Fatigue after stroke: a systematic review of associationswith impaired physical fitness

Fiona Duncan1, Mansur A. Kutlubaev2, Martin S. Dennis2, Carolyn Greig1, andGillian E. Mead1*

Background Fatigue is a common and distressing post strokesymptom. One important hypothesis is that fatigue afterstroke may be triggered by physical deconditioning, whichsets up a vicious, self-perpetuating cycle of fatigue, avoid-ance of physical activity, further deconditioning, and morefatigue. If an association between physical activity andfatigue after stroke could be established, this would pro-vide a rationale for developing a physical activity-basedtreatment.Aims Systematically review all observational studies, whichhave measured both fatigue poststroke and one or moremeasures of physical fitness and/or physical activity at thesame time-point and reported the association betweenfatigue and fitness variables.Method Publications were identified by systematicallysearching databases MEDLINE, EMBASE, CINAHL, PsychInfo,and Sportdiscus using keywords ‘fatigue’, ‘stroke’, ‘fitness’,or ‘activity’ and their associated terms or synonyms. Publi-cations that provided data on associations between fatiguein stroke patients and levels of physical activity, cardiores-piratory fitness and/or muscle strength and mass wereincluded.Results Twenty-nine potential studies were retrieved afterscrutinizing the titles and abstracts, of which only threefulfilled our inclusion criteria. No association betweenfatigue and any measures of physical activity or fitness werefound. One study did find, through structural equation mod-eling techniques that fatigue indirectly influences exercisethrough self-efficacy expectations.Conclusions There is very limited evidence regarding asso-ciations between exercise, fitness, and fatigue after stroke.It still remains highly plausible that exercise can have a

positive influence on fatigue. Future research should belongitudinal in design.

Key words: physical activity, physical fitness, poststrokefatigue, rehabilitation

Introduction

Fatigue is a common and distressing symptom after stroke.For example, one study found that 40% of stroke patients feltthat fatigue was either their worst symptom or one of theirworst symptoms (1). Fatigue may interfere with physiotherapysessions (2) and can negatively affect stroke survivors’ physicaland psychological functioning (1). One study showed thatfatigue is an important predictor for death two- to three-yearsafter stroke onset even after depression had been taken intoaccount (3). The reason why fatigue is associated with reducedsurvival is not known. The frequency of fatigue after strokeis reported as 30% to 68% depending upon whether depres-sion is taken into account (1–8). The etiology of fatigue afterstroke is currently unknown but is likely to be a multidimen-sional construct involving both biological and psychologicalelements.

After stroke, there is often a sudden reduction in physicalactivity as a direct result of neurological impairment. Thisphysical inactivity may lead to decline in physical fitness.One important hypothesis that needs exploring is that fatigueoccurring poststroke is triggered because of physical decondi-tioning, which occurs soon after stroke onset. Several studieshave shown that limb muscle strength (an important compo-nent of physical fitness) on both sides is significantly lower inpatients after stroke compared with controls (9). Anotherstudy demonstrated that the quadriceps strength of the legunaffected by the stroke declined by 30% as early as the firstseven-days after stroke (10). This reduction in muscle strengthmay increase the amount of effort required to carry out dailytasks and therefore induce fatigue. Patients may then avoidfurther activity, thus setting up a vicious, self-perpetuatingcycle of fatigue, avoidance of physical activity, further decon-ditioning, and more fatigue.

In cancer patients, muscle deconditioning has previouslybeen found to be associated with fatigue (11). The role

Correspondence: Gillian Mead*, Geriatric Medicine, University ofEdinburgh, Room S1642, Royal Infirmary of Edinburgh, 51 LittleFrance Crescent, Edinburgh EH16 4SA, UK.E-mail: gillian.e.mead@ed.ac.uk1Geriatric Medicine, University of Edinburgh, Edinburgh, UK2Division of Clinical Neurosciences, University of Edinburgh,Edinburgh, UK

Conflicts of interest: None declared.

DOI: 10.1111/j.1747-4949.2011.00741.x

Systematic review

© 2012 The Authors.International Journal of Stroke © 2012 World Stroke Organization Vol 7, February 2012, 157–162 157

of muscle deconditioning in causing cancer fatigue is sup-ported by the observation that a combination of resistanceand aerobic training significantly reduced sensory, affective,cognitive/mood, behavioral, and total fatigue (12). It is notyet known if muscle deconditioning is associated with fatiguein stroke patients. Given that physical activity levels (13),and aerobic fitness (14) are low after stroke, it is biologicallyplausible that fatigue after stroke might be related to physicaldeconditioning and reduced physical activity. Establishing anassociation would provide a rationale for developing a physi-cal activity-based treatment for fatigue after stroke. Clearly,demonstrating an association does not necessarily imply cau-sation (because fitness levels may be reduced because peoplewith fatigue avoid activity); however, it is necessary to seek onein order to provide a rational basis for starting to developexercise interventions for fatigue after stroke.

The aim of this systematic review was to identify allcross-sectional and longitudinal observational studies, whichmeasured both fatigue poststroke and one or more measuresof physical fitness and/or physical activity at the same time-point and reported the association between fatigue and fitnessvariables.

Method

Procedure

Searches were conducted in MEDLINE (from 1966), EMBASE(from 1980), CINAHL (from 1937), PsychInfo (from 1806),and Sportdiscus (from 1800) on 4 November 2010 using thekeywords ‘fatigue’, ‘stroke’, ‘fitness’ or ‘activity’, and their asso-ciated terms or synonyms.

Potentially relevant papers were identified from their titleand abstract and exported to endnote (Thomson Research-Soft. San Francisco, CA, USA). After duplicates were removed,one author (F. D.) read every abstract and obtained the full textof papers that potentially met the inclusion criteria. Referencelists of the retrieved articles were scrutinized for further poten-tially relevant studies. One reviewer (F. D.) applied the follow-ing inclusion criteria to the retrieved articles:

• written in English

• published in a peer-reviewed journal

• recruited people with stroke (first or recurrent, ischemic, orhemorrhagic) > 18 years

• retained 10 or more participants

• specifically assessed the presence or absence of fatigueusing a single question, a case definition or a specified cutoff ona fatigue scale; or reported fatigue scores as a continuousvariable, and

• provided data on associations between fatigue in strokepatients and levels of physical activity, cardio-respiratoryfitness, and/or muscle strength and mass. Any disagreementabout inclusion was discussed with both second reviewers(G. M. and M. K.)

Papers were excluded if:

• they were only published in abstract form

• they contained no primary data (e.g. reviews, editorials etc),and

• it was not possible to separately extract data for strokepatients from other types of patient.

data extraction – two reviewers (F. D. and M. K.) inde-pendently extracted data (onto paper data collection forms)describing

• age, gender, sample size, time since stroke, type of stroke

• method(s) of measuring fatigue

• method of measuring physical activity and/or fitness

• results of fatigue and physical fitness and physical activitymeasures, and

• any association reported between fatigue and either phy-sical activity or physical fitness.

Data synthesis – we intended to perform a meta-analysis tosynthesize the relative risks but the data were too diverse toallow for this. Instead, we opted for a narrative data synthesisapproach.

Definitions

For this review, we were looking for associations betweenamount of physical activity performed by a stroke survivorand not papers that reported activity limitations. We are defin-ing physical activity as ‘all bodily movement that is producedby the contraction of skeletal muscle and that substant-ially increases energy expenditure’ (15,16). For instance,we included studies that reported stroke survivors’ walking,running, cycling, swimming, playing sports, housework, orgardening but excluded studies that used gait or changes ingait patterns, single limb activity, sitting to standing, toiletingor bathing, or weight-bearing therapy as measures of physicalactivity. We also excluded studies where activity was measuredby activities of daily living scale such as the NottinghamActivities of Daily Living scale (17) or the Frenchay ActivitiesIndex (18) as several items on these scales refer to activities,which do not meet our definition of physical activity such asreading books, writing letters, driving a car, taking a car ride,or participating in gainful work.

We are defining physical fitness as ‘the collective term for aset of physiological attributes, which people have or achievethat determine the ability to perform physical activity.’ (15,16)These attributes include cardiorespiratory fitness, musclestrength, and muscle power. Physical activity and physicalfitness correlate positively with each other (15). The distinc-tion between the two constructs is that fitness is a conditionthat a person can be in at a point in time and activity is anenergy-consuming process (19).

Fatigue was defined as a subjective feeling of lack of energy,weariness, and aversion to effort (20). For this review, we wereinterested in chronic fatigue so we included studies that used aquestionnaire that had been specifically developed to measurefatigue or tiredness in daily life. We excluded studies where

Systematic review F. Duncan et al.

© 2012 The Authors.International Journal of Stroke © 2012 World Stroke Organization Vol 7, February 2012, 157–162158

muscle or exertion fatigue was measured in participantsdirectly after they completed a specific fatigue-inducingexercise.

An observational study was defined as any study where nointervention took place. However, papers were included ifboth poststroke fatigue and one or more measures of physicalfitness and/or physical activity were taken and reported at thebaseline of an intervention study.

We are hypothesizing that if a stroke survivor increases theirlevels of physical fitness and/or activity, then this will reducefatigue levels. Therefore, the independent variable in thisreview is fitness/activity and the dependent variable is fatigue.However, we do recognize that this may not be the direction ofcausality. It is also plausible that higher fatigue levels lead toless activity and/or fitness.

Results

The electronic search identified 1291 citations, after endnotehad removed duplicates. Twenty-nine full texts were retrieved,of which, three papers, recruiting a total of 444 participants,fulfilled inclusion criteria (Fig. 1). Scrutiny of reference listsprovided no further papers for inclusion. The main reasonsfor excluding a study were:

• review with no primary data

• fatigue was not measured, or

• the type of activity measured did not meet the inclusioncriteria, for example, measured gait patterns, single limbactivity, or participants’ self-reported ability to walk in thecommunity (as opposed to quantity of activity).

All three eligible studies were cross-sectional (21–23), twoincluded only ischemic strokes (21,22), and one included ‘anystroke survivor’ (23). Mean participant age was 59 years to 66years. In two studies (21,22), the participants were all commu-nity dwelling and were able to walk with or without a walkingaid. In one study (23), participants were either attendees of aNational Stroke Association support group or participated inthe study by completing a questionnaire online.

The Fatigue Severity Scale (FSS) was used as the measureof fatigue in two of the studies. Mean FSS scores were reportedas 3·9 (21) and 3·28 (22) with 46% and 42% categorized asfatigued using a average score of >4 as a cutoff. In one study(23), 68% either agreed or strongly agreed that fatigue influ-enced their daily activities.

Association between physical fitness and fatigue

Two studies (21,22) investigated whether there was an asso-ciation between economy of gait (rate of oxygen consump-tion, VO2), peak exercise capacity (VO2 peak), and fatigue.Both studies found no association between fatigue and thesemeasures of cardiovascular fitness (Table 1).

Association between physical activity and fatigue

All three included studies explored the relationship betweenone form of physical activity and fatigue. One study measuredparticipant’s daily step count (21), another study measuredthe intensity of ambulatory activity by recording the numberof steps per minute (22), and in a third study (23), participantsindicated through a single question how many times a weekthey participated in a physical activity of at least 20 minsduration that caused sweating or increases in respiratory orheart rate.

No association between fatigue and any of the measuresof physical activity was found (Table 1). One study didfind, through structural equation modeling techniques thatfatigue indirectly influences exercise through self-efficacyexpectations.

Discussion

This is, to our knowledge, the first systematic review of studiesthat has investigated associations between physical fitness,physical activity, and poststroke fatigue. We found only threestudies, which met our inclusion criteria. These studies werecross-sectional, observational studies. Two used the FSS, oneused both the FSS and a visual analog scale and one measuredfatigue with a single question with a 5-point Likert response

MEDLINE 445

EMBASE 606

PsychInfo 42

CINAHL 523

Sportdiscus 113

After duplicates removed

1291

Full text obtained

29

Studies meeting inclusion criteria

3

Reference lists scrutinized – potentially

relevant titles (abstracts obtained)

26

Studies meeting inclusion criteria

0

Fig. 1 Search and selection of publications.

Systematic reviewF. Duncan et al.

© 2012 The Authors.International Journal of Stroke © 2012 World Stroke Organization Vol 7, February 2012, 157–162 159

Tabl

e1

Stud

ies

repo

rtin

gan

asso

ciat

ion

betw

een

post

stro

kefa

tigue

and

eith

erph

ysic

alfit

ness

orph

ysic

alac

tivity

Dat

eA

utho

rTi

tleA

ims

and

obje

ctiv

esSt

udy

desi

gnTi

me

post

stro

keEv

alua

tion

offa

tigue

Mea

sure

(s)

ofph

ysic

alac

tivity

orph

ysic

alfit

ness

n

Ass

ocia

tion

betw

een

fatig

uean

dph

ysic

alac

tivity

and/

orfit

ness

2006

Mic

hael

,A

llen

&M

acko

(21)

Fatig

ueaf

ter

stro

ke:

rela

-tio

nshi

pto

mob

ility

,fit

ness

,am

bula

tory

activ

-ity

,so

cial

supp

ort

and

falls

effic

acy

Toex

plor

eth

ere

latio

nshi

psbe

twee

nfa

tigue

,ca

rdio

-va

scul

arfit

ness

,m

obili

tyde

ficit

seve

rity,

ambu

la-

tory

activ

itypa

tter

ns,

soci

alsu

ppor

t,an

dse

lf-ef

ficac

yfo

rfa

lls.

Obs

erva

tiona

l,cr

oss-

sect

iona

l6–

166

mon

ths

(mea

n10

·3)

Fatig

ueSe

verit

ySc

ale

(FSS

)pa

ired

with

avi

sual

anal

ogsc

ale

(VA

S)

Econ

omy

ofga

it,pe

akex

erci

seca

paci

ty(V

02pe

ak),

ambu

lato

ryac

tivity

(ste

pspe

r24

h).

53(5

8·5%

mal

e)N

osi

gnifi

cant

diff

eren

ces

betw

een

fatig

ued

and

nonf

atig

ued

grou

psin

the

fitne

ssm

easu

res

ofec

onom

yof

gait

and

VO

2pe

akan

dam

bula

tory

activ

ity.

Step

spe

r24

hin

thos

ew

ithfa

tigue

2696

(SD

1524

)St

eps

per

24h

inth

ose

with

out

fatig

ue27

51(S

D15

28)

Econ

omy

ofga

itw

ithfa

tigue

–8·

8m

l/kg/

min

(SD

1·67

)Ec

onom

yof

gait

with

out

fatig

ue–

8·6

ml/k

g/m

in(S

D1·

88)

VO

2Pe

akw

ithfa

tigue

–11

·34

ml/k

g/m

in(S

D3·

04)

VO

2Pe

akw

ithou

tfa

tigue

–11

·69

ml/k

g/m

in(S

D2·

83)

Whe

nus

ing

the

FSS

asa

cont

inuo

usva

riabl

e,lin

ear

regr

essi

onsh

owed

that

econ

omy

gait,

VO

2pe

ak,

and

ambu

lato

ryac

tivity

are

not

sign

ifica

ntpr

edic

tors

offa

tigue

seve

rity.

2007

Mic

hael

&M

acko

(22)

Am

bula

tory

activ

ityin

tens

itypr

ofile

s,fit

ness

and

fatig

uein

chro

nic

stro

ke

Tode

scrib

eho

useh

old

and

com

mun

ityam

bula

tory

activ

itypr

ofile

sin

term

sof

step

coun

tsan

dst

epin

tens

ityle

vels

.To

dete

rmin

ew

heth

erth

ese

profi

les

are

rela

ted

tofit

ness

orse

lf-re

port

edfa

tigue

Obs

erva

tiona

l,cr

oss-

sect

iona

l6–

166

mon

ths

(mea

n10

·3)

Fatig

ueSe

verit

ySc

ale

(FSS

)D

aily

step

coun

tan

din

tens

ityof

ambu

lato

ryac

tivity

:lo

win

tens

ity<1

6st

eps

per

min

ute

Med

ium

inte

nsity

�16

and

<30

step

spe

rm

inut

eH

igh

inte

nsity

�30

step

spe

rm

inut

e.Ec

onom

yof

gait

Peak

exer

cise

capa

city

(VO

2pe

ak)

79(5

3%m

ale)

No

sign

ifica

ntas

soci

atio

nsbe

twee

nfit

ness

,st

epac

tivity

,an

dfa

tigue

.C

orre

latio

nbe

twee

nst

epin

tens

ityan

dfa

tigue

Step

inte

nsity

(Pea

rson

’sr)

Low

(0·0

93)

Med

ium

(0·1

67)

Hig

h(0

·073

)

2006

Shau

ghne

ssy,

Resn

ick

&M

acko

(23)

Test

ing

am

odel

ofpo

st-s

trok

eex

erci

sebe

havi

or

Tote

sta

theo

retic

alm

odel

ofph

ysic

alac

tivity

inst

roke

surv

ivor

s

Surv

eycr

oss-

sect

iona

lby

post

alan

don

line

ques

tionn

aire

.

60·2

mon

ths

Sing

lequ

estio

n:‘D

oes

fatig

uein

fluen

ceda

ilyac

tiviti

es’

with

a5-

poin

tLi

kert

scal

ere

spon

se

Sing

lequ

estio

n‘h

owof

ten

doyo

uen

gage

inac

tivity

/exe

rcis

e?’

Resp

onse

optio

ns:

neve

r,le

ssth

anon

cepe

rw

eek,

one-

thre

etim

espe

rw

eek,

four

orm

ore

days

per

wee

k.A

ctiv

ity/e

xerc

ise

was

defin

edas

part

icip

atio

nin

aph

ysic

alac

tivity

ofat

leas

t20

min

sdu

ratio

nth

atca

used

swea

ting

orin

crea

ses

inre

spira

tory

orhe

art

rate

312

(41%

Mal

e)N

osi

gnifi

cant

asso

ciat

ion

betw

een

self-

repo

rted

exer

cise

beha

viou

ran

dfa

tigue

.St

ruct

ural

equa

tion

mod

elin

gte

chni

ques

show

edth

atfa

tigue

indi

rect

lyin

fluen

ced

exer

cise

thro

ugh

self-

effic

acy

expe

ctat

ions

.

Systematic review F. Duncan et al.

© 2012 The Authors.International Journal of Stroke © 2012 World Stroke Organization Vol 7, February 2012, 157–162160

scale. Physical activity and fitness were measured in differentways.

None of these studies found a statistically significant directrelationship between poststroke fatigue and either physicalfitness or physical activity. One study, however, did find thatparticipants with higher levels of fatigue were more likely tohave lower self-efficacy expectations for exercise and thereforewere less likely to participate in physical activity.

Therefore, there is limited evidence regarding an associa-tion between poststroke fatigue and either exercise or physicalfitness. In light of this lack of evidence, there is a need forfurther research as it still remains highly plausible that exercisecan have a positive influence on fatigue. Exercise is reported tobe the most effective nonpharmacologic intervention forcancer-related fatigue (24), and there is some evidence thatexercise may reduce fatigue in people with multiple sclerosis(25,26) although another study found exercise to have noeffect on fatigue levels of multiple sclerosis patients (27).

There are multiple mechanisms by which exercise mayplausibly improve poststroke fatigue. For instance, physicalexercise can increase cerebral blood flow by activating thesympathetic nervous system (28). Central command duringexercise independently increases regional cerebral blood flowin insular and anterior cingulated cortices (29) and ischemicdamage to these areas is associated with the development oftiredness (30). Development of fatigue in people with multiplesclerosis correlates with atrophy of frontal and posterior pari-etal cortices (31), while aerobic fitness reduces tissue loss inthese areas of the brain in aging humans (32). On a molecularlevel, physical exercise may change the functioning of neuro-transmitters, which may lead to the development of fatigue(33). Finally, a lack of physical activity may cause alterations inthe synthesis of muscle-derived interleukin-6, and this mayalso contribute to the development of fatigue (34).

Shortly after the searches for this review were carried out, across-sectional study that met our inclusion criteria was pub-lished (35). Participants were recruited from local strokesupport groups and a research participant database and werebetween six-months and five-years poststroke. Fitness wasmeasured using a maximal effort graded exercise test (VO2peak) using a stepping ergometer. This study postulated thatthere are two distinct types of fatigue: exertion fatigue andchronic fatigue. Exertion fatigue was measured using a visualanalog fatigue scale and chronic fatigue using FSS. Higherfitness (VO2 peak) was significantly associated with less exer-tion fatigue (r = -0·582, P < 0·01) but like the other studiesidentified in this review, they found no association was shownbetween fitness and chronic fatigue. This study suggests thatexercise may have a positive effect on some aspects of a strokepatient’s experience of tiredness but does not provide a com-plete solution.

Currently, there is a randomized controlled trial runningin the Netherlands investigating whether a new treatmentprogram, Cognitive and Graded Activity Training can have aneffect on poststroke fatigue compared with cognitive training

alone or no treatment. This intervention consists of 12 weeksof cognitive behavioral therapy combined with endurance,strength, and flexibility training. Preliminary results from 40participants have shown this treatment program to signifi-cantly reduce fatigue severity as measured using the ChecklistIndividual Strength fatigue scale (P < 0·001). The effect wasevident on both posttreatment and six-month follow-upassessments (36).

Future studies should be longitudinal in design in order tostart to elucidate temporal associations between fatigue andfitness, i.e. does reductions in fitness generally precede post-stroke fatigue, or does poststroke fatigue generally predatereductions in fitness. Measures of aerobic fitness, daily activity,and muscle strength should be objective rather than self-report. It could be investigated whether certain types ofexercise are more likely to influence fatigue. It should alsobe recognized that there may not be a direct cause and effectrelationship between fatigue and physical fitness and/or activ-ity. For instance, one of the studies included in our review (23)found that fatigue only had an influence on exercise whenself-efficacy expectations were taken into account. In a similarvein, another study found the relationship between fatigueand instrumental activities of daily living was confoundedby depression (37). Therefore, future research should takeinto account variables such as depression, self-efficacy expec-tations, gender, and age as covariates in regression modelingwhen investigating the relationship between fatigue and phy-sical activity and/or physical fitness.

The strengths of the review include a thorough searchstrategy and independent data extraction by two authors (F. D.and M. K.). The limitations are that we included only paperspublished in English, which may have led to the exclusionof relevant studies published in other languages and we didnot do a methodological screening of the included studies.

All three studies included in this review contained limita-tions. For example, two included small samples sizes (n = 53and 79); one study only used a single question to measurefatigue (23); and in two studies, participants had volunteeredthemselves for the exercise program (21,22). In addition, themajority of participants in one study (23) were Caucasian,female, and unmarried (and so unrepresentative of strokesurvivors).

Conclusion

In conclusion, there is insufficient evidence of an associationbetween poststroke fatigue and either physical fitness or phy-sical activity. However, it still remains highly plausible thatexercise could be an effective treatment for fatigue.

Acknowledgements

This work was supported by a Chief Scientist Office of theScottish Government grant to F. D. and a European Federationof Neurological Societies’ Scientific Fellowship to M. K.

Systematic reviewF. Duncan et al.

© 2012 The Authors.International Journal of Stroke © 2012 World Stroke Organization Vol 7, February 2012, 157–162 161

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