[1] 34w A c c e p t e d M a n u s c r i p t Effectiveness of robotics in improving upper extremity functions among people with neurological dysfunction: A Systematic Review

[1] 211w Purpose: the primary focus of this review was to find out the effectiveness of robotics in improving upper extremity functions among people with neurological problems in the arena of physical rehabilitation. Material and Methods: Two reviewers independently scrutinized the included studies. The selected studies underwent quality assessment by PEDro scale. Randomized Controlled Trial (RCT) having a score of 4 or more were included in the review. A search was conducted in PUBMED, MEDLINE, CINAHL, EMBASE, PROQUEST, science direct, Cochrane Library, Physiotherapy Evidence Database (PEDro) and Google Scholar. Results: A total of 202 studies were identified. After removal of duplication, inclusion and exclusion criteria's n = 23 studies were included in the review process. For analysis, only the primary outcome measures of the studies were taken into account. Studies finally included in analysis were n= 21. The included studies were 19 in stroke, 1 in cerebral palsy (CP), and 1 study in multiple sclerosis (MS). No RCTs were reportedly found in spinal cord injury, Parkinson and motor neuron disease. Conclusion: Studies related to stroke showed a clear definiteness in the improvement of upper extremity functions. Whereas on the contrary there still remains a need for quality trials in cerebral palsy, multiple sclerosis to establish the efficacy of robotics in upper extremity rehabilitation.

[1] 59w Neurological disorders have been greatly underestimated worldwide. The study on global burden of disease (GBD) a collaborative endeavour by World Health Organization (WHO), the World Bank and Harvard School of Public Health found that previous studies have underestimated the current burden of neurological problems by the use of traditional statistical estimates on mortality but not on disability rates (1).

[2] 65w In a report published by World Health Organisation (WHO) neurological disorders contribute most to the global burden of disease in the European region (11.2%) and the Western pacific region (10%) (1). Among neurological disorders, more than half of the burden is contributed by cerebrovascular disease alone (1). It is predicted that almost 1 person approximately every 40 seconds suffers from stroke in United States (2).

[3] 107w In the recent years, the researches in robotic, under the arena of rehabilitation has resounded, paving its way as a therapeutic intervention. Robotic rehabilitation has the advantage of high volume and intensity of training, increasing the interface of therapist and individual contact time making it useful in motor disorders caused by stroke or spinal cord disease (3). Robotic rehabilitation is an assuring tool that mechanizes concentrated efforts for rehabilitation and is also useful in various other neurological disorders or dysfunctions. Furthermore, it is assumed that intervention with robotics allows normal kinematic and kinetic of movement in the diseases process which allows the person to progress significantly (4).

[4] 158w On the contrary, under the contemporary circumstances there is a disparity in findings of the current researches in rehabilitation which addresses the use of robotics for evolving the person's functional levels. A recent systematic review in stroke did not report any reduction in muscle tone or daily living activities of the population (5). Similarly, in many other Stroke is the second leading cause of death worldwide (6). Stroke usually unequivocally affects the younger age as well as aged groups in developed countries (7). Stroke has an enormous impact on a person causing physical, cognitive impairments and long term disabilities (8). International classification of Functioning, Disability and Health (ICF) recognizes a conceptual framework for stroke which encapsulates participation and activity limitation experienced by a person afflicted from stroke usually come across obstacles in his or her unique environment (9). Furthermore, the framework focuses on context specific rehabilitation interventions which might be essential in early recovery of the person (9).

[5] 73w Cerebral palsy (CP) on the contrary is the most common developmental disorder accompanying permanent motor impairments and disabilities (10). ICF model prepared by the World Health organization (WHO) also divides the latter into body structure and function (11). However, the framework emphasizes on improvement of quality of life, the specific goals child wants to achieve in a specific environment and the environmental barriers should be recognized and minimized during the rehabilitation process (11).

[6] 199w It is observed that improving hand functions in Spinal Cord Injury (SCI) is greatly linked with improvement in the quality of life of the person (12). Incomplete tetraplegia is the highest reported neurologic grouping next to spinal cord injury (12). Neurological diseases like multiple sclerosis (MS) is categorized by irregular inflammation, gliosis and demyelination within the central nervous system (13). It is estimated to be the third frequent cause of neurological disability in adults between 18 and 50 years of age (14). ICF is an A c c e p t e d M a n u s c r i p t important tool, because it not only evaluates the functions of the body, but also activities of daily living and the involved environmental factors (15). Some investigators have used qualifiers for body functions, activities and participation like "slight", "moderate", "serious" and "complete disability or restrictions". In case of the environmental factors the qualifiers utilized were "facilitator" or "barrier" (15). Whereas Parkinson's disease (PD) is an idiopathic neurodegenerative disorder due to a progressive loss of dopaminergic neurons in the substantia nigra (16). Motor neuron disease (MND) usually affects the upper motor neuron, lower motor neuron or both. (17).

[7] 40w Rehabilitation robotics is the evolving arena of physical rehabilitation. As impact of neurological problems is increasing, it is not only important to promote the usage of robotic rehabilitation as an intensive therapy program but also as a management strategy (17).

[8] 71w Currently various robots are available that may incorporate games, mirror and weight support components to improve the kinetics and kinematics of the effected upper extremities. One befitting advantage is that robotics allows the patient to train independently to improve their functional levels (17,18). Moreover, in the present scenario where due to increased global neurological burden and limited availability of resources usually interventions of high intensity and longer sessions are hindered (1,17).

[9] 76w There are various commercially available designs of robots, available to perform arm therapy like the MIT-MANUS, the ARM Guide (Assisted Rehabilitation and Measurement guide), the MIME (Mirror-Image Motion Enabler) and the Bi-Manu-Track (18). In the past various studies, have utilized the different kind of robots to perform the therapy sessions in various neurological conditions, still a systematic review analysing the cumulative effect of robotics in rehabilitation of various neurological randomized controlled trials seems to be lacking.

[1] 74w Only the study by Volpe et al 2000 (37), examined the effects of robotic intervention in acute stroke and the authors reported considerable enhancement of recovery in this stage. In a study by Fazekas et al 2007 (38), which examined the effect of robotic intervention stated that robotic intervention may be supplemental to the traditional form of physical therapy, but, however the duration of stroke in the population of study wasn't clear (Table 1).

[2] 18w A c c e p t e d M a n u s c r i p t

[3] 39w Only study by Gilliaux et al 2015 (39) examined the effect of robotic intervention in moderate to severe condition of CP, found that the robotic intervention is effective for upper limb management in children with cerebral palsy (Table 1).

[4] 51w In a study by Feys et al 2015 (40), which examined the effect of robotic intervention in moderate to severe condition of MS. The author reported no added benefit from the robotic intervention but however reported that patient group in the intervention groups had a better execution of movement (Table 1).

[5] 60w Though safety measures were taken in most of the studies, still only few studies actually mentioned how they measured the adverse consequences of the interventions during the trial (table 2). In the studies of stroke by following authors Sarah et al 2009 A c c e p t e d M a n u s c r i p t

[6] 90w Adherence is the recent recommendation to be used in the clinical trial. Adherence is defined as an attendance to the prescribed number of sessions and compliance with the prescribed intensity, frequency and duration of the prescribed intervention (20,42). In the present review, we did not find any trial selectively reporting the adherence and compliance levels of their trail in a methodological way. Usually if the therapies are not adhered in a systematic fashion, the optimum dose is not reached and as a result they fail to produce any effect (20).

[1] 39w Summarizing, the systematic review one can say that the evidence for robotic interventions in neurological dysfunction has improved, although the study quality seems to be diverse. Overall quality of studies included in stroke were excellent. Though some studies 3).

[2] 184w During robotic therapy sessions, it is advisable to gauge the oxygen cost for each movement or repetition. Moreover, recent researches have reported that the peak oxygen uptake (VO2peak) is roughly 50% lower compared to normative values of healthy adults 30 days' post-stroke (43). Despite rigorous, inpatient rehabilitation, the aerobic capacity of the affected population remains below the endorsed levels (43). The rapid deterioration of fitness not only predisposes to secondary medical complications, but also restricts the degree to which individuals can participate in rehabilitation programs, compromising the capacity of the individual to perform functional activities independently (43). This will give us an insight into the effectiveness of the training sessions (VO2 peak). It is important to understand that A c c e p t e d M a n u s c r i p t an increased oxygen cost of movement in stroke or other neurological dysfunctions during robotic rehabilitation may contribute to a sedentary life style thereby increasing the risk of depression and recurrence of events. Hence, it is essential to assess, monitor, and improve cardiovascular fitness early following any neurological problems.

[3] 94w There is a need to establish a position statements or a common consensus in the expanse In the study on cerebral palsy with robotic intervention, even though the sample size was sufficient to show significant results, it was too small to stipulate the results for a clinical scenario. Simple measure of stratification was not undertaken to prevent bias thereby making it of low value from methodological point of view. The study lacked the logic of using the duration and frequency of therapy sessions. Moreover, there was no adequate follow-up to confirm the long-term gains.

[4] 44w Studies on MS were also limited because of the small sample size used. Moreover, it is advisable using outcome measures that are specifically designed to address variations in the quality of movement in MS, although improvement of quality of movement doesn't necessarily reflect neuroplasticity.

[5] 126w One way of understanding the personal and social context of individuals suffering from neurological dysfunctions is to use quality of life measures (QoL) (44). One simple way to enhance the implication of QoL in clinical practice is to ensure that treatment and evaluations focus on the patient rather than the disease. QoL measure which form an integral part of A c c e p t e d M a n u s c r i p t treatment planning and evaluation have higher probability to impact clinical decision making (44). In the present review, only study by Kutner et al (2010) (32) addressed this important measure. Moreover, there is a need of integration of the measure in the aspects of treatment to optimize the individuals QOL.

[6] 98w There is an ardent need to measure the neuroplasticity in neuro-rehabilitative procedures using the modern technology like functional magnetic resonance imaging, positron-emission tomography (PET) and there is a believe it may enhance cognitive rehabilitation training by neuroimaging examinations (45). Moreover, advanced imaging technologies, has helped the medical fraternity to analyse the underlying disease process allowing an innovative extrapolation that cannot be essentially made through the standard approaches examining the neurological dysfunction or disease. Hence this neuroimaging data may provide the therapist with valuable inputs to identify the underlying mechanisms for dysfunction and thereby facilitate focussed therapeutic measures (46).

[7] 222w Studies in stroke measured cost effectiveness. Study by McCabe et al (28) compared cost effectiveness of robotics with other therapies. Authors calculated the annual salary of the therapist to be approximately USD 98,000, the cost of robot to be USD 89,000 with a life of 5-year and an additional maintenance (USD 8000). Authors further employed the details like number of visits, duration of sessions for use of each piece of equipment and motor learning (ML) alone; and a ratio of 1:3, therapist to patient interface. Which yielded following expenses, ML alone costed USD 4570, and robotics plus ML costed USD 5686. ML alone was less expensive than the robotics plus ML by USD 1116. Another study by Hesse et al (47) and Valles et al (41) used similar methods to calculate the cost of robotic treatment (USD 18,024) as compared to the traditional (Annual salary USD 19,612). Authors A c c e p t e d M a n u s c r i p t concluded that when treatment time was matched the robot gym would allow six times more patients to be seen than the therapist based care implying an efficiency in meeting up the demand for clinical scenario in stroke. In addition, Lo et al (29) also found that the robotic therapy was more economical than the intensive therapy.

[8] 40w Most imperative entity to be noted down is that in the study authors did not report any significant differences across their robotic and standard care groups, which were equivalent in terms of clinically noteworthy improvement (41, 28, 29, and 47).

[1] 73w In this systematic review, most of the included studies related to stroke, cerebral palsy and spinal cord injury showed improvement in upper extremity related functions. Studies related to stroke showed a clear definiteness in the improvement of upper extremity functions. On the contrary there still remains a need of quality trials in cerebral palsy, multiple sclerosis to establish the efficacy of robotics in upper extremity rehabilitation, as the results were ambiguous in interpretation.

[2] 646w We did not find any RCT under the condition of SCI, MND and Parkinson's, and there remains a research gap for trails to explore and address the decline in upper extremity functions. Further research with high methodological quality needs to be conducted in order to establish evidence-based clinical recommendations for individuals with neurological dysfunction. Moreover, future research should acknowledge the retention of gains after robotic intervention by a follow-up study in the aforementioned conditions. Chronic stroke MIME System 8 weeks and 6 months follow up 3 sessions / week 1.FM of motor impairment, 2.FIM instrument, and biomechani cal measures of strength and reaching kinematics None Compared with conventional treatment, robot assisted movements had advantages in terms of clinical and biomechanical measures Integration of robotic manipulation into current practice holds the promise of improving the quality of physical rehabilitation, alleviating its labour-intensive aspects, and increasing the efficiency of therapists Espina etal (2016) [31] 17 Subacute stroke Robot Amadeus Tyromotion, 8-9 weeks 5 sessions / week 1.Fugl-Meyer and the 2. Motricity Index [MI]. None Robotic intervention in subacute stage leads to significant Due to insufficient sample size the results cannot be generalized A c c e p t e d M a n u s c r i p t improvements in hand motor dexterity in terms of efficacy of treatment in the population Kahn et al (2006) [25] 19 Chronic stroke Assisted Rehabilitati on and Measureme nt (ARM) Guide 8 weeks 3 sessions /week 1.Range and speed of supported arm movement, range, straightness and smoothness of unsupported reaching, and the 2. Rancho Los Amigos Functional Test of Upper Extremity Function [RLAFT] None The robotic assistance incorporated here did not provide any detectable benefits beyond the unassisted movement exercise The interpretation of this result is limited by sample size. Moreover, the interactions with robotic devices may be designed for the patients with specific types of stroke and at specific stages of recovery to amplify the effects seen Daly et al (2005) [26] 12 chronic stroke InMotion 2 Shoulder-Elbow Robot 12 week and 6 months follow-up 5 sessions /week 1.Arm Motor Ability Test [AMAT] Motor learni ng Population with chronic stroke having moderate-tosevere impairments and functional deficits, can improve function in response to treatment using combined Motor Learning and Robotics The reported results should be interpreted with caution because the sample size was small. Moreover, the author suggest that treatment should be individually tailored for each person to optimize gains. Kutner et al (2010) [32] 17 Subacute and chronic Hand Mentor robotic system 3 weeks NS 1.Stroke Impact Scale[SIS] therap ist superv ised repetit ive task practic e (RTP) Robotic-assisted therapy may be an effective alternative or adjunct to the delivery of intensive task practice interventions to enhance hand function recovery in patients with stroke Outcomes of 30 hours of RTP in the absence of robotic-assisted therapy remain unknown. Moreover, conclusion should be taken with caution as the sample size was small to generalise the results. Lum et al (2006) [33] 30 Subacute Mirror Image Movement Enabler (MIME) robotic device 4 weeks and 6 months follow up 3-4 sessions /week 1.Motor Part of upper-limb portion of the Fugl-Meyer, 2. Motor Status Score [MSS], 3.FIM,4. Modified Ashworth scale None The effects of robotics remain unclear. The study indicated that between the end of treatment and the 6-month follow-up, control subjects had greater gains than robot group subjects These finding motivates the development of portable devices that can be used as part of a home-based treatment plan following in clinic treatment. Moreover, A c c e p t e d M a n u s c r i p t larger samples and a need to investigate the optimal training dosage in order to maximize the effects of training *NS-Not specific A c c e p t e d M a n u s c r i p t Cerebral palsy

[3] 9w Gilliaux et al 2015 [39] Spinal cord injury --

[1] 16w The review protocol was registered with PROSPERO (CRD42016050709), and is reported in accordance with PRISMA recommendations.

[2] 9w Review methods: Two reviewers independently scrutinized the included studies.

[3] 25w The selected studies underwent quality assessment by PEDro scale. Randomized controlled trial (RCT) having a score of 4 or more were included in the review.

[4] 99w Search strategy: A search was conducted in PUBMED, MEDLINE, CINAHL, EMBASE, PROQUEST, science direct, Cochrane Library, Physiotherapy Evidence Database (PEDro) and Google Scholar. Studies published from January 1975 to November 2016 were sought. The Medical Subject Headings (MeSH) and text that were taken into account for search were "robotic assisted upper extremity training/therapy/ rehabilitation", stroke, cerebral vascular accident, cerebral vascular disorders, paresis, hemiplegia, spinal cord injury, multiple sclerosis, motor neuron disease, parkinson, randomized controlled trial, upper extremity, arm and robot or robotic rehabilitation was also used in combination with these words. References listed in relevant publications were also screened.

[5] 96w The methodological quality of the studies was evaluated with the PEDro (19) scale and scored by 2 independent reviewers (SD and JT). When no consensus between the 2 reviewers was reached, a third reviewer made the final decision. PEDro scores were classified as for Randomized controlled trials (RCTs), studies scoring 9-10 on the PEDro A c c e p t e d M a n u s c r i p t scale were considered to be of "excellent" methodologically quality, 6-8 of "good" quality, 4-5 of "fair" quality, and below 4 of "poor" quality (20,21).

[6] 50w Level 1 evidence pertains to high quality RCTs (PEDro ≥6) and has been divided into two subcategories, level 1a and level 1b, based on the number of RCTs supporting the evidence statement (20,21). Whereas as the RCTs with level 2 evidence constitutes a score less than 6 (PeDro < 6).

[7] 57w Studies having the following selection criteria were included (1) patients already diagnosed with upper limb loss of functions ( 6) effects of robot-assisted therapy for the upper limb are being investigated, alone or in combination with therapies; (7) the outcome of the included studies were in terms of motor and/or functional recovery of the upper paretic limb.

[8] 10w Studies that applied robotics rehabilitation to populations with neurological deficit.

[9] 42w Studies that had interventions with "Robotic rehabilitation" in combination with standard care, which is defined as the standard physical therapy management techniques applied to various conditions, or other therapies like electrical stimulation, functional electrical stimulation were also considered for the systematic review.

[10] 12w The standard care in physical therapy included primarily combination of other therapies

[11] 8w Studies in hospital outpatient settings, or rehabilitation centres.

[12] 18w Studies included in the review had the following measures for Stroke, 1. Change in functional independence score (FIM).

[13] 79w 2. Change in arm motor section of Fugl Meyer (FM) score. 3. Quality of life scores; for Cerebral palsy 1. Quality of Upper Extremity Skills Test (QUEST), and 2. Fugl-Meyer Assessment (FMA) upper limb; for Multiple Sclerosis 1. Motricity Index (MI) 2. Fugl Meyer (FM); for Spinal Cord Injury 1. Jebsen-Taylor Hand Function Test; for Parkinsons 1. Fugl meyer 2. Unified Parkinson's Disease Rating Scale (UPDRS); and for Motor Neuron Disease 1. Functional Independence Measure 2. Fugl Meyer Scores

[14] 18w Included studies had duration ranging from 1 week to 24 weeks or 6 months' followup were also considered.

[15] 18w A c c e p t e d M a n u s c r i p t

[16] 425w Titles and/or abstracts of studies were retrieved using the search strategy and those from additional sources were screened independently by two review authors to identify studies that potentially met the inclusion criteria outlined for the systematic review. The full text of these potentially eligible studies was retrieved and independently assessed for eligibility by two review team members. Any disagreement between them over the eligibility of particular studies were resolved through discussion with a third reviewer if required. In the current review, we had used the PEDro form to score the study quality and synthesize evidence from the same. Extracted information included: study population staging of disease or its severity; type of intervention with robots; details of the intervention and control conditions; study methodology; recruitment and study completion rates; outcomes and times of measurement; duration of treatment; frequency of treatment; primary outcome measure showing significant difference or no difference; information on co-intervention were sought; implication for clinical practice; recommendation for research; studies showing beneficial effects; studies showing adverse effects; studies that did not report any significant differences between group and suggested mechanisms of intervention action. From the systematic literature search, 202 records were finally included from all the databases. After removal of duplication and further screening of the titles and abstracts, additional 135 records were excluded. We selected only 21 relevant studies after detailed review of records and screening. (Stroke n =20, Cerebral palsy=1, MS=1, SCI, parkinson and motor neuron disease reportedly no RCTs were found). 741 individuals participated A c c e p t e d M a n u s c r i p t in its entirety among various studies with neurological dysfunction. Quality of studies was also rated (Table 3) using model provided by Sackett et al (22). Scoring of the studies included in the review were done and are depicted in table 4. Table 1). On the contrary studies by Lum et al 2002(24), Daly et al 2005(26), Ching Wu et al 2012(27) reported benefits from robotic rehabilitation in chronic stroke (Table 1). Whereas Masiero et al 2014(30), Espina et al 2015(31), Kutner et al 2010(32), Lum et al 2006(33), Hesse et al 2005(34), Takahashi et al 2016(35), Rabadi et al 2008 (36) examined the effects of robotics in subacute stroke. Masiero et al 2014 (30) and Lum et al 2006 (33) did not report any significant improvement with robotic intervention on the contrary Espina et al 2015 (31), Kutner et al 2010 (32), Hesse et al 2005 (34) reported significant improvement with robotic intervention in the same population (Table 1).

[1] 34w The objective of the present systematic review is to find out the effectiveness of robotics in rehabilitation for improving upper extremity related functions among people with neurological dysfunction in the field of physical rehabilitation.

[2] 15w Stroke, multiple sclerosis, motor neuron disease, cerebral palsy, Parkinson's, spinal cord injury, rehabilitation with robotics.

[3] 56w The studies included for the review were randomized controlled trials (RCTs). Studies were excluded from the review process in case after full text reading it was found that the studies were non-randomized controlled trial, non-robotics intervention, score of less than 4 on PeDro scale, combination of drugs with robotics to measure improvement in upper limb functions.

[4] 18w The reviewers reportedly did not find any RCT comparing the effect of robotic intervention in the affected population.