Ankle‐foot orthoses for improving walking in people with calf muscle weakness due to neuromuscular disorders

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the effects of AFOs for improving walking in adults with calf muscle weakness due to slowly progressive NMD.

Background

Description of the condition

Weakness of the calf muscles can occur in many slowly progressive neuromuscular diseases (NMDs), hereditary or acquired,  such as Charcot‐Marie‐Tooth disease, myotonic dystrophy, or poliomyelitis, and lesions of the peripheral nervous system due to injury or compression, such as radiculopathy. Calf muscle weakness due to neuromuscular disorders is one of the prevalent deficits that leads to walking problems.

The calf muscles are essential for providing stability during standing and walking and are the main contributors to forward propulsion (Kepple 1997; Neptune 2001; Winter 1980). Weakness of the calf muscles will compromise both stability and forward propulsion (Perry 1992), leading to major changes in the gait pattern. Calf muscles normally control the forward rotation of the tibia in the stance phase of gait. When the calf muscles are weak, this rotation cannot be sufficiently restrained, which causes the ankle to move into excessive dorsiflexion during stance, accompanied by persistent knee flexion (Perry 1992; Perry 1997; Ploeger 2017). Persistent knee flexion leads to a prolonged and increased external knee flexion moment (Perry 1997; Ploeger 2017), which requires the quadriceps to be active during the entire stance phase (Perry 1992). This substantial prolongation of activation increases walking effort (Brehm 2006; Waters 1999). Alternatively, the person may avoid excessive dorsiflexion by keeping the centre of pressure under the heel during the entire stance phase. This leads to knee extension during the stance phase, requiring compensatory forward trunk flexion and shortening of step length, thereby also increasing walking effort (Ploeger 2017). Furthermore, calf muscle weakness reduces ankle push‐off power (Waterval 2018), which impairs forward propulsion and increases walking effort (Soo 2012).

Previous work in NMD showed that changes in the gait pattern due to calf muscle weakness increase walking effort by 18% to 58% when compared to unaffected healthy individuals (Brehm 2006; Menotti 2011; Ploeger 2014; Waterval 2020), which induces fatigue and reduces ambulatory capacity (Kalkman 2005; Murray 2014; Tersteeg 2011). Also, calf muscle weakness slows walking speed (Waterval 2018) and can cause pain (Tiffreau 2006), impaired balance, and falling (Pieterse 2006). These walking‐related problems hinder activities of daily living (Brogårdh 2015), and reduce quality of life in adults with NMD (Abresch 2002).

Description of the intervention

The mainstay of treatment to improve walking in people with calf muscle weakness is the provision of ankle‐foot‐orthoses (AFOs) (Hsu 2008). An AFO is defined as ‘an externally applied medical device, encompassing (part of) the leg and foot, used to modify characteristics of the neuromuscular and skeletal system’ (ISO 8549‐1). In current clinical practice, a variety of AFOs for non‐spastic lower leg muscle weakness are used, ranging from shaft‐reinforced orthopaedic shoes to off‐the‐shelf and custom‐made AFOs (Van der Wilk 2015), with varying orthotic properties concerning construction, materials, stiffness, weight (Waterval 2020), and alignment (Esquenazi 1997).

How the intervention might work

An AFO for calf muscle weakness aims to restrict the ankle dorsiflexion angle and restrain forward rotation of the tibia during late stance, which can be achieved through the application of different AFO designs (Hsu 2008). Examples include hinged AFOs with a dorsiflexion stop, allowing a limited angle of ankle dorsiflexion, and dorsal leaf AFOs that restrict dorsiflexion by providing a plantar flexion moment proportional to the bending and stiffness of the leaf spring (Waterval 2019). By restricting ankle range of motion, the AFO can improve gait kinematics by preventing excessive ankle dorsiflexion and knee flexion (Ploeger 2014; Van der Wilk 2015). Support from (various types of) AFOs during the stance phase facilitates control of the ground reaction force to progress anteriorly, in front of the knee, thereby creating an external knee extension moment (Ploeger 2014). This reduces quadriceps activation, increases step length, and subsequently reduces walking effort and related fatigue (Duffy 2000; Galli 2000; Waterval 2020). Moreover, dorsal leaf AFOs with energy return capacity can support ankle push‐off by storing energy during the stance phase and releasing this energy during push‐off, which reduces walking effort (Bregman 2012; Waterval 2019). Also, improvement of gait biomechanics through wearing an AFO can increase walking speed and improve balance (Van der Wilk 2015).

Why it is important to do this review

Although in current clinical practice, AFOs are commonly provided to people with NMD (Esquenazi 2019), evidence of the effectiveness of AFOs to improve walking‐related outcomes in adults with calf muscle weakness is scarce (Van der Wilk 2015). Moreover, evidence‐based guidelines for the selection of the most effective AFO for an individual are lacking, and choices are largely based on the preferences of the prescribing physician or orthotist (Chisholm 2012), or available resources. As a result, adults with calf muscle weakness are provided with a wide variety of AFOs with different orthotic properties, which vary greatly in effectiveness (Van der Wilk 2015; Waterval 2020).

To the best of our knowledge, only one previous review has been published on the effects of AFOs for lower leg muscle weakness due to NMD (Van der Wilk 2015). The authors of the review summarised the effects of AFOs for adults and children with calf muscle weakness on a broad spectrum of walking‐related outcomes. The review, however, did not perform meta‐analyses or systematically grade the certainty of the evidence for individual walking‐related outcomes. Finally, the review was conducted almost seven years ago.

This emphasises the need for a comprehensive up‐to‐date evaluation of evidence for the effects of AFOs in comparison to no intervention following a systematic approach for grading the strength of the evidence. Therefore, we intend to review the current evidence to support clinical decision‐making in the prescription of AFOs for adults with NMD.

Objectives

To assess the effects of AFOs for improving walking in adults with calf muscle weakness due to slowly progressive NMD.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs), quasi‐RCTs (e.g. allocation by case record number, date of birth, or alternation), and cluster‐RCTs that compared the effects of AFOs with a control condition. 

In addition, because evidence from RCTs is expected to be very limited and effects are unlikely to be studied in RCTs, we intend to include non‐randomised studies (NRS) that directly address the review question (comparing effects of AFO interventions with a control condition).

Study designs in which participants act as their own controls, i.e. before‐and‐after studies, cross‐sectional studies, or cross‐over studies, in which outcomes are collected (prospectively or retrospectively) while walking with AFO (intervention) and without AFO (control condition) will be eligible. We will only consider studies with a control condition. We will exclude studies with a sample size smaller than five and studies in which it is unclear if included participants had calf muscle weakness (after an attempt to clarify clinical characteristics by contacting the authors).

Types of participants

We will include studies that assessed adults (aged 18 years and older) with calf muscle weakness caused by NMD, including slowly progressive NMDs or peripheral nerve lesions due to injury or compression (such as radiculopathy and lower limb salvage). When classifying the NMDs according to the location of the disorder within the nerve‐muscle complex, disorders of the motor neurons (e.g. poliomyelitis or spinal muscular atrophy), motor nerve roots (e.g. radiculopathy), plexus, peripheral nerve (e.g. Charcot‐Marie‐Tooth disease), neuromuscular transmission and the muscles (e.g. facioscapulohumeral muscular dystrophy) commonly cause slowly progressive calf muscle weakness and fall in the scope of this review. We will not consider patient groups with substantial additional muscle weakness of the upper leg(s).

Studies including participants with muscle weaknesses caused by central nervous system diseases (e.g. stroke) or by rapidly progressive NMDs (in particular, amyotrophic lateral sclerosis) fall outside the scope of this review and will be excluded. We will also exclude studies that assess a combination of NMD and other diagnoses if we are not able to obtain data on the subgroup of interest (after contacting the authors).

Types of interventions

We will include studies comparing AFO interventions with walking with shoes‐only (no AFOs). We will consider all types of AFOs (regardless of e.g. construction and materials) provided for calf muscle weakness including, but not limited to:

• Shaft‐reinforced orthopaedic shoes (OS)

• Ventral AFOs

• Dorsal leaf AFOs

• Dorsiflexion‐stop AFOs

We will not consider rocker sole shoes, functional electrical stimulation devices and robotic exoskeletons as AFO interventions. We will also not consider studies that assess a combination of interventions if we are not able to obtain data for the conditions of interest (AFO versus no AFO). 

Types of outcome measures

Relevant outcome measures to determine the clinical efficacy of AFOs for people with calf muscle weakness include walking effort, walking speed, walked distance, balance, falls, gait biomechanics, acceptance and satisfaction (Brehm 2011; Harlaar 2010). The outcomes listed here are not eligibility criteria for this review, but are outcomes of interest within whichever studies are included.

We plan to analyse final scores rather than change scores. We do not anticipate that outcomes will vary greatly with duration of follow‐up and, therefore, we will consider data for the AFO condition obtained at any time point. We will consider outcomes for the AFO condition that are assessed directly after starting use of the AFO (at less than 4 weeks' follow‐up), as well as outcomes assessed at minimal 4 weeks after starting use of the AFO (without further restrictions on duration of the follow‐up period) in subgroup analyses. When studies report outcomes at more than one time point, we will only extract data from the latest time point.

Primary outcomes

1. Walking effort, measured objectively during steady state of walking by the energy consumption (in J/kg/min) or oxygen consumption (in mL/kg/min), for which the smallest detectable difference is 16% (Brehm 2006)); energy cost (in J/kg/m) or oxygen cost (in mL/kg/m), for which the smallest detectable difference is 9.4% (Brehm 2006); or Physiological Cost Index (PCI) (in beats/m).

Secondary outcomes

1. Perceived walking effort, e.g. measured with the Borg Ratings of Perceived Exertion (Borg 1982).

2. Physical mobility outcomes, such as walking speed (in m/s), walked distance (in m), balance (e.g. assessed with the timed up & go test (Mathias 1986), or the Berg‐Balance Scale (Berg 1989)), and functional abilities, either objectively measured or assessed with questionnaires or self‐reported measures.

3. Gait parameters, including step length (in m), step width (in m), gait kinematics (i.e. ankle and knee joint angles during the stance phase (in degrees)), and gait kinetics (i.e. ankle and knee joint moments and power during the stance phase (in Nm/kg and W/kg)), obtained from instrumented gait analysis.

4. Use, usability and satisfaction with the AFO, assessed from questionnaires.

5. Adverse events related to use of the AFO (such as falls, pressure sores, pain and muscle soreness).

Search methods for identification of studies

Electronic searches

The Cochrane Neuromuscular Information Specialist will search the following databases using and adapting the MEDLINE search strategy in Appendix 1:

• Cochrane Neuromuscular Specialised Register via Cochrane Register of Studies (CRS‐Web) (until search date)

• Cochrane Central Register of Controlled Trials (CENTRAL) via Cochrane Register of Studies (CRS‐Web) (until search date)

• MEDLINE via Ovid SP (1946 ‐ search date)

• Embase via Ovid SP (1974 ‐ search date)

• US National Institutes for Health Clinical Trials Registry via ClinicalTrials.Gov (until search date)

• WHO International Clinical Trials Registry Portal (ICTRP) (until search date)

We will search all databases from their inception to the present, and we will impose no restriction on language, date of publication, publication status, or type of document.

Searching other resources

We will search reference lists of all primary studies and review articles for additional references. We will search relevant manufacturers' websites for trial information. We will search for errata or retractions of included studies.

Data collection and analysis

Selection of studies

For selection of studies, we will use Covidence (Covidence). Two review authors (EvD, NW) will independently screen titles and abstracts of all references we identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full‐text study reports and two review authors (EvD, NW) will independently screen the full text and identify studies for inclusion. We will also identify and record reasons for exclusion of ineligible studies. We will base decisions about suitability on study details concerning participants and interventions as specified in the above sections. We will resolve any disagreement through discussion or, if required, we will consult a third person (MB). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a 'Characteristics of excluded studies' table and PRISMA flow diagram (Moher 2009).

Data extraction and management

We will extract study characteristics and outcome data with a standardised data extraction form. We will pilot the extraction process on at least one study in the review. Two review authors (EvD, NW) will extract study characteristics from included studies. Characteristics to extract from (quasi‐)RCTs and NRS include general information (authors, title and year of publication), study design, setting and country, characteristics of participants (total number, diagnosis, severity of (calf) muscle weakness and age), eligibility criteria, intervention (type, orthotic properties, duration and timing of intervention), control condition, primary and secondary outcomes assessed, the timing of assessments, details about confounders and co‐interventions, source(s) of study funding and any conflicts of interest among investigators.

Two review authors (EvD, NW) will independently extract the outcome data or number of events (for data on use, and adverse events) for the AFO and control condition from included studies. If data are adjusted for confounders in NRS, we will preferably extract the adjusted effect sizes and additionally extract information with respect to the confounders that were controlled for. If adjusted effect sizes are not reported, we will extract unadjusted effect sizes. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third person (MB). One review author (EvD) will transfer data into Review Manager (RevMan). A second author will check the outcome data entries (NW). A second review author (NW) will also spot‐check study characteristics for accuracy against the trial report.

When reports require translation, the translator will extract data directly using a data extraction form, or authors will extract data from the translation provided. Where possible, a review author will check numerical data in the translation against the study report.

Assessment of risk of bias in included studies

Two authors (EvD, NW) will independently assess the risk of bias for all included studies. We will resolve any disagreements by discussion or by involving a third review author (MB). To avoid any conflict of interest, alternative team members will undertake risk of bias assessments of included studies authored by team members. We will assess the risk of bias for the results of the outcomes that will be included in the 'Summary of findings' tables. We will present consensus decisions for risk of bias judgements as supplemental data.

Assessment of risk of bias in RCTs and quasi‐RCTs

We will use version two of the Cochrane risk of bias tool for randomised trials (RoB2) for RCTs and quasi‐RCTs (Sterne 2019). Five domains that will be assessed per outcome measure include; bias arising from the randomisation process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome, and bias in selection of the reported result. For the domain on deviations from intended interventions, the effect of interest concerns assignment to intervention. For each trial result separately, we will judge each domain to be at low risk of bias, some concerns, or high risk of bias using the signalling questions in the RoB2 tool. Subsequently, we will map the overall risk of bias judgements for individual trial results into the same response options: low risk of bias, some concerns, or high risk of bias, together with a justification for our judgement. We will complete the risk of bias assessment using the RoB2 Microsoft Excel tool (available at www.riskofbias.info). For cluster‐RCTs and cross‐over RCTs, we will use the RoB2 tool with additional considerations for these designs, according to Chapter 23 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). When only including data from the first period of a cross‐over RCT, we will use the RoB2 tool without additional considerations.

Assessment of risk of bias in NRS

We will use the ROBINS‐I tool for assessing the risk of bias in NRS (Sterne 2016) according to Chapter 25 of the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2021). The following domains will be assessed: bias due to confounding, bias due to selection of participants into the study, bias in classification of interventions, bias due to deviations from the intended intervention, bias due to missing data, bias in measurement of outcomes, bias in selection of the reported results. For the domain on deviations from intended interventions, the effect of interest concerns assignment to intervention.

For each domain, the risk of bias judgements will lead to the following labels: critical risk, serious risk, moderate risk, low risk, or no information. As specified in the ROBINS‐I tool manual, the judgements of each domain level will lead to an overall risk‐of‐bias judgement for every outcome with the same response options. We will summarise the assessment, together with a justification for our judgement, in a risk of bias table for each outcome.

The following confounding factors and co‐interventions will be considered to be relevant: age, weight, activity level, unilateral or bilateral calf muscle weakness, the severity of calf muscle weakness, presence of comorbidities, previous use (and type) of AFOs, duration of AFO use, prescribing practices, gait training, frequency of use, use of walking aids. 

Conflicts of interest and risk of bias

We will assess whether or not there is a reason for ‘notable concern’ about conflicts of interest for each study. We will include a table indicating our judgement for each study and provide a rationale for each assessment. We will define a notable concern as described in Boutron 2021, "important conflicts of interest expected to have a potential impact on study design, risk of bias in study results or risk of bias in a synthesis due to missing results".

Assessment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review. We will assess the potential for bias arising from changes to the protocol or other decisions made during the review process in the Discussion.

Measures of treatment effect

We will summarise dichotomous data (e.g. data on use, and adverse events) using risk ratios. We will summarise continuous data (for the remaining outcomes) by the mean differences (between AFO and control condition), or standardised mean differences for results across studies with outcomes that are conceptually the same but measured in different ways. We will express uncertainty with 95% confidence intervals (CIs). We will enter data presented as a scale with a consistent direction of effect.

Unit of analysis issues

The unit of analysis will be the individual with NMD. For analyses of gait parameters, the (most) affected side will be considered as the unit of analysis.  For cluster‐RCTs, we will use cluster‐adjusted effects at the level of the individual as reported by the authors. When findings were not adjusted for cluster design, we will adjust their sample sizes using an estimate of the intra‐cluster correlation co‐efficient (ICC) derived from a study with a similar population according to Chapter 23 of the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2021). Where multiple trial arms are reported in a single study, we will include only eligible interventions and comparators. When multiple AFO interventions are eligible, our preferred approach will be to combine intervention groups, if clinically appropriate. When different types of eligible AFO interventions are investigated in a cross‐over design, we will use paired analyses as reported by the authors. When paired analyses are not reported, we will use data from the first period only to avoid unit of analysis errors (Higgins 2021).

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is available as an abstract only). 

Assessment of heterogeneity

We will identify heterogeneity among the studies in each analysis through visual inspection of forest plots and the I² statistic, which will be interpreted as follows:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%: considerable heterogeneity.

We will avoid the use of absolute cut‐off values, but interpret I²in relation to the size and direction of effects and strength of evidence for heterogeneity (Deeks 2021).

Assessment of reporting biases

If we can pool more than 10 trials, we will create and examine a funnel plot to explore possible small study biases.

If searches identify trial protocols, clinical trial registrations or abstracts indicating the existence of unpublished studies, we will attempt to determine the status of any unpublished studies by contact with the investigators.

Data synthesis

For RCTs (and quasi‐RCTs) and NRSs separately, we will undertake random‐effects meta‐analyses for all outcome measures if individual studies are sufficiently similar for pooling data for the treatments, participants, research questions and (methods of) outcome measures. We will include cluster‐RCTs in RCT meta‐analyses if they are adjusted appropriately for the cluster design. Primary analyses will include all eligible studies regardless of the risk of bias judgements.

Data synthesis of RCTs

We will present the outcome data of RCTs collectively using forest plots. When data cannot be pooled (if studies are not sufficiently similar), we will present results in a forest plot, but with summary estimates suppressed. When effect measures are not available or calculable, we will present results in a systematic format using tables.

Data synthesis of NRSs

We will present outcome data of NRSs using forest plots if individual study designs are sufficiently similar (comparing effects of AFO interventions with a control condition). When studies are not sufficiently similar, we will not pool data, but we will present results in a forest plot without summary estimates. When effect measures are not available or calculable, we will present results in a systematic format using tables.

Subgroup analysis and investigation of heterogeneity

If sufficient data are available, we will perform subgroup analyses to explore estimated effects amongst different types of AFOs (OSs, ventral AFOs, dorsal leaf AFOs, dorsiflexion‐stop AFOs); initial effects after AFO delivery (assessed at less than 4 weeks' follow‐up) versus follow‐up effects (assessed at a minimum 4 weeks after delivery and use of the AFO) and effects in participants with and without sensory deficits. We will use the formal test for subgroup interactions in RevMan (RevMan).

If we identify substantial unexplained heterogeneity, we will report it and explore and describe possible reasons for differences between studies.

Sensitivity analysis

We plan to carry out the following sensitivity analyses:

1. Repeat the analysis excluding unpublished studies (if there were any).
2. Repeat the analysis excluding studies at high risk of bias.

Summary of findings and assessment of the certainty of the evidence

We will create a summary of findings table using GRADEpro GDT software (GRADEpro) for the comparison AFO intervention compared to no intervention, for the following outcomes from RCTs: 

1. Objectively measured walking effort.

2. Perceived walking effort.

3. Walking speed, balance (assessed with the Berg‐Balance Scale).

4. Use.

5. Satisfaction (assessed with the QUEST questionnaire (Demers 1996)).

6. Adverse events.

We will present findings from all time points of assessments collectively. When results from RCTs (or quasi‐RCTs) are not available for an outcome, we will present data from NRSs in the summary of findings tables.

Two review authors (EvD, NW) will use the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to independently assess the certainty of a body of evidence. The overall RoB2 and ROBINS‐I assessments will directly feed into the GRADE assessment of study limitations (Schünemann 2019). We will use methods and recommendations described in Chapters 14 and 15 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2021a; Schünemann 2021b). We will resolve any disagreements by discussion or by involving another review author (MB). We will consider included studies, both RCTs and NRS (evaluated with ROBINS‐I), as providing high‐certainty evidence if the five factors above are not present to any serious degree, but may downgrade the certainty to moderate, low or very low according to Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions if a GRADE consideration is present to a serious degree, and twice if very serious. We will consider upgrading NRS for large effect, dose‐response, or the direction of plausible confounding. We will justify all decisions to downgrade or upgrade the certainty of evidence using footnotes and make comments to aid readers' understanding of the review, where necessary.

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. Our implications for research will suggest priorities for future research and outline what the remaining uncertainties are in the area.

Appendices

Appendix 1. MEDLINE via Ovid SP search strategy

Database: Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations and Daily <1946 to December 11, 2020>

1 Lower Extremity/ or Ankle Joint/ or Ankle/ or Foot/ or Leg/ or Tibia/ or (Ankle or Ankles or Foot or Feet or Calf or Calves or Leg or Legs or Lower Extremit* or Distal Extremit* or Lower Limb? or Tibia? or Shank?).ti,ab. (508388)

2 Orthotic Devices/ or Braces/ or Foot Orthoses/ or Exoskeleton Device/ or Shoes/ or (AFO or AFOs or Brace or Braces or Bracing or Exoskelet* or Orthotic* or Orthosis or Orthose or Orthoses or Splint or Splints or Splinting or Robotic or ((Custom Made or Orthop?edic) adj (Boot? or Footwear? or Shoe?))).ti,ab. (70863)

3 Muscular Dystrophy, Duchenne/ or Muscular Diseases/ or exp Compartment Syndromes/ or exp Mitochondrial Myopathies/ or exp Muscular Disorders, Atrophic/ or exp Myopathies, Structural, Congenital/ or exp Myositis/ or exp Myotonic Disorders/ or Myotoxicity/ or exp Neuromuscular Junction Diseases/ or exp Myasthenia Gravis/ or exp Peripheral Nervous System Diseases/ or exp Guillain‐Barre Syndrome/ or Mononeuropathies/ or exp Tibial Neuropathy/ or exp Nerve Compression Syndromes/ or Neuromuscular Diseases/ or Motor Neuron Disease/ or Bulbar Palsy, Progressive/ or exp Muscular Atrophy, Spinal/ or exp Poliomyelitis/ or Radiculopathy/ or exp Brachial Plexus Neuropathies/ or Charcot‐Marie‐Tooth Disease/ or Gait Disorders, Neurologic/ or Hemiplegia/ or "Hereditary Sensory and Motor Neuropathy"/ or Leprosy/ or Meningocele/ or Meningomyelocele/ or Movement Disorders/ or Multiple Sclerosis, Chronic Progressive/ or Muscle Hypotonia/ or Muscle Weakness/ or Muscle, Skeletal/ or Muscular Atrophy/ or Paralysis/ or Paraplegia/ or Paresis/ or Peripheral Nerve Injuries/ or Peripheral Nervous System Diseases/ or Peripheral Nervous System Neoplasms/ or Peripheral Arterial Disease/ or Peroneal Neuropathies/ or Polyneuropathies/ or Quadriplegia/ or Sciatic Neuropathy/ or Spinal Cord Compression/ or Spinal Cord Injuries/ or Spinal Dysraphism/ or (Atroph* or Compartment or Drop?Foot or Dropped Foot or Dystroph* or Flaccid or Floppy or Foot?Drop or Guillain?Barr? or Guillaine?Barr? or Hemipleg* or Neuropath* or HSMN or CMT or Hypoton* or Leprosy or "Luft's" or Lufts or Luft or Meningocele or Meningomyelocele or Monopleg* or Mononeuropath* or Mononeuritis or Mononeuritides or Myastheni* or Myeloschisis or Myoton* or Myotoxic* or Neuromuscular or Palsies or Palsy or Paraly* or Paraparesis or Parapleg* or Pares?s or Paretic or Peripheral Nerve or Peripheral Nervous or Peripheral Artery or Peripheral Arterial or Plegia* or Polyneuropath* or Polyneuritis or Polyradiculoneuropath* or Quadripleg* or Spina Bifida or Spinal Cord Compression? or Spinal Cord Injur* or Spinal Dysraphism or Tetrapleg* or Motor Neuron Disease* or Motor System Disease* or Poliomyelitis or Polio or Polios or Poliomyelitides or Postpoliomyelitis or Fazio Londe or Neuronopath* or Kennedy Disease or Kennedy Syndrome or Kennedy's Disease or Kugelberg Welander or Amyotroph* or Werdnig Hoffman or Myopath* or Myositides or Myositis or Nerve Root Avulsion* or Nerve Entrapment? or Nerve Compression or Nerve Root or Radiculitides or Radiculitis or Radiculopath* or Brachial Neuralgia* or Neuritides or Neuritis or Brachial Plexopathy or Brachial Plexus or Cervicobrachial Neuralgia* or Parsonage Aldren Turner or Parsonage Turner or Charcot?Marie or Hereditary Areflexic Dystasia* or Roussy Levy).ti,ab. (1138123)

4 1 and 2 and 3 (3953)

Contributions of authors

EvD wrote and updated all sections of the protocol. All co‐authors (NFW, FSK, AE, ST, FN, MAB) reviewed the draft, contributed to revised versions of the protocol and approved the final protocol. 

Sources of support

Internal sources

• No sources of support provided

External sources

• ZonMw (The Netherlands Organisation for Health Research and Development), Netherlands

  Support for EvD

Declarations of interest

EvD is employed by a health organisation that conducts clinical trials within the field of orthotics and is currently undertaking a trial at the time of writing that, in the future, will possibly be eligible for inclusion in the review.

NFW is employed by a health institution that conducts clinical trials in the field of orthotics. He has no known conflicts of interest.

FSK works as a rehabilitation physician delivering orthotic care for people with neurological conditions. She is involved in research for which her institution receives funding from orthotics companies (Fior and Gentz, Germany; OIM Orthopedie, The Netherlands). She was involved in a study funded by Princes Beatrix Speirfonds eligible for inclusion in the review. 

AE has received funding for research consulting and research work from Allergan, IPSEN and Ossur. 

ST is employed by the University of Manchester and holds research projects funded by NIHR which are unrelated to the topic of this review.

FN received study grants from the Netherlands Organisation for Health Research and Development, the Prinses Beatrix Muscle Fund, Polio Health International, Fior & Gentz, and from Grifols Pharmaceuticals. All of these grants were paid to his institution.

M‐AB is involved in research for which her institution receives funding from orthotics companies (Fior and Gentz, Germany; OIM Orthopedie, The Netherlands). Her institution receives royalties for a book on orthotics of which she is an author. 

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