Effects of training on upper limb function after cervical spinal cord injury: a systematic review

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1 536411CRE / Clinical RehabilitationLu et al. research-article2014 Article CLINICAL REHABILITATION Effects of training on upper limb function after cervical spinal cord injury: a systematic review Clinical Rehabilitation 2015, Vol. 29(1) 3 13 The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: / cre.sagepub.com Xiao Lu 1, Camilla R Battistuzzo 2, Maryam Zoghi 2 and Mary P Galea 2 Abstract Objective: To summarize the evidence for the effectiveness of exercise training in promoting recovery of upper extremity function after cervical spinal cord injury. Data sources: Medline, Cochrane, CINAHL, EMBASE and PEDro were used to search the literature. Review methods: Two reviewers independently selected and summarized the included studies. Methodological quality of the selected articles was scored using the Downs and Black checklist. Results: A total of 16 studies were included, representing a total of 426 participants. Overall, the internal validity and reporting of the studies was fair to good, while power and external validity were poor. Interventions included exercise therapy, electrical stimulation, functional electrical stimulation, robotic training and repetitive transcranial magnetic stimulation. Most of the studies reported improvements in muscle strength, arm and hand function, activity of daily living or quality of life after intervention. Conclusions: Training including exercise therapy, electrical stimulation, functional electrical stimulation of the upper limb following cervical spinal cord injury leads to improvements in muscle strength, upper limb function and activity of daily living or quality of life. Further research is needed into the effects of repetitive transcranial magnetic stimulation and robotic training on upper limb function. Keywords Spinal cord injury, systematic review, training, upper limb Received: 24 March 2013; accepted: 27 April 2014 Introduction Over the last few decades, various interventions have evolved in an attempt to improve arm and hand function in individuals with spinal cord injury. 1 3 Loss of arm and hand function is one of the most devastating consequences of tetraplegia and it has been shown to be the priority of recovery for this population. Even a small improvement in 1 Department of Rehabilitation, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China 2 Physiotherapy Department, The University of Melbourne, Parkville, Victoria 3010, Australia Corresponding author: Xiao Lu, Department of Rehabilitation, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. luxiao1972@163.com

2 4 Clinical Rehabilitation 29(1) arm and hand function may lead to increased independence in daily activities, improving independence and quality of life. 4,5 Interventions, such as tendon transfer surgery, implanted neuroprostheses and re-training of arm and hand function, are currently used to improve upper limb function. 6,7 Among these methods, retraining is the most common as it is non-invasive and relatively inexpensive. However, studies assessing the effects of training on upper limb or hand function following cervical spinal cord injury are scarce and results are somewhat diverse. 8 Identifying the value and efficacy of these interventions can help clinicians and also future clinical trials, and there are few existing systematic reviews of this topic. Thus, the aim of this review was to summarize the evidence for the effectiveness of training aimed at promoting recovery of upper limb/hand function from clinical trials involving people with cervical spinal cord injury. Methods A systematic literature search of studies published from January 1950 to November 2013 was conducted using Medline, Web of Science, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Physiotherapy Evidence Database (PEDro) databases. In the search strategy, MeSH-terms and text words for participants (tetraplegia, quadriplegia, spinal cord injury, spinal cord lesion), interventions (exercise, strength, robotic, repetitive transcranial magnetic stimulation, electric* stimulation, task specific training, virtual reality, biofeedback) and outcomes (hand function, arm function, upper limb function, upper extremity function) were combined (Appendix I). Reference lists of all selected trials were also screened to identify additional studies. Randomized controlled trials, quasi-randomized controlled trials, crossover and controlled trials published in peer-reviewed journals were included if they compared therapy intervention to a control group in patients with complete or incomplete cervical spinal cord injury and hand function or upper limb function were an outcome measured. The following therapy interventions were included in this study: robotic training, repetitive transcranial magnetic stimulation, functional electrical stimulation, electrical stimulation, resistance training taskspecific repetitive functional training, virtual reality and biofeedback. Case studies, reviews, book chapters and letters were excluded, as well as studies using surgery, orthoses, splints, implants or drugs. All searches were limited to English language articles. Two investigators (XL and CRB) independently evaluated the title and abstract of indentified studies according to selection criteria. Thereafter, the full-text articles of all eligible studies were obtained and evaluated for in/exclusion by the two investigators. In case of disagreement, consensus was reached by discussion between all the authors. The following data were extracted from each included study: (1) patient characteristics (group, number of participants, time since injury, American Spinal Injury Association (ASIA) grade, level of injury, age); (2) intervention(s) implemented in the study (type of therapy, intensity, duration and frequency); (3) outcome measures (strength, hand or arm function, activities of daily living and quality of life); and (4) conclusions. For studies that included paraplegic and tetraplegic patients, only data about tetraplegic participants were extracted. A 27-item checklist developed by Downs and Black was used to assess the methodological quality of included studies. This checklist contains items for reporting (10 items), external validity (three items), internal validity (bias and confounding 13 items) and power (one items). Answers are scored 0 or 1, except for one single item on power, which was scored 0 to 5. The total maximum score was therefore Agreement between investigators on inclusion of studies was assessed using the Kappa statistic and percentage agreement (SPSS software version 17.0, Chicago, Illinois, USA). Findings were summarized using descriptive statistics. Results A total of 15 eligible studies were identified after searching the databases. After full text screening, one article was excluded because no intervention

3 Lu et al. 5 Figure 1. Flowchart of screened, excluded and analyzed articles. was provided and two further articles were added after checking the references of relevant publications, resulting in 16 studies being included in this systematic review (Figure 1). A 99% (Kappa 0.73) inter-rater agreement was found for the study selection. Out of 16 included studies, 13 (81%) were randomized controlled trials, two (12%) were cohort studies and one (6%) was a cross-over study. The results of quality assessment of these studies are listed in Table 1. Overall, scores for reporting and internal validity, which includes bias and confounding, were good, however the scores for external validity and power were poor. Five studies included blinded outcome measures (Table 1). The sizes of the experimental and control groups were comparable in the selected studies ranging from five to 32 participants in each group There was a wide range of time between injury of participants included (2.5 weeks to 28.5 years). The ASIA classification ranging from grades A to D (Table 2).

4 6 Clinical Rehabilitation 29(1) Table 1. Methodological quality assessment of included studies. Reporting (10 items) 8 (2) External validity (3 items) 2 (2) Bias (7 items) 6 (1) Confounding (6 items) 3 (3) Power (1 item) 0 (1) Number of studies median (quartile range) In terms of the type of therapy investigated, the effects of aerobic ergometry, resistance training, massed practice training, task-oriented training, somatosensory stimulation, electrical stimulation and functional electrical stimulation were studied in 14 studies The two most recent published studies focused on the effect of more advanced technology, such as robotic training and repetitive transcranial magnetic stimulation. The length of the training programs ranged from two weeks to nine months, with the majority (56%) lasting between 6 8 weeks (Table 3). Six studies focused on the effect of exercise therapy 10 12,15,16,23 (Table 4). The overall results of exercise therapy on muscle strength and upper limb/ hand function seemed positive. Three studies 12,15,23 observed the impact of exercise therapy on activities of daily living or quality of life. Only one study 15 assessed quality of life and reported positive results. A positive change in activities of daily living measured by the Quadriplegia Index of Function and the Functional Independence Measure was reported by one study, 23 whereas no change was observed in activities of daily living when assessed using the Canadian Occupational Performance Measure. 12 Four studies investigating the effect of electrical stimulation 13,14,18,20 focused on the change in upper limb muscle strength. Most studies 13,14,18 measured change in wrist extensor strength and showed significant improvement after electrical stimulation (ES) therapy. None of these four studies reported changes in upper limb function and only one study 18 evaluated self-feeding abilities, but showed no positive results (Table 4). All four studies investigating functional electrical stimulation 17,19,21,22 showed positive results on upper limb function. Among them two studies 17,21 showed that compared with conventional therapy alone, conventional therapy combined with functional electrical stimulation was more effective in improving upper limb function, while one study 22 showed no extra benefit. One of the four studies 19 showed a significant increase in grasp force after functional electrical stimulation combined with exercise therapy, but there was no improvement of pinch force. A combination of functional electrical stimulation and conventional therapy resulted in significant improvement in activities of daily living 17,19,21 and the gains were maintained at six months follow-up. 17 Robotic training combined with conventional therapy had no significant effect on muscle strength and functional task performance in the patients with partial hand function. 25 Compared with sham stimulation, repetitive transcranial magnetic stimulation for five days increased upper extremity function assessed by the Action Research Arm Test, but that was not significantly different from control group 24 (Table 4). Discussion In general, the results of this systematic review demonstrate that there are a limited number of studies investigating effects of training on arm and hand function in people with cervical spinal cord injury. The studies included in this review had a wide range of functional levels of participants, training, methodology and outcome parameters. Interestingly, these studies revealed that improvement in arm and hand muscle strength and function was possible with training in both the acute and chronic phases. According to the checklist developed by Down and Black, 9 studies included in this systematic review showed fair to good results for reporting and internal validity, but external validity and power was poor. Most studies did not include a sample size calculation and the sample sizes were small, which impacted on the power of the studies. The limited sample sizes might be explained by several factors. First, cervical spinal cord injury have low incidence. Second, patients with cervical

5 Lu et al. 7 Table 2. Study and participant characteristics. Author (year) Design Groups (No.) TSI mean (SD) or range Age mean (SD) or range (years) Neurological level Kohlmeyer et al. (1996) 18 RCT Conventional ET (10), ES (10) 3.0 w (0.9), 3.2 w (0.9) 43 (18), 32 (13) C4-C6 C/I Biofeedback (13), ES+biofeedback (11) 2.8 w (0.8), 2.5 w (1.0) 38 (15), 42 (15) Needham-Shropshire et al. RCT ES-assisted AEE (12), ES-assisted 6 y, 9 y, 4 y 24, 22, 24 Cervical lesion (1997) 20 then voluntary AEE (11), Voluntary AEE (11) Hicks et al. (2003) 15 RCT ET (11), control (12) 7.7 y (6.4), 12.1 y (7.3) 36.9 (11.4), 43.2 (9.3) C4-T2, T3-S1 A-D C4-C7 T7-L2 A-D Hartkopp et al. (2003) 14 RCT ES with Hr (7), ES with Lr (5) 5 38 y, 4 27 y 29-55, C5-C6 Beekhuizen et al. (2005) 10 RCT MP (5), MP+SS (5) 58.6 m (56.1), 29.6 m (12.2) 45 (10.3),32.6 (7.9) C5-C7 ASIA C,D Popovic et al. (2006) 22 RCT COT (9), FES+COT (12) d (75.55), 48.5 d (38.16) 53.2 (13.6), 33.2 (15.6) C3-C7 C/I Glinsky et al. (2008) 12 RCT PRT (15), control (16) 12 m, 4.8 m 37 (16), 47 (20) C4-C7 ASIA A-D Beekhuizen et al.(2008) 11 RCT MP (6), SS (6) MP+SS (6), control (6) 47.5 m (52.93), m (47.35) m (97.11), m (78.84) 22-70, C4-C7 ASIA C,D 21-64, Glinsky et al. (2009) 13 RCT PRT (32), PRT+ES (32) 4 16 m, 4 16 m 38 (16), 38 (16) C4-C7 ASIA A-D Hoffman et al. (2010) 16 RCT Unilateral-MP+SS (5), Bilateral y (1.17), 4.33 y (4.05) 42 (16.9), 34.7 (15.7) C3-C6 ASIA B-D MP+SS (6) Spooren et al. (2011) 23 Cohort ToCUEST+ET in active rehabilitation 8 m (2.8) 49 (19) C5-C7 ASIA A-D (12) ToCUEST+ET in postrehabilitation 59 m (40) 46 (15) (11) ET in active rehabilitation (11) 6.5 m (2) 38 (11) Kapadia et al. (2011) 17 RCT COT (12), COT+FES (10) d (6.55), 69.9 d (14.11) 44.8 (4.7), 43.2 (5.5) C4-C7 incomplete Kowalczewski et al. (2011) 19 RCT Conventional ET (18), ReJoyce ET (18) Popovic et al. (2011) 21 RCT COT (12), FES+COT (9) d (22.70), d (31.76) Kuppuswamy et al. (2011) 24 Crossover Zariffa et al. (2012) 25 Cohort Conventional ET+ robotic (12), Conventional ET (12) 3.62 y (2.12) 35.9 (11.9) C5-C7 C/I 41.6 (17.4), 44.8 (16.3) C3-C6 ASIA B-D rtms (9), sham rtms (6) y 39.6 (5.4) C2-C8 ASIA-D m 41.5 (6.3) C4-C6 ASIA-D AEE: arm ergometry exercise; ASIA: American Spinal Injury Association Impairment Scale; C/I: complete/incomplete; COT: conventional occupational therapy; d: days; ET: exercise therapy; FES: functional electrical stimulation; Hr: high resistance; Lr: lower resistance; m: months; MP: massed practice; PRT: progressive resistance training; rtms: repetitive transcranial magnetic stimulation; SD: standard deviation; SS: somatosensory stimulation; ToCUEST: task-oriented client-centered upper extremity skilled performance training; TSI: time since injury; w: weeks; y: years; ES: electrical stimulation; RCT: randomized controlled trial.

6 8 Clinical Rehabilitation 29(1) Table 3. Training characteristics of included studies. Author (year) Training frequency/duration Type of exercise therapy Kohlmeyer et al. (1996) min/d, 5/w, 5 6 w Conventional treatment: passive ROM, strengthening of available muscles by exercise and functional training of tenodesis grasp. ES and EMG biofeedback on wrist extensor. Needham-Shropshire et al. (1997) min/d, 3/w, 8 w Voluntary arm ergometry training. Neuromuscular stimulation-assisted arm ergometry training Hicks et al. (2003) min/d, 2/w, 9 m Aerobic training (arm ergometry, 70% of HR max.) and resistance circuit training (70% 80% of 1RM) Hartkopp et al. (2003) min/d, 5/w, 12 w Electrical stimulation on Hr 30-Hz stimulation against maximum load Electrical stimulation on Lr 15-Hz stimulation against 50% maximum load Beekhuizen et al. (2005, 2008) 10, min/d, 5/w, 3 w Massed practice: continuous repetitions of tasks: gross upper extremity movement, grip, grip with rotation, pinch and pinch with rotation. Somatosensory stimulation: Median nerve stimulation at wrist Popovic et al. (2006) min/d, 5/w, 12 w Conventional occupational therapy: muscle facilitation exercises, task-specific training; strengthening and stretching exercises; electrical stimulation, ADL training. FES-assisted reaching and grasping Glinsky et al. (2008) 12 3 sets of 10RM 3/w, 8 w Progressive resistance exercise program for wrist flexors or extensors Glinsky et al. (2009) 13 6 sets of 10 repetition maximum 3/w,8 w Progressive resistance exercise program for wrist flexors or extensors Electrical stimulation Hoffman et al. (2010) min/d, 5/w, 3 w Unimanual or bimanual massed practice plus somatosensory stimulation (as per Beekhuizen et al. 2005) 10 Spooren et al. (2011) min/d, 3/w, 8 w Task-oriented client-centered upper extremity skilled performance training module Kapadia et al. (2011) min/d, 5/w, 8 w Conventional therapy: strengthening and stretching exercises and ADL practice. FES: performing ADL assisted by electrical stimulation Kowalczewski et al. (2011) min/d, 5/w, 6 w Conventional exercise therapy: 20 min strength training, 20 min accuracy training, 20 min electrical stimulation; FES-assisted exercise on the ReJoyce workstation. Popovic et al. (2011) min/d, 5/w, 8 w As per Popovic et al. (2006) Kuppuswamy, et al. (2011) min/d, 5 d, and crossover Stimulation:5Hz as 2s trains separated by 8s 80% of the active motor threshold, Zariffa et al. (2012) min/d, 3 5/w, 6 w Conventional therapy: strengthening and stretching exercises and ADL practice, robotic:armeo Spring d: day(s); FES: functional electrical stimulation; Hr: high resistance; Lr: lower resistance; m: months; min: minute(s); w: weeks; ROM: range of motion; ES: electrical stimulation; EMG: electromyography; ADL: activity of daily living; RM: repetition maximum.

7 Lu et al. 9 Table 4. Outcome parameters of included studies. Author (year) Results Strength Endurance Upper limb and hand function ADL or QoL Exercise therapy Hicks et al. (2003) 15 IE of chest, biceps, anterior deltoid pre vs. post(+) Arm ergometry performance pre vs. post(+) QoL ET vs. control(+) Beekhuizen et al. (2005) 10 Maximal pinch grip force : MP+SS(+) WMFT: MP+SS(+) JHFT: MP+SS(+), MP(+) Glinsky et al. (2008) 12 IE of wrist extensor ET vs. control(=) Beekhuizen et al. (2008) 11 Maximal pinch grip force : MP+SS(+), SS(+) Hoffman et al. (2010) 16 pinch grip strength Bi-MP+SS(=), Uni-MP+SS(=) Fatigue resistance of wrist extensor: ET vs. control(=) COPM: ET vs. contro(=) WMFT: MP+SS(+), SS(+) JHFT: MP+SS(+), MP(+), SS(+) JHFT, CAHAI: Bi-MP+SS(+), Uni-MP+SS(+) Spooren et al. (2011) 23 Van Lieshout Test: pre vs. post or pre vs. 3 month: (+), ToCUEST vs. standard(=) QIF, FIM: pre vs. post or pre vs. 3 month(+), ToCUEST vs. standard(=), COPM: pre vs. post or pre vs. 3month(+) Electrical stimulation Kohlmeyer et al. (1996) 18 Wrist extensor, deltoid and biceps: among 4 groups(=), pre vs. post(+) (4 groups together) Needham et al. (1997) 20 Triceps muscle grades ES+voluntary vs. voluntary(+) Hartkopp et al. (2003) 14 Strength of wrist extensors Hr(+), Lr(=) Glinsky et al. (2009) 13 Wrist extensor IE: Pre vs. post both(+), ES+ET vs. ET(=) Self-feeding abilities: among four groups (=). Pre vs. post(+) (four groups together) Fatigue resistance of wrist extensor: Hr(+), Lr(+) Fatigue resistance: pre vs. post both(=), ES + ET vs. ET(=) (Continued)

8 10 Clinical Rehabilitation 29(1) Table 4. (Continued) Author (year) Results Strength Endurance Upper limb and hand function ADL or QoL Functional electrical stimulation Popovic et al. (2006) 22 REL test: pre vs. post both(+) COT+FES vs. COT(=) Kapadia et al. (2011) 21 TRI-HFT: pre vs. post or pre vs. 6 month: both(+), COT+FES vs.: COT(+) Kowalczewski et al. (2011) 19 Grasp and pinch force: ReJoyce ET vs. conventional ET(=). Pre vs. post: grasp both(+), pinch both(=) ARAT, RAHFT: pre vs. post both(+) ReJoyce ET vs. conventional ET(+) Popovic et al. (2011) 21 TRI-HFT: pre vs. post both(+) COT+FES vs. COT(+) rtms and robotic Kuppuswamy, et al. (2011) 24 ARAT; pre vs. post(+), rtms vs. sham rtms(=) Zariffa et al. (2012) upper limb muscles: pre vs. post(=), robotic vs. control(=) ARAT and GRASSP; pre vs. post(=), robotic vs. control(=) FIM, SCIM: pre vs. post both(+) COT+FES vs. COT(=) FIM, SCIM: pre vs. post or pre vs. 6 month: both(+), COT+FES vs.: COT(+) FIM, SCIM: pre vs. post both(+) COT+FES vs. COT(+) ARAT: Action Research Arm Test; Bi-: bimanual; CAHAI: Chedoke Arm and Hand Activity Inventory; COPM: The Canadian Occupational Performance Measure; COT: conventional occupational therapy; ET: exercise therapy; FES: functional electrical stimulation; FIM: Functional Independence Measure; GRASSP: Graded and redefined assessment of strength, sensibility and prehension; Hr: high resistance; IE: isometric exercise; JHFT: Jebsen Hand Function Test; Lr: lower resistance; MP: massed practice; RAHFT: ReJoyce automated hand function test; REL test: Rehabilitation Engineering Laboratory Hand Function Test; rtms: repetitive transcranial magnetic stimulation; SCIM: Spinal Cord Independence Measure; SS: somatosensory stimulation; ToCUEST: task-oriented clientcentered upper extremity skilled performance training; TRI-HFT: Toronto Rehabilitation Institute Hand Function Test; Uni-: unimanual; WMFT: Wolf Motor Functional Test; ADL: activity of daily living; QoL: quality of life; QIF: quadriplegia index of function; ES:electrical stimulation. (=): no significant change; (+): significant improvement; both (+): significant improvement in both groups; both (=): no significant change in both groups.

9 Lu et al. 11 spinal cord injury have, among the total population with spinal cord injury, the most secondary complications, leading to frequent drop-outs and poorer adherence to trial training specifications. Third, these patients are difficult to match owing to the complexity of their pathology. Fourth, both in spinal cord injury and non-spinal cord injury patients, arm and hand function is a complex issue. It encompasses a wide variety of highly non-cyclic movements, which are not always easy to measure objectively, especially at the activity level. 26 Some studies in the literature indicate that early initiation of spinal cord injury-specific rehabilitation is extremely important. A delay in starting these interventions may negatively influence ultimate functional capability. 27,28 However, studies included in this review showed that training initiated in the chronic stage still resulted in improvement of muscle strength, hand function and activities of daily living or quality of life. These findings indicated that improvement in arm and hand muscle strength and function was possible with training in both the acute and chronic phases. The outcome of included studies showed that exercise therapy and functional electrical stimulation improved muscle strength, arm and hand function, activities of daily living or quality of life in patients with cervical spinal cord injury. Studies that focused on electrical stimulation showed improvements in muscle strength of upper extremity, but there were few reports about whether it could improve arm and hand function, activities of daily living or quality of life. New technological innovations, such as repetitive transcranial stimulation, robotic training and virtual reality, have been introduced in rehabilitation in recent years. But most studies were case series, with only two studies on repetitive transcranial stimulation and robotic training, which were included in this review, including a control group. 24,25 Neither of the two studies reported muscle strength improvement after training, only repetitive transcranial magnetic stimulation (rtms) showed an arm function increase after training. The negative results be owing to the small sample size. In this review, we only included English-language articles, which may cause bias owing to missing some published studies in this area in another language. Most of the studies did not include a sample size calculation. The small sample size means that the power of the studies to detect an effect, if the effect actually exists, is compromised. Therefore, conclusions drawn from these studies should be made with caution. A meta-analysis was not possible because of the variety of outcome measures. Comparison of results across studies would be improved by standardization of outcome measures. There are initiatives in the field of spinal cord injury rehabilitation to develop international standards and data sets for spinal cord injury. The Functional Independence Measure and the Spinal Cord Independence Measure are recommended in these guidelines to assess activities of daily living in patients with spinal cord injury. 29,30 Other tests, such as the Jebsen test and the Sollerman test have also been suggested in these guidelines. However, at the present time, there is a lack of consensus on what might be the most useful tests of arm and hand function after spinal cord injury. In conclusion, the results of this systematic review suggest that training of the upper limb following spinal cord injury, including exercise therapy, electrical stimulation and functional electrical stimulation, leads to improvements in muscle strength, upper limb function and activities of daily living or quality of life. Further research is needed on the use of new technology, such as repetitive transcranial stimulation in improving upper limb function. Future studies should be carefully designed to increase trial power and external validity. The routine use of a series of standardized objective tests would allow future meta-analyses of the effectiveness of exercise interventions on upper limb function from a number of smaller studies. Clinical messages Training, including exercise therapy, electrical stimulation and functional electrical stimulation, could improve arm and hand muscle strength and function after spinal cord injury. The use of standardized outcome measures of upper limb function in future clinical trials would facilitate meta-analyses on the effectiveness of training interventions on upper limb function.

10 12 Clinical Rehabilitation 29(1) Conflict of interest The authors declare that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References 1. Wyndaele M and Wyndaele JJ. Incidence, prevalence and epidemiology of spinal cord injury: what learns a worldwide literature survey? Spinal Cord 2006; 44: Nussbaum SB. Epidemiology of cervical spinal cord injury. Top Spinal Cord Inj Rehabil 2004; 9: DeVivo MJ. Epidemiology of traumatic spinal cord injury. In: Kirshblum S, Campagnolo DI and DeLisa JS (eds) Spinal cord medicine. Philadelphia, PA: Lippincott Williams & Wilkins, 2002, pp Snoek GJ, Ijzerman MJ, Hermens HJ, Maxwell D and Biering-Sorensen F. Survey of the needs of patients with spinal cord injury: impact and priority for improvement in hand function in tetraplegics. Spinal Cord 2004; 42: Ginis KA and Hicks AL. Exercise research issues in the spinal cord injured population. Exerc Sport Sci Rev 2005; 33: Murray WM, Hentz VR, Friden J and Lieber RL. Variability in surgical technique for brachioradialis tendon transfer. Evidence and implications. J Bone Joint Surg Am 2006; 88: Rupp R and Gerner HJ. Neuroprosthetics of the upper extremity clinical application in spinal cord injury and challenges for the future. Acta Neurochir Suppl 2007; 97: Kloosterman MG, Snoek GJ and Jannink MJ. Systematic review of the effects of exercise therapy on the upper extremity of patients with spinal-cord injury. Spinal Cord 2009; 47: Downs SH and Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998; 52: Beekhuizen KS and Field-Fote EC. Massed practice versus massed practice with stimulation: Effects on upper extremity function and cortical plasticity in individuals with incomplete cervical spinal cord injury. Neurorehabil Neural Repair 2005; 19: Beekhuizen KS and Field-Fote EC. Sensory stimulation augments the effects of massed practice training in persons with tetraplegia. Arch Phys Med Rehabil 2008; 89: Glinsky J, Harvey L, Korten M, Drury C, Chee S and Gandevia SC. Short-term progressive resistance exercise may not be effective at increasing wrist strength in people with tetraplegia: a randomised controlled trial. Austr J Physiother 2008; 54: Glinsky JHL, van Es P, Chee S and Gandevia SC. The addition of electrical stimulation to progressive resistance training does not enhance the wrist strength of people with tetraplegia: a randomized controlled trial. Clin Rehabil 2009; 23: Hartkopp AHS, Mizuno M, Ratkevicius A, Quistorff B, Kjaer M and Biering-Sorensen F. Effect of training on contractile and metabolic properties of wrist extensors in spinal cord-injured individuals. Muscle Nerve 2003; 27: Hicks AL, Martin KA, Ditor DS, et al. Long-term exercise training in persons with spinal cord injury: effects on strength, arm ergometry performance and psychological well-being. Spinal Cord 2003; 41: Hoffman LR and Field-Fote EC. Functional and corticomotor changes in individuals with tetraplegia following unimanual or bimanual massed practice training with somatosensory stimulation: a pilot study. J Neurol Phys Ther 2010; 34: Kapadia NM, Zivanovic V, Furlan JC, Craven BC, McGillivray C and Popovic MR. Functional electrical stimulation therapy for grasping in traumatic incomplete spinal cord injury: randomized control trial. Artif Organs 2011; 35: Kohlmeyer KM, Hill JP, Yarkony GM and Jaeger RJ. Electrical stimulation and biofeedback effect on recovery of tenodesis grasp: a controlled study. Arch Phys Med Rehabil 1996; 77: Kowalczewski J, Chong SL, Galea M and Prochazka A. In-home tele-rehabilitation improves tetraplegic hand function. Neurorehabil Neural Repair 2011; 25: Needham-Shropshire BM, Broton JG, Cameron TL and Klose KJ. Improved motor function in tetraplegics following neuromuscular stimulation-assisted arm ergometry. J Spinal Cord Med 1997; 20: Popovic MR, Kapadia N, Zivanovic V, Furlan JC, Craven BC and McGillivray C. Functional electrical stimulation therapy of voluntary grasping versus only conventional rehabilitation for patients with subacute incomplete tetraplegia: a randomized clinical trial. Neurorehabil Neural Repair 2011; 25: Popovic MR, Thrasher TA, Adams ME, Takes V, Zivanovic V and Tonack MI. Functional electrical therapy: retraining grasping in spinal cord injury. Spinal Cord 2006; 44: Spooren AI, Janssen-Potten YJ, Kerckhofs E, Bongers HM and Seelen HA. Evaluation of a task-oriented clientcentered upper extremity skilled performance training module in persons with tetraplegia. Spinal Cord 2011; 49: Kuppuswamy A, Balasubramaniam AV, Maksimovic R, et al. Action of 5 Hz repetitive transcranial magnetic stimulation on sensory, motor and autonomic function in human spinal cord injury. Clin Neurophysiol 2011; 122:

11 Lu et al Zariffa J, Kapadia N, Kramer JL, et al. Feasibility and efficacy of upper limb robotic rehabilitation in a subacute cervical spinal cord injury population. Spinal Cord 2012; 50: Spooren AI, Janssen-Potten YJ, Kerckhofs E and Seelen HA. Outcome of motor training programmes on arm and hand functioning in patients with cervical spinal cord injury according to different levels of the ICF: a systematic review. J Rehabil Med 2009; 41: Norrie BA, Nevett-Duchcherer JM and Gorassini MA. Reduced functional recovery by delaying motor training after spinal cord injury. J Neurophysiol 2005; 94: Kirshblum SC, Priebe MM, Ho CH, Scelza WM, Chiodo AE and Wuermser LA. Spinal cord injury medicine. 3. Rehabilitation phase after acute spinal cord injury. Arch Phys Med Rehabil 2007; 88: S Steeves JD, Lammertse D, Curt A, et al. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord 2007; 45: Biering-Sørensen F, Charlifue S, DeVivo M, et al. International spinal cord injury data sets. Spinal Cord 2006; 44: Appendix 1 Search strategy MEDLINE search strategy (the search strategy uses MeSH terms unless indicated otherwise): Set A terms (combined by OR) tetraplegia quadriplegia spinal cord injury spinal cord lesion; Set B terms (combined by OR) hand function arm function upper limb function upper extremity function; Set C (combined by OR) exercise strength robotic electric* stimulation task specific training repetitive transcranial magnetic stimulation virtual reality.

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