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On vascular factors, apathy and dementia

van Dalen, J.-W.

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Citation for published version (APA):van Dalen, J-W. (2018). On vascular factors, apathy and dementia.

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99

Chapter 6

Post-stroke apathy

-

a systematic review and meta-analysis

Jan Willem van Dalen

Eric P. Moll van Charante

Paul J. Nederkoorn

Willem A. van Gool

Edo Richard

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100

Introduction

In addition to acute motor, sensory, and language impairments, sub-acute and chronic neuropsychiatric

disturbances after stroke can have major impact on activities of daily living (ADL).1 Cognitive

impairment and depression are the most commonly reported neuropsychiatric symptoms, both occurring

in approximately in one third of patients after stroke.2;3 Apathy, most commonly defined as a syndrome

of diminished goal-directed behaviour, emotion, and cognition,4 is far less studied but has also been

reported as a frequent consequence of stroke. Apathy can have negative impact on functional recovery,

activities of daily living, general health and quality of life.5-7 It can also lead to significant burden for

caregivers.8;9

Apathy can occur as an independent syndrome, although it may also occur as a symptom of depression

or dementia.10;11 Patients present with loss of motivation, concern, interest and emotional response,

resulting in a loss of initiative, decreased interaction with their environment and a reduced interest in

social life.11-14 Despite its potentially pervasive and negative consequences, the importance of post-stroke

apathy is difficult to interpret. Differences in study design, results and interpretation have lead to a wide

variety in reported characteristics, prevalence and clinical impact.15;16

In this systematic review and meta-analysis we aim to establish the impact of post-stroke apathy by

assessing the prevalence and the association with disability, depression and cognitive impairment. In

addition, the influence of lesion location on the occurrence of apathy and the possibilities for

pharmacological treatment are systematically reviewed.

Methods

Search strategy

We conducted a comprehensive literature search of the Medline, PsycINFO and Embase (from 1980

onwards) databases. Methods were predetermined in a research protocol. Key search terms for stroke

were cross-referenced to apathy, closely related or descriptive terms for apathy and psychometric

instruments to assess apathy. The full search strategy, including all search terms, is specified in appendix

S1. The search was last updated on the 21st of February 2012. Titles, abstracts and papers were reviewed

by two independent observers (JWD and ER) to assess inclusion criteria. If necessary, full text copies of

articles were obtained. Discrepancies of the two separate selections were compared and were resolved by

discussion. A third investigator (PJN) was available for appeal if disagreements persisted. In addition,

references of all included articles and reviews, and key publications were searched for studies that met

inclusion criteria.

Inclusion criteria were based on recommendations by the Centre for Reviews and Dissemination

(CRD).17 Studies were included if they 1) were on patients with symptomatic stroke, 2) included at least

25 patients, 3) clearly specified a definition of apathy, 4) reported on patient characteristics, selection

process and method of inclusion, 5) were not restricted to specific stroke localisations, 6) were written in


101

a European national language, Chinese or Japanese. If there was more than one publication on the same

patient cohort, data were taken from the publication on the most comprehensive stroke-patient group.

Because of a lack of large studies on treatment of post-stroke apathy, our inclusion criteria for this

research question were less strict. Articles on the effect of pharmacological treatment of apathy were

included if they were 1) on patients with symptomatic stroke, and 2) were written in English.

Data extraction

Full text articles of selected studies were obtained for further evaluation. Data from each study were

extracted by two observers (JWD and ER), using a predefined data extraction form (appendix S2).

Authors were contacted if published results lacked information necessary for the meta-analyses. Risk of

bias was assessed using an assessment form based upon the Newcastle–Ottawa quality assessment scale

for cohort studies, and rated selection, confounding and information bias sub-items (appendix S3).18

Statistical analysis

Analysis of statistical heterogeneity of apathy rate between studies was done with I2 tests in every meta-

analysis. Risk of publication bias was assessed by visual interpretation of the funnel plot. The pooled

estimate of the prevalence of apathy in a stroke-population was obtained using the DerSimonian and

Laird random effects binary model. For each proportional characteristic, 95% confidence intervals

(95%CI) were estimated using binomial distribution. When a study provided more than one apathy rate

in a single cohort (e.g. at a different time since stroke or with a different method of assessment used), we

calculated one average apathy rate per study to include in the meta-analysis. To identify variables

associated with post-stroke apathy, separate meta-analyses were performed for age, sex, mini mental state

examination (MMSE) score, depression and disability at assessment. These factors were derived from the

literature. We used a binary random effects model for analysis of the relative risk of apathy for depressed

patients and female patients. A continuous random effects model with unequal within-study variance was

used to estimate associations with age, MMSE score, and disability. Because of the different scales used

to assess disability, we standardized the disability scores using the Hedges’ G method.19 When multiple

values for these factors at different time points were provided in one single cohort, we calculated one

average value and standard deviation for meta-analysis. The relationship of apathy with functional

recovery and with lesion location was assessed qualitatively.

A pre-specified sensitivity analysis was designed to assess the influence of the definition of apathy used

and that of suspected confounding variables. This analysis only included studies reporting on all proposed

explanatory variables and used methods of apathy assessment recommended in an extensive review of

the psychometric evidence on the validity of available apathy measures.15 Two additional analyses were

performed to explore heterogeneity of studies in our main analysis. In the first, to determine the

individual effect of each study on the overall estimate, a range of overall apathy rates was estimated by


102

leaving out one study at the time, for all studies (jackknife analysis). The second analysis only included

studies which we estimated to have a relatively low risk of confounding and selection bias (for criteria

and selected studies see appendix S3). To this analysis, we added a sensitivity analysis in which we

excluded studies with an average age below 60 years old, since these may not be representative for the

general stroke population.

Several further exploratory subgroup analyses were performed on the type of assessment instrument

used, source of information (patient-based, informant-based or clinician-based apathy rating scale),

setting, time passed since stroke, exclusion criteria, prior history of stroke and type of stroke included.

These subgroup analyses were not pre-specified but were defined during analysis to explore potential

reasons for large differences between study results. Univariate inverse-varience weighted meta-regression

was used to estimate the effect of age, depression rates and MMSE scores on reported apathy-rate.

Microsoft Office Excel 2003, PASW Statistics 18, and Meta-analyst beta 3.13 were used for the statistical

analysis.20

Results

Our search yielded 5463 articles, of which 4328 remained after duplicate removal (figure 1). In total, 49

research articles were selected for full text analysis. Eight full articles and two abstracts of case-reports

on treatment could be obtained. For reference search 27 reviews were selected of which 19 could be

obtained. Searching the references yielded one additional article on treatment and none on prevalence

(figure 1). After further evaluation, 24 articles on prevalence and 11 on treatment were included in our

review. Reasons for exclusion of studies are listed in appendix S1. After quality assessment, we included

24 articles on the prevalence of apathy.5;6;21-42 Table 1 shows the study design and demographic details of

all 24 selected studies. To supplement data, 22 authors were contacted, of whom nine were able to

complement the data of ten studies.33-42 Assessment of the risk of bias per study is provided in appendix

S3.


103

Figure 1: article selection

55463 references from electronic search

1942 from Medline 2011 from Embase

4328 abstracts

1135 duplicates removed

74 selected articles41 on prevalence

19 reviews 10 on treatment

36 articles excluded after full review 19 reviews 7 not concerning apathy 6 same cohort 4 cohort restricted to subcategory

1 article from references1 on treatment

35 articles included in review:24 articles on prevalence 11 articles on treatment

88 selected articles 49 on prevalence

27 reviews 11 on treatment 17 articles unavailable

8 reviews 8 conference/dissertation abstracts Treatment: 1 case report


104

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1999

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MM

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(i)

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Tabl

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s


105

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20

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2005

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20

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yes

curr

ent

yes

96%

in

p 20

03-

2006

IH

FR

SBE

>65

excl

uded

FR

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CCN

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(i)

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ou

tp

2005

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09

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in- a

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outp

20

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(s)

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(s

us)

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100

(d)

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(201

1) 34

PC

-

yes

yes

- ye

s 20

%

sub

ac

ute

2000

- 20

02

IH

AES-

10

(c)

MAD

RS

MM

SE

NIH

SS

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RSd

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nos

(201

1) 36

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r. in

- and

ou

tp

2007

- 20

08

I N

PI

>0 (i

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M

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CN

S 7.

4/

11.5

(d)

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2.

0/6

(i),

79/1

00(d

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Mar

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(2

011)

39

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hist

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s 22

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sub

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e 20

09

1st I

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(c)

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2.8/

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all

(201

1) 3

1 PC

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5 -

yes

- ye

s 48

%

in- a

nd

outp

19

97-

2000

I

AESi

>3

7 (i)

SC

ID-1

M

MSE

b ES

S 88

.7/

100

(d)

IADL

c , AD

Lc 7/

8.

5/6

(d)

Plan

ton

(201

2) 41

PC

18

- 80

-

yes

hist

ye

s 80

%

outp

go

od

reco

very

2007

- 20

09

1st I

AS

>13

(s)

BDI-I

I >1

3 Br

oad

test

ing

NIH

SS

2.6/

42

(i)

mRS

0.

7/

6 (i)

~

Tabl

e 1.

Stu

dy c

hara

cter

istic

s con

tinue

d


106

Table 1 Study characteristics legend: Coh: cohort type, PC: prospective cohort, RC: retrospective cohort, CC: case-control, CS: Cross Section, Type of stroke: 1st: no prior history of stroke, I: infarction, H: hemorrhage, Exclusion criteria: Dis: major disability and severe disease,, CI: cognitive impairment, MD: major depression, CD: communication disorder, hist: history, Ex %: excluded percentage, n.a.: not applicable, n.r.: not reported, Apathy measures: (s): self assessment, (c) clinician assessment, (i) informant assessment, AS: apathy scale, AES Apathy Evaluation Scale, NPI: Neuropsychiatric Inverntory, EBIF: Emotion Behavior Index Form, PSDRS: Post-Stroke Depression Rating Scale, WBIBS: modified apathy items from the Williams Brain Impairment Behavior Scale, AES-10: Apathy Evaluation Scale modified to 10 items, Depression measures: articles may have used multiple measures, the measure reported is the one used to assess the prevalence of depression used in this review, HDS, HRSD, HAM-D17, HAM-D: Hamilton Rating Scale for Depression, MADRS: Montgomery and Asberg Depression Rating Scale, SCID: Structural Clinical Interview for DSM-IV, SDS: Zung's Self Rating Scale for Depression, SF-36: short form health survey, BDI-II: Beck Depression Inventory II Cognition measures: MMSE: Mini Mental State Examination, SPSMQ: CAMCOG: cognitive section of the Cambrdige Examination for Mental Disorders of the Elderly-Revised, CCN: Coconuts neurological test, WCST: Wisconsin Card Scoring Test, MMSE (sus): MMSE taken only when patients were suspected to have cognitive impairment, stroke severity: NIHSS: national institute of health stroke scale, ESS: European stroke scale mean: mean/maximum score, (d): score decreases with increased disability, (i): score increases with increased disability,,disability, Disability measures: (d): score decreases with disability, (i): score increases with disability, JHFI: John Hopkins Functional Inventory, FIM: Functional Independence Measure, IADL: Lawton Instrumental Activities of Daily Living scale, ADL: Katz Activities of Daily Living scale, BI: Barthel Index, mRS: modified Rankin Scale, NIHSS: National Institute of Health Stroke Score, MFAQ-IADL: Instrumental Activities of Daily Living scale from the Multi Dimensional Functional Assessment Questionnaire, SIS-phys: physical component of the Stroke Impact Scale, Disability score: underlined: study provided enough information for separate meta-analysis on the association between apathy and disability, Superscript: a: significant association between apathy and depression, b: significant association between apathy and a decrease in performance on cognitive test, c: significant association between apathy and increased disability, d: significant association between apathy and worse functional recovery

Patient characteristics and reported apathy rates can be found in figure 2. The total number of patients

included was 2706 with a median number of 88 per study (range 30-408 patients). The median time since

stroke was 120 days (range 2-850). The median reported average age was 65.1 years (range 49.6-76.6). All

but four studies concerned prospectively collected cohorts of stroke patients. Nine studies assessed

patients in a sub acute setting within 30 days after stroke. Six studies were done in a mixed population of

in- and outpatients, four studies were done exclusively among rehabilitating inpatients and another four

exclusively among outpatients. Four articles provided longitudinal data with the length of follow-up

ranging from 6 to 16 months.6;316;21;31;36


107

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108

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re 3

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109

The estimate for the mean prevalence of apathy across studies was 34.6% (95%CI 29.5-40.2).

Heterogeneity was moderate (I2=46.4%). The funnel plot was roughly symmetrical (appendix S4).19 The

predefined sensitivity analysis of studies using recommended measurement instruments

(n=9),5;21;23;28;29;31;36;37;42 resulted in an estimated prevalence of 26.3% (95%CI 20.5-33.1, I2=42.8%).

Excluding the study identified by the funnel plot as a major source of heterogeneity,42 reduced

heterogeneity (24.2%, 95%CI 20.4-28.4%, I2=25.2%)(appendix S5). Jackknife sensitivity analysis resulted

in estimates ranging from 33.2% (95%CI 28.5-38.3) to 35.7% (95%CI 30.6-41.2). Sensitivity analysis

including studies with low risk of selection and confounding bias (n=10) resulted in a mean prevalence

of 41.4% (95%CI 33.3-50.0) but did not reduce heterogeneity (I2=47.0%). Excluding studies with an

average patient age under 60 years old from this analysis had no significant effect (38,0%, 95%CI 29.9-

47.9, I2=46.0% n=5).

The reported prevalence of apathy seemed to vary with different methods of assessment used. The

pooled prevalence based on studies using informant-based assessment instruments was lower than that

of studies using patient-based instruments, while that of the studies using clinician-based instruments

exceeded both (figure 3). In studies using the NeuroPsychiatric Inventory (NPI), a lower prevalence was

reported compared to studies using other informant based scales (23.0%; 95%CI: 18.4-28.2 I2: 30.0% vs.

39.4; 95%CI: 30.0-49.5%; I2: 45.5%). Additionally, the analysis stratified for most commonly used

assessment instruments showed significantly lower prevalence when apathy was assessed with the NPI

compared to apathy-specific assessment instruments (figure 3). Studies excluding patients with prior

history of stroke had a lower combined estimate compared to those including patients regardless of stroke

history (24.1%; 95%CI: 19.5-29.5 I2: 22.1% vs. 38.9; 95%CI: 38.9-44.9.%; I2: 46.2%) (appendix S6).

Stratification according to study setting revealed a relatively low prevalence and heterogeneity in the sub

group of studies which only included outpatients (25,6%, 95%CI: 19.6-32.6 I2: 26.9%)(Appendix S6).

Additional sub group analyses did not improve heterogeneity (appendix S6). Finally, meta-regression with

age, depression rates and MMSE-scores did not have significant impact on the overall apathy-rate

(P>0.1).

Associations between apathy and its clinical correlates are reported in table 2a-c. Apathetic patients were

on average 3.8 years older (95%CI 2.1-4.7; I2=0%). Women had a slightly higher chance of being

apathetic than men (RR 1.2; 95%CI >1.0-1.5; I2=6.6%). Other associations that are less commonly

reported are listed in table 2c.

The mean MMSE score of apathetic patients (n=10 studies) was 2.7 points lower (95%CI 1.6-3.8;

I2=60.2%) (table 3). Excluding two outliers identified in the funnel plot somewhat reduced these results

(2.1; 95%CI 1.3-2.9), but significantly reduced heterogeneity (I2=0%)(appendix S7).30;33 In seven studies,

a significant association between the presence of apathy and reduced performance on different tests of

cognitive function was found (figure 2).


110

FFactor EEffect of apathy NN studies NN PPSA NNo PSA EEstimate 995% CCI II^2 MMSE Mean Difference 10 808 268 540 -2.7 points -3.8, -1.6 60.2% Age Mean Difference 13 1290 470 820 3.8 years 2.1, 4.7 0.0% Disability Hedges G (SMD) 9 627 194 433 -0.3 -0.7, 0.1 81.6% Female gender Relative Risk 8 681 96/203 180/478 1.2 1.0, 1.5 6.6%

22a. Meta-analysis post-stroke apathy versus no post-stroke apathy

Factor Effect of apathy N studies

N PSA No PSA Estimate 95% CI I^2

PSD Relative Risk 14 1240 179/442 185/798 1.8 1.4, 2.4 52.0%

PSD in PSA Proportion 14 442 179 - 40.1% 0.3, 0.5 42.7% PSD in pop Proportion 14 1240 179 185 28.1% 0.2, 0.4 46.1%

2b. Meta-analysis post-stroke apathy in post-stroke depression

Study Other associations with apathy: Association (95% CI) Test Angelelli (2004) TSS > 2 m p < 0.01 ANOVA Castellanos (2011) TSS > 4 weeks p < 0.05 tTest Caeiro (2011) education < 10 years OR 4.2 (1.3-13.6) Log. Reg. Hama (2007) CT-defined lesion volume p < 0.02 MW U Hochstenbach (2005) low agreement between patients and care givers k=0.5 Kappa Mayo (2009) high comorbidity on Charlson Index OR 2.1 (1.0-4.3) Ord. Reg. Sagen (2009) comorbidity OR: 3.0 ( 1.0-8.3) Log. Reg. Withall (2011) apathy at baseline with depression at follow-up OR: 7.2 (2.2-24.1) Log. Reg. 2c. Reported significant associations with apathy

Table 2. Clinical correlates of poststroke apathy MMSE: mini mental state examination, PSA: post-stroke apathy, PSD: post-stroke depression, pop.: population on which information on depression in apathetic patients was available, TSS: time since stroke, OR: odds ratio, k: kappa value, MW U: Mann-Whitney U-test, Log. Reg.: logistical regression, Ord. Reg.: ordinal regression

The estimated relative risk of depression among apathetic patients (n=11 studies) was 1.8 (95%CI 1.3-

2.4) (table 2b). Depression occurred in 40.1% of patients with apathy (95%CI 29.9-51.1%) and in 46.7%

vice versa (95%CI 36.4-56.3%). The prevalence of depression in the non-apathetic patients was estimated

at 23.6% (95%CI 17.1-31.6%). Six studies reported a significant association between the presence of

post-stroke apathy and post stroke depression (figure 2).

Assessment of the relationship between apathy and disability using Hedges’ g analysis was hampered by

high heterogeneity (I2=81.6%). Visual assessment of the funnel plot did not identify any single obvious

cause and dichotomous stratification based on time since stroke did not substantially improve

heterogeneity. In total, a significant association of apathy with increased disability was reported in nine

of eleven studies. In seven of these, apathy was associated with concurrent increased disability (figure 2).

In two, apathy at baseline was associated with decreased functional status at follow up, 6;33 and in another

two, with decreased functional recovery over time.5;32


111

AAuthor TType of stroke pp--vvalue TTest Santa (2008) Non-hemorrhagic stroke < 0.05 X2 Caeiro (2011) Hemorrhagic stroke < 0.03 X2 33a. Association between apathy and type of stroke AAuthor LLaterality pp--vvalue TTest Right Brodaty (2005) Right Hemisphere < 0.02* tTest Right Frontal Subcortical Circuit < 0.02* tTest Left Santa (2008) Left Basal Ganglia < 0.05 X2 Onoda (2011) Left Basal Ganglia < 0.01 X2 Bilateral Hama (2007) Bilateral Basal Ganglia > Right Hemisphere > Left Hemisphere > none < 0.01 ANOVA Bilateral Basal Ganglia > Left Basal Ganglia < 0.001 Fisher Onoda (2011) Reduced regional cerebral blood flow in Basal Ganglia < 0.001** ANCOVA 33b. Association betweeen apathy and laterality of stroke lesion *: corrected for age, gender and time since stroke, ** corrected for age, no longer significant when Bonferroni correction was applied AAuthor RRegion pp--vvalue TTest Sub Cortical Starkstein (1993) Posterior Internal Capsule < 0.05 X2 Yates Brodaty (2005) Right Frontal Subcortical Circuit < 0.02** tTest Basal Ganglia Hama (2007) Bilateral Basal Ganglia > Right Hemisphere > Left Hemisphere > none < 0.01 ANOVA Bilateral Basal Ganlia > no Basal Ganglia damage < 0.01 Fisher Santa (2008) Left Basal Ganglia < 0.05 X2 Onoda (2011) Left Basal Ganglia < 0.01 X2 Reduced rCBF Basal Ganlia < 0.001*** ANCOVA 33c. Association between apathy and region of stroke lesion *: corrected for age, gender and time since stroke, ** corrected for age, no longer significant when Bonferroni correction was applied, *** corrected for age, gender, MMSE, HDS-R, FAB, SDS and false discovery ratio, AAuthor AAssessment pp--vvalue TTest Angelelli (2004) Laterality > 0.05 ANOVA Kaji (2006) Laterality 0.23 tTest 33d. Studies that did not identify any relation between apathy and the location of the stroke lesion

Table 3: associations between apathy and stroke characteristics, rCBF: regional cerebral blood flow, MMSE: mini mental state examination, HDS-R: Hamilton depression rating scale, FAB: frontal assessment battery, SDS: Zungs self-rating depression scale


112

Information regarding lesion location and treatment was assessed qualitatively (table 3). Of the nine

studies that assessed the relationship between lesion location and presence of post-stroke apathy, six

reported on a significant association between specific lesion locations and an increased risk of apathy,

although in one study all significant associations disappeared after the appropriate Bonferroni correction

(table 3b).23 No significant difference was found between lacunar and cortical infarctions.

Results regarding apathy treatment are listed in table 4. Two clinical trials assessing the effect of

pharmacological treatment on post-stroke apathy were identified, both using apathy as secondary

outcome (table 4a). In one phase II trial, significantly reduced apathy scores were found in the group

treated with 900 mg of the nootropic agent nefiracetam (n=22) compared to groups receiving 600 mg

(n=26) or placebo (n=22).43 In another small (n=22) open study the acetylcholinesterase inhibitor

donepezil had a modest beneficial effect on functional status, which was also associated with a reduction

in apathy score.44 In five case-reports (table 4b), a favourable effect of treatment with bromocriptine was

reported,14;45-48 and in three with methylphenidate.14;49;50 Ropinirole, zolpidem and selegiline were

reportedly beneficial in one case each.14;51;52


113

AAuth

or

YYear

DDe

sign

MMai

n oou

tcom

e SSe

ttin

g DDi

agno

sis

NNI

NND

IInte

rven

tion

DDose

FFo

llow

--uup

OOut

com

e Ro

bins

on 43

20

09

RCT

Depr

essio

n O

utpa

tient

PS

D M

odifi

ed A

S 26

69

N

efira

ceta

m

600

mg

12 w

eeks

IT

T AN

OVA

: 900

mg

vs p

lace

bo:

4 po

int d

ecre

ase

in A

S sc

ore

(p

=0·0

1), A

RR 0

·18

(95-

CI: 0

·02-

0·

34),

mor

e fr

eque

nt re

miss

ions

.

22

90

0 m

g

22

- Pl

aceb

o -

W

hyte

44

2008

OT

+ RC

CI

In

patie

nt

PSCI

AE

S 13

41

Do

nepe

zil

5-10

mg

12 w

eeks

PP

AN

OVA

: Don

epez

il an

d de

crea

se o

f apa

thy

both

in

depe

nden

tly a

ssoc

iate

d w

ith a

n in

crea

se in

FIM

-gai

n ov

er ti

me

13

G

alan

tam

ine

4-12

mg

PS

non

CI

-

98

-

Cont

rol:

none

-

20

wee

ks

44a. T

rials

rega

rdin

g tr

eatm

ent o

f pos

t--sst

roke

apa

thy

AAuth

or

YYear

DDe

sign

MMai

n ou

tcom

e SSe

ttin

g DDi

agno

sis

NN

IInte

rven

tion

DDose

FFo

llow

--uup

SSucc

essf

ully

treaa

ted

Kohn

o 51

20

09

CR

Apat

hy

Inpa

tient

Cl

inic

ian

1 Ro

pini

role

0.

75 m

g/d

-

1 M

arin

14

1995

CS

Ap

athy

O

utpa

tient

Cl

inic

ian

2 M

PH/B

RC, S

eleg

iline

50/

90 m

g/d,

5 m

g 1,

>2

year

s 2

Wat

anab

e 49

1995

CR

Ap

athy

In

patie

nt

Clin

icia

n 1

MPH

5

mg/

d 9

mon

ths

1 Sp

iege

l 50

2009

CS

Ap

athy

In

patie

nt

Clin

icia

n 3

MPH

2.

5 - 1

2,5

mg/

d 1

mon

th

3 Fo

ng 4

6 20

01

CR

Apat

hy

n.a.

n.

a.

1 BR

C 10

mg

n.a.

1

Cats

man

45

1988

CR

CI

, apa

thy

n.a.

n.

a.

1 BR

C n.

a.

n.a.

1

Park

s 47

1992

CR

FL

S In

patie

nt

Clin

icia

n 1

BRC

5 - 6

0 m

g/d

5 m

onth

s 1

Bare

tt 4

8 19

91

CR

Abul

ia

Inpa

tient

Cl

inic

ian

1 BR

C 5

- 55

mg/

d -

1

Mat

hieu

52

2011

CR

Ap

athy

O

utpa

tient

AI

1

Zolp

idem

-

-

1 44b

. Cas

e re

port

s and

serie

s reg

ardi

ng tr

eatm

ent o

f pos

t--sst

roke

apa

thy

Tabl

e 4:

trea

tmen

t of p

ost-

stro

ke a

path

y, R

CT: r

ando

mize

d co

ntro

lled

tria

l, O

T: o

pen

tria

l, RC

: ret

rosp

ectiv

e co

hort

, CS:

cas

e se

ries,

CR:

cas

e re

port

, CI:

cogn

itive

impa

irmen

t, FL

S:

fron

tal l

obe

synd

rom

e, P

SD: p

atie

nts

with

pos

t st

roke

dep

ress

ion,

PSC

I: pa

tient

s w

ith p

ost

stro

ke c

ogni

tive

impa

irmen

t, PS

non

CI:

mat

ched

str

oke

patie

nts

with

out

cogn

itive

im

pairm

ent,

n.a.

: ful

l art

icle

not

ava

ilabl

e, A

S: a

path

y sc

ale,

AES

: apa

thy

eval

uatio

n sc

ale,

AI:

apat

hy in

vent

ory,

NI:

num

ber

for

inte

rven

tion,

ND:

num

ber

of d

rop-

outs

, MPH

: m

ethy

lphe

nida

te, B

RC: b

rom

ocrip

tine,

ITT:

inte

ntio

n to

trea

t, AR

R: a

bsol

ute

risk

redu

ctio

n, P

P: p

er p

roto

col


114

Discussion

We found that apathy occurs in every third patient after stroke. This estimate was not importantly affected

by selection and confounding bias, time since stroke or inclusion criteria apart from prior history of

stroke. Concomitant depression was present in only 40% of apathetic patients, confirming the occurrence

of apathy as a distinct entity. Post-stroke apathy is associated with worse cognitive function. There is

considerable evidence for an association of post-stroke apathy with disability and worse outcome of

rehabilitation. No clear association between post-stroke apathy and specific stroke lesion locations could

be established. Systematic trials on treatment of post-stroke apathy have not been conducted and there

is currently insufficient evidence to start any medical treatment of apathy after stroke.

Strengths and limitations

To our knowledge, this is the first systematic review and quantitative analysis covering several aspects of

post-stroke apathy including prevalence, associated symptoms, lesion localisation and treatment. Several

of the included studies had a high risk of selection bias and information bias. Confounding bias was

generally low. The three factors that we hypothesized to be the most influential (depression, age, and

cognitive function) were reported in all but one study.

Since apathy is mostly assessed as a secondary outcome, there might be over-reporting of higher

prevalence rates. In addition, significantly associated factors are more likely to be reported, also increasing

the risk of publication bias. To minimize these shortcomings, we included all studies including a formal

instrument to assess apathy, and tried to acquire unpublished data by contacting the authors.

Studies differed widely in design and patient characteristics. Heterogeneity was moderately high.

Subgroup analyses on type of stroke, method of assessment used, source of information and time since

stroke did not substantially consistently reduce heterogeneity. In the sensitivity analysis regarding

recommended measurement instruments, heterogeneity improved after exclusion of the main outlier.

However, of the six remaining studies, four employed the NPI as measurement instrument, making this

result difficult to interpret. Other sensitivity analyses, using stricter criteria, hardly affected our results.

The persistence of heterogeneity implies that several other factors are involved that have not been taken

into consideration.

Therefore, it appears that many aspects of post-stroke apathy remain to be elucidated. Different methods

of assessment may lack convergent validity, measuring slightly different conditions.15 Also, the specific

range of symptoms of post-stroke apathy may differ from what is regarded apathetic behaviour in other

conditions e.g. Parkinson’s or Alzheimer’s disease. In addition, high scores on apathy scales may be

caused by several other factors and conditions that were not measured in the studies included in our

review, such as post-stroke fatigue, pre-stroke personality traits and cultural factors. These aspects of


115

post-stroke apathy may all be important sources of the substantial heterogeneity that was found in this

review.

Studies have tried to correct for these factors by asking patients and caregivers to score their behaviour

relative to their behaviour before the stroke occurred. In three studies the association between apathy

and other concurrent neuropsychiatric symptoms was assessed, but none were found.27,36,42 In one study

personality prior to stroke was assessed and no association with apathy was found.37 More research on

the interplay between other factors such as fatigue, and apathy is needed to further elucidate the

nosological position of post-stroke apathy.

The heterogeneity of the results has some implications for the generalisability of our findings. Although

the weighted average age and depression rates (fig. 2) seem representative of the general stroke

population, this is only an indication. Apathy rates in our subgroup analyses may only differ slightly from

each other but the real difference between these subgroups may be confounded by other factors that are

still unknown. Our study provides a clear example of this ecological fallacy. Although analyses of the

difference between apathetic and non apathetic patient groups within studies show clear relations with

age, MMSE scores and depression rates, these results could not be significantly confirmed by meta-

regression or sub group analyses. Therefore results gained at a group level need to be interpreted with

caution.

Prevalence

With a prevalence of 34.6%, post stroke apathy occurs as frequently as post stroke depression (33%)2

and post-stroke dementia (21.0-41.3%)3. Whereas these neuropsychiatric syndromes are frequently

studied and treatments often initiated, post-stroke apathy has so far been largely ignored. Since the

prevalence of apathy in the general population is largely unknown, it is difficult to establish to which

degree post-stroke apathy should be attributed to the stroke. In healthy volunteers of comparable age,

apathy was found in 6.0% and in 15.8% five years later.53 In another study, a community based sample

of elderly, a prevalence of 19.9% was found.54 This suggests that not all cases of post-stroke apathy are

directly attributable to the stroke although its prevalence is higher in patients with a history of multiple

strokes.

The average estimate of studies using informant-based assessment instruments appears to be lower and

that of studies using clinician-based instruments higher than the average estimate of studies using patient-

based assessment instruments. Use of the NPI leads to a lower estimated apathy prevalence compared

to other scales. Results of a study that estimated the prevalence of apathy at 19.2% using the NPI and at

41.4% using the AS in the same cohort confirm this finding.5 The relatively low apathy-rate found in

studies using informant-based instruments may be explained by the NPI being the most used informant-

based instrument. Studies using a different informant-based instrument found a relatively high apathy-

rate (39.4% vs. 23.0%) (figure 2).6;23;24;31 The NPI uses one to three dichotomous (yes/no) screening


116

questions to establish the presence of apathy, which may increase the threshold of its diagnosis, i.e.

through reluctance to describe oneself or someone else as being apathetic. Apathy rates are reported to

be rather stable over time in longitudinal studies,6;31 sometimes after a significantly lower prevalence in

the first months after stroke.21;36 There was insufficient data for pooling the results of longitudinal studies

separately. Stratification of studies according to the average time since stroke shows that reported apathy

rates were generally lower in studies with assessment later after stroke. This is probably due to differences

in study design. In studies with assessment early after stroke, clinician-based instruments, which estimate

higher apathy-rates, were used relatively often. In contrast, studies in which patients were assessed longer

after stroke predominantly used informant-based instruments, which estimate relatively low apathy-rates.

This difference may importantly contribute to the decrease in reported apathy prevalence over time.

Associated symptoms

The association between apathy and age has also been reported in the general population.53;55 Possibly,

post-stroke apathy occurs more frequently in patients with reduced cognitive function, which is more

common in older individuals in both the general and the post-stroke population.55;56 The difference we

observed in MMSE scores between apathetic and non-apathetic patients after stroke supports this

hypothesis.

The association between apathy and reduced cognitive function was also reported in studies that used

more extensive neuropsychological examination.6;37 This association could in turn be confounded by

age,3;55 for which the analysis was corrected in only one study.6 The relationship between post-stroke

apathy and cognitive impairment may be explained by several factors. Incapability of goal oriented

thinking and behaviour may lead to loss of interest en lack of effort in cognitive testing.57;58 Also, both

apathy and cognitive impairment could be a consequence of the same underlying brain damage. Lesions

in distant areas related to memory and learning and their projections may influence anterior cingulate

circuit function, which is associated with motivation.59;60

Apathetic patients have an almost twofold risk of concurrent post-stroke depression. Apathy can occur

as a symptom of depression,10;11 and many instruments to assess depression also contain items that assess

apathy. Therefore, when in studies depression is defined by a cut-off score on a depression scale, high

scores on the apathy items could contribute to misclassification of apathy as depression. Misclassification

of apathetic patients as being depressed could contribute to the reported lack of treatment effect in post-

stroke depression,61 since symptoms of apathy do not to respond well to SSRIs.14;62;63 Distinction between

isolated post-stroke apathy and apathy in the context of post-stroke depression can therefore have

important consequences from a clinical point of view.

Quantitative assessment of the relationship between apathy and disability is difficult due to very high

heterogeneity between studies. Nevertheless, an association between apathy and increased disability was

reported in the majority of studies. In two studies, an association between apathy and increased disability


117

remained significant after correction for the effect of functional status at baseline.5;6 Another study

reported significantly worse functional outcome in apathetic patients compared to non-apathetic patients

with comparable functional status at baseline.32 These findings suggest a detrimental effect of post-stroke

apathy on functional recovery.

Lesion location

We found no clear association between apathy and a specific lesion location nor hemisphere. We also did

not find an association with stroke severity or lesion volume on MRI. An association with sub cortical

lesions, mainly the basal ganglia, is reported most consistently. Two studies with high prevalence of post-

stroke apathy (50-55%) described patients with subcortical infarctions, often affecting the basal

ganglia.64;65 Apathy also occurs more frequently in other neurological conditions involving the basal

ganglia e.g. progressive supranuclear palsy, Parkinson’s and Huntington’s disease.66, 67 These findings are

in line with the hypothesis that apathy arises from defects in the frontal subcortical circuit, of which the

anterior cingulate circuit is associated with motivation.12;59

Treatment

There is currently insufficient evidence to support a pharmacological approach to treat post stroke

apathy. High doses of the nootropic agent nefiracetam showed a positive effect on apathy as a secondary

outcome in a group of post-stroke depression patients in a small controlled trial with small treatment

groups,43 but results are difficult to translate to other post-stroke populations. Evidence for an

advantageous effect of the acetylcholinesterase inhibitor donepezil in patients with acute post stroke

cognitive impairment compared to a retrospective control group is circumstantial.44 A number of case

reports describing a beneficial effect of dopamine agonists and methylphenidate may warrant further

study.14;45-51

Implications for clinical practice and future research

Our findings on the prevalence and clinical characteristics of post stroke apathy in a post-stroke

population are clinically relevant for adequately informing patients, caregivers, and clinicians. Post-stroke

apathy is a pervasive but insufficiently recognised neuropsychiatric symptom. The wide array of

definitions and instruments to assess apathy may provide an important barrier for its recognition after

stroke.15 Consensus on its construct and development of a gold standard of assessment is of major

importance.3,11,15 Post-stroke apathy is consistently associated with higher rates of cognitive impairment,

depression and disability, regardless of method of assessment. This renders it an important symptom to

be studied. Although no effective pharmacological therapy is currently available, rehabilitation programs

could be adapted to patients’ needs. Inadequate treatment with antidepressant drugs might be prevented

through improved discrimination between depression and apathy. Research into successful treatment and


118

coping strategies for post-stroke apathy could increase rehabilitation success-rates. Given its potential

impact, apathy should be included as an outcome measure in future studies on depression, cognitive

impairment and other neuropsychiatric sequelae of stroke. Apathy may also be an important contributor

to post stroke disability and should be taken into account in studies with a long-term follow up of

functional recovery.

Conclusions

Apathy occurs in every third patient after stroke, often without concomitant depression. Post-stroke

apathy is associated with reduced cognitive function, increased disability and may have a negative effect

on rehabilitation outcome. No specific lesion location associated with apathy could be identified. There

is currently insufficient evidence to support any specific pharmacological treatment of post-stroke apathy.

Better recognition could potentially benefit rehabilitation programs and prevent inadequate treatment of

depression. Some promising treatment strategies warrant further research in randomised controlled trials.

Acknowledgements

We thank R.Spijker and J.G. Daams from the AMC medical library for their help with conducting our

search. We also thank all investigators who helped supply original data, in particular the following:

K. Onoda, (Dept. Of Neurology, Shimane University, Japan), L. Caeiro, (Dept of Neurosciences, Servico

de Neurologia Hospital de Santa Maria, Portugal), F. Castellanos-Pinedo, (Dept. Of Neurology, Hospital

Virgen del Puerto, Spain), S. Hama, (Division of Rehabilitation, Hibino Hospital/Dept. Of

Neurosurgery, Hiroshima University, Japan), M. Planton, (CHU Toulouse Purpan, France), A. Iavarone,

(Neurological and Stroke Unit, CTO Hospital, AORN “ Ospedali dei Colli”, Italy), M. Hoffmann, (James

A. Haley Veterans’ Hospital, Tampa, United States of America), K. Greenop, (Division of population

science, TICHR, University of Western Australia, Australia), U. Sagen (Dept. Psychiatry, Telemark

Hospital, Norway), A. Carota (Hildebrand Clinic, Switzerland)


119

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Supplementary material Appendix S1: full search report and excluded studies 1. Clinical Question: Prevalence of apathy among stroke patients 2. PICO

P Patients after stroke I C O Prevalence of apathy

3. Search results: Combined total after duplicate removal: 4328

DDatabase ddate ## Records MEDLINE(R) In-Process & Other Non-Indexed Citations (OvidSP)

21-07-2011 1842

Embase 1980—current (OvidSP) 21-07-2011 1816 PsychINFO 17-08-2011 1426 Total after duplicate removal 4060

DDatabase ddate ## Records MEDLINE(R) In-Process & Other Non-Indexed Citations (OvidSP)

06-2011 – 21-02-2012 100

Embase 1980—current (OvidSP) 30-05 – 21-02-2012 195 PsychINFO 06-2011 – 21-02-2012 84 Total after duplicate removal 329

4. Search Strategy Medline: Platform: OvidSP, Database: MEDLINE® In-Process & Other Non-Indexed Citations, No limits were used, no methodological filters were used

## SSearch Term 1. cerebrovascular disorders/ 2. exp basal ganglia cerebrovascular disease/ 3. exp brain ischemia/ 4. stroke/ 5. exp brain infarction/ 6. hypoxia-ischemia, brain/ 7. exp intracranial arterial diseases/ 8. exp "Intracranial Embolism and Thrombosis"/ 9. exp intracranial hemorrhages/ 10. (stroke or poststroke or post-stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$ or

apoplex$ or isch?emi$ attack$ or tia$1 or neurologic$ deficit$).tw. 11. ((brain$ or cerebr$ or cerebell$ or cortical or vertebrobasilar or hemispher$ or intracran$ or

intracerebral or infratentorial or supratentorial or MCA or anterior circulation or posterior circulation or basal ganglia) adj5 (isch?emi$ or infarct$ or emboli$ or occlus$ or hypox$ or obstruction or vasculopathy)).tw.

12. ((lacunar or cortical) adj5 infarct$).tw. 13. ((brain$ or cerebr$ or cerebell$ or intracerebral or intracran$ or parenchymal or

intraventricular or infratentorial or supratentorial or basal gangli$ or subarachnoid or putaminal or putamen or posterior fossa) adj5 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$)).tw.


123

14. ((brain or intracranial or basal ganglia or lenticulostriate) adj5 (vascular adj5 (disease$ or disorder or event))).tw.

15. ((isch?emic or apoplectic) adj5 (event or events or insult or attack$)).tw. 16. ((intracranial or cerebral art$ or basilar art$ or vertebral art$ or vertebrobasilar or vertebral

basilar) adj5 (stenosis or isch?emia or insufficiency or arteriosclero$ or atherosclero$ or occlus$)).tw.

17. exp aphasia/ or anomia/ or hemiplegia/ or hemianopsia/ or exp paresis/ or deglutition disorders/ or dysarthria/ or pseudobulbar palsy/ or muscle spasticity/

18. (aphasi$ or apraxi$ or dysphasi$ or dysphagi$ or deglutition disorder$ or swallow$ disorder$ or dysarthri$ or hemipleg$ or hemipar$ or paresis or paretic or hemianop$ or hemineglect or spasticity or anomi$ or dysnomi$ or acquired brain injur$ or hemiball$).tw.

19. ((unilateral or visual or hemispatial or attentional or spatial) adj5 neglect).tw. 20. or/1-19 21. Apathy/ 22. exp Motivation/ 23. apathy.ti,ab. 24. abulia.mp. 25. amotivation.mp. 26. avolition.mp. 27. (neuropsychiatric adj inventory).ti,ab. 28. "frontal lobe personality scale".ti,ab. 29. NPI.ti,ab. 30. FLOPS.ti,ab. 31. lars.ti,ab. 32. DAIR.ti,ab. 33. "frontal system behaviour scale".ti,ab. 34. FrSBe.ti,ab. 35. "frontal system behavior scale".ti,ab. 36. KBCI.ti,ab. 37. "Key Behaviors Change Inventory".ti,ab. 38. (flat adj2 affect).ti,ab. 39. bluntness.mp. 40. (emotional adj2 indifferen*).ti,ab. 41. (reduced adj2 volition).ti,ab. 42. ((reduced or loss) adj3 (concern or effort or emotional or "action initiation" or interest or

motivation or behavior or behaviour or cognition or drive)).ti,ab. 43. alexithymia.mp. or exp Affective Symptoms/ 44. emotions/ 45. or/21-44 46. animals/ not humans/ 47. 45 and 20 48. 47 not 46

Embase: Platform: OvidSP, Database: Embase 1980-present, No limits were used, No methodological filters were used

## SSearch Term 1. (exp cerebrovascular disease/ or (stroke or poststroke or post-stroke or cerebrovasc$ or brain

vasc$ or cerebral vasc$ or cva$ or apoplex$ or isch?emi$ attack$ or tia$1 or neurologic$ deficit$).tw. or ((brain$ or cerebr$ or cerebell$ or cortical or vertebrobasilar or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or MCA or anterior circulation or posterior circulation or basal ganglia) adj5 (isch?emi$ or infarct$ or emboli$ or occlus$ or hypox$ or obstruction or vasculopathy)).tw. or ((lacunar or cortical) adj5 infarct$).tw. or


124

((brain$ or cerebr$ or cerebell$ or intracerebral or intracran$ or parenchymal or intraventricular or infratentorial or supratentorial or basal gangli$ or subarachnoid or putaminal or putamen or posterior fossa) adj5 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$)).tw. or ((brain or intracranial or basal ganglia or lenticulostriate) adj5 (vascular adj5 (disease$ or disorder or event))).tw. or ((isch?emic or apoplectic) adj5 (event or events or insult or attack$)).tw. or ((intracranial or cerebral art$ or basilar art$ or vertebral art$ or vertebrobasilar or vertebral basilar) adj5 (stenosis or isch?emia or insufficiency or arteriosclero$ or atherosclero$ or occlus$)).tw. or ((unilateral or visual or hemispatial or attentional or spatial) adj5 neglect).tw.) not (stroke adj volume).tw.

2. exp apathy/ 3. exp motivation/ 4. apathy.ti,ab. 5. abulia.mp. 6. amotivation.mp. 7. avolition.mp. 8. exp alexithymia/ 9. alexithymia.ti,ab. 10. emotion/ 11. (neuropsychiatric adj inventory).ti,ab. 12. "frontal lobe personality scale".ti,ab. 13. NPI.ti,ab. 14. FLOPS.ti,ab. 15. LARS.ti,ab. 16. DAIR.ti,ab. 17. ("frontal system behavior scale" or "frontal system behaviour scale").ti,ab. 18. FrSBe.ti,ab. 19. KBCI.ti,ab. 20. ("key behavior change inventory" or "key behaviour change inventory").ti,ab. 21. (flat adj2 affect).ti,ab. 22. bluntness.ti,ab. 23. (emotional adj2 indifferen*).ti,ab. 24. (reduced adj2 volition).ti,ab. 25. ((reduced or loss) adj3 (concern or effort or emotional or "action initiation" or interest or

behavior or behaviour or cognition or drive)).ti,ab. 26. or/2-25 27. 1 and 26 28. animal/ not human/ 29. 27 not 28

PsycINFO, Platform: OvidSP, Database: PsycINFO 1806-present, no limits used, no methodological filters used

# SSearch term 1 (brain adj 2 infarction?).ab,id,ti. 2 brain infarction.ab,id,ti. 3 (brain adj2 infarction).ab,ti,id. 4 (brain adj2 infactions).ab,id,ti. 5 basal ganglia cerebrovascular disease.ab,id,ti. 6 brain ischemia.ab,id,ti. 7 Ischemic Encephalopathy.ab,id,ti. 8 6 or 7 9 brain isch?emia?.ab,id,ti.


125

10 cerebrovascular disorders/ or cerebral hemorrhage/ or exp cerebral ischemia/ or cerebrovascular accidents/ or subarachnoid hemorrhage/

11 intracranial arterial disease?.ab,id,ti. 12 (stroke or poststroke or post-stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$ or apoplex$ or

isch?emi$ attack$ or tia$1 or neurologic$ deficit$).ab,id,ti. 13 intracranial hemorrhage?.ab,id,ti. 14 intracranial h?emorrhage?.ab,id,ti. 15 ((brain$ or cerebr$ or cerebell$ or cortical or vertebrobasilar or hemispher$ or intracran$ or intracerebral or

infratentorial or supratentorial or MCA or anterior circulation or posterior circulation or basal ganglia) adj5 (isch?emi$ or infarct$ or emboli$ or occlus$ or hypox$ or obstruction or vasculopathy)).ab,id,ti.

16 ((lacunar or cortical) adj5 infarct$).ab,id,ti. 17 ((brain$ or cerebr$ or cerebell$ or intracerebral or intracran$ or parenchymal or intraventricular or infratentorial

or supratentorial or basal gangli$ or subarachnoid or putaminal or putamen or posterior fossa) adj5 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$)).ab,id,ti.

18 ((brain or intracranial or basal ganglia or lenticulostriate) adj5 (vascular adj5 (disease$ or disorder or event))).ab,id,ti.

19 ((isch?emic or apoplectic) adj5 (event or events or insult or attack$)).ab,id,ti. 20 ((intracranial or cerebral art$ or basilar art$ or vertebral art$ or vertebrobasilar or vertebral basilar) adj5 (stenosis

or isch?emia or insufficiency or arteriosclero$ or atherosclero$ or occlus$)).ab,id,ti. 21 ((unilateral or visual or hemispatial or attentional or spatial) adj5 neglect).ab,id,ti. 22 aphasia/ or hemiplegia/ or hemianopsia/ or general paresis/ or paralysis/ or dysarthria/ or muscle spasms/ 23 aphasia/ or hemiplegia/ or hemianopsia/ or general paresis/ or paralysis/ or dysarthria/ or muscle spasms/ or

swallowing/ 24 (aphasi$ or apraxi$ or dysphasi$ or dysphagi$ or deglutition disorder$ or swallow$ disorder$ or dysarthri$ or

hemipleg$ or hemipar$ or paresis or paretic or paralysis or hemianop$ or hemineglect or spasticity or anomi$ or dysnomi$ or acquired brain injur$ or hemiball$ or pseudobulbar palsy).ab,id,ti.

25 Isch?emic Encephalopath$.ab,id,ti. 26 hypoxia.ab,id,ti. 27 or/9-26 28 Frontal Systems Behavioral Inventory.tm. 29 (neuropsychiatric adj5 inventory).ti,ab,tm. 30 (ias or ia or aes or as or dair or lars or flops or frsbe or kbci or npi).ab,id,ti. 31 irritability apathy scale.ab,id,ti,tm. 32 apathy inventory.ab,id,ti,tm. 33 apathy evaluation scale.ab,id,ti,tm. 34 apathy scale.ab,id,ti,tm. 35 dementia apathy interview and rating.ab,id,ti,tm. 36 lille apathy rating scale.ab,id,ti,tm. 37 frontal lobe personality scale.ab,id,ti,tm. 38 frontal system behavior scale.ab,id,ti,tm. 39 frontal system behaviour scale.ab,id,ti,tm. 40 key behavio?r change inventory.ab,id,ti,tm. 41 apathy.ab,id,sh,ti. 42 motivation.mp 43 alexithymia.ab,id,sh,ti or emotional responses/ 44 emotions/ 45 exp motivation/ 46 abulia.ab,id,ti. 47 amotivation.ab,id,ti. 48 avolition.ab,id,ti. 49 (flat adj2 affect).ab,id,ti. 50 bluntness.ab,id,ti. 51 indifference.ab,id,ti.


126

52 volition.ab,id,ti. 53 ((reduced or loss) adj3 (concern or effort or emotional or "action initiation" or interest or motivation or behavior

or behaviour or cognition or drive)).ab,id,ti. 54 or/28-53 55 27 and 54

No results: basal ganglia cerebrovascular disease.ab,id,ti, intracranial arterial disease?.ab,id,ti, (brain adj 2 infarction).ab,id,ti 5. Excluded studies: Eight studies were conference or dissertation abstracts only. Reasons for exclusion of studies were: not concerning apathy,1-7 duplicate publication on a cohort already described earlier,8-13 restriction to patients with subcortical infarctions only,14-16 or to patients diagnosed with post-stroke depression.17 References: 1. Paradise M, Walker Z, Cooper C et al. Prediction of survival in Alzheimer's disease--The LASER-AD longitudinal study. International Journal of Geriatric Psychiatry 2009;24:739-747 2. Van Heugten CM, Smit RA, Schols JMGA. Cognitive problems in the rehabilitation of stroke patients in the nursing home. [Dutch]. Tijdschrift voor Gerontologie en Geriatrie 2007;38:173-184 3. House A, Dennis M, Mogridge L, Warlow C, Hawton K, Jones L. Mood disorders in the year after first stroke. British Journal of Psychiatry 1991;158:83-92 4. Bour A, Rasquin S, Aben I et al. The symptomatology of post-stroke depression: Comparison of stroke and myocardial infarction patients. International Journal of Geriatric Psychiatry 2009;24:1134-1142 5. de Coster L, Leentjens AFG, Lodder J, Verhey FRJ. The sensitivity of somatic symptoms in post-stroke depression: A discriminant analytic approach. International Journal of Geriatric Psychiatry 2005;20:358-362 6. Kotila M, Waltimo O, Niemi ML, Laaksonen R, Lempinen M. The profile of recovery from stroke and factors influencing outcome. Stroke 1984;15:1039-1044 7. Naarding P, de K, I, van KF, Janzing JGE, Beekman ATF, Koudstaal PJ. Post-stroke dementia and depression: Frontosubcortical dysfunction as missing link? International Journal of Geriatric Psychiatry 2007;22: 1-8 8. Hama S, Yamashita H, Kato T et al. 'Insistence on recovery' as a positive prognostic factor in Japanese stroke patients. Psychiatry and Clinical Neurosciences 2008;62: 386-395 9. Hama S, Yamashita H, Shigenobu M et al. Sitting balance as an early predictor of functional improvement in association with depressive symptoms in stroke patients. Psychiatry and Clinical Neurosciences 2007;61:543-551 10. Angelelli P, Bivona U, Serio M et al. Prevalence and evolution of neuropscyhiatric disturbances after stroke. Preliminiary data. Rivista di Neurobiologia 2001;47:251-257 11. Hama S, Yamashita H, Shingenobu M et al. Post-stroke affective or apathetic depression and lesion location: left frontal lobe and bilateral basal ganglia. European Archives of Pychiatry and Clinical Neuroscience 2007;257:149-152 12. Aybek S, Carota A, Ghika-Schmid F et al.motional behaviour in acute stroke: the Lausanne emotion in stroke study. Cognitive and behavioural neurology 2005;18:37-44 13. Brodaty H, Withall A, Altendorf A, Sachdev PS. Rates of depression at 3 and 15 months poststroke and their relationship with cognitive decline: The Sidney Stroke Study. The American Journal of Geriatric Psychiatry 2007;15:477-486 14. Yamagata S, Yamaguchi S, Kobayashi S. Impaired novelty processing in apathy after subcortical stroke. Stroke 2004;35:2437-2441 15. Okada K, Kobayashi S, Yamagata S, Takahashi K, Yamaguchi S. Poststroke apathy and regional cerebral blood flow. Stroke 1997;28:2437-2441 16. Mok VCT, Wong A, Wong K et al. Executive dysfunction and left frontal white matter hyperintensities are correlated with neuropsychiatric symptoms in stroke patients with confluent white matter hyperintensities. Dementia and Geriatric Cognitive Disorders 2010;30: 254-260


127

17. Gainotti G, Azzoni A, Marra C. Frequency, phenomenology and anatomical-clinical correlates of major post-stroke depression. British Journal of Psychiatry 1999;175:163-167 Appendix S2: data extraction form:

DData extraction fields SSub fields Date of extraction Author, Year, Title Hospital and country of origin

Source of funding Study characteristics Aims/objectives Method of inclusion Inclusion/exclusion criteria Inclusion period Number of patients excluded Number of patients included Drop-outs Follow-up Time since stroke Conclusions Apathy Number of patients assessed for apathy Number of apathetic patients Number of non-apathetic patients Measurement, source and cut-off used Significant associations with apathy Remarks Age Age of apathetic patients Age of non-apathetic patients Gender % female of apathetic patients % female of non-apathetic patients Depression Number of patients assessed for depression Number of depressed patients with apathy Number of depressed patients without apathy Measurement and cut-off used Significant associations with depression Remarks Cognitive impairment Non-apathetic score and SD Apathetic score and SD Measurement Significant associations Remarks Motor impairment Apathetic score and SD Non-apathetic score and SD Measurement Significant associations Remarks Outcome: location Significant association Measurement tool Length of follow-up


128

Outcome: treatment Setting of intervention Description of protocol and co-interventions Length of follow-up Number of participants enrolled Number of patients for intervention Number of controls Number of participants included in analysis Number of withdrawals, exclusions, lost to follow-up Summary outcome data Type of analysis Results of analysis Additional outcomes Limitations Declared interests Costs and resource use Adverse events Conclusion


129

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130

Appendix S4: funnel plot prevalence

S4: funnel plot prevalence Circles represent the studies taken into meta-analysis. Apathy-rates are shown on the logaritmical x-axis and estimated precision, based on study size, on the y axis. Asymmetry may point to publication bias. Appendix S5: funnel plot prevalence with more strict inclusion criteria

S5: funnel plot prevalence with more strict inclusion criteria: Funnel plot of the analysis using more strict inclusion criteria. Note that the scale on the x-axis is logarithmical. The study that was identified as the main outlier is marked with an arrow. (Sagen, 2009)


131

Appendix S6: exploratory sub group analyses Study N Proportion 95% CI N studies Scale

Subgroup: setting N Proportion 95% CI N studies I 2sub acute 996 38,2% 29,1-48,2 9 47,0%inpatients 409 40,5% 22,8-53,4 4 44,3%in- and outpatients 863 31,5% 22,4-42,2 6 46,7%outpatients 310 25,6% 19,6-32,6 4 26,9%Subgroup: depression N Proportion 95% CI N studies I 2Excluded 748 33,4% 25,3-42,7 8 45,0%Not excluded 1830 34,7% 28,7-42,3 15 46,9%Subgroup: CI N Proportion 95% CI N studies I 2Excluded 1009 32,6% 26,9-38,8 13 47,2%Not excluded 1569 37,5% 29,4-46,3 10 39,2%Subgroup: disability N Proportion 95% CI N studies I 2Excluded 1215 32,0% 23,9-41,4 8 47,2%Not excluded 1363 36,0% 29,2-43,5 15 46,1%Subgroup: type of stroke N Proportion 95% CI N studies I 2Infarction only 992 33,7% 25,1-43,5 10 46,9%Infarction and hemorrhage 1594 35,3% 28,9-42,4 12 46,1%Subgroup: medical history N Proportion 95% CI N studies I 21st stroke 418 24,1% 19,5-29,5 6 22,1%Any history of stroke 2160 38,9% 33,1-45,0 17 46,2%

N Proportion 95% CI N studies I 2:Pooled 2580 34,7% 29,5-40,2 23 46,4%

0 10 20 30 40 50 60 70 80 90 100 S6: exploratory sub group analyses. N: number of patients, N studies: number of studies, CI: cognitive impairment Appendix S7: funnel plot of the analysis of differences in MMSE scores between apathetic and non-apathetic groups

S7: funnel plot of the analysis of differences in MMSE scores between apathetic and non-apathetic groups. The difference in MMSE scores of apathetic patients compared to non apathetic patients is represented in points on the X-axis. The two main outliers are marked with arrows. (from left to right: Starkstein, 1993 and Greenop, 2009)

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