Scholarly article on topic 'The Effectiveness and Safety of Exoskeletons as Assistive and Rehabilitation Devices in the Treatment of Neurologic Gait Disorders in Patients with Spinal Cord Injury: A Systematic Review'

The Effectiveness and Safety of Exoskeletons as Assistive and Rehabilitation Devices in the Treatment of Neurologic Gait Disorders in Patients with Spinal Cord Injury: A Systematic Review Academic research paper on "Clinical medicine"

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Academic research paper on topic "The Effectiveness and Safety of Exoskeletons as Assistive and Rehabilitation Devices in the Treatment of Neurologic Gait Disorders in Patients with Spinal Cord Injury: A Systematic Review"

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GLOBAL SPINE JOURNAL

EBSJ Special Section: Systematic Review

The Effectiveness and Safety of Exoskeletons as Assistive and Rehabilitation Devices in the Treatment of Neurologic Gait Disorders in Patients with Spinal Cord Injury: A Systematic Review

Christian Fisahn1,2 Mirko Aach2 Oliver Jansen2 Joseph R. Dettori4 Thomas A. Schildhauer2

1 Swedish Neuroscience Institute, Swedish Medical Center, Seattle, Washington, United States

2 Department of Trauma Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany

3 Multiple Sclerosis Center, Swedish Medical Center, Seattle, Washington, United States

4Spectrum Research, Inc., Tacoma, Washington, United States

Global Spine J

Marc Moisi1 Angeli Mayadev3 Krystle T. Pagarigan4

Address for correspondence Christian Fisahn, MD, Swedish Neuroscience Institute, Swedish Medical Center, 550 17th Avenue, Seattle, WA 98122, United States (e-mail: christian.fisahn@swedish.org).

Abstract

Keywords

► exoskeleton

► robotics

► rehabilitation

► spinal cord injury

Study Design Systematic review.

Clinical Questions (1) When used as an assistive device, do wearable exoskeletons improve lower extremity function or gait compared with knee-ankle-foot orthoses (KAFOs) in patients with complete or incomplete spinal cord injury? (2) When used as a rehabilitation device, do wearable exoskeletons improve lower extremity function or gait compared with other rehabilitation strategies in patients with complete or incomplete spinal cord injury? (3) When used as an assistive or rehabilitation device, are wearable exoskeletons safe compared with KAFO for assistance or other rehabilitation strategies for rehabilitation in patients with complete or incomplete spinal cord injury?

Methods PubMed, Cochrane, and Embase databases and reference lists of key articles were searched from database inception to May 2, 2016, to identify studies evaluating the effectiveness of wearable exoskeletons used as assistive or rehabilitative devices in patients with incomplete or complete spinal cord injury.

Results No comparison studies were found evaluating exoskeletons as an assistive device. Nine comparison studies (11 publications) evaluated the use of exoskeletons as a rehabilitative device. The 10-meter walk test velocity and Spinal Cord Independence Measure scores showed no difference in change from baseline among patients undergoing exoskeleton training compared with various comparator therapies. The remaining primary outcome measures of 6-minute walk test distance and Walking Index for Spinal Cord Injury I and II and Functional Independence Measure-Locomotor scores showed mixed results, with some studies indicating no difference in change from

received

June 28, 2016 accepted after revision

September 27, 2016

DOI http://dx.doi.org/ 10.1055/s-0036-1593805. ISSN 2192-5682.

© Georg Thieme Verlag KG Stuttgart • New York

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baseline between exoskeleton training and comparator therapies, some indicating benefit of exoskeleton over comparator therapies, and some indicating benefit of comparator therapies over exoskeleton.

Conclusion There is no data to compare locomotion assistance with exoskeleton versus conventional KAFOs. There is no consistent benefit from rehabilitation using an exoskeleton versus a variety of conventional methods in patients with chronic spinal cord injury. Trials comparing later-generation exoskeletons are needed.

Introduction

According to the National Spinal Cord Injury Statistical Center, ~282,000 persons live with spinal cord injury (SCI) in the United States, and ~17,000 new SCI cases occur each year.1 SCIs have intense consequences, such as the loss of motor or sensory functions in the lower or upper limbs, depending on the level of injury. Therefore, the rehabilitation of locomotion has always been the key priority for patients suffering from SCIs.2

The greatest functional and neurologic recovery is to be expected during the first year after initial SCI; even with continuous and extensive rehabilitation, further improvements are usually not seen.3

Devices have been developed to assist patients suffering from SCI with mobility and to facilitate locomotion rehabili-tation.4 One such device is a powered exoskeleton. Powered exoskeletons are motorized orthoses placed over a person's limb with joint parts corresponding to those of the human body. Their purpose is to facilitate standing and walking, as well as assist in rehabilitation.5

The first powered exoskeleton—the Lokomat (Hocoma, Switzerland)-was a residential (fixed) exoskeleton, also known as a driven gait orthosis.6 However, in recent years, innovative mobility devices have been developed, such as powered lower limb exoskeletons, that help individuals with low-level SCI walk as naturally as possible. Despite the similar frame structure, assistive and rehabilitative exoskeletons differ in their application and clinical objective. Assistive exoskeletons (e.g., Rex-Bionics [Auckland, New Zealand], Wearable Power-Assist Locomotor exoskeleton [WPAL; Fujita Health University, Japan], Re-Walk [Argo Medical Technologies Ltd, Yokneam Ilit, Israel]) allow patients to walk, and rehabilitative exoskeletons (e.g., Lokomat [Hocoma, Switzerland], Hybrid Assistive Limb [HAL; Cyberdyne, Inc.,Tsukuba, Japan], Kinesis [Technaid, Madrid, Spain], and to some extent, Ekso-Bionics [Eksobionics Ltd, Richmond, California, USA]) focus on long-term gait improvement. Another difference is the control mechanism of the exoskeletons, such as joystick control (Rex-Bionics, Lokomat, WPAL, Kinesis), posture control (Re-Walk, Ekso-Bionics, Indego [Parker Hannifin Corp., Macedonia, Ohio, USA]), and electromyographic (EMG) control (HAL).

The aim of this systematic review is to determine if powered exoskeletons are effective as assistive and rehabilitation devices in improving locomotion in patients with SCI. We sought to answer the following clinical questions:

1. When used as an assistive device, do wearable exoskel-etons improve lower extremity function or gait compared with knee-ankle-foot orthoses (KAFOs) in patients with complete or incomplete SCI?

2. When used as a rehabilitation device, do wearable exo-skeletons improve lower extremity function or gait compared with other rehabilitation strategies in patients with complete or incomplete SCI?

3. When used as an assistive or rehabilitation device, are wearable exoskeletons safe compared with KAFOs for assistance or other rehabilitation strategies for rehabilitation in patients with complete or incomplete SCI?

Materials and Methods

Reporting of the methods and results follow the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for reporting systematic reviews.

Study design: Systematic review.

Information sources and search: PubMed, Cochrane, and Embase were searched for publications from database inception to May 2, 2016; bibliographies of included articles were also searched. The search strategy can be found in the online supplementary material.

Eligibility criteria: The inclusion criteria were as follows: (1) SCI resulting in a gait disorder; (2) age >18 and <75 years; and (3) randomized controlled trials. The exclusion criteria were as follows: (1) neurologic conditions other than SCI; (2) no neurologic gait disorder; (3) studies where the intervention is a robotic end-effector device (e.g., Gait Trainer GT1 [Reha-Stim Medtec GmbH & Co. KG, Berlin, Germany]); (4) studies measuring only upper extremity outcomes; and (5) studies measuring only physiologic or metabolic outcomes. A more detailed patient, intervention, comparator, and outcome table can be viewed in the online supplementary material.

Outcomes: Primary outcomes include gait outcomes (e.g., walking speed, 6-minute walk test [6MWT], 10-meter walking test [10MWT]), functional improvement (e.g., Functional Independence Measure [FIM], Spinal Cord Independence Measure [SCIM]), and safety (e.g., fracture, pain, cardiopul-monary episodes); secondary outcomes include neurologic improvement, motor strength, bladder and bowel function, spasticity, and requirement of walking aid. A summary table

of the primary outcome measures can be found in the online supplementary material.

Data collection process and items: Data was extracted by a single individual and verified independently by a second using a pre-established data abstraction form. We attempted to contact authors of publications in cases where data needed confirmation or clarification. The following data items were sought: study design, time from SCI, injury level, study purpose, and rehabilitation treatment details. Risk of bias evaluation: Randomized controlled trials were evaluated for risk of bias using criteria to judge articles on therapy. Crossover studies were evaluated for risk of bias using criteria outlined by Ding et al.7 These ratings are described in the online supplementary material. Analysis and synthesis of results: When possible, the differences between groups' mean change in scores from baseline to follow-up were reported or calculated for continuous outcomes; otherwise, the mean or median differences between groups' scores at last follow-up were calculated. Overall strength of evidence: We used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) System to evaluate the quality of the evidence base for each key question. Details about this system can be found in the online supplementary material.

Results

Study Selection and Characteristics

From among 175 citations identified from our search, we excluded 155 after two individuals reviewed the titles and abstracts. We reviewed the full text of 20 articles and identi-

Fig. 1 Flow diagram showing results of literature search. Abbreviation: KQ, key question.

fied 9 randomized trials in 11 publications meeting the inclusion criteria (►Fig. 1). Nine studies were excluded. A list of excluded articles and reason for exclusion can be found in the online supplementary material. A majority of the patients in the included studies were male with subacute or chronic incomplete SCI of cervical or thoracic etiology. Among the 11 studies identified, 10 utilized the robotic exoskeleton Lokomat,8-17 and the remaining study utilized the robotic exoskeleton MBZ-CPM1 (ManBuZhe [TianJin] Rehabilitation Equipment Co. Ltd., PR China).18 Nine of the included randomized trials were of parallel design, and two were of crossover design. Most studies were of moderately high risk of bias (►Table 1).

Efficacy of Wearable Exoskeletons as an Assistive Device

No studies were identified comparing the efficacy of wearable exoskeletons as an assistive device to standard KAFOs in patients with complete or incomplete SCI.

Efficacy of Wearable Exoskeletons as a Rehabilitation Device

Ten-Meter Walk Test

Six randomized controlled trials in eight publications evaluated walking velocity using the 10MWT comparing exoskel-eton training to a control group with follow-up ranging from 4 to 12 weeks (►Table 2); two measured fast walking velocity,10'12 one self-selected walking velocity,9 one measured both fast and self-selected walking,15 and two did not report the velocity pace for the test.8'14

In general, patients improved slightly with training. However, there were no differences in change from baseline among patients undergoing exoskeleton training compared with treadmill-based training with manual assistance,12 treadmill-based training with electrical stimulation,12 overground ambulation training with or without electrical stim-ulation,8'12'14 therapist-assisted body weight-supported treadmill training (BWSTT),14 no training,10 treatment with tizanidine (dose = 0.03 mg/kg),10 or the Gait Trainer GT1 with conventional therapy.9 One crossover trial found that fast walking velocity improved significantly more after strength training versus exoskeleton training.15

A subgroup analysis of Duffell et al comparing exoskeleton training to no intervention found that patients classified as high walking capacity at baseline (high 10MWT velocity and Timed-Up-and-Go [TUG] test times; high 6MWT distance) had more improvement in 10MWT times with exoskeleton rehabilitation compared with no intervention at 4 weeks of follow-up; patients with baseline low walking capacity (low 10MWT velocity and TUG test times; low 6MWT distance) showed no difference for either treatment (p for interaction = 0.02).10'16 A subgroup analysis of Alcobendas-Maestro et al comparing exoskeleton training with standard physical treatment to conventional overground training with standard physical treatment found that patient baseline upper or lower motor neuron injury did not modify treatment effect for 10MWT velocity at 8 weeks of follow-up.8'11

Table 1 Spinal cord injury studies characteristics table

First author (year), Patient Study purpose Inclusion and Intervention (A)a Comparator (B) Length of Risk of bias Funding

study design characteristics exclusion criteria F/U; % F/U (n¡N)

Alcobendas-Mae- No. randomized To compare a walk- Inclusion: C2-T12 Standard physical Standard physical 8 wks of Low Grant from

stro (2012),8 RCT A: 40 ing re-education SCI; ASIA Cor D; treatment + robot- treatment + OGT F/U; 93.8% Fondo para la

B: 40 program using exo- traumatic or non- ic-assisted locomo- (60 min) (75/80) Investigación

Age (y) skeleton to conven- traumatic, nonpro- tor training via Standard PT: joint Sanitaria en

A: 45.2 ± 15.5 tional OGT among gressive lesions; exoskeletonb mobilization, Castilla la

B: 49.5 ± 12.8 individuals with iSCI onset <6 mo; age (30 min) strengthening of Mancha-

Males of both traumatic 16-70 y; achieved Training duration: supralesional mus- AN/2006/27

A: 77.5% and nontraumatic assisted standing 40 sessions/8 wk culature and re-

B: 78.8% etiology for minimum of maining motor

Months from 1 wk previously functions, muscle

SCI: 4.2 (median) Exclusion: Unstable stretching and pos-

Injury level orthopedic injury; tural relaxation

Levels C1-C8 osteoporosis; le- techniques, trunk

A: 59% sions or ulcers stabilization, and

B: 61% where exoskeleton practice of self-care

Levels T1-T6 harness or straps skills

A: 19% are fitted; joint ri-

B: 13% gidity; leg length

Levels T7-T12 >2 cm; pulmonary

A: 22% heart disease; body

B: 26% weight >1 50 kg; previous SCI

Benito-Penalva No. randomized To report the clini- Inclusion: motor in- Conventional thera- Gait trainer GT 1 + 8 wks of F/ Moderately NR

(2012),9 RCT A: 46 cal improvements complete (ASIA C or py + robotic-as- conventional thera- U; 80.8% high

B: 84 in patients with spi- D), and select mo- sisted locomotor pies (105/130)

Age (y)d nal cord injury as- tor complete SCI training via exoskel- Conventional thera-

A: 45 sociated with (ASIA A or B) when eton13 (20-45 min) py: details NR

B: 45 intensive gait train- voluntary move- Training duration: 5

Malesb ing using electro- ment was present at d a week, 8 wk

A: 66.7% mechanical systems segments L2 and L3;

B: 68.1% according to patient 18+yofage; able to

Months from SCId characteristics tolerate the stand-

<6 mo: 77.1% ing position without

6-12 mo: 7.6% orthostasis

>12 mo: 15.2% Exclusion: cardiore-

Injury level: NR spiratory instability, pressure ulcers that interfered with mechanical components of gait devices, spasticity

First author (year), Patient Study purpose Inclusion and Intervention (A)a Comparator (B) Length of Risk of bias Funding

study design characteristics exclusion criteria F/U; % F/U (nIN)

(Ashworth Scale

>3), severe con-

tractures; weight

> 11 5 kg

Duffell (2015),10 No. randomized To investigate the Inclusion: age Robotic-assisted lo- B: no training 4 wk; A Moderately Supported by

RCT A: 27 effects of locomo- 18-50 y, motor in- comotor training or versus B high the National

B: 29 tor treadmill train- complete SCI (ASIA via exoskeletonb C: tizanidine (0.03 F/U: 95.4% Institutes of

C: 27 ing and tizanidine C or D); level of in- (30-45 min) mg/kg per dose) (54/56), A Health and the

Age (y) on gait impairment juryaboveTIO; >12 Treatment dura- Treatment dura- versus C Craig H. Neil-

A: 46.6 ± 12.6 in people with in- mo postinjury; able tion: 3 times a week tion: 4 times a day F/U: 98.1% sen Founda-

B: 47.8 ± 13.1 complete motor to ambulate; medi- for 4 wk for 4 wk (53/54) tion awards to

C: 47.4 ±11.6 SCI, and to under- cal clearance; spas- M.M.M.

Males stand whether ticity in the ankle

A: 70.3% functional levels af- (Modified Ashworth

B: 65.5% fect recovery with Score >1); lower-

C: 70.3% different limb PROM within

Months from SCI: interventions limits for ambula-

113 ± 111 tion

(mean ± SD) Exclusion: sitting

Level of injury: tolerance <2 h, ex-

above T10: 100% isting infection, severe cardiopulmonary disease, concomitant neurologic injury, fractures post-SCI, orthopedic or peripheral nerve injury in the LL

Esclarin-Ruz No. randomized To compare a walk- Inclusion: C2-T11 Standard physical Conventional OGT 8 wk of F/U Low Supported by

(2014),11 RCT UMN ing re-education SCI ASIA C or D; with treatment (30 min) (30 min) + stan- (no train- the Founding

A: 22 program with ro- only UMN findings; + OGT + robotic- dard physical treat- ing): for Research of

B: 22 botic locomotor T12-L3 SCI ASIA C assisted locomotor ment (30 min) UMN: Castilla La

LMN training plus OGT to or D with only LMN; training via exoskel- Standard physical 95.4% Mancha (grant

A: 22 conventional OGT in traumatic and non- etonb (30 min) treatment (42/44), no. PI

B: 22 individuals with in- traumatic, nonpro- Training duration: LMN: 93.2% 2006-45)

Age (y) complete UMN or gressive lesions; daily sessions for a (41 /44)

UMN LMN injuries having onset < 6 mo; age total of 40 sessions

A: 43.6 ± 12 either traumatic or 16-70 y; achieved over 8 wk

B: 44.9 ± 7 nontraumatic non- assisted standing a

LMN progressive etiology minimum of 1 wk

A: 36.4 ± 12 previously

(Continued)

First author (year), Patient Study purpose Inclusion and Intervention (A)a Comparator (B) Length of Risk of bias Funding

study design characteristics exclusion criteria F/U; % F/U (nIN)

B: 42.7 ± 18 Exclusion: orthope-

Males dic injuries that are

UMN unstable; osteopo-

A: 71.4% rosis with high risk

B: 61.9% of pathologic frac-

LMN ture; cutaneous le-

A: 70% sions and/or

B: 80.9% pressure ulcers in

Months from SCI: areas in which the

(mean ± SD) exoskeleton harness

UMN: 4.4 ± 1.8 or thigh straps are

LMN: 3.6 ± 1.3 fitted; joint rigidity;

Level of injury asymmetry of lower

UMN extremity

Levels C1-C8 length > 2 cm; pul-

A: 57.1% monary or heart

B: 57.1% disease requiring

Levels T1 -6 monitoring during

A: 19% exercise; body

B: 19% weight > 150 kg;

Levels T7-11 history of spinal

A: 24% injury

B: 24%

Levels T12-L1

A: 67%

B: 76%

Levels L2-L3

A: 33%

B: 24%

Field-Fote (2011),12 No. randomized The objective of this Inclusion: chronic A: robotic-assisted B: treadmill-based 4 wk of Moderately Funding pro-

RCT A: 15 study was to com- (>1 y) SCI; ASIA C or locomotor training training with manu- training, 6 high vided by Na-

B: 19 pare changes in D at or above T10; via exoskeletonb al assistance mo F/U; tional Insti-

C: 22 walking speed and ability to take at (60 min) (60 min) 86% tutes of Health

D: 18 distance associated least 1 step with 1 Treatment dura- C: treadmill-based (64/74) grant

Age (y)d with 4 locomotor leg; ability to rise to tion: 5 d/wk for training with stimu- R01HD41487

A: 45 ± 8 training approaches a standing position 12 wk; mean num- lation to common (to Dr. Field-

B: 39.3 ± 14.6 with moderate as- ber of training ses- peroneal n (60 min) Fote) and The

C: 38.5 ± 12.7 sistance (50% ef- sions completed D: OGT with stimu- Miami Project

D: 42.2 ± 15.7 fort) from 1 other was 49 ± 7 (range, lation to common to Cure

Malesd person 27-58) peroneal n (60 min) Paralysis

A: 85.7% Exclusion: current

First author (year), Patient Study purpose Inclusion and Intervention (A)a Comparator (B) Length of Risk of bias Funding

study design characteristics exclusion criteria F/U; % F/U (nIN)

B: 82.3% orthopedic prob- Manual assistance

C: 77.8% lems, history of car- through step phase

D: 73.3% diac condition, or

Months from SCId: radiographic evi-

>12: 100% dence of hip pa-

Injury level: above thology that could

Til: 100% be aggravated by training

Gorman (2016),13 No. randomized To assess the effec- Inclusion: traumatic Robotic-assisted lo- Home stretching 3 or 6 moc; Moderately Funded by De-

crossover RCT A: 27 tiveness of roboti- SCI > 1 y prior to comotor training program (20-25 67% (18/ high partment of

B: 27 cally assisted enrollment, age via exoskeletonb min) 27) Veterans Af-

In final analysis BWSTT for improv- 18-80 y, injury be- (20-45 min) fairs Rehabili-

A: 12 ing cardiovascular tween C4-L2, AISA Treatment dura- tation R&D

B: 6 fitness in chronic C or D, able stand at tion: 3 times a week Service Merit

Age (y) motor iSCI least 30 min for 3 mo Review Award

A: 51.5 ± 12.7 Exclusion: uncon- B4027I; study

B: 52 ± 15.4 trolled hyperten- registered at

Males sion, unstable clinicaltrials.

A: NR angina, CHF, COPD, gov with the

B: NR symptomatic PAD, identifier

Months from SCI: or recent hospitali- number

>12: 100% zation (within 3 mo) NCT00385918

Level of injury: for medical prob-

C4-L2 lem; severe con-

A 100% tractures or

B: 100% frequent uncontrolled bouts of autonomic dysreflexia; BMD T-score < - 3.5

Hornby (2005),14 No. randomized To study the effects Inclusion: traumatic A: robotic-assisted B: Therapist-as- 8 wk train- Moderately NR

RCT A: NR of robotic-assisted or ischemic SCI locomotor training sisted BWSTT (30 ing and F/U; high

B: NR BWSTT on individu- above T10; injury via exoskeletonb (30 min) 85.7% (30/

C: NR als with subacute within 14-180 d; min) C: OGT with mobile 35)

Total: 35 SCI ASIA B, C, or D; re- Treatment dura- suspension system

Age (y): NR quired physical as- tion: 3 sessions/wk (30 min)

Males: NR sistance from at

Months from SCI: least one PT to am-

0.5-0.9 (range) bulate over ground

Level of injury: Exclusion: second-

above T10: 100% ary neurologic injuries, including

(Continued)

First author (year), Patient Study purpose Inclusion and Intervention (A)a Comparator (B) Length of Risk of bias Funding

study design characteristics exclusion criteria F/U; % F/U (nIN)

traumatic brain in-

jury or peripheral

nerve damage

Huang (2015),18 No. randomized To compare the ef- Inclusion: NR Robot-assisted loco- BWSTT + manual 4 wk; % F/U Moderately Research on

RCT A: 12 fects of BWSTT and Exclusion: NR motor training via therapy + standard NR high Design Theory

B: 12 robot-assisted reha- exoskeleton6 + rehabilitation train- and Compliant

Age (y) bilitation on bowel manual therapy (20 ing (20 min) Control for

A: 41.7 ± 3.3 function in patients min) Underactu-

B: 38.4 ± 2.3 with spinal cord in- Treatment dura- ated Lower-Ex-

Males jury with respect to tion: 4 times a week tremity Reha-

A: 75% defecation time and for 4 wk bilitation Ro-

B: 58.3% defecation drug botic Systems,

Months from SCI: dose (enema) Code

NR 51175368

Level of injury: lev-

els T8-L2

A 100%

B: 100%

Labruyere (2014),15 No. randomized To compare Inclusion: age 18- Robot-assisted loco- Strength training 4 wks of Moderately International

crossover RCT A: 5 changes in a broad 70 y, chronic iSCI motor training via (45 min) each inter- low Spinal Re-

B: 4 spectrum of walk- > 1 y; sensorimotor exoskeletonb vention for search Trust

Age (y) ing-related out- incomplete ASIA C (45 min) a total of (Clinical Initia-

A: 59 ± 11 come measures and or D; motor level of Treatment dura- 8 wk of tive Stage 2,

B: 59 ± 11 pain between robot- the lesion C4-T11 ; tion: 32 total ses- training, London, UK;

Males assisted gait train- walk with at most sions over 8 wk, 16 F/U to 6 grant number

A: 55.6% ing and strength moderate assis- sessions of each mo; 100% CLI06), the

B: 55.6% training in patients tance; cognitive ca- treatment (20/20) Henry Smith

Months from SCI: with chronic iSCI, pacity to follow Charity (Lon-

50 ± 56 who needed walk- verbal instructions don, UK), and

(mean ± SD) ing assistance Exclusion: contrain- the EMDO

Level of injury dications for train- Foundation

Cervical ing in the (Zurich,

A: 56% exoskeleton system, Switzerland)

B: 56% had injuries limiting

T1-T6 training, as well as

A: 11% orthopedic, psychi-

B: 11% atric or neurologic

T7-T12 diseases, except for

A: 33% the iSCI

B: 33%

First author (year), Patient Study purpose Inclusion and Intervention (A)a Comparator (B) Length of Risk of bias Funding

study design characteristics exclusion criteria F/U; % F/U (nIN)

Niu (2014),16 RCT No. randomized To characterize the Inclusion: NR Robotic-assisted lo- No interventions 4 wk; F/U Moderately National Insti-

A: 20 distinct recovery Exclusion: NR comotor training NR high tutes of Health

B: 20 patterns of gait im- via exoskeletonb (45 (R01H-

Age (y) pairment for SCI min) D059895])

A: 42.2 ± 12.6 subjects receiving Treatment dura- and the Craig

B: 49.7 ± 7 exoskeleton train- tion: 3 times a week H. Neilsen

Males ing, and to identify for 4 wk Foundation

A: 65% significant predic- awarded to M.

B: 70% tors for these M.M.

Months from SCI: patterns

8.2 ± 7.7 (mean ±

Level of injury:

above T10: 100%

Shin (2014),17 RCT No. randomized To determine the Inclusion: nonpro- Regular PT (60 Conventional OGT 4 wks; Moderately NR

A: 30 effect of robotic-as- gressive traumatic min) + robotic-as- + regular PT (60 88.3% (53/ high

B: 30 sisted gait training or nontraumatic sisted locomotor min) 60)

Age (y) compared with OGT SCI, onset <6 mo, training via exoskel- Treatment dura-

A: 43.2 ± 14.4 ASIA D, age 20-65 y eton13 (40 min) tion: twice a day, 5

B: 48.2 ±11.5 Exclusion: pressure Treatment dura- times a week for

Males ulcers, severe limi- tion: 1 exoskeleton 4 wk

A: 74.1% tation of ROM of + 1 conventional

B: 53.8% hips and knees, se- treatment session/

Months from SCI: vere cognitive im- d, 3 times a week for

3.0 ± 2.0 (mean ± pairment, cardio- 4 wk; 2 convention-

SD) pulmonary disease al treatment ses-

Level of injury requiring monitor- sions/d, 2 times a

Cervical ing during exercise, week for 4 wk

A: 51.9% LMN lesion, previ-

B: 61.5% ously undergone

Thoracic/lumbar robot assisted gait

A: 48.1% training

B: 38.5%

Abbreviations: ASIA, American Spinal Injury Association; BMD, bone mineral density; BWSTT, body weight-supported treadmill training; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; F/U, follow-up; iSCI, incomplete spinal cord injury; LL, lower limb; LMN, lower motor neuron; NR, not reported; OGT, overground training; PAD, peripheral artery disease; PT, physical therapy; RCT, randomized controlled trial; ROM, range of motion; SCI, spinal cord injury; SD, standard deviation; UMN, upper motor neuron. aUnless otherwise noted, training duration is the same for intervention and comparator. bLokomat (Hocoma, Switzerland).

cThree months of follow-up for the robotic group, 6 months of follow-up for control group; the control group crossed over to exoskeleton training after 3 months of home stretching. dData only for those with data at final analysis.

eMBZ-CPM1 (ManBuZhe [Tianjin] Rehabilitation Equipment Co. Ltd., PR China).

Table 2 Differences between groups for primary outcomes at various follow-up periods3

First author (year), F/U, and groups 10MWT (m/s) 6MWT (m) WISCI II (0-20 [best]) FIM-L (2-14 [best]) SCIM (0-100 [best])

Alcobendas-Maestro (2012),8 8 wk A: exoskeleton + PT B: OGT + PT Median (IQR) at 8 wk Velocity unclear A: 0.40 (0.20, 0.60) B: 0.30 (0.20, 0.50) p = NS Median (IQR) at 8 wk A: 169 (69, 228) B: 91 (51, 179) p < 0.05 Median (IQR) at 8 wk A: 16 (9, 19) B: 9 (8, 16) p < 0.05 Median (IQR) at 8 wkb A: 10 (6, 12) B: 7 (5, 10) p < 0.05 NR

Benito-Penalva (201 2),9 8 wk A: exoskeleton + CT B: Gait Trainer GT1 + CT Mean A from baseline Self-selected velocity A: 0.19 ± 0.03 B: 0.18 ± 0.18 Mean diff (95% CI): A versus B: 0.0 (-0.04, 0.05) NR Mean A from baseline A: 5.3 ± 0.7 B: 5.1 ± 0.5 Mean diff (95% CI): A versus B: 0.2 (-0.1, 0.4) NR NR

Duffell (2015),10 4 wk A: exoskeleton B: no training C: tizanidine % attained MIDC Fast velocity A: 15% (4/26) B: 23% (6/26) C: 8% (2/25) % attained MIDC A: 8% (2/24) B: 13% (3/23) C: 12% (3/26) NR NR NR

Esclarin-Ruz (2014),11 8 wkd A: exoskeleton + PT B: OGT + PT Mean A from baseline Self-selected velocity UMN A: 0.06 ± 0.19 B: 0.03 ± 0.19 LMN A: 0.22 ± 0.17 B: 0.17 ± 0.25 Mean diff (95% CI) UMN, A versus B: 0.03 (-0.10, 0.16) LMN, A versus B: 0.05 (-0.09, 0.19) Mean A from baseline UMN A: 65.2 ± 70.8 B: 26.1 ± 56.6 LMN A: 74.8 ± 59.7 B: 51.3 ± 79.1 Mean diff (95% CI) UMN, A versus B: 39.1 (-7.4, 85.6) LMN, A versus B: 23.5 (-23.1, 70.2) Mean A from baseline UMN A: 7.6 ± 3.4 B: 6.1 ± 3.1 LMN A: 6.5 ± 2.5 B: 5.8 ± 2.7 Mean diff (95% CI) UMN, A versus B: 1.5 (-0.5, 3.4) LMN, A versus B: 0.7 (-0.95, 2.25) Mean A from baseline UMN A: 3.9 ± 1.8 B: 2.1 ± 1.8 LMN A: 2.9 ± 1.8 B: 3.7 ± 1.7 Mean diff (95% CI) UMN, A versus B: 1.8 (0.8, 2.9) LMN, A versus B: -0.8 (-1.8, 0.3) NR

Field-Fote (2011),12 12wk A: exoskeleton B: TTwith manual assist C: TTwith stimulation D: OGT with stimulation Mean A from baseline Fast velocity A: 0.01 ± 0.06 B: 0.05 ± 0.10 C: 0.05 ± 0.11 D: 0.09 ± 0.17 Mean diff (95% CI) A versus B: -0.04 (-0.10, 0.02) A versus C: -0.04 (-0.10, 0.02) NR NR NR NR

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A versus D: -0.08 (-0.17, 0.01)

Hornby (2005),14 8 wk A: exoskeleton B: therapist-assist BWSTT C: OGT No significant differences No significant differences Mean A from baselinee,f A: 5.8 ± 2.0 B: 5.2 ± 2.0 C: 6.5 ± 2.2 Mean diff at last F/U (95% Cl)e Aversus B: 0.6 (-1.2, 2.4) Aversus C: -0.72 (-2.6, 1.1) Mean A from baseline' A: 1.8 ± 0.9 B: 1.9 ± 0.6 C: 2.0 ± 0.5 Mean diff at last F/U (95% CI) Aversus B: -0.1 (-0.9, 0.6) Aversus C: -0.2 (-0.9, 0.4) NR

Labruyere (2014),15 8 wk A: exoskeleton B: strength training Mean A from baseline Self-selected velocity A: 0.04 (SD NR) B: 0.06 (SD NR) Mean diff (95% CI)9: Aversus B: 0.02 (-0.04, 0.08), p = NS Mean A from baseline Fast velocity A: 0.01 (SD NR) B: 0.14 (SD NR) Mean diff (95% Cl)f: Aversus B: 0.13 (0.01, 0.25) p = 0.04 NR Mean A from baseline A: 0.8 (SD NR) B: 0.4 (SD NR) Mean diff (95% CI)9: Aversus B: -0.4 (-1.5, 0.6) p = NS NR Mean A from baseline A: 0.8 (SD NR) B: 1.3 (SD NR) Mean diff (95% CI): Aversus B: 0.5 (-2.1, 3.2) p = NS

Niu (2014),16 4 wkh,i A: exoskeleton B: no interventions Mean A from baseline, class lj Velocity unclear A: 0.03 ± 0.01 B: 0.01 ± 0.15 Mean diff (95% CI): class I: 0.02 (-0.08, 0.12) Mean A from baseline, class llj Velocity unclear A: 0.12 ± 0.32 B: 0.02 ± 0.13 Mean diff (95% CI): class II: 0.10 (-0.10, 0.29) Diff between groups' rate of change over 4 wk (m/wk) Class I: 0.8, p = NS Class II: 2.3, p = NS NR NR NR

(Continued)

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6-Minute Walk Test

Three trials in five publications assessed endurance using the 6MWT at 4 or 8 weeks of follow-up. Two found no difference in 6MWT distance among patients undergoing exoskeleton training compared with therapist-assisted BWSTT,14 overground ambulation,14 no training,10 or tizanidine.10 One trial reported a statistically significant median distance following 8 weeks of training in favor of the exoskeleton group compared with overground training plus standard physical ther-apy.8 With the data provided, it is unclear whether this difference is functionally meaningful.

A subgroup analysis of Duffell et al comparing exoskeleton training with no intervention found that baseline low or high walking capacity did not modify the treatment effect for 6MWT distance at 4 weeks of follow-up.10'16 A subgroup analysis of Alcobendas-Maestro et al comparing exoskeleton training with standard physical treatment to conventional overground training with standard physical treatment found that baseline upper versus lower motor neuron injury did not modify treatment effect for 6MWT distance at 8 weeks of follow-up.8'11

Walking Index for Spinal Cord Injury I and II

Five studies in six publications evaluated the level of walking impairment via Walking Index for Spinal Cord Injury I (WISCI) or II (WISCI II) scores at 4 or 8 weeks of follow-up. One trial found no difference in WISCI scores among patients undergoing exoskeleton training versus therapist-assisted BWSTTor overground ambulation.14 Another found no difference in WISCI II scores among patients undergoing exoskeleton training with conventional therapy versus patients undergoing Gait Trainer GT1 training in conjunction with conventional therapy.9 A third study—a crossover trial—found no differences in WISCI scores comparing exoskeleton training to strength training.15 Two studies found that exoskeleton training in conjunction with regular physiotherapy or standard physical treatment significantly improved WISCI II scores more than conventional overground training in conjunction with regular physiotherapy or standard physical treatment; median scores were 11 and 16 in the exoskeleton group plus physical therapy groups compared with 9 and 9 in the overground training plus physical therapy groups.8'17

A subgroup analysis of Alcobendas-Maestro et al comparing exoskeleton training with standard physical treatment to conventional overground training with standard physical treatment found that baseline upper versus lower motor neuron injury did not modify treatment effect for WISCI II at 8 weeks of follow-up.8'11

Functional Independence Measure-Locomotor

Two trials in three publications assessed locomotive function via Functional Independence Measure-Locomotor (FIM-L) scores at 8 weeks of follow-up. One trial found no difference in FIM-L scores among patients undergoing exoskeleton training, therapist-assisted BWSTT, or overground ambula-tion training,14 but another trial found that patients under-5 > going exoskeleton training in conjunction with standard

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physical treatment significantly improved their FIM-L scores compared with patients undergoing conventional overground training in conjunction with standard physical treatment; median scores at last follow-up were 10 (interquartile range [IQR]: 6 to 12) compared with 7 (IQR: 5 to 10), respectively (p < 0.05).8

A subgroup analysis of Alcobendas-Maestro et al found that patients with upper motor neuron injuries had improved FIM-L scores from treatment with exoskeleton therapy with standard physical treatment compared with conventional overground training with standard physical treatment at 8 weeks of follow-up; patients with lower motor neuron injuries at baseline had no improvement with either treatment (p for interaction = 0.013).8,11

Spinal Cord Independence Measure

Two trials evaluated independence via the SCIM at 4 or 8 weeks of follow-up. There was no difference in SCIM scores between exoskeleton training with regular physiotherapy and conventional overground training with regular physiotherapy at 4 weeks of follow-up in one trial.17 In the second trial, there was no difference between exoskeleton training versus strength training in a crossover design after 4 and 8 weeks.15

Lower Extremity Motor Score

Five trials in six publications evaluated lower extremity motor function via the lower extremity motor score (LEMS) at 4 or 8 weeks of follow-up (►Table 3). The results were mixed. One trial found no difference in LEMS between exoskeleton training with regular physiotherapy or conventional overground training with regular physiotherapy.17 A second trial reported that use of the end-effector exoskeleton Gait Trainer GT1 in conjunction with conventional therapy resulted in a greater improvement in the LEMS compared with exoskeleton training in conjunction with conventional therapy; the difference between the mean change scores was -2.17 (95% confidence interval [CI], -2.6 to -1.74).9 However, these results are in contrast to a third trial, which reported exoskeleton training with regular physiotherapy significantly improved LEMS compared with conventional overground training with standard physical treatment; the median score was 40 (IQR: 30 to 45.5) compared with 35 (IQR: 29.7 to 40; p < 0.05).8 Two crossover trials reported no difference between exoskeleton training and strengthening exercises or home stretching exercises.13,15

A subgroup analysis of Alcobendas-Maestro et al comparing exoskeleton training with standard physical treatment to conventional overground training with standard physical treatment found that baseline upper versus lower motor neuron injury did not modify treatment effect for LEMS at 8 weeks of follow-up.8,11

Defecation Measures

A single trial reported defecation measures via defecation time and enema volume at 4 weeks of follow-up (►Table 3). Exoskeleton training in conjunction with manual therapy resulted in better defecation times and enema volumes

compared with BWSTT in conjunction with manual therapy and standard rehabilitation; the defecation time difference between mean change scores was -14.0 minutes (95% CI, -21.4 minutes to -6.6 minutes), and the enema volume difference between mean change scores was -18.5 mL (95% CI, -24.9 mL to -12.0 mL).18

Safety of Wearable Exoskeletons

Adverse events were rare. Two trials reported no adverse events at 8 weeks' follow-up among patients receiving exo-skeleton training with conventional therapy,9 exoskeleton training alone,15 Gait Trainer GT1 training with conventional therapy at 8 weeks' follow-up,9 or strength training.15 One randomized, crossover trial with follow-up at 3 and 6 months found that skin irritation or abrasion occurred in11%(2/18)of subjects completing the trial.13 The sites affected included the hip, groin, penis, back, wrist, glutei, and scapula. The authors indicated that this issue was resolved by adding additional padding to the parachute harness setup. The remaining included trials made no explicit mention of adverse events.

Evidence Summary

Exoskeletons as Assistive Devices

There were no studies comparing exoskeletons as assistive devices to currently used orthotics.

Exoskeletons as Rehabilitation Devices

There were no differences in the 10MWT and 6MWT comparing exoskeleton versus non-exoskeleton rehabilitation in patients with SCI. There were mixed results for the WISCI/WISCI II and FIM-L; the majority of studies found no difference between rehabilitation strategies with a few studies reporting significantly improved scores in the exoskeleton group. Patients with a high walking capacity at baseline (high 10MWT velocity and TUG test times; high 6MWT distance) had more improvement in 10MWT but not the 6MWT with exoskeletal rehabilitation compared with non-exoskeleton rehabilitation, and patients classified as low walking capacity showed no difference between treatments. The overall strength of evidence for these findings is low or very low (►Table 4).

Safety of Exoskeletons

Adverse events were rare; however, they were reported inconsistently.

Illustrative Case

A 29-year-old female acrobat suffered from traumatic SCI after a fall from a 3-m height during an artistic performance. She was instantly unable to move upper and lower limbs.

Diagnosis in the first hospital providing care revealed fractures and fracture dislocation of cervical vertebrae C3 and C4. At the day of admission, she received a decompression operation via laminectomy of the C3 and was immobilized with a cervical collar. On the third postoperative day, the patient was transferred to a level 1 trauma center with an affiliated rehabilitation facility for SCIs.

Table 3 Differences between groups for secondary outcomes at various follow-up periodsa

First author (year), follow-up, and groups Score at follow-up Difference between treatments

LEMS 0-50 (best)

Alcobendas-Maestro (2012),8 8 wk A: exoskeleton + PT B: OGT + PT Median (IQR) at 8 wk A: 40 (35, 45.5) B: 35 (29.7, 40) p < 0.05

Benito-Penalva (2012),9 8 wk A: exoskeleton + CT B: Gait Trainer GT1 + CT Mean A from baseline A: 7.1 ± 1.2 B: 9.3 ± 0.9 Mean diff (95% CI), A versus B: -2.2 (-2.6, -1.7)

Esclarin-Ruz (2014),11 8 wkb A: exoskeleton + PT B: OGT + PT UMN, mean A from baseline A: 8.33 ± 6.64 B: 5.28 ± 6.94 LMN, mean A from baseline A: 6.15 ± 6.81 B: 2.57 ± 6.6 UMN, mean diff (95% CI), Aversus B: 3.05(-1.06, 7.16) LMN, mean diff (95% CI), Aversus B: 3.58 (-0.53, 7.69)

Field-Fote (2011),12 12 wk A: exoskeleton B: TT with manual assist C: TT with stimulation D: OGT with stimulation Mean A from baseline, left legc A: 1.2 ± 4.3 B: 1.7 ± 3.5 C: 1.2 ± 3.8 D: 1.1 ± 4.4 Mean diff (95% CI), left legc Aversus B: -0.5 (-3.28, 2.28) Aversus C: 0.0 (-2.84, 2.84) Aversus D: 0.1 (-3.06, 3.26)

Gorman (2016),13 3 or 6 mo A: exoskeleton B: home stretching program Mean A from baselined A: 0.3 ± 7.06 B: -0.4 ± 5.18 Mean diff (95% CI), A versus B: 0.7 (-5.05, 6.45)

Hornby (2005),14 8 wk A: exoskeleton B: therapist-assist BWSTT C: OGT Mean A from baselinee A: 12.8 ± 2.4 B: 12.6 ± 4 C: 10.8 ± 2.4 Mean diff at last F/U (95% CI) Aversus B: 0.2 (-2.7, 3.09) Aversus C: 2.0 (-0.1, 4.1)

Labruyere (2014),15 8 wk A: exoskeleton B: strength training Mean A from baseline A: 0.7 (SD NR) B: 1 (SD NR) Mean diff (95% CI),f A versus B: 0.3 (-0.9, 1.55) p = NS

Shin (2014),17 4 wk A: exoskeleton + PT B: OGT + PT Median (IQR) at 4 wk A: 37 (20, 49) B: 37 (20, 48) p = NS

Bowel function

Huang (2015),18 4 wk A: exoskeleton + manual therapy B: BWSTT + manual therapy + standard rehabilitation Defecation time (min), mean A from baseline A: -28.5 ± 8.8 B: -14.5 ± 9.8 Enema volume (mL), mean A from baseline A: -29.3 ± 7.5 B: -10.8 ± 8.7 Mean diff (95% CI): -14 (-21.4, -6.6) Mean diff (95% Ci): -18.5 (-24.9, -12.02)

Abbreviations: BWSTT, body weight-supported treadmill training; CI, confidence interval; CT, conventional training; diff, difference; F/U, follow-up;

IQR, interquartile range; LEMS, lower extremity motor score; LMN, lower motor neuron; NR, not reported; NS, not significant; OGT, overground

training; PT, physical therapy; TT, treadmill training; UMN, upper motor neuron; SD, standard deviation.

aUnless otherwise indicated, all values are reported as mean ± SD.

bEsclarin-Ruz et al (2014)11 is a subgroup analysis of Alcobendas-Maestro etal (2012).8

cRight leg lower extremity motor score data also reported, not statistically different from left leg lower extremity motor score data. dIt is unclear if authors evaluated the control group after the initial control treatment (12 weeks) or if they were evaluated after crossing over to robotically assisted body weight-supported treadmill training (24 weeks). eThese values were estimated from Fig. 4.

fThe 95% CIs were estimated from Fig. 4, point estimates were calculated using values in Table 2.

Table 4 Quality of evidence evaluating exoskeletons as assistive or rehabilitative devices in incomplete or complete SCI

Outcome Follow-up Studies (/V) Serious risk of bias Serious inconsistency Serious indirectness Serious imprecision Conclusions Quality

Key question 1: exoskeletons as assistive devices

No comparisons available No data

Key question 2: exoskeletons as rehabilitative devices

Exoskeleton versus nonexoskeleton rehabilitation strategies3

10MWT 8 to 12 wk 5 RCTs8-9-12-14'15 (/V = 319) Yes(-1) No No Yes (-1) No significant difference between groups except for 1 high risk of bias crossover study that reported strength training improved speed more than exoskeleton Subgroup analyses: patients with higher versus lower baseline walking capacity13 improved more with exoskeleton versus non-exoskeleton rehabilitation; LMN versus UMN did not modify the effect of exoskeleton rehabilitation Low

6MWT 8 wk 2 RCTs8'14 (N = 115) No Yes (-1) No Yes (-1) No significant difference between groups Subgroup analyses: neither higher versus lower baseline walking capacity13 nor LMN versus UMN modified the effect of exoskeleton rehabilitation Low

WISCI/ WISCI II 4 to 8 wk 5RCTs8,9,14,15,17(a/ = 314) Yes(-1) Yes (-1) No Yes (-1) Mixed results; a majority of included studies (3/5) found no statistically significant mean difference in scores between exoskeleton and nonexoskeleton rehabilitation; two studies found that median scores were significantly improved in exoskeleton groups Subgroup analyses: LMN versus UMN did not modify the effect of exoskeleton rehabilitation Very low

(Continued)

Outcome Follow-up Studies (N) Serious risk of bias Serious inconsistency Serious indirectness Serious imprecision Conclusions Quality

FIM-L 8 wk 2 RCTs8'14 (N = 115) No Yes (-1) No Yes (-1) Mixed results; one study found no significant difference in mean FIM-L scores between exoskeleton and non-exoskele-ton rehabilitation groups, and the other study found that median FIM-L scores were significantly improved in the exoskeleton group Subgroup analyses: patients with UMN versus LMN improved more with exoskeleton versus non-exoskeleton rehabilitation Low

SCIM 4 wk 2 RCTs15'17 (N = 69) Yes(-1) No No Yes (-1) No significant difference between groups Low

Exoskeleton versus tizanidine

10MWT, Fast velocity 4 wk 1 RCT10 (N = 83) Yes(-1) Unknown No Yes (-1) No significant difference between groups Low

6MWT 4 wk 1 RCT10 (N = 83) Yes(-1) Unknown No Yes (-1) No significant difference between groups Low

Exoskeleton versus no training

10MWT, Fast velocity 4 wk 1 RCT10 (N = 83) Yes(-1) Unknown No Yes (-1) No significant difference between groups Low

6MWT 4 wk 1 RCT10 (N = 83) Yes(-1) Unknown No Yes (-1) No significant difference between groups Low

Key question 3: safety of exoskeletons as assistive or rehabilitative devices

Exoskeletons as rehabilitative devices

Skin irritation or abrasion 3 and 6 mo 1 RCT13 (N = 66) Yes(-1) Unknown No Yes (-1) Skin irritation or abrasion associated with exoskeleton use was rare Low

No adverse events 8 wk 2 RCTs9'15 (N = 139) Yes(-1) No No Yes (-1) No additional adverse events occurred in the two studies that mentioned adverse events explicitly Low

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The neurologic status at the time of admission was American Spinal Injury Association (ASIA) B. Further radiologic diagnostics showed a dislocated fracture and led to dorsal spinal fusion of C2 through C4; additional figures can be seen in the online supplementary material (►Figs. S1 and S2).

Due to expected prolonged dependency on respiratory support, the patient received a percutaneous tracheostomy. Subsequent to fracture consolidation and weaning from the respirator, the patient was started on BWSTT using an EMG-controlled exoskeleton (HAL) using the protocol of Aach etal.19

The neurologic status at the time of enrollment was ASIA C; an additional figure can be seen in the online supplementary material (►Fig. S3).19'20

Throughout the 12-week intervention, treadmill performance improved significantly in terms of speed, distance, and time on the treadmill. Video demonstration can be seen in the online supplementary material (►Video 1). Assessment of functional walking abilities without the exoskeletal device measured by the 10MWT improved significantly as measured by time needed to ambulate a 10-m distance and the assistance needed (WISCI II; ►Video 2, online supplementary material). The patient regained important motor functions as assessed via LEMS, leading to an improved walking ability that enabled her to ambulate short distances and even over everyday obstacles (e.g., stairs) without personal assistance; a video showing the performance on stairs can be found in the online supplementary material (►Video 3). The neurologic status after 12 weeks of HAL BWSTT improved to ASIA D; an additional figure can be seen in the online supplementary material (►Fig. S4).19'20

Discussion

In the 1960s and '70s, initial research was conducted in the field of motorized exoskeletons. Due to the size and weight of the technology, it was deemed unfeasible compared with conventional KAFOs. Therefore, the research was discontinued.21'22

However, SCI remained a devastating and disabling condition often resulting in significant gait limitations. To restore mobility, a weight-bearing locomotion training system was introduced into SCI rehabilitation programs. Over the past 15 years, fixed exoskeletons, primarily the Lokomat, emerged as a relatively frequent technology in SCI rehabilitation.

We looked for but were unable to find any studies evaluating exoskeletons as an assistive device compared with conventional KAFOs. With respect to evaluating exoskeletons as a rehabilitation device, we found nine RCTs. Though there was heterogeneity with respect to comparison groups, co-interventions, outcomes, and study design, these nine studies revealed no significant differences in velocity on the 10MWT and SCIM scores comparing exoskeleton to conventional locomotion rehabilitation. There were mixed results among some of the studies with respect to the 6MWT, WISCI, WISCIII, and FIM-L scores.

Exoskeletons in the Treatment of Neurologic Gait Disorders Fisahn et al. Table 5 Control and purpose of exoskeletons used with patients with spinal cord injuries

Exoskeleton No. of case series No. of patients Purpose

Joystick control

Rex-Bionics (Rex-Bionics, Auckland, New Zealand) None 0 Assistive mobility device

Lokomat (Hocoma, Switzerland) 830-37 159 Rehabilitation

WPAL (Fujita Health University, Japan) 238,39 11 Assistive mobility device

Kinesis (Technaid, Madrid, Spain) 1 40 3 Rehabilitation

Posture control

Re-Walk (Argo Medical Technologies Ltd, Yokneam Ilit, Israel) 741-47 66 Assistive mobility device

Ekso-Bionics (Eksobionics Ltd, Richmond, California, USA) 226,27 10 Rehabilitation

Indego (Parker Hannifin Corp., Macedonia, Ohio, USA) 248,49 21 Assistive mobility device

EMG control

HAL (Cyberdyne, Tsukuba, Japan) 53,23-25,28 30 Rehabilitation

Abbreviations: EMG, electromyographic; HAL, Hybrid Assistive Limb; WPAL, Wearable Power-Assist Locomotor.

As new technologies enabled the development of motorized wearable exoskeletons, several types have been introduced to SCI rehabilitation. The available exoskeletons can be subdivided according to their control mode into joystick, posture, and EMG controlled (►Table 5).

Different applications are possible depending on the control mode of operation. Joystick- and posture-controlled exoskeletons enable the patient to regain mobility while wearing the device to compensate for the functional loss of the lower limbs. In contrast, EMG-controlled devices integrate the patient's voluntary drive in the walking pattern, because it requires an active contribution of the patient's lower limbs. This neuronal feedback may lead to or implicate neuronal plasticity and normalizes cortical excitability. Furthermore, some believe this mechanism leads to increased patient mobility when not wearing the exoskeleton, even in patients with chronic SCI.3,23

There is a certain optimism that exoskeletons, primarily mobile exoskeletons used as rehabilitation devices (e.g., HAL, and to some extent, Ekso-Bionics), have potential to improve walking patterns after the device is removed.3,23-28

In our study, adverse events were infrequently reported in literature, with only one trial indicating skin irritation or abrasion from exoskeleton training. There were no reports of falling or pressure sores.

Although case series provide some optimism with respect to the use of exoskeletons in locomotion rehabilitation for SCI (►Table 5), this optimism has yet to be validated in randomized trials. Studies of newer exoskel-etons comparing them to current rehabilitation strategies are needed.

Conclusion

There is no data to compare locomotion assistance with exoskeleton versus conventional KAFOs. There is no consistent benefit from rehabilitation using an exoskeleton versus a variety of conventional methods in chronic SCI patients. Trials comparing later-generation exoskeletons are needed.

Disclosures

Christian Fisahn: none Mirko Aach: none Oliver Jansen: none Marc Moisi: none Angeli Mayadev: none Krystle T. Pagarigan: none Joseph R. Dettori: none

Thomas A. Schildhauer: Consultant (Cyberdyne, Inc., Japan)

Acknowledgments

Analytic support for this work was provided by Spectrum Research, Inc. with funding from AOSpine International

References

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2 Ditunno PL, Patrick M, Stineman M, Ditunno JF. Who wants to walk? Preferences for recovery after SCI: a longitudinal and cross-sectional study. Spinal Cord 2008;46(7):500-506

3 Aach M, Cruciger O, Sczesny-Kaiser M, et al. Voluntary driven exoskeleton as a new tool for rehabilitation in chronic spinal cord injury: a pilot study. Spine J 2014;14(12):2847-2853

4 Aach M, Meindl RC, GeßmannJ, SchildhauerTA, Citak M, Cruciger O. [Exoskeletons for rehabilitation of patients with spinal cord injuries. Options and limitations]. Unfallchirurg 2015;118(2):130-137

5 Kawamoto H, Sankai Y. Power assist method based on Phase Sequence and muscle force condition for HAL. Adv Robot 2005; 19(7):714-734

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Editorial Perspective

Over the last 30 years, the treatment for acute SCI has largely focused on three areas:

• Optimizing patient retrieval and resuscitation during the postinjury phase

• Timely decompression and surgical stabilization where appropriate

• Rehabilitation with efforts concentrating on returning patients to functional independence, relying largely on wheelchairs or bracing with mobilization aids in some patients

Additional areas of SCI care have largely focused on pharmacologic interventions, such as use of high-dose steroids as a powerful anti-inflammatory medication aimed at decreasing expansion of the secondary injury zone. Continued controversy remains about the role of this medication. Further pharmaceuticals and hypothermia, all largely with similar intent to limit secondary injury zone damage, are currently undergoing prospective trials. Taken together all of these efforts have led to improvements of patient survival but have shown to be limited in their potential for further SCI recovery.

Emerging experimental modalities for potential spinal cord repair attempt to stop neuronal apoptosis or induce cell regeneration through stem cell implantation or molecular interventions. Although these therapeutic concepts have raised substantial public interest through sensationalistic media coverage, there is little actual scientifically confirmed evidence that these treatments work in the lab using large mammals or in patients. For the foreseeable future, this important arm of research will need to grapple with a number of overwhelming foundational obstacles prior to providing SCI patients with veritable hope for meaningful SCI recovery.

Robotic devices that augment paralyzed or paraparetic lower extremity function have been a long-held dream of futurists and part of some attempts of patient care since the 1970s. With mainstream treatments as well as cellular treatments having arrived at somewhat of an impasse, there has been a renewed interest in utilizing robotically driven technol-

ogies for mobilization and perhaps even as a neurorehabilita-tion tool. To our knowledge, this is the first systematic review of the current evidence base for use of these devices and categorizes them into more conventional passive mobilization assis-tive devices versus active neurorehabilitation technologies.

The enclosed assessment provides an important insight into the difficulty of proving recovery in patients with incomplete SCls. Designing a prospectively randomized trial is challenging due to the limited number of patients and the high degree of variability in their circumstances. Doubters will always be able to challenge any recovery claims by asking about the natural recovery potential of patients if they had not been treated. That said, the investigators and patients appear to be very excited about the potential for improved mobility or even functioning in an upright position.

On a positive scientific note, there seems to be increasing consistency in measuring the function of patients with incomplete SCls. ln addition to the conventional lower extremity motor score, the 10-meter walk test, and the 6-minute walk test, as a general functional measure, WlSCl ll appears to be more commonly used as an objective performance assessment. Unfortunately, important additional factors such as spasticity, urinary control, sensory recovery, and defecation measures apparently are not yet part of the routine assessments to measure rehabilitation progress. Similarly, patient satisfaction and other patient-reported outcomes were not assessed in these presented studies. To date, the reported results are inconsistent compared with conventional therapy. Longer-term outcomes of affected patients such osteoporosis, pathologic fractures, or skin breakdown are yet to be assessed. Similarly, the persistence of any motor function gains has yet to be established. Nonetheless, these more recent advances in robotics and their human interface in terms of "neurorobotics" stand to offer far more near-term real-life hope for recovery of function and upright mobilization than current established treatment or neuronal cell regeneration therapies. The other main option is based on using robotic devices such as used in form of motorized braces ("exoskeletons").