Many patients suffer from fatigue after a stroke. 1 3

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1 Poststroke Fatigue A 2-Year Follow-Up Study of Stroke Patients in Sweden Eva-Lotta Glader, MD; Birgitta Stegmayr, PhD; Kjell Asplund, MD, PhD Background and Purpose Fatigue is common among stroke patients. This study determined the prevalence of fatigue among long-term survivors after stroke and what impact fatigue had on various aspects of daily life and on survival. Methods This study was based on Riks-Stroke, a hospital-based national register for quality assessment of acute stroke events in Sweden. During the first 6 months of 1997, 8194 patients were registered in Riks-Stroke, and 5189 were still alive 2 years after the stroke. They were followed up by a mail questionnaire, to which 4023 (79%) responded. Patients who reported that they always felt depressed were excluded. Results To the question, Do you feel tired? 366 (10.0%) of the patients answered that they always felt tired, and an additional 1070 (29.2%) were often tired. Patients who always felt tired were on average older than the rest of the study population (74.5 versus 71.5 years, P); therefore, all subsequent analyses were age adjusted. Fatigue was an independent predictor for having to move into an institutional setting after stroke. Fatigue was also an independent predictor for being dependent in primary activities of daily living functions. Three years after stroke, patients with fatigue also had a higher case fatality rate. Conclusions Fatigue is frequent and often severe, even late after stroke. It is associated with profound deterioration of several aspects of everyday life and with higher case fatality, but it usually receives little attention by healthcare professionals. Intervention studies are needed. (Stroke. 2002;33: ) Key Words: fatigue follow-up studies outcome Many patients suffer from fatigue after a stroke. 1 3 Fatigue often manifests as both physical and mental lack of energy, and many patients mention fatigue as one of the most difficult sequelae to which to adjust. Fatigue often interferes with the rehabilitation process and impairs the patient s ability to regain functions lost because of the stroke. Poststroke fatigue is still a relatively unexplored condition. Fatigue is also a common symptom in many other chronic diseases such as multiple sclerosis, 4 rheumatoid arthritis, 5 and HIV. 6 It has been hypothesized that fatigue after stroke results from a combination of organic brain lesion and psychosocial stress related to adjustment to a new life situation. 7,8 Other clinical dysfunctions such as sleep apnea may also cause fatigue after stroke. 9 Fatigue is a pivotal component of poststroke depression. 10 However, earlier studies have shown that a patient can experience fatigue without other symptoms that are characteristic of depression. 1 Fatigue accompanying poststroke depression is often relieved when the depression is adequately treated. Less is known about the occurrence of fatigue in the absence of depression, and there is uncertainty about how to manage poststroke fatigue. Self-estimation scales are often used to measure fatigue. Some scales are applicable for several types of fatigue, and some scales measure fatigue caused by a specific disease No scale has yet been developed specifically for poststroke fatigue. Most studies use multidimensional self-estimation questionnaires to measure poststroke fatigue. However, a single-item strategy might be an alternative in mailed questionnaires. Both questions and possible answers have to be easily understandable because the patients have to be able to fill in the questionnaire without help. The objective of this study was to estimate the prevalence of subjective poststroke fatigue in a large general stroke population 2 years after stroke. Previous studies have demonstrated that poststroke fatigue is a serious and frequent problem, but the outcome of these studies might have been biased by selection criteria or relatively small groups. 1,2 The present study tries to avoid this bias by addressing all patients having a stroke in Sweden during 6 months in With this follow-up, we also wanted to evaluate whether patients with subjective fatigue have a worse outcome 2 years after the stroke than other stroke patients. Although depression has been shown to increase the risk of dying after stroke, 16 no previous study has been performed to determine whether poststroke fatigue is associated with an increased risk of dying. Therefore, the case fatality rate of the stroke patients in the 2-year follow-up was studied 1 year after follow-up or 3 years after the stroke. Received October 1, 2001; final revision received December 13, 2001; accepted January 22, From the Department of Public Health and Clinical Medicine, University Hospital, Umeå, Sweden. Reprint requests to Eva-Lotta Glader, MD, Medicine, Department of Public Health and Clinical Medicine, University Hospital, Umeå, Sweden. eva-lotta.glader@medicin.umu.se 2002 American Heart Association, Inc. Stroke is available at DOI: /01.STR D6 1327

2 1328 Stroke May 2002 TABLE 1. Relationship Between Feelings of Tiredness and Feelings of Depression Never Sometimes Often Always n % n % n % n % Never tired Sometimes tired Often tired Always tired Total , P. Materials and Methods Riks-Stroke Register This prospective cohort study was based on Riks-Stroke, the Swedish national register for quality assessment of acute stroke events. The register was started in 1994, and since 1997, almost all hospitals in Sweden that treat acute stroke patients have been participating in Riks-Stroke. The register includes both hemorrhagic and ischemic stroke. Subarachnoid hemorrhages and transient ischemic attacks are optional and were not included in this article. Riks-Stroke Questionnaires Data collection in Riks-Stroke is kept simple to ensure maximum coverage. In short, the register provides information about age, sex, history of previous stroke, and the life situation before the current stroke event. Items related to the acute care and discharge from the hospital are registered. Participating hospitals also report whether the patient was treated in an organized stroke care unit. The criteria for a stroke unit are defined in the Riks-Stroke manual. In the Riks- Stroke program, each patient should be followed up 3 months after the stroke. The 3-month questionnaire describes the life situation after discharge from the hospital in terms of living situation, dependency on help for activities of daily living (ADL), and satisfaction with health care after the stroke. Two-Year Follow-Up The present 2-year follow-up of stroke patients was performed within the framework of a project (Äldreuppdraget, the elderly project ) to map the life situation of elderly people in Sweden that was commissioned by the government for the National Board of Health and Welfare. The aim of this follow-up was to survey the life situation of stroke patients 2 years after stroke. The follow-up was performed by Riks-Stroke in cooperation with the National Board of Health and Welfare. During the first 6 months of 1997, 8194 patients had an acute stroke event that was registered in Riks-Stroke. Earlier estimations have shown that Riks-Stroke covers 70% to 75% of all stroke patients in the country. 17 In October 1999, a follow-up by mail questionnaire was performed on these patients. The average follow-up time was 30.4 months (SD, 1.7 month). To identify those who had died between the 3-month and 2-year follow-up, Riks- Stroke data were compared with national mortality data. The number of patients who had died was 3005 of 8194 (36.7%); 5189 patients were still alive. Response Rate The follow-up questionnaire was sent to 5104 patients. An additional 85 patients were still alive at the time of the follow-up, but their current mailing addresses were not found. The patients received 1 reminder to answer the questionnaire. When the data collection phase was finished, 4038 had sent back the questionnaire. Fifteen patients were not included in the analyses because their identification numbers had been lost. Another 218 patients had not answered the question, Do you feel tired? and were excluded from analyses, leaving 3805 patients (73.3% of all surviving patients). The response rate for all patients who received a 2-year follow-up questionnaire was 78.8%. Approximately half of the patients (52.9%) completed the questionnaire by themselves; for 22.4%, it was completed by a next of kin alone; and for another 24.8%, it was completed with the help of healthcare personnel or someone else. Two-Year Follow-Up Questionnaire The 2-year follow-up questionnaire was based on questions from the 3-month follow-up within the Riks-Stroke program and monitored dependency on help for primary ADL (mobility, toilet visits, and dressing/undressing) and living situation. Additional questions concerning the need for help with primary ADL (eating/drinking and personal hygiene) and secondary ADL (preparation of food, grocery shopping, and cleaning) were included in the follow-up questionnaire. Items on the patients self-perceived depression, fatigue, anxiety, and pain and on their cognitive impairments were also included. Questions about health used in an interview study of elderly in Sweden performed by the National Board of Health and Welfare were included in the questionnaire. To the questions, Do you feel tired? and Do you feel depressed? the patient could choose between 4 possible answers: never, sometimes, often, or always. Patients With Depression Fatigue is often a part of a depression, and Table 1 shows the relationship between feelings of tiredness and feelings of depression. There was a statistically significant association between tiredness and depression. The 153 patients who reported that they always felt depressed and the 65 patients who did not answer the question, Do you feel depressed? were excluded from further analyses, leaving 3667 patients. Patients were divided into 3 categories. Those patients who reported often feeling tired were classified as having moderate fatigue, and patients who indicated that they always felt tired were classified as having severe fatigue. Statistical Analysis Statistical analyses were performed with the SPSS statistical package (version 10.0). 18 Comparisons between proportions were performed by the 2 test. All comparisons were also adjusted for age differences by binary logistic regression with age as a covariable. Age was included as a continuous linear variable. All categorical variables included in the analyses were dichotomized. The multiple logistic regression analyses were performed to adjust for differences in background variables seen at the time of the stroke event. All variables from before the stroke and during the acute care were considered potentially prognostic factors and, after checks for confounding and interactions, were included in the analyses. The multiple models were tested in both a backward and a forward design with the same results. The variables included in the regression models were age, sex, living situation, marital status, dependency in ADL functions, previous strokes, treatment in a stroke unit or in a general ward, stroke subtype, CT examination, and level of consciousness on admission to the hospital. The same strategy was used for modeling survival 1 year after the 2-year follow-up by use of the Cox proportional-hazard model. In analyses of survival, outcome was adjusted for other variables included in the 2-year follow up. Variables included were age, sex, dependency in ADL functions,

3 Glader et al Poststroke Fatigue 1329 TABLE 2. Relationships Between Factors at Onset of Stroke Tiredness 2 Years After Stroke Almost Never or Sometimes Tired (n 2231) Often Tired (n 1070) Always Tired (n 366) Patients,* n n % n % n % P Sex 0.01 Female (58.4) (30.5) (11.0) Male (61.5) (28.7) (9.6) Marital status Married/cohabitant (61.5) (28.6) (9.6) Single (57.9) (30.5) (11.3) Living conditions before stroke At home without social support (62.4) (28.1) (9.4) At home with social support (51.2) (35.1) (12.6) In institution (40.5) (42.6) (16.1) Primary ADL function before stroke Independent (60.8) (28.8) (10.1) Dependent (51.1) (36.1) (12.3) Number of strokes First ever (61.5) (28.4) (9.8) Recurrent (55.1) (32.9) (11.8) Stroke subtype 0.07 Ischemic (64.5) (28.4) (6.9) Hemorrhagic (59.8) (29.6) (10.4) Undetermined (57.8) (30.0) (12.4) Level of consciousness on admission 0.13 Alert (60.6) (29.0) (10.2) Impaired (55.6) (32.4) (11.7) *Information missing for 0 to 100 patients in each item. Age-adjusted percentages are given in parentheses. Probability values are not age adjusted. marital status, speech impairments, estimation of depression, and estimation of general health. Even in models in which age was not a significant predictor of outcome, age was included in the final models to adjust the results for age differences. Missing values were 10% or 10% and were excluded in the logistic regression models. In the Cox proportional-hazard model, missing values were first included in the model as a category of its own belonging to a categorical variable. However, missing values were included in the final model only if they statistically significantly affected the results. Estimates of statistically significant differences were based on odds ratios (ORs) with 95% confidence intervals (CIs). Results Of the 3667 patients who did not always feel depressed at the 2-year follow-up, 366 (10.0%) always felt tired. Another 1070 (29.2%) often felt tired (Table 1). Variables at Stroke Onset Predicting Fatigue at 2 Years The mean age of the 3667 patients included in the analyses at the time of the stroke was 71.8 years. Patients who always felt tired 2 years after the stroke were older at stroke onset than the rest of the patients (mean age, 74.5 versus 71.5 years; P). Table 2 shows that for many of the background variables, there was a statistically significant association between more severe feelings of tiredness and less advantageous initial condition. Thus, fatigue 2 years after the stroke was more common among patients who were single before the stroke, lived in an institution, were dependent on others for primary ADL functions before the stroke, and experienced a recurrent stroke. Stroke subtype was not associated with fatigue, nor was any statistically significant association seen between level of fatigue and whether the patient had been treated in a stroke unit or a general ward. Among patients who had been treated in a stroke unit, 9.9% stated that they were always tired compared with 10.2% among patients who had been treated in a general ward. Results of the 2-Year Follow-Up Two years after the stroke, feelings of always being tired were more common among those patients who, after the stroke, were dependent on help for both primary and secondary ADL and those patients living in an institutional setting (Table 3). Even after adjustments were made for other background variables, there was a statistically significant increase in both primary and secondary ADL dependency with more severe feelings of fatigue. (Tables 3 and 4). When analyses were restricted to patients who lived at home before the stroke, a smaller proportion of the

4 1330 Stroke May 2002 TABLE 3. Living Condition, ADL Function, Speech Impairment, and General Health by Distribution of Fatigue Severity at 2 Year Follow-Up Almost Never or Sometimes Tired (n 2231) Often Tired (n 1070) Always Tired (n 366) Patients,* n n % n % n % Living conditions At home (65.3) (26.6) (8.1) In institution (45.7) (37.5) (16.1) Primary ADL function Independent (71.8) (22.8) (5.3) Dependent (45.6) (37.5) (16.7) Secondary ADL function Independent (78.8) (18.0) (2.9) Dependent (53.9) (33.9) (12.0) Speech No impairments (64.6) (26.9) (8.2) Impaired speech (48.2) (37.2) (14.2) General health Very good or fairly good (74.7) (21.3) (3.9) Fairly bad or very bad (20.1) (51.0) (28.0) *Information missing for 46 to 236 patients in each item. Age-adjusted percentages are given in parentheses. Probability p-values are not age adjusted. Patients who lived at home before stroke. Patients who were independent in primary ADL function before stroke. P patients who were always tired had returned to their own homes (Tables 3 and 4). Self-reported feelings of tiredness 2 years after the stroke were highly correlated to other reported health variables such as estimation of general health (r 0.56, P 0.01), feelings of anxiety (r 0.42, P 0.01), pain (0.39, P 0.01), and depression (r 0.51, P 0.01). Table 3 shows that patients who estimated their general health as fairly bad or very bad also stated that they were more tired. Patients who still had speech impairments 2 years after the stroke reported more fatigue (Table 3). Sensitivity Analyses When both patients who often felt depressed and patients who always felt depressed were excluded, no substantial change in key outcome variables was seen compared with when only patients always feeling depressed were excluded. Always being tired was still an independent predictor for ADL dependency at the 2-year follow-up (OR, 3.68; 95% CI, 2.81 to 4.80). After adjustment for other variables from the 2-year follow-up, severe fatigue was close to reaching statistical significance as an independent predictor for dying within 1 year after follow-up or 3 years after the stroke (OR, 1.48; 95% CI, 0.99 to 2.22). In multivariate analyses with depression as an explanatory variable, severe fatigue was still an independent predictor for being dependent in primary ADL functions (OR, 1.57; 95% CI, 1.13 to 2.17) and for estimating general health as very bad (OR, 4.54; 95% CI, 3.37 to 6.12). Patients Included Compared With Patients Not Included in the Follow-Up Study Patients who were still alive but were not included in the analyses because they had not answered the follow-up questionnaire or were always depressed were on average older than the rest of the patients. Differences between the 3 groups are shown in Table 5. In general, the patients who were not included were more dependent on help before the stroke and at 3 months after the stroke. These patients also more often had impaired consciousness on arrival at the hospital. Case Fatality Rate 1 Year After Follow-Up or 3 Years After the Stroke Event Between the time of follow-up at 2 years and 1 year later (3 years after the stroke event), 297 of the 3667 patients had died. During this period, more patients who were always tired had died (17.3% versus 7.1%, P). This was true even after adjustment for the background variables available at the 2-year follow-up (Table 6). Discussion Riks-Stroke has been shown to cover 70% to 75% of all stroke patients in Sweden. 17 Together with a response rate of almost 80% for the follow-up questionnaire, this study is unique in its coverage of stroke patients in a whole country. The study was designed to include a very large number of patients, many of whom were very old and had severe impairments after stroke. Therefore, a mail questionnaire with simple questions and response alternatives was used. A

5 Glader et al Poststroke Fatigue 1331 TABLE 4. Multivariate Analyses of ADL Function and Living Condition at 2-Year Follow-Up P OR 95% CI Outcome: living in an institution at follow-up Selection: living at home, without community support, before the stroke (n 3242) Age Living alone before the stroke Dependent primary ADL function before stroke Impaired consciousness Cerebral hemorrhage Fatigue at follow-up Often Always Outcome: dependent in primary ADL at follow-up Selection: independent in primary ADL function before stroke (n 3317) Age Men Living condition At home without social support At home with social support In institution Previous stroke Impaired consciousness on admission Stroke unit treatment Fatigue at follow-up Often Always Outcome: dependent in secondary ADL at follow-up Selection: all patients (n 3667) Age Men Stroke unit treatment Dependent primary ADL before the stroke Impaired consciousness on admission Living condition before the stroke At home without community support At home with community support In institution Previous stroke Fatigue at follow-up Often Always single question rather than an extensive fatigue scale was used. In the present study, the prevalence of patients always being tired was 10%, and another 29% were often tired. Most patients with moderate to severe and disabling poststroke fatigue have probably been identified. However, this was done at the expense of specificity, meaning that the prevalence of severe fatigue could have been overestimated. On the other hand, patients who were alive at the time of follow-up but did not respond to the follow-up questionnaire or were always feeling depressed and therefore were not included in analyses were on average older and more disabled before the stroke. This finding indicates that more patients with fatigue probably could be found among those who did

6 1332 Stroke May 2002 TABLE 5. Comparisons Between Responders and Nonresponders in the 2-Year Follow-Up Study Included in Analyses in Follow-Up Study (n 3667) Nonresponders (n 1522) Patients Always Feeling (n 153) n n % n n % n n % P Before stroke Mean age, y Living at home, without community support (89.0) (77.7) (80.9) Living alone (39.1) (50.6) (46.1) Independent of help for primary ADL (91.2) (84.8) (85.5) Previous stroke (22.7) (27.7) (31.6) Cerebral hemorrhage (9.6) (10.4) (11.1) 0.38 Impaired consciousness (10.1) (15.6) (14.2) CT (96.8) (96.4) (98.0) mo after stroke Living at home, without community support (69.2) (51.8) (49.0) Living alone (43.6) (57.4) (54.2) Independent of help for ADL (70.5) (58.1) (46.9) Values for age are mean SD. not return the follow-up questionnaires. This would lead to underestimation of the prevalence of poststroke fatigue. Overall, the prevalence rates presented here seem to reflect reasonably well the situation among survivors 2 years after stroke who are not severely depressed. In a study performed by Ingles et al, 2 the self-reported prevalence of fatigue without depression was 39% at 3 to 13 months after stroke. More than 1 year after the stroke, in a study performed by Van der Werf et al, 1 the estimated prevalence of patients with severe fatigue without elevated depression scores was 30%. These observations closely coincide with our prevalence estimate of 39% who were always or often tired 2 years after stroke. Differences in case-mix and the use of different self-estimation scales to study poststroke fatigue hamper direct comparisons of the prevalence of poststroke fatigue between studies. To define TABLE 6. Multivariate Analyses of Case Fatality 1 Year After 2-Year Follow-Up (3 Years After Stroke Event) P OR 95% CI Age Men Cerebral hemorrhage Dependent primary ADL functions at follow-up Speech impairment Marital status Living together Living alone Missing patients Fatigue Often Always various forms and severity of poststroke fatigue and to help to understand underlying mechanisms, a stroke-specific instrument to measure fatigue is probably needed. 19 Patients with poststroke fatigue were older and had a less advantageous condition before the stroke. As a consequence, they were probably also more tired. The study design did not allow us to differentiate between fatigue already present before the stroke and fatigue debuting after the stroke. However, the most clinically important aspect is to estimate the prevalence of patients feeling tired after the stroke, which also was the aim of the study. Results from the follow-up show that fatigue is associated with a more negative outcome 2 years after stroke even after adjustment for differences in baseline variables and hence preexisting fatigue. This indicates that fatigue also is a consequence of stroke and that this affects outcome. Before stroke, patients who suffered poststroke fatigue were more often living alone or in an institution, more often had impaired ADL function, and more often had a previous stroke. There was also a small female preponderance for poststroke fatigue. The differences were still present after age adjustment. Thus, a group at particularly high risk for poststroke fatigue can be identified. It is possible that many of them actually were fatigued before the stroke occurred. At follow-up, institutional care, being ADL dependent, having a speech impairment, and experiencing a feeling of poor general health were all factors associated with fatigue. The association between fatigue and adverse outcome is probably reciprocal. Impairment in functional ability and general health probably induces a condition with fatigue, and severe fatigue affects functional ability and general health. It seems that poststroke fatigue results from a combination of an organic brain lesion and inappropriate coping with a new life situation after the stroke. Right-hemispheric strokes especially have been associated with fatigue or lack of energy. 8,20 It has been hypothesized that the subjective feeling of lack of

7 Glader et al Poststroke Fatigue 1333 energy is a result of disconnection between the right insula and the frontal lobe or anterior cingulate cortex. 21 Fatigue is associated with other mental and physical consequences of stroke, perhaps most importantly depression. However, as shown in this and previous studies, 1,2 after exclusion of patients with depression, there was still a group of patients with symptoms of fatigue. In sensitivity analyses that also excluded patients who always and those who often felt depressed, fatigue still emerged as an independent predictor for poor functional outcome. Furthermore, in multivariate logistic models with depression as an explanatory variable, fatigue still was an independent predictor for being dependent in primary ADL functions and for perceiving general health as very poor. The close association between depression and poor survival after stroke has been amply demonstrated. 16 We now show, for the first time, that fatigue is also an important predictor for death late after stroke, even after adjustment for depression and other important predictors of survival. It has previously been shown that vital exhaustion, a syndrome of unusual fatigue and loss of energy, increased irritability, and depressive symptoms, increases risk of acute myocardial infarction and other manifestations of coronary heart disease Fatigue in association with other diseases and conditions is treated many different ways, including cognitive behavioral therapy, hydrocortisone, diaminopyrimidine, and psychotropic drugs. 14,25 27 However, in different diseases or medical conditions, different mechanisms probably cause the fatigue, and specific treatments are needed. Clinical trials to find an effective treatment for patients with poststroke fatigue are warranted. Acknowledgments Riks-Stroke is funded by the Swedish National Board of Health and Welfare. We also acknowledge the Swedish Medical Research Council (projects K G A and K P B to Dr Stegmayr). We wish to thank Lennarth Johansson at the Swedish National Board of Health and Welfare for cooperation with the 2-year follow-up of stroke patients. We also wish to thank Ann Staaf for her assistance in organizing data. References 1. van der Werf SP, van den Broek HL, Anten HW, Bleijenberg G. Experience of severe fatigue long after stroke and its relation to depressive symptoms and disease characteristics. Eur Neurol. 2001;45: Ingles JL, Eskes GA, Phillips SJ. Fatigue after stroke. Arch Phys Med Rehabil. 1999;80: Staub F, Bogousslavsky J. Fatigue after stroke: a major but neglected issue. Cerebrovasc Dis. 2001;12: Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ. The impact of fatigue on patients with multiple sclerosis. 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