Cerebral blood flow changes in maintenance hemodialysis patients with restless legs syndrome and their clinical significance:a cross-sectional case-control study

Restless legs syndrome (RLS) constitutes a prevalent clinical neurological motor-sensory ailment. Its primary clinical attributes encompass an intense urge to shift the limbs prompted by discomfort in the legs, exacerbation or emergence of symptoms following periods of rest, partial or complete alleviation of symptoms through sustained activity, and an escalation or onset of symptoms during nighttime. This syndrome serves as a common neurological complication in individuals undergoing maintenance hemodialysis (MHD) [1]. Moreover, the prevalence of MHD patients with RLS (MHD-RLS) ranges from 19.4 to 57.3% [2], which is typically accompanied by symptoms including sleep disorders, cognitive impairments, cardiovascular events, anxiety, and depression, which deteriorates the patient’s quality of life and even worsens their prognosis [3]. Therefore, it is essential to identify clinical risk factors for the development of RLS in patients with MHD.

Recently, studies have indicated that arterial spin labeling (ASL) serves as a noninvasive, magnetic resonance technique for quantitatively assessing cerebral blood flow (CBF) perfusion status [4], in which CBF is a valid neuroimaging marker for assessing microvascular distribution, tissue metabolism, as well as organ function [5]. Furthermore, ASL is considered to have superior clinical applications due to the fact that it is non-invasive, safe, cost-effective, and reproducible. It has been indicated in the literature that ASL imaging technology has been able to visualize the CBF perfusion patterns of diseases including Alzheimer's disease and Parkinson's disease [6, 7] and examine the changes of CBF in local brain regions, which can assist in the diagnosis of the above-mentioned diseases by providing a visual foundation for the objective elucidation of pathophysiological disease mechanisms from an imaging perspective. Nonetheless, to date, there are fewer studies related to changes in CBF in patients with MHD-RLS. Consequently, research in this area is needed.

The objective of this study was to utilize the ASL technique to evaluate alterations in CBF across different brain regions in patients with MHD-RLS, to investigate the independent risk factors for the development of RLS in MHD patients, and to analyze their clinical significance.

No statistical differences were observed in age, gender, years of education, MoCA scores, hypertension, as well as diabetes between the participants in the two groups (P > 0.05). In the MHD-RLS group, the duration of hemodialysis exhibited a significantly greater length when compared to the MHD-nRLS group [26.0 (17.0,60.0) months vs 12.0 (6.0,24.0) months, P = 0.004]. Furthermore, the MHD-RLS group displayed notably reduced serum iron levels in contrast to the MHD-nRLS group (8.8 ± 3.0 umol/L vs 11.5 ± 3.6 umol/L, P = 0.002). TS was also markedly lower in the MHD-RLS group in comparison to the MHD-nRLS group (21.7 ± 7.8% vs 28.0 ± 10.7%, P = 0.010), whereas PSQI scores demonstrated a substantial elevation in the MHD-RLS group as opposed to the MHD-nRLS group (11.7 ± 3.3 scores vs 9.9 ± 3.3 scores, P = 0.038). Moreover, the difference in the remaining clinical indicators was not statistically significant (P > 0.05), and specific results are shown in Table 2.

In this study, we determined that there were changes in CBF in several brain regions in patients with MHD-RLS, in which decreased CBF in the left precentral gyrus possible valid neuroimaging marker for MHD-RLS. Similarly, long dialysis duration and relative deficiency of serum iron levels are independent risk factors for MHD-RLS.

Neuroimaging techniques have been adopted to assess the pathophysiologic mechanisms of RLS, and ASL has been used in the present study to provide evidence of CBF changes associated with RLS symptoms in MHD patients. Accordingly, we determined that MHD-RLS patients have abnormal CBF changes in multiple brain regions. In our study, the MHD-RLS group had increased CBF values in the right superior temporal gyrus in comparison to the MHD-nRLS group, indicating that the increased blood flow may be due to abnormal conditioning to sensory stimulation in RLS patients, which may be associated with their ill feelings in the legs [11]. Besides, the temporal lobe is part of the default mode network (DMN), the research results of Lee et al. recommend that the resting-state connectivity of the brain in the thalamus, bilateral lingual gyrus, as well as right middle temporal gyrus is a noteworthy finding in RLS, which is unaffected by dopamine agonist treatment [12], which offers conceptual support for our findings. Additionally, diminished CBF values were identified in the right hippocampus, left middle frontal gyrus, inferior frontal gyrus of the right triangle, middle frontal gyrus of the left orbit, left precentral gyrus, and left precuneus. This decrease in CBF could potentially be linked to the impairment of cerebrovascular autoregulation mechanisms. Moreover, the brain is the body's highest oxygen-consuming organ, and it has its regulatory mechanisms. Under normal conditions, decreasing oxygen levels promote vasodilation, which increases CBF and oxygen delivery to the brain, nevertheless, through the results of Salminen et al., the manifestation of peripheral hypoxia in RLS patients was observed to be highly related to the severity of RLS, and the hypothesis of microvascular abnormality in RLS was also supported [13], Thus, RLS causes a persistent chronic hypoxic state, which contributes to cerebral vascular damage and the loss of self-regulatory mechanisms, as well as ultimately results in a decrease in CBF [14]. Moreover, the frontal, precuneus, and precentral gyrus belong to the sensory-motor network (SMN), and the hippocampus is part of the limbic system, patients with MHD-RLS have reduced CBF in the sensorimotor network, indicating sensory-motor symptoms with abnormal regulation and a strong desire to move both lower extremities as a result of abnormal limbic system regulation [15].

Our study further found, left precentral gyrus CBF values were negatively correlated with RLS scores, and there was no significant correlation in the remaining brain regions, suggesting that the left precentral gyrus CBF values were related to the severity of RLS. We hypothesized that abnormal CBF in this brain region may be involved in the underlying pathophysiological mechanisms in patients with MHD-RLS. Except for the precentral gyrus is the predominant element of the primary motor cortex and is associated with controlling motor performance in RLS [16]. Hypoperfusion of CBF in this region leaded to vascular damage, causing altered cerebral regeneration and reduced volume in the precentral gyrus, which ultimately produced a lack of control of leg movements in patients with MHD [17]. Similarly, Wang et al. demonstrated by voxel-based morphometry (VBM) analysis that the gray matter volume (GMV) of the left primary motor cortex was reduced in HD-RLS, primarily in the precentral gyrus, demonstrating that this abnormal decreased GMV in the sensorimotor cortex provides evidence for a sensory processing disorder in RLS [18]. The above findings may indicate that the symptoms of RLS are primarily related to the motor and somatosensory cortex, which, in connection with the present study, may validate further the hypothesis that RLS is linked to alterations in spontaneous brain activity and brain perfusion in the basal ganglia-thalamic-cortical circuit (CST) [11]. The CST, as a white matter motor pathway starting at the cortex that terminates on motor neurons in the spinal cord, is an essential structure that contains many communication pathways, controlling movements of the limbs and trunk [19]. There was also some literature on other imaging methods, such as, functional magnetic resonance (fMRI), Liu et al. found that patients with idiopathic RLS have reduced amplitude of low-frequency fluctuations(ALFF) in the sensorimotor and visual processing systems [20]; and with iron-sensitive MRI, Han et al. obtained, by quantitative weighted imaging (QSM) analysis, reduced magnetization of the caudate and shell nuclei in HD-RLS patients [21]. In the future, we can also increase research in these areas. In conclusion, cerebral perfusion imaging measurements could potentially serve as an early detection biomarker for MHD-RLS, aiding in the identification of alterations in sensory-motor pathways linked with potentially anomalous sensorimotor function, and facilitating the monitoring of treatment effectiveness within MHD-RLS populations.

The duration of dialysis in MHD patients was substantially associated with the occurrence of RLS, which is consistent with the results of a study by Tsai L H et al. [2], whose results demonstrated that individuals undergoing dialysis for more than 5 years exhibited a 2.32 times higher likelihood of developing RLS compared to those with less than 5 years of dialysis history. Furthermore, the intensity of RLS demonstrated a positive correlation with the duration of dialysis. However, some studies have also found no significant association between the onset of RLS and the duration of dialysis, and it is considered that this may be related to patient heterogeneity [22]. In our study, dialysis times was significantly longer in the MHD-RLS group than in the MHD-nRLS group, as well as independently constituting a risk factor for the development of RLS. Similar results were obtained by Wang et al. [21]. It has been revealed in the literature that the duration of dialysis in MHD patients is associated with increased oxidative stress as well as decreased serum antioxidant enzymes [23], oxidative stress is prevalent in chronic kidney disease and may heighten the risk of cardiovascular disease, cachexia, anemia, and other comorbid conditions, oxidative stress is an imbalance between pro-oxidant production and antioxidant defense mechanisms. Besides, the pro-oxidant and antioxidant activities of patients in distinct stages of chronic kidney disease are divergent, while hemodialysis patients have the most impaired renal function. Consequently, they have the highest amount of oxidative stress, which contributes to the elevation of serum markers F2-isoacids and a corresponding notable decline in antioxidant activity, predominantly in the decline of metabolic enzyme and glutathione peroxidase activity [24], and likewise due to the fact that RLS causes a persistent chronic hypoxic state, which may longer dialysis times may increase the incidence of RLS by promoting the development of oxidative stress. In addition, Salman SM et al. noted the presence of hyperexcitability of motor nerves in patients with MHD and the occurrence of peripheral neuropathy in patients with MHD in correlation with the duration of dialysis [25], which may also reflect the higher susceptibility to RLS as the duration of dialysis increases in patients with MHD.

We identified notably diminished serum iron levels within the MHD-RLS group in comparison to the MHD-nRLS group and that serum iron levels independently contributed as a risk factor for the onset of RLS. Previous studies have also reported that low serum iron levels may be a risk factor for RLS [26] and that there is a positive correlation between body iron stores, as measured by serum iron and ferritin levels, and symptom severity [27]. However, there is also a part of the literature that suggests that the majority of patients with RLS do not present with iron deficiency considerations may be related to the long-term use of iron therapy in patients with MHD [22, 28]. The literature suggests that the possible pathogenesis of the disease is iron deficiency with damage to dopaminergic neurons [29]. Furthermore, iron is a cofactor for tyrosine hydroxylase, an enzyme that regulates tyrosine metabolism as well as affects dopamine synthesis [30], and low levels of iron may induce or exacerbate RLS by decreasing the activity of the dopamine system, ultimately, the body's speed of movement and exercise endurance decreases, which in turn inhibits motor nerve conduction and increases the incidence of RLS [31]. Additionally, previous studies have indicated that decreased iron in the brain of RLS patients also causes downregulation of the dopaminergic system, particularly in the substantia nigra, the nucleus accumbens, as well as the medial thalamic area, which in turn leads to an increase in the excitability of the spinal cord, which ultimately manifests itself in RLS symptoms [32]. Secondly, whether correction of the lack of serum iron levels can enhance the symptoms of RLS was addressed by Park et al. Their results indicated that repeated intravenous iron sucrose is an effective treatment for secondary RLS associated with iron deficiency, which also suggested that iron deficiency may be associated with the development of RLS in patients with MHD [26].

Nonetheless, there are some limitations to our study. Firstly, its cross-sectional nature restricts the ability to establish definitive causal relationships. Secondly, the diagnosis of patients with MHD-RLS was based on questionnaires and clinical presentation without polysomnographic monitoring recordings, which may have overlooked cases of mild RLS among the study participants. Thirdly, according to the literature, hemoglobin and ferritin are mostly recognized as clinical risk factors for the development of RLS, which was not reflected in our results, which may be related to the insufficient sample size or the heterogeneity of individuals. Fourthly, the enrolled patients were on dialysis for a relatively short period of time, which may have introduced some bias. Finally, the relatively small sample size could introduce bias in the assessment of RLS prevalence and associated clinical risk factors among MHD patients. Therefore, an expanded sample size would be necessary for more comprehensive insights.

Changes in CBF in the presence of multiple brain regions in MHD-RLS patients, the left precentral gyrus may play a significant role in the development of RLS in MHD patients, and the long duration of hemodialysis and relative deficiency of serum iron levels are independent risk factors for the development of RLS in MHD patients. This provides an important basis for exploring the mechanism of the occurrence of RLS in patients with MHD and clinical practice,and contribute to early recognition and treatment of MHD-RLS, thereby enhancing patients’ quality of life.