Baseline characteristics
The demographic characteristics of the subjects are shown in Table 1. The average ages of the RLS patients and normal controls were 52.4 (±15.4) and 57.4 (±11.3), respectively. The mean IRLSS in RLS patients was 27.9 (±7.0).
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Table 1. Basic characteristics and clinical features
Group RLS
(n=34)
Controls (n=36) P
Age 52.4 (15.4) 57.4 (11.3) 0.171
Sex (number of men, %) 12 (48%) 12 (48%) 1.0
FMD (%) 7.1 (1.5) 8.5 (1.8) 0.001
VMR (%) Rt MCA 50.8 (10.4) 57.7 (7.4) 0.006
Lt MCA 51.3 (9.5) 58.9 (9.2) 0.003
BA 51.1 (9.6) 57.1 (11.3) 0.030
IRLSS 27.9 (7.0) N/A N/A
Values are mean (SD). RLS, Restless Legs Syndrome; FMD, Flow-mediated Diameter;
VMR, Vasomotor Reactivity; MCA, Middle Cerebral Artery; BA, Basilar Artery; IRLSS, International Restless Legs Syndrome Study Group Scale
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FMD & VMR responses
The values of VMR in both MCA (Lt MCA 51.3±9.5%, vs 58.9±9.2%, p=0.003, Rt MCA 50.8±10.4%, vs 57.7±7.4%, p=0.006) and BA (51.1±9.6%, vs 57.1±11.3%, p=0.030) were significantly lower in RLS group than control group.
The values of FMD (7.1±1.5% vs 8.5±1.8%, p=0.006) also was significantly lower in RLS patients. The significant correlation between FMD and VMR of every arteries was noted (p=0.006 in Rt MCA, p=0.008 in Lt MCA, p=0.046 in BA). Age and severity of RLS (IRLSS) was not correlated with neither VMR nor FMD (Table 2).
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Table 2. Correlation between FMD and other values in RLS group FMD
R P
VMR (Rt MCA) 0.46 0.006
VMR (Lt MCA) 0.45 0.008
VMR (BA) 0.35 0.046
Age -0.17 0.339
IRLSS -0.13 0.490
RLS, Restless Legs Syndrome; FMD, Flow-mediated Diameter; VMR, Vasomotor Reactivity; MCA, Middle Cerebral Artery; BA, Basilar Artery; IRLSS, International Restless Legs Syndrome Study Group Scale
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Relationship between responsiveness to dopaminergic treatment and cerebral VMR & FMD
Of the 34 RLS patients, 11 (32.4%) patients reported completely responsive, 13 (38.2%) patients were partially responsive and 10 (29.4%) patients were nonresponsive to dopaminergic treatment. Baseline cerebral VMR (right MCA:
complete responsive vs partial responsive vs nonresponsive 44.9±6.2% vs 49.9±11.3 vs 59.1±8.5%, p=0.004) showed significant difference between these three groups.
As compared each groups, patients with complete response to dopamine had significantly lower values of VMR in all of tested vessels (both MCA and BA).
(Table 3). Patients with partial response to dopamine showed no significant difference with other groups, except values of VMR in BA compared with no response group. But, although no statistical significance, VMR values of partial response group were lower than values of no response group and higher than complete response group (Figure 1). FMD showed no significant difference with other groups (6.7±1.1% vs 6.8±1.3 vs 7.9±2.0%, p=0.11).
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Table 3. Relationship between responsiveness to dopaminergic treatment and cerebral VMR & FMD
Values are mean (SD). P, comparison among three groups; P1, comparison between complete response and partial response; P2, comparison between complete response and no response; P3, comparison between partial response and no response.
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Figure 1. Relationship between responsiveness to dopaminergic treatment and cerebral VMR & FMD
Patients with complete response to dopamine had significantly lower values of VMR in all of tested vessels (Lt, Rt MCA and BA p=0.003, 0.008, 0.018). VMR values of partial response group were lower than values of no response group and higher than complete response group (without statistical significance)
0 10 20 30 40 50 60 70
FMD VMR (Rt MCA) VMR (Lt MCA) VMR (BA)
complete partial no
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Ⅵ. Discussion
This study shows that VMR & FMD were significantly impaired in RLS patients than healthy controls, and those values of FMD and VMR had a correlation.
And, relationship between dopamine response and VMR & FMD is also identified.
These findings imply the impaired endothelial function in RLS, that support the correlation between cerebrovascular disease, especially stroke, and RLS. To the best of our knowledge, this study is the first to evaluate both cerebral and systemic peripheral endothelial function in patients with RLS.
The pathophysiology of RLS is poorly understood. The dysfunction of dopaminergic system and iron dysregulation, but definite mechanisms of disease is unclear. Other many hypothesis are suggested, such as opioid system, glutamatergic system, genetics, anatomical network vulnerability, alterations in vascular structure or hypoxia2,18. Of that, the hypothesis that vascular pathologies in the central nervous system or the periphery lead to RLS or PLMS also proposed7. In a number of studies supporting this, RLS patients have shown changes in the peripheral microvasculature or cardiovascular autonomic system, including altered leg blood flow, capillary tortuosity, skin temperatures, heart rate variability and peripheral hypoxia19-23.
Although recent studies have observed the association between RLS and cardiovascular disease, the specific mechanisms underlying this relationship are not yet clear. The periodic limb movement disorder (PLMD) present in the majority of patients with RLS, and these limb movements may induce transient increases in heart rate and blood pressure. These sympathetic hyperactivity was suggested for one of risk factors of cardiovascular disaease7,24. However, Bauer et al reported that, during polysomnography, blood pressure elevation event was occurred but more than half of these events were recorded during non-PLMD period25. Sleep disturbance possibly caused by sensory symptoms in RLS also suggested to be a cause of vascular events in RLS4.
14
Our findings could be one of theories to support these vascular pathologies in RLS. Endothelial function is associated with cardiovascular risk factor and is considered to be an early process of atherosclerosis26,27. Shimbo et al reported that endothelial dysfunction assessed by impaired FMD predicted cardiovascular events (MI, stroke and vascular death)11. Leukoaraiosis, migraine and obstructive sleep apnea, which were known to be associated with vascular pathogenesis, demonstrate the impaired FMD and VMR, suggest the relationship between cerebral & systemic endothelial dysfunction and vascular pathologies28-31. In RLS, several research about relationship between vascular disease and RLS was reported, but this study is the first to approach to the vascular event with endothelial dysfunction.
The mechanisms of endothelial dysfunction in RLS could be explained by NO signal pathway. A few studies report that RLS patients have decreased NO levels, increased NOS expression23 and variation in the NOS gene22. As is well known, NO plays an important role in the endothelial function of blood vessel32, thus decrement of NO production can lead to a decreased local blood flow and localized hypoxia.
These changes may trigger main clinical symptoms in RLS, as the lower oxygen partial pressure could trigger the firing of peripheral nociceptive C fibers in the legs, and this firing may trigger pain and sensory symptoms in lower limbs33. In addition, hypoxia inducible factor pathway activation occurs in substantia nigra and brain microvasculature in patients with RLS, and this pathway also associated with NO signal. This hypoxia inducible pathway can result from, or contribute to cellular iron deficiency, which suggest novel model to explain the sequential relationship of iron deficiency, microvascular alteration and development of RLS23.
Dopaminergic agents are widely used to improve the RLS. Levodopa treatment is associated with a higher prevalence of daytime augmentation, in which the symptoms worsen earlier in the day after administration of the drug,34 thus dopamine agonists were preferred now. As there is probably no degeneration of dopaminergic neurons in RLS patients, the mechanism of therapeutic effect from
15
dopaminergic agents were questionable. Even though hypodopaminergic pathology has long been suspected from these therapeutic effect of dopaminergic agents, but consistent dopamine deficiency has not been identified35. Dopamine is known to be associated with heart and vascular system and is an important regulator of systemic BP36. In vascular wall, dopamine induced vascular smooth muscle relaxation to reduce BP36. Also dopamine is reported to modulate functions of endothelial cells via vascular permeability factor/vascular endothelial growth factor37. From this study, we figured out that patients with good responsiveness with dopaminergic treatment showed poorer cerebral endothelial function than patients with no response to dopamine. We consider that vascular effect of dopaminergic therapy improves RLS symptoms, thus impairment of endothelial function is related with therapeutic response. Furthermore, this findings suggest the mechanism of how dopaminergic therapy improves the symptoms of RLS, in which not fully understood yet. Recently, Bauer et al identified that the number of blood pressure elevation events during polysomnography was significantly decreased after administration of dopamine agonist, which support our findings about vascular components in dopaminergic therapy25.
Our previous study suggested the impaired systemic endothelial function in RLS patients, assessed by FMD13. But the mechanism of cerebral endothelial function is a bit differ from systemic endothelial system, as VMR represents cerebral autoregulation and cerebral vasodilation is mainly response to hypercapnia, and influence of NO is only partial38. Thus, in healthy subjects, they did not appear to correlation between VMR and FMD39. The assessment of cerebral endothelial dysfunction in RLS patients is meaningful, as the evidence to support the association with RLS and cerebrovascular events. Also, anatomical involvements of brain was reported, as iron deficiency or hypoxia inducible factor in substantia nigra, hence only association with peripheral microvascular hypoxia and sensory symptoms in legs is not enough to demonstrate the vascular-related pathophysiology of RLS. To
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the best of our knowledge, this study is the first study applying VMR to evaluate cerebral endothelial dysfunction, and comparing it to systemic endothelial dysfunction via FMD.
There are several limitations in this study. First, despite age & sex matching between two groups and exclusion process for secondary RLS or RLS mimicking disease was done, other confounding factors on FMD, VMR and RLS such as dietary or lifestyle factors. Second, the cross-sectional design of the study and relatively small number of samples limit the generalization of these results of study to a direct causative effect between RLS and the impairment of FMD and VMR. Third, although sleep fragmentation and sympathetic hypersensitivity caused by PLMD may considered mechanism of association between RLS and vascular events, these were not assessed in this study due to lack of polysomnographic evaluation. Fourth, because patients were recruited from a tertiary referral hospital, patients with more severe RLS symptoms possibly tend to be enrolled in this study, which had been described in a study at a different tertiary hospital in korea40. Fifth, the responsiveness to dopaminergic agonist was evaluated by patients’ subjective feeling, thus objectively documented data or quantitative instruments were not used. IRLSS is commonly used to evaluate the severity of RLS, but there was no standard cut-off value to determine whether RLS is improved or not. Finally, because FMD follow standard circadian rhythms41, RLS symptoms were not actively ongoing around the study time, as FMD was performed in the early morning (8:00 AM).
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Ⅴ. Conclusion
This study demonstrated that RLS patients have poorer cerebral and systemic endothelial function than normal healthy subjects. This findings provide further evidence of a possible association between RLS and cardiovascular disease, including ischemic stroke, and also the role of vascular pathologies in the pathogenesis of the RLS. Further prospective, large-scale, randomized controlled studies about endothelial dysfunctions in RLS and the results of vascular-targeted therapy are needed.
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23
수치를 보였다 (7.1±1.5% vs 8.5±1.8%, p=0.006). 하지불안증후군 환자에서 도파민 효능제에 반응이 좋을수록 VMR 값이 더 낮은 결과를 보였다 (좋은 반응군 vs 부분적인 반응군 vs 반응없음 44.9±6.2% vs 49.9±11.3 vs 59.1±8.5%, p=0.004).
결론: 본 연구를 통해 하지불안증후군 환자들은 대뇌혈관과 말초혈관에서 내피세포의 기능저하가 있는 것을 확인하였다. 이 결과를 통해 하지불안증후군과 심혈관질환 사이에 병태생리학적인 연관성이 있으며 하지불안증후군의 발생에 혈관의 문제가 일부 기여할 수 있음을 시사한다.
핵심어 : 하지불안증후군, 내피세포 기능, 혈관운동 반응도 검사