Fatigue After Stroke

SPECIAL REPORT

Fatigue after stroke

PJ Tyrrell Fatigue is a common symptom after stroke. It is not invariably related to stroke severity & DG Smithard† and can occur in the absence of depression. It is one of the most troublesome symptoms for †Author for correspondence many patients and yet nothing is known of its causation. There are no specific treatments. William Harvey Hospital, Richard Steven’s Ward, This article assesses the available literature in the context of what is known about fatigue Ashford, Kent, in other disorders. Post-stroke fatigue may be a manifestation of sickness behavior, TN24 0LZ, UK mediated through the central effects of the cytokine interleukin-1, perhaps via effects on Tel.: +44 123 361 6214 Fax: +44 123 361 6662 glutamate neurotransmission. Possible therapeutic strategies are discussed which might be [email protected] a logical basis from which to plan randomized control trials.

Following stroke, approximately a third of common and disabling symptom of Parkinson’s patients die, a third recover and a third remain disease [7,8] and of systemic lupus [9]. More than significantly disabled. Even those who recover 90% of patients with poliomyelitis develop a physically may be left with significant emotional delayed syndrome of post-myelitis fatigue [10]. and psychologic dysfunction – including anxi- Fatigue is the most prevalent symptom of ety, readjustment reactions and depression. One patients with cancer who receive radiation, cyto- common but often overlooked symptom is toxic or other therapies [11], and it may persist fatigue. This may occur soon or late after stroke, for years after the cessation of treatment [12]. It may be completely debilitating, and does not also occurs following infectious disease, classi- seem to be related to stroke severity [1,2]. Fatigue cally infectious mononucleosis, and can persist may have significant effects on quality of life for years following diagnosis [13]. (QoL) and affect the chance of a patient return- ing to work [3]. Despite this, it is rarely men- Fatigue after stroke tioned in the stroke literature. For example, it is Fatigue after stroke is a common phenomenon – not referred to in the National Stroke many patients describe it as the most difficult Guidelines [101] and there is scant reference to it symptom that they have to cope with [3]. It is an in one of the most commonly used stroke text- independent predictor of dependence in activi- books [4]. It needs to be recognized by health and ties of daily living and may be associated with social care teams in both primary and secondary higher mortality. It contributes to a decline in care. Warning the patient and their family that QoL after discharge from hospital in some fatigue is a likely consequence of even mild patients with stroke. It may particularly affect stroke is important as it can be a worrisome and those with good physical recovery, impairing or debilitating symptom. even preventing their ability to return to normal life. A qualitative study of young peoples’ experi- Definition of fatigue ences of stroke rehabilitation emphasized the There is no exact definition of fatigue because of negative effect of fatigue on their attempts to its inherent subjectivity. It may usefully be return to normality [14]. A further qualitative described as difficulty initiating or sustaining study of older stroke patients concluded that voluntary activities [5]. It occurs in response to fatigue significantly affected performance in a activities requiring a sustained effort, or as a pri- variety of activities as well as their [15] Keywords: fatigue, mary state associated with a sense of near-con- independence . interleukin-1, stant exhaustion which differentiates it from the Depression is associated with fatigue (indeed proinflammatory cytokines, universal experience of intermittent tiredness. it is a component in most depression scales) sickness behavior, stroke but is not a prerequisite for it. In a study of Fatigue in medical conditions patients following stroke, 51% of stroke Fatigue is a common feature of many chronic patients compared with 16% of controls expe- disorders. Two-thirds of patients with multiple rienced severe fatigue, while 20 and 16% had Future Drugs Ltd sclerosis report excessive fatigue [6]. It is a elevated depression scores respectievly [1]. At

15 months post-stroke 57% of 220 patients of physical and/or mental tiredness (where studied had post-stroke fatigue – a significant 0 = none, 1 = mild/moderate and 2 = severe) [21]. proportion reported fatigue prior to the The Health-Related QoL scale (HR-QoL) has a stroke [16]. At 3 to 13 months after stroke, subscale for vitality which assesses fatigue [19]. Ingles found fatigue without depression in One stroke-specific QoL measure has been 39% of patients [17]. Even 2 years after stroke developed with input from patients – this the incidence of fatigue remained high. A total includes a fatigue subscale consisting of three of 10% of responders to the question ‘Do you questions [24]. feel tired?’ responded ‘always’ and 29.2% A number of scales have been developed for ‘sometimes’, 2 years after stroke [18]. Risk fac- the assessment of fatigue in other disorders, par- tors for post-stroke fatigue in this study ticularly in cancer [25–27]. Some scales test general included increasing age and pre-stroke morbid- fatigue [28], others mental [29] or physical fatigue ity. Fatigue was a predictor for worse outcome, (e.g., the fatigue subscale of the Checklist Indi- including more dependence in activities of vidual Strength used in Van der Werf’s study). In daily living and worse general health, inde- post-stroke fatigue there are likely to be a pendently of depression. It was also a predictor number of contributing factors which are both for death independently of depression and physical and psychologic. A multidimensional other predictors of survival. instrument is therefore probably required [30]. Functional outcome using the health-related An international classification of diseases QoL score (SF36) shows deterioration in QoL (ICD) criteria set has been developed for the for some domains, particularly emotional ones diagnosis of cancer-related fatigue [102]. These following discharge and for up to 3 years after include physical (general weakness, limb heavi- stroke in another follow-up study [19]. A small ness) and psychologic symptoms (emotional pilot study of 20 patients assessed at a mean of reactivity, perceived need to struggle to overcome 63 days post stroke found that 40% had signifi- activity) which cause clinically significant dis- cant fatigue, which in many cases interfered tress or impairment in social or other function- with their ability to participate in physiotherapy ing. Similar criteria might be useful in post- sessions [20]. stroke fatigue as they are multidimensional and Fatigue following stroke is not necessarily applicable to a group of patients with other associated with severity of physical impairment. physical symptoms. A study of patients with mild stroke (Oxford Handicap Score 0–1) 1 year after stroke found Mechanisms of fatigue fatigue in 72% of patients, with adverse conse- Fatigue is a characteristic symptom of depression, quences for QoL and the ability to self care [21]. and patients may be depressed by fatigue, but it is In patients with subarachnoid hemorrhage who clear from observational studies that post-stroke had made a good neurologic recovery (Glasgow fatigue can exist in the absence of depression. The outcome Score 4–5 at discharge from hospital) frequency of fatigue in physical disorders such as followed up at 3, 9 and 18 months post dis- infections, multiple sclerosis and cancer suggests charge, 58% reported severe fatigue at 3 months that there may be common underlying mecha- and 17% at 9 months, with little improvement nisms. Sickness behavior refers to a coordinated by 18 months [22]. A population-based study of set of subjective behavior and physiologic symp- 232 young adults (15–49 years) at a mean fol- toms that characteristically occur in infection low-up of 6 years after ischemic stroke reported including; fatigue, malaise, nausea, anorexia and fatigue. This was independently associated in aching joints. These symptoms are part of an multivariate analyses with impaired functional organized adaptive survival strategy that allows state (higher modified Rankin score) and with the organism to deal most effectively with infec- basilar artery infarction [23]. tion. The mediators of these changes are the proinflammatory cytokines, particularly inter- Measurement of fatigue leukin (IL)-1. The naturally occurring antagonist The measurement of fatigue after stroke is diffi- of IL-1, IL-1 receptor antagonist (IL-1ra) attenu- cult because of the subjective nature of the symp- ates sickness behavior in experimental models as toms and the difficulties controlling for measured by reduction in social interaction or coexistent physical impairments and depression. food intake [31]. Activation of the brain cytokine One option is simply to ask patients whether system in a noncompromized individual allows they feel tired – for example a three-point scale the organism to respond in a coordinated way to

866 Therapy (2006) 2(6) Fatigue after stroke – SPECIAL REPORT

infectious pathogens. However, there is good defined mechanism, the approach to management evidence to suggest that excessive activation of needs to be general. Some of these treatment the brain cytokine system, for example by the options might be applicable to post-stroke fatigue. cytokines released by cancer cells or induced by chemotherapy and radiotherapy, may be respon- Physical activity sible for many symptoms of cancer including Graded aerobic exercise is associated with fatigue [32]. In other disorders associated with improvements in physical work capacity, and chronic inflammation, central cytokines may also some psychologic and cognitive variables in be responsible for mood disorders and fatigue. patients with chronic fatigue syndrome [42,43]. Multiple sclerosis for example is associated with Exercise training leads to decreased fatigue and brain cytokine changes. Stroke is associated with reduced effort [44]. Significantly lower levels of inflammation [33] and IL-1 is clearly implicated fatigue are found in cancer patients who take exer- in the pathogenesis of damage following cise, although these studies are mainly in patients ischemia. Inflammatory markers are elevated in with breast cancer [11]. Most exercise studied was plasma for some months after stroke [34] and cor- aerobic with walking or treadmill protocols [45]. relate with stroke severity [35]. Activation of brain Patients undergoing radiotherapy for prostate cytokines with a form of sickness behavior may cancer advised to rest if they became fatigued, had be responsible for fatigue after stroke. Proinflam- a significant deterioration in physical function matory cytokines impair astroglial glutamate and a significant increase in fatigue compared uptake and clearance. Glutamate signaling is with an exercise intervention group [46]. Exercise essential for information processing and one might be difficult for stroke patients with physical mechanism suggested through which cytokines disability but chair-based or other suitable exercise might contribute to mental fatigue is through programs could be developed and mobile patients dynamic alterations in glutamate activity [36]. could be encouraged to take up regular exercise.

Imaging in fatigue Rest & sleep In order to determine whether fatigue is associ- It is not known whether additional rest and sleep ated with particular brain regions, a prospective has any effect on fatigue. Patients with cancer magnetic resonance (MR) study would be fatigue report sleep disturbances with poor qual- required in a large number of patients, followed- ity of sleep and stroke patients anecdotally report up to determine the association between regional that they wake unrefreshed from sleep. It would damage and the presence of fatigue. MR spectros- seem likely that good sleep patterns should be copy (MRS) of the brain and muscle has been beneficial and patients can be encouraged to try used in chronic fatigue syndrome showing abnor- to avoid excessive daytime sleeping. mal muscle metabolism in some patients with early intracellular acidosis and changes in regional Cognitive interventions N-acetyl-aspartate peaks [37]. The significance of A brief psychoeducational intervention has been this is unclear but may suggest changes in cell shown to improve outcome in chronic fatigue membrane turnover. Reduced gray matter volume syndrome [47,48] and in the fatigue of infectious has also been found in the prefrontal cortex in mononucleosis [49] and systemic lupus [50]. A chronic fatigue patients [38]. There are a number number of interventions to increase psychosocial of techniques being developed for the imaging of support have been assessed in cancer. These brain inflammation [39,40] which could be of value interventions (support groups, counseling and in determining the role of proinflammatory comprehensive coping-strategy programs) have cytokines in fatigue. MRS techniques can be used tended to demonstrate a reduction in fatigue and to measure regional glutamate concentrations [41]. distress [11]. Simply warning patients and carers If successful, brain imaging could provide a surro- about the likelihood of post-stroke fatigue may gate outcome for therapeutic studies in stroke, also be of benefit. prior to large randomized controlled trials. Pharmacologic interventions Potential interventions in the No specific pharmacologic interventions have management of fatigue shown to be of conclusive benefit in chronic A number of interventions have been proposed for fatigue syndrome [51]. Cancer-related fatigue has the management of fatigue in cancer and chronic been targeted with treatments specific to the type fatigue syndrome. In the absence of a clearly of tumor (e.g., erythropoietin for fatigue in www.future-drugs.com 867 SPECIAL REPORT – Tyrrell & Smithard

cancer-related anemia) and megestrol in breast to reduce the symptoms of sickness behavior. cancer. Psychostimulants have been used in fatigue IL-1ra is undergoing trials in acute stroke [54] associated with HIV-1 infection [52] and multiple and might benefit post-stroke fatigue – other sclerosis [53]. There have been no published trials anti-inflammatory agents might theoretically be in post-stroke fatigue. of value. Pharmacologic treatment of pain, spasticity and poor sleep are important as these affect the Expert commentary & outlook severity of fatigue. Central post-stroke pain Fatigue is common and disabling. The exact typically disturbs sleep and will contribute to prevalence of fatigue in those with stroke is fatigue, therefore appropriate treatment may help. uncertain, but may be as high as 70%. As yet, the However, there are no specific treatments for mechanism is poorly understood and its man- post-stroke fatigue per se. The most logical agement even less so. Pharmacologic agents have pharmacologic approach to post-stroke fatigue been tried in other medical conditions, but as yet would be an agent that acts on IL-1 in the brain none have a license in stroke. At this time, IL-1 would appear to be the most likely mechanism Highlights associated with fatigue, suggesting a possible • Fatigue following stroke is common. therapeutic approach. • Post-stroke fatigue can hinder the patient’s rehabilitation. Further work is required to describe the scale • Post-stroke fatigue may be due to an inflammatory response related to of the problem in all stroke patients irrespective interleukin-1. of age, and randomiszd controlled trials are • The treatment options for post-stroke fatigue are limited. needed to investigate possible therapeutic agents, • Further research is required to accertain prevalence and thus devise such as those that have been tried in multiple appropriate therapeutic managements strategies. sclerosis and IL-1 antagonists.

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