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

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

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.

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.

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).

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].

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.