Idiopathic restless legs syndrome: Abnormalities in central somatosensory processing

Schattschneider, Jörn; Bode, Andre; Wasner, Gunnar; Binder, Andreas; Deuschl, Günther; Baron, Ralf

doi:10.1055/s-2005-916310

Cited by 34 publications

(61 citation statements)

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“…Previous clinical studies in RLS patients have identified a change in A␦-and C-fiber function (Schattschneider et al, 2004;Stiasny-Kolster et al, 2004). The hot-plate test as performed in the current study mainly assesses pain transmission through A␦-fibers (Frölich et al, 2005), whereas phase II of the formalin test mostly describes C-fiber-mediated pain transmission (Dubuisson and Dennis, 1977;Yaksh et al, 1999).…”

Section: D3r؊/؊ and Iron Deficiency Alter Circadian Motor Activitymentioning

confidence: 95%

“…The formalin test assesses mixed A␦-and C-fiber function during the initial (phase I) stage of the test (Heapy et al, 1987;Ishizaki et al, 1999), where at the latter stage (phase II), formalininduced tissue injury and inflammation causes sensitization of primary afferents, leading to the phenomenon of windup (Mendell, 1966;Li et al, 1999), which itself dominates during this phase and only occurs upon sufficient C-fiber activation (Mendell, 1966;Dickenson and Sullivan, 1987;Yamamoto and Yaksh, 1992;McCall et al, 1996). As patients suffering from secondary RLS present impaired C-fiber function (Schattschneider et al, 2004), the formalin test was used to experimentally evaluate any possible change of murine C-fiber function, moreover, to assess the differences in the persistent pain response compared to the short acute pain measurement described by the hot-plate test.…”

Section: Methodsmentioning

confidence: 99%

“…These symptoms are usually worse in the evening and during rest, but they are relieved by movement. The additional symptoms of a sensory perception deficit (Schattschneider et al, 2004;Stiasny-Kolster et al, 2004) and hyperalgesia (Stiasny-Kolster et al, 2004) have been described in both primary and secondary forms of RLS. Despite the successful use of dopaminergic drugs in treating RLS, no evidence of a primary dopaminergic deficit has been identified .…”

Section: Introductionmentioning

confidence: 99%

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Dopamine D₃Receptor Specifically Modulates Motor and Sensory Symptoms in Iron-Deficient Mice

Dowling¹,

Klinker²,

Stadelmann³

et al. 2011

J. Neurosci.

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Restless legs syndrome (RLS) is a common neurological disorder whose exact pathophysiological mechanism remains unclear despite the successful use of dopaminergic treatment and recent discovery of predisposing genetic factors. As iron deficiency has been associated with RLS for some patients and there is evidence for decreased spinal dopamine D 3 -receptor (D3R) signaling in RLS, we aimed at establishing whether D3R activity and iron deficiency share common pathways within the pathophysiology of RLS sensory and motor symptoms.Using a combined mouse model of iron deficiency and dopamine D 3 -receptor deficiency (D3RϪ/Ϫ), circadian motor symptoms were evaluated by continuous recording of spontaneous wheel running activity. Testing the acute and persistent pain responses with the hot-plate test and formalin test, respectively, assessed sensory symptoms.A 15 week iron-deficient (ID) diet alone increased acute and persistent pain responses as compared to control diet. As compared to C57BL/6 (WT), homozygous D3RϪ/Ϫ mice already exhibited elevated responses to acute and persistent pain stimuli, where the latter was further elevated by concurrent iron deficiency. ID changed the circadian activity pattern toward an increased running wheel usage before the resting period, which resembled the RLS symptom of restlessness before sleep. Interestingly, D3RϪ/Ϫ shifted this effect of iron deficiency to a time point 3-4 h earlier.The results confirm the ability of iron deficiency and D3RϪ/Ϫ to evoke sensory and motor symptoms in mice resembling those observed in RLS patients. Furthermore this study suggests an increase of ID-related sensory symptoms and modification of ID-related motor symptoms by D3RϪ/Ϫ.

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Section: D3r؊/؊ and Iron Deficiency Alter Circadian Motor Activitymentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dopamine D₃Receptor Specifically Modulates Motor and Sensory Symptoms in Iron-Deficient Mice

Dowling¹,

Klinker²,

Stadelmann³

et al. 2011

J. Neurosci.

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show abstract

“…Impaired temperature perception has been demonstrated in up to 72% of patients with idiopathic RLS. 7 Another study shows increased temporal summation of heat pain in RLS patients compared to healthy controls. 8 However, thresholds for thermal perception are not altered in idiopathic RLS.…”

Section: Discussionmentioning

confidence: 99%

Pramipexole Alters Thermoregulation in Restless Legs Syndrome

Salminen

Rimpilä

Polo

2014

Journal of Clinical Sleep Medicine

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Study Objectives: Previous studies have associated restless legs syndrome (RLS) with peripheral hypoxia and impaired thermoregulation in the lower extremities. We performed longterm monitoring of skin temperatures in order to investigate whether these fi ndings could be explained by reduced blood fl ow to the peripheral tissues. Methods: 96-hour continuous measurements of skin temperature were performed both in the distal and proximal parts of the body of 15 patients with RLS and 14 healthy controls. During the recording, the patients participated in suggested immobilization tests both with and without pramipexole medication. Results: We found no baseline differences in distal or proximal skin temperature between patients and controls in daytime or during immobilization. However, pramipexole signifi cantly increased distal skin temperature in the patient group during immobilization (31.1°C vs. 32.9°C, p < 0.05). Daytime temperatures were not affected by therapy or disease status. Conclusions:The data suggest that patients with RLS and healthy controls have similar blood fl ow to the peripheral skin tissue. Pramipexole, however, alters thermoregulation and the previous studies might have been biased by medication. Dopaminergic medication is a major confounding factor when assessing peripheral phenomena in RLS and should be controlled for in the future studies. S C I E N T I F I C I N V E S T I G A T I O N SR estless legs syndrome (RLS), recently known as Willis-Ekbom disease, is associated with discomfort precipitated by immobility in the evening hours.1 Traditionally, RLS is believed to be of central origin, but recently RLS has also been associated with several fi ndings suggesting peripheral abnormalities. Most importantly, a recent study suggested the appearance of peripheral hypoxia during immobilization in patients with RLS.2 In addition, the skeletal muscles of the legs of RLS patients have been shown to have higher capillary tortuosity 3 and up-regulated vascular endothelial growth factor (VEGF).4 These fi ndings imply that these patients suffer from peripheral hypoxia. The hypoxia could result from insuffi cient blood fl ow to the legs either during daytime or only during immobility. To assess this hypothesis, continuous blood fl ow measures are warranted in RLS patients.Continuous measurement of skin blood fl ow may be achieved by measuring changes in skin temperature. Skin temperatures are commonly measured both distally and proximally, and a distal-to-proximal gradient (DPG) is calculated to assess the blood fl ow to the distal parts of the body.5 Distal skin temperature rises at sleep onset while the DPG of skin temperature shifts closer to zero, coinciding with the increase in melatonin secretion. 6 These data show that DPG is a selective tool for continuously assessing the thermoregulatory blood fl ow.Body temperature could be an important factor in RLS. Thermal hypoesthesia, on the other hand, is associated with secondary but not idiopathic RLS.9 Recently, it was demonstrated that RLS could be as...

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“…15 Pain associated with RLS can satisfy at least in part these criteria, considering that history and pain distribution are appropriate, and impairment of somatosensory pathways in RLS has been demonstrated by quantitative sensory testing. 16 Further insight into possible mechanisms shared with neuropathic pain has been provided by the individuation in RLS of a peculiar somatosensory profile, characterized by profound hyperalgesia, without allodynia, in RLS patients. [17][18][19] Hyperalgesia (increased sensitivity to pinprick stimuli) is a hallmark of central sensitization of dorsal horns to A-delta fiber nociceptor input, a mechanism operating in neuropathic pain.…”

Section: Sensory Manifestations Of Rls and Painmentioning

confidence: 99%

Restless legs syndrome: a new entity of neuropathic pain? Treatment with prolonged release oxycodone/naloxone combination

Gemignani

Melpignano²,

Milioli³

et al. 2016

JPRLS

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Idiopathic restless legs syndrome: Abnormalities in central somatosensory processing

Cited by 34 publications

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Dopamine D₃Receptor Specifically Modulates Motor and Sensory Symptoms in Iron-Deficient Mice

Dopamine D₃Receptor Specifically Modulates Motor and Sensory Symptoms in Iron-Deficient Mice

Pramipexole Alters Thermoregulation in Restless Legs Syndrome

Restless legs syndrome: a new entity of neuropathic pain? Treatment with prolonged release oxycodone/naloxone combination

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Idiopathic restless legs syndrome: Abnormalities in central somatosensory processing

Cited by 34 publications

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Dopamine D3Receptor Specifically Modulates Motor and Sensory Symptoms in Iron-Deficient Mice

Dopamine D3Receptor Specifically Modulates Motor and Sensory Symptoms in Iron-Deficient Mice

Pramipexole Alters Thermoregulation in Restless Legs Syndrome

Restless legs syndrome: a new entity of neuropathic pain? Treatment with prolonged release oxycodone/naloxone combination

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Dopamine D₃Receptor Specifically Modulates Motor and Sensory Symptoms in Iron-Deficient Mice

Dopamine D₃Receptor Specifically Modulates Motor and Sensory Symptoms in Iron-Deficient Mice