Restless legs syndrome

from Wikipedia, the free encyclopedia
Classification according to ICD-10
G25.8 Other specified extrapyramidal diseases and movement disorders [restless legs syndrome]
ICD-10 online (WHO version 2019)

The restless legs syndrome ( RLS , English for the syndrome of restless legs ) refers to a type of movement disorder that is characterized by discomfort and an urge to move the legs and feet (less often in the arms). RLS is often accompanied by involuntary movements. These symptoms worsen at rest and at night, while they are less pronounced during the day and during exercise.

The syndrome is counted among the extrapyramidal hyperkinesias and belongs to the sleep-related movement disorders according to the classification system for sleep disorders (" International Classification of Sleep Disorders ", ICSD-2). Other names are also Wittmaack-Ekbom syndrome or Willis-Ekbom disease .

In German one speaks of restless legs , but the abbreviation RLS is also becoming increasingly popular as a name for the disease. The symptoms vary from person to person, including neurological disease.

discovery

In the second half of the 17th century, Thomas Willis described the symptoms for the first time. In 1861 the German clinician Theodor Wittmaack named the disease after its most noticeable symptom , restless legs, as Anxietas tibiarum . The term Restless Legs was coined in 1945 by the Stockholm neurologist Karl-Axel Ekbom . This is why the Wittmaack-Ekbom syndrome or Willis-Ekbom disease is also sometimes used .

Symptoms

Symptoms RLS patients
Sleep disorders
(all forms) 		95%
Urge to move
(rest situation) 		95%
Hearing loss
(rest position) 		91%
Complaints
(during the day) 		76%
spontaneous movement
(resting situation) 		50%

Frequency of symptoms in patients with
idiopathic RLS (after Trenkwalder 1997)

The RLS manifests itself in the form of abnormal sensations, so-called paresthesias , in the legs and / or feet, less often in the arms and / or hands and in the back. The symptoms can manifest themselves in a wide variety of ways, such as pulling, tensing, tingling, pins and needles, pain, pressure or warmth, and are accompanied by an almost irresistible urge to move the affected body regions, to tense or stretch the muscles. The symptoms in the extremities are often limited to the lower legs or forearms, but can extend to the thighs or shoulders. With regard to the exact location in the legs, there are various statements. The shins, starting from the ankle to the knee, are often described as the starting point for the complaints, while elsewhere the calves are described. The sensations are described as deep in the muscles, sometimes as seated in the bones, only rarely as superficial. For those affected, the nature of the complaints is generally difficult to put into words, insofar as there is hardly any adequate comparison. The symptoms usually occur symmetrically on both sides, but can also only affect one side or alternate right and left.

Typically, the abnormal sensations appear only or predominantly during phases of physical inactivity, i.e. when sitting or lying down relaxed, and occasionally when standing still, and worsen towards the evening. For some sufferers, the symptoms are limited to the evening and night, while the rest of the day remains symptom-free. RLS is characterized by immediate relief through muscle activity, i.e. moving the affected limbs by walking around, squats, cycling, periodic tensing, etc. However, after the short-term improvement achieved through movement, the symptoms usually return immediately or only after the next rest situation a few minutes back. The RLS can occur in attacks lasting days or months, followed by periods of symptom-free duration that are just as long. Symptoms can only appear occasionally on a few days, especially with milder RLS.

The accumulation of complaints in the evening and at night (for many people roughly between 10 p.m. and 4 a.m.) is attributed to circadian rhythms . So it is probably not solely due to the physical rest that is typical at this time of day. On the other hand, relaxation situations, boredom and restricted mobility can aggravate the symptoms regardless of the time of day.

Frequent side effects of RLS are periodic twitching of the legs or arms during sleep ( periodic limb movements ) without the patient being aware of them. These movements can also occur less frequently when the patient is awake. These jerks often lead to unnoticed disturbances in sleep through repeated brief waking up (so-called arousals ).

Sequelae

“Ideal-typical”, disturbed sleep pattern of an RLS patient (red), which is characterized by constant arousals . In comparison, the sleep stages of a healthy person (blue).

The agonizing restlessness in the limbs and the unrestrainable compulsion to move often lead to problems falling and staying asleep. Especially in the case of more pronounced symptoms, those affected do not necessarily have to be aware of the actual cause of their problem, as the urge to move is often involuntarily given in without this being consciously perceived, let alone recognized as a sign of illness.

The extent of sleep deprivation due to conscious or unconscious sleep disorders can be enormous in RLS patients. This often leads to chronic daytime sleepiness , listlessness , exhaustion , irritability, concentration disorders, restlessness, forgetfulness, dizziness , migraines , a weakening of the immune system, a shift in the day-night rhythm or other sequelae typical for long-term sleep deprivation. Frequent long-term consequences of untreated continuation are therefore a general decline in performance, social isolation and - as the most serious consequence - depression . In the case of painful manifestations, as with all persistent pain conditions, a chronic pain syndrome can also develop. Due to the various complaints, the RLS can lead to a massive loss of quality of life.

Affected people sometimes also report other symptoms that could either be related to the impaired dopamine metabolism or the consequences of lack of sleep. Examples would be cravings at night, intolerance to alcohol and caffeine , chronic gastrointestinal complaints, tension headaches and worsening of the RLS after exercise or from heat or cold.

diagnosis

The diagnosis is often first made by a neurologist ( neurologist or psychiatrist ). In the diagnosis, the clinical symptoms are in the foreground. A validated scale is available as a tool to determine the severity of the clinical picture ( RLS Severity Scale ). Even a single administration of L-Dopa or sublingually applied apomorphine improves the symptoms dramatically in almost all RLS patients, so that a successfully carried out experiment can serve as a demonstrative test ( ex juvantibus ). A so-called immobilization test , in which the affected person's legs are fixed for a period of time, can cause the aforementioned accompanying involuntary, i.e. H. not voluntarily suppressable periodic twitches of the muscles come to light. In unclear cases, polysomnography in the sleep laboratory is required.

The differential diagnosis must RLS especially against polyneuropathy , funicular myelosis (vitamin B12 deficiency), radiculopathy , akathisia , vein problems , leg cramps ( Crampi nocturni ), vascular disease ( " claudication "), pruritus and sleep myoclonus are deferred.

The side effects of RLS very often lead to a wrong diagnosis, as the underlying disease is often not recognized. Experience in sleep laboratories shows that up to 20% of general sleep disorders are caused by undetected forms of RLS. The erroneous assumption that there is a psychosomatic disorder , depression or hypochondria leads in extreme cases to long-term "patient careers" characterized by frequent changes of doctor, in which suicide attempts or unnecessary stays in inpatient psychiatric facilities can occur.

distribution

It is estimated that about 5–10% of the population in Germany are affected by RLS, depending on the severity. It is therefore one of the most common neurological diseases. 60% of the patients are women. However, in around 80% of those affected, the symptoms are so weak that they do not require any therapy. In the United States, the proportion of the population in need of treatment is estimated at 2.7%.

The predisposition to this disease can be inherited as an autosomal dominant trait. The prevalence of the idiopathic form of RLS among first-degree relatives of RLS patients is three to five times as high as among people without RLS. More than 50% of patients with idiopathic RLS have a “positive family history”. The familial predisposition has been confirmed by twin studies , but the degree of genetic influence remains uncertain. Research is being carried out into the localization of the causative gene . If the RLS is passed on in a family, one observes the tendency that the symptoms appear earlier and are more pronounced with each subsequent generation ( anticipation ).

to form

A distinction is made between a secondary (symptomatic) and a primary (idiopathic) form of RLS:

Secondary form

The secondary form of RLS occurs frequently together with or can be triggered by pregnancy as well as by diseases or conditions such as iron deficiency anemia , deficiency in folic acid or vitamin B12 , pernicious anemia , uremia , renal insufficiency with dialysis , arthritis , diabetes mellitus , hypothyroidism , hyperthyroidism , Parkinson's disease and the like a. neurological diseases as well as through a number of drugs (mainly dopamine antagonists and various antidepressants ). Even after serious surgical interventions such as a total knee replacement , RLS often worsens or the first appearance of RLS occurs. On the other hand, RLS occurs only slightly more often in high blood pressure, after a heart attack or stroke.

By definition, the secondary form of the RLS disappears after the trigger is removed.

Idiopathic form

This manifestation of the disease often becomes apparent in the third decade of life.

In milder cases or in the early stages of the disease, the form, frequency and severity of the symptoms can vary considerably from person to person. Even if the disease is not considered to be degenerative , there is a tendency for the symptoms to worsen with advancing age. The increase in complaints is then rather gradual and not necessarily continuous. A spontaneous improvement of the clinical picture is considered unusual. A cure for the idiopathic form of RLS by eliminating the cause is currently not possible (as of 2017).

Unilateral symptoms

More or less one-sided complaints do not rule out the possibility of an RLS. In a sample of 195 patients with RLS, 17% had a unilateral disorder for no apparent reason. In five of 17 patients who developed RLS for the first time within one month of a stroke, the RLS symptoms were unilateral. After knee surgery, the affected side is often more clearly or alone disturbed.

causes

Diagram showing the disruption of dopamine metabolism. In the case of healthy brain metabolism (left), the vesicles in the neuron transport dopamine, which can be released, in the case of a disturbed (right) the vesicles are empty, so that activation does not take place.

The causes of Restless Legs Syndrome have not yet been clearly clarified. The neurotransmitter dopamine plays a central role ; the extrapyramidal disorders are certainly the result of an altered transmitter metabolism .

Studies using imaging techniques such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and single photon emission computed tomography (SPECT) have produced some controversial results in the observation of the pre- and postsynaptic dopaminergic neurotransmitter system and brain metabolism. These indicate a malfunction of the central dopaminergic system. Whether this is caused by a change in certain areas of the brain (e.g. the substantia nigra ) or whether these phenomena are only secondary phenomena of the restless legs syndrome has not yet been conclusively clarified.

Sonographic, laboratory chemical and individual neuropathological examinations are also compatible with a reduced iron store in the brain of RLS patients.

In an opiate (such as heroin or morphine) is the restless legs syndrome, which is a known complaint due to the familiarity of dopamine receptors by opiates.

The studies have also shown that the red nuclei ( nuclei rubri ) and the brain stem or thalamus near the reticular formation are activated while the symptoms appear. This indicates involvement of subcortical generators.

Since no single explanatory model has yet been able to explain all clinically occurring symptoms, it is assumed that impairments on different neuronal levels lead to different manifestations and combinations of symptoms.

Parallels to Parkinson's are obvious, but previous studies have not been able to establish a connection between the two diseases. RLS patients are therefore no more often affected by Parkinson's disease than the rest of the population.

A study published in 2014 took a different approach. According to the researchers, RLS is not a global disorder of the dopaminergic system, but rather an intramuscular oxygen deficiency ( hypoxia ) of the muscles of the lower extremities due to decreased blood flow. In the study, the oxygen saturation (SpO 2 ) of the lower extremities with and without medication was measured in 15 subjects with RLS and a control group of 14 symptom-free subjects, taking into account the normalized RLS severity. A significantly reduced SpO 2 was found in RLS patients , which improved with L-Dopa administration. The vasodilatory side effect of L-Dopa via the NO system is probably responsible for this, and not the cerebral neurotransmitter deficiency in dopamine, as is prevalent in Parkinson's disease.

treatment

Overview diagram of the most common therapy options for RLS.

Treatment must be geared towards the patient's subjective suffering. The primary focus is usually on improving the quality of sleep. Demand-oriented or long-term drug therapy should be inevitable for the majority of those affected with pronounced symptoms.

With the secondary form of RLS, the underlying cause must be eliminated if possible; for example, contraindicated drugs should be avoided and increased kidney values ​​should be reduced by dialysis if necessary. Treating RLS during pregnancy can be very difficult.

In cases in which treatment with only a certain group of active substances ( monotherapy ) proves to be unsuccessful or, after prolonged use, increasingly inefficient, the doctor can also use a combination therapy (e.g. dopamine agonist + L-dopa).

Aggravation

Aggravation is a serious side effect, especially during long-term treatment with levodopa and dopamine agonists. A distinction must be made between therapy-independent (“spontaneous”) and worsening of the RLS symptoms that occurs after the drug is discontinued (“ rebound ”). The core symptom of aggravation is an earlier onset of symptoms in the course of the day (at least 4 hours compared to the start of current therapy). Aggravation is also shown by the fact that the period of rest until the symptoms appear is shorter: For example, if RLS symptoms previously only appeared after hours, they are now there after just a few minutes. The third symptom of aggravation is the spread of discomfort from the legs to other parts of the body, especially the arms. The guideline currently applicable to RLS recommends switching to opiates, gabapentin or pregabalin in such cases, even if these active ingredients are currently not approved for this indication .

Levodopa (L-Dopa)

The main therapy for mild and only occasional complaints is the administration of levodopa (e.g. Restex, Madopar), a precursor of dopamine . It leads to almost instant relief from the discomfort. However, long-term administration leads to aggravation in some patients after prolonged use (see above): It is the most common and most important of the side effects of levodopa. In some cases, the aggravation can be reversed with a lower daily dose or by dividing the dose into several small doses. In addition, the development of tolerance and the rapid waning of the effects over the course of the night are common problems.

Dopamine agonists

In the treatment of severe or daily complaints, dopamine- like substances ( dopamine agonists ) are now the means of choice. These substances stimulate dopamine receptors .

  • Dopamine agonists derived from ergot alkaloids (also known as “ergoline dopamine agonists” or “ergot derivatives”) such as cabergoline (Cabaseril®) and pergolide (Parkotil®), which are also used in the treatment of Parkinson's disease , are highly effective, although not undisputed, active ingredients with side effects in RLS . However, if they are tolerated, they can be taken indefinitely and increase the quality of life of those affected considerably (approx. 50% of users are symptom-free for more than a year). Other substances used in this group of active ingredients are bromocriptine and lisuride . The German health insurances usually no longer pay for the costly RLS therapy with these substances ( off-label use ).
  • The (nonergoline) dopamine agonists ropinirole (Adartrel® or Requip®) and pramipexole (Sifrol® or Mirapexin®), which were both approved for the treatment of RLS in early 2006, can also alleviate the symptoms of RLS. With long-term treatment with pramipexole, for example, augmentation does not occur as often as with L-Dopa. The drugs are therefore currently the gold standard in the treatment of RLS in addition to the treatment with L-Dopa preparations .
  • Studies on dopamine agonists in transdermal application (patch) with the active ingredient rotigotine (Neupro® patch, Leganto® patch) have shown the effectiveness and tolerance of this active ingredient and the dosage form. A special feature of transdermal rotigotine therapy seems to be that the risk of augmentation is particularly low. It is now used successfully for Parkinson's disease and RLS. Another candidate for this application is lisuride .

Opioids

Opioids such as tilidine (e.g. Valoron N), oxycodone (e.g. Targin) or codeine are available as the (strongest) treatment in severe and severe, especially painful cases or when other therapy attempts have failed. In addition, like levodopa, they can be used as a supplement to basic therapy. After the effectiveness of the fixed combination of retarded oxycodone with naloxone (Targin®) was demonstrated in pretreated patients with RLS, this preparation was approved for the RLS in May 2014.

With this group of substances, the analgesic effect that is often desired is less of a priority for the treatment of RLS . Rather, the dopaminergic component of this group of substances is used, which has an influence on extrapyramidal motor mechanisms by activating central μ-receptors. The increasing development of tolerance and the ceiling effect pose a problem here, so the use of this group of substances is delayed as long as possible. Therapy with methadone may be necessary in individual cases in order to guarantee the therapeutic goal of maintaining a minimal quality of life in the most severe RLS cases.

Gift of iron

One of the discussed causes of RLS is a disruption of the iron metabolism with the consequence of a lack of oxygen in the muscles. Sonographic, laboratory chemical and individual neuropathological examinations are also compatible with a reduced iron store in the brain of RLS patients. The iron saturation there is closely related to that in the blood. Ferritin is one of the parameters for the iron available in the blood . In fact, patients with deeply normal ferritin (<50 ng / ml) suffer from rather severe RLS symptoms. Therefore, laboratory tests with determination of the ferritin in the serum are carried out if RLS has been diagnosed. In general, a guideline value of <50 µg / l is given as a pragmatic limit value for any iron administration. However, ferritin is an acute phase protein , so it increases with inflammation, even when iron levels are low. Therefore, some authors suggest transferrin saturation as a more meaningful parameter for the iron inventory. In principle, a significantly reduced iron level in the body is disadvantageous and should therefore be corrected. With regard to RLS, however, a meta-analysis of numerous studies in 2012 showed that neither intravenous nor oral administration of iron leads to a significant improvement in RLS symptoms. The aim of the o. A. According to the guideline of the German Society for Neurology, the ferritin benchmark is therefore not an evidence-based measure in RLS.

Other methods

Alternative medications

Various anticonvulsants - such as gabapentin (Gabax / Neurontin) or pregabalin (Lyrica), which is currently again attracting research interest - have shown a certain effectiveness in RLS. In a large comparative study carried out in 2014, pregabalin was as effective in RLS as pramipexole, but the augmentation rate was five times lower. However, side effects such as drowsiness and somnolence are a limiting factor. Pregabalin is also considered to be abuse and addictive in certain patients.

As alternative medication or for certain indications, a. also clonazepam , carbamazepine , clonidine and valproic acid are available. No studies are available on the efficacy of tetrahydrocannabinol , but at least individual patients have shown significant improvements in RLS symptoms after the administration of dronabinol .

There is a dispute about the effectiveness of magnesium supplements. In a scientific study by the Freiburg University Clinic, no significant improvements in magnesium supplements compared to placebo could be found, but the author of the study points to possible weaknesses in the study design and the need for further investigations and therefore does not want to rule out the effectiveness of magnesium supplements.

Non-drug measures

RLS patients have a reduced blood flow to the skin compared to control persons. The application of vibrations to the entire body for about 1/4 hour a day for 1 week not only normalized the skin blood flow, but also improved symptoms typical of RLS. Another week of daily vibrations did not result in any additional improvement. However, it has not yet been proven whether and, if so, under what conditions and to what extent the experiences of individual patients can also be transferred to other patients, according to which further non-drug measures alleviate RLS symptoms such as improving sleep hygiene , light sport, gymnastic exercises ( like stretching ), Pilates , yoga , Taijiquan , Qigong , massages , avoiding caffeine , showering with cold or hot water, eating and brushing the feet and calves with a dry root brush.

Detrimental or ineffective measures

The use of sleeping pills , antidepressants , neuroleptics and beta blockers is disadvantageous and therefore contraindicated , as this increases the neuromuscular disorders of the RLS. RLS sufferers report an improvement in their symptoms if and as long as they exercise. On the other hand, physical rest, including immobilization as part of a test, leads to an increase in symptoms, especially if this occurs late in the evening and at night. Although psychotherapeutic measures cannot eliminate the RLS themselves, they can help with everyday coping with the symptoms and consequences of the RLS.

Others

A study published in 2006 showed that the increased media coverage generated by restless legs syndrome - especially in the context of the dedicated marketing of drugs - can be seen as a paradigmatic example of disease mongering . It does not fundamentally question the existence or the individual severity of the disease in those affected, but rather the consequences of the awareness generated by the media (possibly specifically launched by lobby groups) , which in turn has consequences for the probability of a certain selection of diagnoses and the attribution of symptoms by doctors and patients. Although RLS can occur as a serious disease, the majority of those affected do not or do not yet need urgent treatment. The media presence of the disease and the promotion of drugs, however, lead to pressure on doctor and patient: The "informed patient" exerts influence on the diagnosis of his practitioner, doctors, in turn, are often involved in relationships with pharmaceutical companies, especially since they are also not immune to it Are advertising. In the opinion of the authors, all of these factors can increase the likelihood of a diagnosis of "RLS" and thus of the start of drug treatment (possibly too early or even unnecessary if the diagnosis is careless) at the expense of the patient and the healthcare system.

However, this investigation is based only on the evaluation of a collection of press releases and articles. To what extent this information actually contributes to an increased diagnosis and treatment of RLS and what proportion of it is justified (e.g. as a result of an actually eliminated information deficit) or really unnecessary, the investigation does not show.

literature

Scientific literature
  • Roland Depner: Is it all a matter of nerves? How our nervous system works - or not , Schattauer, Stuttgart 2012, ISBN 978-3-7945-2887-5 .
  • Peter A. Berg (ed.): Chronic fatigue and fibromyalgia syndrome: a location determination , Springer, Berlin / Heidelberg 1999, ISBN 978-3-540-65093-5 .
  • Boris Stuck et al .: Practice of Sleep Medicine. Sleep disorders in adults and children Diagnostics, differential diagnostics and therapy , Springer, Heidelberg 2009.
  • Helga Peter, Thomas Penzel, Jörg Hermann Peter (eds.): Encyclopedia of Sleep Medicine , Springer, Heidelberg 2007, ISBN 978-3-540-28840-4 .
  • Jan Geisendörfer: Dream content and stress in patients with restless legs syndrome and / or periodic leg movements during sleep (PLMS) , dissertation, Heidelberg 2019.
  • Veronika Schneider: The Restless Legs Syndrome. An overview for doctors of all specialties. Springer, Wiesbaden 2017, ISBN 978-3-658-18244-1 .
  • Peter Clarenbach, Heike Benes: Restless Legs Syndrome: The restless legs. Clinic, diagnostics, therapy. 2nd Edition. UNI-MED, Bremen a. a. 2006, ISBN 3-89599-631-9 ( UNI-MED science )
  • DB Rye, LM Trotti: Restless legs syndrome and periodic leg movements of sleep. In: Neurol Clin. 30, 2012, pp. 1137-1166. PMID 23099132 (Review).
  • Claudia Trenkwalder: Restless legs syndrome. Clinic, differential diagnosis, neurophysiology, therapy. Springer, Berlin 1998, ISBN 3-540-63314-6 .
Guidelines
Literature for those affected
  • Jörn P. Sieb, German RLS Association: Restless Legs: Finally calm legs again. With self-tests for reliable diagnosis. Restful sleep again. The new drugs. 3rd, completely revised Edition. Trias, 2010, ISBN 978-3-8304-3544-0 .
  • Frithjof Tergau, Marion Zerbst: When your legs don't come to rest. Restless legs syndrome. 5th edition. Ehrenwirth, Munich 2001, ISBN 3-431-04017-9 .
  • RLS e. V. German Restless Legs Association: When the legs are upside down. Living with Restless Legs Syndrome. 1st edition. Kochan & Partner, Munich 2015, ISBN 978-3-932317-20-0 .

Individual evidence

  1. ↑ S3 guideline for non-restful sleep / sleep disorders of the German Society for Sleep Research and Sleep Medicine (DGSM). In: AWMF online (as of 2009).
  2. ↑ Karl-Axel Ekbom: Restless legs: A clinical study of a hitherto overlooked disease in the legs characterized by peculiar parasthesia ("Anxietas tibiarum"), pain and weakness and occuring in two main forms, Asthenia crurum paraesthetica and asthenia crurum dolorosa; a short review of paresthesias in general. (= Acta medica Scandinavica. Suppl. 158). Hæggström, Stockholm 1945.
  3. ↑ a b c Karin Stiasny-Kolster: Encyclopedia of Sleep Medicine . Ed .: Helga Peter, Thomas Penzel, Jörg Hermann Peter. Springer, Heidelberg 2007, ISBN 978-3-540-28840-4 , pp. 1018 f .
  4. ↑ a b c d Peter A. Berg (Ed.): Chronic fatigue and fibromyalgia syndrome: A location determination . Springer, Berlin / Heidelberg 1999, ISBN 978-3-540-65093-5 , pp. 96 f .
  5. ↑ RESTLESS LEGS SYNDROME - DETECT AND TREATMENT - drug telegram. Retrieved March 23, 2020 .
  6. ↑ Roland Depner: Is it all a matter of nerves? How our nervous system works - or not . Schattauer, Stuttgart 2012, ISBN 978-3-7945-2887-5 , pp. 115 .
  7. ↑ Daniel J Blum, Emmanuel During, Fiona Barwick, Polina Davidenko, Jamie M Zeitzer: 0009 Restless Leg Syndrome: Does It Start With A Gut Feeling? In: Sleep . tape 42 , Supplement_1, April 13, 2019, ISSN  0161-8105 , p. A4 – A4 , doi : 10.1093 / sleep / zsz067.008 ( oup.com [accessed March 23, 2020]).
  8. ↑ a b c d e f S1 guidelines for Restless Legs Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD) of the German Society for Neurology (DGN). In: AWMF online (as of 2012), dgn.org (PDF; 1.7 MB).
  9. ^ RP Allen et al: Restless legs syndrome prevalence and impact: REST general population study. In: Arch. Intern. Med. 165, 2005, pp. 1286-1292. PMID 15956009 .
  10. ↑ Genetic risk factors identified for Restless Legs Syndrome. Federal Ministry of Education and Research.
  11. ↑ Nadine B. Groß: Restless Legs Syndrome in monozygous and dizygotic twins . (PDF; 1.1 MB) Dissertation. TU Munich, 2010, p. 84. A rather sobering result, but the number of subjects was very low, so that no final conclusions can be drawn.
  12. ↑ Silke Schubach: Analysis of candidate genes for Restless Legs Syndrome. Dissertation. Hamburg 2006.
  13. ↑ Barbara Schormair: Genome-wide and regional case-control association studies in the genetic analysis of restless legs syndrome. (PDF) Dissertation. Technical University of Munich, 2010 (PDF; 3.9 MB).
  14. ↑ Yang Lu: Genetics of restless legs syndrome: mutational analysis of candidate genes at the RLS5 locus in a German family. Dissertation. Kiel 2007.
  15. ↑ Paulo Daubian-Nosé, Miriam K. Frank, Andrea Maculano Esteves: Sleep disorders: A review of the interface between restless legs syndrome and iron metabolism. In: Sleep Sci. 7 (4), Dec 2014, pp. 234–237, doi: 10.1016 / j.slsci.2014.10.002 , PMC 4608891 (free full text)
  16. ^ F. Hohl-Radke, F. Aedtner, U. Domröse, KH Neumann, J. Staedt: Restless legs syndrome in renal failure requiring dialysis: Influence of medication. In: German Medical Weekly. 133, 3, 2008, pp. 71-75.
  17. ↑ Torsten Gallwitz: Restless Legs Syndrome as a side effect of "modern" antidepressants . (PDF; 299 kB) Dissertation. Munich 2007.
  18. ↑ a b José Carlos Pereira Júnior, João Luiz Pereira da Silva Neto, Márcia Pradella-Hallinan: Restless legs syndrome in subjects with a knee prosthesis: evidence that symptoms are generated in the periphery. In: Clinics. 66, 2011, p. 1955, doi: 10.1590 / S1807-59322011001100017 .
  19. ↑ a b Raja Mehanna, Joseph Jankovic: Restless legs syndrome and cerebrovascular disease - Authors' reply . In: The Lancet. March 3, 2014, doi: 10.1016 / S1474-4422 (13) 70126-1 , thelancet.com (PDF; 56 kB).
  20. ↑ See however: Juliane Hellwig: Frequency of RLS (Restless Legs Syndrome) -related symptoms in pediatrician patients aged six to 17 years in connection with psychopathological characteristics. Dissertation. Göttingen 2005.
  21. ^ Restless Legs Syndrome Fact Sheet . United States National Institutes of Health (NIH) , 2015.
  22. ^ Restless Leg Syndrome (RLS) . In: Pocket Notes for Adult Medicine. 2008.
  23. ↑ G. Shukla, A. Gupta, RM Pandey, M. Kalaivani, V. Goyal, A. Srivastava, M. Behari: What features differentiate unilateral from bilateral restless legs syndrome? A comparative observational study of 195 patients. In: Sleep medicine. Volume 15, number 6, June 2014, pp. 714–719, doi: 10.1016 / j.sleep.2014.01.025 . PMID 24813392 .
  24. ↑ TC weather, I. Iron Very, C. Trenkwalder: Functional neuroimaging studies in restless legs syndrome. In: Sleep Med. 5, 2004, pp. 401-406. PMID 15223000 .
  25. ↑ Aaro Salminen: Peripheral Hypoxia and Autonomic Responses in Restless Legs Syndrome . (PDF).
  26. ↑ RLS due to hypoxia in the legs? In: Doctors newspaper. 23rd July 2014.
  27. ↑ Augmentation - An experience from clinical research and drug studies . German RLS Association.
  28. ↑ Mark Fuhrer book: allaying augmentation . 2015.
  29. ↑ L. Ferini-Strambi et al.: Effect of pramipexole on RLS symptoms and sleep: A randomized, double-blind, placebo-controlled trial. In: Sleep Med. 2008 Oct 24. J. Montplaisir u. a .: Ropinirole is effective in the long-term management of restless legs syndrome: a randomized controlled trial. In: Mov Disord. 21 (10), Oct 2006, pp. 1627-1635.
  30. ↑ C. Trenkwalder u. a .; SP790 Study Group: Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomized, double-blind, placebo-controlled trial. 2008.
  31. ↑ CM Baldwin, GM Keating: Rotigotine transdermal patch: in restless legs syndrome. In: CNS Drugs . 22 (10), 2008, pp. 797-806.
  32. ↑ Annett Deißler: Lisurid in the therapy of the Restless Legs Syndrome . Dissertation. Univ. Rostock, 2012. PPN 687954282.
  33. ^ A. Walters et al.: Long-term therapy of restless legs syndrome with opiates ( Memento from April 29, 2005 in the Internet Archive ). In: Movement Disorders. 16, 2001, pp. 1105-1109.
  34. ↑ Kathrin Helmschmied: Investigation of the extrastriatal dopaminergic system with the low-dose apomorphine test of patients with idiopathic Parkinson's syndrome and restless legs syndrome. Dissertation. Göttingen 2006.
  35. ↑ a b Claudia Trenkwalder, Heike Beneš, Ludger Grote, Diego García-Borreguero, Birgit Högl, Michael Hopp, Björn Bosse, Alexander Oksche, Karen Reimer, Juliane Winkelmann, Richard P Allen, Ralf Kohnen: Prolonged release oxycodone – naloxone for treatment of Severe restless legs syndrome after failure of previous treatment: a double-blind, randomized, placebo-controlled trial with an open-label extension. In: The Lancet Neurology . 12, 2013, pp. 1141-1150, doi: 10.1016 / S1474-4422 (13) 70239-4 .
  36. ↑ Beate Fessler: Oxycodon / Naloxon against Restless Legs. In: Deutsche Apotheker Zeitung. 20th June 2014.
  37. ^ Sarah von Spiczak Brzezinski: The role of opioids in restless legs syndrome: an 11C-diprenorphine positron emission tomography study. Dissertation. Göttingen 2006.
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This version was added to the list of excellent articles on August 1, 2005 .