- behavioral neurology
- cognitive impairment
- stroke recovery
In 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.8,9
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 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.15,16
In 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.
We 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.
Full 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).18
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 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.20
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 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.
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.5,6,21–42 Table 1 shows the study design and demographic details of all 24 selected studies.
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.6,21,31,36
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.
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.5,32
Information 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.
Two 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.14,51,52
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 history of stroke. Concomitant depression was present in only 40% of apathetic patients, confirming the occurrence of apathy as a distinct entity. Poststroke apathy is associated with worse cognitive function. There is considerable evidence for an association of poststroke apathy with disability and worse outcome of rehabilitation. No clear association between poststroke apathy and specific stroke lesion locations could be established. Systematic trials on treatment of poststroke 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 poststroke apathy, including prevalence, associated symptoms, lesion localization, and treatment. Several of the included studies had a high risk of selection bias and information bias. Confounding bias was generally low. The 3 factors that we hypothesized to be the most influential (depression, age, and cognitive function) were reported in all but 1 study.
Because apathy is mostly assessed as a secondary outcome, there might be overreporting 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 6 remaining studies, 4 used 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 seems that many aspects of poststroke 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 poststroke apathy may differ from what is regarded apathetic behavior in other conditions (eg, Parkinson or Alzheimer 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 poststroke fatigue, prestroke personality traits, and cultural factors. These aspects of poststroke 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 behavior relative to their behavior before the stroke occurred. In 3 studies, the association between apathy and other concurrent neuropsychiatric symptoms was assessed, but none were found.27,36,42 In one study, personality before 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 poststroke apathy.
The heterogeneity of the results has some implications for the generalizability of our findings. Although the weighted average age and depression rates (Figure 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 nonapathetic 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 subgroup analyses. Therefore, results gained at a group level need to be interpreted with caution.
With a prevalence of 34.6%, poststroke apathy occurs as frequently as poststroke depression (33%)2 and poststroke dementia (21.0%–41.3%).3 Whereas these neuropsychiatric syndromes are frequently studied and treatments often initiated, poststroke apathy has so far been largely ignored. Because the prevalence of apathy in the general population is largely unknown, it is difficult to establish to which degree poststroke apathy should be attributed to the stroke. In healthy volunteers of comparable age, apathy was found in 6.0% and in 15.8% 5 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 poststroke 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 seems 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 with 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% versus 23.0%) (Figure 2).6,23,24,31 The NPI uses 1 to 3 dichotomous (yes/no) screening questions to establish the presence of apathy, which may increase the threshold of its diagnosis (ie, 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 were 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 owing 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.
The association between apathy and age has also been reported in the general population.53,55 Possibly, poststroke apathy occurs more frequently in patients with reduced cognitive function, which is more common in older individuals in both the general and the poststroke population.3,55 The difference we observed in MMSE scores between apathetic and nonapathetic 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 1 study.6 The relationship between poststroke apathy and cognitive impairment may be explained by several factors. Incapability of goal-oriented thinking and behavior may lead to loss of interest and lack of effort in cognitive testing.56,57 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.58,59
Apathetic patients have an almost 2-fold risk of concurrent poststroke 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 cutoff 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 poststroke depression60 because symptoms of apathy do not to respond well to selective serotonin reuptake inhibitors.14,61,62 Distinction between isolated poststroke apathy and apathy in the context of poststroke depression can, therefore, have important consequences from a clinical point of view.
Quantitative assessment of the relationship between apathy and disability is difficult owing to very high heterogeneity between studies. Nevertheless, an association between apathy and increased disability was reported in most of the studies. In 2 studies, an association between apathy and increased disability 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 with nonapathetic patients with comparable functional status at baseline.32 These findings suggest a detrimental effect of poststroke apathy on functional recovery.
We found no clear association either between apathy and a specific lesion location or hemisphere. We also did not find an association with stroke severity or lesion volume on magnetic resonance imaging. An association with subcortical lesions, mainly the basal ganglia, is reported most consistently. Two studies with high prevalence of poststroke apathy (50%–55%) described patients with subcortical infarctions, often affecting the basal ganglia.63,64 Apathy also occurs more frequently in other neurological conditions involving the basal ganglia (eg, progressive supranuclear palsy, Parkinson, and Huntington disease).65,66 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.12,58
There is currently insufficient evidence to support a pharmacological approach to treat poststroke apathy. High doses of the nootropic agent nefiracetam showed a positive effect on apathy as a secondary outcome in a group of poststroke depression patients in a small controlled trial with small treatment groups,43 but results are difficult to translate to other poststroke populations. Evidence for an advantageous effect of the acetylcholinesterase inhibitor donepezil in patients with acute poststroke cognitive impairment compared with 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 poststroke apathy in a poststroke population are clinically relevant for adequately informing patients, caregivers, and clinicians. Poststroke apathy is a pervasive but insufficiently recognized 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 Poststroke 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 coping strategies for poststroke 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 poststroke disability and should be taken into account in studies with a long-term follow-up of functional recovery.
Apathy occurs in every third patient after stroke, often without concomitant depression. Poststroke 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 poststroke apathy. Better recognition could potentially benefit rehabilitation programs and prevent inadequate treatment of depression. Some promising treatment strategies warrant further research in randomized controlled trials.
We thank R. Spijker and J.G. Daams from the Academic Medical Centre, Amsterdam medical library for their help with conducting our search. We also thank all investigators who helped supply original data, in particular L. Caeiro (Department of Neurosciences, Servico de Neurologia, Hospital de Santa Maria, Portugal), A. Carota (Clinique de Genolier, Neurocentre GSMN, Switzerland), F. Castellanos-Pinedo (Department of Neurology, Hospital Virgen del Puerto, Spain), K. Greenop (Telethon Institute for Child Health Research, Center for Child Health Research, University of Western Australia, Australia); S. Hama (Division of Rehabilitation, Hibino Hospital/Department of Neurosurgery, Hiroshima University, Japan), M. Hoffmann, (James A. Haley Veterans’ Hospital, Tampa), A. Iavarone (Neurological and Stroke Unit, CTO Hospital, AORN Ospedali dei Colli, Italy), K. Onoda (Department of Neurology, Shimane University, Japan), M. Planton and J. Pariente (Service de Neurologie, Center Hospitalier Universitaire de Toulouse, CHU Purpan, France), and U. Sagen (Department of Psychiatry, Telemark Hospital, Norway).
J. van Dalen contributed to study design, literature search, data extraction, data synthesis, data interpretation, statistical analysis, and writing; E.P. Moll van Charante for data interpretation and writing; P.J. Nederkoorn for data synthesis, data interpretation, and writing; W.A. Gool for data interpretation and writing; and E. Richard contributed to study design, literature search, data extraction, data interpretation, and writing.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.112.674614/-/DC1.
- Received August 22, 2012.
- Revision received November 21, 2012.
- Accepted November 28, 2012.
- © 2013 American Heart Association, Inc.
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