Artigo cientifico neuromuscular fisioterapia
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Artigo cientifico neuromuscular fisioterapia

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The effectiveness of Robot-Assisted Gait
Training versus conventional therapy on
mobility in severely disabled progressIve
MultiplE sclerosis patients (RAGTIME): study
protocol for a randomized controlled trial
Sofia Straudi1, Fabio Manfredini1,2* , Nicola Lamberti2, Paolo Zamboni3, Francesco Bernardi4, Giovanna Marchetti2,
Paolo Pinton5, Massimo Bonora5, Paola Secchiero6, Veronica Tisato6, Stefano Volpato7 and Nino Basaglia1

Abstract

Background: Gait and mobility impairments affect the quality of life (QoL) of patients with progressive multiple
sclerosis (MS). Robot-assisted gait training (RAGT) is an effective rehabilitative treatment but evidence of its superiority
compared to other options is lacking. Furthermore, the response to rehabilitation is multidimensional, person-specific
and possibly involves functional reorganization processes. The aims of this study are: (1) to test the effectiveness on
gait speed, mobility, balance, fatigue and QoL of RAGT compared to conventional therapy (CT) in progressive MS and
(2) to explore changes of clinical and circulating biomarkers of neural plasticity.

Methods: This will be a parallel-group, randomized controlled trial design with the assessor blinded to the group allocation
of participants. Ninety-eight (49 per arm) progressive MS patients (EDSS scale 6–7) will be randomly assigned to receive
twelve 2-h training sessions over a 4-week period (three sessions/week) of either: (1) RAGT intervention on a robotic-driven
gait orthosis (Lokomat, Hocoma, Switzerland). The training parameters (torque of the knee and hip drives, treadmill speed,
body weight support) are set during the first session and progressively adjusted during training progression or (2) individual
conventional physiotherapy focusing on over-ground walking training performed with the habitual walking device. The
same assessors will perform outcome measurements at four time points: baseline (before the first intervention session);
intermediate (after six training sessions); end of treatment (after the completion of 12 sessions); and follow-up (after
3 months from the end of the training program). The primary outcome is gait speed, assessed by the Timed 25-Foot
Walk Test. We will also assess walking endurance, balance, depression, fatigue and QoL as well as instrumental
laboratory markers (muscle metabolism, cerebral venous hemodynamics, cortical activation) and circulating
laboratory markers (rare circulating cell populations pro and anti-inflammatory cytokines/chemokines, growth
factors, neurotrophic factors, coagulation factors, other plasma proteins suggested by transcriptomic analysis and
metabolic parameters).

Discussion: The RAGT training is expected to improve mobility compared to the active control intervention in progressive
MS. Unique to this study is the analysis of various potential markers of plasticity in relation with clinical outcomes.
(Continued on next page)

* Correspondence: fabio.manfredini@unife.it
1Neuroscience and Rehabilitation Department, Ferrara University Hospital, Via
Aldo Moro 8, 44124 Ferrara, Italy
2Department of Biomedical and Specialty Surgical Sciences, University of
Ferrara, Ferrara, Italy
Full list of author information is available at the end of the article

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Straudi et al. Trials (2017) 18:88
DOI 10.1186/s13063-017-1838-2

(Continued from previous page)

Trial registration: ClinicalTrials.gov, identifier: NCT02421731. Registered on 19 January 2015 (retrospectively registered).

Keywords: Robot-assisted gait training, Progressive multiple sclerosis, Mobility, Motor recovery, Biological markers,
Rehabilitation, Plasticity

Background
Multiple sclerosis (MS) is a chronic inflammatory
disease causing widespread degeneration of the central
nervous system. The disease, with different features and
progression according to the clinical phenotype [1],
gradually results in severe neurological deficits [2] with
complex, variable and unpredictable patterns of
symptoms [2] including different motor deficits [1].
Locomotor disability and balance disorders affect
approximately 75% of persons with MS, with altered co-
ordination of posture and gait [3, 4], mobility problems
[5, 6], reduced walking competency [3] and increased
risk of falling [7]. In progressive MS, the high prevalence
of motor disorders and gait disabilities, the negative im-
pact on personal activities and quality of life (QoL), and
the limited effects of specific medications [8] make gait
rehabilitation a crucial part of the management. The aim
is to increase patients’ levels of activity and independ-
ence [9] and their QoL, even independent of symptom
regression [10, 11]. Gait disabilities showed improve-
ment following physical therapy [4, 12–14] and low-to-
moderate-intensity aerobic over-ground or treadmill
training, which represents a useful option for rehabi-
litation, also in combination with body weight support
[15–17]. To this end, a robot-driven gait orthosis was re-
cently developed, studied and considered a feasible and
effective therapeutic option in MS subjects with severe
walking disabilities. Robot-assisted gait training (RAGT)
allows a more effective support of walking movements
and imitation of a nearly normal gait pattern during
treadmill training at a higher speed, with improvements
in walking distance, velocity and knee extensor strength
compared to conventional therapy [18, 19]. Several
studies have tested in samples of MS patients the effects of
interventions, such as treadmill training [4], bodyweight-
supported training on a treadmill [20, 21], RAGT [18, 19,
22–26], or both treatments combined within a single
session [27], reporting small but positive effects on func-
tional status [4, 18–20, 23–26] or QoL [10, 21]. Recently,
improvements were reported in the 6-min Walking Test
and in the balance domain after RAGT [25] but not in gait
speed measured by the 10-m Walk Test [26]. Unfortunately
these studies, using different devices and training protocols
(12 to 15 sessions over 3–6 weeks), including heteroge-
neous MS subgroups with a limited number of subjects
and a wide range of gait disabilities (Expanded Disability

Status Scale, EDSS 3–7.5), failed to offer an exhaustive evi-
dence of the superiority of RAGT over other specific gait
trainings, so larger trials are necessary [28]. Otherwise, this
might be partially explained by the fact that the rehabilita-
tion process in MS subjects is complex and person-specific
[28] as the response to treatments regarding neuronal plas-
ticity is highly individual. Functional recovery in MS is
achieved by repair of damage through remyelination, with
resolution of inflammation and functional reorganization.
Evidence from brain systems supports an adaptive role for
neuroplastic changes in MS despite its widespread path-
ology. Specifically, it may limit the negative effects of MS
on behavior [29–32] and differs between patients and
various disease types, with lower response according to pa-
tient age and disease duration [33, 34]. Moreover, different
rehabilitation treatments might switch on different adaptive
response. High-intensity interventions might be more ef-
fective on neural reorganization and motor recovery involv-
ing synaptic transmission and formation of