Restless legs syndrome: differential diagnosis and management with pramipexole
Clinical Interventions in Aging
restless legs syndrome: differential diagnosis and management with pramipexole
0 Department of Neurosciences, University of Parma , Italy
Restless legs syndrome (RLS) is a condition characterized by discomfort at rest and urge to move focused on the legs. RLS may occur as an idiopathic, often hereditary condition (primary RLS), or in association with medical conditions (secondary RLS) including iron deficiency, uremia, and polyneuropathy. Current understanding of the pathophysiology of RLS points to the involvement of three interrelated components: dopaminergic dysfunction, impaired iron homeostasis, and genetic mechanisms. The diagnosis of RLS is made according to the consensus criteria by a National Institutes of Health panel: 1) an urge to move the legs, usually accompanied by uncomfortable sensations; 2) beginning or worsening during rest; 3) relieved by movement; and 4) worse, or only occurring, in the evening or at night. The differential diagnosis of RLS aims to: 1) distinguish RLS from other disorders with RLS-like symptoms and 2) identify secondary forms, with investigation of underlying diseases. The treatment of RLS demands a clinical evaluation to rule out and cure causes of secondary RLS, including iron supplementation when deficient, and to eliminate the triggering factors. The presence of neuropathy should be especially investigated in nonhereditary, late-onset RLS, in view of a possible treatment of the underlying disease. The first line treatment for idiopathic RLS is represented by dopamine agonists, in particular nonergot-derived ropinirole and pramipexole, whereas ergot dopamine agonists (cabergoline and pergolide) are no longer in first-line use given the risks of cardiac valvulopathy. Although no comparative trials have been published, a meta-analysis of pramipexole versus ropinirole suggests differences in efficacy and tolerability favoring pramipexole.
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end-stage renal diseases,9 pregnancy,10 rheumatologic
disorders,11,12 diabetes,13,14 as well as neurologic conditions
such as Parkinson’s disease,15 spinal cord lesions,16 multiple
sclerosis,18 and polyneuropathy.18
The association of RLS with polyneuropathy is of
particular interest from epidemiological, mechanistic, and
diagnostic viewpoints, but is still controversial, in spite of
extensive studies. Prevalence estimates of RLS in
neuropathy are extremely variable, ranging from 5.2%19 to 54%.20
In a series of 104 consecutive patients with miscellaneous
neuropathies, we found a 29% prevalence of RLS, compared
to 9% in controls.18 A prevalence of RLS of 54% was found
in a selected series of patients with neuropathy with
symptoms of pain or dysesthesia.20 On the contrary, in a recent
controlled, double-blind study, the prevalence of RLS in
neuropathy patients (12.2%) did not differ significantly
from controls (8.2%), but in the subgroup of patients with
hereditary neuropathy a higher prevalence of 19.4% was
.rvdoepww ll.syeuon fdoisucnrde.p21anCcoiensfliincttihneg dreessiuglntsomf athyebsetudduieestaonmdeinthtohdeoalossgeiscsa-l
://sw oan ment of RLS and of neuropathy, and variations in etiology
h pe of neuropathy between cohorts; in addition, it should be
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from roF considered that, as polyneuropathy is usually an evolutive
de condition, the appearance or disappearance of RLS may be
laod related to different phases of the disease. As it has been shown
onw that RLS can be triggered by small fiber sensory
neuropangd thy,18,22–24 it is expected that RLS prevalence in neuropathy
igA will be higher when considering the forms with prevailing
isn small fiber involvement, such as diabetic neuropathy.14,25 In
itnno conclusion, we think that the prevalence of RLS in the course
ltIrvnee doifffpeorleynntesuurbotpyapthesy, ssheogureldgabteedfueritthheerr absyseestsieodlosgeypaorratoenlythine
ilicanC basiCsuorfrepnretfuenrednetrisatlalnydiinnvgolovfedthneeprvaethfoibpehrypsiooplouglaytioonf.RLS
points to the involvement of three interrelated components:
dopaminergic dysfunction, impaired iron homeostasis, and
genetic mechanisms.26 In particular, dopamine dysfunction
plays a central role, as suggested by the early observation that
dopaminergic drugs are highly effective in treating RLS.27
Increasing data support the hypothesis that dysfunctioning
dopaminergic pathway resides in the small
diencephalospinal tract originating from the hypothalamic A11 nucleus,16
modulating the excitability of sensorimotor spinal circuits
presumably subserving RLS.28,29 Dysfunction of endogenous
opioidergic circuits, possibly mediated by an interaction
with the dopaminergic system, has been also implicated,
based on the positive clinical response to opioidergic
agents.30 Recently, in a PET study with an aspecific opioid
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receptor ligand, von Spiczak and colleagues found a negative
correlation between RLS sever (...truncated)