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 10.1586/14750708.2.6.865 © 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 2(6), 865-869 865 SPECIAL REPORT – Tyrrell & Smithard 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.