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Abstract

Background:

Parkinsonian patients in advanced stages of disease suffer from many motor and non-motor symptoms, whose responsiveness to dopamine replacement therapy and deep brain stimulation is poor. It is necessary to find complementary strategies in order to improve the clinical conditions of patients in advanced Parkinson’s disease (PD) stages.

Objective:

We aimed to understand whether an inpatient, motor-cognitive, multidisciplinary, aerobic, intensive and goal-based rehabilitation treatment (MIRT), specifically designed for PD, is effective for patients in advanced stages of disease.

Methods:

638 Parkinsonian patients, hospitalized to undergo a 4-week MIRT, were retrospectively identified. According to the Hoehn & Yahr (H&Y) scale, 496 were in H&Y stage 3 and 142 in H&Y stage 4-5. Outcome measures included: Unified Parkinson’s Disease Rating Scale (UPDRS), Berg Balance Scale (BBS), Timed Up and Go Test (TUG), Six Minute Walk Test (6MWT), and Parkinson’s Disease Disability Scale (PDDS).

Results:

At baseline all measures, except UPDRS IV, significantly worsened passing from H&Y stage 3 to H&Y stage 4-5 (p≤0.002 all). After rehabilitation all outcome measures significantly improved in both groups of patients (p < 0.0001 all). Comparing the amount of improvement in the two groups, significant differences were observed only for the changes in BBS and TUG (both p < 0.0001 after adjustment), with a better improvement in the H&Y stage 4-5 group.

Conclusions:

A multidisciplinary, motor-cognitive, intensive and goal-based rehabilitation treatment, such as MIRT, could be an effective complementary treatment in PD patients in advanced stages of disease.

Keywords

Advanced stages of disease multidisciplinary treatment Parkinson’s disease rehabilitation

INTRODUCTION

Parkinson’s disease (PD) is the second most common neurodegenerative disorder [1]. The dopaminergic neuronal loss in the pars compacta of the substantia nigra represents the neuropathological hallmark of the disease. Despite the progress in the pharmacological and surgical therapies, PD remains difficult to treat and its management still represents a challenge. During the disease course, PD patients develop a plethora of motor and non-motor symptoms, and the disability worsens over time [2]. The result is a progressive worsening of the quality of life for patients and caregivers, as well as a dramatic economic burden [3].

The most widely used tool for the staging of PD is the Hoehn and Yahr (H&Y) scale [4], which classifies patients in five stages, according to the relative level of disability. The transition from the early-medium stages of disease to the advanced stages marks a significant moment in PD clinical history. This occurs in the H&Y stage 3, when PD patients develop balance and gait dysfunctions, which are poor or unresponsive to dopaminergic therapies and deep brain stimulation [5 –7]. Furthermore, in the advanced stages of disease, patients may develop drug-related side effects [7], such as motor fluctuations and dyskinesia, which further worsen the neurological clinical state.

It follows that the clinicians’ approach for the therapeutic management of “advanced” PD patients should be different. Varanese S et al. [7] suggested that patients in advanced PD stages could benefit from intensive and multidisciplinary treatments, including physical therapy. Recently, different rehabilitation treatments have been proposed as effective and complementary for the treatment of PD [8 –11]. In particular, in PD patients in early-medium stages of disease, it has been demonstrated the effectiveness of rehabilitative approaches, entailing specific features in terms of intensity, specificity and complexity of practice [12 –15]. Conversely, there are only a few data about physical interventions in PD patients in advanced stages of disease. To the best of our knowledge, the only study about this issue was carried out by Kaseda et al. (2016) [16] on a little group of PD patients in H&Y stages 3 and 4; the authors found that an intensive inpatient conventional rehabilitation treatment was associated with substantial improvements in clinical, functional and motor outcomes.

The aim of the present study is to evaluate whether an inpatient, motor-cognitive, multidisciplinary, aerobic, intensive and goal-based rehabilitation treatment, specifically designed for PD, is effective for Parkinsonian patients in advanced stages of disease.

MATERIALS AND METHODS

Participants

PD patients were retrospectively identified from our Department of Parkinson’s disease, Movement Disorders and Brain Injury Rehabilitation (“Moriggia-Pelascini” Hospital - Gravedona ed Uniti, Como, Italy). From January 2013 to December 2016 we hospitalized one thousand and twenty-four patients, suffering from different movement disorders, for a 4-week Multidisciplinary Intensive Rehabilitation Treatment (MIRT) [13 , 17]. We excluded from the analysis all subjects suffering from movement disorders different from PD (n = 117) and patients who had other clinical problems during hospitalization (n = 24). Finally, we identified eight hundred and eighty-three subjects with PD. Parkinsonian patients were diagnosed according to the UK Brain Bank criteria [18] and staged in accordance with the H&Y scale [4].

The study design and protocol were approved by the local Scientific Committee (“Moriggia-Pelascini” Hospital, Gravedona ed Uniti – Como, Italy) and were in accordance with the code of Ethics of the World Medical Association (Declaration of Helsinki, 1967). All patients included in the study had previously signed an informed written consent to use their clinical data for scientific purposes. This trial was registered on ClinicalTrials.gov website (NCT02731170).

Rehabilitation treatment

MIRT is an inpatient, multidisciplinary, aerobic, motor-cognitive, intensive and goal-based rehabilitation treatment specifically designed for PD patients [13 , 17]. It is known that PD pathology results in an impaired ability to learn and express habitual-automatic actions [19]. Therefore, the aim of the treatment is to re-learn the dysfunctional movements using explicit and implicit learning strategies and to re-acquire and, finally, execute correctly the automatic actions through executive, goal-based and volitional processes.

MIRT consists of a 4-week program in a hospital setting, composed of four daily rehabilitative sessions for five days, and one hour of physical exercise on the sixth day. The duration of each session, including recovery periods, is of about one hour:

The first session consists of a one-to-one treatment with a physical therapist. It comprises cardiovascular warm-up activities, active and passive exercises to improve the joints range of motion, stretching of the abdominal muscles, strengthening of paravertebral muscles, postural changes, and exercises operating on balance and postural control.

The second session includes the use of various devices: a stabilometric platform with biofeedback (patients have to follow a pathway on a screen by using a cursor sensitive to the movements of their feet on the platform), a treadmill plus (treadmill training with visual cues, auditory cue and feedback) [20], a crossover [21], and a cycloergometer with feedback. The maximum tolerated walking speed for treadmill training is determined for each patient during the first days of hospitalization. Treadmill speed is initially set at 1.0–1.5 km/h and progressively increased until a maximum of 3.5 km/h, depending on the patients’ physical abilities. Patients are trained with the treadmill for no more than 15 minutes, two times per day.

The third session consists of occupational therapy aimed to improve the autonomy in everyday activities.

The fourth session includes one hour of speech therapy.

On the sixth day patients are trained with the devices for one hour.

The rehabilitation program is personally tailored and may also include hydrotherapy, in case of severe balance and postural disorders, robotic-assisted walking training for complex gait disorders, virtual-reality training and psychoeducational groups with neuropsychologists.

During the different activities, the heart rate reserve is kept between 70 and 80%.

A weekly team meeting defines the rehabilitation program for each patient and assesses its benefits during the course of the hospitalization.

Outcome measures and neuropsychological assessment

Neurologists and physiotherapists with expertise in movement disorders administered clinical, functional and motor scales at the admission and at the end of the 4-week MIRT. All evaluations were performed in the morning, on the day of the admission, one hour after taking the first dopaminergic drug dose, in medication “on” state. The assessment included: Unified Parkinson’s Disease Rating Scale (UPDRS), Berg Balance Scale (BBS), Timed Up and Go Test (TUG), Six Minute Walk Test (6MWT) and Parkinson’s Disease Disability Scale (PDDS). Since many PD patients present cognitive dysfunctions, which worsen with the disease course [22], a cognitive assessment was carried out by an expert Neuropsychologist in the morning, on the second day of hospitalization, in medication “on” state. The neuropsychological profile was explored by using the Mini Mental State Examination (MMSE), for the assessment of the cognitive status, and the Frontal Assessment Battery (FAB), to study the executive profile. We used normative MMSE and FAB scores for the analysis.

Statistical analysis

Descriptive statistics are reported as mean±SD for continuous data and as number (percentage frequency) for discrete variables.

Shapiro–Wilk test, supported by visual inspection, was used to assess the normality of the distribution of continuous variables. Since most outcome measures severely violated the normality assumption, non-parametric statistics were used. Accordingly, between- and within-group comparisons were performed by the Mann-Whitney U test and Wilcoxon signed-rank test, respectively.

We first compared the outcome variables (values at discharge vs values at admission) in each group to assess the effect of MIRT. Then, we computed the difference (values at discharge-values at admission in each group) for all outcome variables and afterwards we compared these differences between groups.

The possible role of age, cognitive impairment and l-dopa equivalent dosage was investigated by multiple regression analysis.

All statistical tests were two-tailed and statistical significance was set at p < 0.05. When appropriate, false discovery rate was controlled at 5% using the Benjamini-Hochberg method.

All analyses were carried out using the SAS/STAT statistical package, release 9.2 (SAS Institute Inc., Cary, NC, U.S.A.).

RESULTS

Amongst all the Parkinsonian patients, 638 were in H&Y stages 3-4-5: specifically, we identified 496 subjects in H&Y stage 3, 135 subjects in H&Y stage 4 and 7 subjects in H&Y stage 5.

Demographical, neuropsychological data and amount of l-dopa equivalent dosage for the 3 groups of patients are reported in Table 1. Patients’ mean age increased passing from H&Y stage 3 to H&Y stages 4 and 5. The total amount of dopaminergic therapy did not significantly differ between groups.

Table 1

Demographical, neuropsychological data and amount of L-dopa equivalent dosage of patients subdivided according to the H&Y stage and comparison between patients in H&Y stage3 and patients in H&Y stage 4-5

Variable	All patients (n. 638)	H&Y 3 (n. 496)	H&Y 4 (n. 135)	H&Y 5 (n. 7)	p value
Age	70.7±8.1	69.9±8.2	73.3±7.1	73.3±4.7	<0.0001
Males (%)	369 (56.5)	284 (57.1)	74 (54.4)	4 (57.1)	0.58
MMSE	25.8±3.9	26.5±3.1	23.6±5.1	17.5±4.2	<0.0001
FAB	12.6±3.5	13.0±3.2	11.6±4.2	6.7±4.5	0.004
L-dopa	749.4±328.7	745.7±318.7	784.8±360.6	566.9±252.0	0.74

H&Y, Hoehn & Yahr scale; MMSE, Mini-Mental State Examination; FAB, Frontal Assessment Battery; L-dopa, total amount of levodopa equivalent dose per day. MMSE and FAB scores have been previously corrected according to normative data.

Given the small number of patients in H&Y stage 5, we included these patients in the group of H&Y stage 4 (obtaining H&Y stage 4-5 group) for all subsequent analysis.

In Table 2, the values of the clinical, motor and functional outcome variables at baseline for patients in H&Y stage 3 and in H&Y stage 4-5 are reported, with p-values for between group comparisons.

Table 2

Comparison between baseline clinical, motor and functional performances of patients subdivided according to the H&Y stage

Variable	H&Y 3	H&Y 4-5	p value	Adjusted p value
Total UPDRS	45.6±11.7	61.2±12.7	<0.0001	<0.0001
UPDRS III	21.2±5.8	28.8±6.3	<0.0001	<0.0001
UPDRS II	16.8±5.2	23.7±5.5	<0.0001	<0.0001
UPDRS IV	4.6±3.5	4.5±3.4	0.77	0.84
6MWT	289.3±110.7	125.0±97.6	<0.0001	<0.0001
BBS	43.5±8.2	25.0±14.3	<0.0001	<0.0001
TUG	16.3±14.9	32.0±31.0	<0.0001	<0.0001
PDDS	74.0±15.9	91.7±13.8	<0.0001	<0.0001

H&Y, Hoehn & Yahr scale; UPDRS, Unified Parkinson’s Disease Rating Scale; 6MWT, Six Minute Walk Test; BBS, Berg Balance Scale; TUG, Timed Up and Go Test; PDDS, Parkinson’s Disease Disability Scale.

As expected, all outcomes at baseline, except UPDRS IV, significantly worsened passing from H&Y stage 3 to H&Y stage 4-5 (p≤0.002 all, after Benjamini-Hochberg adjustment).

Table 3 reports the scores in the outcome measures concerning the effect of MIRT (values at discharge vs values at admission).

Table 3

Differences of outcome variables (value at discharge – value at admission) in the groups of patients subdivided according to the H&Y stage and comparison between groups of the delta improvement (value after MIRT–value at baseline) for all clinical, motor and functional outcomes

Variable	H&Y 3	p value H&Y 3 (T0 vs T1)	H&Y 4-5	p value H&Y 4-5 (T0 vs T1)	p value delta H&Y 3 vs delta H&Y 4-5	Adjusted p value
delta - Total UPDRS	–14.0±5.4	<0.0001	–13.3±5.5	<0.0001	0.169	0.296
delta-UPDRS III	–6.2±2.8	<0.0001	–6.1±3.0	<0.0001	0.524	0.612
delta-6MWT	66.2±66.8	<0.0001	61.8±67.2	<0.0001	0.291	0.408
delta-BBS	7.6±5.4	<0.0001	11.8±8.3	<0.0001	<0.0001	<0.0001
delta-TUG	–5.6±12.0	<0.0001	–11.5±21.1	<0.0001	<0.0001	<0.0001
delta-PDDS	–16.0±8.3	<0.0001	–15.9±7.9	<0.0001	0.843	0.843

T0, before MIRT; T1, after MIRT; UPDRS, Unified Parkinson’s Disease Rating Scale; delta, delta of improvement; UPDRS, Unified Parkinson’s Disease Rating Scale; 6MWT, Six Minute Walk Test; BBS, Berg Balance Scale; TUG, Timed Up and Go Test; PDDS, Parkinson’s Disease Disability Scale; H&Y, Hoehn & Yahr scale.

Specifically, after rehabilitation all outcome variables improved significantly in both groups of patients (p < 0.0001 all).

Comparing the amount of improvement in the two groups, significant differences were observed only for the changes in BBS and TUG (both p < 0.0001 after adjustment), with a better improvement in the H&Y stage 4-5 group.

MMSE score progressively decreases with the disease progression and with the advancement from H&Y stage 3 to H&Y stage 4-5. Among patients in H&Y stage 3, 51.5% had normal global cognition, 41,5% showed mild cognitive impairment and only 7% were affected by dementia. Conversely, among patients in H&Y stage 4, 28.6% were affected by dementia, 42.8% showed mild cognitive impairment, and only 28.6% had preserved global cognition. Finally, we found that all patients in H&Y stage 5 were globally impaired in cognitive functions.

Data from FAB scores evidence that 54.3% of patients in H&Y stage 3 were affected by a dysexecutive syndrome, and that this percentage increased just a little in patients in H&Y stage 4-5, reaching 61.7% of them.

In patients with pathological FAB, the MMSE score ranges from 12.24 to 30; in patients with pathological MMSE, the FAB score ranges from 0 to 12.3.

Finally, modeling the improvement in BBS and TUG as a function of H&Y stage, age, sex, levodopa-equivalent dosage, MMSE and FAB, H&Y stage was the only significant independent predictor.

DISCUSSION

The advanced stages of PD still represent a challenge for clinicians. This study shows that patients in H&Y stages 3-4-5, undergoing a multidisciplinary, aerobic, goal-based, intensive and motor-cognitive rehabilitation treatment can improve their motor-functional performances.

In our population, the age progressively increased passing from lower to higher H&Y stages, as well as the motor-functional performances, assessed with UPDRS, BBS, TUG, 6MWT and PDDS, got worse passing from H&Y stage 3 to more advanced disease stages, as expected. Patients’ global cognitive status, evaluated with the MMSE, worsened with the disease progression, while a different trend was observed with respect to executive functions, assessed by using FAB. Specifically, while we found patients with a dysexecutive syndrome but no evidence of dementia, we did not find demented subjects with preserved executive functions. These findings confirm that the dysexecutive syndrome is the main cognitive dysfunction in PD [23] and that higher age and more advanced disease are the most relevant factors related to the development of dementia in Parkinsonian patients [24].

We found that all patients gained benefits from rehabilitation and improved their performances after the treatment, regardless of their baseline H&Y stage. The level of improvement was the same between groups for all the outcomes variables, except for TUG and BBS scores.

It is interesting to note that PD patients in H&Y stage 3 showed pathological BBS and TUG scores at admission but reached normal performances at the end of treatment. Indeed, the 13% of patients in H&Y stage 3 reached the maximum BBS score at the end of treatment. In patients in H&Y stage 4-5 the improvement in BBS and TUG was higher than the Minimal Detectable Change [25] and its amount was greater in comparison to that observed in patients in H&Y stage 3. We hypothesize that, for BBS, this finding might be partially explained by the ceiling effect. BBS was adopted for the assessment of balance, while TUG was used for the evaluation of the executive component of action, including gait and balance control [26]. Being the postural instability one of the main indexes of disease severity that marks the transition from early-medium to advanced disease stages, these results appear to be even more remarkable. Despite the fact that motor and clinical conditions worsened passing from lower to higher H&Y stages, the total amount of dopaminergic drugs did not differ between groups: this is likely due to the inconsistent and limited effectiveness of DRT in advanced stages of disease [7], as well as to its negative effect on cognitive aspects [7]. This issue is worthy of further considerations: along time, the DRT leads to the onset of motor fluctuations (‘wearing off’, ‘on-off phenomenon’) and motor complications (dyskinesia) [27]. Further, DRT is one of the main factors contributing to the development and to the worsening of cognitive deficits, behavioral disorders and psychotic symptoms in advanced PD [7]. Clinicians have to address the occurrence of these side effects by reducing the total amount of dopaminergic medications. This fact could explain why DRT did not differ between the different stages of H&Y.

Data from this study suggest that an intensive, motor-cognitive rehabilitative approach based on explicit and implicit learning strategies, such as MIRT [13 , 28], is effective for PD patients regardless of the disease severity and the amount of dopaminergic drugs. We observed similar results in a previous study [28], in which we compared the rehabilitative outcomes in different groups of Parkinsonian patients (undergoing MIRT) subdivided on the basis of the cognitive status (assessed by using the MMSE and FAB scores). By evaluating patients’ motor-functional performances, we found that all subjects gained benefits from MIRT and that the level of improvement in most of the outcome measures was comparable among groups [28]. In the study presented here and in the previous one [28], the H&Y stage and the cognitive status affected the patients’ clinical, motor and functional performances. Nevertheless, neither the H&Y stage nor the cognitive status affected the percentage of improvement after MIRT.

This means that, even though patients’ performances are influenced by motor problems and by cognitive status, none of these aspects impacts negatively on the rehabilitation outcome.

It is arguable that an intensive and goal-based rehabilitation approach, such as MIRT, entailing constant and repetitive exercises might promote motor learning. Indeed, within MIRT, different implicit and explicit strategies, aimed at bypassing the dysfunctional basal ganglia-supplementary motor area circuit, are adopted: i) explicit verbal and non-verbal strategies to overcome the motor programming deficits, ii) cues and feedback to maintain attention toward a specific goal, iii) instructions to maintain attention between movements (e.g walking) and concurrent cognitive tasks during the dual-task training, iv) feedback in order to improve different motor aspects, such as balance or coordination, and v) incremental stimulus-response associations.

Moreover, it is conceivable that other factors are involved in the mechanism of motor learning: the treadmill, by providing adequate sensory inputs, could stimulate the spinal locomotor circuitry and promote a sort of implicit “motor learning” in the spinal motor-generating circuitry [29].

Study limitations

This study has some limitations that need to be acknowledged. This is a retrospective study analysing a database prospectively collected. The lack of a prospective randomised controlled trial design might constitute a potential limitation. However, the efficacy of MIRT has been demonstrated on early PD in previous randomized controlled studies [13, 14], and these data clearly show that the same treatment is effective also for Parkinsonian patients in more advanced stages of disease. No follow-up data about motor-functional measures were collected and we cannot say how long the improvements we found last for.

Finally, in this study we did not evaluate the effect of other, non goal-based or non-intensive rehabilitation protocols different from MIRT in another group of advanced Parkinsonian patients.

Conclusion

We have found that a multidisciplinary, motor-cognitive, intensive and goal-based rehabilitation treatment is effective in PD patients in advanced stages of disease. Patients gained benefits from the rehabilitative treatment in clinical, motor and functional performances. Data from this study are important in the context of rehabilitative care for PD: indeed, these findings open a perspective for the treatment of those Parkinsonian patients in advanced stages of disease, suffering from disturbances which are poor responsive or unresponsive to pharmacological therapies and surgical treatments.

CONFLICT OF INTEREST

PO, DF, RB, LS, RM and GF declare no disclosures or conflict of interest.

NG serves as consultant to Teva-Lundbeck, Intec Pharma, NeuroDerm, Arsmon Neuromedical Ltd∖Dexel, Monfort and Lysosomal Therapeutic Inc. He received payment for lectures at Teva-Lundbeck, Novartis, UCB, Abviee, Shaier and Genzyme. Prof. Giladi received research support from the Michael J Fox Foundation, the National Parkinson Foundation, the European Union 7th Framework Program and the Israel Science Foundation as well as from Teva NNE program, LTI, and Abviee and CHDI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the Journal of Parkinson’s Disease policies on sharing data and materials, as detailed online in the guide for authors.

All authors declare that there is no conflict of interest regarding this work. All authors have approved the final article.

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Effectiveness of a Goal-Based Intensive Rehabilitation in Parkinsonian Patients in Advanced Stages of Disease

Abstract

Background:

Objective:

Methods:

Results:

Conclusions:

Keywords

INTRODUCTION

MATERIALS AND METHODS

Participants

Rehabilitation treatment

Outcome measures and neuropsychological assessment

Statistical analysis

RESULTS

DISCUSSION

Study limitations

Conclusion

CONFLICT OF INTEREST

References