Original Article
Poststroke Fatigue: Hints to a Biological Mechanism

https://doi.org/10.1016/j.jstrokecerebrovasdis.2014.10.008Get rights and content

Background

Poststroke fatigue (PSF) is common, but the biological basis of this fatigue is unknown. We explored the possibility that PSF is related to systemic inflammation by investigating polymorphisms in 2 genes that affect the immune response.

Methods

In a substudy of a larger trial that evaluated the role of the immune response on stroke outcome, fatigue was assessed at 30, 90, 180, and 365 days after ischemic stroke using the Fatigue Assessment Scale. Subjects were genotyped for 3 single nucleotide polymorphisms, one in the interleukin-1 receptor antagonist gene (IL1RN; rs4251961, a T/C substitution) and two in the in toll-like receptor-4 (TLR4) gene (1063 A/G [Asp299Gly] rs4986790 and 1363 C/T [Thr399Ile] rs4986791).

Results

Of the 39 participants, 22 (56%) endorsed fatigue during the study. The degree of fatigue was remarkably constant over time and independent of stroke outcome. The C allele of the rs4251961 single nucleotide polymorphism (SNP) in IL1RN was associated with self-reported fatigue (P = .03), whereas the cosegregating polymorphisms in TLR4 were associated with lower levels of fatigue (P = .04).

Conclusions

SNPs in 2 genes with opposing effects on inflammatory immune responses were significantly, but differentially, associated with PSF. These findings suggest a direct link between immune signaling dysregulation and PSF.

Section snippets

Research Subjects

The parent–patient population is described elsewhere.10 Briefly, patients with ischemic stroke admitted to Harborview Medical Center from September 2005 through May 2009 who were at least 18 years of age were enrolled within 72 hours of symptom onset. Individuals with ongoing therapy for malignancy, known history of human immunodeficiency virus, hepatitis B or C, history of brain tumor, anemia (hematocrit <35 on admission), and those taking immunomodulatory drugs were excluded. All study

Results

Individual FAS scores over time are shown in Figure 1. Median FAS scores did not differ over time and were similar among those with good outcome (mRS <2) and those without. Among our 39 participants, 17 (44%) did not endorse fatigue (FAS, 10-21) at any time point after stroke, 14 (36%) had fatigue (FAS, 22-34) at one or more time points, and 8 (20%) felt extremely fatigued (FAS, 35-50) at one or more time points in the year after stroke. The clinical characteristics of these subjects are shown

Discussion

Fatigue is a common and disabling symptom that affects over half of stroke survivors. Few studies have addressed the biological basis of this symptom, and to our knowledge, this study is the first to evaluate a genetic contribution to PSF. Although this exploratory study is small, it indicates a potentially substantial role for genetic factors in PSF. Large studies found that individuals with one or more IL1RN rs4251961 C alleles (those with more fatigue in our study) had lower circulating

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This study was funded by NINDS R01NS049197.

None of the authors have anything to disclose.

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