Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Mark, 2018

Type of study:

RCT

Setting and country:

USA

Funding and conflicts of interest:

-government & non-government funding

-GC serves on the Data and Safety Monitoring boards of AMO Pharmaecuticals, Apotek, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck/Opko Biologics, Merck, Neuren, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva Pharmaceuticals, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee), and on the consultation or advisory boards of Atara Biotherapeutics, Bioeq GmBH, Cerespir, Inc., Consortium of MS Centers (grant), Genzyme, Genetech, Innate Therapeutics, Jamsen Pharmaceticals, Klein-Buendel Incorporated, Medimmune, Medday, Nivalis, Novartis, Opexa Therapeutics, Roche, Savara, Inc., Somahlution, Teva pharmaceuticals, Transparency Life Sciences, and TG Therapeutics. GC also is the President of Pythagoras, Inc, a private consulting company located in Birmingham AL.

Inclusion criteria:

-average item score < 3/5 concerning the more-affected arm on the Motor Activity Log (MAL) indicating substantially reduced real-world use of the more affected arm;

-mild-moderate motor deficit on active hand movement (at least 20° extension of the wrist and 10° at each of the fingers against gravity);

-able to stand without another person’s assistance at least 2 minutes; no more than mild-moderate pain during arm movement;

-relapse-free at least 3 months; absence of other neurological disorder associated with altered CNS structure;

-absence of other disorder that could substantially limit hand use (e.g., arthritis);

-no prior exposure to CIMT;

-agreement not to participate in other rehabilitation during the training period.

Exclusion criteria:

-

N total at baseline:

Intervention: 11

Control: 11

Important prognostic factors²:

age ± SD:

I: 47.2 ±7.6

C:51.9 ±8.5

Sex:

I: 10% M

C: 40% M

Groups comparable at baseline?

Group differences were not tested

Describe intervention (treatment/procedure/test):

Constraint-Induced Movement therapy (CIMT) for patients with learned nonuse involves (1) intensive training with the more-affected arm on movements and activities of functional significance 3 hours per day with rest periods as needed; (2) training by behavioral shaping, which involves approaching motor goals in small increments, with encouragement to improve on personal best performance and positive feedback at each step; (3) restraint of the less-affected hand with a padded mitt for a target 90% of waking hours; and (4) a set of behavioral procedures, termed the Transfer Package, to facilitate transfer of training benefits from the clinic to the real world.19 Transfer Package procedures include (1) behavioral contracting, (2) home practice assignments to be conducted during and after the end of formal treatment, (3) keeping an activity diary, and (4) the therapist conducting 30-minute daily interviews with the patient that include administering the MAL, reviewing the diary, and problemsolving discussions to overcome perceived barriers to arm use.

Describe control (treatment/procedure/test):

The Complementary and Alternative Medicine (CAM) program included (1) aquatic therapy, (2) massage, (3) gentle yoga, and (4) relaxation techniques (meditation with attention to breathing).

Length of follow-up:

10 weekdays

Loss-to-follow-up:

Intervention:

N (%): 1 (90.9%)

Reasons (describe):

-did not show up for treatment

Control:

N (%): 1 (90.9%)

Reasons (describe)

-did not want control intervention

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Wolf Motor Function Test:

Mean ±SD scores at pre- and post-test assessment:

I:

Pre: 41,5 ±5,2

Post: 47,9 ±9,0

C:

Pre: 34,7 ±12,0

Post: 41,0 ±10,1

Between-group effect size: 0

Motor Activity Log, Arm Use Score

Mean ±SD scores at pre- and post-test assessment:

I:

Pre: 1.7 ±0.4

Post: 4.4 ±0.7

C:

Pre: 1.6 ±0.7

Post: 2.2 ±1.3

Between-group effect size: 1.6

Rocca, 2018

Type of study:

RCT

Setting and country:

Italy

Funding and conflicts of interest:

-government & non-government funding

-MAR received

speakers honoraria from Biogen Idec, Novartis, Teva

Neurosciences, Merck-Serono, Genzyme, and Roche

and received research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. AM, SF, EP, RG, FE, and CC have nothing to disclose. FMB received honoraria for consulting, research grant, and travel expenses from

TEVA Neuroscience, Biogen Idec, Merck-Serono. PP received speakers honoraria from Biogen Idec,

Novartis, and EXCEMED. G.C. has received compensation

for consulting services for Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, EXCEMED,

Roche, Almirall, Chugai, Receptos, and Forward Pharma and compensation for speaking activities for

Novartis, Teva, Sanofi, Genzyme, Merck, Biogen,

EXCEMED, and Roche. MF is Editor-in-Chief of the Journal of Neurology has received compensation

for consulting services and/or speaking activities

from Biogen Idec, Merck-Serono, Novartis, Teva

Pharmaceutical Industries and receives research support from Biogen Idec, Merck-Serono, Novartis, Teva

Pharmaceutical Industries, Roche, Italian Ministry of

Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA.

Inclusion criteria:

-MS patients had to have, at

neurological examination, hyposthenia of ⩾1 righthand muscles (i.e. flexors, extensors, adductors, and

abductors) with or without spasticity, determining an

activity limitation of the right hand, without severe

sensory or cerebellar deficits (sensory and cerebellar

functional system scores of EDSS ⩽ 1 in the right hand).

Exclusion criteria:

-

N total at baseline:

Intervention: 20

Control: 21

Important prognostic factors²:

age (range):

I: 50.4 (33-70)

C: 51.5 (35-66)

Sex:

I: 45% M

C: 28.6% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Action observation training - During the 2 weeks of study, each subject underwent a 40-minute daily session dedicated to upper arm rehabilitation and a 40-minute daily standard rehabilitation session not specific for upper limb impairment. The ordering of rehabilitation type was randomized across patients between the two sessions. The training consisted of 10 minutes of right upper limb passive mobilization, viewing of three videos and execution of right-hand daily-life activities. The intervention group watched video sequences containing daily-life right-hand and arm actions.

Describe control (treatment/procedure/test):

During the 2 weeks of study, each subject underwent a 40-minute daily session dedicated to upper arm rehabilitation and a 40-minute daily standard rehabilitation session not specific for upper limb impairment. The ordering of rehabilitation type was randomized across patients between the two sessions. The training consisted of 10 minutes of right upper limb passive mobilization, viewing of three videos and execution of right-hand daily-life activities. The control group watched videos of inanimate landscapes which are unlikely to elicit activity in the motor or MNS areas.

Length of follow-up:

2 weeks

Loss-to-follow-up:

Not described

Incomplete outcome data:

Not described

Outcome measures and effect size (include 95%CI and p-value if available):

Handgrip strength: right hand

Mediaan (IQR):¹

I:

Pre: 15,9 (2-45)

Post: 19,2 (2-47)

Within-group difference: p<0,001

C:

Pre: 13 (1-38)

Post: 15,3 (1-32)

Within-group difference: p=0,3

Between-group difference: p=0,04

Handgrip strength: left hand

Mediaan (IQR):¹

I:

Pre: 19.6 (0-44)

Post: 20.7 (0-49)

Within-group difference: p=0.03

C:

Pre: 23.3 (1-48)

Post: 24 (0-56)

Within-group difference: p=0.1

Between-group difference: not reported

Pinch strength: right hand

Mediaan (IQR):

I:

Pre:4.9 (0,5-10)

Post: 5.2 (1-13)

Within-group difference: p<0.001

C:

Pre: 4.2 (0,4-13)

Post: 4.6 (0,4-11)

Within-group difference: p=0,004

Between-group difference: p=0.01

Pinch strength: left hand

Mediaan (IQR):

I:

Pre: 5.3 (0-13)

Post: 6.7 (0-13)

Within-group difference: p=0.09

C:

Pre: 6.5 (0.3-12)

Post: 6.6 (0-13)

Within-group difference: p=0.7

Between-group difference: not reported

FIM:

Mediaan (IQR):

I:

Pre: 33.0 (12-42)

Post: 34.5 (14-42)

Within-group difference: p=0.02

C:

Pre: 36 (23-42)

Post: 36 (23-42)

Within-group difference: p=0.1

Between-group difference: not reported

Ortiz-Rubio, 2016

Type of study:

RCT

Setting and country:

Spain

Funding and conflicts of interest:

Funding not reported.

Conflicts of interests: none

Inclusion criteria:

-diagnosis of relapsing-remitting MS,

secondary progressive MS, or primary progressive MS according to the criteria formulated by McDonald et al;

-adults between the ages of 18-65 years;

-patients with an EDSS<7.5;

-patients with a MMSE>24.

-Patients reported upper limb impairment;

-at least on 1 hand a pathological 9-HPT with 2 SD above the mean normal values published by

Oxford Grice et al at screening.

Exclusion criteria:

-exacerbation of MS during the

previous 3 months;

-steroid treatment within the preceding 2

months;

-rapidly progressive MS;

-presence of concomitant

neurologic, rheumatic, or orthopedic disorders that might interfere

with the intervention;

-comprehension deficits that prevented

them from following verbal commands;

-presenting with musculoskeletal disorders affecting

hand or finger mobility and/or a previous trauma or fracture of an upper extremity.

N total at baseline:

Intervention: 19

Control: 18

Important prognostic factors²:

age ± SD:

I: 42.2 ±7.5

C: 44.9 ±10.9

Sex:

I: 73.7% M

C: 66.7% M

Groups comparable at baseline?

yes

Describe intervention (treatment/procedure/test):

Home-based upper limb training program consisting of two 60-minute sessions per week for 8 consecutive weeks. The first session was an introduction session and was not included in the

8-week program. Sessions were individually developed and supervised by an occupational therapist and a physical therapist. Both were present at each home session. Sessions began with 10 minutes of warm-up of active mobility of the upper limbs. Afterward, each session was divided into 3 parts: fine motor

(15 minutes), manual coordination and dexterity (15 minutes), and

strengthening exercises for the upper limbs (15 minutes). At the end, patients performed 5 minutes of stretching exercises. All exercises were performed bilaterally with a primary focus on the more affected upper limb. For fine motor exercises, resistance therapeutical puttyc was used. Exercises proposed included the following (1.5 minutes each exercise per arm): rolling the putty into a ball, placing the ball in the hand and squeezing as hard as they could for a count of 5, rolling the putty into a thick rope, pushing with the fingers into the putty, and twisting the putty along the rope. Dexterity and coordination exercises were based on handling activities; in-hand manipulation; transfer (1.5 minutes each per arm); and assembly of small objects such as pins, nuts, rings, marbles, and beads (6 minutes using both hands). Strengthening exercises were performed with elastics bands

including the major muscles of the upper limbs in diagonal combinations. Two exercises were included with a duration of 7.5

minutes each, alternating both upper limbs. They started slowly from the distal to the proximal joints. The first exercise finished in

shoulder flexion, abduction and external rotation, elbow extension, and wrist extension position and the second one in shoulder

extension, adduction and internal rotation, elbow extension, and wrist flexion position. Upper limb stretching exercises were performed for 5 minutes

at the end of each session including the major upper limb muscles.

The intervention program was developed with both visual feedback and continuous verbal orders from the therapists. The

program was individually adapted to each patient, increasing the range of motion, the resistance of the putty, the size of the objects, the speed of the exercises, and the resistance of the elastic bands. Fatigue was assessed with a visual analog scale at the start and end of every session. Resistance progression was based on a protocol in which when subjects could complete 2 sets of 10 repetitions

through the available range of motion and without a significant increase on fatigue resistance, the exercise increased in difficulty. The exercises were adapted according to the levels of fatigue using the visual analog scale and the feedback of patients.

Cointerventions such as ongoing physical or occupational therapies were continued unchanged during the study for all patients.

Describe control (treatment/procedure/test):

Patients allocated to the control group received a booklet with information regarding upper limb alterations and a schedule

explaining basic exercises for active mobilization and stretching with pictures and a short text to be performed twice per week for 60 minutes at home. They also received information about how to

regulate the training intensity taking into account fatigue levels. These patients received a phone call to supervise the performance of the exercises at the end of weeks 4 and 8. Cointerventions such as ongoing physical or occupational therapies were continued unchanged during the study for all patients.

Length of follow-up:

8 weeks

Loss-to-follow-up:

Intervention:

N (%): 0

Reasons (describe)

Control:

N (%): 0

Reasons (describe)

Incomplete outcome data:

Not described

Outcome measures and effect size (include 95%CI and p-value if available):

Handgrip strength:

Most affected arm, mean difference within groups:

I: 6.4 ±4.1, p<0.001

C: 0.7 ±4.3, p=0.50

Between-group difference: p=0.009

Least affected arm, mean difference within groups:

I: 3.8 ±4.1, p=0.001

C: 1.4 ±5.5, p=0.29

Between-group difference: p=0.08

Pinch strength:

Most affected arm,

mean difference within groups:

I: 1.3 ±0.8, p=0.03

C: 0.01 ±1.5, p=0.97

Between-group difference: p=0.02

Least affected arm,

mean difference within groups:

I: 0.3 ±1.7, p=0.46

C: 0.6 ±1.6, p=0.14

Between-group difference: p=0.79

ARAT

Most affected arm,

mean difference within groups:

I: 2.2 ±0.6, p=0.04

C: 0.2 ±0.9, p=0.45

Between-group difference: p=0<0.001

Least affected arm,

mean difference within groups:

I: 0.7 ±0.4, p=0.04

C: 0.2 ±0.5, p=0.19

Between-group difference: p<0.001

Feys, 2015

Type of study:

RCT

Setting and country:

Belgium

Funding and conflicts of interest:

Funding: not reported

Conflicts of interest: none declared.

Inclusion criteria:

-diagnosed according to the McDonald

Criteria;

-upper limb weakness determined by the

Motricity Index (MI< 85).

Exclusion criteria:

-(nearly) total paralysis of both upper limbs

based on the Motricity Index

-presenting with visual, cognitive

and cerebellar dysfunctions, as detected by the neurologist

during evaluation of the related functional

systems of the EDSS and potentially interfering with

task execution;

-having a relapse in the last month before study onset or receiving relapse related

glucocorticosteroid treatment

N total at baseline:

Intervention: 9

Control: 8

Important prognostic factors²:

age median (IQR):

I: 58 (56-65)

C: 61 (47-75)

Sex:

I: 67% M

C: 50% M

Groups comparable at baseline?

Control group had shorter disease duration (25 (14-27) yrs versus. 14 (9-19.5) yrs, p=0.09)

Describe intervention (treatment/procedure/test):

Robot training in addition to usual care.

Usual care: Participants were either hospitalised in the Rehabilitation and MS Center Overpelt (Belgium) for multiple weeks receiving treatment from multiple disciplines, or bi-weekly attended rehabilitation

sessions at the rehabilitation center on an ambulant basis, i.e. with the participant living in the community and coming to the center for therapy purposes. The conventional rehabilitation program consisted of 2 h

multidisciplinary treatment per day including 30 min

physiotherapy, 30 min occupational therapy and 60 min group physiotherapy, speech therapy or psychotherapy

depending on the needs of the participant.

Robot training was provided

for the duration of 8 consecutive weeks at a frequency of 3 times per week, on Mondays, Wednesdays and Fridays. The training sessions always took place at the same time

of day and lasted for 30 min. In total the participants

received 12 h of robot training in addition to usual care.

The HapticMaster robot (MOOG, the Netherlands) functioned both as an output device, providing haptic feedback during

the training by guiding or hindering movements with

exerted forces, but also as an input device, allowing

navigation within a virtual learning environment. Training occurred in a sitting position in a chair or in a wheelchair. The participant’s hand was placed in a small palmar brace embedded in an ADL gimbal that was connected to the endpoint of the HapticMaster. Participant’s hand movements were unrestrained, allowing spontaneous opening

and closing of the hand. A large 40” screen was placed at 1.5 m in front of the participant to display the virtual learning environment. At the beginning of each session, the need for gravity

compensation was individually determined. The virtual learning environment permits training of different skill components separately

such as lifting, transporting, pushing, pulling, reaching

and retrieving and rubbing. Each training session consisted of 30 min training, starting with basic motor function exercises of different skill components

separately, followed by the serious games. Training in the virtual learning environment was personalized.

The initial selection of the basic motor function

exercises of different skill components and serious

games that was provided to the patient was based on a

semi-structured interview.

Describe control (treatment/procedure/test):

Usual care: Participants were either hospitalised in the Rehabilitation and MS Center Overpelt (Belgium) for multiple weeks receiving treatment from multiple disciplines, or bi-weekly attended rehabilitation

sessions at the rehabilitation center on an ambulant basis, i.e. with the participant living in the community and coming to the center for therapy purposes. The conventional rehabilitation program consisted of 2 h

multidisciplinary treatment per day including 30 min

physiotherapy, 30 min occupational therapy and 60 min group physiotherapy, speech therapy or psychotherapy

depending on the needs of the participant.

Length of follow-up:

8 weeks

Loss-to-follow-up:

Intervention:

N (%): 0

Reasons (describe)

Control:

N (%): 1 (11.1%)

Reasons (describe)

-diagnosed with cancer

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Hand grip strength:

Median (interquartile range) within-group difference:

I: -0.3, p=n.s.

C: 0.7, p=n.s.

Between-group difference: not reported

ARAT

Median (interquartile range) within-group difference:

I: -0.2, p= n.s.

C: -1.0 p= n.s.

Between-group difference: not reported

MI

Median (interquartile range) within-group difference:

I: -8, p= n.s.

C: -6.5, p= n.s.

Between-group difference: not reported

FMA

Median (interquartile range) within-group difference:

I: 0, p= n.s.

C: 1, p= n.s.

Between-group difference: not reported

MAL

“After 8 weeks training, a near threshold significant difference (p=0.048) was present between both groups for the MAL amount of use and total MAL.”

Median (interquartile range) within-group difference:

I: -0.1 p= n.s.

C: -0.1, p= n.s.

Bonzano, 2014

Type of study:

RCT

Setting and country:

Italy

Funding and conflicts of interest:

-Funding: non-government

-conflicts of interest: none declared.

Inclusion criteria:

-Righthanded patients with MS in a stable phase of disease;

-presenting with moderate sensorimotori deficits in one or both upper limbs

Exclusion criteria:

-relapses and steroid-use or a worsening on the EDSS in the last three months

-psychiatric disorders

-severe cognitive impairment

N total at baseline:

Intervention: 15

Control: 15

Important prognostic factors²:

age ± SD:

I: 43.4 ±9.1

C: 43.2 ±8.6

Sex:

I: 33% M

C: 47% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Active upper limb rehabilitation.

Patients underwent twenty 1-hour treatment sessions, three times aweek, at AISM Rehabilitation Centre, Italian Multiple Sclerosis Society, Genoa, Italy

The treatment group was rehabilitated with an active protocol based on voluntary exercises for neuromuscular control to improve proprioceptive sensibility, muscle strength, stability and coordination of the upper limbs, mainly

including task-oriented exercises with the goal to improve activities of daily living (Nelson, 1996). The first 5 sessions of the rehabilitative protocol were focused on voluntary exercises executed unilaterally with the right and left upper limbs (60% of treatment time). This part of the treatment dealt with both non task-oriented exercises, such as grasping wooden cubes of different sizes, pinching, reaching

a target displayed in front of the patient, and task-oriented exercises such as ironing a shirt and putting a dish in a draining board. In

the last 40% of the treatment, bimanual task-oriented exercises, such

as sewing, doing patchwork and paper mandala, cooking, sweeping,

and screwing a cap on a bottle,were administered to the patients. Gradually,

from the 6th to the 12th sessions, the percentage of bimanual

task-oriented exercises increased to reach 100% in the last 5 sessions.

Thus, unimanual and bimanual voluntary exercises were differently

weighted in each session along the rehabilitative program (sessions

1–5: 60%–40%, respectively; sessions 6–10: 40%–60%, respectively;

sessions 11–15: 20%–80%, respectively; and sessions 16–20: 0%–100%,

respectively).

The control

Describe control (treatment/procedure/test):

Passive upper limb mobilisation.

Patients underwent twenty 1-hour treatment sessions, three times a week, at AISM Rehabilitation Centre, Italian Multiple Sclerosis Society, Genoa, Italy

The control group only performed tasks without detectable muscle activity, through passive mobilization of the shoulder, elbow, wrist and fingers delivered by a physical therapist. Analogously, in the passive

rehabilitation protocol the percentage of unimanual and bimanual passive

mobilizations delivered by the therapist followed the scheme used for the “treatment group” (i.e., sessions 1–5: 60%–40%, respectively; sessions 6–10: 40%–60%, respectively; sessions 11–15: 20%–80%,

respectively; and sessions 16–20: 0%–100%, respectively).

Length of follow-up:

2 months

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Hand grip strength:

ANCOVA: time-by-group interaction: p=0,92

ARAT

ANCOVA: time-by-group interaction: p=0,51

results only presented in figure 2.

Gandolfi, 2018

Type of study:

RCT

Setting and country:

Italy

Funding and conflicts of interest:

-Funding: non-governmental

-conflict of interests: Not reported

Inclusion criteria:

-confirmed MS diagnosis,

-aged 18-65 years,

-EDSS=1.5≤x≤8,

-MMSE ≥24/30

-Modified Ashworth Scale

score <2 evaluated at the elbow, wrist, and fingers,

-9-HPT score >30 and <300s.

Exclusion criteria:

-relapse or relapse-related treatments in the 3

months before entering the study,

-musculoskeletal impairments

or visual analog scale (VAS) for pain score > 7/10 in any joint

that could interfere with the training program,

-severe visual

dysfunction, any type of rehabilitation in the month prior to

recruitment,

-other concomitant neurological or orthopedic

diseases involving the upper limb and interfering with their function.

N total at baseline:

Intervention: 23

Control: 21

Important prognostic factors²:

For example

age ± SD:

I:

C:

Sex:

I: % M

C: % M

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Robot-assisted handtraining:

Patients received individualized treatment for 50min/day, 2 days/week for 5 weeks at the physical

therapy facility of the Neurorehabilitation Unit (AOUI Verona). At the end of each session, upper limb passive mobilization

was performed in supine position for 10min.

Patients underwent robot-assisted hand training on an Amadeo (Tyromotion, Austria). This mechatronic end-effector computer-assisted robotic device is specifically designed to

improve sensorimotor functions in patients with restricted hand function. Therapy sessions were conducted by a physical therapist experienced in use of the device. The patient

was seated in a comfortable position and the arm strapped into an adjustable stabilizing splint attached to the robotic device, with the wrist in neutral position and the forearm pronated. The

wrist was stabilized to the body of the device by means of a spring-loaded hinge, which allowed for some degree of passive

flexion and extension during use. The height of the device was adjusted to an angle of about 30◦ of elbow flexion. Each finger was attached to the robotically driven slide with magnets taped to the distal phalanx of each finger. Three different training modes were performed: (1) continuous passive motion (CPM) during which the hand is passively stimulated in finger flexion and extension (10min); (2) assistive therapy in which the hand is functional but is actively trained at the patient’s limit of performance (10min); (3) interactive therapy via active training with specifically developed virtual therapy games (10min) in which the patient exerts isometric force in flexion or extension to avoid obstacles or to reach a target (fire) shown on the

video. The isometric force produces proportional movement of a virtual figure. The physiotherapist sets task difficulty from

among 30 pre-selected levels graded by duration, force, and accuracy in completing the task. Each exercise was repeated

several times according to the patient’s ability and task complexity was increased as performance improved.

Describe control (treatment/procedure/test):

Upper limb rehabilitation:

Patients received individualized treatment for 50min/day, 2 days/week for 5 weeks at the physical

therapy facility of the Neurorehabilitation Unit (AOUI Verona). At the end of each session, upper limb passive mobilization

was performed in supine position for 10min.

The protocol for upper limb rehabilitation was designed

according to the neuro-developmental technique and consisted of upper limb mobilization (shoulder girdle, elbow, wrist, and finger joints), facilitation of movements, and active tasks chosen out of 15 that are challenging for patients. The exercises were focused on improving muscle strength in flexion and extension, dexterity, and motor control. At the end of each treatment session, the patient received feedback about her/his performance

in terms of the number of errors and comments on execution of movement.

Length of follow-up:

5 weeks

Loss-to-follow-up:

Intervention:

N (%): 2 (8.7%)

Reasons (describe)

-discontinued intervention

Control:

N (%): 3 (14.3%)

Reasons (describe)

-discontinued intervention

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

ARAT

I:

Pre: 41.6 ±15.2

Post: 46.5 ±14.4

C:

Pre: 41.6 ±14.6

Post: 45.1 ±13.4

ANOVA: time-by-group interaction: p= n.s.

MI

I:

Pre: 81.2 ±17.1

Post: 84.9 ±14.2

C:

Pre: 80.7 ±14.0

Post: 84.7 ±13.3

ANOVA: time-by-group interaction: p= n.s.

FMA

I:

Pre: 51.7 ±14.9

Post: 54.6 ±13.7

C:

Pre: 52.7 ±12.6

Post: 57.1 ±11.3

ANOVA: time-by-group interaction: p= n.s.

MAL – Quality of movement

I:

Pre: 97.0 ±41.4

Post: 102.2 ±42.2

C:

Pre: 95.9 ±40.0

Post: 100.7±41.4

ANOVA: time-by-group interaction: p= n.s.

MSQoL-54

Physical health

I:

Pre: 42.5 ±19.2

Post: 44.8 ±18.6

C:

Pre: 43.9 ±17.2

Post: 43.2 ±18.8

ANOVA: time-by-group interaction: p= n.s.

Mental health

I:

Pre: 54.6 ±25.8

Post: 58.8 ±22.1

C:

Pre: 56.8 ±19.4

Post: 60.8 ±23.2

ANOVA: time-by-group interaction: p= n.s.

Kamm, 2015

Type of study:

RCT

Setting and country:

Switzerland

Funding and conflicts of interest:

-Funding: Commercial

-Conflicts of interests: none declared

Inclusion criteria:

-Patients with clinically isolated syndrome, relapsing–

remitting MS, secondary progressive MS or primary progressive MS according to the 2010 McDonald’s

criteria

-acknowledge impaired manual dexterity upon asking,

-pathological Coin Rotation Task on at least one hand (>19 s) and/or 9-HPT 2 SD above the mean normal values,

Exclusion criteria:

-relapses and/or steroid treatment within the prceding 2 months,

-Rapidly progressive MS,

Additional diseases or conditions apart from MS that affect manual dexterity or compromise the adequate performance of the study procedures.

N total at baseline:

Intervention: 20

Control: 19

Important prognostic factors²:

age ± SD:

I: 49.2 ±10.9

C: 51.9 ±8.0

Sex:

I: 30% M

C: 37% M

Groups comparable at baseline?

yes

Describe intervention (treatment/procedure/test):

Dexterity training:

Patients were instructed into their homebased

training programs by one occupational therapist or neurologist with expertise in MS. Patients trained 5 days per week (approx. 30 min/day) for 4 weeks.

All exercises were performed with both hands.

Patients received a booklet explaining all exercises with pictures and a short text. This booklet contained a diary to document if an exercise was performed and, if applicable, the time needed to accomplish the exercise.

The dexterity program

was adapted from a published Arm Ability Training program that showed high efficacy in improving manual

dexterity and timed performance in dexterity-related ADL in patients with mild arm paresis after

stroke and traumatic brain injury. Patients had to

perform six different exercises. Exercises 1–4 were performed at baseline as fast as possible and the number of achieved task in 1 minute was noted. At home, patients had to perform the achieved number at baseline as fast as possible, and note the time needed. Exercises 5 and 6 were performed

without measuring the time.

Describe control (treatment/procedure/test):

Theraband training:

Patients were instructed into their homebased

training programs by one occupational therapist or neurologist with expertise in MS. Patients trained 5 days per week (approx. 30 min/day) for 4 weeks.

All exercises were performed with both hands.

Patients received a booklet explaining all exercises with pictures and a short text. This booklet contained a diary to document if an exercise was performed and, if applicable, the time needed to accomplish the exercise.

Patients had to perform

seven upper extremity strength-training exercises

using a Theraband. Exercises are commonly used in the rehabilitation of many diseases including MS.

Patients had to note whether they performed the exercise or not.

Length of follow-up:

4 weeks

Loss-to-follow-up:

Intervention:

N (%): 1 (5%)

Reasons (describe)

-relapse

Control:

N (%): 0

Reasons (describe)

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Hand grip strength:

Mean within-group difference:

I:

Rechts: 2.3 (0.7 tot 3.8), p=0.02

Links: 2.7 (0.3 tot 5.1), p=0.38

C:

Rechts: 0.8 (−0.6 tot 2.1) p=0.3

Links: 0.9 (-0.6, 2.4), p=0.27

Adjusted between-group difference:

Rechts: −1.6 (–3.6 to 0.5) P=0.27

Links: -1.5 (-4.2 to 1.3), p=0.46

CAHAI-8

Mean within-group difference:

I: 1.4 (0.7 to 2.2), p=0.003

C: 1.0 (0.1 to 1.8) p=0.10

Adjusted between-group difference:

−0.3 (–1.4 to 0.7) P=0.62

Study reference

(first author, publication year)

Describe method of randomisation

Bias due to inadequate concealment of allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?

(unlikely/likely/unclear)

Bias due to loss to follow-up?

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?

(unlikely/likely/unclear)

Mark, 2018

The study coordinator entered the identity code of participants into a computer application after participants gave informed consent; participants were assigned to treatment group by a computer-generated random numbers table.

Unlikely

Unclear

Likely

Likely

Unlikely

Unlikely

Likely

Rocca, 2018

Not described

Unclear

Unclear

Unclear

Unclear

Unlikely

Unclear

Unlikely

Ortiz-Rubio, 2016

To ensure concealment of allocation, eligibility was determined by a blinded assessor. The randomization sequence (1:1) was drawn up and kept off-site by an independent body using a random

number generator in blocks of 4 with no stratification. The sequence of subjects included in every treatment group was

mailed from the independent body to the recruiter.

Unlikely

Likely

Likely

Unlikely

Unlikely

Unlikely

Unlikely

Feys, 2015

Included pwMS were randomly allocated in an MS intervention group (n = 9) and a MS control group (n = 8) by the sealed envelope method by a person not involved in the trial.

Unlikely

Likely

Likely

Unclear

Unlikely

Unlikely

Unlikely

Bonzano, 2014

Therefore, the 30 recruited PwMS were randomly assigned to two groups, with the use of a computer-generated schedule: one receiving an active motor rehabilitation treatment (“treatment group”—15 patients) and one receiving a passive motor rehabilitation treatment (“control group”—15 patients).

Unlikely

Unclear

Unclear

Unclear

Unlikely

Unclear

Unlikely

Gandolfi, 2018

Eligible patients were assigned to either the EG or the CG by a simple randomization scheme using an automated randomization system (www.randomization.com). Group allocation was kept concealed. The randomization list was locked in a desk drawer accessible only to the principal investigator.

Unlikely

Likely

Likely

Unlikely

Unlikely

Unclear

Likely

Kamm, 2015

Eligible patients were randomized 1:1 into the dexterity training or theraband training group in blocks of four using sealed envelopes.

Unlikely

Likely

Likely

Unlikely

Unlikely

Unlikely

Unlikely