Duration of step initiation predicts freezing in Parkinson s disease

Acta Neurol Scand DOI: 10.1111/ane.12361 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA Duration of step initiation predicts freezing in Parkinson s disease Chong RK, Lee K-H, Morgan J, Wakade C. Duration of step initiation predicts freezing in Parkinson s disease. Acta Neurol Scand: DOI: 10.1111/ane.12361 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives In some individuals with idiopathic Parkinson s disease (PD), freezing of gait episodes develops as the disease progresses. The neural mechanism underlying freezing in PD is poorly understood. Here, we report a 2-year follow-up on the novel discovery of prolonged step initiation duration as a potential marker of impending freezing. Methods Non-freezing PD participants in stages 2.5 4 of the Hoehn and Yahr disease severity scale were recruited from an earlier study which determined the effect of semi-virtual cues on walking. Responders were those who completed the first step faster in the presence of the virtual cues while non-responders either did not change or took longer to complete the first step. Both groups of participants were interviewed 2 years later to determine who had developed freezing of gait. Results Participants in the responder group had a 13-fold risk of developing freezing of gait within 2 years following the cueing study (OR = 13.3, 95% CI = 1.1 167). A cutoff score of 2.6% (i.e., a decrease in the duration of the first step with visual cues by 2.6% relative to no cues) gave a sensitivity and specificity of 100% and 89%, respectively. Conclusions To the best of our knowledge, this is the first novel discovery of a physical predictor of freezing in PD. The time to complete the first step is a simple test to administer in the clinic or at home and may therefore be easily incorporated into a fall prevention training program for PD before the inception of freezing. R. K. Chong 1, K.-H. Lee 1, J. Morgan 2, C. Wakade 1 1 Department of Physical Therapy, Georgia Regents University, Augusta, GA USA; 2 Department of Neurology, Georgia Regents University, Augusta, GA USA Key words: gait; questionnaire; falls; fear of falling; walking Raymond K. Chong, Department of Physical Therapy Georgia Regents University 987 St. Sebastian Way EC-1304 Augusta, GA 30912 USA Tel.: 706-721-2141 e-mail: rchong8@hotmail.com Accepted for publication November 11, 2014 Introduction Freezing of gait develops in 30 60% of individuals in the advanced stages of idiopathic Parkinson s disease (PD) (1 3). It is a feature of the disease that is not as commonly included in the description of the disease progression compared to the more well-known motor symptoms of postural instability, bradykinesia, tremor, rigidity, and dyskinesia (4, 5). Freezing can significantly increase the risk of falling as it can sometimes occur unexpectedly. In instances where freezing is predictable, patients often do not have the knowledge or skills to anticipate and adapt to it (6). High levels of anxiety, stress, or fatigue seem to increase the severity of freezing (7). One way to better understand freezing is to look for features of walking performance which might indicate that a patient is likely to develop freezing soon. Intervention programs in the form of education and training can then be implemented before the patient starts to experience it. For reasons that are still unclear, individuals with PD who experience freezing episodes improve their walking in the presence of external cues. Among the various sensory augmentations, visual cueing appears to be the most widely studied modality (8 10). Visual cues may serve to compensate or substitute for the so-called automatic gait initiation and walking patterns that is defective in PD when freezing of gait is present (8). We hypothesize that individuals who are predisposed to develop freezing of gait acquire this compensatory mechanism before the onset of freezing can be detected or perceived. The ability to predict which individual may be at risk for freezing of gait would be an important step toward a better understanding of its occurrence. 1

Chong et al. We previously reported the findings of a study in which participants who had not yet developed freezing of gait walked in the presence or absence of semi-virtual visual cues (8). Some participants initiated the first step faster in the presence of the cues while others either showed no change or started slower. Although this finding appears to be consistent with a random distribution of varying walking performance, we hypothesized that the beneficial effect of the visual cues may be a symptom of impending freezing which may be detected by the duration of the first step. Here, we report a 2-year follow-up pilot study on those participants. To our knowledge, this is the first time that a potential physical marker of freezing in PD has been discovered. Material and methods Participants The study was approved by the Institutional Review Board. Participants gave verbal consent to be included in the phone survey study. A total of 17 participants participated. They comprised non-freezing participants with idiopathic PD from a previous study (8) who were rated 2.5 4 on the Hoehn and Yahr (H and Y) disease severity scale (11). The median stage was 3. Procedure Previous study In the previous study, participants in their usual anti-parkinson drug regime walked 10 m per trial while wearing a semi-virtual reality cueing goggle (44, 45). When it was turned On, two stripes of alternating black and white squares were projected along the subject s nasal field of view while the landscape surrounding the subject remained unobstructed (Fig. 1). The goggle was connected to a sensor unit that is worn on one side of the waist. It sensed the subject s forward walking speed and scrolls the tiles backwards at the same speed as the subject s walking. This produced the impression that the squares were stationary and the subject perceived that they were stepping over the tiles. The tiles remained stationary when the subject was not walking (i.e., sitting or standing). In the Off condition, subjects continued wearing the goggle and viewed the surrounding scene through the lens of the goggles but without the tiles. The On Off conditions were alternated thrice each. Timing started when the go command was given to the subjects to start walking. To test the true effect of the visual cues, participants underwent the two cueing conditions without the benefit of practice trials. Walking performance including duration of step initiation, walking speed, step length, and cadence was measured. Current study In this study, these participants were assigned to one of two groups based on the duration of their step initiation from the previous study. Responders (n = 9, 6 men and 3 women, median H and Y = 3) were those who completed the first step faster with the visual cues (relative to no cues) either in the first trial, the average of three trials, or both (1.2 0.3 s without cues compared to 1.0 0.2 s with cues, P = 0.0009). Non-responders (n = 8, 5 men and 3 women, median H and Y = 3) were participants who completed the first step that was either of similar or slower duration either with or without the visual cues (1.2 0.5 s). A summary of the participants disease characteristics and walking performance is presented in Table 1. Note that all the attributes were similar between the groups except for the duration of the first step (P < 0.001, Fig. 2). The step length for both groups averaged 0.48 0.16 m, speed was 0.84 0.3 m/s, and cadence was 104.2 17.4 per minute. The Folstein test for dementia (12) in both groups was within normal limits. There was a trend in the responder group to have a longerduration diagnosis and more severe motor symptoms than the non-responder group, but they did not reach statistical significance. There were four participants from the earlier study who were not Figure 1. The visual cueing device (44, 45). The contrasting squares take up a small strip of the subject s field of view and do not block the landscape. They are enlarged for illustration only. Refer to the text for details. 2

Physical predictor of freezing Table 1 Subject characteristics Responders (n = 9) Nonresponders (n = 8) P-value Effect size Disease characteristics Follow-up period (months) 24 (4) 22 (3) 0.380 0.57 Age (years) 71 (6) 68 (6) 0.339 0.50 Duration of disease (years) 11 (6) 7 (5) 0.132 0.73 UPDRS Section 3 total 34 (12) 27 (10) 0.232 0.64 score Bradykinesia score 7 (4) 6 (3) 0.482 0.29 Hoehn and Yahr (11) 3.1 (0.6) 2.8 (0.3) 0.295 0.67 Parkinson s Disease Quality of Life Questionnaire (13) 13 (6) 14 (5) 0.746 0.18 Rapid Assessment of Postural Instability in Parkinson s Disease (14, 15) Section 1 5 (4) 5 (4) 0.796 0.00 Section 2 4 (2) 4 (2) 0.697 0.00 Section 3 15 (40) 40 (93) 0.486 0.38 Mini-Mental State 27 (2) 29 (1) 0.055 1.3 Examination Walking performance Step length (% change) First trial 5 (9) 4 (8) 0.698 0.12 Average 4 (5) 3 (6) 0.831 0.18 Walking speed (% change) First trial 6 (12) 8 (9) 0.703 0.19 Average 4 (6) 5 (6) 0.780 0.17 Cadence (% change) First trial 0.8 (11) 5 (4) 0.316 0.66 Average 4 (11) 1 (3) 0.495 0.43 Step initiation (% change) First trial 14 (17) 23 (37) 0.018* 1.4 Average 13 (10) 5 (4) <0.001* 2.6 Comparison of responders [participants whose step initiation improved in the presence of closed-loop visual cues in a previous study (8)] and non-responders on disease characteristics and walking performance. Values (mean SD) were measurements taken during the previous visual cueing study. UPDRS = Unified Parkinson s Disease Rating Scale motor section (16); % change is expressed as a ratio of visual cues turned On minus Off and divided by Off in the previous study; Average = mean of three trials; Effect size is based on Cohen s d using the averaged SD of the two groups. * indicates the only two parameters which differentiated subjects whose duration of step initiation shortened with the cueing device versus those who did not. participants in both groups to determine whether they had developed the condition since their participation in the previous visual cueing study 2 years ago (8) and to ensure that they did not misconstrue their bradykinesia or postural instability as freezing (19, 20). The FOG-Q freezing questionnaire was administered to participants who experienced freezing (17). Statistics A one-tailed chi-square analysis for a 2 9 2 contingency table was used to test the hypothesis that the beneficial effect of visual cueing portents the development of freezing within 2 years of the visual cueing test. Measures of effect size (odds ratio), sensitivity, and specificity were also calculated. A receiver operating curve (ROC) comparing the percent change in duration of the first step (average of three trials) between the responders and non-responders was created to visualize its diagnostic potential. The area under the curve (AUC) and 95% confidence intervals were also calculated. The cutoff score and its 95% confidence interval were determined by choosing the highest likelihood value to achieve the optimal trade-off between sensitivity and specificity. The alpha level for significance testing was set at 0.05 for all analyses. Results In the responder group, 88.9% (eight of nine participants) developed freezing within 2 years following the previous visual cueing study (8) whereas in the non-responder group, freezing occurred in 37.5% (three of eight participants), v 2 (1, N = 17) = 4.9, P = 0.013 (Fig. 3). Responders had a 13-fold risk for developing freezing within 2 years. The sensitivity and specificity of the visual cueing test for the time to complete the step initiation were 73% and 83%, respectively (Table 2). The severity of freezing based on the Figure 2. Percent change in duration of first step with the cueing device turned On (average of three trials). *P < 0.001. included in this study. Two were lost to followup and two withdrew consent. During the interview, the phenomenon of freezing of gait (17, 18) was carefully explained to the Figure 3. Two-year follow-up of responders and non-responders. 3

Chong et al. Table 2 Acquisition of freezing Mean (95% CI) Responders (%) 88.9% Non-responders (%) 37.5% Strength of association Odds ratio 13 (1.1 167) Sensitivity and specificity Sensitivity (%) 73 (39 94) Specificity (%) 83 (36 100) Positive predictive value (%) 89 (52 100) Negative predictive value (%) 63 (25 92) FOG-Q questionnaire in the responder group was 17.4 5.4 and 20.7 2.1 in the non-responder group. A summary of the receiver operating curve (ROC) analyses, including the area under the curve (AUC), sensitivity, specificity, and cutoff score for the percent change in duration of the first step (average of three trials) between the responders and non-responders is presented in Table 3, along with the corresponding 95% confidence intervals. A plot of the ROC is shown in Fig. 4. At a cutoff score of 2.6% (i.e., a decrease in the duration of the first step with visual cues by 2.6% relative to no cues), the sensitivity and specificity were 100% and 89%, respectively. Table 3 ROC curve analysis Percent Change in Duration of First Step Area under the curve (standard error) 0.98 (0.03) 95% confidence interval 0.9 1.0 P-value <0.001 Cutoff score > 2.6% Sensitivity, Se 100% 95% confidence interval (Se) 63.1 100% Specificity, Sp 88.9% 95% confidence interval (Sp) 51.8 99.7% Likelihood ratio 9.0 Figure 4. Plot of the receiver operating characteristic of impending freezing in PD. Discussion The results of the study suggest that a decrease in the duration of the first step when visual cues are present is potentially a reliable physical predictor of the development of freezing of gait in PD. It is important to note that a shorter duration of the first step (in the presence of visual cues) can mean at least two things. First, the patient s step length could be the same relative to the nocues condition but is moving the feet faster. It may also indicate that the patient is taking a shorter step while moving at the same speed. Both cases produce a shorter duration of the first step. In the first instance, there could be a subtle presence of hesitation in gait initiation which is removed with visual cues, thereby resulting in a shorter first-step duration. The second instance could be where the patient exhibits festination, whereby the patient takes shorter and quicker steps and eventually either stops walking or falls. We stress here that neither of these possibilities was grossly evident during the study. We did not observe, nor were they reported by the subjects that they had already acquired freezing of gait episodes at the time of the study. Classically, step initiation includes the automatic postural adjustment and step execution (swing phase) components. Unfortunately, we did not use a computerized motion capture system to test our subjects. Knowledge of these parameters may be useful to better understand the mechanisms behind the increased duration of step initiation in patients with PD who are at risk for developing freezing of gait. The mechanism of freezing of gait in PD remains controversial. While some researchers ascribe the frontal executive functioning areas of the brain to be the source of the freezing (3, 21), possibly due to depleted frontal dopamine output (22), other neurotransmitter systems (23, 24), long-term levodopa therapy (4, 25), or hemispheric asymmetry (26), other studies have not found support for some of these hypotheses (27 29). Abnormal inhibition of the thalamus and pedunculopontine regions which produces an increase in synchronization of the striatal networks is also thought to contribute to freezing (30, 31). Patients with PD who develop freezing may represent a special classification of the disease condition that is yet to be discovered or characterized (24, 27, 32 34). Certain features of PD may increase the likelihood of the appearance of freezing. These include initial walking difficulty, severity of the disease 4

Physical predictor of freezing (walking, balance control, and speech), cognitive decline, and depression (20). Interestingly, older age at onset of diagnosis does not appear to increase the odd of developing freezing (20), although freezing is more commonly experienced in older patients (20). Off-freezing may be addressed by changing the medication regimen. However, it is the on-freezing which is most bothersome because of its resistance to anti-pd medications (6, 18, 27, 35 37). Although these variables have been shown to associate with the appearance of freezing of gait, none of them provide the prospective and quantitative physical parameters needed to preempt its inception. The results of the current study are promising despite the small and biased sample. A larger study may possibly allow us to identify more or correlated physical markers of freezing, for example, executive or postural set-shifting difficulties (8, 38 42). The ultimate goal is to refer at-risk patients to adaptive training for fall prevention (43). Acknowledgements Funded by the National Parkinson s Foundation CSRA chapter. Funding None to declare. Conflict of interest None to declare. References 1. LAMBERTI P, ARMENISE S, CASTALDO V et al. Freezing gait in Parkinson s disease. Eur Neurol 1997;38:297 301. 2. MACHT M, KAUSSNER Y, MOLLER JC et al. Predictors of freezing in Parkinson s disease: a survey of 6,620 patients. Mov Disord 2007;22:953 6. 3. OKUMA Y. Freezing of gait in Parkinson s disease. J Neurol 2006;253(Suppl 7):VII27 32. 4. GARCIA-RUIZ PJ. Gait disturbances in Parkinson disease. Did freezing of gait exist before levodopa? Historical review. J Neurol Sci 2011;307:15 7. 5. JANKOVIC J. Parkinson s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79: 368 76. 6. STERN GM, LANDER CM, LEES AJ. Akinetic freezing and trick movements in Parkinson s disease. J Neural Transm Suppl 1980;16:137 41. 7. GILADI N, HAUSDORFF JM. The role of mental function in the pathogenesis of freezing of gait in Parkinson s disease. J Neurol Sci 2006;248:173 6. 8. CHONG RK, LEE KH, MORGAN J et al. Closed-loop VRbased interaction for improving walking in Parkinson s disease. J Nov Physiother 2011;1:101. 9. COHEN RG, HORAK FB, NUTT JG. Peering through the FoG: visual manipulations shed light on freezing of gait. Mov Disord 2012;27:470 2. 10. LEE SJ, YOO JY, RYU JS, PARK HK, CHUNG SJ. The effects of visual and auditory cues on freezing of gait in patients with Parkinson disease. Am J Phys Med Rehabil 2012;91:2 11. 11. GOETZ CG, POEWE W, RASCOL O et al. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 2004;19:1020 8. 12. FOLSTEIN MF, FOLSTEIN SE, MCHUGH PR. Mini-mental state A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189 98. 13. JENKINSON C, FITZPATRICK R. Cross-cultural evaluation of the short form 8-item Parkinson s Disease Questionnaire (PDQ-8): results from America, Canada, Japan, Italy and Spain. Parkinsonism Relat Disord 2007;13: 22 8. 14. CHONG RK, MORGAN J, MEHTA SH et al. Rapid assessment of postural instability in Parkinson s disease (RAPID): a pilot study. Eur J Neurol 2011;18:260 5. 15. CHONG RK, LEE KH, MORGAN J, MEHTA SH, HALL P, SETHI K. Diagnostic value of the rapid assessment of postural instability in Parkinson s disease (RAPID) questionnaire. Int J Clin Pract 2012;66:718 21. 16. Anonymous. The Unified Parkinson s Disease Rating Scale (UPDRS): status and recommendations. Mov Disord 2003;18:738 50. 17. GILADI N, SHABTAI H, SIMON ES, BIRAN S, TAL J, KOR- CZYN AD. Construction of freezing of gait questionnaire for patients with Parkinsonism. Parkinsonism Relat Disord 2000;6:165 70. 18. NUTT JG, BLOEM BR, GILADI N, HALLETT M, HORAK FB, NIEUWBOER A. Freezing of gait: moving forward on a mysterious clinical phenomenon. Lancet Neurol 2011;10:734 44. 19. BARTELS AL, BALASH Y, GUREVICH T, SCHAAFSMA JD, HAUSDORFF JM, GILADI N. Relationship between freezing of gait (FOG) and other features of Parkinson s: FOG is not correlated with bradykinesia. J Clin Neurosci 2003;10:584 8. 20. GILADI N, MCDERMOTT MP, FAHN S et al. Freezing of gait in PD: prospective assessment in the DATATOP cohort. Neurology 2001;56:1712 21. 21. AMBONI M, COZZOLINO A, LONGO K, PICILLO M, BARONE P. Freezing of gait and executive functions in patients with Parkinson s disease. Mov Disord 2008;23:395 400. 22. SANDYK R. Improvement in word-fluency performance in Parkinson s disease by administration of electromagnetic fields. Int J Neurosci 1994;77:23 46. 23. DEVOS D, DEFEBVRE L, BORDET R. Dopaminergic and non-dopaminergic pharmacological hypotheses for gait disorders in Parkinson s disease. Fundam Clin Pharmacol 2010;24:407 21. 24. HASHIMOTOR T. Speculation on the responsible sites and pathophysiology. Parkinsonism Relat Disord 2006;12: S55 62. 25. THANVI BR, LO TC. Long term motor complications of levodopa: clinical features, mechanisms, and management strategies. Postgrad Med J 2004;80:452 8. 26. BARTELS AL, DE JONG BM, GILADI N et al. Striatal dopa and glucose metabolism in PD patients with freezing of gait. Mov Disord 2006;21:1326 32. 27. BLOEM BR, HAUSDORFF JM, VISSER JE, GILADI N. Falls and freezing of gait in Parkinson s disease: a review of 5

Chong et al. two interconnected, episodic phenomena. Mov Disord 2004;19:871 84. 28. VANDENBOSSCHE J, DEROOST N, SOETENS E et al. Freezing of gait in Parkinson disease is associated with impaired conflict resolution. Neurorehabil Neural Repair 2011;25: 765 73. 29. FAHN S. Does levodopa slow or hasten the rate of progression of Parkinson s disease? J Neurol 2005;252(Suppl 4):IV37 42. 30. LEWIS SJ, BARKER RA. A pathophysiological model of freezing of gait in Parkinson s disease. Parkinsonism Relat Disord 2009;15:333 8. 31. THEVATHASAN W, POGOSYAN A, HYAM JA et al. A block to pre-prepared movement in gait freezing, relieved by pedunculopontine nucleus stimulation. Brain 2011;134: 2085 95. 32. BROWNER N, GILADI N. What can we learn from freezing of gait in Parkinson s disease? Curr Neurol Neurosci Rep 2010;10:345 51. 33. FAHN S. Description of Parkinson s disease as a clinical syndrome. Ann N Y Acad Sci 2003;991:1 14. 34. SCHIESS MC, ZHENG H, SOUKUP VM, BONNEN JG, NAUTA HJ. Parkinson s disease subtypes: clinical classification and ventricular cerebrospinal fluid analysis. Parkinsonism Relat Disord 2000;6:69 76. 35. LEWIS NL, BRISMEE JM, JAMES CR, SIZER PS, SAWYER SF. The effect of stretching on muscle responses and postural sway responses during computerized dynamic posturography in women and men. Arch Phys Med Rehabil 2009;90:454 62. 36. PLOTNIK M, HAUSDORFF JM. The role of gait rhythmicity and bilateral coordination of stepping in the pathophysiology of freezing of gait in Parkinson s disease. Mov Disord 2008;23(Suppl 2):S444 50. 37. SCHAAFSMA JD, GILADI N, BALASH Y, BARTELS AL, GUREVICH T, HAUSDORFF JM. Gait dynamics in Parkinson s disease: relationship to Parkinsonian features, falls and response to levodopa. J Neurol Sci 2003; 212:47 53. 38. CHONG RK, JONES CL, HORAK FB. Postural set for balance control is normal in Alzheimer s but not in Parkinson s disease. J Gerontol A Biol Sci Med Sci 1999;54: M129 35. 39. CHONG RK, HORAK FB, WOOLLACOTT MH. Parkinson s disease impairs the ability to change set quickly. J Neurol Sci 2000;175:57 70. 40. COOLS R, BARKER RA, SAHAKIAN BJ, ROBBINS TW. Mechanisms of cognitive set flexibility in Parkinson s disease. Brain 2001;124:2503 12. 41. HAYES AE, DAVIDSON MC, KEELE SW, RAFAL RD. Toward a functional analysis of the basal ganglia. J Cogn Neurosci 1998;10:178 98. 42. NAISMITH SL, SHINE JM, LEWIS SJ. The specific contributions of set-shifting to freezing of gait in Parkinson s disease. Mov Disord 2010;25:1000 4. 43. KING LA, HORAK FB. Delaying mobility disability in people with Parkinson disease using a sensorimotor agility exercise program. Phys Ther 2009;89:384 93. 44. BARAM Y. Virtual sensory feedback for gait improvement in neurological patients. Frontiers in Neurology 2013;4:138. doi: 10.3389/fneur.2013.00138 45. GaitAid. GaitAid device. from http://medigait.com/main/ how-the-gaitaid-works/ 2014. 6