Review of the relationship of restless legs syndrome and periodic limb movements in sleep to hypertension, heart disease, and stroke

Abstract

Evidence is reviewed documenting an intimate relationship among restless legs syndrome (RLS) / periodic limb movements in sleep (PLMS) and hypertension and cardiovascular and cerebrovascular disease. Sympathetic overactivity is associated with RLS/PLMS, as manifested by increased pulse rate and blood pressure coincident with PLMS. Causality is far from definitive. Mechanisms are explored as to how RLS/PLMS may lead to high blood pressure, heart disease, and stroke: (a) the sympathetic hyperactivity associated with RLS/PLMS may lead to daytime hypertension that in turn leads to heart disease and stroke; (b) in the absence of daytime hypertension, this sympathetic hyperactivity may predispose to heart disease and stroke either directly or indirectly via atherosclerotic plaque formation and rupture; and (c) comorbidities associated with RLS/PLMS, such as renal failure, diabetes, iron deficiency, and insomnia, may predispose to heart disease and stroke. One theoretical cause for sympathetic hyperactivity is insufficient All diencephalospinal dopaminergic neuron inhibition of sympathetic preganglionic neurons residing in the intermediolateral cell columns of the spinal cord. We cannot exclude the possibility that peripheral vascular, cardiovascular, and cerebrovascular disease may also contribute to RLS/PLMS, and mechanisms for these possibilities are also discussed.

Figures

Figure 1

Decreased dopamine (DA) may lead to increased sympathetic drive in Restless Legs Syndrome/Periodic Limb Movements in Sleep (RLS/PLMS).Increased sympathetic drive in RLS/PLMS may lead to hypertension, heart disease, and stroke. Spinal somatosensory (left) and sympathetic autonomic circuits (right) are depicted separately. The consequences of a compromise of spinal dopaminergic inhibitory controls are presented as a sequential series of events numbered 1 through 4. Proposed circuitry leading to increased sympathetic drive. (1) In the spinal cord, DA actions from the A11 exert direct inhibitory actions on sympathetic preganglionics in the intermediolateral cell column (IML). In contrast, serotonergic dorsal raphe descending neurons have strong excitatory actions in the IML. Thus, any compromise in A11 inhibitory function would shift the balance of descending control of the sympathetic preganglionics toward excitation. Sympathetic hyperactivity in turn could lead to vasoconstriction and subsequently to hypertension, heart disease, and stroke. The authors of the original publication in which this figure appeared—Clemens S, Rye D, Hochman S—propose a theoretical model of how DA deficiency could lead to the symptoms of RLS: (1) DA inhibits preganglionic sympathetics, thus, in its absence, basal sympathetic tone may increase; (2) increased adrenaline via innervation of skeletal muscle, in turn, might irritate muscle spindles;(3) the resulting enhanced input from pain-encoding high-threshold muscle afferents in lamina I are insufficiently suppressed in the absence of DA or D2-like receptors; (4) Abnormal sensations, in turn, are perceived at the cortical level. These abnormal sensations are further enhanced by compromised A 11 dopaminergic input at the cortical level. Reproduced from Clemens S, Rye D, Hochman S. Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 2006;67:125-130. Reprinted with permission—Lippincott, Williams & Wilkins, Baltimore, MD.

Figure 2

Hypothetical relationships among restless legs syndrome (RLS)/periodic limb movements in sleep(PLMS) and hypertension, heart disease, and stroke. One-way arrows indicate 1-way causation, and 2-way arrows indicate 2-way causation or, alternatively, cooccurrence. Possible comorbidities include insomnia, renal failure, anemia and sleep apnea. Htn refers to hypertension, HD, heart disease, CVA, cerebrovascular accident. See text for details. Not shown on diagram: The 4 recently identified susceptibility genes that could potentially interact at most, if not all, nodal points.