Elsevier

Clinical Neurophysiology

Volume 115, Issue 9, September 2004, Pages 1975-1988
Clinical Neurophysiology

Invited review
Why do restless legs occur at rest?—pathophysiology of neuronal structures in RLS. Neurophysiology of RLS (part 2)

https://doi.org/10.1016/j.clinph.2004.01.031Get rights and content

Abstract

Restless legs syndrome (RLS) is a heterogeneous disorder encompassing genetically caused types with early onset and acquired varieties occurring later in life. Genetic studies in the near future will most likely discover more than one causative gene. The acquired cases too have different etiologies ranging from idiopathic types to secondary forms with uremia, iron depletion, polyneuropathy and others. Here we aim to correlate typical RLS symptoms, such as the sensory symptoms at rest, the reduction of the complaint in response to movement or other physical stimuli, the dominant involvement of the legs, pain, circadian rhythm, and the responsiveness to dopaminergic drugs with neurophysiological features of the central nervous system. We outline the complexity of the neural structures involved and their connections. A diversity of hypothetical affections of different neuronal levels might lead to various combinations of RLS symptomatology. No single pathophysiological explanation has yet been developed that covers all clinical features.

Introduction

Restless legs syndrome is a heterogeneous disorder. The common feature is a circadian occurrence of disabling sensory symptoms at rest, responsive in almost all (but not in 100%) of the patients to dopaminergic drugs (for details see Hening (2004)). It can be separated into a genetic disease form, with a more than 50% likelihood, that the age of onset is below 30 years of age (Winkelmann et al., 2002) and into an acquired variant with a more likely higher age of onset. Causes of genetic and acquired disease forms are heterogeneous, genetic analyses published so far pointing towards different chromosomes. Although knowledge of the involved genes will greatly advance the understanding of the molecular pathophysiology, an outline of a general concept of pathophysiology which is able to encompass congenital as well as acquired disease forms does not exist so far. Here we approach features of the complex and interrelated neuronal systems affiliated with symptoms of RLS on the basis of modern neurophysiology, neuroanatomy and neuropharmacology. Nowadays, although the disease can already be treated efficiently, looking at the pathophysiology could also lead us to more specific drugs for specific subgroups of the disease.

Section snippets

Why do restless legs occur at rest?

The occurrence of symptoms at rest and the associated urge to move with the consequence of amelioration during movement, is one of the key symptoms of the disease. In order to localize the phenomenon of ‘movement per se reducing sensory symptoms’, one has to look for structures providing a ‘gate control’ mechanism, i.e. a decrease of sensory input caused by active movement or by sensory stimulation. The latter mechanism is rather unspecific, since almost all sensory stimuli, such as vibration,

Does the A11 cell group play a specific role in RLS origin?

Several lines of argument favor the dopaminergic A11 neurons more as a ‘RLS-generator’ (if any is existing) than the nigrostriatal dopaminergic system (A9 neurones) responsible for the major symptoms of Parkinson's disease. Ondo and co-workers claimed to have produced a possible rat model for RLS (Ondo et al., 2000). They injected 6-hydroxy-dopamine (6-OHDA) into the A11 dopaminergic group and measured behavioral changes in the animals. They found an increased average number of standing

Are PLM in RLS correlated with the firing characteristics of dopaminergic or other neurons?

The bursting pattern of dopamine neurons is characterized by a bi-stable bursting mode and could explain the neurophysiological pattern of PLM in respect to their determined periodicity, activity period and inactive period (intermovement interval). The neurochemical interactions of DA and NMDA receptor behavior also play a role in the pathophysiological context and may facilitate further treatment options in RLS. The motor discharge pattern of spinal motoneurons in periodic limb movements in

Opioids

A link between the opiate system and RLS is suggested by the excellent treatment responses. According to Schomburg and Steffens (1998) there are two important reasons for comparing the spinal motor actions of L-DOPA with the known effects of opioids: (1) Opioids, like L-DOPA, have quite a selective depressant effect on spinal FRA pathways (Schmidt et al., 1991) and (2) monoaminergic systems show multiple interactions on nociception at different levels of the nervous system including the spinal

The role of noradrenergic neurotransmission

The noradrenaline system (NA) may also have a role in inducing RLS since DA is a precursor for the synthesis of NA (overview in Weil-Fugazza and Godefroy (1993)). The levels of DA detected in the spinal cord are about one-tenth the levels of norepinephrine (NE). L-DOPA is assumed to increase the turnover and release of noradrenaline from the terminals of descending reticulospinal pathways.

All pontine noradrenergic groups, including the LC, the A5, and A7 cell groups, contribute to the

Is RLS a disease of deficient gain control or perceptual threshold shift?

The central nervous system requires sensory information that is both sensitive to impinging inputs (with a high gain) and unambiguous (with a high signal to noise ratio). In the case of paraesthesia or pain in RLS, patients perceive somatosensory signals either without a physical correlate or with distorted central somatosensory perception. RLS could thus be defined as a syndrome of somatosensory misperception, disturbed gain regulation and/or a shifted threshold.

Gain control by efferent

Why is RLS a disease of older age?

The severity of RLS symptoms increases with older age (Winkelmann et al., 2000). In healthy subjects the perceptual pain threshold rises slightly or even remains unchanged with advancing age. Chronic pain conditions in general seem to be more prevalent in senescent individuals which, however, may be due to increasing prevalence of orthopedic and other diseases. If pain perception and pain tolerance is different in the elderly is still subject of research (Pickering et al., 2002). Aging does not

Acknowledgements

We greatly appreciated helpful comments and suggestions from Drs Wayne Hening, S. Happe, F. Tergau, R.D. Treede and E.D. Schomburg for critical reading of the manuscript and thank Mrs Crozier for editing the English.

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