One step closer to understanding poststroke fatigue.

Neurology 2012;79:1414–1415 Pathologic fatigue is common in neurologic disorders and can be defined as “a state of weariness unrelated to previous exertion levels which is usually not ameliorated by rest.”1 A case definition for poststroke fatigue (PSF) has been developed,2 based on this definition,1 to identify clinically important fatigue in stroke survivors.2 The frequency of PSF ranges from 23% to 75%.3 It develops early after stroke and seems to persist.4 PSF is associated with a reduced quality of life, lower likelihood of resuming social and professional activities, and a higher risk of institutionalization and death.3,5 There is evidence for associations between PSF and low mood, increasing age, and female sex, but not all PSF can be explained by these factors.5 Several studies have sought biological associates of PSF.6 One population-based study showed that fatigue was more frequent after minor strokes than TIAs, suggesting that the presence of a brain lesion itself might be important in its etiology.7 Some studies have reported an association between PSF and lesions in posterior circulation territory and the basal ganglia.3,6 Inflammation, pituitary dysfunction, and neurotransmitter changes may all, in theory, play a role in the development of fatigue in stroke survivors.6 However, there is still no clarity regarding biological mechanisms of PSF.3,6 The paucity of evidence about the etiology of PSF is one reason why there are so few clinical trials in this area.8 One trial suggested that a combination of cognitive therapy with graded activity training reduces PSF,9 but this needs to be tested in a larger trial. In this issue of Neurology, Radman et al.10 report the results of their study of the associated factors of fatigue in patients at 6 and 12 months after minor ischemic stroke. The authors have shown, for the first time, that PSF is related to specific cognitive dysfunction, i.e., attentional and executive impairment. Although we do not know whether the relationship between fatigue and cognitive impairment is causal, and if so, whether fatigue causes cognitive impairment, or vice versa, the study results are consistent with the hypothesis that a stroke lesion affecting the neural circuits involved in regulation of attention and executive function may contribute to the development of tiredness and aversion to effort, and subsequently to the development of the behavioral phenomenon of fatigue. Identification of these neuropsychological correlates is important because it furthers our understanding of potential mechanisms of PSF, and because it provides evidence that targeting attentionalexecutive impairment might improve PSF. The authors found no association between lesion location and PSF. The neural circuits involved with attention and executive function are widely distributed across the entire brain, including the brainstem, thalamus, basal ganglia, and frontal and parietal lobes. Thus, if PSF is associated with attentionalexecutive impairment, it is not surprising that lesions in different parts of the brain may all contribute to the development of fatigue, by disrupting these neural circuits. The use of more sensitive techniques such as fMRI, PET, or diffusion tensor imaging would help to assess functional and anatomic integrity of neural circuits in stroke patients and elucidate their role in the development of PSF. The authors also reported the level of morning cortisol, adrenocorticotropic hormone (ACTH), thyroxin, and thyroid-stimulating hormone in plasma and found no association with PSF. These data suggest that PSF is unlikely to be associated with hypothyroidism. However, a single sample of plasma cortisol and ACTH may not be sensitive enough to identify subtle hypothalamo-pituitary-adrenal axis dysfunction, which in theory may contribute to the development of PSF. Finally, the results of this study10 support the previous findings3 that fatigue may be one of the reasons for a reduction in professional activities. Hence treatment of fatigue is likely to improve the chances that survivors of minor stroke will return to work.