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Objective We aimed to validate the rapid eye movement (REM) sleep behavior disorder (RBD) screening questionnaire (RBDSQ) in 2 independent samples of patients with Parkinson's disease (PD) using different settings when performing the investigations. Methods The RBDSQ was administered to two independent samples of 52 and 75 consecutive PD patients investigated with video-polysomnography (vPSG). Results In sample A, the RBDSQ identified 46/52 (88.5%) patients correctly. In sample B, 50/75 (66.7%) patients were identified correctly. Considering a cut-off score of ≥ 5 as a positive test result, sample A showed a sensitivity of 0.90 and a specificity of 0.87, sample B showed a sensitivity of 0.68 and a specificity of 0.63. Main differences between both groups were that patients of sample A underwent a sleep history including RBD assessment prior to administration of the RBDSQ, whereas in sample B the RBDSQ was administered during routine work-up. Conclusions The diagnostic value of the RBDSQ strongly depends on the clinical setting and may be influenced by the individual's awareness on RBD. This finding is a critical issue which deserves clarification before use of this and other questionnaires can be recommended in epidemiological studies.

Pain and other sensory signs in patients with restless legs syndrome (RLS) are still poorly understood, as most investigations focus on motor system dysfunctions. This study aimed to investigate somatosensory changes in patients with primary RLS and the restoration of somatosensory function by guideline-based treatment. Forty previously untreated RLS patients were investigated unilaterally over hand and foot using quantitative sensory testing (QST) and were compared with 40 age- and gender-matched healthy subjects. The predominant finding in RLS patients was 3- to 4-fold increase of sensitivity to pinprick stimuli in both extremities (hand: P

Objective We aimed to assess effectiveness and tolerability of rotigotine in patients with moderate to severe idiopathic restless legs syndrome (RLS) under daily practice conditions in Germany. Methods In this 3-month noninterventional study, effectiveness was assessed using RLS-6 (primary variables were symptom severity when falling asleep [item 2] and during the night [item 3]). Data were collected at baseline and at the end of treatment. Safety assessments included adverse events (AEs). Results Six hundred and eighty-four patients were treated with rotigotine and 418 (61%) completed the study. The full analysis set (FAS) comprised 564 patients (106 de novo; 458 pretreated [454 had complete rotigotine dosing data]). Mean rotigotine dose of longest duration was 2.4 ± 1.4 mg/24 h. Rotigotine improved all RLS-6 items (mean change from baseline [item 2], −2.4 ± 3.6; [item 3], −2.7 ± 3.4), with the most pronounced improvement observed in daytime symptoms while at rest (item 4, −2.9 ± 3.2). AEs were typical of dopaminergic treatment and transdermal administration. De novo patients generally started rotigotine on 1 mg/24 h (85% [90/106]) and pretreated patients on 1 (50% [227/454]) or 2 mg/24 h (40% [183/454]). Most patients who were pretreated with levodopa (57%), pramipexole (84%), or ropinirole (78%) monotherapy discontinued these medications on initiation of rotigotine. Conclusions Rotigotine was effective and well-tolerated when used in routine clinical practice.

Background: Pancreatic polypeptide is released immediately after food ingestion. The release is operated by vagal-abdominal projections and has therefore been suggested as a test for vagal nerve integrity. Pathoanatomical and clinical studies indicate vagal dysfunction in early Parkinson's disease (PD). Methods: We assessed the postprandial secretion of pancreatic polypeptide and motilin in healthy controls (n = 18) and patients with idiopathic rapid-eye-movement sleep behavior disorder (iRBD, n = 10), a potential premotor stage of PD, as well as in drug-naive (n = 19) and treated (n = 19) PD patients. Results: The postprandial pancreatic polypeptide secretion showed a physiological pattern in all groups and even an enhanced response in drug-naive PD and iRBD. Motilin concentrations correlated with pancreatic polypeptide concentrations. Conclusions: Postprandial pancreatic polypeptide secretion is not a suitable test for vagal nerve integrity in PD. The unimpaired pancreatic polypeptide response in iRBD and PD might be explained by partially intact vagal-abdominal projections or compensatory mechanisms substituting a defective neuronal brain–gut axis. © 2012 Movement Disorder Society

Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder.Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors.A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR = 1.59, p = 0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p0.001), and were more likely to report having worked as farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008).Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder.

REM sleep behavior disorder (RBD) is a parasomnia characterized by dream-enactment behavior, diagnosed by clinical history in combination with video-polysomnography to document REM atonia loss. Idiopathic RBD (iRBD) is receiving increased attention as an important risk factor for neurodegenerative diseases, especially alpha-synucleinopathies.2–4 Despite increasing recognition of its importance, knowledge of RBD epidemiology is limited. Except for two studies, which primarily screened for sleep injury (a subtype of RBD)5,6 no large-scale epidemiologic surveys have estimated RBD prevalence. A major barrier to conducting prevalence studies is that RBD is probably uncommon, thus requiring very large epidemiologic surveys. Such large surveys are generally broad, assessing many nonsleep outcomes, with strict limitations upon the time demands upon respondents. This precludes the use of polysomnographic diagnosis and lengthy screening questionnaires. Therefore, simple (i.e., one- or two-question) screens are needed to assess RBD in large-scale epidemiologic surveys. To meet this need, we designed the RBD Single-Question Screen (RBD1Q) a single “yes-no” question that queries the classic dream-enactment behavior of RBD. We present here the validation results of this question, in relation to gold-standard polysomnographic diagnosis, in a 12-center case-control study.

Background: Delayed gastric emptying is a non-motor symptom of Parkinson's disease. Few data exist on gastric emptying in early-stage Parkinson's disease. In idiopathic rapid-eye-movement sleep behavior disorder, a presumable pre-motor stage of Parkinson's disease, gastric emptying has not yet been investigated. Methods: Twenty healthy controls, 13 patients with idiopathic rapid-eye-movement sleep behavior disorder, and 39 patients with Parkinson's disease patients underwent standardized testing for gastric emptying with the 13C-octanoate breath test. Results: Gastric emptying was significantly delayed in drug-naive (P < .001) and in treated Parkinson's disease patients (P < .001), but normal in patients with idiopathic rapid-eye-movement sleep behavior disorder. Conclusions: Our study confirms delayed gastric emptying in drug-naive, early-stage Parkinson's disease. Normal gastric emptying in idiopathic rapid-eye-movement sleep behavior disorder might be explained by the fact that neurodegenerative changes in structures modulating gastric motility are not severe enough to cause a functional deficit that can be detected by the 13C-octanoate breath test. © 2011 Movement Disorder Society

Pain in the legs belongs to the five most frequent regional pain symptoms. Restless legs syndrome (RLS) presents a particular differential diagnosis for pain in the legs, which is characterized by a nocturnal urge to move the legs often associated with painful sensations in the legs. It is one of the most common neurological disorders and probably the leading cause of nocturnal pain in the legs. In this overview, the diagnosis and therapy of RLS as well as aspects of pain therapy of the disorder are presented. In addition, the differential diagnoses for exclusion of other specific causes of nocturnal pain in the legs are discussed.

RAPID EYE MOVEMENT (REM) SLEEP BEHAVIOR DISORDER (RBD) IS A REM-PARASOMNIA THAT CLINICALLY PRESENTS WITH NOCTURNAL SPEECH AND motor activity reflecting the dream content of the patient during REM sleep.1,2 Idiopathic RBD (iRBD), i.e., the occurrence of RBD in the absence of other medical (neurologic) conditions, is considered to represent a clinical risk marker, with the—at present—highest positive predictive value for the subsequent development of an α-synucleinopathy, i.e., for Parkinson disease (PD), dementia with Lewy bodies, or multiple system atrophy.3 In the context of evolving PD, iRBD is thought to be an early clinical correlate of a slowly progressing neurodegenerative process in the brainstem. Identification of such a neurodegenerative process with a routinely available technique such as magnetic resonance imaging (MRI) could be of value for the preclinical (premotor) detection of PD and other α-synucleinopathies. During physiologic REM sleep, the activity of spinal α-motor neurons is suppressed by a complex interaction of superordinate brainstem nuclei (REM-on and REM-off areas, including the sublaterodorsal nucleus4). In RBD, this interaction between REM-on and REM-off areas is considered to be disturbed, leading to a disinhibition of spinal α-motor neurons and, subsequently, to movements during the dream phase. The sublaterodorsal nucleus is presumably one major efferent pathway for mediating muscle atonia during REM sleep,5 pointing to the brainstem as a potential area to be investigated for structural changes in iRBD. Until now, structural brain changes have not been described in patients with iRBD. Functional imaging studies have reported normal or conflicting findings: a single-photon emission computed tomography (SPECT) study showed that decreased blood flow in the pons and in the superior frontal lobes of patients with iRBD,6 whereas other studies have confirmed the decreased perfusion in the frontal cortices, they have also found an increased perfusion in the pons, putamina, and right hippocampus.7 SPECT studies using ligands to visualize the presynaptic dopamine transporter have reported that tracer uptake in the striatum is frequently reduced in patients with iRBD.8–11 The latter finding must be interpreted in the context of iRBD as a putative “preclinical (premotor)” stage of the α-synucleinopathy PD, rather than as a finding that directly relates to the disruptive nocturnal behavior of RBD-related pathophysiology. The results of previous magnetic resonance spectroscopy studies are conflicting, reporting either no metabolic changes12 or a pathologic choline/creatine ratio in the brainstem.13 Recently, transcranial sonography has revealed hyperechogenicity in the substantia nigra in a group of patients with iRBD,11,14 a sonographic marker that is seen in 90% of all patients with PD. In summary, in vivo imaging studies have not consistently demonstrated disease-specific structural abnormalities in patients with iRBD. Diffusion tensor imaging (DTI) is a novel MRI technique that enables noninvasive in vivo visualization of brain white-matter microstructure. DTI has been applied successfully to several neurodegenerative disorders, providing insights into the pathophysiology of the respective disorders.15–18 Most DTI studies have focused on fractional anisotropy (FA) as an unspecific summary measure of brain-tissue integrity. More recently, 2 components of the diffusion signal, namely axial diffusivity (AD) and radial diffusivity (RD), have been used to describe different aspects of mechanisms of degeneration. In the current study, the microstructural properties of the brains of patients with iRBD and age-matched healthy volunteers were examined using an automated whole-head analysis of the DTI measures of FA, RD, and AD.

The European Restless Legs Syndrome (RLS) Study Group performed the first multi-center, long-term study systematically evaluating RLS augmentation under levodopa treatment. This prospective, open-label 6-month study was conducted in six European countries and included 65 patients (85% treatment naive) with idiopathic RLS. Levodopa was flexibly up-titrated to a maximum dose of 600 mg/day. Presence of augmentation was diagnosed independently by two international experts using established criteria. In addition to the augmentation severity rating scale (ASRS), changes in RLS severity (International RLS severity rating scale (IRLS), clinical global impression (CGI)) were analyzed. Sixty patients provided evaluable data, 35 completed the trial and 25 dropped out. Augmentation occurred in 60% (36/60) of patients, causing 11.7% (7/60) to drop out. Median time to occurrence of augmentation was 71 days. The mean maximum dose of levodopa was 311 mg/day (SD: 105). Patients with augmentation compared to those without were significantly more likely to be on higher doses of levodopa (≥300 mg, 83 vs. 54%, P = 0.03) and to show less improvement of symptom severity (IRLS, P = 0.039). Augmentation was common with levodopa, but could be tolerated by most patients during this 6-month trial. Patients should be followed over longer periods to determine if dropout rates increase with time. peerReviewed

Depressive Storungen sind eine haufige Komorbiditat beim Restless-legs-Syndrom (RLS). Vergleichbare Pravalenzraten von Begleitdepressionen finden sich zwar auch bei anderen Erkrankungen, die Assoziation zwischen RLS und Depression ist jedoch durch die RLS-bedingten erheblichen Schlafstorungen besonders komplex. Klinisch von Bedeutung ist zudem, dass verfugbare Daten, uberwiegend aus Fallberichten, zeigen, dass eine Vielzahl antidepressiver Medikamente die RLS-Symptomatik verstarken kann. Eine komorbide Depression beeinflusst den Therapieerfolg der Grunderkrankung und sollte deshalb berucksichtigt werden. Bislang gibt es keine systematischen Untersuchungen und daher keine evidenzbasierten Empfehlungen zur pharmakologischen Therapie von depressiven Symptomen bei RLS. In der vorliegenden Ubersicht werden die klinische Relevanz von depressiven Storungen bei RLS und die Auswirkung einer antidepressiven Behandlung auf die RLS-Symptomatik diskutiert sowie ein Therapiealgorithmus (Evidenzklasse C) zur Behandlung einer komorbiden Depression bei RLS vorgestellt.

Background Although the diagnosis of restless legs syndrome (RLS) is largely based on the presence of the four essential criteria, no validated diagnostic questionnaire exists for use in epidemiological studies or clinical practice.

The pathogenesis of sleep attacks in Parkinson's disease (PD) is still unresolved. We investigated seven matched pairs of PD patients with and without a history of sleep attacks using continuous sleep EEG recording. According to the event marker altogether 12 sleep attacks were identified in three patients with a history of sleep attacks. All sleep attacks were characterized by NREM stage 1 and 2 sleep, whereas no sleep onset REM episodes were recorded. Five sleep attacks fulfilled our criteria for microsleep episodes lasting less than 120 s. The cumulative duration of microsleep episodes during the day was 27.7+/-20 min in patients with a history of sleep attacks vs. 6.4+/-4.1 min in patients without a history of sleep attacks (p=0.03), i.e., the majority of microsleep episodes were not perceived by the patients. In summary, our study suggests that sleep attacks are intrusions of NREM stage 1 and 2 sleep into wakefulness and can be identical to microsleep episodes. Future studies should systematically address the awareness of short sleep episodes in patients with PD and other disorders with increased daytime sleepiness.

Long-term efficacy and tolerability data are not yet available for patch formulations of dopamine agonists in restless legs syndrome.Efficacy and safety of rotigotine (0.5-4mg/24h), formulated as a once-daily transdermal system (patch), were investigated in an open extension (SP710) of a preceding 6-week placebo-controlled trial (SP709, 341 randomized patients) in patients with idiopathic restless legs syndrome. For efficacy assessment the international RLS severity scale (IRLS), the RLS-6 scales, the clinical global impressions (CGI) and the QoL-RLS questionnaire were administered. In addition, long-term tolerability and safety were assessed.Of 310 patients who finished the controlled trial, 295 (mean age 58+/-10 years, 66% females) with a mean IRLS score of 27.8+/-5.9 at baseline of SP709 were included. We report results after one year of this ongoing long-term trial. Two hundred twenty patients (retention rate=74.6%) completed the 12-month follow-up period. The mean daily dose was 2.8+/-1.2mg/24h with 4mg/24h (40.6%) being the most frequently applied dose; 14.8% were sufficiently treated with 0.5 or 1.0mg/24h. The IRLS total score improved by ?17.4+/-9.9 points between baseline and end of Year 1 (p0.001). The other measures of severity, sleep satisfaction and quality of life supported the efficacy of rotigotine (p0.001 for pre-post-comparisons of all efficacy variables). The tolerability was described as "good" or "very good" by 80.3% of all patients. The most common adverse events were application site reactions (40.0%), which led to withdrawal in 13.2%. Further relatively frequent adverse events were nausea (9.5%) and fatigue (6.4%). Two drug-related serious adverse events, nausea and syncope, required hospitalization. Symptoms of augmentation were not reported by the patients.Rotigotine provided a stable, clinically relevant improvement in all efficacy measures throughout one year of maintenance therapy. The transdermal patch was safe and generally well tolerated by the majority of patients. Comparable to any transdermal therapy, application site reactions were the main treatment complication.

Background: Patients suffering from Parkinson’s disease (PD) often complain about painful sensations. Recent studies detected increased subjective pain sensitivity and increased spinal nociception, which appeared to be reversible by dopaminergic treatment. Possibly, reduced descending pain inhibition contributes to this finding. Objective: Subjective pain thresholds as well as nociceptive reflex thresholds were investigated to isolate potential loci of the pathophysiological changes within the pain pathway. In addition, the diffuse noxious inhibitory control (DNIC) system as one form of descending control was assessed. Method: 15 patients with PD and 18 controls participated in the study. Electrical and heat pain thresholds as well as the nociceptive flexion reflex (NFR) thresholds were determined. Thereafter, the electrical pain thresholds were measured once during painful heat stimulation (conditioning stimulation) and twice during innocuous stimulation (control stimulation). Results: Patients with PD exhibited lower electrical and heat pain thresholds as well as lower NFR thresholds. Suppression of the electrical pain thresholds during painful heat stimulation (conditioning stimulation) compared with control stimulation did not differ significantly between the groups. No differences in the thresholds between patients with PD with and without clinical pain were seen. Conclusions: Finding the NFR threshold to be decreased in addition to the decreased electrical and heat pain thresholds indicates that the pathophysiological changes either already reside at or reach down to the spinal level. Reduced activation of the DNIC system was apparently not associated with increased pain sensitivity, suggesting that DNIC-like mechanisms do not significantly contribute to clinical pain in PD.

In a pilot placebo-controlled study, low dosages of 0.5-2mg/24h rotigotine showed a dose-dependent beneficial effect in restless legs syndrome (RLS) patients.Efficacy and safety of the dopamine agonist rotigotine, formulated as a once-daily transdermal system (patch), was investigated for five fixed dosages and compared to placebo in patients with idiopathic RLS in a double-blind, randomized, parallel-group, multicenter, six-week dose-finding trial. Primary efficacy measure was the total score of the International RLS Severity Scale (IRLS); in addition, the RLS-6 scales and the Clinical Global Impressions (CGI) were administered.Of 371 enrolled patients, 341 patients (mean age 58+/-10years, 67% females) were randomized. The IRLS total score improved between baseline and end of the six-week treatment period by -10.6 (0.5mg/24h rotigotine; patch area 2.5cm2), -15.1 (1mg/24h; 5cm2), -15.7 (2mg/24h; 10cm2), -17.5 (3mg/24h; 15cm2), and -14.8 (4mg/24h, 20cm2) as compared to placebo (-9.2). The hierarchical statistical test procedure demonstrated superiority of rotigotine over placebo for 4mg/24h, 3mg/24h, 2mg/24h, and 1mg/24h, with p-values of 0.0013,0.0001, 0.0003, and 0.0004, respectively. Only the 0.5mg/24h dose was not different compared to placebo (p=0.2338). The CGI and the RLS-6 severity items supported the efficacy of the rotigotine doses beyond 0.5mg/24h. The most frequent side effects were application site reactions and nausea and tended to be more frequent with higher doses.This dose-finding trial identified the range for a maintenance dose of rotigotine from 1mg/24h to 3mg/24h. The lowest dose was ineffective and, with the highest dose, no additional benefit was observed.

Idiopathic rapid-eye-movement (REM) sleep behavior disorder (iRBD) has been suggested to be a risk factor for subsequent development of neurodegenerative disorders, especially Parkinson's disease (PD) and other alpha-synucleinopathies. At present, it is not possible to predict whether or not an iRBD patient will eventually develop PD. Here, we report 5 iRBD patients who underwent a test battery comprising a neurological examination (including UPDRS rating), mini mental state examination testing, transcranial sonography, olfactory function testing, and presynaptic dopamine transporter imaging with FP-CIT-SPECT. Our preliminary data show the diverse pattern of individual combinations of pathological findings when a multimodal assessment approach is applied in this patient group. Large-size longitudinal studies in iRBD patients are required to evaluate the usefulness of diagnostic tests to identify the subgroup of iRBD patients that is prone to develop PD.

Background Augmentation is the main complication during long-term dopaminergic treatment of restless legs syndrome (RLS) and reflects an overall increase in RLS severity. Its severity varies considerably from a minor problem to a devastating exacerbation of disease. Despite its clinical relevance, systematic evaluations have rarely been undertaken and there has been no development of methods to assess the severity of augmentation. To fill this gap, the European RLS Study Group (EURLSSG) has developed the Augmentation Severity Rating Scale (ASRS), using three items that assess the degree of change in three specific dimensions of augmentation. The changes in each dimension are summed to give an ASRS total score. Methods The ASRS was developed to cover the basic dimensions defining RLS augmentation. The items were developed by an interactive process involving professional and patient input. The ASRS that was evaluated included four major items and two alternative forms of one item. The validation was conducted using 63 (85%) mostly untreated RLS patients from six centers, who were treated for six months with levodopa (l-Dopa) (up to 500mg/day, as clinically needed). Two consecutive assessments before and at baseline measured test–retest reliability. Consecutive ASRS ratings by two independent raters on a subsample of patients evaluated inter-rater reliability. Comparison with clinical severity ratings of two independent experts provided external validation of the ASRS. Comparison of patients with and without augmentation with regard to the items and the total score of the ASRS added discriminant validity. Results Sixty patients (63% females, mean age: 53years, baseline International RLS Severity Rating (IRLS) score 24.7±5.2) were treated with a median daily dose of 300mg l-Dopa (range: 50–500mg). Thirty-six patients (60%) experienced augmentation. Item analyses indicated that one item could be removed as it did not contribute significantly to the test score and only one form of the duplicated item needed to be used. The final ASRS then included three items. Test–retest reliability for the total score was ρ =0.72, and inter-rater reliability was rcc=0.94. Cronbach's α was 0.62. Validity as assessed by the correlation between the worst ASRS total score during the trial and the expert rating was ρ =0.72. ASRS total score differed between patients without versus with augmentation (mean: 7.4 (standard deviation (SD)=4.0) vs. 2.0 (2.7) ( P Conclusions The ASRS is a reliable and valid scale to measure the severity of augmentation. Due to the need to systematically quantify augmentation for both long-term efficacy and tolerability, the ASRS may become a useful tool to monitor augmentation in future clinical trials.

Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.

Data from a survey of 6,620 Parkinson's disease patients were examined for correlation of freezing with age, sex, duration, subjective severity of Parkinson's disease, and antiparkinsonian medication. Forty-seven percent of the patients reported experiencing freezing regularly. Logistic regression analysis showed that freezing was significantly associated with a longer disease duration and a more advanced stage of the disease. Freezing episodes were more likely in men than in women and in patients taking, in addition to levodopa, Entacapone, Amantadine, or dopamine agonists. Finally, patients considering tremor as their main symptom reported freezing less frequently. Common antiparkinsonian drugs given in combination with levodopa were not negatively correlated with freezing. The results underline the necessity to develop appropriate countermeasures against this phenomenon, which is widely known to cause significant impairment of patients' quality of life and—as our data also showed—may cause traffic accidents in licensed patients. © 2007 Movement Disorder Society

Dopaminergic agents are the best-studied agents and are considered first-line treatment of restless legs syndrome (RLS). Extensive data are available for levodopa, pramipexole, and ropinirole, which have approval for the indication RLS, and to a smaller extent for cabergoline, pergolide, and rotigotine. Apart from one recent study, comparing two active drugs (levodopa and cabergoline), no comparative studies have been published. The individual treatment regimen with the most appropriate agent concerning efficacy and side effects has to be selected by the treating physician. On the basis of these clinical trials and expert opinion of the authors, a treatment algorithm is proposed to support the search for the optimal individual treatment. Opioids and anticonvulsants such as gabapentine are second-line options in individual patients. Iron substitution is justified in people with iron deficiency related RLS (ferritin concentration lower than 50 microg/L).

BACKGROUND AND PURPOSE: We evaluated cerebral white and gray matter changes in patients with iRLS in order to shed light on the pathophysiology of this disease. METHODS: Twelve patients with iRLS were compared to 12 age- and sex-matched controls using whole-head diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) techniques. Evaluation of the DTI scans included the voxelwise analysis of the fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). RESULTS: Diffusion tensor imaging revealed areas of altered FA in subcortical white matter bilaterally, mainly in temporal regions as well as in the right internal capsule, the pons, and the right cerebellum. These changes overlapped with changes in RD. Voxel-based morphometry did not reveal any gray matter alterations. CONCLUSIONS: We showed altered diffusion properties in several white matter regions in patients with iRLS. White matter changes could mainly be attributed to changes in RD, a parameter thought to reflect altered myelination. Areas with altered white matter microstructure included areas in the internal capsule which include the corticospinal tract to the lower limbs, thereby supporting studies that suggest changes in sensorimotor pathways associated with RLS.

Gutachterliche Fragestellungen bei Patienten mit einem Restless-Legs-Syndrom (RLS) nehmen stetig zu. Darum hat die “AG Motorik und Schlaf” der DGSM erstmals Empfehlungen zur Begutachtung und sozialmedizinischen Einschatzung des RLS erarbeitet. Im Folgenden werden die spezifischen Empfehlungen zur Beurteilung des RLS im Rahmen gutachterlicher Verfahren zusammengefasst (aus [5]). Diese Konsensusleitlinie soll eine Grundlage zur Vereinheitlichung und Qualitatssicherung in der Begutachtung des RLS darstellen und nicht in individuelle Begutachtungen eingreifen.

Objective: To assess the efficacy and safety of the dopamine agonist cabergoline in the treatment of patients with idiopathic restless legs syndrome (CATOR study). Methods: Patients with moderate to severe restless legs syndrome (RLS) were randomly assigned to cabergoline (single evening dose: 2 mg) or placebo and treated for 5 weeks in a double-blind, multicenter polysomnography (PSG) trial. The primary efficacy measures were the periodic leg movements during sleep arousal index (PLMS-AI) and sleep efficiency. These and further PSG variables were monitored by centrally evaluated PSG. Severity of RLS was assessed using the International RLS Study Group Severity Scale (IRLS), the RLS-6 scales, the Sleep Questionnaire Form A (SF-A; quality of sleep), and the Quality of Life for RLS questionnaire. Results: Forty-three patients were treated and 40 patients were evaluated with PSG (age 56 ± 10 years, 73% women). Cabergoline was superior to placebo in terms of the PLMS-AI (−17.7 ± 16.4 vs −4.5 ± 20.0 placebo; p = 0.0024), sleep efficiency (+6.2 ± 13.9% vs +3.3 ± 11.7%; p = 0.0443), PLMS index ( p = 0.0014), PLM index ( p = 0.0012), and total sleep time ( p = 0.0443). Improvements in IRLS total score (−23.7 ± 11.2 vs −7.9 ± 11.0 placebo; p = 0.0002), RLS-6 severity scales during the night ( p = 0.0010) and during the day ( p = 0.0018), Clinical Global Impressions severity item ( p = 0.0003), sleep quality ( p = 0.0180), SF-A sleep quality ( p = 0.0371), and QoL-RLS ( p = 0.0247) were larger in patients treated with cabergoline compared with the placebo group. Adverse events were only mild and well-known side effects of dopamine agonists. Conclusion: Single-evening cabergoline is an efficacious and well-tolerated short-term therapy for sensorimotor symptoms of restless legs syndrome and associated sleep disturbances.

We developed and validated a standardized test procedure to evaluate the accuracy of the supportive diagnostic criterion "response to dopaminergic treatment" in restless legs syndrome (RLS). Forty-eight patients who fulfilled at least three of the four essential criteria for RLS, thus including uncertain clinical cases for a nonexpert, were recruited. Patients received a preliminary diagnosis of RLS or non-RLS. All patients underwent a polysomnography (PSG) and were then asked to perform the diagnostic L-DOPA test at home, which consisted in the application of one single dose of 100/25 mg L-DOPA/benserazide and a subsequent observational period of 2 hours. Before, and in 15-minute intervals after, drug intake, the patients rated the severity of the "symptoms in the legs" and the "urge to move the legs" using a 100-mm visual analogue scale. Considering a 50% improvement as a positive test result, we found a sensitivity of 88% ("symptoms in the legs") and 80% ("urge to move the legs") with a specificity of 100% for both test items. A rate of 90% or 83% of all patients could be correctly diagnosed by the L-DOPA test. Both scales were able to predict the response to dopaminergic agents in the subsequent course of the treatment by 100%. The periodic leg movements arousal index as assessed by polysomnography was less appropriate for the prediction of the correct diagnosis. We recommend the L-DOPA test for diagnostic decision making in all patients with an unclear RLS diagnosis according to the essential diagnostic criteria of the International RLS Study Group.

The term ‘sleep attack’ is used in patients with Parkinson's disease (PD) to designate a sudden onset of sleep (SOS) without any prior sleepiness. Clinically, sleep attacks can be distinguished from unintended sleep episodes, i.e. SOS with prior sleepiness. This study aimed to assess the prevalence of SOS and to identify its predictors in patients with sleep-disordered breathing (SDB). A total of 114 consecutive patients with the clinical suspicion of obstructive sleep apnoea syndrome (OSAS) and a respiratory disturbance index (RDI) of >5/h were examined using a questionnaire and polysomnography (PSG). Altogether 57.7% reported SOS, with 5.2% of the total population describing exclusively sleep attacks. SOS was observed in both patients with obstructive sleep apnoea-hypopnoea (OSAH) or increased upper airway resistance (UAR). Increased scores on the Epworth Sleepiness Scale (ESS) were the best predictor of SOS. Logistic regression showed a possible association of SOS with a low PLMS index, while no definite effect was observed for other PSG parameters. Our data show that SDB is frequently associated with SOS. Future studies should address in more detail whether SDB patients with sleep attacks pose an increased accident risk.

Treatment standards or guidelines have been developed for most features of Parkinson's disease (PD). However, data on the actual treatment that is put into practice are scarce. In 2000, a nationwide survey on the topic of sudden onset of sleep (SOS) in PD was initiated among the members of the German patient support group (deutsche Parkinson-Vereinigung, dPV). A part of this mailed questionnaire survey covering the antiparkinsonian and concomitant medication of the participants is presented here. This study analyses data sets from more than 6,500 PD patients. The mean dopaminergic dose was equivalent to 599 +/- 387 mg levodopa/die. The most frequently administered drugs were levodopa (94.2 %), dopamine agonists (DA) (71.7 %), amantadine (40.1 %), selegiline (27.6 %), entacapone (20.4 %), budipine (12.3 %), and anticholinergics (11.8 %). Costs of pharmacotherapy were estimated to be approximatelyeuro399 million/year in Germany. PD drug therapy in general strongly depended on age, disease duration, and the level of care. The treatment guidelines were apparently not consistently followed underlining the need for their continuous propagation throughout the medical community. In addition our data suggest that non-motor symptoms in PD are not adequately treated and that concomitant sedative medication contributes to the occurrence of SOS.

With respect to the ongoing discussion of “sleep attacks” in Parkinson's disease (PD), we sought to estimate the prevalence of sudden onset of sleep (SOS) with and without preceding sleepiness in PD, to identify associated factors, and to define the role of antiparkinsonian medication in SOS. We sent a questionnaire about SOS, sleep behaviour, and medication to 12,000 PD patients. The response rate was 63%, from which 6,620 complete data sets could be analysed. A total of 42.9% of our population reported SOS, 10% of whom never experienced sleepiness before the appearance of SOS (4.3% of all), and we identified the administration of all dopaminergic drugs as a risk factor for SOS. However, SOS occurred earlier after introduction of nonergoline dopamine agonists (DA) and was more strongly associated with nonergoline DA in younger patients (below 70 years) with a shorter disease duration (up to 7 years) but, actually, medication was less efficient in predicting SOS than most other factors considered such as higher age, male sex, longer disease duration, and the report of sleep disturbances. This survey strongly suggests that SOS is a multifactorial phenomenon. Some subgroups are at particular risk of experiencing SOS under nonergoline DA, especially at the beginning of this therapy. Our results support the current notion that SOS, in part, can be attributed to PD-specific pathology because disease duration and subjective disease severity have been shown to be predictors of SOS. We recommend the development of a standardised question to recognise SOS and to facilitate the comparison of prevalence estimates. © 2004 Movement Disorder Society

Efficacy and safety of the dopamine agonist rotigotine (RTG) was investigated in patients with moderate to severe idiopathic restless legs syndrome (RLS), including daytime symptoms. Three fixed doses of rotigotine (1.125 mg, 2.25 mg, and 4.5 mg) and placebo were applied by patches (size, 2.5 cm2 per 1.125 mg) in a double-blind, randomized, parallel-group, multicenter, 1-week, proof-of-principle trial. The primary efficacy measure was the total score on the International Restless Legs Syndrome Scale (IRLS). Additionally, the RLS-6 scale, the Clinical Global Impressions (CGI), and a sleep diary were used. Of 68 enrolled patients, 63 (mean age, 58+/-; 9 years; 64% women) were randomly assigned. RLS severity improved related to dose by 10.5 (1.125 mg RTG/die; P = 0.41), 12.3 (2.25 mg RTG/die; P = 0.18), and 15.7 points (4.5 mg RTG/die; P < 0.01) on the IRLS compared to placebo (8 points). According to the RLS-6 scales, daytime symptoms significantly improved with all rotigotine doses. The CGI items supported the favorable efficacy of the 4.5-mg dose. Skin tolerability of the patches and systemic side effects were similar between rotigotine and placebo. This pilot study suggests that continuous delivery of rotigotine by means of a patch may provide an effective and well-tolerated treatment of RLS symptoms both during night and day.

Cerebrospinal fluid (CSF) and blood obtained from 22 untreated or scarcely treated patients with moderate to severe restless legs syndrome (RLS; mean age, 58.6 +/- 13 years) and 11 control subjects (mean age, 56.6 +/- 12.9 years) were investigated for biogenic amines between 6:00 and 8:00 PM. We did not find any significant differences in the CSF concentrations of homovanillic acid, 3-ortho- methyl-dopa, levodopa, 5-hydroxytryptophan, 5-hydroxyindoleacetic acid, tetrahydrobiopterin, dihydrobiopterin, 5-methyltetrahydrofolate, and neopterin. In addition, serotonin in whole blood and plasma activity of aromatic amino acid decarboxylase were all normal. Our results suggest that dopaminergic and serotonergic release is not substantially affected in RLS.

Dopaminergic agents are considered the treatment of choice for restless legs syndrome (RLS); levodopa is the only substance licensed for this disorder in some European countries. However, in a substantial proportion of patients symptoms are not adequately controlled for a whole night due to the short half-life of levodopa or because symptom augmentation may develop. To further investigate the impact of pramipexole on the management of RLS we performed a short-term open label trial with pramipexole in 17 patients who were being insufficiently treated with levodopa or for whom pramipexole was primarily being considered because of the severity of the RLS symptoms. A single dose of 0.125–0.75 mg pramipexole (mean 0.3 ± 0.2 mg) in the evening resulted in a significant improvement of subjective RLS symptoms as rated by the International RLS Study Group Severity Scale (IRLS scores: 29.8 ± 4.7 baseline vs. 7.3 ± 5.9 endpoint; p = 0.0001). Polysomnographic recordings showed a significant improvement of the periodic leg movements (PLM) index, PLM sleep arousal index, sleep-onset latency, total sleep time and sleep efficiency. All patients who had developed a worsening of RLS symptoms under levodopa recovered from daytime symptoms after their medication was switched to pramipexole. Since pramipexole was well tolerated, an ideal dosage to control RLS symptoms could be reached rapidly. Pramipexole has proven a suitable alternative in patients with moderate to severe RLS, particularly when their therapy has to be switched to a dopamine agonist.

Die selbstberichtete Pravalenz von Tagesmudigkeit und Schlafstorungen bei Parkinson-Patienten vor und seit ihrer Erkrankung sollte abgeschatzt und auf Zusammenhange zueinander uberpruft werden. Ferner sollte erhoben werden, worauf die Patienten diese Symptome attribuieren und wie diese mit der Menge an Tagschlaf korreliert sind. Ein Fragebogen zu Schlafstorungen, Schlafverhalten, Tagesmudigkeit etc. wurde an 12 000 Parkinson-Patienten verschickt. Bei einer Rucklaufquote von 63% konnten die Daten von 6620 Patienten analysiert werden. Die Pravalenz von Tagesmudigkeit (35% vs. 71%) und Schlafstorungen (23% vs. 76%) war akut signifikant hoher als vor der Parkinson-Krankheit (P

Patients with idiopathic REM sleep behavior disorder (iRBD) are at very high risk of developing neurodegenerative synucleinopathies, which are disorders with prominent autonomic dysfunction. Several studies have documented autonomic dysfunction in iRBD, but large-scale assessment of autonomic symptoms has never been systematically performed. Patients with polysomnography-confirmed iRBD (318 cases) and controls (137 healthy volunteers and 181 sleep center controls with sleep diagnoses other than RBD) were recruited from 13 neurological centers in 10 countries from 2008 to 2011. A validated scale to study the disorders of the autonomic nervous system in Parkinson's disease (PD) patients, the SCOPA-AUT, was administered to all the patients and controls. The SCOPA-AUT consists of 25 items assessing the following domains: gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, and sexual dysfunction. Our results show that compared to control subjects with a similar overall age and sex distribution, patients with iRBD experience significantly more problems with gastrointestinal, urinary, and cardiovascular functioning. The most prominent differences in severity of autonomic symptoms between our iRBD patients and controls emerged in the gastrointestinal domain. Interestingly, it has been reported that an altered gastrointestinal motility can predate the motor phase of PD. The cardiovascular domain SCOPA-AUT score in our study in iRBD patients was intermediate with respect to the scores reported in PD patients by other authors. Our findings underline the importance of collecting data on autonomic symptoms in iRBD. These data may be used in prospective studies for evaluating the risk of developing neurodegenerative disorders.

Restless legs syndrome (RLS) is a common neurologic disorder characterized by nightly dysesthesias affecting the legs primarily during periods of rest and relieved by movement. RLS is a complex genetic disease and susceptibility factors in six genomic regions have been identified by means of genome-wide association studies (GWAS). For some complex genetic traits, expression quantitative trait loci (eQTLs) are enriched among trait-associated single nucleotide polymorphisms (SNPs). With the aim of identifying new genetic susceptibility factors for RLS, we assessed the 332 best-associated SNPs from the genome-wide phase of the to date largest RLS GWAS for cis-eQTL effects in peripheral blood from individuals of European descent. In 740 individuals belonging to the KORA general population cohort, 52 cis-eQTLs with pnominal

The relationship between Restless Legs Syndrome (RLS) and Parkinson's disease (PD) is still controversial. Most genetic, pathological, and imaging data argue against a close association of these two disorders. Still, many studies reported an increased prevalence of RLS in PD patients. These studies are difficult to interpret because the current diagnostic criteria for RLS have not been validated in PD patients. Although many PD patients suffer from motor restlessness due to parkinsonism and may thus mimic RLS, the risk for (secondary) RLS in PD patients is probably slightly increased. This review provides an overview of the current pertinent literature and discusses the possible association between RLS and PD.

We identified association of restless legs syndrome (RLS) with PTPRD at 9p23-24 in 2,458 affected individuals and 4,749 controls from Germany, Austria, Czechia and Canada. Two independent SNPs in the 5' UTR of splice variants expressed predominantly in the central nervous system showed highly significant P values (rs4626664, P(nominal/lambda corrected) = 5.91 x 10(-10), odds ratio (OR) = 1.44; rs1975197, P(nominal/lambda corrected) = 5.81 x 10(-9), OR = 1.31). This work identifies PTPRD as the fourth genome-wide significant locus for RLS.

Luigi Ferini-Strambi • Wolfgang Oertel • Yves Dauvilliers • Ronald B. Postuma • Sara Marelli • Alex Iranzo • Isabelle Arnulf • Birgit Hogl • Raffaele Manni • Tomoyuki Miyamoto • Maria-Livia Fantini • Monica Puligheddu • Poul Jennum • Karel Sonka • Joan Santamaria • Marco Zucconi • Paola M. V. Rancoita • Smeranda Leu-Semenescu • Birgit Frauscher • Michele Terzaghi • Masayuki Miyamoto • Marcus Unger • Karin Stiasny-Kolster • Alex Desautels • Christina Wolfson • Amelie Pelletier • Jacques Montplaisir

Currently, it is unclear whether sleep attacks in Parkinson's disease (PD) represent a novel entity or just a phenomenon of daytime sleepiness. We investigated 10 PD patients with sleep attacks and compared them with 10 PD patients without any daytime sleepiness. The patients were matched according to their dopaminergic medication and subjected to a sleep medical investigation. The mean sleep latency on the multiple sleep latency test was in the normal range and not significantly different between the groups. These data suggest that sleep attacks can occur against a background of normal alertness.

Pancreatic polypeptide is released immediately after food ingestion. The release is operated by vagal-abdominal projections and has therefore been suggested as a test for vagal nerve integrity. Pathoanatomical and clinical studies indicate vagal dysfunction in early Parkinson's disease (PD).We assessed the postprandial secretion of pancreatic polypeptide and motilin in healthy controls (n = 18) and patients with idiopathic rapid-eye-movement sleep behavior disorder (iRBD, n = 10), a potential premotor stage of PD, as well as in drug-naive (n = 19) and treated (n = 19) PD patients.The postprandial pancreatic polypeptide secretion showed a physiological pattern in all groups and even an enhanced response in drug-naive PD and iRBD. Motilin concentrations correlated with pancreatic polypeptide concentrations.Postprandial pancreatic polypeptide secretion is not a suitable test for vagal nerve integrity in PD. The unimpaired pancreatic polypeptide response in iRBD and PD might be explained by partially intact vagal-abdominal projections or compensatory mechanisms substituting a defective neuronal brain-gut axis.

Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that is an important risk factor for Parkinson's disease (PD) and Lewy body dementia. Its prevalence is unknown. One barrier to determining prevalence is that current screening tools are too long for large-scale epidemiologic surveys. Therefore, we designed the REM Sleep Behavior Disorder Single-Question Screen (RBD1Q), a screening question for dream enactment with a simple yes/no response.Four hundred and eighty-four sleep-clinic-based participants (242 idiopathic RBD patients and 242 controls) completed the screen during a multicenter case-control study. All participants underwent a polysomnogram to define gold-standard diagnosis according to standard criteria.We found a sensitivity of 93.8% and a specificity of 87.2%. Sensitivity and specificity were similar in healthy volunteers, compared to controls or patients with other sleep diagnoses.A single-question screen for RBD may reliably detect disease, with psychometric properties favorably comparable to those reported for longer questionnaires.

An affiliation and its funding information were omitted from the published paper. Siong-Chi Lin and Zbigniew Wszolek are also affiliated with: Mayo Clinic, Jacksonville, Florida, United States of America. Research at the Mayo Clinic Florida was supported by NIH/NINDS P50NS072187 and Mayo Clinic Florida Research Committee CR program.

Summary Background Safety and efficacy of non-ergot dopamine agonists for the treatment of idiopathic restless legs syndrome have been shown in short-term trials. We did a prospective open-label extension of a 6-week, double-blind randomised trial to assess the safety, tolerability, and efficacy of rotigotine transdermal patch for up to 5 years in patients with restless legs syndrome. Methods Patients (aged 18–75 years) with moderate-to-severe idiopathic restless legs syndrome were treated with once-daily rotigotine transdermal patch in 33 centres in Austria, Germany, and Spain between July 31, 2003, and April 15, 2009. The dose was titrated in weekly increments (up to 4 weeks) from 0·5 mg/24 h to a maximum of 4 mg/24 h, and was followed by up to 5 years of maintenance at the optimum dose. Primary safety outcomes included occurrence of adverse events and dropouts. Efficacy assessments were secondary and included the International Restless Legs Syndrome study group severity rating scale (IRLS). Augmentation of symptoms was assessed by means of standard diagnostic criteria and was confirmed by an international expert panel. All patients who received at least one dose of study drug were included in assessments. This study is registered with ClinicalTrials.gov, number NCT00498186. Findings 295 patients entered the open-label study, of whom 126 (43%) completed 5 years of follow-up. 169 (57%) patients discontinued treatment, 89 (30%) because of adverse events and 31 (11%) because of lack of efficacy. 70 patients (24%) discontinued during year 1 of maintenance. The most common adverse events were application site reactions, which occurred in 37% (106/290) of patients in year 1, 17% (38/220) of patients in year 2, 14% (27/191) of patients in year 3, and in less than 6% of patients during year 4 (8/159) and year 5 (8/147). 56 patients (19%) discontinued because of application site reactions. Mean rotigotine dose was 2·43 mg/24 h (SD 1·21) after initial titration and 3·09 mg/24 h (1·07) at the end of maintenance. Of 89 patients who discontinued because of adverse events, 28 (31%) were on 4 mg/24 h rotigotine. Mean IRLS score of patients entering the open-label study was 27·8 (SD 5·9) at baseline of the double-blind trial. In patients who completed the maintenance period, mean IRLS score was reduced from a baseline score of 27·7 (SD 6·0) by a mean of 18·7 points (SD 9·5) to a score of 9·0 (SD 9·2) at the end of maintenance. 39% (48/123) of patients who completed the trial were classified as symptom free according to the IRLS. Clinically significant augmentation was recorded in 39 patients (13%), of whom 15 (5%) were receiving a dose of rotigotine within the range approved by the European Medicines Agency (EMA; 1–3 mg/24 h) and 24 (8%) were receiving 4 mg/24 h rotigotine. Interpretation Rotigotine transdermal patch is generally well tolerated after 1 year and provides sustained efficacy for patients with moderate-to-severe restless legs syndrome at a stable dose for up to 5 years. Thus, rotigotine transdermal patch is an appropriate long-term treatment option for moderate-to-severe restless legs syndrome, a disorder that often requires lifelong treatment. Funding UCB BioSciences, on behalf of Schwarz Pharma, Ireland.

Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10−11, OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10−19, OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5′-end of TOX3 and the adjacent non-coding RNA BC034767., Author Summary Restless legs syndrome (RLS) is one of the most common neurological disorders. Patients with RLS suffer from an urge to move the legs and unpleasant sensations located mostly deep in the calf. Symptoms mainly occur in resting situations in the evening or at night. As a consequence, initiation and maintenance of sleep become defective. Here, we performed a genome-wide association study to identify common genetic variants increasing the risk for disease. The genome-wide phase included 922 cases and 1,526 controls, and candidate SNPs were replicated in 3,935 cases and 5,754 controls, all of European ancestry. We identified two new RLS–associated loci: an intergenic region on chromosome 2p14 and a locus on 16q12.1 in a linkage disequilibrium block containing the 5′-end of TOX3 and the adjacent non-coding RNA BC034767. TOX3 has been implicated in the development of breast cancer. The physiologic role of TOX3 and BC034767 in the central nervous system and a possible involvement of these two genes in RLS pathogenesis remain to be established.

Ghrelin, an orexigenic peptide, has multiple functions, which include promoting gastrointestinal motility and influencing higher brain functions. Experimental data suggest that ghrelin has neuroprotective potential in the MPTP mouse model of Parkinson’s disease (PD). PD patients show delayed gastric emptying and other symptoms that may relate to disturbed excretion of ghrelin. No data are available on postprandial ghrelin response in patients with PD and idiopathic REM sleep behaviour disorder (iRBD)––a condition considered a putative preclinical stage of PD. We measured fasting and postprandial ghrelin serum concentrations in 20 healthy controls, 39 (including 19 drug-naive) PD patients and 11 iRBD patients using a commercial radioimmunoassay for total ghrelin. For statistical analysis we employed ANCOVA and post-hoc testing with Bonferroni’s method. Controls showed a decrease of mean fasting ghrelin serum concentrations in the early postprandial phase, followed by a recuperation starting 60 min after the test meal and reaching a maximum at 300 min. This recuperation was less pronounced in PD and iRBD; the slope of relative postprandial ghrelin recovery was different between the investigated groups (p = 0.007). Post-hoc testing showed a difference between controls and PD patients (p = 0.002) and between controls and iRBD patients (p = 0.037). The dynamic regulation of ghrelin in response to food intake is partially impaired in subjects at putative preclinical (iRBD) and clinical stages of PD. Reduced ghrelin excretion might increase the vulnerability of nigrostriatal dopaminergic neurons as suggested by animal studies. The impaired ghrelin excretion might qualify as a peripheral biomarker and be of diagnostic or therapeutic value.