Peripheral Muscle Changes

Fig. 9.1

A cross-section of m tibialis anterior, immunohistochemically stained for capillaries (CD31), from an age-matched control (a) and from a RLS patient with a larger capillary network (b)

The expression of VEGF could be stimulated by inflammation in the muscle but that is not the case in these patients. None of the subjects showed any expression of MHC class I according to the criteria for grading the expression of MHC class I. All patients with RLS as well as the control group were graded as normal (0–1) [41].

Staining for T-cells (anti-CD3) and macrophages (anti-CD68) showed presence of both T-cells and macrophages in both groups, but there were no significant difference between the groups according to CD3 + cells and CD68 + cells [41].

This means that the higher expression of VEGF is not due to any inflammation in the muscle of RLS patients.

Increased capillary network is in agreement with earlier reported findings after endurance training [16, 42]. The cause for this adaptation is proposed to be the occurrence of local hypoxia within the muscle during exercise. VEGF and HIF are also enhanced during exercise, most probably due to local hypoxia in the muscle, thus stimulating angiogenesis [7, 8].

RLS patients do not show arterial hypoxia; however, local hypoxia due to vasoconstriction might exist in these patients. This hypothesis is strengthened by the relief of symptoms by limb movement which cause muscle contraction that are known to increase blood flow and oxygen supply [18, 43]. The fact that RLS patients often move their legs to temporarily relieve the symptoms; this could therefore be a strategy to increase the blood flow.

It is well known that the endothelium reacts to and also produces a variety of vasoactive substances, including vasoconstrictors as well as vasodilators. To provide adequate blood flow to the muscle, there should be a balance between the activity of vasoconstriction and vasodilatation. An imbalance favoring a vasoconstriction might induce local hypoxia. In RLS patients, there may be an imbalance between vasoconstriction and vasodilatation as the symptoms are temporarily relieved by limb movements, which increase the blood flow. Vasoconstriction as well as systemic hypoxia may cause capillary growth in skeletal muscle.

Regarding systemic hypoxia which occurs at high altitude or under pulmonary insufficiency there are conflicting results [44–46]. As our RLS patients have not experienced systemic hypoxia, this factor cannot account for the observed effect on the capillarization. However, a vasoconstriction might cause a local tissue hypoxia in these patients.

It was claimed by Ekbom in 1945 that the symptoms of RLS were due to impaired circulation in the small vessels of the lower extremities [47]. Very recently, Anderson and collaborators demonstrated impaired microvascular circulation in patients with RLS in comparison to matched controls by using bilateral great toe laser Doppler flowmetry together with whole-body thermography [48]. This is in line with our results showing that patients suffering from RLS are affected by hypoxia.

According to these current scattering data on impaired microvascular circulation in the legs of RLS patients, it may give a hypothesis open for speculation that the urge to move the legs during nighttime might be an efficacy of a circadian downregulation of dopamine, which has vasodilative characters.

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