Model of Understanding Fatigue After Stroke

HomeStrokeVol. 46, No. 3Model of Understanding Fatigue After Stroke Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBModel of Understanding Fatigue After Stroke Simiao Wu, MSc, Gillian Mead, FRCP, Malcolm Macleod, FRCP and Trudie Chalder, PhD Simiao WuSimiao Wu From the Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK (S.W., G.M., M.M.); Department of Psychological Medicine, Kings College London, London, UK (T.C.); and Department of Neurology, West China Hospital, Sichuan University, Chengdu, China (S.W.). Search for more papers by this author , Gillian MeadGillian Mead From the Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK (S.W., G.M., M.M.); Department of Psychological Medicine, Kings College London, London, UK (T.C.); and Department of Neurology, West China Hospital, Sichuan University, Chengdu, China (S.W.). Search for more papers by this author , Malcolm MacleodMalcolm Macleod From the Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK (S.W., G.M., M.M.); Department of Psychological Medicine, Kings College London, London, UK (T.C.); and Department of Neurology, West China Hospital, Sichuan University, Chengdu, China (S.W.). Search for more papers by this author and Trudie ChalderTrudie Chalder From the Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK (S.W., G.M., M.M.); Department of Psychological Medicine, Kings College London, London, UK (T.C.); and Department of Neurology, West China Hospital, Sichuan University, Chengdu, China (S.W.). Search for more papers by this author Originally published3 Feb 2015https://doi.org/10.1161/STROKEAHA.114.006647Stroke. 2015;46:893–898Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2015: Previous Version 1 Fatigue is ubiquitous but it is more common and more severe in patients with acute and chronic conditions, including stroke. The reported proportion of people with fatigue after stroke ranges from 23% to 75%.1 The variation in proportion between studies reflects the heterogeneity in the studied populations, time since stroke, and assessment methods for fatigue. Fatigue is common immediately after stroke, and it tends to persist in most but not all patients. It contributes to lower quality of life and a higher risk of death.2,3 How to manage and prevent fatigue is ranked by stroke survivors and health professionals among the top 10 research priorities relating to life after stroke.4 However, there is no effective treatment, which is partly because of our lack of knowledge of its mechanisms.Fatigue after stroke may share some common underlying mechanisms with other conditions. For example, Zedlitz and colleagues found that the psychosocial profiles of stroke patients with fatigue were similar to those reported in patients with cancer, multiple sclerosis, and chronic fatigue syndrome.5 Several fatigue models have been developed for patients with other conditions; a myriad of biological,6,7 psychosocial,8,9 and behavioral factors,9 as well as other symptoms, such as pain and sleep problems,10 are involved. In this review, we explored whether these factors contribute to fatigue after stroke.We systematically reviewed studies of post-stroke fatigue (PSF) and discussed the definition of PSF, its natural history, and its associations. By drawing on literature of fatigue in other conditions alongside evidence from stroke studies, we propose a conceptual model of PSF. This model is potentially useful in understanding the mechanisms of PSF and informing the development of its treatment.Definition of Post-Stroke FatigueIn stroke studies, PSF is usually defined by cut-off scores on fatigue scales, which are often devised in nonstroke populations. Among over 50 fatigue scales used in research studies, only 7 have been tested for their psychometric properties in a stroke population, and all showed feasibility and validity in assessing PSF.11,12 Furthermore, dichotomizing patients by a single cut-off score does not fully characterize fatigue that matters to stroke survivors. To address this weakness, a case definition for PSF was developed, of which the criterion was self-reported significant fatigue that interfered with daily activities.13 This definition is valid and reliable in identifying clinically significant fatigue in stroke survivors.13 A study found that a third of stroke survivors met this case definition 1 month after stroke.14Natural History of Post-Stroke FatigueFive longitudinal studies (n=762) investigated the course of PSF in individual patients and found that more than one third of patients had fatigue at the initial assessment (usually within the first 3 months after stroke).14–18 Among patients with fatigue at the initial assessment, about two thirds of them had fatigue at a later stage (usually over 1 year after stroke), with perhaps one third of them recovering by this time. Among patients without fatigue at the initial assessment, fatigue developed in ≈12% to 58% of them during the course of follow-up.14–18 These findings reveal 3 patterns of temporal course of fatigue after stroke, that is, persistent fatigue, recovered fatigue, and late onset fatigue (Figure 1).Download figureDownload PowerPointFigure 1. Temporal course of poststroke fatigue.Concept of Early Fatigue and Late FatigueFatigue present early after stroke (ie, early fatigue) and fatigue present at a later stage after stroke (ie, late fatigue) could be viewed as part of an evolving process; in longitudinal studies of PSF, early fatigue is always associated with late fatigue.16,19 However, it is plausible that different factors contribute to PSF experienced at different times. Two studies investigated associations of fatigue at different time points after stroke. In one study, infratentorial stroke was associated with fatigue at 2 months but not18 months after stroke; however, baseline depression and anxiety were associated with fatigue at both assessments.16 In another study, the 3 strongest correlates of fatigue at 6 months were initial stroke severity, disability, and depression, whereas at 1 year, the strongest correlates were depression, anxiety, and language impairments.18 These findings suggest that the nature of the stroke itself may be a more important determinant of early rather than late fatigue, with psychological factors important for both phases.Factors Associated With Post-Stroke FatigueA myriad of biological, psychosocial, and behavioral factors might be associated with fatigue. Given the concepts of early and late fatigue after stroke and the observation in one study that lesion location was associated with early but not late fatigue,16 it is important to consider the time at which any related factor might exert most influence on PSF. Here we reviewed associations of PSF and explore their relationship with fatigue at early and later stages after stroke. (A summary of these associations is provided in Table I in the online-only Data Supplement of this review.)Pre-Stroke ConditionsThree studies (n=471) asked about the presence of pre-stroke fatigue in stroke survivors, and all found that pre-stroke fatigue was associated with both early and late fatigue after stroke.14,20,21 These findings should be interpreted with caution though because pre-stroke fatigue was assessed retrospectively and there is a risk of recall bias.In an underpowered study (n=108), no association was found between PSF and pre-stroke depression or age-related white matter changes at either 2 months or 18 months after stroke.16 It should be noted that only 14 people had pre-stroke depression and none had white matter changes.16 In a larger study (n=377), people with pre-stroke depression or those with leucoaraiosis (nonspecific white matter changes) were more likely to have fatigue 6 months after stroke.22Stroke LesionsAccording to a systematic review of biological correlates of PSF, there is no conclusive evidence on the association between PSF and lesion site.23 However, the uncertainty regarding any association between PSF and lesion site might be attributed to 2 factors: the time of fatigue assessment and how lesion site was classified. In studies where a significant association between PSF and lesion site was reported, fatigue was usually assessed within the first few months after stroke, and the associations were found with specific brain structures, such as brain stem or basal ganglia.16,24–28 In contrast, in studies which reported no association, fatigue was often assessed during a later stage after stroke, and lesion site was classified more broadly as anterior or posterior circulation or by the affected hemisphere.13,20,29–33Among 10 studies which investigated the association between stroke severity at admission (a surrogate marker of stroke lesion size, usually measured by scales for neurological deficits) and follow-up fatigue, 8 studies (n=1502) found no significant association.16,24,26,29,31,32,34,35 Although another 2 studies (n=159) found an association between stroke severity at admission and fatigue within 6 months after stroke, this association was confounded by the effects of depression and anxiety.18,33Affective FactorsA systematic review reported a strong association between PSF and depressive symptoms (19 studies, 6712 patients; pooled odds ratio=4.14; 95% confidence interval, 2.73–6.27) and a trend toward an association between PSF and anxiety (4 studies, n=3884; pooled odds ratio=2.34; 95% confidence interval, 0.98–5.58).36 Furthermore, two longitudinal studies (n=204) reported that baseline depression and anxiety were both associated with follow-up fatigue.19,37 Finally, another study (n=108) found cross-sectional associations between PSF and depression and anxiety at both 2 months and 18 months and reported that depression and anxiety at 2 months were both independent predictors of fatigue at 18 months.16Other AssociationsIn addition to pre-stroke conditions, stroke lesions, and affective factors, we have identified several other factors associated with PSF. However, for some of these factors, there is limited data with which to claim a causal relationship with PSF, and some of these studies are of small sample size.Biological FactorsAssociations between PSF and inflammatory biomarkers were investigated in small studies. Associations were found with cytokines38 but not with cortisol18 or C-reaction protein.39 One study (n=45) found neuroendocrine changes within 3 days after stroke were associated with fatigue at 12 months but not 18 months.40Physical ImpairmentsSix studies (n=1295) found a cross-sectional association between PSF and residual neurological deficits or perceived disability during the acute phase to several years after stroke.20,24,29,35,41,42 One study (n=108) reported that physical impairments at 3 months after stroke were associated with fatigue 1 year later.37 Furthermore, 2 studies (n=217) found a significant association between disability and fatigue within 6 months after stroke, but this association was no longer significant at 1 year after stroke or after controlling for the effects of depression and anxiety.16,18Cognitive ImpairmentsEight studies (n=1184) investigated the association between PSF and global cognition (measured by the Mini-mental State Examination), but none found a significant association.15–17,24,29,30,34,43 However, one study (n=109) found a cross-sectional association between PSF and attentional deficits at both 6 months and 12 months18 and another study (n=108) reported that baseline cognitive impairments (including attentional deficits) was associated with fatigue 1 year later.37Psychosocial FactorsIn addition to the affective factors discussed in the previous section, some other psychosocial associations of PSF were reported. One study (n=167) reported that locus of control directed to significant others was an independent baseline predictor of fatigue 1 year after stroke.15 Cross-sectional associations were found between PSF, and both lower level of self-efficacy of managing chronic diseases (one study, n=77)44 and lower level of social support (one study, n=46)45 in patients 6 months after stroke.Behavioural FactorsTwo studies investigated the association between PSF and coping patterns. A cross-sectional study (n=50) found that higher level of fatigue at 3 months after stroke was positively associated with emotional-oriented coping and negatively associated with task-oriented coping.33 A longitudinal study (n=108) reported that patients using passive coping at baseline were more likely to have fatigue 1 year later.37Two cross-sectional studies investigated the association between PSF and physical activity. One (n=84) found that higher level of fatigue was associated with less standing and stepping but more sitting and lying during the day in patients 1 month after stroke.46 Another (n=32) found no significant difference in scores of daily activities between fatigued and nonfatigued patients 3 months after stroke.47Other SymptomsFive studies investigated the association between PSF and sleep problems, of which 4 (n=937) found a cross-sectional association between PSF and the presence of sleep disturbances (eg, insomnia or frequent wakening during night).15,22,29,43 One study (n=115) found an association between poor sleep quality and higher level of fatigue.21 Sleep apnoea is common after stroke, but no study has directly investigated its association with PSF, apart from a small study (n=32), which used a scale of daytime sleepiness to evaluate symptoms of sleep apnoea and found the mean scores were not different between patients with and without PSF.47Five studies investigated the cross-sectional association between PSF and pain: 2 (n=4044) found an association2,22 and the other 3 (n=362) did not.29,44,47Potential Mechanisms of Post-Stroke FatigueBiological Mechanisms for Early FatigueAssociations between PSF and inflammatory biomarkers, neuroendocrine changes, and attentional deficits were found in small studies in stroke. Together with the findings that stroke lesions at certain brain structures are associated with fatigue, a brain generator mechanism of cancer-related fatigue may apply to PSF where structural damages and consequent neuroendocrine changes of the reticular activating system might impair the ability to maintain attention and induce fatigue.6 However, this mechanism may only apply to early but not late fatigue after stroke. Ormstad and colleagues observed that the relationship between fatigue and cytokines found at 12 months disappeared at 18 months, whereas fatigue itself and depressive symptoms had not declined by this time. Thus, they speculated that psychosocial factors had contributed to sustained fatigue.38 This hypothesis was supported by Passier and colleagues who reported that in a subgroup of stroke survivors without physical or cognitive impairments, baseline depressive symptoms, anxiety, and passive coping were associated with follow-up fatigue.37Psychosocial, Behavioral, and Physical MechanismsPsychosocial and behavioral mechanisms of fatigue were reported in studies of chronic fatigue syndrome8 and multiple sclerosis.9 In this review, people with pre-stroke fatigue14,20,21 or those with pre-stroke depression22 were more likely to have fatigue after stroke, suggesting that they were already vulnerable to fatigue before stroke. Locus of control and self-efficacy are potential predisposing factors for PSF, and once fatigue develops, they may play a role in maintaining fatigue. There is robust evidence for the causal effects of depressive symptoms and anxiety on both early and late fatigue. Coping patterns, physical activity, and social support may be associated with both early and late fatigue, but there is limited data to illustrate a causal direction. Furthermore, residual neurological deficits or physical disability may maintain PSF over time,20,24,29,35,41,42 although this association may be confounded by psychological factors.16,18Pain and Sleep ProblemsThe interaction of sleep problems, pain, and fatigue has been reported in cancer studies.10 In stroke studies, PSF is associated with disturbed sleep patterns; however, the association between PSF and pain is inconclusive across studies, although pain is common after stroke and could coexist with fatigue in one third of stroke survivors.22Conceptual Model for Post-Stroke FatigueBy drawing on literature of fatigue in other conditions alongside evidence from stroke studies, we propose a conceptual model of PSF (Figure 2). In this model, stroke lesions and related biological factors contribute to early but not late fatigue. Psychosocial and behavioral factors act as predisposing and perpetuating factors for PSF. Residual neurological deficits may influence PSF through the effects of psychological factors.Download figureDownload PowerPointFigure 2. A conceptual model of poststroke fatigue. The unidirectional arrows indicate a causal direction; the bidirectional arrows indicate unknown direction of the association; the dotted arrows indicate potential interactions between factors. Other symptoms may coexist with and maintain symptoms of fatigue.This model was based on the current available evidence from stroke studies. It is limited in that it may not cover all associations of PSF and other factors may be identified in future. Furthermore, there are limited data for some factors in the model. Future studies should therefore explore the temporal relationship and causal directions between PSF and each of these factors. Finally, some factors in the model may interact with each other. For example, the association between PSF and anxiety may be confounded by the effect of depressive symptoms.36 Also some patients reported that the lack of external support would complicate their coping process and invoke emotional distress.48 Such interactions need to be clarified in patients with PSF.Implications for Treatment of Post-Stroke FatigueThis review identified several factors associated with PSF (Figure 2). Some of these factors are reversible and might be targets for treatment in PSF.Early fatigue after stroke may be associated with damage to brain structures and neuroendocrine systems responsible for maintaining attention and wakefulness. Neuroendocrine regulators, for example, Modafinil49 and (−)-OSU616250, have been tested for PSF in small studies and exhibited tolerance in stroke survivors. Their efficacy needs to be investigated in randomized controlled trials and compared between patients with fatigue at early and later stages after stroke.Psychosocial and behavioral factors may play an important role in triggering and maintaining fatigue symptoms. Although depressive symptoms have a direct effect on PSF, antidepressants showed no effect on reducing fatigue after stroke.51,52 One possible explanation is that PSF is a complex symptom that is influenced by different factors, and there are interactions between these factors. Complex interventions targeting these psycho-behavioral factors are effective in treating fatigue in other conditions53,54 and have shown feasibility in small studies with stroke survivors.55,56 Furthermore, a randomized controlled trial reported that the combination of cognitive–behavioral therapy (a psychotherapeutic approach which addresses emotional dysregulation, unhelpful behaviors, and cognitive processes) and graded activity training (COGRAT) was more effective than cognitive–behavioral therapy alone in treating PSF.57 However, the specific effect of either graded activity training or cognitive–behavioral therapy on PSF cannot be established because the trial did not include a usual medical care group. Therefore, effectiveness of psychological interventions and physical training on PSF should be investigated in future trials.ConclusionFatigue is a common and distressing symptom in stroke survivors. Although early fatigue may be triggered by biological factors, late fatigue may be more attributable to psychological and behavioral factors. Prospective longitudinal studies are expected to clarify the temporal relationship and causal direction between PSF and these factors. Complex interventions targeting these psycho-behavioral factors are effective in treating fatigue in other conditions, and feasibility studies are promising in stroke survivors. Further studies are needed to test the efficacy of these interventions for PSF.DisclosuresS. Wu is funded by the China Scholarship Council/University of Edinburgh Joint Scholarship. G. Mead received grant funding on exercise and fatigue after stroke, honoraria from a book, and lectures and expenses for conference speaking on these topics. T. Chalder is supported in part by the National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, Kings College London. T. Chalder receives royalties for self-help books on fatigue. The other author reports no conflicts.FootnotesThe online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.006647/-/DC1.Correspondence to Trudie Chalder, PhD, Department of Psychological Medicine, Weston Education Centre, King’s College London, Cutcombe Road, London SE5 9RJ, UK. E-mail [email protected]References1. Choi-Kwon S, Kim JS. Poststroke fatigue: an emerging, critical issue in stroke medicine.Int J Stroke. 2011; 6:328–336. doi: 10.1111/j.1747-4949.2011.00624.x.CrossrefMedlineGoogle Scholar2. Glader EL, Stegmayr B, Asplund K. 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