JNS-13808; No of Pages 4 Journal of the Neurological Sciences xxx (2015) xxx–xxx
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Overground robot assisted gait trainer for the treatment of drug-resistant freezing of gait in Parkinson disease Manuela Pilleri a,⁎, Luca Weis a, Letizia Zabeo a, Konstantinos Koutsikos a, Roberta Biundo a, Silvia Facchini a, Simonetta Rossi a, Stefano Masiero b, Angelo Antonini a a b
Department of Parkinson disease, IRCCS San Camillo, Via Alberoni 70, Venice-Lido, Italy Rehabilitation Unit, Department of Neurosciences, University of Padova, via Giustiniani 1, 35128 Padova, Italy
a r t i c l e
i n f o
Article history: Received 1 December 2014 Received in revised form 5 May 2015 Accepted 19 May 2015 Available online xxxx Keywords: Parkinson disease Gait Freezing of gait Balance Rehabilitation Robot assisted gait trainer
a b s t r a c t Freezing of Gait (FOG) is a frequent and disabling feature of Parkinson disease (PD). Gait rehabilitation assisted by electromechanical devices, such as training on treadmill associated with sensory cues or assisted by gait orthosis have been shown to improve FOG. Overground robot assisted gait training (RGT) has been recently tested in patients with PD with improvement of several gait parameters. We here evaluated the effectiveness of RGT on FOG severity and gait abnormalities in PD patients. Eighteen patients with FOG resistant to dopaminergic medications were treated with 15 sessions of RGT and underwent an extensive clinical evaluation before and after treatment. The main outcome measures were FOG questionnaire (FOGQ) global score and specific tasks for gait assessment, namely 10 meter walking test (10 MWT), Timed Up and Go test (TUG) and 360° narrow turns (360 NT). Balance was also evaluated through Fear of Falling Efficacy Scale (FFES), assessing self perceived stability and Berg Balance Scale (BBS), for objective examination. After treatment, FOGQ score was significantly reduced (P = 0.023). We also found a significant reduction of time needed to complete TUG, 10 MWT, and 360 NT (P = 0.009, 0.004 and 0.04, respectively). By contrast the number of steps and the number of freezing episodes recorded at each gait task did not change. FFES and BBS scores also improved, with positive repercussions on performance on daily activity and quality of life. Our results indicate that RGT is a useful strategy for the treatment of drug refractory FOG. © 2015 Elsevier B.V. All rights reserved.
1. Background Freezing of gait (FOG) is a disabling feature of Parkinson disease (PD), characterized by sudden and unwanted arrests of gait, which frequently occurs when initiating walking and in presence of obstacle or narrow tracks [1]. In the early PD about 20% of patients report FOG, but the prevalence of this phenomenon raises up to 50% in the advanced disease stages [2]. Moreover, while in early patients, FOG occurs during the off periods and is relieved by levodopa administration, with disease progression it often becomes refractory to dopaminergic therapy [3], and shows poor or no response to advanced treatments, including deep brain stimulation [4]. Different rehabilitative strategies have been proposed for the treatment of FOG. Walking training with visual or auditory cues showed variable results in different studies [5]: generally the number of FOG episodes recorded during laboratory assessment did not change [6] and only few studies showed an improvement in anamnestic FOG questionnaire [7–9]. Recently, Frazzitta et al. showed that training on
⁎ Corresponding author. E-mail address: [email protected] (M. Pilleri).
treadmill, combined with visual and auditory cues, is more efficacious than unspecific physical therapy [10]. Similarly, robot assisted treadmill training improved FOG in limited cohorts of PD patients [11,12]. Over-ground robot-assisted Gait Training (RGT) has been shown to be equally or even more efficacious than treadmill training in improving several gait parameters and balance in moderate to severe PD [13,14]. However, the effect of RGT on FOG has not been specifically assessed. The primary aim of the present study was to evaluate the effectiveness of RGT on FOG severity and gait abnormalities in PD patients with FOG resistant to dopaminergic medications. Moreover we investigated the impact of this treatment on global motor impairment, functional ability and health related quality of life.
2. Methods 2.1. Patients In this open label study we enrolled PD patients consecutively hospitalized for rehabilitative therapy at Movement Disorder Unit of the Hospital San Camillo in Venice between March 2012 and March 2013. The protocol was approved by local Ethical Committee.
http://dx.doi.org/10.1016/j.jns.2015.05.023 0022-510X/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: M. Pilleri, et al., Overground robot assisted gait trainer for the treatment of drug-resistant freezing of gait in Parkinson disease, J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.05.023
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M. Pilleri et al. / Journal of the Neurological Sciences xxx (2015) xxx–xxx
The inclusion criteria were diagnosis of PD according to United Kingdom Brain Bank Criteria, presence of FOG refractory to pharmacological therapy, H&Y stages 2.5–4 in on medication condition, stable antiparkinsonian treatment in the 4 weeks before enrolment in the study, and willingness to participate to the study expressed through written informed consent. The presence of severe dyskinesias was an exclusion criterion, since abnormal movements might interfere with training performance. We also excluded patients with medical conditions which could preclude training execution or affect treatment safety, such as severe painful musculoskeletal disease, severe orthostatic hypotension, uncontrolled hypertension, ischemic cardiopathy or other serious cardiovascular comorbidies. Patients with weight N 90 Kg were excluded from the study, according to the bearing limit of the RGT device. 2.2. Study treatment All patients included in the study were trained on RGT (Rehastim, Berlin). This device consists in over-ground motor driven footboards moving at a constant speed (ranging from 0 to 2 Km/h), regulated according to patient capabilities. The footboards run on a constant trajectory, and wideness can be individually adjusted to obtain a step length ranging from 28 to 48 cm. The machine is provided with a harness for body-weight support. Walking speed was set for each patient at a comfortable velocity (ranging from 0.5 to 2 Km/h). Progressive increase of gait speed was allowed in successive training session according to patient tolerability. Step length was individually adjusted according to patient stature (from 40 to 48 cm), in order to allow comfortable leg movements. Patients were ensured to the harness and body weight support was set at 5 Kg for all the patients. Training sessions were supervised by a physiotherapist for correct performance of the exercise and eventual speed modulation. During exercise patients were repeatedly reminded to adjust posture and to maintain an active control on the legs, avoiding to passively follow the footboard movements. Thirty minutes training sessions were performed 5 days a week for three consecutive weeks. Pharmacological treatment was kept stable throughout the study period. 2.3. Clinical assessments The same clinical assessments were performed before starting and one week after the end of treatment. Motor evaluations were performed in the morning, 60 to 90 min after levodopa intake; a trained neurologist (MP) verified that patients were in “on phase” at the time of evaluation. Primary outcomes were FOG severity, assessed by FOG questionnaire (FOGQ) [15] and gait parameters measured by objective clinical evaluation, including Timed Up and Go test (TUG), 10 m walking test (10-MWT), 10 MWT associated with a cognitive task (patients were asked to list words starting with the same letter while performing walking test) (DT 10 MWT), 360° narrow turns (360 NT) to the left and to the right side [16]. For each clinical objective evaluation we recorded: 1) number of FOG episodes occurring during the task, 2) time taken to complete the task (seconds) and 3) number of steps. Secondary outcome measures were the Fear of Falling Efficacy Scale (FFES) to assess the fear of falling during daily activities [17] and the Berg Balance Scale (BBS), which evaluates balance abilities while sitting, standing and during positional changes [18]. Global motor impairment and performance in activities of daily living were assessed by the validated Italian version of the Movement Disorder's society Unified Parkinson's Disease Rating Scale [19] (UPDRS) part III and part II, respectively. Moreover, quality of life was measured by the Parkinson's Disease Questionnaire-8 (PDQ-8) [20].
Antiparkinsonian therapy was recorded for each patient and levodopa equivalent daily dose was calculated according to a pubblished formula [21]. 2.4. Statistical analysis Statistical analysis was carried out using the IBM-Statistical Package for the Social Sciences (SPSS 20.0). Non-parametric Asymptotic Signed (2-tailed) Wilcoxon Signed Rank Test was used to assess differences in the distribution of clinical continuous variables between pre and post evaluation. 3. Results Twenty PD patients fulfilled selection criteria and entered the study. Two patients dropped out after the first session, due to inability to follow trainer's instructions and insufficient collaboration while the remaining 18 completed the study without any adverse event. Patients' demographic and clinical data are reported in Table 1. Among primary outcome measures, FOGQ score was reduced from 13 ± 3.39 at baseline to 9.2 ± 5.44 after treatment (P 0.023) time needed to perform TUG,10 MWT and 360 NT was reduced (P = 0.009, 0.004 and 0.04, respectively). The number of steps needed to carry out each gait task was also decreased, but did not reach statistical significance. Only 360 NT showed a trend for lower number of FOG episodes (P = 0.06); DT 10 MWT did not change after treatment for any of the observed variables (Table 2). Results for secondary outcomes are reported in Table 2. After treatment, FFES was significantly decreased (P = 0.04) and BBS significantly increased (P = 0.04) indicating an improvement of self perceived steadiness and objective balance performances. PDQ-8 improved from 10.2 ± 5.7 to 7.9 ± 5.2 (P = 0.03), while MDS-UPDRS II improved from 13.6 ± 4.3 to 10.6 ± 5.2 (P = 0.005). Global motor score (UPDRS III) was unchanged (Table 3) 4. Discussion FOG increases the risk of falls and negatively impacts on quality of life [22]. The development of rehabilitative strategies to improve this phenomenon is crucial for the management of Parkinson's disease, especially when FOG is refractory to pharmacological therapy. In patients with severe FOG traditional rehabilitative strategies, such as ground or treadmill gait training, can be limited by the onset of FOG episodes and patients need to be carefully monitored during training to prevent falls. Overground RGT has been shown to improve several gait parameters in patients with PD, but it has been never specifically studied in patients with drug refractory FOG. Our study demonstrates that RGT is feasible and safe in this particular subgroup of patients. Indeed, 18 out of 20 patients included in the study, despite severe motor disability (all the patients had an H&Y score included between 3 and 4). Two patients were unable to complete the rehabilitation protocol because they could not understand training Table 1 Clinic and demographic data.
Age (years) Disease duration (years) Levodopa equivalent dose (mg) MMSE Hoehn and Yahr stage 3.0 4.0
Median
Range
64.5 11.5 903.3 27.5 Number of patients 10 8
45–71 8–22 300–1744 24–30
This table illustrates clinic and demographic characteristics of study population.
Please cite this article as: M. Pilleri, et al., Overground robot assisted gait trainer for the treatment of drug-resistant freezing of gait in Parkinson disease, J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.05.023
M. Pilleri et al. / Journal of the Neurological Sciences xxx (2015) xxx–xxx
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Table 2 Primary outcome measures before and after treatment. Assessment
FOGQ score TUG
10 MWT
DT 10 MWT
360° NT
Pre-RGT
Freezing (n) Steps (n) Time (sec) Freezing (n) Steps (n) Time (sec) Freezing (n) Steps (n) Time (sec) Freezing (n) Steps (n) Time (sec)
Post-RGT
Wilkoxon signed rank test
Mean
SD
Median
Mean
SD
Median
Asymp. Sign. (2-tailed)
13 0.52 22.17 18.20 0 22 13.59 0.12 24 17.38 1.35 22.29 27.35
3.3912 0.717 8.76 8.88 0 9.05 7.47 0.33 10.47 9.78 1.36 9.09 24.41
13 0 21 15.84 0 20 12.2 0 23 15.31 1 24 13.26
9.294 0.47 19.17 14.15 0 19.76 11.97 0.23 21.88 16.09 0.82 19.88 16.72
5.4402 0.62 6.12 5.69 0 5.01 5.13 0.56 6.60 7.63 1.18 6.518 13.49
9 0 18 11,7 0 20 11,15 0 20 15 0 20 10.8
0.023* 1.000 0.059§ 0.004* 1.000 0.059 0.004 0.317 0.07 0.586 0.064 0.083 0.009
This table illustrates changes in freezing of gait questionnaire (FOGQ), and in timing, number of freezings and number of steps recorded at each specific gait assessment, namely Timed Up and Go (TUG), 10 meter walking test (10 MWT), dual task 10 MWT (DT 10 MWT) and 360° narrow turns (360 NT) before and after robot assisted gait training (RGT).
increase of walking cadence, but possibly to increased step length. Interestingly, gait speed on DT-10 MWT did not improve after treatment, indicating that pure motor training cannot overcome gait impairment produced by cognitive dual tasking. RGT also produced an improvement of balance, recorded at BBS. The improvement of self-perceived steadiness (FFES), may be due to the beneficial effect of gait training on balance but may also reflect the improvement of FOG, which is frequently related to falls or near-tofalling episodes. RGT did not improve UPDRS motor score, possibly because it is specifically focused on gait and balance, with few or no impact on other motor features, such as rigidity, bradykinesia, or tremor, which strongly impact on global scoring. Nevertheless, the improvement in axial features, resulted in a significant improvement in functionality and quality of life scores, which are largely conditioned by gait and balance disturbances. Likewise other rehabilitative strategies employed in PD gait disorders, such as exercise on treadmill (assisted or not by robotic orthoses), RGT is based on gait training [10–14]. Theoretically the use of task specific training relies on the concept that the best way to restore an impaired task is to repeatedly practice that particular task [25,26]. In other words, enacting motor sequences needed to walk, should promote relearning and retaining of gait related motor skills, through a process of neuroplasticity [25]. In recent years, growing knowledge about the specific abnormalities characterizing FOG, contributed to the development of specific rehabilitative programs. Gait analysis studies revealed that FOG episodes are sudden arrests of walking preceded by asymmetric, irregular steps. Even during continuous walking, in the absence of evident gait arrests, patients with FOG present reduction and variability of step amplitude and inconstant speed, resulting in arrhythmic and asymmetric gait [27–29]. Different rehabilitative strategies tested for the treatment of FOG, are aimed at contrasting such abnormalities. For instance, walking training with visual cues induces the patient to step on visual signals located at regular distance on the floor, generating steps of wide and
procedures and carry out the task, indicating that RGT should be reserved to patients with relatively preserved cognitive function. RGT improved FOG severity and several objective gait parameters. Moreover, after RGT training, patients showed an improvement of balance, and reported better performances in activities of daily living, which positively impacted quality of life. The improvement of FOG was reflected by a reduction of FOGQ score, but the number of freezing episodes recorded at objective clinical evaluation including TUG, 10 MWT and DT 10 MWT remained unchanged, showing only a trend for reduction at the 360 NT task. Such discrepancy between self-reported and objective clinical assessments reflects the difficulty to record FOG episodes through laboratory evaluations [23,24]. Indeed, both frequency and severity of FOG episodes, commonly fluctuate during the day and among different days, making the FOGQ, a self-assessed retrospective questionnaire referred to a 7-day period, possibly more reliable in capturing the true extent of this phenomenon than relatively brief observation during laboratory tests. As a matter of fact, we recorded few FOG episodes during objective assessment (both at baseline and final visit) despite introducing cognitive DT challenges, which are known to trigger FOG. Although all patients included in the study reported FOG as a major complaint, the median number of FOG episodes observed at evaluation was “0” in almost all walking tasks, such that no improvement could be expected. Only for 360° narrow turns, the median number of freezing was = 1 at baseline, and showed a trend to improvement (P value 0.064) after treatment, suggesting, in agreement with previous reports, that this assessment may be more sensitive than other motor tasks in revealing freezing and detect treatment-induced changes [16]. Despite similar number of freezing episodes, time taken to carry out 10 MWT, TUG and 360 NT was significantly reduced after RGT, indicating an increased gait speed. On the other hand, the number of steps needed to complete each gait task showed a trend to reduction. We could argue that the improvement of gait speed is not related to the
Table 3 Secondary outcome measures before and after treatment. PD patients (N = 18)
Wilkoxon signed rank test
Pre
UPDRS II UPDRS III BBS FFES PDQ8
Post
Mean
SD
Median
Mean
SD
Median
Asymp. Sign. (2-tailed)
13.588 24.235 40.882 24.765 10.188
4.2875 9.7438 7.356 19.5561 5.7064
14 22 40 20 8
10.588 22.235 43.529 16 7.941
5.2566 10.311 8.5156 7.5 5.2138
10 23 45 13 8
0.005 0.131 0.043 0.044 *0.033
This table illustrates changes in secondary outcome measures, namely unified Parkinson disease rating scale functional score (UPDRS II) and motor score (UPDRS III), Berg Balance Scale (BBS), Fear of Falling Efficacy Scale (FFES) and the short version of Parkinson's disease quality of life scale (PDQ 8).
Please cite this article as: M. Pilleri, et al., Overground robot assisted gait trainer for the treatment of drug-resistant freezing of gait in Parkinson disease, J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.05.023
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M. Pilleri et al. / Journal of the Neurological Sciences xxx (2015) xxx–xxx
constant amplitude and promoting inter-limb symmetry during gait [7]. Similarly, training with auditory cues restores gait rhythm by inviting patients to walk following regularly paced auditory inputs [5]. Indeed improvement of freezing produced by treadmill training associated with visual and auditory cues paralleled the improvement of gait asymmetry [10]. RGT allows the patient to repeat walking-like sequences, keeping constant speed and constant step amplitude, equal for left and right legs. Thus, during RGT patients enact a regular motor sequence, avoiding shortening of steps, loss of rhythm, and asymmetry. Compared with other gait training techniques, such as treadmill and gait orthoses assisted treadmill training (i.e. Locomat), RGT may offer some advantages. Treadmill training is often precluded to patients with very severe FOG, since gait arrests may occur during exercise, such that patients are not able to conclude treatment sessions, despite being sustained by a safety harness. By contrast we never observed the occurrence of arrests of walking during RGT sessions. During robot assisted treadmill training patient steps on the walking belt, but the movement of the legs is mainly passively imparted by an automated exoskeleton. By contrast during RGT patient is required to maintain an active control on legs' movements, which is crucial to promote retention of motor skills [30]. Specifically designed comparative studies are warranted to test these hypotheses. We acknowledge that our study is limited by methodological issues, mainly its open label design and lack of controls. Although timed motor tasks used in our study, are not likely to be affected by placebo, self reported outcome measures, namely FOG-Q, UPDRS II and PDQ-8, might be associated to a certain degree of subjectivity. Nevertheless, in our study, the level of improvement of FOGQ was striking, despite the relatively small sample size. As many other studies on rehabilitative strategies, our work had relatively short follow up. Indeed study evaluations and treatment were performed in in-patient regimen and many of the patients lived far from our center and were not available for further follow up. Summarizing, our study suggests that RGT maybe a suitable strategy to improve gait and balance in PD patients with drug refractory FOG. The improvement of axial symptoms may also positively impact motor functionality and quality of life. We acknowledge that our selection criteria were quite restrictive, excluding “a priori” patients with severe musculoskeletal or systemic diseases. Nevertheless, RGT may be tried also in patients with such comorbidities, after proper safety evaluation and monitoring patients' tolerability.
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Please cite this article as: M. Pilleri, et al., Overground robot assisted gait trainer for the treatment of drug-resistant freezing of gait in Parkinson disease, J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.05.023
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Overground robot assisted gait trainer for the treatment of drug-resistant freezing of gait in Parkinson disease Manuela Pilleri a,⁎, Luca Weis a, Letizia Zabeo a, Konstantinos Koutsikos a, Roberta Biundo a, Silvia Facchini a, Simonetta Rossi a, Stefano Masiero b, Angelo Antonini a a b
Department of Parkinson disease, IRCCS San Camillo, Via Alberoni 70, Venice-Lido, Italy Rehabilitation Unit, Department of Neurosciences, University of Padova, via Giustiniani 1, 35128 Padova, Italy
a r t i c l e
i n f o
Article history: Received 1 December 2014 Received in revised form 5 May 2015 Accepted 19 May 2015 Available online xxxx Keywords: Parkinson disease Gait Freezing of gait Balance Rehabilitation Robot assisted gait trainer
a b s t r a c t Freezing of Gait (FOG) is a frequent and disabling feature of Parkinson disease (PD). Gait rehabilitation assisted by electromechanical devices, such as training on treadmill associated with sensory cues or assisted by gait orthosis have been shown to improve FOG. Overground robot assisted gait training (RGT) has been recently tested in patients with PD with improvement of several gait parameters. We here evaluated the effectiveness of RGT on FOG severity and gait abnormalities in PD patients. Eighteen patients with FOG resistant to dopaminergic medications were treated with 15 sessions of RGT and underwent an extensive clinical evaluation before and after treatment. The main outcome measures were FOG questionnaire (FOGQ) global score and specific tasks for gait assessment, namely 10 meter walking test (10 MWT), Timed Up and Go test (TUG) and 360° narrow turns (360 NT). Balance was also evaluated through Fear of Falling Efficacy Scale (FFES), assessing self perceived stability and Berg Balance Scale (BBS), for objective examination. After treatment, FOGQ score was significantly reduced (P = 0.023). We also found a significant reduction of time needed to complete TUG, 10 MWT, and 360 NT (P = 0.009, 0.004 and 0.04, respectively). By contrast the number of steps and the number of freezing episodes recorded at each gait task did not change. FFES and BBS scores also improved, with positive repercussions on performance on daily activity and quality of life. Our results indicate that RGT is a useful strategy for the treatment of drug refractory FOG. © 2015 Elsevier B.V. All rights reserved.
1. Background Freezing of gait (FOG) is a disabling feature of Parkinson disease (PD), characterized by sudden and unwanted arrests of gait, which frequently occurs when initiating walking and in presence of obstacle or narrow tracks [1]. In the early PD about 20% of patients report FOG, but the prevalence of this phenomenon raises up to 50% in the advanced disease stages [2]. Moreover, while in early patients, FOG occurs during the off periods and is relieved by levodopa administration, with disease progression it often becomes refractory to dopaminergic therapy [3], and shows poor or no response to advanced treatments, including deep brain stimulation [4]. Different rehabilitative strategies have been proposed for the treatment of FOG. Walking training with visual or auditory cues showed variable results in different studies [5]: generally the number of FOG episodes recorded during laboratory assessment did not change [6] and only few studies showed an improvement in anamnestic FOG questionnaire [7–9]. Recently, Frazzitta et al. showed that training on
⁎ Corresponding author. E-mail address: [email protected] (M. Pilleri).
treadmill, combined with visual and auditory cues, is more efficacious than unspecific physical therapy [10]. Similarly, robot assisted treadmill training improved FOG in limited cohorts of PD patients [11,12]. Over-ground robot-assisted Gait Training (RGT) has been shown to be equally or even more efficacious than treadmill training in improving several gait parameters and balance in moderate to severe PD [13,14]. However, the effect of RGT on FOG has not been specifically assessed. The primary aim of the present study was to evaluate the effectiveness of RGT on FOG severity and gait abnormalities in PD patients with FOG resistant to dopaminergic medications. Moreover we investigated the impact of this treatment on global motor impairment, functional ability and health related quality of life.
2. Methods 2.1. Patients In this open label study we enrolled PD patients consecutively hospitalized for rehabilitative therapy at Movement Disorder Unit of the Hospital San Camillo in Venice between March 2012 and March 2013. The protocol was approved by local Ethical Committee.
http://dx.doi.org/10.1016/j.jns.2015.05.023 0022-510X/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: M. Pilleri, et al., Overground robot assisted gait trainer for the treatment of drug-resistant freezing of gait in Parkinson disease, J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.05.023
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M. Pilleri et al. / Journal of the Neurological Sciences xxx (2015) xxx–xxx
The inclusion criteria were diagnosis of PD according to United Kingdom Brain Bank Criteria, presence of FOG refractory to pharmacological therapy, H&Y stages 2.5–4 in on medication condition, stable antiparkinsonian treatment in the 4 weeks before enrolment in the study, and willingness to participate to the study expressed through written informed consent. The presence of severe dyskinesias was an exclusion criterion, since abnormal movements might interfere with training performance. We also excluded patients with medical conditions which could preclude training execution or affect treatment safety, such as severe painful musculoskeletal disease, severe orthostatic hypotension, uncontrolled hypertension, ischemic cardiopathy or other serious cardiovascular comorbidies. Patients with weight N 90 Kg were excluded from the study, according to the bearing limit of the RGT device. 2.2. Study treatment All patients included in the study were trained on RGT (Rehastim, Berlin). This device consists in over-ground motor driven footboards moving at a constant speed (ranging from 0 to 2 Km/h), regulated according to patient capabilities. The footboards run on a constant trajectory, and wideness can be individually adjusted to obtain a step length ranging from 28 to 48 cm. The machine is provided with a harness for body-weight support. Walking speed was set for each patient at a comfortable velocity (ranging from 0.5 to 2 Km/h). Progressive increase of gait speed was allowed in successive training session according to patient tolerability. Step length was individually adjusted according to patient stature (from 40 to 48 cm), in order to allow comfortable leg movements. Patients were ensured to the harness and body weight support was set at 5 Kg for all the patients. Training sessions were supervised by a physiotherapist for correct performance of the exercise and eventual speed modulation. During exercise patients were repeatedly reminded to adjust posture and to maintain an active control on the legs, avoiding to passively follow the footboard movements. Thirty minutes training sessions were performed 5 days a week for three consecutive weeks. Pharmacological treatment was kept stable throughout the study period. 2.3. Clinical assessments The same clinical assessments were performed before starting and one week after the end of treatment. Motor evaluations were performed in the morning, 60 to 90 min after levodopa intake; a trained neurologist (MP) verified that patients were in “on phase” at the time of evaluation. Primary outcomes were FOG severity, assessed by FOG questionnaire (FOGQ) [15] and gait parameters measured by objective clinical evaluation, including Timed Up and Go test (TUG), 10 m walking test (10-MWT), 10 MWT associated with a cognitive task (patients were asked to list words starting with the same letter while performing walking test) (DT 10 MWT), 360° narrow turns (360 NT) to the left and to the right side [16]. For each clinical objective evaluation we recorded: 1) number of FOG episodes occurring during the task, 2) time taken to complete the task (seconds) and 3) number of steps. Secondary outcome measures were the Fear of Falling Efficacy Scale (FFES) to assess the fear of falling during daily activities [17] and the Berg Balance Scale (BBS), which evaluates balance abilities while sitting, standing and during positional changes [18]. Global motor impairment and performance in activities of daily living were assessed by the validated Italian version of the Movement Disorder's society Unified Parkinson's Disease Rating Scale [19] (UPDRS) part III and part II, respectively. Moreover, quality of life was measured by the Parkinson's Disease Questionnaire-8 (PDQ-8) [20].
Antiparkinsonian therapy was recorded for each patient and levodopa equivalent daily dose was calculated according to a pubblished formula [21]. 2.4. Statistical analysis Statistical analysis was carried out using the IBM-Statistical Package for the Social Sciences (SPSS 20.0). Non-parametric Asymptotic Signed (2-tailed) Wilcoxon Signed Rank Test was used to assess differences in the distribution of clinical continuous variables between pre and post evaluation. 3. Results Twenty PD patients fulfilled selection criteria and entered the study. Two patients dropped out after the first session, due to inability to follow trainer's instructions and insufficient collaboration while the remaining 18 completed the study without any adverse event. Patients' demographic and clinical data are reported in Table 1. Among primary outcome measures, FOGQ score was reduced from 13 ± 3.39 at baseline to 9.2 ± 5.44 after treatment (P 0.023) time needed to perform TUG,10 MWT and 360 NT was reduced (P = 0.009, 0.004 and 0.04, respectively). The number of steps needed to carry out each gait task was also decreased, but did not reach statistical significance. Only 360 NT showed a trend for lower number of FOG episodes (P = 0.06); DT 10 MWT did not change after treatment for any of the observed variables (Table 2). Results for secondary outcomes are reported in Table 2. After treatment, FFES was significantly decreased (P = 0.04) and BBS significantly increased (P = 0.04) indicating an improvement of self perceived steadiness and objective balance performances. PDQ-8 improved from 10.2 ± 5.7 to 7.9 ± 5.2 (P = 0.03), while MDS-UPDRS II improved from 13.6 ± 4.3 to 10.6 ± 5.2 (P = 0.005). Global motor score (UPDRS III) was unchanged (Table 3) 4. Discussion FOG increases the risk of falls and negatively impacts on quality of life [22]. The development of rehabilitative strategies to improve this phenomenon is crucial for the management of Parkinson's disease, especially when FOG is refractory to pharmacological therapy. In patients with severe FOG traditional rehabilitative strategies, such as ground or treadmill gait training, can be limited by the onset of FOG episodes and patients need to be carefully monitored during training to prevent falls. Overground RGT has been shown to improve several gait parameters in patients with PD, but it has been never specifically studied in patients with drug refractory FOG. Our study demonstrates that RGT is feasible and safe in this particular subgroup of patients. Indeed, 18 out of 20 patients included in the study, despite severe motor disability (all the patients had an H&Y score included between 3 and 4). Two patients were unable to complete the rehabilitation protocol because they could not understand training Table 1 Clinic and demographic data.
Age (years) Disease duration (years) Levodopa equivalent dose (mg) MMSE Hoehn and Yahr stage 3.0 4.0
Median
Range
64.5 11.5 903.3 27.5 Number of patients 10 8
45–71 8–22 300–1744 24–30
This table illustrates clinic and demographic characteristics of study population.
Please cite this article as: M. Pilleri, et al., Overground robot assisted gait trainer for the treatment of drug-resistant freezing of gait in Parkinson disease, J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.05.023
M. Pilleri et al. / Journal of the Neurological Sciences xxx (2015) xxx–xxx
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Table 2 Primary outcome measures before and after treatment. Assessment
FOGQ score TUG
10 MWT
DT 10 MWT
360° NT
Pre-RGT
Freezing (n) Steps (n) Time (sec) Freezing (n) Steps (n) Time (sec) Freezing (n) Steps (n) Time (sec) Freezing (n) Steps (n) Time (sec)
Post-RGT
Wilkoxon signed rank test
Mean
SD
Median
Mean
SD
Median
Asymp. Sign. (2-tailed)
13 0.52 22.17 18.20 0 22 13.59 0.12 24 17.38 1.35 22.29 27.35
3.3912 0.717 8.76 8.88 0 9.05 7.47 0.33 10.47 9.78 1.36 9.09 24.41
13 0 21 15.84 0 20 12.2 0 23 15.31 1 24 13.26
9.294 0.47 19.17 14.15 0 19.76 11.97 0.23 21.88 16.09 0.82 19.88 16.72
5.4402 0.62 6.12 5.69 0 5.01 5.13 0.56 6.60 7.63 1.18 6.518 13.49
9 0 18 11,7 0 20 11,15 0 20 15 0 20 10.8
0.023* 1.000 0.059§ 0.004* 1.000 0.059 0.004 0.317 0.07 0.586 0.064 0.083 0.009
This table illustrates changes in freezing of gait questionnaire (FOGQ), and in timing, number of freezings and number of steps recorded at each specific gait assessment, namely Timed Up and Go (TUG), 10 meter walking test (10 MWT), dual task 10 MWT (DT 10 MWT) and 360° narrow turns (360 NT) before and after robot assisted gait training (RGT).
increase of walking cadence, but possibly to increased step length. Interestingly, gait speed on DT-10 MWT did not improve after treatment, indicating that pure motor training cannot overcome gait impairment produced by cognitive dual tasking. RGT also produced an improvement of balance, recorded at BBS. The improvement of self-perceived steadiness (FFES), may be due to the beneficial effect of gait training on balance but may also reflect the improvement of FOG, which is frequently related to falls or near-tofalling episodes. RGT did not improve UPDRS motor score, possibly because it is specifically focused on gait and balance, with few or no impact on other motor features, such as rigidity, bradykinesia, or tremor, which strongly impact on global scoring. Nevertheless, the improvement in axial features, resulted in a significant improvement in functionality and quality of life scores, which are largely conditioned by gait and balance disturbances. Likewise other rehabilitative strategies employed in PD gait disorders, such as exercise on treadmill (assisted or not by robotic orthoses), RGT is based on gait training [10–14]. Theoretically the use of task specific training relies on the concept that the best way to restore an impaired task is to repeatedly practice that particular task [25,26]. In other words, enacting motor sequences needed to walk, should promote relearning and retaining of gait related motor skills, through a process of neuroplasticity [25]. In recent years, growing knowledge about the specific abnormalities characterizing FOG, contributed to the development of specific rehabilitative programs. Gait analysis studies revealed that FOG episodes are sudden arrests of walking preceded by asymmetric, irregular steps. Even during continuous walking, in the absence of evident gait arrests, patients with FOG present reduction and variability of step amplitude and inconstant speed, resulting in arrhythmic and asymmetric gait [27–29]. Different rehabilitative strategies tested for the treatment of FOG, are aimed at contrasting such abnormalities. For instance, walking training with visual cues induces the patient to step on visual signals located at regular distance on the floor, generating steps of wide and
procedures and carry out the task, indicating that RGT should be reserved to patients with relatively preserved cognitive function. RGT improved FOG severity and several objective gait parameters. Moreover, after RGT training, patients showed an improvement of balance, and reported better performances in activities of daily living, which positively impacted quality of life. The improvement of FOG was reflected by a reduction of FOGQ score, but the number of freezing episodes recorded at objective clinical evaluation including TUG, 10 MWT and DT 10 MWT remained unchanged, showing only a trend for reduction at the 360 NT task. Such discrepancy between self-reported and objective clinical assessments reflects the difficulty to record FOG episodes through laboratory evaluations [23,24]. Indeed, both frequency and severity of FOG episodes, commonly fluctuate during the day and among different days, making the FOGQ, a self-assessed retrospective questionnaire referred to a 7-day period, possibly more reliable in capturing the true extent of this phenomenon than relatively brief observation during laboratory tests. As a matter of fact, we recorded few FOG episodes during objective assessment (both at baseline and final visit) despite introducing cognitive DT challenges, which are known to trigger FOG. Although all patients included in the study reported FOG as a major complaint, the median number of FOG episodes observed at evaluation was “0” in almost all walking tasks, such that no improvement could be expected. Only for 360° narrow turns, the median number of freezing was = 1 at baseline, and showed a trend to improvement (P value 0.064) after treatment, suggesting, in agreement with previous reports, that this assessment may be more sensitive than other motor tasks in revealing freezing and detect treatment-induced changes [16]. Despite similar number of freezing episodes, time taken to carry out 10 MWT, TUG and 360 NT was significantly reduced after RGT, indicating an increased gait speed. On the other hand, the number of steps needed to complete each gait task showed a trend to reduction. We could argue that the improvement of gait speed is not related to the
Table 3 Secondary outcome measures before and after treatment. PD patients (N = 18)
Wilkoxon signed rank test
Pre
UPDRS II UPDRS III BBS FFES PDQ8
Post
Mean
SD
Median
Mean
SD
Median
Asymp. Sign. (2-tailed)
13.588 24.235 40.882 24.765 10.188
4.2875 9.7438 7.356 19.5561 5.7064
14 22 40 20 8
10.588 22.235 43.529 16 7.941
5.2566 10.311 8.5156 7.5 5.2138
10 23 45 13 8
0.005 0.131 0.043 0.044 *0.033
This table illustrates changes in secondary outcome measures, namely unified Parkinson disease rating scale functional score (UPDRS II) and motor score (UPDRS III), Berg Balance Scale (BBS), Fear of Falling Efficacy Scale (FFES) and the short version of Parkinson's disease quality of life scale (PDQ 8).
Please cite this article as: M. Pilleri, et al., Overground robot assisted gait trainer for the treatment of drug-resistant freezing of gait in Parkinson disease, J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.05.023
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M. Pilleri et al. / Journal of the Neurological Sciences xxx (2015) xxx–xxx
constant amplitude and promoting inter-limb symmetry during gait [7]. Similarly, training with auditory cues restores gait rhythm by inviting patients to walk following regularly paced auditory inputs [5]. Indeed improvement of freezing produced by treadmill training associated with visual and auditory cues paralleled the improvement of gait asymmetry [10]. RGT allows the patient to repeat walking-like sequences, keeping constant speed and constant step amplitude, equal for left and right legs. Thus, during RGT patients enact a regular motor sequence, avoiding shortening of steps, loss of rhythm, and asymmetry. Compared with other gait training techniques, such as treadmill and gait orthoses assisted treadmill training (i.e. Locomat), RGT may offer some advantages. Treadmill training is often precluded to patients with very severe FOG, since gait arrests may occur during exercise, such that patients are not able to conclude treatment sessions, despite being sustained by a safety harness. By contrast we never observed the occurrence of arrests of walking during RGT sessions. During robot assisted treadmill training patient steps on the walking belt, but the movement of the legs is mainly passively imparted by an automated exoskeleton. By contrast during RGT patient is required to maintain an active control on legs' movements, which is crucial to promote retention of motor skills [30]. Specifically designed comparative studies are warranted to test these hypotheses. We acknowledge that our study is limited by methodological issues, mainly its open label design and lack of controls. Although timed motor tasks used in our study, are not likely to be affected by placebo, self reported outcome measures, namely FOG-Q, UPDRS II and PDQ-8, might be associated to a certain degree of subjectivity. Nevertheless, in our study, the level of improvement of FOGQ was striking, despite the relatively small sample size. As many other studies on rehabilitative strategies, our work had relatively short follow up. Indeed study evaluations and treatment were performed in in-patient regimen and many of the patients lived far from our center and were not available for further follow up. Summarizing, our study suggests that RGT maybe a suitable strategy to improve gait and balance in PD patients with drug refractory FOG. The improvement of axial symptoms may also positively impact motor functionality and quality of life. We acknowledge that our selection criteria were quite restrictive, excluding “a priori” patients with severe musculoskeletal or systemic diseases. Nevertheless, RGT may be tried also in patients with such comorbidities, after proper safety evaluation and monitoring patients' tolerability.
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Please cite this article as: M. Pilleri, et al., Overground robot assisted gait trainer for the treatment of drug-resistant freezing of gait in Parkinson disease, J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.05.023
