Poststroke Apathy
2013; Lippincott Williams & Wilkins; Volume: 44; Issue: 3 Linguagem: Inglês
10.1161/strokeaha.112.674614
ISSN1524-4628
AutoresJan Willem van Dalen, Eric P. Moll van Charante, Paul J. Nederkoorn, Willem A. van Gool, Edo Richard,
Tópico(s)Attention Deficit Hyperactivity Disorder
ResumoHomeStrokeVol. 44, No. 3Poststroke Apathy Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBPoststroke Apathy Jan Willem van Dalen, MSc, Eric P. Moll van Charante, MD, PhD, Paul J. Nederkoorn, MD, PhD, Willem A. van Gool, MD, PhD and Edo Richard, MD, PhD Jan Willem van DalenJan Willem van Dalen From the Department of Neurology (J.W.v.D., P.J.N., W.A.v.G., E.R.) and Department of General Practice (E.P.M.v.C.), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. , Eric P. Moll van CharanteEric P. Moll van Charante From the Department of Neurology (J.W.v.D., P.J.N., W.A.v.G., E.R.) and Department of General Practice (E.P.M.v.C.), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. , Paul J. NederkoornPaul J. Nederkoorn From the Department of Neurology (J.W.v.D., P.J.N., W.A.v.G., E.R.) and Department of General Practice (E.P.M.v.C.), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. , Willem A. van GoolWillem A. van Gool From the Department of Neurology (J.W.v.D., P.J.N., W.A.v.G., E.R.) and Department of General Practice (E.P.M.v.C.), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. and Edo RichardEdo Richard From the Department of Neurology (J.W.v.D., P.J.N., W.A.v.G., E.R.) and Department of General Practice (E.P.M.v.C.), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. Originally published29 Jan 2013https://doi.org/10.1161/STROKEAHA.112.674614Stroke. 2013;44:851–860Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 IntroductionIn addition to acute motor, sensory, and language impairments, subacute and chronic neuropsychiatric disturbances after stroke can have major impact on activities of daily living.1 Cognitive impairment and depression are the most commonly reported neuropsychiatric symptoms, both occurring in approximately one third of patients after stroke.2,3 Apathy, most commonly defined as a syndrome of diminished goal-directed behavior, 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.8,9Apathy 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 poststroke 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.15,16In this systematic review and meta-analysis, we aim to establish the impact of poststroke 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.MethodsSearch StrategyWe conducted a comprehensive literature search of the Medline, PsycINFO, and Embase (from 1980 onward) 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 SI in the online-only Data Supplement. The search was last updated in February 21, 2012. Titles, abstracts, and articles were reviewed by 2 independent observers (J.W.D. and E.R.) to assess inclusion criteria. If necessary, full text copies of articles were obtained. Discrepancies of the 2 separate selections were compared and were resolved by discussion. A third investigator (P.J.N.) 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 Center for Reviews and Dissemination.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 localizations, (6) were written in a European national language, Chinese, or Japanese. If there was >1 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 poststroke 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) written in English.Data ExtractionFull text articles of selected studies were obtained for further evaluation. Data from each study were extracted by 2 observers (J.W.D. and E.R.), using a predefined data extraction form (Appendix SII in the online-only Data Supplement). Authors were contacted if published results lacked information necessary for the meta-analyses. Risk of bias was assessed using an assessment form based on the Newcastle–Ottawa quality assessment scale for cohort studies, and rated selection, confounding, and information bias subitems (Appendix SIII in the online-only Data Supplement).18Statistical AnalysisAnalysis 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 effect binary model. For each proportional characteristic, 95% confidence intervals (95% CIs) were estimated using binomial distribution. When a study provided >1 apathy rate in a single cohort (eg, 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 poststroke 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 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 1 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 prespecified 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 were estimated by 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 SIII in the online-only Data Supplement). To this analysis, we added a sensitivity analysis in which we excluded studies with an average age below 60 years because 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, history of stroke, and type of stroke included. These subgroup analyses were not prespecified 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.20ResultsOur 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 2 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 1 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. Two articles reported on apathy prevalence in the same cohort at different time points.23,44 Results reported in these articles were combined using size weighted averages for all analyses except for those regarding time since stroke and population age.Download figureDownload PowerPointFigure 1. Article selection.Reasons for exclusion of studies are listed in Appendix SI in the online-only Data Supplement. After quality assessment, we included 24 articles on the prevalence of apathy.5,6,21–42Table 1 shows the study design and demographic details of all 24 selected studies.Table 1. Study Characteristic DesignAuthorMajor Exclusion CriteriaExcludedStroke SeverityDisability at AssesmentYearDesignAgeDisab.Cog. I.Major Depr.Com. Dis.%SettingRecruitment PeriodType of StrokeApathy CriterionDepression MeasureCognition MeasureMeasureMean ScoreMeasureMean ScoreStarkstein301993PC……Yes……17Subacute 13 (s)HDSaMMSEb……JHFIc6/27 (i)*Marin281994RC45–85Yes………n.r.Outpatients 38 (c)HRSDMMSE…………Andersson221999CC……YesHistoryYesn.a.Inpatient rehabilitationn.r.IHAES > 33 (c)MADRSa……………Angelelli212004CS…YesYes…Yesn.r.In- and outpatients1999–2002First INPI > 95 p of control (c)NPIRaven test……FIM85.7/10 (d)Piamarta272004PC 85…Yes…Yes34In- and outpatients1997–2000IAES > 37 (i)SCID-1aMMSEbESS93.5/100 (d)IADLc, ADLc7/8, 5/6 (i)*Carota352005PC…Yes………16Inpatient1995–1999IEBIF nurse > 0 (c)Subjective yes or no………BI80/100 (d)Hochstenbach242005PC>69Yes… 15 (s)HAM-D17a + MINI……………Hama52007PC………HistoryYes40Inpatient rehabilitation2002–2006IHAS > 15 (s), NPI > 0 (i)SDSMMSE……FIMd77/126 (d)Jarzebska262007PC…………Yes18Subacute2004–2005IAS > 13 (s)HAM-DMMSEb…………Santa322008PC45–90…Yes…Yesn.r.Inpatient rehabilitation1999–2001First IHAS > 15 (s)SDSMMSENIHSS9.2/42 (i)NIHSSd9/42 (i)*Greenop372009PC…Yes……Yes90In- and outpatients2003–2005IHNPI > 0 (i)NPI-iCAMCOGb……MFAQ-IADL2.8/8 (i)Mayo62009PC…Yes………40In- and outpatients2003–2004IHWBIBS (i)SF-36MMSE telephonebCNS8.3/1.5 (d)SIS-physc, d65.6/100 (d)Hoffmann382010PC18–90YesYesCurrentYes96Inpatients2003–2006IHFRSBE > 65 (s, i)excludedFRSBE, CCN, WCSTNIHSS3.3/42 (i)NIHSS3.3/42 (i)*Onoda402011PC………HistoryYesn.r.In- and outpatients2005–2009IAS > 15 (s)SDSaMMSEb……mRSc3/6 (i)Rush292010CC……Yes……n.a.Outpatient replicants2005–2007INPI > 0 (i)BDI-II > 13MMSENIHSS3.0/42 (i)BI97/100 (d)Sagen422010PC……Yes…Yes43In- and outpatients2003–2005IHAES > 33 (s)HADS-DMMSE (sus)……BI87/100 (d)Caeiro342012PC…YesYes…Yes20Subacute2000–2002IHAES-10 (c)MADRSMMSENIHSSn.r.mRSdn.r.Castellanos362011PC……Yes……n.r.In- and outpatients2007–2008INPI > 0 (i)HAM-DMMSECNS7.4/11.5 (d)mRSc, BI2.0/6 (i), 79/100 (d)*Marasco392011PC……YesHistoryYes22Subacute2009First IPSDRS > 0 (c)PSDRSMMSENIHSS2.9/42 (i)mRS2.8/6 (i)*Withall312011PC>85…Yes…Yes48In- and outpatients1997–2000IAESi >37 (i)SCID-1MMSEbESS89/100 (d)IADLc, ADLc7/8, 5/6 (d)Planton412012PC18–80…YesHistoryYes80Outpatients with good recovery2007–2009First IAS > 13 (s)BDI-II > 13Broad cognitive testingNIHSS2.6/42 (i)mRS0.7/6 (i)*CC indicates case–control; CS, cross-section; Com. Dis, communication disorder; Cog. I., cognitive impairment; Depr., depression; Disab., major disability and severe disease; First, no history of stroke; H, hemorrhage; I, infarction; n.a., not applicable; n.r., not reported; PC, prospective cohort; RC, retrospective cohort; 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, PostStroke 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 Institutes 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 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.aSignificant association between apathy and depression; bsignificant association between apathy and a decrease in performance on cognitive test; csignificant association between apathy and increased disability; and dsignificant association between apathy and worse functional recovery.To supplement data, 22 authors were contacted, of whom 9 were able to complement the data of 10 studies.33–42 Assessment of the risk of bias per study is provided in Appendix SIII in the online-only Data Supplement.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 4 studies concerned prospectively collected cohorts of stroke patients. Nine studies assessed patients in a subacute setting within 30 days after stroke. Six studies were done in a mixed population of in- and outpatients, 4 studies were done exclusively among rehabilitating inpatients and another 4 exclusively among outpatients. Four articles provided longitudinal data with the length of follow-up ranging from 6 to 16 months.6,21,31,36Download figureDownload PowerPointFigure 2. Clinical characteristics. AES-10 c indicates Apathy Evaluation Scale modified to 10 items clinician assessment; AES c, Apathy Evaluation Scale clinician assessment; AES i, Apathy Evaluation Scale informant assessment; AS s, apathy scale self-assessment; CI, confidence interval; Dep, depression; EBIF c, Emotion Behavior Index Form clinician assessment; Fem, female; MMSE, Mini-Mental State Examination; n.r., measured but not reported fully; n.m., not measured; NPI i, Neuropsychiatric Inverntory informant assessment; PSDRS c, PostStroke Depression Rating Scale clinician assessment; Qi, questionnaire informant assessment; Qs, questionnaire self assessment; TSS, time since stroke in days; and WBIBS i, modified apathy items from the Williams Brain Impairment Behavior Scale informant assessment. *denotes values averaged between assessments within article; **denotes values averaged between article on baseline and article on follow-up; ***denotes assessment with the most additional information used. Underlined: Studies provided information for separate meta-analysis on the clinical factor; Italic: additional information supplied by author. ≈ denotes estimated value; ^ denotes multiple apathy rates allowed per study when measured with different measures; ^^ denotes multiple rates allowed per study when measured with different sources; ^^^ denotes multiple rates allowed when measured at different time since stroke.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 SIV in the online-only Data Supplement).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 heterogeneity42 reduced heterogeneity (24.2%; 95% CI, 20.4%–28.4%; I2=25.2%) (Appendix SV in the online-only Data Supplement). 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 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, whereas that of the studies using clinician-based instruments exceeded both (Figure 2). In studies using the NeuroPsychiatric Inventory (NPI), a lower prevalence was reported compared with studies using other informant-based scales (23.0%; 95% CI, 18.4–28.2; I2=30.0% versus 39.4; 95% CI, 30.0%–49.5%; I2=45.5%). In addition, the analysis stratified for most commonly used assessment instruments showed significantly lower prevalence when apathy was assessed with the NPI compared with apathy-specific assessment instruments (Figure 2). Studies which excluded patients with history of stroke had a lower combined estimate compared with those including patients regardless of stroke history (24.1%; 95% CI, 19.5–29.5; I2=22.1% versus 38.9; 95% CI, 38.9%–44.9%; I2=46.2%) (Appendix SVI in the online-only Data Supplement). Stratification according to study setting revealed a relatively low prevalence and heterogeneity in the subgroup of studies, which only included outpatients (25.6%; 95% CI, 19.6–32.6; I2=26.9%) (Appendix SVI in the online-only Data Supplement). Additional subgroup analyses did not improve heterogeneity (Appendix SVI in the online-only Data Supplement). 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 2. 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 (relative risk, 1.2; 95% CI, >1.0–1.5; I2=6.6%). Other associations that are less commonly reported are listed in Table 3.Table 2. Associations With Apathy Identified by Meta-analysisFactorEffect of ApathyNo. of StudiesNPSANo PSAEstimate95% CII2 (%)Poststroke apathy vs no poststroke apathy MMSEMean difference10808268540−2.7 points−3.8, −1.660.2 AgeMean difference1312904708203.8 y2.1, 4.70.0 DisabilityHedges G (SMD)9627194433−0.3−0.7, 0.181.6 WomenRelative risk868196/203180/4781.21.0, 1.56.6Poststroke apathy vs poststroke depression PSDRelative risk141240179/442185/7981.81.4–2.452.0 PSD in PSAProportion14442179…40.1%0.3. 0.542.7 PSD in pop.Proportion14124017918528.1%0.2. 0.446.1CI indicates confidence interval; MMSE, Mini-Mental State Examination; pop., population on which information on depression in apathetic patients was available; PSA, poststroke apathy; PSD, poststroke depression; and SMD, standardized mean difference.Table 3. Significant Associations With ApathyStudyOther Associations With ApathyAssociation (95% CI)TestAngelelli21TSS > 2 moP 4 wkP<0.05tCaeiro34Education < 10 yOR, 4.2 (1.3–13.6)Log. reg.Hama5CT-defined lesion volumeP<0.02Mann–Whitney UHochstenbach24Low agreement between patients and care giversκ=0.5Kappa coefficientMayo6High comorbidity on Charlson IndexOR, 2.1 (1.0–4.3)Ord. reg.Sagen42ComorbidityOR, 3.0 (1.0–8.3)Log. reg.Withall31Apathy at baseline with depression at follow-upOR, 7.2 (2.2–24.1)Log. reg.CI indicates confidence interval; κ, kappa value; Log. reg., logistical regression; MSE, Mini-Mental State Examination; OR, odds ratio; Ord. reg., ordinal regression; and TSS, time since stroke.The mean MMSE score of apathetic patients (n=10 studies) was 2.7 points lower (95% CI, 1.6–3.8; I2=60.2%). Excluding 2 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 SVII in the online-only Data Supplement).30,33 In 7 studies, a significant association between the presence of apathy and reduced performance on different tests of cognitive function was found.The estimated relative risk of depression among apathetic patients (n=11 studies) was 1.8 (95% CI, 1.3–2.4) (Table 2). 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 nonapathetic patients was estimated at 23.6% (95% CI, 17.1%–31.6%). Six studies reported a significant association between the presence of poststroke apathy and poststroke depression.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 because stroke did not substantially improve heterogeneity. In total, a significant association of apathy with increased disability was reported in 9 of 11 studies. In 7 of these, apathy was associated with concurrent increased disability (Table 1). In 2, apathy at baseline was associated with decreased functional status at follow-up,6,33 and in another 2, with decreased functional recovery over time.5,32Information regarding lesion location and treatment was assessed qualitatively. Of the 9 studies that assessed the relationship between lesion location and presence of poststroke apathy, 6 reported on a significant association between specific lesion locations and an increased risk of apathy, although in 1 study all significant associations disappeared after the appropriate Bonferroni correction (Tables 4–7).23 No significant difference was found between lacunar and cortical infarctions.Table 4. Association Between Apathy and Type of StrokeAuthorType of StrokePTestSanta32Nonhemorrhagic stroke<0.05χ2Caeiro34Hemorrhagic stroke<0.03χ2Table 5. Association Between Apathy and Laterality of Stroke LesionAuthorLateralityPTestRight Brodaty23Right hemisphere<0.02*tRight frontal subcortical circuit<0.02*tLeft Santa32Left basal ganglia<0.05χ2 Onoda40Left basal ganglia right hemisphere > left hemisphere > none left basal ganglia<0.001Fisher Onoda40Reduced regional cerebral blood flow in basal ganglia<0.001**ANCOVAFAB indicates frontal assessment battery; HDS-R, Hamilton Depression Rating Scale; MMSE, Mini-Mental State Examination; rCBF, regional cerebral blood flow; and SDS, Zungs Self-rating Depression Scale.*Corrected for age, no longer significant when Bonferroni correction was applied;**corrected for age, sex, MMSE, HDS-R, FAB, SDS, and false discovery ratio.Table 6. Association Between Apathy and Region of Stroke LesionAuthorRegionPTestSubcortical Starkstein30Posterior internal capsule<0.05χ2 Yates Brodaty23Right frontal subcortical circuit right hemisphere > left hemisphere > none no basal ganglia damage<0.01Fisher Santa32Left basal ganglia<0.05χ2 Onoda40Left basal ganglia<0.01χ2Reduced rCBF basal ganglia 0.05ANOVAKaji25Laterality0.23tTwo clinical trials assessing the effect of pharmacological treatment on poststroke apathy were identified, both using apathy as secondary outcome (Tables 8 and 9). In 1 phase II trial, significantly reduced apathy scores were found in the group treated with 900 mg of the nootropic agent nefiracetam (n=22) compared with 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 5 case reports, a favorable effect of treatment with bromocriptine was reported,14,45–48 and in 3 with methylphenidate.14,49,50 Ropinirole, zolpidem, and selegiline were reportedly beneficial in one case each.14,51,52Table 8. Trials Regarding Treatment of Poststroke ApathyAuthorYearDesignMain OutcomeSettingDiagnosisNINDInterventionDoseFollow-up, wkOutcomeRobinson432009RCTDepressionOutpatient PSDModified AS2669Nefiracetam600 mg12ITT ANOVA: 900 mg vs placebo: 4 point decrease in AS score (P=0·01), ARR 0.18 (95 CI, 0.02–0.34), more frequent remissions22900 mg22…Placebo…Whyte442008OT + RCCIInpatient PSCIAES1341Donepezil5–10 mg12PP ANOVA: Donepezil and decrease of apathy both independently associated13Galantamine4–12 mgPS non-CI…98…Control: none…20 with an increase in FIM-gain over timeAES indicates Apathy Evaluation Scale; ARR, absolute risk reduction; AS, apathy scale; FIM, functional independence measure; ITT, intention to treat; ND, number of drop-outs; NI, number for intervention; OT, open trial; PP, per protocol; PSCI, patients with poststroke cognitive impairment; PSD, patients with poststroke depression; PS non-CI, matched stroke patients without cognitive impairment; RC, retrospective cohort; and RCT, randomized controlled trial.Table 9. Case Reports and Series Regarding Treatment of Poststroke ApathyAuthorYearDesignMain OutcomeSettingDiagnosisReported PatientsInterventionDoseFollow-upSuccessfully TreatedKohno512010CRApathyInpatientClinician1Ropinirole0.75 mg/d…1Marin141995CSApathyOutpatientClinician2MPH/BRC, Selegiline50/90 mg/d, 5 mg1, >2 y2Watanabe491995CRApathyInpatientClinician1MPH5 mg/d9 mo1Spiegel502009CSApathyInpatientClinician3MPH2.5–12.5 mg/d1 mo3Fong462001CRApathyn.a.n.a.1BRC10 mgn.a.1Catsman451988CRCI, apathyn.a.n.a.1BRCn.a.n.a.1Parks471992CRFLSInpatientClinician1BRC5–60 mg/d5 mo1Barett481991CRAbuliaInpatientClinician1BRC5–55 mg/d…1Mathieu522011CRApathyOutpatientAI1Zolpidem……1AI indicates apathy inventory; ARR, absolute risk reduction; BRC, bromocriptine; CI, cognitive impairment; CR, case report; CS indicates case series; FLS, frontal lobe syndrome; ITT, intention to treat; MPH, methylphenidate; n.a., full article not available; and PP, per protocol.DiscussionWe found that apathy occurs in every third patient after stroke. This estimate was not importantly aff
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