Poststroke fatigue is a common symptom that can have debilitating effects. Moreover, up to 40% of stroke survivors report it as their worst or one of their worst symptoms.1,2 This increasingly recognized symptom has been reported to have a prevalence that varies widely.3,4 Whereas, a systematic review and meta-analysis found marked variabilities in estimates of poststroke-fatigue prevalence, ranging from 25% to 85%.2 This wide variability across studies has been attributed to the multifactorial features underlying fatigue, the varying times of assessment, and the methodological differences among studies including assessment techniques and diagnostic cut offs-used. A recent study has concluded that the Fatigue Severity Scale can be reliably used for diagnosis of poststroke fatigue, although it lacks specificity.5 Moreover, patient characteristics may be associated with differences in poststroke fatigue prevalence.
Low fatigue prevalence has been reported in Asian populations that have different epidemiologies of stroke, due to younger age and a high incidence of hemorrhagic stroke; however, these 2 variables have not been clearly associated to low fatigue prevalence. Cumming et al2 hypothesized that a more generalized cultural difference in psychosocial factors might contribute to fatigue.
The aims of this narrative review were (1) to provide an overview of current literature on the definitions, clinical characteristics, time courses, influences on clinical outcome, causes and treatments of poststroke fatigue; (2) to summarize these findings, discuss and suggest existing conceptual models, and highlight controversial issues on poststroke fatigue; (3) to propose steps that could better explain the underlying pathophysiology of poststroke fatigue.
Definition and Clinical Characteristics
A proposed definition of poststroke fatigue is a self-reported perceived lack of physical or mental energy that interferes with daily activities.6,7 Clinical characteristics of poststroke fatigue have been reported to include self-control and emotional instabilities, reduced mental capacity, as well as a reduction in energy needed for daily activities.8
Poststroke fatigue is generally qualitatively different from fatigue experienced before stroke, as the former can be exacerbated by stress and physical exercise, and generally responds well to rest and adequate sleep.9 This type of poststroke fatigue, commonly known as exertion fatigue, is experienced typically after intense physical exertion or use of mental effort. It is manifested in the early phase of poststroke as acute episode, with a rapid onset, short duration, and short recovery.10–12 The other type of poststroke fatigue is chronic fatigue, manifesting in the late phase of poststroke, and characterized by mental and psychological symptoms; the former appears with cognitively demanding tasks, whereas the latter is associated with a lack of interest or poor motivation.13 Both types of poststroke fatigue are not considered mutually exclusive, although early fatigue has been reported to be more prevalent in patients after stroke, whereas late fatigue has been reported to be more prevalent in patients with other neurological chronic diseases, including multiple sclerosis.9,14 Tseng et al10 reported aerobic fitness and depression to be strong independent predictors of early fatigue and late fatigue, respectively. The authors suggested that these 2 poststroke fatigue types are distinct.
Time Courses and Influences on Outcome
A prospective study has reported that, at 6 months after stroke, approximately half (51%) of all patients complained of fatigue. Of those reporting early fatigue, 69% continued to report fatigue. Whereas, of those reporting late fatigue, 38% had not experienced early fatigue.15
A Danish study16 analyzing the course of fatigue over a 2-year follow-up after first-ever stroke found the poststroke fatigue level to decrease over the first 3 months from hospital discharge. This result remained unchanged at 2-year follow-up. Conflicting findings have come from a study by Schepers et al17 who reported an increase in the prevalence of fatigue during the first year after stroke. This could be explained by the high prevalence of depression in Schepers’s study, as it could have influenced the time course of fatigue.
Regarding the duration of fatigue after stroke, acute fatigue can last up to 6 months, whereas the chronic type can persist in 40% of patients after 2 years.16 Another study reported fatigue to be still present in one-third of patients up to 6 years after stroke onset.18 The initial level of fatigue is considered the main predictor of increasing fatigue over time.19
Several studies have reported poststroke fatigue to be an independent predictor of shorter survival,20,21 institutionalization,20,22 poorer functional outcome,16,23 and greater dependency for activities of daily living along with instrumental activities of daily living.24 Moreover, in young patients, poststroke fatigue has been reported to be a determinant to resuming work, independent of physical disability or cognitive deficit.25 In addition, in patients aged 18 to 50 years, poststroke fatigue has been associated with a poor functional outcome, as assessed by the modified Rankin Scale (odds ratio, 4.0; 95% CI, 1.6–9.6), instrumental activities of daily living (odds ratio 2.2; 95% CI, 1.1–4.6), and impairment in speed of information processing (odds ratio, 2.2; 95% CI, 1.3–3.9) even after almost a decade of follow-up.26
Causes
Several factors have been reported to be associated with poststroke fatigue in a proposed model: predisposing factors (prestroke fatigue or prestroke depression), triggers (brain lesions, stroke-related inflammatory and neuroendocrine changes), and perpetuating factors (affective disorders, residual neurological deficits, cognitive decline, passive coping, reduced physical activity, locus of control, and self-efficacy).7,27
Predisposing Factors for Poststroke Fatigue
Prestroke Conditions
Several studies have reported conflicting results on whether prestroke fatigue and prestroke depression are associated with both early and late fatigue after stroke because of their small sample sizes and the fact that prestroke fatigue was assessed retrospectively.22,28–31 Other prestroke conditions that might influence the onset of poststroke fatigue include cognitive impairment, lower level of social support, passive coping patterns,7 as well as sleep problems such as insomnia, frequent wakening, and apnea.17,29,32–35
Trigger Factors
Stroke Type, Stroke Side, and Stroke Location
Associations between fatigue and stroke topography remain unclear. Several studies have reported no significant relationships between fatigue and stroke location or fatigue and stroke type.1,8,16,17,20–22,32,36–39 One study has reported a relationship between the number of strokes and fatigue, reporting a lower level of fatigue for patients who had a first stroke, compared with those who had recurrent strokes.20 Regarding pathological type of stroke and fatigue, few studies have concluded that fatigue is more severe after ischemic stroke than after intracerebral hemorrhage.40 In a study including patients with minor stroke, there was no observed correlation between infarct type and location and fatigue severity, except for a tendency toward left parietal lesions.38 However, Tang et al41 found fatigue after stroke to be associated with acute infarcts in the basal ganglia and internal capsule detected on magnetic resonance imaging, whereas Snaphaan et al42 observed that fatigue after stroke was more common in patients with infratentorial lesions detected on either computed tomography or magnetic resonance imaging. Regarding the latter finding, 2 other studies have reported a relationship between fatigue and lesions in the posterior circulation territory: either brain stem or thalamic stroke in 1 study43 and basilar artery infarction in the second study.37 A later study39 reported that patients with posterior circulation syndrome had higher fatigue scores than those with other stroke subtypes. Some authors have hypothesized that damage to the ascending reticular activating system in the brain stem may lead to mild impairment in arousal, changes in attention, and subsequent development of fatigue.44 Other authors have suggested that the disruption of serotoninergic pathways in the brain stem might be a potential mechanism of fatigue after stroke.45
It has been suggested that the more appropriate method for investigating association between brain lesions and poststroke fatigue is functional magnetic resonance imaging. This is because it better permits to visualize any connections between functional cortical networks and fatigue compared with other currently available diagnostic exams.46,47
Biological Factors
Stroke induces a systemic inflammatory response that triggers comorbidities of which fatigue is a predominant symptom, but the association between inflammatory biomarkers and poststroke fatigue has been investigated in only a few small studies.48 In one of these studies, a positive correlation between acute IL (interleukin)-1β levels and fatigue 6 months after stroke was observed, whereas IL-1ra and IL-9 levels negatively correlated with fatigue at 12 months.49 From other studies, only one reported CRP (C-reactive protein) levels to be associated with fatigue.45
Serum thyroid-stimulating hormone (TSH) levels have been reported to be negatively associated with the risk of poststroke fatigue in all its phases.50 Furthermore, Choi-Kwon51 reported an association between poststroke fatigue and a genetic polymorphism involving the promoter region of MAO-A (monoamine oxidase), suggesting a serotoninergic involvement in the manifestation of poststroke fatigue.
Perpetuating Factors
Affective Disorders
A strong relationship between depression and poststroke fatigue has been described, and the presence of fatigue indeed constitutes one of component in many depression scales.44 Moreover, depression is widely recognized as one of the most critical concomitant poststroke symptoms associated with fatigue, making it difficult to differentiate between them as independent conditions. Spalletta et al52 included 200 patients with first-ever stroke surveyed for depression at 3 months. Scores for fatigue or loss of energy tended to be significantly higher among those who were diagnosed with a depressive disorder, compared with those without depressive disorder. Similar findings were reported by a study53 where reduced appetite, psychomotor retardation, and fatigue independently contributed to poststroke depression. Likewise, a relationship between depression and high levels of fatigue has been reported in several other studies.17,20,24,37,47,54 Carlsson et al8 concluded that the odds ratio for having fatigue 1 year after stroke in the presence of depression was 3.2 (95% CI, 1.7–6.0). However, poststroke fatigue can also occur in the absence of depression, with the latter found to be independent of fatigue in stroke survivors.1,22 van der Werf et al55 found that only 38% of patients with severe fatigue were also depressed. Ingles et al1 reported similar findings, with 29% of patients having both symptoms.
Cognitive Impairment
Cognitive deficit has been reported to worsen fatigue after subarachnoid hemorrhage56,57 and brain injuries. Few studies have investigated an association between cognitive impairment and poststroke fatigue with conflicting results. Of these, a review of 11 studies stated that 4 studies found significant correlations between fatigue and memory, attention, speed of information processing, and reading speed, whereas the remaining seven failed to do so.58 Additionally, a quality of life subanalysis of data from the International Stroke Trial reported that a worse mental health score and worse emotional role function measured with Short Form 36 were independently associated with poststroke fatigue.21 Conversely, a long-term study37 reported no association between fatigue and cognitive impairment, but the results could be explained by the fact that the authors used only the Mini-Mental State Examination, which does not assess attention or executive function. Another study reported an association between poststroke fatigue and cognition but indirectly via depressive symptoms.59
Regarding neuroradiological findings associated to cognitive decline, a study suggested that severe leucoaraiosis on computed tomography was predictive of developing fatigue 1 year after hemorrhage.60 Likewise, Naess et al33 have reported that the presence of damage to the white matter on computed tomography was independently associated with poststroke fatigue in patients with ischemic or hemorrhagic injury. These aforementioned findings support the hypothesis, yet to be tested, that neuroanatomical changes may underlie the development of fatigue.
Motor Recovery and Residual Disability
Patients who do not make a full recovery are significantly more likely to be fatigued than those who do. In fact, fatigue has been associated with poorer lower limb motor function.59 However, in patients with excellent neurological and neuropsychological recovery, as in patients with minor stroke or transient ischemic attack, poststroke fatigue may be the only persisting sequela and may severely limit a full recovery. Even if the prevalence of fatigue after a minor stroke is usually higher than after transient ischemic attack, it can also be present after a transient neurological deficit. In the latter case, the influence of additional depressive and anxious factors on the impact of fatigue should be addressed.44 However, Winward et al61 have described that patients with minor stroke experienced significantly higher levels of fatigue at 6-month follow-up than those with transient ischemic attack; this difference was independent of measured potential confounders for fatigue, including anxiety, depression, recent life events, relevant blood tests, and medication. Accordingly, excess of fatigue in patients with minor stroke may be causally correlated to cerebrovascular events. Although fatigue can be associated to increased physical efforts due to severe neurological deficits, poststroke fatigue with little or no motor deficit can indicate that, compared with transient ischemic attack patients, it is most likely attributable to central mechanisms.
Functional neuroimaging studies have reported that physical activity is associated with activation of the prefrontal brain, as well as the insula and anterior cingular cortex.62 In fact, these areas have been implicated in the development of tiredness after stroke.63 One plausible model for poststroke fatigue is that reduced physical activity after stroke leads to physical deconditioning and in turn exertional fatigue, which then is responsible for the avoidance of physical activity, contributing to the development of chronic fatigue.64
There are multiple underlying mechanisms by which exercise may minimize poststroke fatigue: it can increase cerebral blood flow by activating the sympathetic nervous system, whereas, on a molecular level, it is thought to modulate the functioning of neurotransmitters, which have been suggested for their role in the development of fatigue.65,66
Psychosocial and Behavioral Factors
Psychosocial factors, such as a locus of control directed to significant others, a lower level of self-efficacy, a lower level of social support,17,67,68 as well as behavioral factors, including emotional-oriented coping and passive coping,35,56,69,70 have been suggested as ulterior perpetuating risk factors for poststroke fatigue.
Other Associated Factors
Age
The role of age as a contributing factor underlying poststroke fatigue has yet to be fully determined. A study by Lerdal et al19 has suggested that advanced aging is correlated to increased risk of fatigue after stroke. Likewise, this finding was also suggested by Mead et al.21 Conversely, Snaphaan et al42 have reported an increased risk of fatigue in younger patients with stroke.
Sex
Several studies on fatigue comparing sex have reported higher incidences of fatigue among women, compared with men.71–73 This result could be explained by endocrine and stress-related factors. However, regarding poststroke fatigue, there remains conflicting evidence on whether there truly exists an association between sex and poststroke fatigue.1,21,32,37,39,42
Headache
Poststroke fatigue has been associated with poststroke pain, whereas there is a paucity of literature to support a possible correlation between poststroke fatigue and poststroke headache.74 One study reported that poststroke fatigue was a risk factor for headache at 6 months after stroke40; Lai et al74 suggested to enter persistent poststroke headache as a new entry in the International Classification of Headache Disorders. In light of this, it is plausible that treatment of fatigue should include the treatment of headache if present.
Treatment
Unlike previous investigations that have focused on prevalence, correlates, effects, and measurements, investigations on possible treatment approaches of poststroke fatigue have been limited. In fact, a recent Cochrane review has concluded that there is insufficient evidence to support any pharmacological or nonpharmacological intervention for the treatment of poststroke fatigue.76 Despite this, a multidisciplinary approach is usually adopted based on the conceptual model of Wu et al7 with an emphasis on predisposing, triggers, and perpetuating factors (Table).
| Factors Associated With Poststroke Fatigue | Interventions |
|---|---|
| Predisposing factors | |
| Symptomatic sleep apnoea syndrome | CPAP77 |
| Other sleep disorders | Physical activity78 |
| Pain | Analgesics and/or chronic treatments |
| Triggering factors | |
| Biological | Modafenil80 |
| Perpetuating factors | |
| Affective disorders | Antidepressants*81,82 |
| Psychosocial counselling, problem solving sessions, motivational interviewing and cognitive behavioural therapy83,84 | |
| Cognitive impairment | A combination of a graded activity training program and cognitive-behavioural therapy (a psychotherapeutic approach which addresses emotional dysregulation, unhelpful behaviours, and/or cognitive processes)83,84,96 |
| Residual disability | Graded physical activity programs89–92 |
| Psychological and behavioural | Group education programs (sleep hygiene, relaxation exercise, physical exercise education, nutrition and mood)95,96 |
| Improvements to the rehabilitation environment97–100 | |
CPAP indicates continuous positive airway pressure.
*
But with a risk of side effects.
Interventions on Predisposing Factors
Sleep apnea has been frequently diagnosed in patients with poststroke fatigue. However, an improvement in sleep-disordered breathing with a continuous positive airway pressure does not seem to be effective in relieving poststroke fatigue, unless accompanied by symptomatic sleep apnea syndrome.77 Moreover, Shepherd et al78 reported that more time spent on physical activity, lead to increased sleep quality for stroke survivor. Furthermore, treatment of pain may improve poststroke fatigue because it tends to allow participation in exercises and, therein, improves on mood disturbances related to pain.79
Interventions on Trigger Factors
Modafinil, a neuroendocrine regulator and wakefulness-promoting agent that stimulates monoaminergic pathways with neuroprotective properties, has been reported to significantly reduce poststroke fatigue and improve quality of life,80 without significant adverse events. However, this trial recruited patients ≥3 months poststroke, not in the more acute phase of poststroke fatigue.
Interventions on Perpetuating Factors
Regarding interventions on affective disorders, antidepressants that are commonly used to treat poststroke depression, such as fluoxetine, citalopram, duloxetine, and sertraline have not been reported to improve poststroke fatigue, despite some beneficial effects concerning concomitant emotional disturbances.54,81 These findings suggest that depression and fatigue may be 2 distinct impairments for stroke survivors. However, antidepressant or counseling may address the mental aspects of fatigue.79 A Cochrane review of 16 randomized clinical trials reported that the use of certain antidepressants (13 trials) led to significant improvements in depressive symptom but increased side effects including gastrointestinal and central nervous system symptoms.82
Nonpharmacological treatments for poststroke depression have been less studied. The aforementioned Cochrane82 reported no significant difference between the investigated psychotherapy and control groups. Subsequently, 3 out of 4 randomized clinical trials assessing the efficacy of the psychosocial intervention in poststroke depression reported favorable results when psychosocial counseling, problem-solving sessions, motivational interviewing, or cognitive behavioral therapy were made available.83 Similarly, Wu et al84 developed a manualized psychological intervention for poststroke fatigue, based on a cognitive behavioral therapy that was acceptable to stroke patients and was feasible in the local health service.
Regarding interventions on motor recovery and residual disability, observational studies of stroke patients have reported that physical activity is generally low after stroke; most patients are inactive during their hospital stays in both acute and rehabilitation wards, spending up to 74% of their day sedentary.85–88 Graded physical activity programs have been suggested for their contribution to the treatment of poststroke fatigue. This is based on the fact that exercise improves both physical and functional outcomes and therein reduces fatigue, as has been reported for medical conditions including cancer and multiple sclerosis.89–92
Interventions seeking to target psychological and behavioral factors seem to be effective in treating fatigue.93,94 Therein, similar cognitive strategies might also be beneficial for poststroke patients as well. A pilot study95 suggested that a group education program, made up of fatigue management strategies, sleep hygiene, relaxation exercise, physical exercise education, nutrition, and mood, significantly improved poststroke fatigue symptoms. Furthermore, the results from a randomized controlled trial indicated that a Cognitive and Graded Activity Training, a combination of a graded activity training programme and cognitive behavioral therapy (a psychotherapeutic approach which addressed emotional dysregulation, unhelpful behaviors, and cognitive processes) over a 12-week period led to a greater reduction in persistent poststroke fatigue, compared with cognitive therapy alone.96 Moreover, the environment is thought to play an important role in promoting physical activity after stroke. Specifically, a recent study has reported that stroke survivors spent less time sitting and more time standing and walking in their first week at home than in the final week of hospital-based rehabilitation.97 In fact, a home environment may provide more opportunities for activities of daily living.98 Moreover, many patients report disturbed sleep while in hospital that can increase fatigue. This finding suggests that changes to the rehabilitation environment are needed to reduce this influencing factor on poststroke fatigue: communal areas promoting more time spent upright, regular access to fresh air, a home-like environment, good personal attention, as well as access to communicative vehicles, such as television, internet, and ward activities.99,100
Concluding Remarks and Future Perspectives
Fatigue is a multidimensional, distressing and increasingly reported phenomenon in stroke survivors. The cause of poststroke fatigue is highly complex and pathophysiology largely unknown. Moreover, there are difficulties in appropriately characterizing it due to an appreciation of methodological problems, and the fact it has symptoms common to post stroke depression. Several factors are generally recognized to be associated with its onset and progression. Early poststroke fatigue may be triggered by biological factors, whereas late fatigue may be more attributable to psychological and behavioral factors. The currently proposed management strategies for poststroke fatigue reflect its multifaceted nature. What seems to be required is a multidisciplinary approach, including pharmacological and nonpharmacological treatments specifically targeting physical and psycho-behavioral factors, as well as a greater emphasis on improving in-hospital modifiable factors.
Regarding future perspectives, recent investigations provide indirect evidence that pathological fatigue might be a disorder of sensory attenuation in neurological conditions. Specifically, using transcranial magnetic stimulation, a study reported that the overall excitability of cortical motor pathways, both the motor outputs and the inputs that drive motor output, seem to be diminished in patients with poststroke fatigue. Moreover, neural excitability was reported to be partly dependent on spontaneous neuronal firing rates, and reduced neuronal firing rates that were seen immediately after stroke would have, therefore, reduced the excitability of those neurons.101,102 These results suggest that poststroke fatigue was most likely triggered by reduced homeostatic rebalancing of spontaneous neuronal firing rates in the period after stroke, therein, leading to the lowered corticomotor excitability. If confirmed, these results might open the way to improved management strategies for poststroke fatigue.
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© 2019 American Heart Association, Inc.
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Received: 10 January 2019
Revision received: 4 April 2019
Accepted: 8 April 2019
Published online: 14 June 2019
Published in print: July 2019
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Dr Paciaroni received honoraria as a member of the speaker bureau of Aspen, Sanofi-Aventis, Boehringer Ingelheim, Bayer, Bristol Meyer Squibb, Daiichi Sankyo, and Pfizer. The other author reports no conflicts.
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- Technology for Young Adults with Stroke: An Australian Environmental Scan, International Journal of Environmental Research and Public Health, 21, 9, (1254), (2024).https://doi.org/10.3390/ijerph21091254
- Relationships of post-stroke fatigue with mobility, recovery, performance, and participation-related outcomes: a systematic review and meta-analysis, Frontiers in Neurology, 15, (2024).https://doi.org/10.3389/fneur.2024.1420443
- Causal associations of fatigue and functional outcome after ischemic stroke: a mediation Mendelian randomization study, Frontiers in Neurology, 15, (2024).https://doi.org/10.3389/fneur.2024.1415553
- Early poststroke clinically significant fatigue predicts functional independence: a prospective longitudinal study, Frontiers in Neurology, 15, (2024).https://doi.org/10.3389/fneur.2024.1364446
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