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. 2019 Sep 30;9(9):e032092. doi: 10.1136/bmjopen-2019-032092

Table 3.

Summary of studies exploring interventions to promote walking and moving around for people with MJD

Staying strong domain: exercising your body
Study characteristics Participant characteristics Intervention Measurement and Outcomes
Author, year, country Design Level of evidence
NHMRC		 Quality MMAT Participants (n=);
diagnosis		 Age (y)
mean (SD)		 Mobility status Description Duration (week) Frequency
(/week)		 Intensity Outcome measures Assessment timepoints Significant
outcomes
Wang et al 2018
China		 RCT II **** n=9;
MJD		 Exp:
54 (51–60)
Control: 57 (44–61)		 Ambulant Exergames training vs conventional balance +coordination training 4 3 40 min

  • SARA (I)

  • Limit of stability test (A)

  • Spatiotemporal gait parameters (A)

  • Pre and post

 Between groups: not significant
Within group (exp group):

  • Improved SARA gait-posture (p=0.038)*, SARA total (p=0.042)*
Kaut et al
2014
Germany		 Pseudo RCT III-1 **** n=31;
MJD (n=2)
SCA1
SCA2
SCA6		 Exp:
61.2 (12.3)
Control:
57.3 (12.7)		 Ambulant Stochastic vibration therapy vs sham 8 days 4 sessions total 5×60 s on/60 s off

  • SARA (I)

  • SCAFI (A)

  • INAS (I)

  • Pre and post

 Between groups: not significant
Within group (exp group):

  • Improved SARA gait and posture (p<0.01)*, 8MWT (p=0.02)*
Conte et al
2017
Italy		 Non-randomised experimental trial III-2 **** n=13;
MJD (#)
SCA1
SCA2
SAOA		 50.2 (9.5) Ambulant Wide BOS walking vs walking between two white lines (width determined by healthy controls) 6×10 m walking trials per session, 1 min rest between trials 2 walking sessions on
2 separate days
1 week interval between days		 Gait speed matched to healthy controls

  • Spatiotemporal gait parameters (A)

  • Upper body and lower body kinematics (A)

  • Muscle coactivation (A)

  • Energy recovery and expenditure (I)

  • Each session recorded

 Between groups: not significant
Within group:

  • Narrow BOS walking: reduced speed*, step length*, hip and knee ROM*, energy recovery*; increased double support,* gait variability,* trunk oscillation,* ankle joint muscle coactivation*

  • Widened BOS walking—increased dynamic stability*; reduced compensatory mechanisms*, mechanical energy*
Tabbassum et al 2013
India		 Non-randomised experimental trial III-2 * n=20;
MJD (#)
SCA1
SCA2
SCA3
OPCA		 Not reported Ambulant Core stability training+balance training vs balance training+relaxation 4 3 1 hour/day

  • BESTest (A)

  • MFES (Falls) (A)

  • Pre and post

  • 4 weeks post

 Between groups (exp group):

  • BEStest each assessment*

  • Not significant: MFES
Fonteyn et al
2014
The Netherlands		 Case series with pretest/post-test outcomes IV **** n=10;
MJD (n=1)
SCA6
SAOA		 61.4 (5.7) Ambulant Gait adaptability training on treadmill with visual cues on treadmill 5 2 6 gait adaptability exercises for 60 min
No handrail used. Difficulty gradually progressed

  • Obstacle avoidance task success rate (A)

  • SARA (I)

  • 10MWT (A)

  • TUG (A)

  • BBS (A)

  • EFAP (A)

  • ABC (A)

  • No of falls (A)

  • Experience of training questionnaire (Q)

  • 1-week pre

  • 1-week post

 Between groups: NA
Within group:

  • Improved SARA and EFAP obstacle subtask*, increased short-step strategy preference (p=0.003)*, success rates increased (78.5%–94.8%)*

  • Not significant: BBS, TUG, 10MWT, Obstacle Avoidance Task
Im et al
2017
Korea		 Case series with pretest/post-test outcomes IV **** n=19;
MJD (n=3)
SCA2
SCA6
Idiopathic
MSA-C		 53.2 (13.8) Ambulant Task specific walking training: part practice (weight shifting, stepping)+whole practice of walking
Manual support provided and weaned as required		 12 2 1.5 hours each session

  • ICARS (I)

  • Spatiotemporal gait parameters (A)

  • Pre and post

  • 3 months post

 Between groups: NA
Within group:

  • Improved ICARS each assessment*; reduced spatiotemporal gait parameter variability*
Leonardi et al 2017
Italy		 Case series with pretest/post-test outcomes IV **** n=9;
MJD (n=2)
SCA1
SCA2
FA		 35.3 (16.3) Ambulant Wearable proprioceptive stabiliser+conventional balance training
(limit of stability training+external perturbations practice in protected conditions)		 Device wear: 3
Usual balance training:
6		 Device wear: 5
Usual balance training: 5		 Device wear:
3 (hour)
Usual balance training: 40

  • SARA (I)

  • 6MWT (A)

  • Spatiotemporal gait parameters (A)

  • Pre and post 3 weeks of device wear (T1)+usual training

  • 3 weeks postdevice discontinuation+usual training only (T2)

 Between groups: NA
Within group:

  • Improved SARA*, 9HPT-dominant hand*, PATA*, 6MWT*, spatiotemporal gait parameters (T1)*, length of gait cycle (T2)*
de Oliveira et al 2018
Brazil		 Case series with pretest/post-test outcomes IV ** Stage 1: n=9
Stage 2: n=5
MJD (n=6)
SCA1
SCA7		 43 (11) Ambulant PBWS treadmill training:
Stage 1: CV training
Stage 2: dynamic balance training		 Stage 1:8
Stage 2:10		 2 (days) 50 min

  • CPET (A)

  • BORG (A)

  • BBS (A)

  • DGI (A)

  • SARA (I)

  • BARS (I)

  • Katz ADL (Q)

  • Treadmill inclination (A)

  • Prestage 1 (S0)

  • Prestage 2 (S1)

  • Poststage 2 (S2)

 Between groups: NA
Within group:

  • S1: Improved DGI (p=0.03)*, CPET duration (p<0.01)*, treadmill inclination (p<0.01)*

  • S2: Improved BBS compared with S1 (p=0.04)*

  • Not significant: SARA, Katz ADL, BARS, VE peak/VO2 max
de Oliveira et al 2015
Brazil		 Case series with pretest/post-test outcomes IV **** n=11;
MJD (n=8)
SCA2
SCA7		 46.1 (range 28–59)
SD not reported		 Ambulant Balance training 4 2–3 1 (hour)

  • BBS (A)

  • Pre and post

 Between groups: NA
Within group:

  • Improved BBS (p=0.0034)*
Sawant and Gokhale
2015
India		 Case series with pretest/post-test outcomes IV *** n=3;
MJD (n=1)
Hereditary SCA		 24.6 (3.4) Ambulant Occupational therapy+intensive functional physical training
(tailored programme meaningful to participant)		 12 5
(supervised=3; home/ unsupervised=2)		 45 min–1 hour

  • BBS (A)

  • FIM+FAM (A)

  • Pre and post

 Between groups: NA
Within group:

  • Improved BBS (p=0.05)*, FIM+FAM (p=0.01)*
Silva et al
2010
Brazil		 Case series with pretest/post-test outcomes IV **** n=23;
MJD		 42.4 (10) Ambulant Occupational therapy: training priorities on functional limitations 6 months Once/week:
0–3 months
Once/month:
3–6 months		 40 min

  • FIM (A)

  • Barthel Index (A)

  • Hamilton rating scale (Q)

  • WHOQOL-BREF (Q)

  • NESSCA (I)

  • SARA (I)

  • Pre and post

  • Mid intervention

 Between groups: NA
Within group:

  • Improved Hamilton depression score at 6 months (p<0.0001)*

  • Not significant: FIM, Barthel Index, WHOQOL-BREF
D’Abreu et al
2010
Brazil		 Review (expert opinion section) V (JBI) NA n=23;
MJD		 NA NA NA NA NA NA Recommendations:

  • Physical therapy assessment +exercise programme.

  • Falls assessment and assistive device prescription

  • Trial levodopa for those with dystonia affecting mobility

  • Exercise improves ability to cope, increases self-esteem, boosts patients’ mood and sense of control over their disease.

  • Source of pain should be identified and managed appropriately (musculoskeletal/neuropathic/secondary to dystonia/mixed)
Staying strong domain: searching for good medicine
Study characteristics Participant characteristics Intervention Measurement and outcomes
Author,
year, country		 Design Level of evidence
NHMRC		 Quality MMAT Participants (n=);
diagnosis		 Age (y) mean (SD) Mobility status Description Duration (week) Frequency
(/week)		 Intensity Outcome measures Assessment timepoints Significant outcomes
Assadi et al
2007
USA		 RCT II *** n=19
MJD (n=2)
SCA1
SCA2
SCA17
FA
Idiopathic		 40.5 (17.3) Not stated Buspirone HCl
30 mg twice daily vs placebo
Crossover after
4 week washout		 Each treatment arm: 12
2 weeks of each arm consisted of titration period.		 Twice daily NA

  • ICARS (I)

  • Pre and post each treatment phase

 Between groups: not significant
Lei et al
2016
China		 RCT II ** n=34
MJD		 Multidose exp:
800 mg: 36.5 (5.4)
1200 mg: 33.9 (7.1)
sham:
33.9 (4.5)		 Ambulant Valproic acid
low-dose VPA (800 mg/day), high-dose VPA (1200 mg/day) vs placebo		 12 Twice daily NA

  • SARA (I)

  • Predose

  • Week 4

  • Week 8

  • Week 12

 Between groups:

  • Improved SARA in 1200 mg/day group (−2.05) compared with 800 mg/day (−1.58) and placebo (−0.75) (p=0.021)*

  • Improved SARA subscores in placebo and VPA groups (800 mg/day and 1200 mg/day) (p<0:05)*
Saute et a lˆˆ
2014
Brazil		 RCT II **** n=60
MJD		 Exp:
40.5 (9.6);
sham:
40.4 (9.2)		 Ambulant Lithium carbonate vs placebo  48 300 mg once/day; increased to twice daily until 0.5–0.8 mEQ/L NA

  • NESSCA (I)

  • SARA (I)

  • 8MWT (A)

  • SCAFI (A)

  • CCFS (A)

  • Barthel Index (A)

  • WHOQOL-BREF (Q)

  • BDI (Q)

  • PGI (Q)

  • Pre dose

  • 24 weeks

  • 48 weeks

 Between groups (exp group):

  • Improved SCAFI (24, 48 week)*; CCFS (48 week)*

  • Not significant —NESSCA, SARA, 8MWT, 9HPT, BDI, Barthel Index, WHOQOL-BREF, PGI
Schulte et al
2001
Germany		 RCT II ** n=20
MJD		 44.7 (11) Standing (minimum) Trimethoprim-sulfamethoxazole
trimethoprim (160 mg)+sulfamethoxazole (800 mg) 2/52; trimethoprim
(80 mg)+sulfamethoxazole (400 mg) remainder of 6 months		 Phase 1:
6 months exp or placebo
Washout: 4
Phase 2:
crossover to alternate preparation.		 Twice daily NA

  • Posturography (A)

  • ACRS (I)

  • SF36 (Q)

  • Pre

  • Post 2/52

  • Post each 6 months treatment phase

 Between groups: not significant
Wessel et al
1997
Germany		 RCT II *** n=18
MJD (n=2)
SCA1
idiopathic CA		 46.8
SD not reported		 Not stated Physostigmine (30 mg) patch vs sham patch Each treatment arm: 4
Washout: 1		 Patch worn continuously 24 hour/day

  • ACRS (I)

  • Posturography (A)

  • Pre and post each treatment phase

 Between groups: not significant
Zesiewicz et al
2012
USA		 RCT II *** n=13
MJD		 Exp
47.44 (10.83); Sham:
53.78 (11.18)		 Not stated Varenicline
4 weeks for titration and 4 weeks at 1 mg twice daily		 8 Max dose, twice daily NA

  • SARA (I)

  • T25FWT (A)

  • BDI (Q)

  • BAI (Q)

  • CGI (I)

  • PGI (Q)

  • SF36 (Q)

  • Pre and post

 Between groups (exp group)

  • Improved SARA subs scores (gait, stance, rapid alternating movements)*, T25FWT*, BDI (p<0.05)*

  • Not significant: CGI, PGI, BAI, SF36
Shiga et al
2002
Japan		 Non-randomised experimental trial III-2 *** n=74
MJD (#)
sporadic OPCA
SCA1
SCA6		 Exp:
58.83 (1.47)
Sham:
56.31 (1.96)		 Ambulant TMS over cerebellum vs sham 21 days Once daily

  •  10 pulses

  •  Pulse duration: 0.1 ms

  •  Output adjusted to 100% of maximum output

  • 10MWT (A)

  • Walking capacity (A)

  • Standing capacity (A)

  • Tandem steps (A)

  • Pre and post

 Between groups (exp group):

  • Improved 10MWT time (p<0.05)*, 10 m steps (p<0.05)*, tandem steps (p<0.005)*, standing capacities (p<0.05)*


Within group (sham group):

  • Improved 10 m time (p<0.05)*, 10 m steps (p<0.05)*, standing capacities (p<0.05)
Liu et al
2005
Taiwan		 Interrupted time series without a parallel control III-3 *** n=6
MJD		 27
SD not reported		 Ambulant Lamotrigine Week 0–1:
No meds
Week 2–7:
LTG (6 weeks)
Week 8–9: Withdrawal		 25 mg daily NA

  • TGI (A)

  • OLS (A)

  • Weekly

    (0–9 week)

 Between groups: NA
Within groups:

  • Improved TGI with LTG (p<0.05; week 4, 5, 6, 7)*, OLS scores (p<0.05; week 7)* but not during withdrawal
Arpa et a l
2015
Spain		 Case series with pretest/post-test outcomes IV **** n=12
MJD (7)
SCA7		 51 (13) Not stated Human IGF-1 (subcutaneous administration) 2 years Twice daily 0.05 mg/kg

  • SARA (I)

  • Pre

  • 4 months

  • 8 months

  • 12 months

  • 16 months

  • 20 months

  • 24 months

 Between groups: NA
Within group:

  • Improved SARA for SCA3 after IGF-1 treatment at 8 months (p=0.0061)*
Giordano et al
2013
Germany		 Case series with pretest/post-test outcomes IV ** n=14
MJD (2)
SCA1
SCA6
ADCA
POLG
SAOA		 60 (11.3) Ambulant Slow release 4-Aminopyridine 14 days Once daily 2×10 mg

  • SARA (I)

  • EQ-5D (Q)

  • 8MWT (A)

  • SCAFI (A)

  • Pre

  • 4 hour post 4-AP

  • 14 days post 4-AP

 Between groups: NA
Within group:

  • Improved SCAFI after 4 hours and after 14 days (p=0.01)*, 8MWT after 14 days*, but not after 4 hours (p<0.01)*

  • Not significant: SARA, 9HPT, EQ-5D
Monte et al
2003
Brazil		 Case series with pretest/post-test outcomes IV ** n=13
MJD		 41 (13) Ambulant Fluoxetine 6 Once daily 20 mg

  • EDSS (A)

  • UPDRS (A)

  • Pre and post

 Between groups: NA
Within group: not significant
Sanz-Gallego et al 2014
Spain		 Case series with pre/post-test outcomes IV *** n=26
MJD (n=19)
SCA6
SCA7		 SCA3: 50.3 (13)
Total: 49.3 (14.1)		 Ambulant IGF-1 therapy 12 months Twice daily NA

  • SARA (I)

  • SF36 (Q)

  • Pre

  • 4 months

  • 8 months

  • 12 months

 Between groups: NA
Within group:

  • Improved SARA (p=0.013), 8 and 12 months) in SCA3* and SCA7 subgroups after 12 months (p values not provided)*

  • SF36: 18.5% were dissatisfied, 14.8% had poor satisfaction, 37% had fair satisfaction, and 29.6% showed high satisfaction over study durations
Takei et al
2004
Japan		 Case series with pretest/post-test outcomes IV *** n=10
MJD		 41.9 (2.4) Ambulant and non-ambulant Tandospirone
15 mg/day, increased to 30 mg/day after 1 week		 7
Week 0–1:
Nil therapy
Week 1–4: Tandospirone
Week 5: Withdrawal
Week 6–7:
Follow-up with Tandospirone		 Once daily NA

  • ARS (I)

  • TLT (A)

  • SDS (Q)

  • Leg pain questionnaire (I)

  • ARS:

    Week 0, 4, 5, 7

  • SDS:

    Week 0, 4, 5, 6

  • Leg pain questionnaire: Week 0, 4, 5, 6

  • TLT:

    Week 0– 7

 Between groups: NA
Within group:

  • Improved ARS (from week 3) and SDS (from week 2) (p<0.05)*; Increased ICARS in withdrawal but decreased significantly to lower than pre-therapy level after restart (p<0.05)*

  • TLT reduced in 5/7 patients more than 10%

  • Leg pain alleviated in 5/7 patients (significance level not provided)

  • Not significant: SDS
Takei et al
2010
Japan		 Case series with pre-test/post-test outcomes IV ** n=39
MJD (n=14)
SCA1
SCA2
SCA6
MSA-C
MSA-P		 52.4 (14.5) Ambulant Tandospirone
15 mg/day		 4 Once daily NA

  • ICARS (I)

  • TLT (A)

  • SDS (Q)

  • Pre and post

 Between groups: NA
Within group:

  • Improved ICARS (p=0.005) (MJD)*, TLT (p=0.002) (MJD)*

  • SDS (significance not reported): 5/14 MJD scored>50 indicating depression; 3/5 improved to<50 after therapy
Tsai et al
2017
Taiwan		 Case series with pretest/post-test outcomes IV **** n=7
MJD (n=6)
MSA-C		 41.57
(range 21–66)
SD not reported		 Not stated Adipose mesenchymal stem cells Once Once NA

  • SOT—

    posturography (A)

  • SARA (I)

  • 1 month before baseline

  • 0.5, 1, 3, 6, 9 and 12 months after AD-MSC

 Between Groups: NA
Within group:

  • Improved SOT (p<0.05 at 3 and 6 months) (MJD)*

  • Not significant: SARA
Yang et al
2011
China		 Case series with pretest/post-test outcomes IV *** n=30
MJD (n=5)
SCA1
SCA2
SCA6
Unknown
FA		 43.14 (12.77) Not stated Stem cell treatment+balance training 4–6 weeks Stem cells:
4– 6 times
(5–7 day interval)
Balance training:
Twice daily		 Stem cells;
15–30 min
Balance training: 30 min/session

  • BBS (A)

  • Pre and post

 Between groups – NA
Within group:

  • Improved BBS (p=0.0001)*
Berntsson et al
2017
Scandinavia		 Qualitative III (JBI) *** n=4
MJD (n=1)
SCA4
SCA
FA		 56.7
(range 51–72)
SD not reported		 Not stated NA—qualitative investigation on patients’ experiences with cerebellar ataxia and intrathecal baclofen NA NA NA Overall theme: Living in the present/taking 1 day at a time.
Main categories:

  1. Uncertainty about the future

  2. Impact on life as a whole

  3. Feeling forced to terminate employment

  4. Limiting daily activities: helped manage cramps =+ve impact on mobility

  5. Intrathecal baclofen therapy: 3/4 recommended baclofen. Other participant not discussed.


+ves: improved control of body, improved sleep quality
-ves: Increased body weight
Staying strong domain: keeping yourself happy
Study characteristics Participant characteristics Intervention Measurement and outcomes
Author,
year, country		 Design Level of evidence
NHMRC		 Quality MMAT Participants (n=);
diagnosis		 Age (y) mean (SD) Mobility status Description Duration
(week)		 Frequency
(/week)		 Intensity Outcome measures Assessment timepoints Outcome
Lo et al
2016
Taiwan/USA		 Case series with pretest/post-test outcomes IV **** n=295
MJD (n=123)
SCA1
SCA2
SCA6		 SCA3: 51.1 (12.4) Not stated No intervention.
Evaluated the prevalence and influence of depressive symptoms on people with SCA		 NA NA NA

  • SARA 9I)

  • UHDRS-IV (A)

  • PHQ-9 (Q)

  • EQ-5D (Q)

  • Baseline

  • 6 months

  • 12 months

  • 18 months

  • 24 months

  • Depression common in SCAs (26%); significantly higher in SCA3

  • Depression associated with SARA but did not significantly progress over time or deteriorate with increased CAG repeats

  • Depression significantly impacted negatively on functional status and QOL in all SCAs, independent of ataxia progression
Sawant and Gokhale
2015
India
(also reported in ‘exercising your body’)		 Case series with pretest/post-test outcomes IV *** n=3
MJD (n=1)
Hereditary SCA		 24.6 (3.4) Ambulant Occupational therapy+intensive functional physical training
(tailored programme meaningful to participant)		 12 5
(supervised=3; home or unsupervised=2)		 0.45–1

  • BBS (A)

  • FIM+FAM (A)

  • Prior to intervention

  • Post intervention

 Between groups: NA
Within group:

  • Improved BBS (p=0.05)*, FIM+FAM (p=0.01)*

Symbols: (?), Participant numbers per condition not provided; ˆˆ, randomised, double-blind, placebo-controlled—dose-controlled study phase analysed only; +, combined with; *, significance change <0.005.

ABC, Short version of Activities-specific Balance Scale; ACRS, Ataxia clinical rating scale; 4-AP, 4-Aminopyridine; BAI, Beck Anxiety Inventory; BARS, Brief Ataxia Rating Scale; BBS, Berg Balance Scale; BDI, Beck Depression Inventory; BESTest, Balance Evaluation System Test; BORG, Borg rating of perceived exertion scale; BOS, base of support; CCFS, Composite Cerebellar Functional Score; CGI, Clinical Global Impression; COM, Centre of MASS; CPET, Cardiopulmonary Exercise Test; CV, cardiovascular; DGI, Dynamic gait index; EDSS, Extended Disability Status Scale of Kurtzke; EFAP, Emory Functional Ambulation Scale: Obstacle subtask; EQ-5D, EuroQol health related quality of life measure; Exp, experimental group; FA, Friedreich’s ataxia; FIM, Functional Independence Measure; FIM+FAM, Functional Independence Measure + Functional Assessment Measure; 25FWT, Timed 25-foot walk test; 9HPT, 9-hole peg test; 9HPT, 9-hole peg test; ICARS, International Cooperative Ataxia Rating Scale; IGF-1, Insulin-like growth factor; INAS, Inventory of Non-Ataxia Symptoms; JBI, Joanna Briggs Institute Levels of Evidence for Meaningfulness; Katz ADL, Katz index of independence in activities of daily living; LTG, Lamotrigine; mEQ/L, milliequivalents per litre; MFES, Modified Falls Efficacy Scale; mg, milligrams; MJD, Machado-Joseph disease; MMAT, Mixed Methods Appraisal Tool; MSA-C, multisystems atrophy-cerebellar ataxia predominates; MSA-P, multisystems atrophy-Parkinson’s type; 6MWT, 6-minute walk test; 8MWT, 8-minute walk test; 10MWT, Timed 10m walk test; NESSCA, Neurological Examination Score for SCA; NHMRC, National Health and Medical Research Council; OLS, one leg standing; OPCA, olivopontocerebellar atrophy; PBWS, partial body weight support; PGI, Patient Global Impression; PHQ-9, Patient health questionnaire; QOL, quality of life; RCT, randomised controlled trials; ROM, Range of movement; S, Significant difference within groups; SAOA, sporadic adult-onset ataxia of unknown origin; SARA, Scale for Assessment and Rating of Ataxia; SCA, spinocerebellar ataxia; SCAFI, SCA Functional Index: Incudes 9HPT, 8MWT, PATA syllables within 10 sec test (PATA); SDS, Self-rating depression scale; SF36, short form 36 health survey; SOT, sensory organisation test; TGI, Tandem Gait Index; TLT, total length travelled; TMS, Transcutaneous Magnetic Stimulation; TUG, Timed Up and Go Test; UHDRS-IV, Unified Huntington’s Disease Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale; WHOQOL-BREF, World Health Organisation Quality of Life Questionnaire.