Being predominantly subjective, it is clearly challenging trying to reliably define and determine clinically significant fatigue, however general consensus describes any symptom as pathological when it is excessive and prolonged, culminating in functional impairment for the person subjected. This has specific importance in the context of an underlying medical condition associated with fatigue, as it may complicate the course of treatment and may well affect recovery of function.

Great attention has focused on fatigue as it occurs in chronic disease and its ensuing impact on patients' quality of life. Studies have examined and recognised its effect in multiple sclerosis, Parkinson's disease, systemic lupus erythematous and cholestatic liver disease, to name a few.1-4 The symptom of fatigue in these conditions is often cited as a common complaint by patients, and remains a challenging entity to the clinician in terms of its recognition and management.

Despite a poor understanding of its genesis, it is evident that if ignored it can have serious functional consequences for patients and impact on their quality of life.

Fatigue in stroke is of particular interest due to growing evidence of its presence as a prevalent symptom for patients; however, relatively little is known regarding factors associated
with its origin, the relevance to post-stroke rehabilitation including management strategies, and its impact on various aspects of daily living.

Stroke and post-stroke fatigue

Stroke is a major health issue, the second commonest cause of death worldwide and leaves a significant number of people dependent on others for their activities of daily living.5 Over the past decade, the dramatic surge in research into elucidating the nature of acute stroke and pioneering treatment strategies, has resulted in what is presently a preventable and treatable disease. However, the under-diagnosis of post-stroke emotional and behavioural disturbances has led to a relatively novel focus of research into these aspects that contribute to functional disability and cognitive impairment. In particular, post-stroke fatigue, the presence of which is linked to institutionalisation, dependency, and higher mortality rate,6-8 is thought to affect a significant proportion of stroke survivors.

Fatigue is often a feature of emotional and behavioural disturbances that occur following a stroke, this is most notable in post-stroke depression.7,9-11 A study in the early 1980s found that a large proportion of patients up to 26 months following a stroke complained of diffuse cerebral symptoms characteristic of depression, including fatigue, poor memory, low mood and difficulty concentrating; fatigue being the most frequently reported symptom impacting on functional ability.12 However, significant advances in our understanding advocate the concept of an independent post-stroke fatigue syndrome.6,9,10,13 This concept encompasses a multifaceted interaction of motor, psychosocial, emotional and cognitive experiences for the patient, thus making it difficult to clinically define and measure.

In 2007, Lynch et al14 proposed a case definition feasible in practice to help detect clinically significant fatigue in both hospital inpatients and community patients post-stroke. This tool has yet to be validated in a larger sample population and across different settings, but is analogous to the definition of fatigue in other neurological disorders; primarily a subjective experience of lack of energy or early exhaustion affecting everyday activities of daily living. For stroke patients, this definition also encompasses the aversion to effort and observable decrement in performance during rehabilitation therapies.

The fundamental element was that whilst fatigue might be associated with depression in some of these patients, a significant majority of those with this syndrome experienced clinically significant fatigue independent to a depressed effect.9,13,15

Depending on the study measure, the population type, and methods of compilation, the prevalence of this post-stroke fatigue syndrome can range between 39% and 72%.6,9,16-20 Glader et al6 conducted a two year follow up study in Sweden determining the prevalence of fatigue amongst long-term survivors to be approximately 39% using a single item strategy in a mailed questionnaire.

This compares to Ingles et al9 who conducted similar research in a smaller community setting and found that 68% of patients complained of fatigue when using the self-report Fatigue Impact Scale. This particular tool remains one of the most widely used tools for reflecting the degree of functional limitation due to fatigue experienced, and is externally validated across a range of chronic conditions. Christensen et al16 were amongst the first to demonstrate fatigue in patients not only in the long-term, but also in the acute phase following a stroke (59% reporting fatigue 10 days after stroke), and suggested a direct correlation between functional outcomes and protracted periods of fatigue.

As the nature of fatigue is predominantly subjective, measuring its impact can be challenging. Many tools exist in aid of estimating the nature and severity of fatigue in different population groups. Point scales and question checklists are the most frequently used measures which attempt to measure the perception and severity of fatigue in everyday life.21,22 The validated Fatigue Impact Scale mentioned above is unique in categorising fatigue in terms of psychosocial, cognitive and physical aspects and rating each on a four-point scale.9,23 There is no guideline for which scale or measure is the most appropriate to be used in the setting of post-stroke fatigue, however the general consensus is that this decision should be guided by the population type and the aspects of fatigue that need to be measured.24 Fewer objective measurements exist and are generally limited in evaluating the multiple dimensions of fatigue; however there is evidence of objective measures being utilised to correlate physical activity with the subjective report of fatigue and in monitoring outcomes post-treatment.25, 26

Current literature reveals inconclusive and often conflicting findings regarding the association of pre-morbid personal variables and post stroke fatigue. Glader et al6 reported an association with increasing age and those who were single whilst other studies have reported no such relationship.9,10, 18,27,28

Similar confliction arose with regards to gender, as some studies reported a higher proportion of fatigue particularly amongst women whereas others report no differences in gender.6,9,10,18,19,27,28 Research will continue to evaluate pre-morbid factors potentially associated, as elucidating any underlying association could support the development of discrete treatment approaches that not only alleviate, but also prevent the development of the fatigue syndrome.

Other factors such as lesion type and comorbidities have also been studied and have provided little evidence of significant linkage to post-stroke fatigue.9 Naess et al10 are the only group to demonstrate higher fatigue scores in relation to a particular lesion type; specifically basilar artery infarction. This is the first study to agree with the preliminary evidence that location of stroke may increase likelihood of fatigue.17 However other studies have refuted a relationship between fatigue symptoms and site of lesion, and currently large prospective studies on this area are lacking.9, 12

Impact of post-stroke fatigue

In both the post-acute and chronic stages, there is good evidence that the extent of physical and mental lack of energy in post-stroke fatigue has a major impact on patients' daily functioning and dependency.8, 17 Of particular note is the hindrance in regaining functions lost as a sequel of the stroke, particularly motor and psychosocial domains.

Consistent findings one year and two year's post stroke have corroborated this and demonstrate the barrier this poses to daily activities, health related quality of life and rehabilitation efforts.6, 18 A postal survey by Ingles et al9 found that out of 68% of patients that reported fatigue, 40% reported this to be the worst of their symptoms. This fatigue was different to any pre-stroke fatigue experienced, affected functioning across a number of activities and was not usually relieved with rest. Given the indisputable burden of this syndrome on stroke patients it is vital that effective therapeutic strategies are identified and directed at prevention and/or limitation of impact.

Treatment

Assessment and treatment of post-stroke fatigue is currently a challenge, and complicated by the presence of other comorbidities and the absence of clear treatment guidelines.

As with any patient presentation, a thorough assessment begins with a review of the patient's history; in this case making particular note of onset, severity, duration and effects of fatigue on activities of daily living. In conjunction with a physical examination, appropriate investigations and possibly an objective assessment of fatigue using one of the scales discussed above will help exclude other conditions and ascertain whether this is indeed pathological fatigue. It also serves to identify potential predisposing factors which can be separated into subcategories of physiological or psychological parameters.25 Physiological factors include: electrolyte imbalances, poor nutritional status, certain comorbidities (eg. renal failure, hypothyroidism, diabetes, anaemia), and importantly a medication review (eg. anticonvulsants, antihypertensives, hypnotics, corticosteroids). Psychological factors include not only comorbid mood disorders such as anxiety or depression, but also the individual's perceived mental or physical effort during activities. In most cases, a multidisciplinary approach is the most effective way forward to eliminate or reduce the impact of these factors. This involves stopping medications that exacerbate fatigue, involving a dietician to help assess and recommend appropriate nutritional adjustments, treating comorbid conditions and correcting any electrolyte or metabolic disturbances. Furthermore, taking steps to reduce chronic pain or stress by addressing sleep pattern, coping strategies, appropriate analgesia and incorporating regular physiotherapy-led exercises will help increase the patient's overall ability to function. Once an effort has been made to identify and manage these impacting factors, therapeutic interventions can then be aimed at the central fatigue characteristic of the post-stroke fatigue syndrome. Current evidence advocates non pharmacological (physical and cognitive tools) and pharmacological treatments as possible interventions.

It was initially presumed that selective serotonin reuptake inhibitors such as fluoxetine, which are helpful in improving fatigue in depressed patients might also be of benefit in post-stroke fatigue. A trial by Choi-Kwon et al29 concluded that fluoxetine was ineffective for post-stroke fatigue but did confirm a reduction in depressive symptoms experienced by the patients. No significant difference was found when fatigue severity scores were compared between those in the placebo group and those taking fluoxetine at six month follow up, but they did observe a 17.5% reduction in the number of patients reporting fatigue in the fluoxetine group compared to 7.5% reduction in placebo group at three months.

A smaller trial by Ogden et al30 looked at Tirilazad, an amino steroid thought to have neuroprotective properties, and noted that five out of nine patients in the treatment arm reported less fatigue at there months compared to all nine patients in the placebo group. It is impossible to draw robust conclusions from these trials due to the small number of patients and methodological limitations in identifying appropriate patients and their follow up post treatment.

A more promising intervention for post-stroke fatigue is found in the cognitive and graded activity programme. It consists of cognitive education or "reprogramming" the patients' perception and insight regarding fatigue, using concepts akin to cognitive behavioural therapy. The graded activity focuses on endurance, strength training and flexibility which are taught and practiced during the sessions and through homework assignments. This protocol is based on the premise that fatigue is due to the additional compensatory effort used to deal with the demands of everyday life.31 It does not focus on restoring baseline energy levels, but aims to provide alternative compensation strategies to manage and prevent further fatigue. Preliminary data from a trial evaluating combined therapy against cognitive treatment is encouraging, suggesting positive short and long-term effects from combined therapy in chronic post-stroke fatigue patients.32

Conclusion

Post-stroke fatigue is a debilitating condition that negatively impacts on recovery of function. There are gaps in current understanding of causal mechanisms, diagnostic criteria and sustainable treatment. Additional research in each of these areas will be useful in overcoming an important barrier posed to post stroke rehabilitation.

Conflict of interest: none declared

References

1. Swain M. Fatigue in Chronic Disease. Clin Sci 2000; 99: 1-8

2. Krupp L, Alvarez L, LaRocca N, Scheinberg, L. Fatigue in multiple sclerosis. Arch. Neurol 1988; 45: 435-37

3. Denburg S, Carbotte R, Denburg, J. Psychological aspects of systemic lupus erythematosus: cognitive function, mood, and self-report. J Rheumatol 1997; 24: 998-1003

4. Jones E. Fatigue associated with chronic liver disease : a riddle wrapped in a mystery inside an enigma. Hepatology 1995; 22: 1606-608

5. NICE 2008. Stroke Diagnosis and initial management of acute stroke and transient ischaemic attack CG68.

6. Glader E, Stegmayr B, Asplund K. Poststroke fatigue: a two year follow up study of stroke patients in Sweden. Stroke 2002; 33 (5): 1327-33

7. Van der Werf S, van den Broek H, Anten H, Bleijenberg G. Experience of severe fatigue long after stroke and its relation to depressive symptoms and disease characteristics. Eur Neurol 2001; 45: 28-33

8. Binder L, Howieson D, Coull B. Stroke: causes, consequences, and treatment. In: Caplan B, editor. Rehabilitation psychology. Rockville (MD): Aspen; 1987: 65-99

9. Ingles J, Eskes G, Phillips S. Fatigue after stroke. Arch Phys Med Rehab 1999; 80: 173-78

10. Naess H, Nyland H, Thomassen L, Aarseth J. Fatigue at long term follow up in young adults with cerebral infarction. Cerebrovasc Dis 2005; 20: 245-50

11. Ferro J, Caeiro L, Santos C. Poststroke Emotional and Behaviour Impairment: A Narrative Review. Cerebrovasc Dis 2009; 27: 197-203

12. Leegaard O. Diffuse cerebral symptoms in convalescents from cerebral infarction and myocardial infarction. Acta Neurol Stand 1983; 67: 348-55

13. Fedoroff J, Starkstein S, Parikh R, Price T, Robinson R. Are depressive symptoms nonspecific in patients with acute stroke? Am J Psychiatry 1991; 148: 1172-76

14. Lynch J, Mead G, Greig C, et al. Fatigue after stroke: The development and evaluation of a case definition. Journal of Psych Res 2007; 63: 539-44

15. Malec J, Richardson J, Sinaki M, O'Brien M. Types of affective response to stroke. Arch Phys Med Rehabil 1990; 71: 279-84

16. Christensen D, Johnsen S, Watt T, et al. Dimensions of post-stroke fatigue: a two-year follow-up study. Cerebrovasc Dis 2008; 26: 134-41

17. Staub F, Bogousslavsky J. Fatigue after stroke: a major but neglected issue. [Review]. Cerebrovascular Diseases 2001; 12(2): 75-81

18. Appelros P. Prevalence and predictors of pain and fatigue after stroke: a population-based study. International Journal of Rehabilitation Research 2006; 29(4):329-33

19. Schepers V, Visser-Meily A, Ketelaar M, Lindeman E. Poststroke fatigue: course and its relation to personal and stroke-related factors. Archives of Physical Medicine & Rehabilitation 2006; 87(2): 184-8

20. Colle F, Bonan I, Gellez Leman M, Bradai N, Yelnik A. Fatigue after stroke. [Review]. Annales de Réadaptation et de Médecine Physique 2006; 49(6): 361-4

21. Beurskens A, Bultmann U, Kant I, Verkoulen J, Bleijenberg G, Swaen G. Fatigue among working people: validity of a questionnaire measure. Occup Environ Med 2000; 57: 353-7

22. Van der Werf S, Van den Broek H, Anten HWM, Bleijenberg G. Experience of severe fatigue long after stroke and its relation to depressive symptoms and disease characteristics. Eur Neurol 2001; 45:28-33

23. Fisk J, Ritvo P, Ross L, Haase D, Marrie T, Schlech W. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis 1994; 18(5): 79-83

24. Dittner A, Wessely S, Brown R. The assessment of fatigue: a practical guide for clinicians and researchers. [Review]. Journal of Psych Res 2004; 56(2): 157-70

25. De Groot M, Phillips S, Eskes G. Fatigue associated with stroke and other neurologic conditions: Implications for stroke rehabilitation. Archives of Physical Med & Rehab 2003; 84(11): 1714-20

26. Riley N, Bilodeau M. Changes in upper limb joint torque patterns and EMG signals with fatigue following a stroke. Dis & Rehab 2002; 24(18): 961-9

27. Carlsson G, Moller A, Blomstrand C. Consequences of mild stroke in persons <75 years- a 1-year follow-up. Cerebrovasc Dis 2003; 16: 383-388

28. Choi-Kwon S, Han S, Kwon S, Kim J. Poststroke fatigue: characteristics and related factors. Cerebrovasc Dis 2005; 19: 84-90

29. Choi-Kwon S, Choi J, Kang DW, Kim J. Fluoxetine is not effective in the treatment of post-stroke fatigue. Cerebrovasc Dis 2007; 23: 102-8

30. Ogden J, Mee E, Utley T. Too little, too late: does tirilazad mesylate reduce fatigue after subarachnoid haemorrhage? Neurosurgery 1998; 4: 782-87

31. Cantor J, Ashman T, Gordon W, et al. Fatigue after traumatic brain injury and its impact on participation and quality of life. J Head Trauma Rehabil 2008; 23: 41-51

32. Zedlitz A, Fasotti L, Geurts. A Post-stroke fatigue: a treatment protocol that is being evaluated. Clin Rehabil 2011; 25: 487