2004 exercise for people with peripheral neuropathy

8/9/2019 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

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2011, Issue 6http://www.thecochranelibrary.com

Exercise for people with peripheral neuropathy (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/


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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

5BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

11 ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .

15DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16 AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Strengthening exercise versus no exercise, Outcome 1 Change in time taken for 6m comfortable

walk (seconds). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Analysis 1.2. Comparison 1 Strengthening exercise versus no exercise, Outcome 2 Change in isokinetic knee extension

torque (Nm). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Analysis 1.3. Comparison 1 Strengthening exercise versus no exercise, Outcome 3 Change in endurance at 80% MVC

(seconds). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Analysis 1.4. Comparison 1 Strengthening exercise versus no exercise, Outcome 4 Change in isokinetic knee flexion torque

(Nm). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Analysis 1.5. Comparison 1 Strengthening exercise versus no exercise, Outcome 5 Change in maximal isometric voluntary

contraction force (Nm). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

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. . . . . . . . . . . . . . 30

Analysis 3.1. Comparison 3 Home exercise versus no exercise, Outcome 1 Change in average muscle scores. . . . 31

Analysis 3.2. Comparison 3 Home exercise versus no exercise, Outcome 2 Change in left handgrip force (Kg). . . . 31

Analysis 3.3. Comparison 3 Home exercise versus no exercise, Outcome 3 Change in right handgrip force (Kg). . . 32

32 APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42 WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iExercise for people with peripheral neuropathy (Review)



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[Intervention Review]

Exercise for people with peripheral neuropathy

Claire Margaret White1, Jane Pritchard2, Lynne Turner-Stokes3

1 Applied Biomedical Research Division, King’s College London, London Bridge, UK. 2 Neuromuscular Unit 3 North, Charing Cross

Hospital, London, UK. 3 Regional Rehabilitation Unit, King’s College London and Northwick Park Hospital, Harrow, UK

Contact address: Claire Margaret White, Applied Biomedical Research Division, King’s College London, Room 3.6, Shepherd’s House,

Guy’s Campus, London Bridge, London, SE1 1UL, UK. [email protected] .

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.


A B S T R A C T

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.

1Exercise for people with peripheral neuropathy (Review)


mailto:[email protected]:[email protected]


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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.

P L A I N L A N G U A G E S U M M A R Y

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.




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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 neuropathySettings:

Intervention: Strengthening exercise versus no exercise

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No of Participants

(studies)

Quality

(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 comfort-able walk(seconds)in the

control groups was

0.3 seconds

The mean Change in time

taken for 6m comfortablewalk (seconds) in the in-

tervention groups was

0.7 higher

(0.23 to 1.17 higher)

26

(1 study)

⊕⊕⊕

modera

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 inter-

vention groups was

17.7 higher

(5.11 to 30.29 higher)

26

(1 study)

⊕⊕⊕

modera

Change in endurance at

80% MVC (seconds)

Follow-up: 8 weeks

The mean change in en-

durance at 80% mvc

(seconds) in the control

groups was

1.5 seconds

The mean Change in en-

durance at 80% MVC

(seconds) in the interven-

tion groups was

0.3 higher

(11.04 lower to 11.64

higher)

23

(1 study)

⊕⊕⊕

modera

3

E x er ci s ef or p e o pl e

wi t h p er i ph er al n e ur o p a t h y ( R e vi e w )

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h e C o ch r an e C ol l a b or a t i on .P u b l i s h e d b y J oh n Wi l e y & S on s ,L t d .

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Change in isokinetic

knee flexion torque

(Nm)

Follow-up: 8 weeks

Themeanchangeinisoki-

netic knee flexion torque

(nm) in thecontrol groups

was-1.1 Newton metres

The mean Change in

isokinetic knee flexion

torque (Nm) in the inter-

vention groups was0.5 lower

(9.78 lower to 8.78

higher)

26

(1 study)

⊕⊕⊕

modera

Change in maximal iso-

metric voluntary con-

traction force (Nm)

Follow-up: 8 weeks

The mean change in max-

imal isometric voluntary

contraction force (nm) in

the control groups was

4 Newton metres

Themean Changein max-

imal isometric voluntary

contraction force (Nm) in

the intervention groups

was

12.6 higher

(1.51 lower to 26.71

higher)

26

(1 study)

⊕⊕⊕

modera

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and

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 estimat

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 es

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.

4



C o p yr i gh t ©2 0 1 1 T



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B A C K G R O U N D

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 collec-

tively 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 in-

sulating sheath), the axon (the central nerve fibre), or a mixture

of the two. Damage to the myelin sheath, or demyelination, pro-

duces 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 symptomsof 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. Re-

duced 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 his-

tory in any individual case of neuropathy is largely dependent

upon the underlying cause. Acute neuropathies, such as Guillain-

Barré syndrome, reach their worst and then slowlyrecover. Others,

e.g. chronic inflammatory demyelinatingpolyradiculoneuropathy,

tend to relapse and remit, whilst others gradually deteriorate over

many years (e.g. Charcot-Marie-Tooth disease (CMT), alcohol-

related neuropathy).

Symptoms during and residual problems after peripheral neuropa-

thy include muscle weakness, pain, sensory deficits, increased fati-

gability (Merkies 1999), psychological dysfunction and difficulties

with poor social adjustment (Lennon 1993; Pfeiffer 2001; Padua

2008). The extent of an individual’s physical recovery is not neces-

sarily related to recovery of nerve function (Molenaar 1999). As in

other chronic neurological disorders, the extent to which individ-

uals 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 agree-

ment in the literature regarding whetherstrengthening (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 sig-

nificant improvements in muscle strength, functional ability and

fatigue (Chetlin 2008; Garssen 2004; Graham 2007). Recent rec-

ommendations for exercise prescription for people with periph-

eral 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. Thesecan be isometric (performed against maximal resistance where no

associated jointmovementis possible),isotonic(performedagainst

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). En-

durance programmes typically involve gradually increasing the du-

ration and intensity of aerobic activity for example cycling, run-

ning, 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 un-

dertake in both acuteneuropathy, which is recovering, and chronicneuropathy, in which their exercise tolerance is reduced. They can

be fearful that excessive exercise might exacerbate their symptoms.

Indeed, insome patients where markedweaknessis 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 car-

diorespiratory response to exercise testing has been shown to be re-

duced 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 sol-

diers after recovery from GBS.

Since the previous update, two cohort studies of exercise for peo-

ple with inflammatory neuropathy show that participants were

stronger, fitter and experienced less fatigue after a 12 week exer-

cise 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 in-

creased neuromuscular activity during reinnervation may be detri-

mental. Whilst there is some evidence that intensive exercise car-

ried 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 sur-

rounding the safety, type, timing and effectiveness of exercise in

the treatment of people with peripheral neuropathy.




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O B J E C T I V E S

The objective was to systematically review the evidence from ran-

domised clinical trials concerning the effect of exercise therapy on

peripheral neuropathy.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Any randomised controlled trial (RCT) or quasi-randomised con-

trolled trial comparing exercise therapy to treat peripheral neu-

ropathy 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 present-

ing 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 neu-

ropathy 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 pro-

gressive 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.

Types of outcome measures

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 dis-

ability or activity limitation ( WHO 2001)), as measured by a val-

idated tool, at least eight weeks after the start of the intervention/

control period. Functional ability may include measures of mobil-

ity 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

Secondary outcome measures included were those validated out-

come measures used to assess:

(1) muscle strength at least eight weeks after the start of the inter-

vention (or on completion of the exercise programme);

(2) endurance at least eight weeks after the start of theintervention

(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 exerciseprogramme);

(4) return to work at least twelve months after the start of the

intervention.

In addition unfavourable secondary outcomes were assessed in-

cluding:

(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 ’guillainbarre’ or ’chronic inflammatory demyelinating polyradiculoneu-

ropathy’ or ’polyradiculoneuritis’ or ’polyneuropathy’ or ’polyneu-

ritis’ , combined using AND with ’strength training’ or ’endurance’

or ’exercise’ or ’physical therapy’ or ’physiotherapy’ or ’rehabilita-

tion’ as search terms in September 2009. MEDLINE (from 1966

to September 2009), EMBASE (from January 1980 to Septem-

ber 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 orunpublished data.

Search methods for electronic databases

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




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Titles and abstracts identified by the search were checked by two

authors (CMW, JP). The full texts of all potentially relevant stud-ies 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 SystematicReviews of Interventions (Higgins2008). Items considered were allocation concealment, participant

blinding, observer blinding, explicit diagnostic criteria, documen-

tation 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 us-

ing a standardised data extraction form.

Measures of treatment effect

Results were expressed as risk ratios (RR) with 95% confidence

intervals (CI) andrisk differences (RD) with 95% CIsfor dichoto-

mous outcomes and mean differences (MD) with 95% CIs for

continuous outcomes.

Data synthesis

Data from clinically homogenous studies were pooled where pos-

sible and sensitivity analysis undertaken for methodological qual-

ity.

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 neuropa-

thy either: hereditary, metabolic or inflammatory, mode of onset:

acute, relapsing or progressive);

(b) patients with less severe disease/disability (walks unaided) com-

pared with patients with severe disease (unable to walk or only

able to walk with assistance).

R E S U L T S

Description of studies

See: Characteristicsof included studies; Characteristicsof excluded

studies; Characteristics of studies awaiting classification.

The search strategy for the databases resulted in a list of 481 cita-

tions. The other searches did not add any further references. Au-

thors 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 identi-

fied 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 ex-

cept 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 pe-

riods, 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 peripheralneuropathy 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. Guillain-

Barré syndrome (GBS) or recent drug or toxin exposure. The tri-

als 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 periph-

eral neuropathy associated with diabetes mellitus. Ruhland and

Shields (Ruhland 1997) recruited 28 subjects with chronic pe-

ripheral neuropathy including 12 with chronic inflammatory de-

myelinating polyradiculoneuropathy (CIDP), six with CIDP with

monoclonal gammopathy, three with CIDP with central demyeli-nation or possible toxic neuropathy, four with idiopathic axonal

degeneration and three with hereditary peripheral neuropathy.

Two trials compared progressive resisted exercise with a non-inter-

vention control (Lindeman 1995; Ruhland 1997). One of these

included aerobic conditioning exercise alongside progressive resis-

tance exercises (Ruhland 1997). The third trial compared progres-

sive 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.




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Electronic searches were updated prior to submission of the review

and a further potentially relevant study, published only in abstractform, was identified from the Cochrane Neuromuscular Disease

Group Register (Zifko 2003). The study is included in the studies

awaiting assessment since theauthors are currently seeking to pub-

lish 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, perfor-

mance 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 con-

sistent with peripheral neuropathy. They also required conclusiveelectrodiagnostic evidence of diffuse, primarily axonal, peripheral

polyneuropathy. In the second trial Lindeman (Lindeman 1995)

includedpatientsdiagnosed with CMT disease on thebasisof 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 di-

agnosis 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 com-parisons of groups were made on the basis of other characteristics.

All trials considered differences in baseline characteristics, al-

though this was based on different clinical characteristics in each

case. There was no consistent examination of severity or dura-

tion of neuropathy. The first trial matched patients on muscle

strength and stair-climbing performance and no obvious base-

line differences in age or gender of patients was noted (Lindeman

1995). The second trial, where group randomisation was per-

formed, showed significant baseline differences in severity of neu-

ropathy 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 differ-ences in the Short Form-36 questionnaire (SF-36) for role limita-

tion (emotional) and social function scale scores and despite non-

randomised 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 ambula-

tory capability of: “must be able to walk household distances with-

out assistance or assistive device indoors” (Richardson 2001) and,

“the ability to ambulate 4.6 m with or without assistance or assis-

tive 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, in-

tensity and duration of exercise were given in both cases. In the

third trial (Richardson 2001) the intensity and frequency of ex-

ercise 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 tri-

als. The authors initially planned that only trials where the out-

come measures utilised validated measures of disability at leasteight 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 suit-

able outcome measures had been utilised on completion of an ex-

ercise programme, even where the programme was less than eight

weeks in duration. This alteration to the original protocol subse-

quently 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 pro-vide 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 pos-

sible. 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 as-

sessments, due to knee problems. There was no attempt to re-

place 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




11/45

control patients dropped out during the course of the trial. The

intervention patient dropped out due to exercises aggravating anunderlying arthritic condition, two control patients dropped out

giving no reason and the final control patient developed an un-

related 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 non-

exercise trials.

Figure 1. Methodological quality summary: review authors’ judgements about each methodological quality

item for each included study.




12/45

Effects of interventions

See: Summary of findings for the main comparison

Strengtheningexercise versusno exercise for people withperipheral

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.

Intheprimaryincludedtrial(Lindeman 1995)meanchangescores with standard deviations were presented. In the two secondary in-

cluded 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 re-

view 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 avail-

able for the stated apparent improvement in aspects of upper-leg

strength related functional activities of the modified Western On-

tario 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 addi-

tion to the majority of items pertaining to an individuals level of

participation, also contains items pertaining to physical function-

ing. 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 physi-

cal function scale. Unfortunately, no standard deviations were pre-

sented in the text of this study so no overall effect size can be cal-culated. 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 weeklyintervalsfor 24 weeks.

However, in the secondary included trials the follow-upperiod was

less than the stated eight weeks recommended by the review proto-

col. 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% CI5.11 to 30.29) ( Analysis 1.2). However, there was no improve-

ment 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 con-

trol 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 pub-

lished 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 con-

traction at 80%maximumvoluntary contraction (MVC) as a mea-

sure of muscle endurance (Lindeman 1995) but there was no im-

provement 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

Theprimary included trial (Lindeman 1995) didnot 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 psy-

chological status or quality of life and since no standard deviations

were presented in the text, no overall effect size may be calculated.




13/45

Return to work at 12 months after randomisation

This was not measured in any of the included trials.

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).

Subgroup analysis

Theinformationreportedin theincludedtrials wasinsufficient forclearly 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 dia-

betes-related diffuse primarily axonal peripheral polyneuropathy

in one trial (Richardson 2001) and predominantly presumed in-

flammatory neuropathies (25 patients) or hereditary neuropathy

(three patients) in the other (Ruhland 1997).

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 qual-

ity. Therefore no analysis of the subgroups of interest (type of neu-

ropathy and disease severity) was possible.




14/45

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

Patient or population: patients with people with peripheral neuropathySettings:

Intervention: Lower limb strengthening and balance exercise versus upper limb strengthening exercise


(95% CI)

No of Participants

(studies)

Quality

(GRADE


Control Lower limb strengthen-

ing and balance exer-

cise versus upper limb

strengthening exercise

% Change in activities

specific balance confi-

dence scale scores

ABC scale. Scale from: 0

to 100.

Follow-up: 3 weeks

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)

16

(1 study)

⊕⊕⊕

modera







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 es

Very low quality: We are very uncertain about the estimate.

1 High risk of bias for sequence generation, allocation concealment and incomplete outcome data and uncertain risk of bias for blinding1 2



C o p yr i gh t ©2 0 1 1 T


http://www.thecochranelibrary.com/view/0/SummaryFindings.htmlhttp://www.thecochranelibrary.com/view/0/SummaryFindings.html


15/45

Home exercise versus no exercise for people with peripheral neuropathy

Patient or population: patients with people with peripheral neuropathy

Settings:Intervention: Home exercise versus no exercise


(95% CI)

No of Participants

(studies)

Quality

(GRADE


Control Home exercise versus

no exercise

Change in average mus-

cle scores

AMS.Scale from: 0 to10.Follow-up: 6 weeks

The mean change in aver-

age muscle scores in the

control groups was8.6 score

Themean Changein aver-

age muscle scores in the

intervention groups was0.6 higher

(0.29 to 0.91 higher)

28

(1 study)

⊕⊕⊕

modera

Change in left handgrip

force (Kg)

Follow-up: 6 weeks

The mean change in left

handgrip force (kg) in the

control groups was

28.9 kilograms

The mean Change in left

handgrip force (Kg) in the

intervention groups was

0.3 higher

(2.03 lower to 2.63

higher)

28

(1 study)

⊕⊕⊕

modera

Change in right handgrip

force (Kg)

Follow-up: 6 weeks

The mean change in right

handgrip force (kg) in the

control groups was29.1 kilograms

The mean Change in right

handgrip force (Kg) in the

intervention groups was1.7 higher

(0.6 lower to 4 higher)

28

(1 study)

⊕⊕⊕

modera




1 3



C o p yr i gh t ©2 0 1 1 T



16/45




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 esVery low quality: We are very uncertain about the estimate.

1 High risk of bias for sequence generation, allocation concealment and blinding.

xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

1 4



C o p yr i gh t ©2 0 1 1 T



17/45

D I S C U S S I O N

The main finding of the review is that there is insufficient evidenceavailable from randomised controlled trials to confidently evaluate

the effect of exercise on functional ability in patients with periph-

eral 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

furthertwo trialsthat metall criteria except forthe need forstudies

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 pa-

tients 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 cri-

teria for methodological quality are difficult to satisfy. Neverthe-

less, 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 strength-

ened 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 re-

sistance (Lindeman 1995; Ruhland 1997) demonstrated some sig-

nificant 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 cardiovas-

cular 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

inthereview.Whilstalltrialsusedbetweenoneandfivetimescored

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 couldbe argued that neither

of these measures unequivocally evaluates functional ability since

they include questions to evaluate the impact of deficits in func-tional 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 walk-

ing 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, Lindemanet al.(Lindeman 1995) did notreport improve-

ments 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 tri-

als. 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 greatestimprovement in strength observed where the methods for deter-

mining 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 improve-

ment 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-




18/45

ing ( Young 1985) these are largely due to improved neural effec-

tiveness 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 mus-

cle imbalance may predispose patients to soft tissue injury during

exercise. The included trials did not discuss this or the use of or-

thotic 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 neu-

rological 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 stim-ulation 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 ax-

onal loss due to partial denervation, moderate intensity exercise

was effective in increasing muscle strength with no deleterious ef-

fects 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 fibromyal-

gia syndrome (Busch 2004) and physical disability in older peo-

ple (Latham 2004) suggests that exercise programmes aimed at

strengthening muscles are feasible in people with peripheral neu-

ropathy.

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 preva-

lence of peripheral neuropathy in the population (Martyn 1998)

the varied diagnostic types and severity of disease makes recruit-

ment 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 groupis 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 reha-

bilitation that may include prescription of exercise in response to

patients symptoms and individual needs. In addition many peo-

ple with stable or chronic peripheral neuropathy may not be in

receipt of treatment for their symptoms. This means that accu-

rate 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 influencethe 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 con-

cern. 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 theincludedtrials didnot show that strength-

ening and endurance exercise programmes improve functional

ability or reduce disability in patients with peripheral neuropa-

thy. However, there was limited evidence that strengthening exer-cise 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 rel-

evant studies for inclusion and in evaluating the methodological

quality of included studies, disagreements regarding inclusion cri-teria andqualitywere resolved by discussion andit wasnot deemed

necessary to refer these to a third author. In addition whilst a stan-

dardised 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.

A U T H O R S ’ C O N C L U S I O N S




19/45

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, clini-

cal guidelines must remain based largely on evidence from uncon-

trolled 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 neu-

ropathy strongly supports the need to develop future high qual-ity sufficiently powered trials. Future research designs should con-

sider compatible diagnostic groups and include adequate alloca-

tion concealment, blinding of outcome assessor, clear description

of exercise intervention and standardization of outcome measures.

A C K N O W L E D G E M E N T S

Professor RAC Hughes for advice and comments, Ms K Jewitt

for practical assistance and training in the use of Review Man-

ager. Editorialsupport from the Cochrane Neuromuscular Disease

Group was funded by the TREAT NMD European Union Grant036825.

R E F E R E N C E S

References to studies included in this review

Lindeman 1995 {published data only}

Lindeman E, Drukker J. Specificity of strength training in

neuromuscular disorders. Journal of Rehabilitation Sciences 1994;7(Suppl):13–15.∗ Lindeman E, Leffers P, Spaans F, Drukker J, Reulen J,

Kerckhoffs M, et al.Strength training in patients with

myotonic dystrophy and hereditary motor and sensory

neuropathy: a randomized clinical trial. Archives of Physical Medicine and Rehabilitation 1995;76(7):612–20.

Richardson 2001 {published data only}

Richardson J, Sandman D. A focussed exercise regime

improves clinical measures of balance in patients with

peripheral neuropathy. Archives of Physical Medicine and

Rehabilitation 2001;82:205–9.

Ruhland 1997 {published data only}

Ruhland J, Shields R. The effects of a home exercise

programme on impairment and health related quality of life

in persons with chronic peripheral neuropathies. Physical

Therapy 1997;77(10):1026–39.

References to studies excluded from this review

Becker 1986 {published data only}

Becker-Casademont R, Esser B. Course and outcome in

rehabilitating acute polyneuritis patients. Rehabilitation1986;25(4):160–165.

Benyamine 1991 {published data only}

Benyamine D, Poirot I, Tell L, Eysette M, Boisson D,

Rode G, et al.Guillain-Barré syndrome and rehabilitation.

Annales de Réadaptation et de Medicine Physique 1991;34(5):409–14.

Boccignone 1997 {published data only}

Boccignone A, Gargiulo O, Ortolani M, Ortolani L, Ferraro

C. Functional outcome among elderly subjects following

rehabilitation of gait disorders. Europa Medicophysica 1997;

33(2):97–102.

Carter 1995 {published data only}

Carter GT, Abresch RT, Fowler Jr WM, Johnson ER,

Kilmer DD, McDonald CM. Hereditary motor and sensory

neuropathy types I and II. American Journal of Physical Medicine & Rehabilitation 1995;74(5 Suppl):S140–S149.

Dijs 2000 {published data only}

Dijs HM, Roofthooft JM, Driessens MF, De Bock PG,

Jacobs C, Van Acker KL. Effect of physical therapy on

limited joint mobility in the diabetic foot: a pilot study.

Journal of the American Podiatric Medical Association 2000;

90(3):126–32.

Eldar 2000 {published data only}

Eldar R, Marincek C. Physical activity for elderly persons

with neurological impairment: A review. Scandinavian

Journal of Rehabilitation Medicine 2000;32(3):99–103.

Estacio 1998 {published data only}

Estacio RO, Regensteiner JG, Wolfel EE, Jeffers B,

Dickenson M, Schrier RW. The association between

diabetic complications and exercise capacity in NIDDMpatients. Diabetes Care 1998;21(2):291–295.

Florence 1984 {published data only}

Florence JM, Hagberg JM. Effect of training on the exercise

responses of neuromuscular disease patients. Medicine and

science in sports and exercise 1984;16(5):460–5.

Forrest 1999 {published data only}

Forrest G, Qian X. Exercise in neuromuscular disease.

Neurorehabilitation 1999;13(3):135–9.

Gutenbrunner 1999 {published data only}

Gutenbrunner C, Gundermann G, Hager G, Hager V,

Gehrke A. Prospective study of the long term effectiveness

of inpatient rehabilitation of patients with chronic

cervicobrachial syndromes and the effect of prescribing




20/45

special functional pillows. Rehabilitation 1999;38(3):

170–6.

Haslbeck 1996 {published data only}

Haslbeck M. Therapy of diabetic polyneuropathies.

Therapiewoche 1996;46(28):1554–58.

Jiang 1997 {published data only}

Jiang G-X, Cheng Q, Ehrnst A, Link H, De Pedro-Cuesta

J. Guillain-Barré syndrome in Stockholm County, 1973-

1991. European Journal of Epidemiology 1997;13(1):25–32.

Kilmer 2000 {published data only}

Kilmer DD. Response to aerobic exercise training in humans

with neuromuscular disease. American Journal of Physical Medicine & Rehabilitation 2002;81(11 Suppl):S148–150.

Kingery 1997 {published data only}Kingery WS. A critical review of controlled clinical trials

for peripheral neuropathic pain and complex regional pain

syndromes. Pain 1997;73(2):123–139.

Koch 2002 {published data only}∗ Koch JW, Burgunder J-M. Rehabilitation in

neuromuscular disease: effects of strength and endurance

training. Schweizer Archiv fur Neurologie und Psychiatrie 2002;153(2):69–81.

Levoska 1993 {published data only}

Levoska S, Keinanen-Kiukaanniemi S. Active or passive

physiotherapy for occupational cervicobrachial disorders? A

comparison of two treatment methods with a 1-year follow-

up. Archives of Physical Medicine and Rehabilitation 1993;

74(4):425–30.

Lindeman 1994b {published data only}

Lindeman E, Leffers P, Reulen J, Spaans F, Drukker J.

Reduction of knee torques and leg-related functional

abilities in hereditary motor and sensory neuropathy.

Archives of Physical Medicine and Rehabilitation 1994;75(11):1201–5.

LoVecchio 1997 {published data only}

LoVecchio F, Jacobson S. Approach to generalized weakness

and peripheral neuromuscular disease. Emergency Medicine Clinics of North America 1997;15(3):605–23.

Melillo 1999 {published data only}

Melillo EM, Sethi JM, Mohsenin V. Guillain-Barre syndrome: Rehabilitation outcome and recent

developments. Yale Journal of Biology and Medicine 1999;71(5):383–89.

Meythaler 1997 {published data only}

Meythaler JM, DeVivo MJ, Braswell WC. Rehabilitation

outcomes of patients who have developed Guillain-Barré

syndrome. American Journal of Physical Medicine & Rehabilitation 1997;76(5):411–19.

Palacios 1996 {published data only}∗ Palacios JM, De Dios Alvarez RM, Nunez MCN, Riano

OA, De Ruz AE, et al.Functional recuperation in a series

of patients with Guillain Barre syndrome [Spanish].

Rehabilitacion 1996;30(5):339–343.

Persson 2001 {published data only}

Persson LC, Lilja A. Pain, coping, emotional state andphysical function in patients with chronic radicular neck

pain. A comparison between patients treated with surgery,

physiotherapy or neck collar - a blinded, prospective

randomized study. Disability and Rehabilitation 2001;23(8):325–35.

Rundcrantz 1991 {published data only}

Rundcrantz BL, Johnsson B, Moritz U, Roxendal G.

Cervico-brachial disorders in dentists. A comparison

between two kinds of physiotherapeutic interventions.

Scandinavian Journal of Rehabilitation Medicine 1991;23(1):

11–17.

Videler 2002 {published data only}

Videler AJ, Beelen A, Aufdemkampe G, De Groot IJ, Van

Leempute M. Hand strength and fatigue in patients withhereditary motor and sensory neuropathy (types I and II).

Archives of Physical Medicine and Rehabilitation 2002;83(9):

1274–78.

Zelig 1988 {published data only}

Zelig G, Ohry, A, Shemesh Y, Bar-On Z, Blumen M,

Brooks ME. The rehabilitation of patients with severe

Guillain-Barré syndrome. Paraplegia 1988;26(4):250–4.

References to studies awaiting assessment

Zifko 2003 {published data only}

Zifko U, Herceg M, Grisold W. Neurorehabilitation

is effective in patients with neuropathies - results of a

randomized, prospective study. Journal of the Peripheral Nervous System 2003;8:78.

Additional references

Burrows 1990

Burrows DS, Cuetter AC. Residual subclinical impairment

in patients who totally recovered from Guillain-Barré

syndrome: impact on military performance. Military

Medicine 1990;155(9):438–40.

Busch 2004

Busch A, Schachter CL, Peloso PM, Bombadier C. Exercise

for treating fibromyalgia syndrome. Cochrane Database of Systematic Reviews 2004, Issue 2. [DOI: 10.1002/

14651858.CD003786.pub2]

Cedraschi 2004

Cedraschi C, Desmeules J, Rapiti E, Baumgartener E,

Cohen P, Finckh A, et al.Fibromyalgia: a randomised,

controlled trial of a treatment programme based on self-

management. Annals of Rheumatological Disease 2004;63(3):290–96.

Chan 2003

Chan KM, Amirjani N, Sumrain, M, Clarke A, Strohschein

FJ. Randomized controlled trial of strength training in post-

polio patients. Muscle & Nerve 2003;27(3):332–338.

Chetlin 2004

Chetlin RD, Gutmann L, Tarnopolsky M, Ullrich IH,

Yeater RA. Resistance training effectiveness in patients




21/45

with Charcot-Marie-Tooth disease: recommendations for

exercise prescription. Archives of Physical Medicine and Rehabilitation 2004A;85(8):1217–23.

Chetlin 2008

Chetlin RD, Gutmann L, Tarnopolsky MA, Ullrich IH,

Yeater RA. Resistance training exercise and creatine in

patients with Charcot-Marie-Tooth disease. Muscle & Nerve 2004B;30(1):69–76.

DoH 2004

Department of Health. National Service Framework

for Long Term Conditions. http://www.dh.gov.uk/

PolicyAndGuidance/HealthAndSocialCareTopics/

LongTermConditions.

Einsiedel 1994

Einsiedel LJ, Luff AR. Activity and motor unit size in

partially denervated rat medial gastrocnemius. Journal of Applied Physiology 1994;76(6):2663–71.

Fulcher 1997

Fulcher KY, White PD. Randomised controlled trial

of graded exercise in patients with the chronic fatigue

syndrome. BMJ 1997;314(7095):1647–52.

Gardiner 1986

Gardiner PF, Faltus RE. Contractile responses of rat

plantaris muscles following partial denervation and the

influence of daily exercise. Pfleugers Archiv: European

Journal of Physiology 1986;406(1):51–6.

Garssen 2004

Garssen MP, Bussmann JB, Schmitz PI, Zandbergen A,

Welter TG, Merkies IS, et al.Physical training and fatigue,fitness, and quality of life in Guillain-Barré syndrome and

CIDP. Neurology 2004;63(12):2393–5.

Graham 2007

Graham RC, Hughes RA, White CM. A prospective study

of physiotherapist prescribed community based exercise in

inflammatory peripheral neuropathy. Journal of Neurology 2007;254(2):228–35.

Hakkinen 1985

Hakkinen K, Komi PV, Alen M. Effect of explosive type

strength training on isometric force - and relaxation-time,

electromyographic and muscle fibre characteristics of leg

extensor muscles. Acta Physiologica Scandinavia 1985;125(4):587–600.

Hakkinen 2001

Hakkinen A, Hakkinen K, Hannonen P, Alen M. Strength

training induced adaptations in neuromuscular function of

premenopausal women with fibromyalgia: comparison with

healthy women. Annals of Rheumatological Disease 2001;60(1):21–26.

Herbison 1983

Herbison GJ, Jaweed MM, Ditunno JF Jr. Exercise

therapies in peripheral neuropathies. Archives of Physical

Medicine and Rehabilitation 1983;64(5):201–5.

Higgins 2008

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated

September 2009] . The Cochrane Collaboration, 2009.

Available from www.cochrane–handbook.org.

Hughes 2005

Hughes RA, Wijdicks EF, Benson E, Cornblath DR, Hahn

AF, et al.Multidisciplinary Consensus Group. Supportive

care for patients with Guillain-Barré syndrome. Archives of

Neurology 2005;62(8):1194–8.

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, Issue2. [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 to90: a meta-analysis. Journal of Sports Medicine and Physical

Fitness 2000;40(1):1–10.

Lennon 1993

Lennon SM, Koblar S, Hughes RAC, Goeller J, Riser AC.

Reasons for persistent disability in Guillain-Barré syndrome.

Clinical Rehabilitation 1993;7(1):1–8.

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 well-

being in older adults. Preventative Medicine 2000;31(5):

608–17.

Merkies 1999

Merkies ISJ, Schmitz PIM, Samijn JPA, van der Meché

FGA, van Doorn PA. Fatigue in immune-mediated

polyneuropathies. American Academy of Neurology 1999;53(8):1648–54.

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):151–56.

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):115–130.

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):47–61.




22/45

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-Barré syndrome

following combined neurological and rehabilitation

management. Disability and Rehabilitation 2000;22(10):451–5.

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):199–203.

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):548–50.

Pitetti 1993

Pitetti KH, Barrett PJ, Abbas D. Endurance exercise training

in Guillain-Barré syndrome. Archives of Physical Medicine

and Rehabilitation 1993;74(7):761–5.

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):387–90.

Ribchester 1988

Ribchester RR. Activity-dependent and -independent

synaptic interactions during reinnervation of partially

denervated rat muscle. Journal of Physiology 1988;401:

53–75.Sebum 1996

Sebum KL, Gardiner PF. Properties of sprouted motor

units: effect of period of enlargement and activity level.

Muscle & Nerve 1996;19:1100–9.

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):654–57.

Valkeinen 2004

Valkeinen H, Alen M, Hannonen P, HakkinenA, 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):225–28.

Wearden 1998

Wearden AJ, Morriss RK, Mullis R, Strickland PL, Pearson

DJ, Appleby L, et al.Randomised, double-blind, placebo-

controlled treatment trial of fluoxetine and graded exercise

for chronic fatigue syndrome. British Journal of Psychiatry 1998;172:485–90.

WHO 2001

World Health Organization. ICF: International classificationof functioning, disability and health. 1st Edition. Geneva:

World Health Organization, 2001.

Young 1985

Young K, McDonagh MJ, Davies CT. The effects of twofo

2004 exercise for people with peripheral neuropathy

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