Poststroke drowsiness is a common complication that seriously affects the quality of life and functional rehabilitation of stroke patients. The aim of our study was to investigate the correlation between sex and daytime sleepiness in stroke patients and the sex differences in EDS affecting sleep. We found that, in addition to partial differences in laboratory measures of daytime sleepiness between males and females, the level of depression in female patients was strongly associated with EDS, and women with EDS appeared to have worse sleep quality.
The present study revealed that white blood cell counts were significantly lower in women with EDS than in those without EDS, whereas lower white blood cell counts were also detected in men with EDS than in those without EDS, although the difference was not statistically significant in men. Although studies in the literature have generally linked sleepiness to the inflammatory response and the resulting increase in leukocyte counts [14, 15], other studies have confirmed the existence of circadian rhythms in leukocytes, regulated by cortisol and epinephrine, which cause leukocytes to reach peaks during the daytime and nighttime, and sleep reinforces these opposite leukocyte rhythms by stabilizing the rhythms of cortisol and epinephrine [16]. Since most patients with daytime sleepiness after stroke have nighttime insomnia and decreased sleep quality, we hypothesized that this difference in leukocyte counts may be due to the disruption of hormonal rhythms caused by sleep disturbances in narcoleptic patients, which in turn affects leukocyte rhythms. In addition, studies have shown that females are more likely to experience leukopenia, and the severity of leukopenia is greater in females than in males [17], which is related to females being more susceptible to immune system-related diseases than males are. We hypothesize that women are more likely to have lower leukocyte counts and that hormonal disturbances affecting leukocyte rhythms are more likely to occur in women than in men; thus, sex differences in leukocyte counts occur, but larger samples of clinical data as well as objective basic research are needed to confirm these findings.
In addition, we found that blood creatinine values were greater in male patients with EDS than in patients without EDS and that men had higher creatinine values when comparing men with EDS to women. Blood creatinine is a marker of renal impairment, and the lower the creatinine clearance and the higher the blood creatinine concentration are, the greater the risk of atherosclerosis and cardiovascular disease [18] A study in a middle-aged and elderly population revealed that men had higher creatinine levels than women and were at greater risk for kidney damage and stroke development [19]. In addition, patients with chronic kidney disease have a greater prevalence of sleep-disordered breathing (SDB) and daytime sleepiness [20], and creatinine levels are an independent influence on sleep disturbance [21]. This also explains the higher creatinine level in male patients with EDS than in patients without EDS in our study; therefore, we hypothesized that, in stroke patients, sleep is more likely to be affected by serum creatinine levels in males than in females.
In terms of sleep-related scores and data, patients with EDS were more likely to have daytime dysfunction than patients without EDS, both men and women, which is understandable, as daytime sleepiness is more likely to be accompanied by generalized fatigue, as well as inattention, emotional instability, loss of energy, and a concomitant decrease in work or school productivity [1]. For women with EDS, women with EDS show worse subjective sleep quality, and in a comparison of men and women with EDS, we also found that women patients have worse sleep quality than men, which is mainly manifested in subjectively longer nighttime sleep onset versus shorter nighttime sleep duration in women patients. It has been demonstrated that female sex is more significantly associated with self-rated sleep disturbances [22, 23], and the results of the present study are consistent with previous findings, which suggests the need to focus not only on patients' sleep disturbances but also on the impact of sex on sleep quality in clinical practice.
Poststroke sleep disorders lead to alterations in the sleep-wake cycle, which are mainly characterized by abnormalities in sleep structure. The staging of sleep is mainly divided into the NREM stage and REM stage, and the NREM stage can be further divided into the N1, N2, and N3 stages, with the N1 and N2 stages being the light sleep stage, and the N3 stage, also known as slow-wave sleep, being the deep sleep stage [24]. The present study further revealed that in the analysis of polysomnographic data from EDS patients, female EDS patients had fewer N2 phases than male EDS patients did, i.e., female EDS patients had a decreased percentage of light sleep compared to males, as well as a longer sleep latency. Previous experiments using a rat model to study female hormones and sleep have shown that sex hormones play a role in sleep, and female rats are more susceptible to sleep problems than male rats, partly due to their exposure to oestrogen [25], which can increase the stability of sleep. Whereas oestrogen has positive preventive and protective effects on the occurrence and prognosis of stroke, oestradiol levels decrease rapidly in postmenopausal women and are strongly associated with infarct incidence and disease severity [26]. Decreased oestrogen levels in stroke patients may also disrupt sleep rhythms and affect sleep architecture, resulting in decreased sleep quality in female patients and detrimental effects on stroke prognosis.
The present study revealed a significant association between EDS and depressed mood in female patients. EDS has been associated with depression in a number of previous studies, which have shown that EDS is independently associated with depressive symptoms and that the relationship may be bidirectional, with depression being an important factor in the development of EDS and that EDS increases the risk of subsequent depression in patients [27]. In stroke patients, depression has likewise been proposed to be a factor in EDS, while the risk of depressive symptoms in stroke patients also increases long after the stroke has occurred [28]. Stroke patients are more prone to depression and pessimism due to the imbalance in their psychological balance caused by their neurological deficits, reduced ability to take care of themselves, and the discrepancy in their social and family status compared to before the onset of the disease, and depression-induced sleep deprivation, loss of efficiency, and fragmentation may be a precursor to EDS [29]. However, due to the effects of stress, social status, oestrogen, and serotonin, females are at greater risk of depression, and some studies have shown that women are more likely to suffer from poststroke depression than men are [30], which could also explain this difference. In addition, in the correlation analysis, we found that the ESS scores of female patients were significantly positively correlated with the HADS-D scores, which further indicated that the degree of depression in female stroke patients was closely related to the degree of drowsiness. Studies have shown that depression has a substantial impact on the sleep of female patients and that the sleep structure of female patients with depression is more disrupted than that of male patients, which is mainly manifested in the reduction in the NREM sleep period and the decrease in the actual sleep time [31]. Clinical attention should be given to the mood changes of female patients, and the prevention and treatment of stroke can be facilitated by timely identification and intervention to reduce sleep disorders through depression and other psychosomatic problems.
Additionally, although SDB has been shown to be strongly associated with daytime sleepiness in the general population and ESS scores increase with the severity of obstructive sleep apnoea hypopnea syndrome (OSHAS) [32], in the present study, Spearman's correlation analysis revealed that there was a weak correlation between ESS scores and the maximum duration of hypopnea in male patients. The analysis did not reveal significant differences in major sleep breathing-related parameters, such as the AHI, ODI, or oxygen saturation, between patients with and without EDS. A study showed no general correlation between SDB and EDS in patients with cardiovascular diseases such as atrial fibrillation who had comorbid SDB [27, 33]]; similar findings were found in stroke patients, and a study involving stroke patients with OSA [34] revealed that stroke patients with comorbid OSA were less likely to suffer from EDS compared with the general population and that subjective somnolence was not significantly correlated with sleep apnoea in stroke patients compared with the general population. Due to the lack of a significant association between subjective drowsiness and sleep disorders in stroke patients, the mechanism of sleepiness in stroke patients with SDB is more complex than that in the general population, and there are more factors influencing the occurrence of sleepiness, such as lack of exercise and the use of stroke medications such as statins and antiplatelet drugs. In addition, the decline in the cognition of subjective sleepiness caused by stroke is also a possibility, and the prediction of SDB in stroke patients based on subjective sleepiness scores alone might not be a highly efficient method.
4.1. Limitations
The limitation of our study is that although the ESS is a more commonly used method for assessing sleepiness, it relies on the patient's subjective perception, and the multiple sleep latency test (MSLT) is a method to objectively evaluate the degree of drowsiness and is the gold standard for measuring EDS; however, due to the limitations of the test site and the number of researchers, the MSLT still cannot be carried out on a large scale at present.
In addition, this was a single-centre, small-sample study, and the lack of patients with severe stroke and large-vessel disease is another limitation of this trial. The participation of these patients may help us to better explore the association between sleep and stroke, and the sample size should be enlarged for inclusion in future studies.