2004 Exercise For People With Peripheral Neuropathy

Exercise for people with peripheral neuropathy (Review)
White CM, Pritchard J, Turner-Stokes L
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2011, Issue 6
http://www.thecochranelibrary.com

Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Strengthening exercise versus no exercise, Outcome 1 Change in time taken for 6m comfortable
walk (seconds). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.2. Comparison 1 Strengthening exercise versus no exercise, Outcome 2 Change in isokinetic knee extension
torque (Nm). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.3. Comparison 1 Strengthening exercise versus no exercise, Outcome 3 Change in endurance at 80% MVC
(seconds). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.4. Comparison 1 Strengthening exercise versus no exercise, Outcome 4 Change in isokinetic knee flexion torque
(Nm). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.5. Comparison 1 Strengthening exercise versus no exercise, Outcome 5 Change in maximal isometric voluntary
contraction force (Nm). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.1. Comparison 2 Lower limb strengthening and balance exercise versus upper limb strengthening exercise,
Outcome 1 % Change in activities specific balance confidence scale scores. . . . . . . . . . . . . .
Analysis 3.1. Comparison 3 Home exercise versus no exercise, Outcome 1 Change in average muscle scores. . . .
Analysis 3.2. Comparison 3 Home exercise versus no exercise, Outcome 2 Change in left handgrip force (Kg). . . .
Analysis 3.3. Comparison 3 Home exercise versus no exercise, Outcome 3 Change in right handgrip force (Kg). . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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1
1
2
2
5
6
6
7
9
11
15
16
17
17
20
27
28
28
29
29
30
30
31
31
32
32
42
42
43
43
43
[Intervention Review]
Exercise for people with peripheral neuropathy

Claire Margaret White1 , Jane Pritchard2 , Lynne Turner-Stokes3
1
Applied Biomedical Research Division, Kings College London, London Bridge, UK. 2 Neuromuscular Unit 3 North, Charing Cross
Hospital, London, UK. 3 Regional Rehabilitation Unit, Kings College London and Northwick Park Hospital, Harrow, UK
Contact address: Claire Margaret White, Applied Biomedical Research Division, Kings College London, Room 3.6, Shepherds House,
Guys Campus, London Bridge, London, SE1 1UL, UK. Claire.white@kcl.ac.uk.
Editorial group: Cochrane Neuromuscular Disease Group.
Publication status and date: Edited (no change to conclusions), published in Issue 6, 2011.
Review content assessed as up-to-date: 23 September 2009.
Citation: White CM, Pritchard J, Turner-Stokes L. Exercise for people with peripheral neuropathy. Cochrane Database of Systematic
Reviews 2004, Issue 4. Art. No.: CD003904. DOI: 10.1002/14651858.CD003904.pub2.
ABSTRACT
Background
Peripheral neuropathies are a wide range of diseases affecting the peripheral nerves. Demyelination or axonal degeneration gives rise to
a variety of symptoms including reduced or altered sensation, pain, muscle weakness and fatigue. Secondary disability arises and this
may result in adjustments to psychological and social function. Exercise therapy, with a view to developing strength and stamina, forms
part of the treatment for people with peripheral neuropathy, particularly in the later stages of recovery from acute neuropathy and in
chronic neuropathies.
Objectives
The primary objective was to examine the effect of exercise therapy on functional ability in the treatment of people with peripheral
neuropathy. In addition, secondary outcomes of muscle strength, endurance, broader measures of health and well being, as well as
unfavourable outcomes were examined.
Search methods
In September 2009 we updated the searches of the Cochrane Neuromuscular Disease Group register, MEDLINE (from January 1966),
EMBASE (from January 1980), CINAHL (from January 1982) and LILACS (from January 1982). Bibliographies of all selected
randomised controlled trials were checked and authors contacted to identify additional published or unpublished data.
Selection criteria
Any randomised or quasi-randomised controlled trial in people with peripheral neuropathy comparing the effect of exercise therapy
with no exercise therapy or drugs or an alternative non-drug treatment on functional ability (or disability) for at least eight weeks after
randomisation was included.
Data collection and analysis
Two authors independently selected eligible studies, rated the methodological quality and extracted data.
Main results
Only one trial fully met the inclusion criteria. An additional two trials assessed outcomes less than eight weeks after randomisation
and were also included. Methodological quality was poor for several criteria in each study. Data used in the three studies could not be
pooled due to heterogeneity of diagnostic groups and outcome measures. The results of the included trials failed to show any effect of
strengthening and endurance exercise programmes on functional ability in people with peripheral neuropathy. However, there is some
evidence that strengthening exercise programmes were moderately effective in increasing the strength of tested muscles.
Authors conclusions
There is inadequate evidence to evaluate the effect of exercise on functional ability in people with peripheral neuropathy. The results
suggest that progressive resisted exercise may improve muscle strength in affected muscles.
PLAIN LANGUAGE SUMMARY

Exercise for treating people with diseases of their peripheral nerves (peripheral neuropathy)
Peripheral neuropathies are a wide range of diseases (both genetic and acquired) affecting the peripheral nerves. Symptoms can include
pain, altered sensation such as tingling or numbness, muscle weakness and fatigue. Exercise therapy, with a view to improving strength
and stamina, forms part of many rehabilitation programmes after a peripheral neuropathy. This review found inadequate evidence
from randomised controlled trials to evaluate the effect of exercise in disability in peripheral neuropathy. There was evidence that
strengthening exercises moderately improve muscle strength in people with a peripheral neuropathy.


S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Strengthening exercise versus no exercise for people with peripheral neuropathy

Patient or population: patients with people with peripheral neuropathy
Settings:
Intervention: Strengthening exercise versus no exercise
Outcomes
Illustrative comparative risks* (95% CI)
Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence

(GRADE)
Assumed risk
Corresponding risk
Control
Strengthening exercise
versus no exercise
Change in time taken

for 6m comfortable walk
(seconds)
Follow-up: 8 weeks
The mean change in time

taken for 6m comfortable walk (seconds) in the
control groups was
0.3 seconds
The mean Change in time

taken for 6m comfortable
walk (seconds) in the intervention groups was
0.7 higher
(0.23 to 1.17 higher)
26
(1 study)

moderate1
Change in isokinetic
knee extension torque
(Nm)
Follow-up: 8 weeks
The mean change in

isokinetic knee extension
torque (nm) in the control
groups was
-5.3 Newton metres
The mean Change in

isokinetic knee extension
torque (Nm) in the intervention groups was
17.7 higher
(5.11 to 30.29 higher)
26
(1 study)

moderate1
Change in endurance at The mean change in en80% MVC (seconds)

durance at 80% mvc
Follow-up: 8 weeks
(seconds) in the control
groups was
1.5 seconds
The mean Change in endurance at 80% MVC

(seconds) in the intervention groups was
0.3 higher
(11.04 lower to 11.64
higher)
23
(1 study)

moderate1
Comments

Change in isokinetic
knee flexion torque
(Nm)
Follow-up: 8 weeks
The mean change in isokinetic knee flexion torque

(nm) in the control groups
was
-1.1 Newton metres
The mean Change in

isokinetic knee flexion
torque (Nm) in the intervention groups was
0.5 lower
(9.78 lower to 8.78
higher)
26
(1 study)

moderate1
Change in maximal isometric voluntary contraction force (Nm)

Follow-up: 8 weeks
The mean change in maximal isometric voluntary

contraction force (nm) in
the control groups was
4 Newton metres
The mean Change in maximal isometric voluntary

contraction force (Nm) in
the intervention groups
was
12.6 higher
(1.51 lower to 26.71
higher)
26
(1 study)

moderate1
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1
High risk of bias for sequence generation, allocation concealment, blinding and incomplete outcome data.
BACKGROUND
Peripheral nerves connect the sensory receptors and muscles to
the central nervous system. Peripheral nerves are subject to a very
wide range of diseases called peripheral neuropathies that collectively affect about 2.4% of the population (Martyn 1998). The
peripheral neuropathies are a heterogeneous group of disorders in
which one or all of the elements of the peripheral nervous system
are damaged, primarily affecting either the myelin (the nerve insulating sheath), the axon (the central nerve fibre), or a mixture
of the two. Damage to the myelin sheath, or demyelination, produces dysfunction which may be quite rapidly reversed in a matter
of weeks as the myelin regenerates. Damage to the nerve axon is
repaired by regeneration or sprouting from the intact elements,
which may take many months and recovery is often incomplete.
Patients with peripheral neuropathy typically develop symptoms
of numbness, or altered sensation (e.g. pins and needles), starting
at the extremities and progressing more proximally with advancing
disease. Strength is affected when motor nerves are involved. Reduced or absent reflexes are a characteristic examination finding.
Peripheral neuropathies can be genetic or acquired. Some may
be insidious in onset whilst others are acute. The natural history in any individual case of neuropathy is largely dependent
upon the underlying cause. Acute neuropathies, such as GuillainBarr syndrome, reach their worst and then slowly recover. Others,
e.g. chronic inflammatory demyelinating polyradiculoneuropathy,
tend to relapse and remit, whilst others gradually deteriorate over
many years (e.g. Charcot-Marie-Tooth disease (CMT), alcoholrelated neuropathy).
Symptoms during and residual problems after peripheral neuropathy include muscle weakness, pain, sensory deficits, increased fatigability (Merkies 1999), psychological dysfunction and difficulties
with poor social adjustment (Lennon 1993; Pfeiffer 2001; Padua
2008). The extent of an individuals physical recovery is not necessarily related to recovery of nerve function (Molenaar 1999). As in
other chronic neurological disorders, the extent to which individuals with similar residual deficits experience limitations in activity
and how they perceive the impact of this on their daily lives varies
(Lennon 1993; Nicholas 2000).
Rehabilitation for people after peripheral neuropathy has focused
on symptomatic treatment and exercise therapy with little agreement in the literature regarding whether strengthening (Lindeman
1995) or endurance (Pitetti 1993) programmes are more effective
(Herbison 1983).
However, several uncontrolled studies since the last update of this
review, show that exercise interventions are associated with significant improvements in muscle strength, functional ability and
fatigue (Chetlin 2008; Garssen 2004; Graham 2007). Recent recommendations for exercise prescription for people with peripheral neuropathy include a combination of aerobic and functional
exercises as well as strengthening exercises to target specific weak
muscle groups (Chetlin 2004; Hughes 2005).
Strengthening programmes typically involve progressive resisted

exercise utilising repetitions of specific muscle contractions. These
can be isometric (performed against maximal resistance where no
associated joint movement is possible), isotonic (performed against
a submaximal known resistance, this is typically greater than 70%
of the maximal load possible, where joint movement and limb
excursion is permitted) or isokinetic (performed against variable
resistance but where the speed of contraction is constant). Endurance programmes typically involve gradually increasing the duration and intensity of aerobic activity for example cycling, running, or walking. Specific muscle endurance programmes may also
involve the use of low load high repetition muscle contractions.
Patients are often unsure as to how much exercise they should undertake in both acute neuropathy, which is recovering, and chronic
neuropathy, in which their exercise tolerance is reduced. They can
be fearful that excessive exercise might exacerbate their symptoms.
Indeed, in some patients where marked weakness is a feature, joints
may be at a mechanical disadvantage and exercising may result in
soft tissue damage.
There is some consensus that fatigue may be a common feature
in people with peripheral neuropathy (Merkies 1999). The cardiorespiratory response to exercise testing has been shown to be reduced in people with CMT (Carter 1995) and subclinical deficits
in aerobic capacity and/or muscular strength and endurance are
revealed by army physical fitness testing (Burrows 1990) in soldiers after recovery from GBS.
Since the previous update, two cohort studies of exercise for people with inflammatory neuropathy show that participants were
stronger, fitter and experienced less fatigue after a 12 week exercise programme that included aerobic activity. The reduction in
fatigue was also associated with an improvement in overall mood
and quality of life (Garssen 2004; Graham 2007). The extent to
which subjective feelings of fatigue are related to objective muscle
fatigue is unclear. Thus graded exercise programmes such as those
which have been shown to be effective in improving functional
performance, and participation by people with chronic fatigue
syndrome (Fulcher 1997; Powell 2001; Wearden 1998) in RCTs
may be appropriate.
It has been suggested that judicious timing of exercise therapy is
necessary because evidence from animal studies suggests that increased neuromuscular activity during reinnervation may be detrimental. Whilst there is some evidence that intensive exercise carried out early in the reinnervation process is detrimental to nerve
sprouting (Tam 2001), the bulk of studies show either no effect
(Gardiner 1986; Sebum 1996) or a beneficial effect (Einsiedel
1994; Ribchester 1988) of exercise during reinnervation on the
recovery of function.
Therefore it is important to examine critically the evidence surrounding the safety, type, timing and effectiveness of exercise in
the treatment of people with peripheral neuropathy.

OBJECTIVES
The objective was to systematically review the evidence from randomised clinical trials concerning the effect of exercise therapy on
peripheral neuropathy.
control period. Functional ability may include measures of mobility such as walking, stair climbing and running, functional use of
the affected arm/s and/or independence in activities of daily living
such as washing, dressing, preparing food etc.
Secondary outcomes
METHODS
Criteria for considering studies for this review
Types of studies
Any randomised controlled trial (RCT) or quasi-randomised controlled trial comparing exercise therapy to treat peripheral neuropathy with no exercise therapy or drugs or an alternative form
of non-drug treatment, was included. Quasi-randomised trials are
those in which randomisation was intended but may be biased.
Types of participants
Trials including participants (adults or children) with a diagnosis
of peripheral neuropathy, including sensory, motor and combined
sensory and motor neuropathies were selected. Trials including
cases of poliomyelitis were not included. Trials involving cases of
local entrapment neuropathies with pain as the primary presenting feature (e.g. cervical radiculopathy, carpal tunnel syndrome
etc) were not included. The diagnosis of peripheral neuropathy
offered by the authors, provided that it stipulated the presence of
clinical impairment characteristic of peripheral neuropathy, was
accepted. Diagnoses dependent on symptoms suggestive of neuropathy alone or neurophysiological abnormalities in the absence
of clinical signs, were not accepted.
Types of interventions
Trials including any form of exercise therapy including either progressive resisted exercise (isometric, isotonic or isokinetic) and/or
endurance training compared with either no exercise or drugs or
an alternative form of non-drug treatment, were selected.
Secondary outcome measures included were those validated outcome measures used to assess:
(1) muscle strength at least eight weeks after the start of the intervention (or on completion of the exercise programme);
(2) endurance at least eight weeks after the start of the intervention
(or on completion of the exercise programme);
(3) psychological status or quality of life at least eight weeks after
the start of the intervention (or on completion of the exercise
programme);
(4) return to work at least twelve months after the start of the
intervention.
In addition unfavourable secondary outcomes were assessed including:
(5) relapse as evidenced by an increase in neurological deficit;
(6) development or increase in pain sufficient to require the use,
or increased use, of analgesics.
Search methods for identification of studies

The Cochrane Neuromuscular Disease Group Register was
searched using neuritis or neuropathy or CIDP or guillain
barre or chronic inflammatory demyelinating polyradiculoneuropathy or polyradiculoneuritis or polyneuropathy or polyneuritis , combined using AND with strength training or endurance
or exercise or physical therapy or physiotherapy or rehabilitation as search terms in September 2009. MEDLINE (from 1966
to September 2009), EMBASE (from January 1980 to September 2009), CINAHL (from January 1982 to September 2009),
AMED (from January 1985 to September 2009) and LILACS
(January 1982 to September 2009) were searched using the search
strategy stated in the Cochrane Neuromuscular Disease Group
module in combination with terms used identify potential RCTs
(see below for strategy). Bibliographies of all selected RCTs were
checked and authors contacted to identify additional published or
unpublished data.
Types of outcome measures

Search methods for electronic databases
Primary outcomes
Functional ability at a timeframe less than eight weeks after the

start of the intervention/control period.
The review aimed to select only trials where the primary outcome
measure was a measure of functional ability (sometimes called disability or activity limitation (WHO 2001)), as measured by a validated tool, at least eight weeks after the start of the intervention/
The search strategies used are listed in the Appendices: Appendix

1, Appendix 2, Appendix 3, Appendix 4, Appendix 5.
Data collection and analysis

Selection of studies

Titles and abstracts identified by the search were checked by two

authors (CMW, JP). The full texts of all potentially relevant studies were obtained and independently assessed by both authors.
The authors decided which trials fulfilled the inclusion criteria
and graded their methodological quality. Any disagreement about
inclusion criteria was resolved by discussion between the authors
without need for the third author.
Data extraction and management

The assessment of methodological quality of the trials was redone
for the 2009 update according to the methods now favoured by
the Cochrane Collaboration and published in Chapter 8 of the
Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2008). Items considered were allocation concealment, participant
blinding, observer blinding, explicit diagnostic criteria, documentation of therapy input, explicit outcome criteria, how studies deal
with baseline differences of experimental groups and completeness
of follow-up. The items were graded: low risk of bias, high risk
of bias or unclear: unknown risk of bias or the entry was not
relevant in the study.
Assessment of risk of bias in included studies

Data extraction was performed independently by two authors using a standardised data extraction form.
Measures of treatment effect

Results were expressed as risk ratios (RR) with 95% confidence
intervals (CI) and risk differences (RD) with 95% CIs for dichotomous outcomes and mean differences (MD) with 95% CIs for
continuous outcomes.
Data synthesis
Data from clinically homogenous studies were pooled where possible and sensitivity analysis undertaken for methodological quality.
Subgroup analysis and investigation of heterogeneity

Subgroups of interest were identified in advance and were chosen
for their prognostic importance. The subgroups were defined as
follows:
(a) type and mode of onset of neuropathy (ie type of neuropathy either: hereditary, metabolic or inflammatory, mode of onset:
acute, relapsing or progressive);
(b) patients with less severe disease/disability (walks unaided) compared with patients with severe disease (unable to walk or only
able to walk with assistance).
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies; Characteristics of studies awaiting classification.
The search strategy for the databases resulted in a list of 481 citations. The other searches did not add any further references. Authors CMW and JP selected a total of 29 citations of full-length
articles and abstracts describing 28 exercise therapy trials. Out of
these, three trials reported in four full-length articles were identified as RCTs by the authors (Lindeman 1994a; Lindeman 1995;
Richardson 2001; Ruhland 1997). The two articles (Lindeman,
1994a; Lindeman 1995) describe only one trial. For the purposes
of the review, only Lindeman 1995 will be referred to. Only one
trial fulfilled all selection criteria (Lindeman 1995) and will be
referred to as the primary included trial in the results section,
whilst a further two were included as they fulfilled all criteria except the outcome criteria of primary and secondary outcomes at
least eight weeks after commencement of the intervention/control
period (Richardson 2001; Ruhland 1997). The two trials assessed
outcome on completion of shorter intervention and control periods, at three weeks (Richardson 2001) and six weeks (Ruhland
1997) after commencement and shall be referred to hereafter as
the secondary included trials in the results section.
The three identified trials included 82 patients with peripheral
neuropathy of either hereditary (37 patients), inflammatory (25
patients) or metabolic (20 patients) aetiology. There were no trials
involving patients with acute peripheral neuropathy e.g. GuillainBarr syndrome (GBS) or recent drug or toxin exposure. The trials were of similar sizes. The trial by Lindeman et al. (Lindeman
1995) recruited 34 patients with CMT disease: 21 subjects had
type I, six had type II and in two subjects the type was unknown.
Richardson (Richardson 2001) recruited 20 subjects with peripheral neuropathy associated with diabetes mellitus. Ruhland and
Shields (Ruhland 1997) recruited 28 subjects with chronic peripheral neuropathy including 12 with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), six with CIDP with
monoclonal gammopathy, three with CIDP with central demyelination or possible toxic neuropathy, four with idiopathic axonal
degeneration and three with hereditary peripheral neuropathy.
Two trials compared progressive resisted exercise with a non-intervention control (Lindeman 1995; Ruhland 1997). One of these
included aerobic conditioning exercise alongside progressive resistance exercises (Ruhland 1997). The third trial compared progressive resisted exercise and balance exercises with a non-therapeutic
exercise control (Richardson 2001). The non-therapeutic exercises
consisted of progressive resisted exercises of muscle groups in the
upper limb that were considered unlikely to influence the selected
focal lower limb outcome measures of unipedal stance, tandem
stance, functional reach and the activities specific balance scale.

Electronic searches were updated prior to submission of the review

and a further potentially relevant study, published only in abstract
form, was identified from the Cochrane Neuromuscular Disease
Group Register (Zifko 2003). The study is included in the studies
awaiting assessment since the authors are currently seeking to publish the study in full. The information from the full publication
will be included in the review as an update, once available.
Risk of bias in included studies

Since blinding of patients and researchers is difficult in exercise
trials, the trials are susceptible to bias including detection, performance and attrition bias. Even in the trial where participants were
randomised into active exercising and control exercising groups,
the very different nature of the exercises (upper versus lower limb)
and the use of outcome measures reflecting lower limb function,
could prevent true patient blinding to the intervention.
The methods of randomisation were unclear in one trial (
Lindeman 1995) and inadequate in the other two (Richardson
2001; Ruhland 1997) due to matching of subjects in intervention
and control groups. Allocation concealment was not described in
any trial and in both trials where randomisation with matching
was carried out, allocation concealment was not possible.
Only one of the three trials included explicit diagnostic criteria.
Richardson (Richardson 2001) included patients with a known
history of diabetes mellitus and lower extremity symptoms consistent with peripheral neuropathy. They also required conclusive
electrodiagnostic evidence of diffuse, primarily axonal, peripheral
polyneuropathy. In the second trial Lindeman (Lindeman 1995)
included patients diagnosed with CMT disease on the basis of their
clinical picture, electromyography and nerve conduction studies
but not genetic testing. However, no explicit details of diagnostic
criteria were given. In the third trial the criteria were not explicitly
stated and subjects were selected on the basis of their clinical diagnosis as recorded in a clinical database. Subjects were included
if they had a clinical diagnosis of CIDP, chronic idiopathic axonal
degeneration, CMT disease or toxic neuropathy as long as the
toxin was no longer detectable through blood sampling (Ruhland
1997). Duration, severity or degree of recovery from neuropathy
was not indicated in any of the included trials and baseline comparisons of groups were made on the basis of other characteristics.
All trials considered differences in baseline characteristics, although this was based on different clinical characteristics in each
case. There was no consistent examination of severity or duration of neuropathy. The first trial matched patients on muscle
strength and stair-climbing performance and no obvious baseline differences in age or gender of patients was noted (Lindeman
1995). The second trial, where group randomisation was performed, showed significant baseline differences in severity of neuropathy as indicated by the Michigan Diabetes Neuropathy Score
(MDNS) (Richardson 2001). Eight out of the 28 patients in the
final trial were non-randomly placed into control and experimen-
tal groups to maintain similar baseline characteristics for age and

gender (Ruhland 1997). In this trial there were significant differences in the Short Form-36 questionnaire (SF-36) for role limitation (emotional) and social function scale scores and despite nonrandomised placement of patients, the mean age of patients in the
intervention group (63.6 10.5 years) was significantly higher
than the control group (52.9 16.2 years). However in this case
baseline differences were accounted for by using these factors as
co-variates in the subsequent data analysis.
In two trials the inclusion criteria included a minimum ambulatory capability of: must be able to walk household distances without assistance or assistive device indoors (Richardson 2001) and,
the ability to ambulate 4.6 m with or without assistance or assistive device(Ruhland 1997). In the third trial there was no such
requirement but the baseline data included a stair climbing test,
and a qualification period for recruited subjects was employed
to exclude subjects with motivational problems (Lindeman 1995).
Thus, it appears that only ambulant patients were included in the
reviewed studies.
Documentation of therapy input was adequate in two trials
(Lindeman 1995; Ruhland 1997). Clear descriptions of type, intensity and duration of exercise were given in both cases. In the
third trial (Richardson 2001) the intensity and frequency of exercise was less in the control group than the intervention group
exposing the trial to moderate risk of bias.
Clear descriptions of outcome criteria were included in all trials. The authors initially planned that only trials where the outcome measures utilised validated measures of disability at least
eight weeks after randomisation, would be selected. However this
retrieved only one suitable study (Lindeman 1995). Under these
circumstances it was decided to include those studies where suitable outcome measures had been utilised on completion of an exercise programme, even where the programme was less than eight
weeks in duration. This alteration to the original protocol subsequently retrieved two further suitable studies (Richardson 2001;
Ruhland 1997). No included trial had disability as the primary
outcome measure. In one case the primary outcome measure, the
SF-36, was described as a measure of health related quality of life
(Ruhland 1997). Whilst it might be argued that this instrument
includes some items relating to disability, its primary focus is on
handicap (participation) and quality of life and it does not provide data which could be combined in any robust way with the
commonly used standard measures of disability.
In one trial follow-up was complete for the intended follow-up
period (Ruhland 1997) and an intention-to-treat analysis was possible. In the two other trials, follow-up was incomplete due to
drop-outs. In the case of (Lindeman 1995) one control patient
was unable to undertake the final 24 week follow-up strength assessments, due to knee problems. There was no attempt to replace data for intention to treat analyses and the matched pair to
which the control patient belonged was removed from the analysis.
In the other trial (Richardson 2001) one intervention and three

control patients dropped out during the course of the trial. The
intervention patient dropped out due to exercises aggravating an
underlying arthritic condition, two control patients dropped out
giving no reason and the final control patient developed an unrelated illness, preventing completion of the trial. Follow-up was
not extended beyond the length of the intervention period in any
of the included trials. The intervention periods varied as follows:
three weeks (Richardson 2001), six weeks (Ruhland 1997) and 24
weeks (Lindeman 1995).
None of the trials fulfilled all of the criteria for methodological
quality and all three trials failed to reach adequate methodological
quality in a number of items. The scores for each trial for the risk
of bias are summarised in Figure 1. In addition the criterion for
patient blinding was waived in the case of exercise versus nonexercise trials.
Figure 1. Methodological quality summary: review authors judgements about each methodological quality
item for each included study.

Effects of interventions
See: Summary of findings for the main comparison
Strengthening exercise versus no exercise for people with peripheral
neuropathy; Summary of findings 2 Lower limb strengthening
and balance exercise versus upper limb strengthening exercise
for people with peripheral neuropathy; Summary of findings
3 Home exercise versus no exercise for people with peripheral
neuropathy
Authors decided by consensus not to pool data because of the
differences in presentation of the results as well as the variety of
outcome measures used.
In the primary included trial (Lindeman 1995) mean change scores
with standard deviations were presented. In the two secondary included trials, mean baseline and follow-up scores with standard
deviations were presented, in addition to mean change scores with
standard deviations (Richardson 2001; Ruhland 1997). The review will present data as mean change scores where possible.
Primary outcome measure
The primary included trial showed a significant reduction in the
time taken for a six metre walk (Lindeman 1995) at 24 weeks after
starting the exercise with a MD of 0.7 (95% CI 0.23 to 1.17)
(Analysis 1.1). No other significant improvements in time scored
functional activities were observed. There were no data available for the stated apparent improvement in aspects of upper-leg
strength related functional activities of the modified Western Ontario and McMaster University Osteoarthritis Index (WOMAC)
used in this study. One of the two secondary included trials, used
the SF-36 to assess what the authors stated to be health related
quality of life (Ruhland 1997). However the SF-36 scale, in addition to the majority of items pertaining to an individuals level of
participation, also contains items pertaining to physical functioning. These items assess functional ability and could therefore more
readily be interpreted as relating to activity limitation. However,
no within or between group differences were found for the physical function scale. Unfortunately, no standard deviations were presented in the text of this study so no overall effect size can be calculated. In the final trial there were no significant changes in the
chosen disability outcome measure, the Activities Specific Balance
Confidence (ABC) scale score (Richardson 2001) at three weeks
after randomisation, MD 8.00 (95% CI -8.47 to 24.47) (Analysis
2.1).
The follow-up duration was different in each trial. In the primary
included trial, follow-up was at eight weekly intervals for 24 weeks.
However, in the secondary included trials the follow-up period was
less than the stated eight weeks recommended by the review protocol. Since, in these trials the duration of the exercise intervention
was also less than eight weeks, in one only three weeks (Richardson
2001) and in the other only six weeks (Ruhland 1997), shorter
follow-up periods were permitted.
Secondary outcome measures:
Muscle strength at follow-up
Significant improvements in isokinetic knee extension torque in

the exercise group at 24 weeks after starting the programme were
reported by Lindeman 1995 with an effect size of 17.7 (95% CI
5.11 to 30.29) (Analysis 1.2). However, there was no improvement in knee flexion torque, MD -0.50 (95% CI -9.78 to 8.78)
(Analysis 1.4) or maximal isometric voluntary contraction force,
MD 12.6 (95% CI -1.51 to 26.71) (Analysis 1.5).In the secondary
included trials, where outcomes were assessed at less than eight
weeks after commencement of the intervention/control period, a
fixed effects analysis showed that there was a greater change in
average muscle scores (AMS) for the exercise group than the control and significant within group improvements in AMS reported
by Ruhland (Ruhland 1997), MD 0.60 (95% CI 0.29 to 0.91)
(Analysis 3.1). Standard deviations were estimated from the published paired t test P values with the help of a statistician. No
significant changes in right handgrip MD 1.70 (95% CI -0.60 to
4.00) (Analysis 3.3) or left handgrip, MD 0.30 (95% CI -2.03 to
2.63) (Analysis 3.2) were shown. Muscle strength was not assessed
in one trial (Richardson 2001).
Endurance at follow-up
The primary included trial utilised the maximum duration of contraction at 80% maximum voluntary contraction (MVC) as a measure of muscle endurance (Lindeman 1995) but there was no improvement in the duration of a sustained 80% maximal voluntary
contraction force following 24 weeks of exercise. The MD was
0.3 (95% CI -11.04 to 11.64) (Analysis 1.3). The two secondary
included trials did not assess endurance.
Psychological status or quality of life at follow-up
The primary included trial (Lindeman 1995) did not assess quality
of life. Only one of the secondary included trials assessed quality
of life using the SF-36 (Ruhland 1997). It should be noted that
this measure also includes items that assess functional ability and
mobility. The study reported no significant improvement in psychological status or quality of life and since no standard deviations
were presented in the text, no overall effect size may be calculated.

10
Return to work at 12 months after randomisation
Subgroup analysis
This was not measured in any of the included trials.
The information reported in the included trials was insufficient for

clearly identifying data for the subgroups of interest. In addition,
due to the variety of outcome measures used, pooling of data was
not appropriate. The primary included trial included only CMT
as a cause of peripheral neuropathy (Lindeman 1995). In the two
secondary included trials the participants had a diagnosis of diabetes-related diffuse primarily axonal peripheral polyneuropathy
in one trial (Richardson 2001) and predominantly presumed inflammatory neuropathies (25 patients) or hereditary neuropathy
(three patients) in the other (Ruhland 1997).
Unfavourable outcomes
Relapse as defined by an increase in neurological deficit
This was not measured in any of the included trials.
Pain
This was not consistently reported in the included trials. In the

primary included trial, one control patient dropped out due to
knee pain prior to final follow-up (Lindeman 1995). In one of
the secondary included trials, one exercising patient dropped out
during the intervention period due to ankle pain (Richardson
2001).
We had planned to pool data from clinically homogeneous studies

for meta-analysis, however this was not possible due to differences
in outcomes and interventions between studies. As a consequence,
we did not conduct a sensitivity analysis for methodological quality. Therefore no analysis of the subgroups of interest (type of neuropathy and disease severity) was possible.

11

A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Lower limb strengthening and balance exercise versus upper limb strengthening exercise for people with peripheral neuropathy
Settings:
Intervention: Lower limb strengthening and balance exercise versus upper limb strengthening exercise
Outcomes
% Change in activities
specific balance confidence scale scores
ABC scale. Scale from: 0
to 100.
Follow-up: 3 weeks
Assumed risk
Corresponding risk
Control
Lower limb strengthening and balance exercise versus upper limb

strengthening exercise
The mean % change in

activities specific balance
confidence scale scores
in the control groups was
80 score
The mean % Change in

activities specific balance
confidence scale scores
in the intervention groups
was
8 higher
(8.47 lower to 24.47
higher)
Relative effect
(95% CI)
No of Participants
(studies)

(GRADE)
16
(1 study)

moderate1
Comments
1
12
High risk of bias for sequence generation, allocation concealment and incomplete outcome data and uncertain risk of bias for blinding

Home exercise versus no exercise for people with peripheral neuropathy

Settings:
Intervention: Home exercise versus no exercise
Outcomes
Relative effect
(95% CI)
No of Participants
(studies)

(GRADE)
Assumed risk
Corresponding risk
Control
Home exercise versus

no exercise
The mean change in average muscle scores in the

control groups was
8.6 score
The mean Change in average muscle scores in the

intervention groups was
0.6 higher
(0.29 to 0.91 higher)
28
(1 study)

moderate1
Change in left handgrip The mean change in left

force (Kg)
handgrip force (kg) in the
control groups was
Follow-up: 6 weeks
28.9 kilograms
The mean Change in left

handgrip force (Kg) in the
0.3 higher
(2.03 lower to 2.63
higher)
28
(1 study)

moderate1
Change in right handgrip The mean change in right

force (Kg)
handgrip force (kg) in the
Follow-up: 6 weeks
control groups was
29.1 kilograms
The mean Change in right

handgrip force (Kg) in the
1.7 higher
(0.6 lower to 4 higher)
28
(1 study)

moderate1
Change in average muscle scores

AMS. Scale from: 0 to 10.
Follow-up: 6 weeks
Comments
13


1
High risk of bias for sequence generation, allocation concealment and blinding.
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
14
DISCUSSION
The main finding of the review is that there is insufficient evidence
available from randomised controlled trials to confidently evaluate
the effect of exercise on functional ability in patients with peripheral neuropathy. Only one trial examining the effect of exercise
in 34 patients with CMT met the full inclusion criteria and was
initially included in the review (Lindeman 1995). Subsequently, a
further two trials that met all criteria except for the need for studies
to examine follow-up at least eight weeks after commencement of
the intervention or control period, were also included (Richardson
2001; Ruhland 1997). All three trials were small with only 82 patients examined in total. The authors acknowledge that blinding
of patients and to a lesser extent observers is difficult in exercise
therapy trials. If blinding is carried out, it generally remains at
least at risk of exposure and hence bias, and therefore these criteria for methodological quality are difficult to satisfy. Nevertheless, the included trials failed to meet several of our other criteria
for methodological quality and this inevitably limits the certainty
with which any conclusions may be viewed.
Interpreting the findings from included trials

The cause of neuropathy was different in each trial (metabolic,
CMT disease, CIDP) and mixed causes were evident in one trial
(Ruhland 1997). The severity of disease and the duration since
onset was not adequately documented in the three trials. However,
inclusion and exclusion criteria based on functional mobility may
have reduced variability of these factors in the reviewed trials.
Nevertheless, the response to exercise in patients with different
types, severity and/or duration of peripheral neuropathy may be
different and therefore reduce the validity and generalisability of
findings.
Whilst all trials included exercises to improve muscle strength, the
intensity of exercise was variable and the muscle groups strengthened were different across the three trials. Only Lindeman 1995
utilised a standardised method of determining load for exercise
intensity. Ruhland 1997 used progressive strengthening exercises
determined by the subjects ease of completion and the final study
(Richardson 2001) used a fixed load with increased repetitions
during the intervention period. Both studies using progressive resistance (Lindeman 1995; Ruhland 1997) demonstrated some significant improvements in muscle strength over the period of the
intervention.
The effect of exercise on cardiovascular fitness was not evaluated
in any of the included trials, despite the inclusion of 20 minutes of
aerobic cycling in the training programme for one study (Ruhland
1997). This is an unfortunate omission since the evidence from
RCTs for the benefits of regular exercise on improving cardiovascular fitness (Lemura 2000; McArdle 1996), mood and mental
well-being in the general population (McAuley 2000; Moses 1989)
and in patients with neuromuscular disorders (Cedraschi 2004) is

growing.
Reporting of outcome measures

A lack of consensus in reporting of outcome measures was evident
in the review. Whilst all trials used between one and five time scored
functional activities to assess functional ability no single activity
was the same across trials. Two trials used additional measures,
namely, subscales of the SF-36 (Ruhland 1997) or a modification
of the functional component of the WOMAC (Lindeman 1995)
to assess functional ability. However, it could be argued that neither
of these measures unequivocally evaluates functional ability since
they include questions to evaluate the impact of deficits in functional ability on general functioning or societal participation. No
significant changes in the composite measures were demonstrated.
Indeed, only an improvement in the six metre comfortable walking speed at 24 weeks after starting the exercise programme was
demonstrated by Lindeman 1995.This suggests that exercise may
have a limited effect on functional ability, at least in the reviewed
trials. However, the authors suggested that this small change in
preferred six metre gait speed may be influenced by motivation
since the subjects were not blinded for intervention allocation. It
is also important to note that the intervention period in two of
the trials was less than the eight weeks initially identified by the
review protocol. It could be that in these trials (Richardson 2001;
Ruhland 1997) the exercise was not continued for long enough.
Indeed, Lindeman et al. (Lindeman 1995) did not report improvements in any of the measures of functional ability at either of the
earlier time points for assessing outcome (eight and 16 weeks after
starting exercising).
Secondary outcomes
Of the stated secondary outcomes, muscle strength, endurance
and quality of life were evaluated in some of the included trials. The only beneficial effects of exercise presented were small
but significant changes in muscle force which were demonstrated
in two trials (Lindeman 1995; Ruhland 1997) with the greatest
improvement in strength observed where the methods for determining load for progressive resisted exercise was clearly described
and standardised (Lindeman 1995). The authors claim that this
change in muscle strength represents only a moderate improvement in response to strengthening exercise compared with healthy
people (Hakkinen 1985). However the response to strengthening
exercise varies due to the type, intensity and duration of exercise
and the percentage change in strength of leg extensors in this study
is comparable with more recent studies of similar interventions
in patient populations and healthy exercising controls (Hakkinen
2001; Valkeinen 2004). Interestingly, it is well recognised that
whilst there are early increases in muscle strength due to train-

15
ing (Young 1985) these are largely due to improved neural effectiveness and changes to muscle structure take longer to establish
(Moritani 1979).Thus improvements in muscle strength may not
be sufficient in the shorter trials to have an impact on functional
ability. The modest evidence from this review supports the view
that progressive resisted exercise may be effective in improving
muscle strength in people with peripheral neuropathy.
Adverse effects of exercise

Only one participant who was undertaking exercise dropped out
of the trial (Richardson 2001) due to pain in the lower limb.
This was attributed to the programme aggravating an underlying
arthritic condition. No other adverse events were documented.
This is an important finding for two reasons. Firstly, it should be
noted that in peripheral neuropathy, where motor and/or sensory
signs and symptoms are present, altered joint mechanics and muscle imbalance may predispose patients to soft tissue injury during
exercise. The included trials did not discuss this or the use of orthotic support to protect affected joints during exercise. Secondly,
controversy exists regarding the use of strengthening exercises in
conditions where partial denervation and reinnervation may be a
feature. The possibility of overwork leading to an increase in neurological signs and symptoms has been investigated in both animal
and human studies. Recent evidence from animal studies suggests
that during the early reinnervation phase after partial denervation
high levels of neuromuscular activity as a result of electrical stimulation or exercise prevents axonal sprouting and increases motor
unit loss (Tam 2001). However in people with post-poliomyelitis
where enlarged motor units are compensating for progressive axonal loss due to partial denervation, moderate intensity exercise
was effective in increasing muscle strength with no deleterious effects on motor unit number (Chan 2003). Therefore the limited
evidence available from this review and others evaluating the effect
of exercise in people with similar problems such as in fibromyalgia syndrome (Busch 2004) and physical disability in older people (Latham 2004) suggests that exercise programmes aimed at
strengthening muscles are feasible in people with peripheral neuropathy.
Limitations of the review

The search strategy of the review identified 481 citations, of which
only one trial fulfilled all the selection criteria and a further two
trials met all but one of the criteria. This highlights the paucity of
trials and evidence in this important area of investigation. Several
factors regarding the patient group and type of intervention may
be responsible for this. Firstly, despite the relatively high prevalence of peripheral neuropathy in the population (Martyn 1998)
the varied diagnostic types and severity of disease makes recruitment to trials of large numbers of sufficiently similar participants
difficult. Secondly, the willingness of participants to be randomly

allocated into either an exercise or non-intervention control group
is particularly important for exercise trials where the motivation
and commitment of the individual participants to undertake the
exercise component may deter them from agreeing to participate.
Finally, the current clinical provision for patients with peripheral
neuropathy is likely to be predominantly by individualised rehabilitation that may include prescription of exercise in response to
patients symptoms and individual needs. In addition many people with stable or chronic peripheral neuropathy may not be in
receipt of treatment for their symptoms. This means that accurate description of exercise therapy in clinical trials is not always
documented. This final point is important since the continued
lack of high quality evidence regarding the efficacy of exercise in
the treatment of people with peripheral neuropathy may influence
the availability, accessibility and quality of service provision for
this client group. Medical charities (NAlliance 2002) and others
(DoH 2004) have identified the needs of people with neurological
and/or chronic conditions and service provision is a major concern. No true assessment of the cost and benefits of exercise in
the treatment of people with peripheral neuropathy can be made
until relevant research evidence is available, including the effect
of exercise treatment on the overall economic burden of care to
health service providers.
Overall the results of the included trials did not show that strengthening and endurance exercise programmes improve functional
ability or reduce disability in patients with peripheral neuropathy. However, there was limited evidence that strengthening exercise programmes were effective in increasing the strength of tested
muscles (Lindeman 1995; Ruhland 1997). There was no impact
on the level of disability in these patients but this may be related
to the duration of the exercise intervention and methodological
quality of included trials.
Limitations in the methods of the review

Whilst two authors were independently involved in checking titles
and abstracts identified by the search, in assessing potentially relevant studies for inclusion and in evaluating the methodological
quality of included studies, disagreements regarding inclusion criteria and quality were resolved by discussion and it was not deemed
necessary to refer these to a third author. In addition whilst a standardised data extraction sheet was devised by two authors (CMW,
JP) no wider consultation of experts in the field, regarding the
content of the data extraction form was carried out. It is possible
that these omissions may have introduced some personal bias in
interpretation of the studies for inclusion in the review.
AUTHORS CONCLUSIONS

16
Implications for practice

There is little evidence from the presented RCTs to evaluate the
effect of exercise on functional ability in peripheral neuropathy.
The included trials failed to meet some of the selected criteria
for risk of bias and the outcome measures used were too varied
for accurate comparisons. However, there is some evidence that
strengthening exercises moderately improve muscle strength in
tested muscles.
No further RCTs were identified in the current update thus, clinical guidelines must remain based largely on evidence from uncontrolled trials.
Implications for research

The lack of high quality evidence with which to evaluate the effect
of exercise on functional ability in people with peripheral neuropathy strongly supports the need to develop future high quality sufficiently powered trials. Future research designs should consider compatible diagnostic groups and include adequate allocation concealment, blinding of outcome assessor, clear description
of exercise intervention and standardization of outcome measures.
ACKNOWLEDGEMENTS
Professor RAC Hughes for advice and comments, Ms K Jewitt
for practical assistance and training in the use of Review Manager. Editorial support from the Cochrane Neuromuscular Disease
Group was funded by the TREAT NMD European Union Grant
036825.
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Systematic Reviews of Interventions Version 5.0.2 [updated
September 2009]. The Cochrane Collaboration, 2009.

Available from www.cochranehandbook.org.
Hughes 2005
Hughes RA, Wijdicks EF, Benson E, Cornblath DR, Hahn
AF, et al.Multidisciplinary Consensus Group. Supportive
care for patients with Guillain-Barr syndrome. Archives of
Neurology 2005;62(8):11948.
Latham 2004
Latham N, Anderson C, Bennet D, Stretton C. Progressive
resistance strength training for physical disability in older
people. Cochrane Database of Systematic Reviews 2004, Issue
2. [DOI: 10.1002/14651858.CD002759.pub2]
Lemura 2000
Lemura LM von Duvillard SP Mookerjee S. The effects of
physical training of functional capacity in adults: Ages 46 to
90: a meta-analysis. Journal of Sports Medicine and Physical
Fitness 2000;40(1):110.
Lennon 1993
Lennon SM, Koblar S, Hughes RAC, Goeller J, Riser AC.
Reasons for persistent disability in Guillain-Barr syndrome.
Clinical Rehabilitation 1993;7(1):18.
Martyn 1998
Martyn C, Hughes RAC. Peripheral neuropathies. In:
Martyn C, Hughes RAC editor(s). The Epidemiology of
Neurological Disorders. 1st Edition. London: BMJ Books,
1998.
McArdle 1996
McArdle WD, Katch FI, Katch VL. Exercise Physiology:
Energy, nutrition and human performance. 4th Edition.
Baltimore: Williams & Wilkins, 1996.
McAuley 2000
McAuley E, Blissmer B, Marquez DX, Jerome GJ, Kramer
AF, Katula J. Social relations, physical activity and wellbeing in older adults. Preventative Medicine 2000;31(5):
60817.
Merkies 1999
Merkies ISJ, Schmitz PIM, Samijn JPA, van der Mech
FGA, van Doorn PA. Fatigue in immune-mediated
polyneuropathies. American Academy of Neurology 1999;53
(8):164854.
Molenaar 1999
Molenaar DSM, Vermeulen M, De Visser M, De Haan R.
Impact of neurological signs and symptoms on functional
status in peripheral neuropathies. American Academy of
Neurology 1999;52(1):15156.
Moritani 1979
Moritani T, deVries HA. Neural factors versus hypertrophy
in the time course of muscle strength gain. American Journal
of Physical Medicine 1979;58(3):115130.
Moses 1989
Moses J, Steptoe A, Mathews A, Edwards S. The effects
of exercise training on mental well-being in the normal
population: a controlled trial. Journal of Psychosomatic
Research 1989;33(1):4761.

19
NAlliance 2002
Neurological Alliance. Levelling Up. Neurological Alliance,
http://www.neurologicalalliance.org.uk/ 2002.
Nicholas 2000
Nicholas R, Playford ED, Thompson AJ. A retrospective
analysis of outcome in severe Guillain-Barr syndrome
following combined neurological and rehabilitation
management. Disability and Rehabilitation 2000;22(10):
4515.
Padua 2008
Padua L, Pareyson D, Aprile I, Cavallaro T, Quattrone A,
Rizzuto N, et al.Natural history of CMT1A including QoL:
a 2-year prospective study. Neuromuscular disorders 2008;18
(3):199203.
Pfeiffer 2001
Pfeiffer G, Wicklein EM, Ratusinski T, Schmitt L, Kunze
K. Disability and quality of life in Charcot-Marie-Tooth
disease type I. Journal of Neurology, Neurosurgery and
Psychiatry 2001;70(4):54850.
Pitetti 1993
Pitetti KH, Barrett PJ, Abbas D. Endurance exercise training
in Guillain-Barr syndrome. Archives of Physical Medicine
and Rehabilitation 1993;74(7):7615.
Powell 2001
Powell P, Bentall RP, Nye FJ, Edwards RH. Randomised
controlled trial of patient education to encourage graded
exercise in chronic fatigue syndrome. BMJ 2001;322
(7283):38790.
Ribchester 1988
Ribchester RR. Activity-dependent and -independent
synaptic interactions during reinnervation of partially
denervated rat muscle. Journal of Physiology 1988;401:

5375.
Sebum 1996
Sebum KL, Gardiner PF. Properties of sprouted motor
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Muscle & Nerve 1996;19:11009.
Tam 2001
Tam SL, Archibald V, Jassar B, Tyreman N, Gordon T.
Increased neuromuscular activity reduces sprouting in
partially denervated muscles. Journal of Neuroscience 2001;
21(2):65457.
Valkeinen 2004
Valkeinen H, Alen M, Hannonen P, Hakkinen A, Airaksinen
O, Hakkinen K. Changes in knee extension and flexion
force, EMG and functional capacity during strength
training in older females with fibromyalgia and healthy
controls. Rheumatology 2004;43(2):22528.
Wearden 1998
Wearden AJ, Morriss RK, Mullis R, Strickland PL, Pearson
DJ, Appleby L, et al.Randomised, double-blind, placebocontrolled treatment trial of fluoxetine and graded exercise
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1998;172:48590.
WHO 2001
World Health Organization. ICF: International classification
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World Health Organization, 2001.
Young 1985
Young K, McDonagh MJ, Davies CT. The effects of two
forms of isometric training on the mechanical properties of
the triceps surae in man. Pflugers Archiv: European Journal
of Physiology 1985;405(4):384388.
Indicates the major publication for the study

20
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Lindeman 1995
Methods
Prospective randomised controlled single blind trial. 34 subjects underwent a prior qualification period to exclude subjects not suitable for exercise training. Four subjects excluded at this stage, some may have been due to motivational problems. Matching of
patients in intervention and control group on knee extension muscle strength and performance on stair-climbing task. Method of randomisation not stated. Losses after randomisation 2 of 30 (1 prior to allocation)
Participants
29 patients with CMT disease (Type I or Type II). Age 16 - 60 years. Controls, mean
age 38 (11) years, Intervention, mean age 35 (10) years. Inclusion criteria: diagnosis
supported by clinical picture, electromyography and nerve conduction studies and living
within 100 km.
Exclusion criteria: contraindications to muscle strengthening, other disabling disorder
that may influence scoring in functional tests
Interventions
Intervention group: knee and hip strengthening exercises progressing at 8 weekly intervals
from 60% to 80% of 1 repetition maximum and reducing the repetitions from 75 to 30
for 24 weeks. Control group: No exercise
Outcomes
Follow-up at 8-weekly intervals for 24 weeks after commencing exercise or control period.
1. Muscle strength.
2. Time-scored functional activities.
3. Functional component of Western Ontario McMaster University Osteoarthritis Index
(WOMAC)
Notes
Improvements in isokinetic knee extensor torque and 6 m comfortable speed walk
Risk of bias
Bias
Authors judgement
Support for judgement
Random sequence generation (selection High risk

bias)
Participants matched for knee extensor

muscle strength and performance on stairclimbing test
Allocation concealment (selection bias)
High risk
As above for adequate sequence generation.
Blinding (performance bias and detection High risk

bias)
All outcomes
Outcome assessors were blinded to treatment allocation but participants were not.
Difficult to blind participants in exercise
intervention studies

21
Lindeman 1995
(Continued)
Incomplete outcome data (attrition bias)

All outcomes
High risk
6 participants lost to follow up throughout the study. 4 dropped out prior to allocation in accordance with exclusion criteria, 1 dropped out prior to baseline assessment but it was not possible to determine
the cause (either medical or social problem)
and 1 dropped out prior to final outcome
session (28 week follow up) due to knee
problems
Selective reporting (reporting bias)
Low risk
All outcomes reported.
Other bias
Low risk
Richardson 2001
Methods
Prospective quasi-randomised controlled single blind trial. The first 10 subjects recruited
were placed in the intervention group and the next 10 in the control group
Participants
20 patients with peripheral neuropathy associated with diabetes mellitus.

Age: 50 - 80 years of age. Controls, mean age - 63.3 (7.6) years, intervention, mean
age - 64.0 (6.3) years. Inclusion criteria: 50 - 60 years of age, known history of diabetes
mellitus, lower extremity symptoms consistent with peripheral neuropathy, ability to
walk household distances, at least MRC grade 3 muscle strength at ankle, electrodiagnostic evidence of diffuse, axonal peripheral polyneuropathy. Exclusion criteria: significant
CNS dysfunction, significant musculoskeletal deformity, lower extremity pain limiting
standing or weightbearing, electrodiagnostic evidence of any diagnosis other than peripheral neuropathy, vestibular dysfunction, angina, postural hypotension, plantar skin
ulcers
Interventions
Intervention group: upright, unipedal and bipedal toe raises, heel raises, inversion and
eversion with no use of upper limbs except where minimal support was required. Exercises
were performed daily and progressed from 10 repetitions to between 20 - 30 repetitions
over the 3 week intervention period.
Control group: Seated. Neck flexion and rotation, upper limb strengthening exercise 5
times per week
Outcomes
Follow-up at 3 weeks after commencing intervention.

1. Tandem stance time.
2. Functional reach 3. Unipedal stance time.
4. Activities-specific balance and confidence (ABC) scale scores
Notes
Improvements in unipedal and tandem stance times.
Risk of bias
Bias
Authors judgement

22
Richardson 2001
(Continued)

bias)
Allocation based on rule about date of recruitment. first ten subjects were placed
in the intervention group and the next 10
subjects were placed in the control group
As above
High risk
Blinding (performance bias and detection Unclear risk

bias)
All outcomes
Not clear if participants blinded but they

did receive non-active control exercise. Unable to evaluate blinding of outcome assessors from information given

All outcomes
High risk
At 3 week follow-up 1/10 from intervention group dropped out due to foot-ankle
pain and 3/10 control group dropped out,
one due to developing an illness and 2 gave
no reason for withdrawal
Low risk
All outcomes reported at follow-up
Other bias
Low risk
Authors reported greater severity of neuropathy at baseline (based on the Michigan

diabetes neuropathy score) in the intervention group than control but this was not
statistically significant
Ruhland 1997
Methods
Prospective quasi-randomised controlled trial. Sixty-eight people were contacted to participate in the trial, 31 were recruited for initial evaluations and 28 completed the study.
Twenty out of 28 subjects were randomly assigned to the control or intervention groups
and non-randomised placement of the remaining 8 was necessary to balance demographics, eg age and gender across the two groups
Participants
28 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

, CIDP with monoclonal gammopathy or central demyelination or toxic neuropathy,
idiopathic axonal degeneration or hereditary peripheral neuropathy. Age: control group,
mean age - 52.9 (16.2) years, intervention, mean age - 63.6 (10.5) years. Inclusion
criteria: clinical diagnosis of included conditions, ability to ambulate at least 4.6m with
or without assistive device. Exclusion criteria: Alteration to drug treatment or current
regimen within 1 month of entering the trial
Interventions
Intervention group: general muscle stretches and free active exercises for trunk and
shoulder girdle. Progressive resisted shoulder abduction, flexion and lateral rotation and
resisted elbow flexion 10 times daily using light to strong resistance therapeutic elastic
bands for 6 week intervention period. Lower limb exercise was either by a progressive
walking or cycling programme at 60-70% of their age-predicted heart rate maximum of
up to 20 minutes duration for 6 weeks.

23
Ruhland 1997
(Continued)
Control group: no exercise.

Outcomes
Follow-up at 6 weeks after commencement of intervention or control period.

1. Average muscle scores (AMS).
2. Handgrip force.
3. FVC.
4. Timed 9.1m walk.
5. Medical outcomes study (MOS) Short-Form Health Survey (SF-36)
Notes
Improvements in AMS only.
Risk of bias
Bias
Authors judgement

bias)
Non-random allocation of 8/28 participants to allow matching on basis of age and

gender
High risk
As above for adequate sequence generation
Blinding (performance bias and detection High risk

bias)
All outcomes
Not described but evaluator telephoned

each subject at the end of the first week
and during week 5 to monitor progress and
encourage adherence

All outcomes
Low risk
28/28 participants available at follow-up
Low risk
Yes all outcomes reported.
Other bias
Low risk
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Becker 1986
Not a RCT. Review of post-acute rehabilitation in 31 patients with acute polyneuritis
Benyamine 1991
Not a RCT. Retrospective study of rehabilitation procedure in patients with Guillain-Barr syndrome
Boccignone 1997
Not a RCT. Study of the effectiveness of a protocol to treat various forms of ataxia in 10 elderly subjects
Carter 1995
Prospective survey of impairment and disability in 86 patients with CMT disease

24
(Continued)
Dijs 2000
Not a RCT. Study of passive joint mobilization on joint mobility
Eldar 2000
Review of studies of the effects of activity and exercise in patients with neurological impairment
Estacio 1998
Not a RCT. Comment only.
Florence 1984
Pilot study of 8 patients with neuromuscular disease including two patients with CMT disease
Forrest 1999
Non-systematic review of clinical trials examining the efficacy of exercise in patients neuromuscular disease
Gutenbrunner 1999
RCT comparing standard physiotherapy rehabilitation (including exercise) with standard physiotherapy plus
the provision of a special pillow
Haslbeck 1996
Not a RCT. Clinical review and comments.
Jiang 1997
Retrospective epidemiological survey of 556 patients with Guillain-Barr syndrome including length of rehabilitation
Kilmer 2000
Review of response to aerobic exercise training in patients with neuromuscular disease
Kingery 1997
Critical review and meta-analysis of RCTs for treatment of peripheral neuropathic pain
Koch 2002
Non-systematic review of effect of strength and endurance training in neuromuscular disease
Levoska 1993
Quasi RCT including passive and active (dynamic muscle training) physiotherapy for head and neck pain
Lindeman 1994b
Not a RCT. Comparison of knee strength and functional ability between a group of patients with CMT disease
and healthy controls
LoVecchio 1997
A review of diagnostic characteristics in several case studies of patients with neuromuscular disease
Melillo 1999
Study of rehabilitation outcome in 37 patients with Guillain-Barr syndrome
Meythaler 1997
Retrospective case review of rehabilitation outcome in 39 patients with Guillain-Barr syndrome
Palacios 1996
Not a RCT. Study of functional outcome in 58 patients with Guillain-Barr syndrome
Persson 2001
RCT including surgical management, cervical collar or individualised physiotherapy treatment for cervical
radicular pain
Rundcrantz 1991
RCT including psychosomatic and ergonomic approaches to treatment of neck pain
Videler 2002
Not a RCT. Comparison of hand strength and fatigue between patients with CMT disease and healthy controls
Zelig 1988
Not a RCT. Survey of rehabilitation of 24 patients with Guillain-Barr syndrome

25
Characteristics of studies awaiting assessment [ordered by study ID]

Zifko 2003
Methods
Participants
Interventions
Outcomes
Notes
Available in abstract only - awaiting publication of full study report

26
DATA AND ANALYSES
Comparison 1. Strengthening exercise versus no exercise
Outcome or subgroup title

1 Change in time taken for 6m
comfortable walk (seconds)
2 Change in isokinetic knee
extension torque (Nm)
3 Change in endurance at 80%
MVC (seconds)
4 Change in isokinetic knee
flexion torque (Nm)
5 Change in maximal isometric
voluntary contraction force
(Nm)
No. of
studies
No. of
participants
26
Mean Difference (IV, Fixed, 95% CI)
0.7 [0.23, 1.17]
26
17.7 [5.11, 30.29]
26
0.30 [-11.04, 11.64]
26
-0.5 [-9.78, 8.78]
26
12.60 [-1.51, 26.71]
Statistical method
Effect size
Comparison 2. Lower limb strengthening and balance exercise versus upper limb strengthening exercise

1 % Change in activities specific
balance confidence scale scores
No. of
studies
No. of
participants
16
Statistical method
Effect size
8.0 [-8.47, 24.47]
Comparison 3. Home exercise versus no exercise

1 Change in average muscle scores
2 Change in left handgrip force
(Kg)
3 Change in right handgrip force
(Kg)
No. of
studies
No. of
participants
1
1
28
28

0.60 [0.29, 0.91]

0.30 [-2.03, 2.63]
28
1.70 [-0.60, 4.00]
Statistical method

Effect size
27
Analysis 1.1. Comparison 1 Strengthening exercise versus no exercise, Outcome 1 Change in time taken for
6m comfortable walk (seconds).
Review:
Comparison: 1 Strengthening exercise versus no exercise

Outcome: 1 Change in time taken for 6m comfortable walk (seconds)
Study or subgroup
Exercise
Mean
Difference
No exercise
Mean(SD)
Mean(SD)
Lindeman 1995
13
1 (0.5)
13
0.3 (0.7)
Total (95% CI)
13
Weight
Mean
Difference
100.0 %
0.70 [ 0.23, 1.17 ]
100.0 %
0.70 [ 0.23, 1.17 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
13
Heterogeneity: not applicable

Test for overall effect: Z = 2.93 (P = 0.0033)
Test for subgroup differences: Not applicable
-2
-1
Favours no exercise
Favours exercise
Analysis 1.2. Comparison 1 Strengthening exercise versus no exercise, Outcome 2 Change in isokinetic
knee extension torque (Nm).
Review:

Outcome: 2 Change in isokinetic knee extension torque (Nm)
Study or subgroup
Exercise
Mean
Difference
No exercise
Mean(SD)
Mean(SD)
Lindeman 1995
13
12.4 (15.4)
13
-5.3 (17.3)
Total (95% CI)
13
Weight
Mean
Difference
100.0 %
17.70 [ 5.11, 30.29 ]
100.0 %
17.70 [ 5.11, 30.29 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
13

-50
-25
Favours no exercise

25
50
Favours exercise
28
Analysis 1.3. Comparison 1 Strengthening exercise versus no exercise, Outcome 3 Change in endurance at
80% MVC (seconds).
Review:

Outcome: 3 Change in endurance at 80% MVC (seconds)
Study or subgroup
Exercise
Mean
Difference
No exercise
Mean(SD)
Mean(SD)
Lindeman 1995
13
1.8 (17.4)
13
1.5 (11.5)
Total (95% CI)
13
Weight
Mean
Difference
100.0 %
0.30 [ -11.04, 11.64 ]
100.0 %
0.30 [ -11.04, 11.64 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
13

-50
-25
25
Favours no exercise
50
Favours exercise
Analysis 1.4. Comparison 1 Strengthening exercise versus no exercise, Outcome 4 Change in isokinetic
knee flexion torque (Nm).
Review:

Outcome: 4 Change in isokinetic knee flexion torque (Nm)
Study or subgroup
Exercise
Mean
Difference
No exercise
Mean(SD)
Mean(SD)
Lindeman 1995
13
7.3 (16.6)
13
7.8 (4)
Total (95% CI)
13
Weight
Mean
Difference
100.0 %
-0.50 [ -9.78, 8.78 ]
100.0 %
-0.50 [ -9.78, 8.78 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
13

-20
-10
Favours no exercise

10
20
Favours exercise
29
Analysis 1.5. Comparison 1 Strengthening exercise versus no exercise, Outcome 5 Change in maximal
isometric voluntary contraction force (Nm).
Review:

Outcome: 5 Change in maximal isometric voluntary contraction force (Nm)
Study or subgroup
Exercise
Mean
Difference
No exercise
Mean(SD)
Mean(SD)
Lindeman 1995
13
16.6 (19.7)
13
4 (16.9)
Total (95% CI)
13
Weight
Mean
Difference
100.0 %
12.60 [ -1.51, 26.71 ]
100.0 %
12.60 [ -1.51, 26.71 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
13

-50
-25
25
Favours no exercise
50
Favours exercise
Analysis 2.1. Comparison 2 Lower limb strengthening and balance exercise versus upper limb
strengthening exercise, Outcome 1 % Change in activities specific balance confidence scale scores.
Review:
Comparison: 2 Lower limb strengthening and balance exercise versus upper limb strengthening exercise
Outcome: 1 % Change in activities specific balance confidence scale scores
Study or subgroup Lower limb exercise
Mean
Difference
Upper limb exercise
Mean(SD)
Mean(SD)
Richardson 2001
88 (11)
80 (20)
Total (95% CI)
Weight
Mean
Difference
100.0 %
8.00 [ -8.47, 24.47 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
100.0 % 8.00 [ -8.47, 24.47 ]

-50
-25
Upper limb exercise

25
50
Lower limb exercise
30
Analysis 3.1. Comparison 3 Home exercise versus no exercise, Outcome 1 Change in average muscle scores.
Review:
Comparison: 3 Home exercise versus no exercise

Outcome: 1 Change in average muscle scores
Study or subgroup
Home exercise
Mean
Difference
No exercise
Mean(SD)
Mean(SD)
Ruhland 1997
14
0.4 (0.4)
14
-0.2 (0.44)
Total (95% CI)
14
Weight
Mean
Difference
100.0 %
0.60 [ 0.29, 0.91 ]
100.0 %
0.60 [ 0.29, 0.91 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
14

-4
-2
No exercise
Home exercise
Analysis 3.2. Comparison 3 Home exercise versus no exercise, Outcome 2 Change in left handgrip force
(Kg).
Review:

Outcome: 2 Change in left handgrip force (Kg)
Study or subgroup
Exercise
Mean
Difference
No exercise
Mean(SD)
Mean(SD)
Ruhland 1997
14
1.1 (3.29)
14
0.8 (2.99)
Total (95% CI)
14
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
14
100.0 %
0.30 [ -2.03, 2.63 ]
100.0 %
0.30 [ -2.03, 2.63 ]

-20
-10
No exercise

10
20
Home exercise
31
Analysis 3.3. Comparison 3 Home exercise versus no exercise, Outcome 3 Change in right handgrip force
(Kg).
Review:

Outcome: 3 Change in right handgrip force (Kg)
Study or subgroup
Home exercise
Mean
Difference
No exercise
Mean(SD)
Mean(SD)
Ruhland 1997
14
2.2 (3.46)
14
0.5 (2.69)
Total (95% CI)
14
Weight
Mean
Difference
100.0 %
1.70 [ -0.60, 4.00 ]
100.0 %
1.70 [ -0.60, 4.00 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
14

-10
-5
No exercise
10
Home exercise
APPENDICES
Appendix 1. Ovid MEDLINE Search Strategy
1 Polyradiculoneuritis.mp. or Polyradiculoneuropathy/
2 (Guillain and Barre).mp.
3 1 or 2
4 Demyelinating diseases.mp. or Demyelinating Diseases/
5 demyelin$.mp.
6 4 or 5
7 (Inflammatory adj polyradiculoneuropath$).mp.
8 (Inflammatory adj polyneuropath$).mp.
9 (Inflammatory adj mononeuropath$).mp.
10 or/7-9
11 6 and 10
12 CIDP.mp. or Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/
13 (multifocal and neuropath$).mp.
14 (paraprot$ adj neuropath$).mp.
15 Peripheral Nervous System Diseases/
16 Neuropath$.mp.
17 15 or 16
18 PARAPROTEINEMIAS/
19 17 and 18
20 POEMS Syndrome/
21 (Poems adj Syndrome).mp.
22 Amyloid Neuropathies/
23 (Amyloid adj neuropath$).mp.
32
24 HEREDITARY MOTOR AND SENSORY NEUROPATHIES/

25 (Motor and Sensory and Neuropath$ and Heredity).mp.
26 HEREDITARY SENSORY AND AUTONOMIC NEUROPATHIES/
27 (Hereditary and Sensory and Autonomic and Neuropath$).mp.
28 (Heredit$ and Neuropath$).mp.
29 or/24-28
30 (Toxic adj neuropath$).mp.
31 (chemically or toxicity).tw.
32 17 and 31
33 ((Drug or Chemically) and induced and Neuropath$).mp.
34 30 or 32 or 33
35 ALCOHOLISM/
36 17 and 35
37 (alcohol adj neuropath$).mp.
38 Paraneoplastic Syndromes/
39 17 and 38
40 BORRELIA/
41 Borrelia$.mp.
42 LEPROSY/
43 (leprosy or leper$).mp.
44 Herpes Zoster/
45 (Herpes adj zoster).mp.
46 NEURALGIA/
47 (Herpes or herpetic).mp.
48 46 and 47
49 Diabetic Neuropathies/
50 (Diabetic adj neuropath$).mp.
51 49 or 50
52 (vasculitic$ and neuropath$).mp.
53 NEURITIS/
54 Brachial Plexus/
55 53 and 54
56 (Brachial adj neuritis).mp.
57 (neuralgic and amyotropath$).mp.
58 (radiation and plexopath$).mp.
59 Brachial Plexus Neuritis/
60 exp PAIN/
61 pain$.mp.
62 60 or 61
63 17 and 62
64 (cervical adj spondylotic adj radiculopath$).mp.
65 (lumbosacral adj radiculopath$).mp.
66 Wounds and Injuries/
67 Peripheral Nerves/
68 66 and 67
69 (Nerve adj trauma).mp.
70 (nerve$ and graft$).mp.
71 Tissue Transplantation/
72 67 and 71
73 Nerve Compression Syndromes/
74 (entrapment adj neuropath$).mp.
75 (carpal adj tunnel).mp.
76 (tarsal adj tunnel).mp.
33
77 (thoracic adj outlet).mp.

78 (ulnar adj nerve adj compression).mp.
79 (cubital adj tunnel).mp.
80 (bell$ adj pals$).mp.
81 Facial Paralysis/
82 pals$.mp.
83 81 and 82
84 (cranial adj nerve$ adj pal$).mp.
85 80 or 83 or 84
86 Trigeminal Neuralgia/
87 (trigeminal adj neuralgia$).mp.
88 Peripheral Nervous System Neoplasms/
89 3 or 11 or 12 or 13 or 14 or 19 or 20 or 21 or 22 or 23 or 29 or 34 or 36 or 37 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 48 or 51
90 52 or 55 or 56 or 57 or 58 or 59 or 64 or 65 or 68 or 69 or 70 or 72 or 73 or 74 or 75 or 76 or 77 or 78 or 79 (29615)
91 85 or 86 or 87 or 88 or 89 or 90
92 rehabilitat$.mp.
93 exp Rehabilitation/
94 exercise$.mp.
95 exp Exercise Therapy/
96 exp SPORTS/
97 Physical education.mp. and training.tw.
98 exp Exertion/
99 exp Physical Therapy Techniques/
100 Physiotherap$.mp.
101 (physical$ adj5 fit$).mp.
102 (physical adj5 train$).mp.
103 (physical$ adj5 activit$).mp.
104 strength$.mp.
105 (strength$ adj5 (exercise$ or train$)).tw.
106 (isometric$ adj5 (exercise$ or strength$)).tw.
107 (isotonic$ adj5 (exercise$ or strength$)).tw.
108 (isokinetic$ adj5 (exercise$ or strength$ or train$)).tw.
109 (aerobic$ adj5 (exercise$ or train)).tw.
110 (endurance adj5 (exercise$ or train)).tw.
111 (walk$ adj5 (exercise$ or train$)).tw.
112 (gait adj5 train$).tw.
113 (step up$ adj5 (exercise$ or train$)).tw.
114 ((stair$ adj5 exercise$) or train$).tw.
115 (cycle$ adj5 (exercise$ or train$)).mp.
116 (rowing adj5 (exercise$ or train$)).tw.
117 (run$ adj5 (exercise$ or train$)).tw.
118 (runnin$ adj5 (exercise or train$)).tw.
119 (treadmill adj5 (exercise$ or train$)).tw.
120 ((weight$ adj5 exercise$) or train$).tw.
121 Kinesiotherap$.mp.
122 (exercise$ adj5 train$).tw.
123 or/92-122
124 91 and 123
125 randomized controlled trial.pt.
126 controlled clinical trial.pt.
127 randomized.ab.
128 placebo.ab.
129 drug therapy.fs.
34
130 randomly.ab.
131 trial.ab.
132 groups.ab.
133 or/125-132
134 (animals not (animals and humans)).sh.
135 133 not 134
136 124 and 135
Appendix 2. Ovid EMBASE search strategy

1 Polyradiculoneuritis.mp. or Polyradiculoneuropathy/
3 1 or 2
4 Demyelinating diseases.mp. or Demyelinating Diseases/
5 demyelin$.mp.
6 4 or 5
7 (Inflammatory adj polyradiculoneuropath$).mp.
8 (Inflammatory adj polyneuropath$).mp.
9 (Inflammatory adj mononeuropath$).mp.
10 or/7-9
11 6 and 10
12 CIDP.mp. or Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/
14 (paraprot$ adj neuropath$).mp.
15 Peripheral Nervous System Diseases/
16 Neuropath$.mp.
17 15 or 16
18 PARAPROTEINEMIAS/
19 17 and 18
20 POEMS Syndrome/
22 Amyloid Neuropathies/
23 (Amyloid adj neuropath$).mp.
24 HEREDITARY MOTOR AND SENSORY NEUROPATHIES/
25 (Motor and Sensory and Neuropath$ and Heredity).mp.
26 HEREDITARY SENSORY AND AUTONOMIC NEUROPATHIES/
27 (Hereditary and Sensory and Autonomic and Neuropath$).mp.
28 (Heredit$ and Neuropath$).mp.
29 or/24-28
32 17 and 31
33 ((Drug or Chemically) and induced and Neuropath$).mp.
34 30 or 32 or 33
35 ALCOHOLISM/
36 17 and 35
37 (alcohol adj neuropath$).mp.
38 Paraneoplastic Syndromes/
39 17 and 38
40 BORRELIA/
41 Borrelia$.mp.
42 LEPROSY/
35
43 (leprosy or leper$).mp.
44 Herpes Zoster/
45 (Herpes adj zoster).mp.
46 NEURALGIA/
47 (Herpes or herpetic).mp.
48 46 and 47
51 49 or 50
52 (vasculitic$ and neuropath$).mp.
53 NEURITIS/
54 Brachial Plexus/
55 53 and 54
57 (neuralgic and amyotropath$).mp.
58 (radiation and plexopath$).mp.
59 Brachial Plexus Neuritis/
60 exp PAIN/
61 pain$.mp.
62 60 or 61
63 17 and 62
68 66 and 67
71 Tissue Transplantation/
72 67 and 71
82 pals$.mp.
83 81 and 82
85 80 or 83 or 84
88 Peripheral Nervous System Neoplasms/
89 3 or 11 or 12 or 13 or 14 or 19 or 20 or 21 or 22 or 23 or 29 or 34 or 36 or 37 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 48 or 51
90 52 or 55 or 56 or 57 or 58 or 59 or 64 or 65 or 68 or 69 or 70 or 72 or 73 or 74 or 75 or 76 or 77 or 78 or 79
91 85 or 86 or 87 or 88 or 89 or 90
92 rehabilitat$.mp.
93 exp Rehabilitation/
94 exercise$.mp.
36
96 exp SPORTS/
98 exp Exertion/
99 exp Physical Therapy Techniques/
104 strength$.mp.
123 or/92-122
124 91 and 123
125 crossover-procedure/
126 double-blind procedure/
127 randomized controlled trial/
128 single-blind procedure/
129 (random$ or factorial$ or crossover$ or cross over$ or cross-over$ or placebo$ or (doubl$ adj blind$) or (singl$ adj blind$) or
assign$ or allocat$ or volunteer$).tw.
130 or/125-129
131 human/
132 130 and 131
133 nonhuman/ or human/
134 130 not 133
135 132 or 134
136 124 and 135

37
Appendix 3. Ovid AMED search strategy

1 Polyradiculoneuritis/
2 (Polyradiculoneuritis or Polyradiculoneuropath$ or Polyradiculopath$).mp.
4 1 or 2 or 3
5 Demyelinating Disease/
6 demyelin$.mp.
7 5 or 6
8 (Inflammatory and polyneuropath$).mp.
9 ((inflammatory adj polyneuropath$) or (inflammatory adj mononeuropath$)).mp.
10 8 or 9
11 7 and 10
12 CIDP.mp.
14 (paraprot$ and neuropath$).mp.
15 Peripheral Nervous System Disease/
16 Neuropath$.mp.
17 15 or 16
19 (Amyloid and neuropath$).mp.
20 neuropathies, HEREDITARY MOTOR AND SENSORY/
21 (motor and sensory and heredit$ and Neuropath$).mp
22 (hereditary and sensory and autonomic and neuropath$).mp.
23 (heredit$ and neuropath$).mp.
24 20 or 21 or 22 or 23
27 17 and 26
28 ((Drug or Chemically) and induced and Neuropath$).mp. and 17
29 (neurotoxicity and syndrome$).mp.
30 25 or 27 or 28 or 29
31 ALCOHOLISM/
32 17 and 31
33 (alcohol and neuropath$).mp.
34 (paraneoplastic and neuropath$).mp.
35 borrelia/ or Borrelia$.mp.
36 35 and 17
37 neuroborreliosis.mp.
38 leprosy/ or leprosy.mp. or leper$.mp.
39 38 and 17
40 Herpes Zoster/ or Herpes zoster.mp.
41 NEURALGIA/
42 (Herpes or herpetic or posther$ or post-herp$).mp.
43 41 and 42
46 44 or 45
47 (vasculit$ and neuropath$).mp.
48 NEURITIS/
49 Brachial Plexus/
50 48 and 49
38
52 brachial neuropath$.mp.
53 ((neuralg$ and amyotropath$) or (radiation and plexopath$)).mp.
54 exp PAIN/
55 pain$.mp.
56 54 or 55
57 17 and 56
62 60 and 61
74 pals$.mp.
75 73 and 74
77 facial nerve injur$.mp.
78 72 or 75 or 76 or 77
81 peripheral neuropath$.mp.
82 iodopathic dysautonomia$.mp.
83 glossopharyngeal neuralgia.mp.
84 foot ulcer$.mp.
85 gastroparesis.mp.
86 gustatory sweating.mp.
87 postural hypotension.mp.
88 (mononeuropath$ or polyneuropath$).mp.
89 charcot marie tooth.mp.
90 (heredit$ and (demyelinat$ or neuropath$)).mp.
91 ((peroneal or median or femoral) and neuropath$).mp.
92 complex regional pain syndrome$.mp.
93 (paraneoplastic and (polyneuropath$ or nervous)).mp.
94 bulbar palsy.mp.
95 stiff man syndrome$.mp.
96 (alcohol induced and disorder and nerv$).mp.
97 or/4,11-14,18-19,24
98 or/30,32-40,43
99 or/46-47,50-53,57-59,62-64
100 or/65-71,78-81
101 or/82-91
102 or/92-101
103 rehabilitat$.mp.
104 Rehabilitation/
39
105 exercise$.mp.
107 exp SPORTS/
109 exp Exertion/
110 physiotherapy/
115 strength$.mp.
134 or/103-133
135 Randomized controlled trials/
136 Random allocation/
137 Double blind method/
138 Single-Blind Method/
139 exp Clinical Trials/
140 (clin$ adj25 trial$).tw.
141 ((singl$ or doubl$ or treb$ or trip$) adj25 (blind$ or mask$ or dummy)).tw.
142 placebos/
143 placebo$.tw.
144 random$.tw.
145 research design/
146 Prospective Studies/
147 cross over studies/
148 meta analysis/
149 (meta?analys$ or systematic review$).tw.
150 control$.tw.
151 (multicenter or multicentre).tw.
152 ((study or studies or design$) adj25 (factorial or prospective or intervention or crossover or cross-over or quasi-experiment$)).tw.
153 or/135-152
154 102 and 134 and 153

40
Appendix 4. EBSCOhost CINAHL search strategy

S41 S40 and S12
S40 S39 or S38 or S37 or S36 or S35 or S34 or S33 or S32 or S31 or S30 or S29 or S28 or S27 or S26 or S25 or S24 or S23 or S22
or S21 or S20 or S19 or S18 or S17 or S16 or S15 or S14 or S13
S39 (cycl*) or (MH Cycling)
S38 (physical fit*) or (MH Physical Fitness)
S37 Kinesiotherap*
S36 weight*
S35 (treadmill) or (MH Treadmills)
S34 (row*) or (MH Rowing)
S33 (run*) or (MH Running)
S32 (stair*) or (MH Stair Climbing)
S31 step*
S30 (gait) or (MH Gait) S
S29 (walk*) or (MH Walking)
S28 endurance
S27 (aerobic*) or (MH Aerobic Exercises)
S26 (isokinetic*) or (MH Isokinetic Exercises)
S25 (isotonic*) or (MH Isotonic Exercises)
S24 (isometric*) or (MH Isometric Exercises)
S23 (strength*) or (MH Muscle Strengthening)
S22 physical activit*
S21 physical train*
S20 Physiotherap*
S19 (Physical Therapy Techniques) or (MH Physical Therapy)
S18 (Exertion) or (MH Exertion)
S17 ((Physical education AND training)) or (MH Physical Education and Training)
S16 (sport*) or (MH Sports)
S15 (exercise*) or (MH Exercise)
S14 (MH Rehabilitation)
S13 rehabilitat*
S12 S11 or S10 or S9 or S8 or S7 or S6 or S5 or S4 or S3 or S2 or S1
S11 (polyneuritis) or (MH Polyneuritis)
S10 (polyradiculoneuritis) or (MH Polyradiculoneuritis)
S9 chronic inflammatory demyelinating polyradiculoneuropathy
S8 guillain barre Search modes
S7 CIDP
S6 (neuritis) or (MH Neuritis)
S5 (peripheral nerves) or (MH Peripheral Nerves)
S4 polyneuropath*
S3 peripheral* nervous* system* disease*
S2 (MH Peripheral Nervous System Diseases)
S1 peripheral neuropath*

41
Appendix 5. LILACS search strategy

(peripheral neuropath$ OR Mh Peripheral Nervous system diseases OR peripheral$ nervous$ system$ disease$ OR polyneuropath$
OR Mh peripheral nerves OR peripheral nerves OR Mh neuritis OR neuritis OR CIDP OR guillain barre OR chronic inflammatory
demyelinating polyradiculoneuropathy OR Mh polyradiculoneuritis OR polyradiculoneuritis OR Mh polyneuritis OR polyneuritis)
AND (rehabilitat$ OR Mh Rehabilitation OR exercise$ OR Mh exercise OR sport$ OR Mh sport OR (Physical education AND
training) OR Exertion OR Mh exertion OR Physical Therapy Techniques OR Mh Physical Therapy OR Physiotherap$ OR physical
fit$ OR physical train$ OR physical activit$ OR strength$ OR Mh Muscle Strengthening OR isometric$ OR Mh Isometric Exercises
OR isotonic$ OR Mh Isotonic Exercises OR isokinetic$ OR Mh Isokinetic Exercises OR aerobic$ OR Mh Aerobic Exercises OR
endurance OR walk$ OR Mh Walking OR gait OR Mh gait OR step$ OR stair$ OR Mh stair climbing OR cycle$ OR Mh cycling OR
row$ OR Mh rowing OR run$ OR Mh running OR treadmill Mh treadmills OR weight$ OR Kinesiotherap$) AND ((Pt randomized
controlled trial OR Pt controlled clinical trial OR Mh randomized controlled trials OR Mh random allocation OR Mh double-blind
method OR Mh single-blind method) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Pt clinical trial OR Ex
E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$)) OR ((Tw singl$
OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw
ciego$ OR Tw mask$ OR Tw mascar$)) OR Mh placebos OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR Tw casual$ OR
Tw acaso$ OR Tw azar OR Tw aleator$) OR Mh research design) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR
(Ct comparative study OR Ex E05.337$ OR Mh follow-up studies OR Mh prospective studies OR Tw control$ OR Tw prospectiv$
OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct animal AND NOT (Ct human and Ct animal)))
WHATS NEW
Last assessed as up-to-date: 23 September 2009.
Date
Event
Description
11 May 2011
Amended
Added additional acknowledgement
HISTORY
Protocol first published: Issue 4, 2002
Review first published: Issue 4, 2004
Date
Event
Description
14 September 2009
New search has been performed
Changes to background text, references. Risk of bias,

Summary of findings tables added. Searches updated
to September 2009, no new studies
4 August 2008
Amended
Converted to new review format.
1 April 2006
New search has been performed
We updated the searches of the Cochrane Neuromuscular Disease Group Register (September 2005)
, MEDLINE (January 1966 to August 2005), EMBASE (January 1980 to August 2005), CINAHL (Jan-

42
(Continued)
uary 1982 to October 2005) and AMED (January

1985 to October 2005). No new relevant randomised
controlled trials were found
14 July 2004
New citation required and conclusions have changed
Substantive amendment
CONTRIBUTIONS OF AUTHORS
CW developed and wrote the first draft of the protocol and incorporated comments from JP and LTS and Cochrane peer reviewers
into the final version.
DECLARATIONS OF INTEREST
Two of the authors (CW, LTS) have been involved in a pilot study examining the effects of exercise on disability in peripheral neuropathy.
The aims of the study are i) to determine the suitability and sensitivity of outcome measures, ii) to identify the most appropriate exercise
programme and iii) to provide data for appropriate power calculations, for a subsequent randomised controlled trial.
INDEX TERMS
Medical Subject Headings (MeSH)
Exercise Therapy;
Peripheral Nervous System Diseases [ rehabilitation]; Randomized Controlled Trials as Topic; Treatment Outcome
MeSH check words

Humans

43

2004 Exercise For People With Peripheral Neuropathy

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2004 Exercise For People With Peripheral Neuropathy

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Exercise for people with peripheral neuropathy (Review)

White CM, Pritchard J, Turner-Stokes L

Exercise for people with peripheral neuropathy (Review)

Exercise for people with peripheral neuropathy (Review)

Exercise for people with peripheral neuropathy

PLAIN LANGUAGE SUMMARY

Exercise for people with peripheral neuropathy (Review)

Exercise for people with peripheral neuropathy (Review)

Strengthening exercise versus no exercise for people with peripheral neuropathy

Illustrative comparative risks* (95% CI)

Quality of the evidence

Change in time taken

The mean change in time

The mean Change in time

The mean change in

The mean Change in

Change in endurance at The mean change in en80% MVC (seconds)

The mean Change in endurance at 80% MVC

Exercise for people with peripheral neuropathy (Review)

The mean change in isokinetic knee flexion torque

The mean Change in

Change in maximal isometric voluntary contraction force (Nm)

The mean change in maximal isometric voluntary

The mean Change in maximal isometric voluntary

Strengthening programmes typically involve progressive resisted

Exercise for people with peripheral neuropathy (Review)

Criteria for considering studies for this review

Search methods for identification of studies

Types of outcome measures

Functional ability at a timeframe less than eight weeks after the

The search strategies used are listed in the Appendices: Appendix

Data collection and analysis

Exercise for people with peripheral neuropathy (Review)

Titles and abstracts identified by the search were checked by two

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Subgroup analysis and investigation of heterogeneity

Exercise for people with peripheral neuropathy (Review)

Electronic searches were updated prior to submission of the review

Risk of bias in included studies

tal groups to maintain similar baseline characteristics for age and

Exercise for people with peripheral neuropathy (Review)

Exercise for people with peripheral neuropathy (Review)

Secondary outcome measures:

Muscle strength at follow-up

Significant improvements in isokinetic knee extension torque in

Psychological status or quality of life at follow-up

Exercise for people with peripheral neuropathy (Review)

Return to work at 12 months after randomisation

This was not measured in any of the included trials.

The information reported in the included trials was insufficient for

Relapse as defined by an increase in neurological deficit

This was not measured in any of the included trials.

This was not consistently reported in the included trials. In the

We had planned to pool data from clinically homogeneous studies

Exercise for people with peripheral neuropathy (Review)

Exercise for people with peripheral neuropathy (Review)

Illustrative comparative risks* (95% CI)

Lower limb strengthening and balance exercise versus upper limb

The mean % change in

The mean % Change in

Quality of the evidence