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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

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.

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.

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

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.

Substantia nigra (SN) hyperechogenicity--a sonographic vulnerability marker for Parkinson's disease (PD)--has been recently described in patients with idiopathic REM sleep behaviour disorder (RBD). It is not known whether subjects with narcolepsy (who frequently have associated RBD) also show SN hyperechogenicity. The aim of this study was to (1) evaluate SN echogenicity in narcolepsy and (2) determine whether transcranial sonography (TCS) differs in narcoleptic subjects with and without RBD. A total of 16 patients with narcolepsy-cataplexy (7 had a concomitant, video-polysomnographically based diagnosis of RBD) were examined with TCS by two investigators blinded to the clinical data. The size of the SN echogenic area in both subgroups was within the range previously described for healthy subjects. The brainstem raphe, however, was reduced in five of seven narcoleptic subjects with RBD, whereas only two of nine narcoleptic subjects without RBD exhibited this TCS finding. We conclude that evaluation of SN echogenicity does not discriminate between both subgroups. The absence of SN hyperechogenicity in narcoleptic patients with RBD supports the hypothesis that SN hyperechogenicity in patients with presumed idiopathic RBD is an additional risk marker for subsequent evolvement of PD rather than an RBD-immanent finding. Reduced echogenicity of the brainstem raphe might indicate an involvement of the serotonergic system in narcoleptic subjects with RBD.

We summarize recent advances in the clinical definition of restless legs syndrome (RLS), in understanding the basic mechanisms, and the successful treatments of RLS. New diagnostic instruments and severity scales have been developed for better phenotyping of the individual patient. Iron metabolism related components and the dopaminergic system have been extensively investigated in respect to the pathophysiology of RLS. The presence of mechanical hyperalgesia to pin-prick points towards an involvement of the nociceptive system. Genetic research has reported loci on chromosome 12q and 14q to play a role in the vulnerability to RLS. Placebo-controlled large-scale phase II and III treatment trials have shown that dopamine agonists are safe and efficacious agents for the treatment of this disorder.