Criteria

Specific requirements

1. Was an 'a priori' design provided?

The research question and inclusion criteria should be established before the conduct of the review.

2. Was there duplicate study selection and data extraction?

There should be at least two independent data extractors and a consensus procedure for disagreements should be in place.

3. Was a comprehensive literature search performed?

At least two electronic sources should be searched. The report must include years and databases used (e.g. CENTRAL, Embase, and MEDLINE). Key words and/or MESH terms must be stated and where feasible the search strategy should be provided. All searches should be supplemented by consulting current contents, reviews, textbooks, specialised registers, or experts in the particular field of study, and by reviewing the references in the studies found.

4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?

The authors should state that they searched for reports regardless of their publication type. The authors should state whether or not they excluded any reports (from the systematic review), based on their publication status, language, etc.

5. Was a list of studies (included and excluded) provided?

A list of included and excluded studies should be provided.

6. Were the characteristics of the included studies provided?

In an aggregated form such as a table, data from the original studies should be provided on the participants, interventions and outcomes. The ranges of characteristics in all the studies analysed e.g. age, race, sex, relevant socioeconomic data, disease status, duration, severity, or other diseases should be reported.

7. Was the scientific quality of the included studies assessed and documented?

'A priori' methods of assessment should be provided (e.g. for effectiveness studies if the author(s) chose to include only randomised, double‐blind, placebo controlled studies, or allocation concealment as inclusion criteria); for other types of studies alternative items will be relevant.

8. Was the scientific quality of the included studies used appropriately in formulating conclusions?

The results of the methodological rigour and scientific quality should be considered in the analysis and the conclusions of the review, and explicitly stated in formulating recommendations.

9. Were the methods used to combine the findings of studies appropriate?

For the pooled results, a test should be done to ensure the studies were combinable, to assess their homogeneity (i.e. Chi² for homogeneity, I²). If heterogeneity exists a random‐effects model should be used and/or the clinical appropriateness of combining should be taken into consideration (i.e. is it sensible to combine?).

10. Was the likelihood of publication bias assessed?

An assessment of publication bias should include a combination of graphical aids (e.g. funnel plot, other available tests) and/or statistical tests (e.g. Egger regression test).

11. Was the conflict of interest stated?

Potential sources of support should be clearly acknowledged in both the systematic review and the included studies.

Total Score

Study

Reason for exclusion

Abdul Wahid 2015

Protocol only

Disease‐modifying treatments (since published in CENTRAL, Issue 10, 2016 in the Cochrane Library)

Maguire 2014

Protocol only

Young 2014

Protocol only

Pastula 2012

Disease‐modifying treatment

Beauverd 2012

Disease‐modifying treatment

Yi 2012

Protocol only

Miller 2012

Disease‐modifying treatment

Benatar 2009

Disease‐modifying treatment

Bongioanni 2009

Protocol only

Not related to treatment

Sathasivam 2007

Protocol only

Disease‐modifying treatment

Orrell 2007

Disease‐modifying treatment

Diana 2006

Protocol only

Disease‐modifying treatment

Bongioanni 2004

Disease‐modifying treatment

Annane 2014

Results for people with MND are not reported separately

Payne 2012

Studies included in this review for people with MND are already covered in the included studies

Lee 2012

Not a systematic review

Good 2014

Studies included in this review for people with MND are already covered in the included studies

Paolo 2015

Not a systematic review

Author/year

Date assessed as up to date

Interventions

Comparisons

Primary and secondary outcomes

Limitations*

Brettschneider 2013

July 2012

Any drug therapy, given by any route, in any dose, administered to relieve pain in ALS/MND

Not stated but assumed one intervention to another or to placebo or no intervention

Primary outcome (impairment):

• Pain relief (after 24 hours) (VAS or any other validated scales)

Secondary outcomes:

Impairment

• Pain relief (after 7 days)

Adverse events

No RCTs found

Baldinger 2012

Feb 2011

Any drug therapy (oral, subcutaneous or intravenous) or physical treatment which potentially relieves cramps in ALS/MND

Not stated but assumed one intervention to another or to placebo or no intervention

Primary outcome (impairment):

• Reduction in subjective global impression of muscle cramp burden measured through VAS

Secondary outcomes:

Impairment

• Cramp intensity/number of cramps in 24 hours preceding assessment by VAS

• Ratio of participants experiencing cramps to total number of participants (in studies where cramps were assessed as adverse events)

Activity and participation

• QoL

Adverse events

Ashworth 2012

July 2011

1) Physical therapy/physiotherapy

2) Modalities (e.g. heat, cold, vibration, electrical stimulation)

3) Non‐prescription medications (e.g. vitamins, herbals, diet supplements)

4) Chemical neurolysis (e.g. phenol blocks, botulinum toxin)

5) Surgical intervention (e.g. intrathecal pumps, tenotomy, dorsal rhizotomy)

6) Alternative therapies (e.g. reflexology, aromatherapy, relaxation techniques)

Not stated but assumed one intervention to another or to placebo or no intervention

Primary outcome (impairment):

• Reduction in spasticity at three months as measured by Ashworth (or modified Ashworth) spasticity scale

Secondary outcomes:

Impairment

• Reduction in spasticity based on history (e.g. spasm frequency score), physical examination (e.g. reflex score) or physiology (e.g. pendulum test)

Activity and participation

• Disability/activity limitation (e.g. functional independence measure)

• QoL

Adverse events

Cost‐effectiveness

Radunovic 2013

May 2012

All forms of non‐invasive ventilation (NIV) and tracheostomy assisted ventilation

No intervention or best standard care

Primary outcome:

• Survival as assessed by pooled hazards ratio using life table/Cox regression methods to combine disparate periods of observation from all studies

Secondary outcomes:

• Survival at 1 month and 6 months and longer

Activity and participation

• Function – such as ALSFRS

• QoL

Adverse events

Young 2011

September 2010

1) Any drug treatment administered via any route

2) Injection of botulinum toxin in parotid and/or submandibular glands

3) Radiotherapy to the salivary glands

4) Surgical techniques, for example the ligation of parotid and submandibular salivary ducts

5) Other treatments identified in the literature such as complementary therapies

One intervention to another or to placebo or no intervention

Primary outcome (impairment):

• Subjective improvement in sialorrhoea

Secondary outcomes:

Impairment

1. Reduction in amount of saliva production using an objective measure such as weight of swabs or amount of tissue used

Activity and participation

1. QoL

Adverse events

Katzberg 2011

September 2009

Placement of percutaneous endoscopic gastrostomy (PEG) or other tube feeding

No feeding tube and continued oral intake

Primary outcome:

• Survival time

Secondary outcomes:

Impairment

1. Quantitative index of change in nutritional status (e.g. weight change, change in body mass index, other nutritional markers such as pre‐albumin level)

Activity and participation

1. QoL

Adverse events (safety of PEG)

No RCTs found

Fang 2013

July 2012

Repetitive transcranial magnetic stimulation (rTMS)

No intervention or sham rTMS or physiotherapy or medications or different methods of applications of rTMS such as high‐frequency (> 1 Hz) compared to low frequency (≤ 1 Hz) rTMS

Primary outcome (activity and participation):

• Disability or limitation in activity as measured by ALSFRS‐R (6 months)

Secondary outcomes:

Impairment

• Changes to muscle strength as measured by Manual Muscle Testing (1 and 6 months or longer)

• Changes to fatigue as measured by Fatigue Severity Scale (1 and 6 months or longer)

Activity and participation

• Disability or limitation in activity as measured by ALSFRS‐R (12 months)

Adverse events

Dal Bello‐Haas 2013

July 2012

Progressive resistance or strengthening exercise and endurance or aerobic exercise

No exercise or standard rehabilitation management

Primary outcome (activity and participation):

• Improvement in functional ability, decrease in disability or reduction in rate of decline as measured by ALSFRS‐R or other validated outcome measures (3 months)

Secondary outcomes:

Impairment

• Decrease in fatigue

• Change in rate of decline of muscle strength

• Change in rate of decline of aerobic endurance

Activity and participation

• Improvement in psychological status or QoL

Adverse events

(all at 3 months)

Ng 2011

July 2011

Multidisciplinary care as defined by any intervention delivered by two or more allied health disciplines (includes nursing physiotherapy, occupational therapy, speech therapy, etc.), directed by a physician, designed to be patient‐centred and aimed at maximising activity and participation.

Lower level or different type of intervention such as “routinely available local services” or “minimal intervention” (such as information only), waiting list conditions

Primary outcomes (activity and participation):

• Improvement in QoL

Secondary outcomes:

Impairment

• Improvement in Impairment (e.g. FVC)

Activity and participation

• Improvement in functional ability (e.g. ALSFRS)

• Participation and environmental or personal context (e.g. caregiver strain index)

Survival

Hospitalisation such as readmission and hospital length of stay

Adverse events

Cost‐effectiveness of care

No RCTs found

Author/year

Brettschneider 2013

Baldinger 2012

Ashworth 2012

Radunovic 2013

Young 2011

Katzberg 2011

Fang 2013

Dal Bello‐Haas 2013

Ng 2011

'A priori' design for the systematic review provided

Y

Y

Y

Y

Y

Y

Y

Y

Y

Duplicate study selection and data extraction

Y

Y

Y

Y

Y

Y

Y

Y

Y

Comprehensive literature search

Y

Y

Y

Y

Y

Y

Y

Y

Y

Search for studies regardless of their publication type

Y

Y

Y

Y

Y

Y

Y

Y

Y

List of included and excluded studies provided

Y

Y

Y

Y

Y

Y

Y

Y

Y

Characteristics of included studies provided

NA

Y

Y

Y

Y

NA

Y

Y

NA

Scientific quality of included studies assessed and documented

NA

Y

Y

Y

Y

NA

Y

Y

NA

Scientific quality of included studies used appropriately in formulating conclusions

NA

Y

Y

Y

Y

NA

Y

Y

NA

Appropriate methods used to combine study findings

NA

Y

Y

Y

Y

NA

Y

Y

NA

Likelihood of publication bias assessed

NA

Y

Y

NA

NA

NA

Y

Y

NA

Conflict of interest stated for both the systematic review and included studies

NA

N

N

N

N

NA

N

N

NA

Total score (n/11)

11

10

10

10

10

11

10

10

11

Interventions at the level of impairment/symptoms

Drug therapy for pain

Author/year

Participants

Interventions

Comparisons

Outcomes in the review for which data are available

Quality of the evidence (GRADE) for reported efficacy outcomes

Brettschneider 2013

None

Not applicable

Not applicable

Not applicable

No RCTs found

Treatment for cramps

Baldinger 2012

13 RCTs

N = 4012¹

Tetrahydrocannabinol (THC), vitamin E, baclofen, riluzole, L‐threonine, xaliproden, memantine, gabapentin,

Placebo

Primary outcome:

• Memantine, tetrahydrocannabinol (THC) are probably ineffective (moderate‐quality evidence)

• vitamin E may be ineffective

• It is uncertain whether L‐threonine, gabapentin, xaliproden, riluzole, or baclofen are effective (very low quality evidence, or data not reported)

Secondary outcomes:

1. Cramp intensity/number of cramps in 24 hours preceding assessment by VAS – no statistical difference for THC (not assessed in other studies)

2. Ratio of participants experiencing cramps to total number of participants (in studies where cramps were assessed as adverse events) – not an outcome of interest in this review

3. QoL – not measured

4. Adverse events

Adverse effects for riluzole 100 mg/day – increased asthenia, spasticity, increase in liver enzymes, impaired respiratory function, and elevation in blood pressure

Adverse effects for vitamin E, baclofen, gabapentin, L‐threonine, xaliproden, memantine and THC not stated

Very low:

L‐threonine – 3 studies with very high risk of bias (very small sample sizes, unclear randomisation process and allocation concealment, incomplete outcome data)

Baclofen – 1 study with high risk of bias and very small sample sizes; subjective impression of cramps listed as an outcome but data not reported

Low:

Vitamin E – 1 study with clear randomisation, allocation concealment, and blinding, but high risk of selective reporting given change in protocol and no information given on number of participants at 12 months or date of last examination

Moderate:

THC – 1 study with low risk of bias

Memantine – 1 study with low risk of bias

Outcome not reported:

Riluzole – 3 studies, 2 of which had high risk of bias due to incomplete reporting and 1 at low risk of bias; cramps listed as an outcome but data not reported

Xaliproden – 2 studies with low risk of bias; cramps an outcome but results not given

Gabapentin – 1 study with low risk of bias. Cramps an outcome but data not reported

Treatment for spasticity

Ashworth 2012

1 RCT N = 25

Endurance exercises

“Usual activities”

Primary outcome:

Reduction in spasticity in favour of treatment group (mean reduction of −0.43, 95% CI −1.03 to 0.17 in intervention vs increase of 0.25, 95% CI −0.46 to 0.96 in control)

Secondary outcomes:

No statistically significant differences between exercise and placebo groups in muscle strength (manual muscle testing, fatigue (fatigue severity scale) and QoL (SF‐36). No adverse effects reported.

Very low:
1 trial with high risk of bias, unclear randomisation, no allocation concealment, no blinding, 50% attrition by 6 months.

Mechanical ventilation for supporting respiratory function

Radunovic 2013

1 RCT N = 41

Non‐invasive ventilation (NIV)

"Standard care"

Primary outcome:

Median survival was 48 days longer (219 days vs 171 days) compared to the standard care group (estimated 95% CI 12 to 91 days, P = 0.0062). In subgroup analyses, median survival of subgroup with good or moderately impaired bulbar function was significantly different in favour of NIV group (P = 0.0059) with survival 205 days longer than standard care participants (median 216 in NIV group vs 11 days in standard care group). In participants with poor bulbar function, NIV did not confer survival advantage (P = 0.92).

Secondary outcomes:

1) QoL – significant benefit in favour of NIV in maintenance of QoL in good or moderately impaired bulbar function subgroup (P = 0.0017 SF‐35 Health Survey mental component summary score; P = 0.0013 mean symptoms domain of the sleep apnoea QoL index) and significant benefit in favour of NIV in subgroup of poor bulbar function in improvement in mean symptoms domain of the sleep apnoea QoL index but not in the SF‐36 Health Survey mental component summary score

2) Function – such as ALSFRS – not measured

3) No adverse events reported.

Moderate:
1 trial with low risk of bias (clear random sequence generation, adequate allocation concealment, data was complete and there was no selective reporting or other bias. Blinding of participants was not possible and it was unclear if outcome assessors were blinded).

Originally 2 RCTs were identified with a total of 54 participants; however, 1 was a pilot study with no study protocol and incomplete data (data available for 6 out of the 13 participants) and was therefore not included in meta‐analysis.

Treatment for sialorrhoea

Young 2011

1 RCT N = 20

Botulinum toxin B injection into parotid and submandibular glands

Placebo (normal saline)

Primary outcome:
Subjective improvement in sialorrhoea at week 2 and 4 in favour of treatment group (treatment 82% improved, placebo 38%, P < 0.05 at week 2; treatment 90% improved, placebo 44%, P < 0.05 at week 4. No statistically significant difference at week 8 or 12.

Secondary outcomes:

1) Volume of saliva produced as measured with funnel and tube over 5 min – significant difference in favour of treatment group at week 2 (treatment 0.07, SD 0.2; placebo 0.84, SD 0.8, P < 0.05) and week 4 (treatment 0.02, SD 0.04; placebo 0.97, SD 0.5, P < 0.05), but not at week 8 or 12.

2) QoL as measured by clinicians' assessment of marked improvement using the SEIQOL‐DW showed a statistically significant difference from baseline with botulinum toxin but not placebo at week 2 but not at later time points

3) No adverse events reported

Moderate:
1 trial, small sample size but low risk of bias. By 12 weeks, 70% of investigators and 90% of participants guessed treatment allocation correctly suggesting that despite excellent attempts to maintain blinding, the double‐blind was not preserved.

Enteral tube feeding for supporting nutrition

Katzberg 2011

None

Not applicable

Not applicable

Not applicable

No RCTs found

Interventions at the level of activity and participation

Repetitive transcranial magnetic stimulation

Fang 2013

3 RCTs, N = 50

Repetitive transcranial magnetic stimulation (rTMS)

Sham rTMS

Primary outcomes: not measured.

Secondary outcomes:

No statistical difference in disability or limitation in activity as measured by ALSFRS‐R (12 months) or muscle strength.

Changes to fatigue not measured.

No adverse effects reported

Very low:
All trials of poor methodological quality (2 of the 3 were missing raw numerical data), insufficiently homogenous to pool results, small sample sizes and high attrition (30% to 40%)

Therapeutic exercise

Dal Bello‐Haas 2013

2 RCTs, N = 43

Exercise (endurance or resistance)

“Usual activities” or “usual care” (stretching exercise)

Primary outcome:
Significant improvement in disability or limitation in activity as measured by ALSFRS in favour of exercise groups (3 months) (MD 3.21, 95% CI 0.46 to 5.96)

Secondary outcomes:
No statistically significant differences between exercise and placebo groups in QoL (SF‐36), fatigue (fatigue severity scale) or muscle strength (manual muscle testing).

No adverse effects reported

Low:
Both trials had small sample sizes. 1 trial had a low risk of bias, whilst the other had high attrition (close to 30% by 3 months), no allocation concealment, and no blinding.

Multidisciplinary care

Ng 2011

None

Not applicable

Not applicable

Not applicable

No RCTs found