T. C. Wetter

A controlled study of additional sr-l-dopa in l-dopa–responsive restless legs syndrome with late-night symptoms

Objective: To investigate whether a combination treatment of regular-release levodopa (rr-l-dopa) and sustained-release levodopa (sr-l-dopa) compared with monotherapy of rr-l-dopa improves sleep quality and reduces periodic limb movements (PLM) in patients with restless legs syndrome (RLS) and problems with maintaining sleep. Background: Reappearance of RLS symptoms during the second half of the night while being treated with rr-l-dopa is a common problem in the treatment of sleep disturbances caused by RLS. Methods: A randomized, controlled, double-blind crossover trial was undertaken. Eligible patients fulfilled the diagnostic criteria of the International RLS Study Group, and met an actigraphically confirmed higher number of PLM per hour time in bed (PLM index) during the second half compared with the first half of the night under treatment with rr-l-dopa. During the crossover periods the patients received 100 to 200 mg rr-l-dopa plus either placebo or 100 to 200 mg sr-l-dopa at bedtime for 4 weeks each period. Results: Thirty patients with RLS (11 men and 19 women) were assessed by actigraphy and subjective sleep quality, and showed a significant improvement in PLM index (p < 0.0001), in “time in bed without movements” (p < 0.0001), and in subjective sleep quality (p < 0.001). Eight of 30 patients reported an altered pattern of RLS symptoms, characterized by a time shift of RLS symptoms into the afternoon or evening, five of these during monotherapy with rr-l-dopa. Conclusions: A combination therapy of rr-l-dopa and sr-l-dopa is better than monotherapy with rr-l-dopa in reducing the frequency of PLM and problems maintaining sleep, even in patients who are severely affected.

Efficacy of pergolide in treatment of restless legs syndrome: The PEARLS study

Objective: To evaluate the short- and long-term safety and efficacy of pergolide therapy for restless legs syndrome (RLS) in a double-blind, placebo-controlled, randomized trial (Pergolide European Australian RLS [PEARLS] study). Methods: We randomized 100 patients with idiopathic RLS were randomized to pergolide, 0.25 to 0.75 mg, in the evening or placebo for 6 weeks (phase 1); thereafter, patients with response on the Patient Global Impression (PGI) scale continued on double-blind pergolide or placebo, and nonresponders received open-label pergolide up to 1.5 mg/d for 12 months of treatment (phase 2). Sleep efficiency (SE) and periodic limb movements during sleep (PLMS) arousal index were monitored by centrally evaluated polysomnography (PSG). The severity of RLS was assessed using the validated International RLS Scale (IRLS). Results: In phase 1 (change from baseline to week 6), pergolide reduced PLMS arousal index vs placebo (mean ± SD, −12.6 ± 10.0 vs −3.6 ± 15.9; p = 0.004), and SE did not improve (mean ± SD, +11.3 ± 11.9% vs +6.1 ± 18.6%; p = 0.196). Pergolide improved RLS severity score (−12.2 ± 9.9 vs −1.8 ± 7.5 placebo; p < 0.001) and was associated with a higher PGI response (68.1% vs 15.1%; p < 0.001) and improvements in periodic limb movements (PLM) index, PGI improvement scale, Clinical Global Impression improvement, and IRLS (all p < 0.001), patient-reported SE (p = 0.019), and quality of sleep (p < 0.001). After 12 months (phase 2), double-blind pergolide maintained improvements in PLMS arousal index and PLM index. Placebo patients switched to open-label pergolide in phase 2 exhibited marked improvements in these measures that were maintained at 12 months. Pooled results from the blinded and open-label pergolide groups demonstrated improvements at 12 months in the PLMS arousal index (p = 0.028) and PLM index (p < 0.0001) compared with placebo. Nausea and headache were more frequent with pergolide than with placebo treatment. Conclusions: Pergolide substantially improves periodic limb movement measures and subjective sleep disturbance associated with restless legs syndrome. Low-dose pergolide was well tolerated and maintained its efficacy in the long term.

Long-term effects of pergolide in the treatment of restless legs syndrome

An open follow-up of a controlled study in patients with restless legs syndrome (RLS) shows that the beneficial effect of pergolide on RLS symptoms persists throughout at least 1 year. Twenty-two patients of 28 (78.6%) continued to take pergolide. Polysomnographic measurements showed a persistent improvement of PLM index, PLMS arousal index, total sleep time, and sleep efficiency (p = 0.0001). Side effects, in particular nausea, were common but were well controlled by domperidone in most patients.

Presynaptic dopaminergic function in patients with restless legs syndrome: Are there common features with early Parkinson's disease?

The cause of restless legs syndrome (RLS) is unknown, but an involvement of the dopaminergic system and a possible relation to Parkinsons disease (PD) is suggested by the positive response to dopaminergic treatment. We imaged the striatal dopamine transporter with [123I] N‐(3‐iodopropen‐2‐yl)‐2β‐carbomethoxy‐3β‐(chloro‐phenyl) tropane ([123I]IPT) and single‐photon emission computed tomography (SPECT) in 28 RLS patients, and compared the results with transporter binding in 29 patients with early PD and 23 age‐matched controls. No difference in IPT binding was found between RLS patients and controls. IPT binding was correlated significantly with age in RLS patients and controls, whereas there was no relation with the duration of symptoms or severity of RLS. PD patients presented significant lower presynaptic IPT binding ipsi‐ and contralateral to the affected body side compared with RLS patients or controls. We found no common characteristics between RLS patients and patients with early PD detectable by dopamine transporter SPECT. Our results do not strengthen an identical pathophysiologic pathway between RLS and PD on the level of nigrostriatal presynaptic terminal function.

Restless legs syndrome and its treatment by dopamine agonists

The restless legs syndrome (RLS) characteristically presents with an irresistible urge to move that is most often accompanied by creeping sensations deep in the limbs. Occasionally the upper limbs can also be affected. RLS symptoms occur at rest and are typically more intense at night and at bedtime. Some patients complain about involuntary leg movements, so-called periodic limb movements (PLM), while at rest or PLM have been observed by the bed partner. Often, patients have to get out of bed several times at night, to relieve themselves of their disagreeable sensations.The prevalence of RLS is estimated to be about 5%. Up to now only three classes of drugs have been systematically evaluated for treatment of RLS: benzodiazepines, opioids and dopaminergic agents.The most consistent results have been obtained with dopaminergic drugs. Several studies have shown that L-dopa given with a peripheral decarboxylase inhibitor at a 10:4 ratio is effective in treating RLS. Controlled studies using polysomnographic recordings in a double-blind design showed that L-dopa administered at night produces a significant reduction of RLS occurring at bedtime and of PLM, which are often associated with nocturnal arousals. In most cases, L-dopa 100mg, in conjunction with the decarboxylase inhibitor carbidopa or benserazide 25mg, suppresses RLS although a rebound of PLM may be observed in the last part of the night. The two major adverse effects frequently seen in patients treated with L-dopa are:Augmentation is one of the limiting factors of L-dopa therapy; thus, alternative treatment options are of major interest. In several open treatment trials performed with pergolide, patients reported a marked improvement of RLS symptoms including sleep problems. Mild symptoms of augmentation under pergolide treatment have been reported from single patients. In another 6-month open label trial, pergolide proved to be effective in patients who developed augmentation under L-dopa by relieving daytime symptoms after switching to pergolide.Most recently, the results of these open label trials have been replicated in a randomized, placebo-controlled, double-blind multicenter trial. Treatment with a single evening dose of 0.25-0.75mg pergolide resulted in a significant improvement of almost all subjective and objective parameters. Under pergolide, patients rated their RLS symptoms and sleep disturbances much less severe and polysomnographic recordings also revealed a significant improvement of all important sleep parameters. To prevent peripheral side-effects such as nausea or orthostatic hypotension, pergolide should be slowly up-titrated or domperidone should be added. Under these conditions, no major side-effects have been observed in treatment trials with pergolide in dosages up to 1.25mg.Pergolide with a half-life of 12-16h thus appears to be an appropriate drug in the therapy of RLS especially in those patients who developed augmentation under L-dopa therapy. Owing to the remarkable therapeutic effect of pergolide on RLS symptom control, other dopamine agonists are presently being tested for the treatment of RLS.

Restless-legs-Syndrom und “periodic limb movements in sleep”

ZusammenfassungDas Restless-legs-Syndrom (RLS) zählt mit einer Prävalenz von 2% bis zu 9% in der älteren Bevölkerung zu den häufigsten neurologischen Erkrankungen. Sensible und motorische Beschwerden der Beine, die in Ruhe auftreten, sowie ein Bewegungsdrang, der zu ausgeprägten Schlafstörungen führen kann, gehören zu den charakteristischen Symptomen. Die typische Anamnese und ein unauffälliger neurologischer Untersuchungsbefund ermöglichen rasch die klinische Diagnosestellung. Zusätzliche laborchemische und elektrophysiologische Untersuchungen sind notwendig, um assoziierte Erkrankungen zu erfassen. Die Indikation zu einer schlafpolygraphischen Untersuchung zur Registrierung der bei RLS-Patienten üblicherweise auftretenden periodischen Beinbewegungen (PLM) muss differenziert gestellt werden. Die therapeutischen Maßnahmen richten sich hauptsächlich nach der Art und dem Schweregrad des RLS.In der vorliegenden Arbeit wird eine Übersicht der klinischen Symptomatik des RLS mit einer Empfehlung diagnostischer und therapeutischer Maßnahmen gegeben sowie eine Abgrenzung zum Phänomen der “periodic limb movements” erarbeitet. Die Arbeitsgruppe Motorik und Schlaf der DGSM hat hierbei versucht, modifizierte Richtlinien für Diagnostik und Therapie des RLS in Anlehnung an die Guidelines der American Sleep Disorder Association zu erstellen.SummaryRestless legs syndrome is one of the most common neurological disorders, with a prevalence of 2% to 9% in the elderly population. Sensory and motor symptoms of the legs and an urge to move that occur at rest may lead to severe sleep disturbances and are part of the syndrome. Typical history and normal neurological examination lead to the clinical diagnosis. Additional laboratory and neurophysiological investigations are necessary to rule out associated diseases. The indication for polysomnography to record periodic limb movements in sleep must be discussed in individual cases. Treatment strategies will be recommended individually according to the disease severity. In this article we present an overview of the clinical symptomatology and include recommendations on diagnosis and treatment of RLS and differentiation of RLS from periodic limb movement disorder. To this purpose, the Motor System and Sleep Work Group of the German Society of Sleep Medicine presents modified guidelines for diagnosis and treatment of RLS according to recent recommendations of the American Sleep Disorder Association.

Clinical trials in restless legs syndrome - Recommendations of the European RLS study group (EURLSSG)

The European Restless Legs Syndrome (RLS) Study Group (EURLSSG) is an association of European RLS experts who are actively involved in RLS research. A major aim of the Study Group is the development and continuous improvement of standards for diagnosis and treatment of RLS. Several members developed study designs and evaluation methods in investigator‐initiated trials early in the 1990s, and all members have since contributed to many pivotal and nonpivotal drug trials for the treatment of RLS. The recommendations on clinical investigations of pharmacological treatment of RLS patients summarize the groups expertise and knowledge acquired through clinical trials. The recommendations primarily address how to plan and conduct confirmatory, randomized clinical studies in patients with idiopathic RLS. Advice is presented for the diagnosis of RLS and clinical and polysomnographic inclusion and exclusion criteria. Primary and secondary endpoints for an evaluation of efficacy are based on a critical description of validated methods for both short‐ and long‐term trials, also in special populations (children, pregnant women, elderly patients). The recommendations include the assessment of augmentation. Finally, general issues including the evaluation of safety and tolerability, as well as specific neurological and cardiovascular risks and sleep attacks/daytime somnolence, are discussed. The aim of these recommendations is to support research groups or pharmaceutical companies in the design of optimized study protocols.

Pathophysiologie, Klinik und Therapie von Schlafstörungen beim Morbus Parkinson

ZusammenfassungIm Rahmen des Morbus Parkinson treten Schlafstörungen auf, welche in erster Linie auf den Dopaminmangel selbst, die nächtliche Akinese, Pharmakotherapie sowie Begleitfaktoren wie Alter und Depression zurückgeführt werden. Diese Störungen betreffen sowohl die Mikro- und Makrostruktur des NonREM- und REM-Schlafes als auch Motorik, respiratorische und autonome Funktionen. Seit kurzem finden auch Tagesschläfrigkeit sowie die Frage der Wechselwirkungen zwischen Schlaf- und Wachmotorik beim M. Parkinson vermehrt Beachtung.Die Erkennung und Behandlung von Schlafstörungen ist nicht nur wegen des assoziierten Selbst- und Fremdgefährdungspotenzials (z. B. bei REM sleep behavior disorder, Tagesschläfrigkeit) von herausragender Bedeutung, sondern auch für die Lebensqualität des Patienten und seiner Angehörigen. Aufgrund der außergewöhnlichen Häufigkeit (ca. 70%) von Schlafstörungen beim M. Parkinson und diesen u. U. weitreichenden Konsequenzen sollte eine systematische Schlafanamnese und ggf. die spezifische Therapie bei jedem Parkinson-Patienten integraler Bestandteil der Behandlung sein.SummaryParkinsons disease (PD) is associated with sleep disorders which are attributed mainly to dopamine deficiency, nocturnal akinesia, drug therapy, and cofactors such as age and depression. These disturbances affect the macro- and microstructure of both REM and non-REM sleep and motor, respiratory, and autonomic functions. Excessive daytime sleepiness and the interactions between sleep and daytime motor performance in PD are not yet completely understood. Correct diagnosis and treatment of sleep disorders is essential due to the risk of harm to the patient and others and due to their effect on quality of life for all concerned. As sleep disorders in PD are extremely common (about 70%) and may have severe consequences, a systematic sleep history and specific therapy should be considered integral to treatment in every PD patient.

Klinische Elektrophysiologie im Schlaf

Die Grundlage der modernen Schlafforschung und Schlafmedizin wurde 1929 mit der Entdeckung des menschlichen Elektroenzephalogramms (EEG) durch Hans Berger gelegt (Berger 1929). Loomis und Mitarbeiter konnten zeigen, dass Schlaf in Abhangigkeit von der jeweiligen Schlaftiefe durch unterschiedliche Muster der hirnelektrischen Aktivitat gekennzeichnet ist und somit in verschiedene Schlafstadien eingeteilt werden kann (Loomis et al. 1937). Im Jahr 1953 beschrieben Aserinsky und Kleitman erstmals ein Schlafstadium, das nach den charakteristischen raschen Augenbewegungen als REM-Schlaf (REM: rapid eye movement) bezeichnet wurde (Aserinsky u. Kleitman 1953). Dem gegenubergestellt wird der Non-REM- und REM-Schlaf sind zwei fundamental unterschiedliche Schlafzustande, die sich im Verlauf der Nacht regelhaft abwechseln. Beide unterscheiden sich nicht nur hinsichtlich des Auftretens rascher Augenbewegungen und der Auspragung des Elektroenzephalogramms, sondern auch in einer Vielzahl anderer physiologischer Parameter wie beispielsweise der Regulation der Atmung, des Herz-Kreislauf-Systems, der hormonellen Sekretion oder der Motorik.

Das Restless-legs-Syndrom (RLS).

Das Restless-legs Syndrom (RLS) ist eine eigenstandige neurologische Erkrankung, die durch unangenehme MIssempfindungen in den Beinen, seltener auch in den Armen, charakterisiert ist. Mit diesen Sensationen ist ein starker innerer Drang verbunden, die jeweilige Extremitat zu bewegen, sodass die Betroffenen gezwungen sind, aufzustehen und umherzugehen. Durch die Bewegung kommt es zu einer Besserung der Beschwerden. Die Symptome treten typischerweise nur in Ruhepositionen auf und unterliegen einer zirkadianen Rhythmik mit einem Schwerpunkt in den Abendstunden.