by one of the investigators. Safety was ensured during the off-TBZ time period by asking a family member to drive them to the testing site and by close monitoring by the investigators or family members. Previous studies have shown no significant adverse effects from the sudden withdrawal of TBZ [16,17]. All statistical analyses were performed using SPSS Version 21. All data was examined for normality using the Shapiro–Wilk Test of Normality. Accordingly, all analyses of gait and functional data were performed using paired t-tests or the Wilcoxon matched-pairs signed-rank test. A sample size of 13 participants was determined a priori to detect a change of 0.5 m/s in gait velocity with 95% power. To examine the variability of spatiotemporal measures of gait, coefficient of variation (CV) values were calculated for step time, stride length, swing time and double support time. Increased variability of gait measures has been associated with an increased fall risk in individuals with HD [1]. The alpha level for each test was adjusted using a Bonferroni correction. 3. Results A total of fifteen individuals were recruited within a 2 year period; four subjects were excluded due to a previously undocumented history of a mild CVA (n = 1), an inability to participate in follow-up testing due to family issues (n = 2), and an elected termination of the medication (n = 1). Eleven ambulatory individuals with HD [mean age ± SD (range) = 52.2 ± 10.0 (33–69 years); 9 women; mean time since symptom onset = 8.1 ± 5.7 (2.5–21 years); mean CAG repeat size = 44.6 ± 1.6 (41–51)] completed the study. All subjects historically had chorea scores N10 before starting on TBZ. The average daily dosage of TBZ was 64.7 ± 20.8 mg with a range of 37.5 mg to 100 mg. All other medications taken by subjects were stable during the month prior to testing. In addition, none of the subjects or caregivers reported deviation from their usual daily activities or initiation of any new exercise regimen in the month preceding the testing. Tetrabenazine use was associated with significant improvements in mean UHDRS total motor scores [off-TBZ = 55.27 ± 12.09 (32–78) and on-TBZ = 47.73 ± 12.51 (27–69); p = .001] with the change in total motor scores driven primarily by the increase in the chorea scores in the off state [chorea scores off-TBZ = 17.09 ± 3.3 (13–25) and onTBZ = 12.91 ± 2.8 (10–19)]. However, total motor scores excluding chorea measures of the face, trunk, upper extremity and lower extremity [off-TBZ = 38.18 ± 11.03 (19–61) and on-TBZ = 34.82 ± 11.50 (17–58)] were also still significantly better (p = .008) on TBZ. Spatiotemporal parameters of gait including CVs remained stable in the on-TBZ and off-TBZ conditions (Table 1). Gait parameters of the left and right leg were also compared and showed no significant differences side to side. Subjects exhibited significantly better TMT total and balance subscale scores (p = .002; 10/11 participants' scores were improved) and FTSST scores (p = .009; 9/11 participants had faster


use improved performance on the Berg Balance Scale and the Dynamic Gait Index in individuals with HD.

Table 1 Comparison of gait parameters on and off tetrabenazine. Outcome measures (n = 11)

Mean ± SD Off

On

Velocity (m/s) Stride length (cm) Swing percent of gait cycle (%) Double support percent of cycle (%) Stride length CV Double support time CV

1.23 ± 0.35 125.45 ± 27.65 36.02 ± 2.82

1.17 ± 0.27 124.24 ± 19.42 36.53 ± 4.12

0.76 0.24 −0.72

0.464 0.816 0.488

27.98 ± 4.23

28.94 ± 4.23

−1.30

0.224

6.87 ± 4.37 11.65 ± 6.70

6.35 ± 2.95 11.70 ± 8.90

Ζ

221

t

Sig. (2-tailed)

0.61 0.62Ζ

4.2. Gait Spatiotemporal gait parameters and CVs measured on the GAITRite did not change in the on-TBZ state compared to off-TBZ. Our findings concur with those of Ferrara et al. [7] and Fekete et al. [8] who reported no change in gait velocity on-TBZ versus off-TBZ. Walking in a straight path does not place as high of demands on control of center of mass, especially in the medial-lateral direction as turning while walking, sit-tostand and sit to walk transitions [19] which may account for the lack of effect of TBZ on spatiotemporal gait measures. Documented side effects of TBZ include an increase in parkinsonian symptoms, such as bradykinesia and rigidity [6] due to the dopamine depleting properties of TBZ. We postulated that a parkinsonian gait disorder might be observed in the on-TBZ state as suggested by decreased velocity or stride length. However, this was not observed; TBZ did not have a parkinsonian impact on spatiotemporal measures of gait or gait variability in any of the participants. In fact, gait variability measures (CVs) were comparable to findings in previous studies of TBZ naïve individuals with HD [20] indicating that the use of TBZ did not increase gait variability and its associated fall risk.

0.557 0.534

Z value; CV, coefficient of variation; TBZ, tetrabenazine.

times) when on-TBZ compared to off –TBZ (Table 2). There were no significant changes in the Six Item Romberg total time. There was a trend toward improved UHDRS forearm and hand function scores (items 6–8) (Table 2). All individuals who participated in the study stated that they felt “more stable” and “have better balance” while on TBZ. Additionally some of the participants stated that they felt their hand function improved while on TBZ. The study authors noted qualitatively that the individuals who respond well to TBZ appear to be more consistent stride to stride during gait with less large amplitude trunk sway.

4.3. Hand and forearm function 4. Discussion

Although there was not a significant change in the UHDRS forearm and hand function scores between on-TBZ and off-TBZ, improvement in these measures warrants further investigation utilizing more quantitative measures such as the Nine Hole Peg Test [21] or Q-motor testing [22]. The UHDRS motor scale has only three items examining hand function and uses an ordinal scale, with limited sensitivity to change. Our work is in agreement with Fekete et al. [8] who examined hand function using the Jebsen Hand Function Test but did not find any difference between the on-TBZ and off-TBZ states. The Jebsen test primarily examines manipulation of objects of different sizes and weights and may not be sensitive to finer motor changes. The Nine Hole Peg Test examines fine motor control of the fingers while the Q-motor test examines isometric grip force measurements with a weighted object and finger tapping speed, which may make these tests more sensitive measures of potential effects of anti-choreic medication on upper extremity function. In the context of the current study, we are unable to determine whether the improvements in motor function that we observed were due solely to changes in severity of chorea or possibly to other neurologic effects of TBZ or perhaps to a combination of effects. The 4 point reduction (indicating improvement) in chorea scores in the on-TBZ versus off-TBZ state was similar to the 5 point reduction reported by Poon et al. [23] A significant improvement in the total UHDRS motor scores on-TBZ versus off-TBZ was observed, even when the chorea scores were removed. The decrease noted in total UHDRS motor scores excluding chorea scores appears to be related to combined improvements in the hand and forearm function items and in the retropulsion pull test, gait, and tandem walking items, as none of these items were

Our findings contribute information to the growing body of evidence from preliminary, non-randomized studies showing that TBZ may contribute to improvements in balance and functional mobility in individuals with a good response to TBZ [8]. We also showed that this small group of TBZ responders did not exhibit parkinsonian gait changes. This study confirms previous work demonstrating a significant improvement in UHDRS total motor and chorea scores on-TBZ than offTBZ [6,7]. 4.1. Balance The significantly better total TMT score on-TBZ is explained primarily by improvements in the balance subscale rather than the gait subscale. The balance subscale includes observations of the individual rising from and returning to a sitting position and turning 360°. Improvements in these activities on TBZ may have important clinical implications since patients with HD commonly report falls while standing up, sitting down and executing turns. In contrast, the six condition Romberg test, a test of static standing balance under altered somatosensory conditions, was not significantly improved in the on-TBZ state. Taken together these findings suggest that TBZ has a greater impact on balance control systems that maintain balance during dynamic functional tasks (i.e., transfers, turning, walking) compared to those that control balance during static tasks (i.e., standing with a narrowed base of support or with altered vision) [18]. The improved TMT scores found in our study support the findings of Fekete et al. [8] that TBZ Table 2 Comparison of functional outcome measures on and off tetrabenazine. Outcome measures (n = 11)

Mean ± SD Off

Tinetti Mobility Test (scores) Tinetti Mobility Test Balance Subscale (scores) Tinetti Mobility Test Gait Subscale (scores) Five Times Sit-to-Stand Test (s) Six Item Romberg Test (total time completed in s)* UHDRS forearm and hand function scores (items 6–8) (scores) Ζ

= Z value; * = statistically significant with Bonferroni correction; p ≤ .010.

17.09 11.18 5.91 15.52 73.26 12.73

t

Sig. (2-tailed)

4.20 −4.61 −1.84 3.20 1.58Ζ 2.24

.002* .001* .096 .009* .114 .049

On ± ± ± ± ± ±

4.04 2.08 2.43 3.81 16.29 4.03

19.91 13.09 6.82 12.61 83.08 11.36

± ± ± ± ± ±

3.53 2.02 1.72 3.00 27.57 4.15

222


significantly different on-TBZ and off-TBZ when analyzed independently. The improvements in the pull test, gait, and tandem walking items are most likely related to improved dynamic balance as supported by our findings on the TMT and previous findings of Fekete et al. [8] on the Dynamic Gait Index. However, Fekete et al. [8] did not note a significant change in the residual UHDRS score when the chorea scores were removed. Differences in study designs, patient populations, other concomitant medications or patient age distributions between studies may explain this dissimilarity in findings.

and transfers and that individuals with improvement in chorea on TBZ may also experience improvements in functional mobility such as turning and getting up and down from a chair. Qualitative observations indicate that future studies examining trunk movements and fine motor function of the hand on and off TBZ using more quantitative measures may be indicated. Future attempts to identify which patients would benefit most from TBZ might include not only presence of chorea, but also the degree of impairments in balance and gait. Conflict of interest statements

4.4. Limitations This was an exploratory study with a small sample size selected from one clinical site, limiting the extrapolation of these findings to a larger and broader population. More robust differences between onand off-states may have been seen if we had not limited the time offdrug to a relatively short time (slightly more than 18 hours), unlike the 3–4 days participants were off-drug for the Fekete et al. study [8]. The primary reason for using a shorter time was to make the study less of an imposition on the participants' regular routine. In addition, Kenney et al. [16] have demonstrated that chorea scores begin to worsen on average around 5.4 ± 1.3 h after administration suggesting that there should have been significant wash out and concomitant decrease in the effect of TBZ by 18 h. Despite the longer wash out period in the Fekete et al. study [8], we still noted significant differences in similar study measures of dynamic balance. Another limitation of this study is that the examiners and participants were not blinded and therefore the results could be biased. However, the majority of the outcome measures involved quantitative assessments that are not easily biased. The TMT has a subjective component that makes it more susceptible to bias, but the test has high test– retest reliability [13] in the HD population and the researchers who administered the test were highly experienced in using the tool and thus less likely to make errors. The GAITRite is a useful tool for quantitative assessment of gait; however, measures of gait variability are limited to comparison across a mean of 60 steps due to the length of the GAITRite and thus may be insufficient to adequately analyze variability seen in daily ambulation. This study included only those individuals who did not experience significant side effects from TBZ, who had been maintained on the medication successfully for over a month, and who reported and had confirmed improvement in their chorea scores prior to enrollment. TBZ has been associated with a fairly wide range of potential side effects and many individuals do not continue on the medication. Thus, this study does not examine the impact of TBZ across all individuals with Huntington's chorea. It would be clinically useful to identify disease features that would predict individuals who are more likely to respond well to TBZ. While several of our patients have reported less falls on TBZ, some patients have reported deterioration in gait or increased falls as reasons for stopping the medication. Older individuals are reportedly more likely to develop parkinsonian features on TBZ [24]. Anecdotally, an increase in parkinsonian gait features including festination and decreased stride length in two elderly male patients with HD led to discontinuation of TBZ before reaching a stable dose. Future studies should consider administering a detailed gait assessment and a falls history prior to starting TBZ, allowing comparison of gait parameters, fall rates, and other contributing factors in those who choose to continue versus stop TBZ. 4.5. Conclusions The current study provides further confirmation that TBZ improves chorea and supports the hypothesis that TBZ improves functional mobility by improving dynamic balance in individuals who benefitted from TBZ administration. Our study provides preliminary evidence suggesting that TBZ does not negatively impact motor function in walking

SKK received grant support from the Huntington's Disease Foundation of America, the Lundbeck LLC, the Robert A Vaughan Fund, the National Institutes of Health, Neurosearch, Prana Biotechnologies, has served as a paid consultant for the Food and Drug Administration and the NIH and has received meeting expenses from the HDSA, Lundbeck and the Huntington's Study Group. DAK and ADK received grant support from the Lundbeck LLC, the Robert A Vaughan Fund and the Mangurian Family Fund. DAK also receives funding from the Institute for Optimal Aging. NEF has nothing to disclose. SW received funding from the Institute for Optimal Aging, Ambulatory Surgery Foundation, National Institute of Neurological Disorders and Stroke, Ohio Bureau of Worker's Compensation, National Center for Complementary and Alternative Medicine and Truven Health Analytics. Support for travel/meetings: AHIMA The contractual agreement between Lundbeck and the authors prior to grant submission and funding stipulated that study design, data collection, data analysis and interpretation of data as well as manuscript revisions were to be at the sole discretion of the authors. Lundbeck LLC was afforded the opportunity to review the manuscript for medical accuracy before submission. Financial disclosure/conflict of interest concerning the research related to the manuscript Funding sources for study: Lundbeck LLC and the Robert A Vaughan Family Fund Acknowledgments This research was funded by Lundbeck LLC as an investigatorinitiated study. Support was also provided by the Robert A Vaughan Family Fund. References [1] Grimbergen YA, Knol MJ, Bloem BR, Kremmer BP, Roos RA, Munneke M. Falls and gait disturbances in Huntington's disease. Mov Disord 2008;23(7):970–6. [2] Koller WC, Trimble J. The gait abnormality of Huntington's disease. Neurology 1985; 35(10):1450–4. [3] Girotti F, Carella F, Scigliano G, Grassi MP, Soliveri P, Giovannini P, et al. Effect of neuroleptic treatment on involuntary movements and motor performances in Huntington's disease. J Neurol Neurosurg Psychiatry 1984;47(8):848–52. [4] Bonelli RM, Niederwieser G, Tribl GG, Koltringer P. High-dose olanzapine in Huntington's disease. Int Clin Psychopharmacol 2002;17(2):91–3. [5] Bonelli RM, Niederwieser G, Lahousen T, Hofmann P. Zotepine in Huntington's disease. Hum Psychopharmacol 2003;18(3):227–9. [6] Frank S. Tetrabenazine as anti-chorea therapy in Huntington disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators. BMC Neurol 2009;9:62. [7] Ferrara J, Mostile G, Hunter C, Adam O, Jankovic J. Effect of tetrabenazine on motor function in patients with Huntington disease. Neurol Ther 2012;1(5):1–8. [8] Fekete R, Davidson A, Jankovic J. Clinical assessment of the effect of tetrabenazine on functional scales in Huntington disease: a pilot open label study. Tremor Other Hyperkinet Mov (N Y) 2012:2 [epub 2012 Aug 6]. [9] Rao AK, Gordon AM, Marder KS. Coordination of fingertip forces during precision grip in premanifest Huntington's disease. Mov Disord 2011;26(5):862–9. [10] Huntington's Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. Mov Disord 1996;11(2):136–42.

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