Restless legs syndrome

Restless legs syndrome (RLS) is a sensorimotor neurological disorder characterised by an urge to move the limbs with a circadian pattern (occurring in the evening/at night), more prominent at rest, and relieved with movements. RLS is one of the most prevalent sleep disorders, occurring in 5%-10% of the European population. Thomas Willis first described RLS clinical cases already in the 17th century, and Karl-Axel Ekbom described the disease as a modern clinical entity in the 20th century. Despite variable severity, RLS can markedly affect sleep (partly through the presence of periodic leg movements) and quality of life, with a relevant socio-economic impact. Thus, its recognition and treatment are essential. However, screening methods present limitations and should be improved. Moreover, available RLS treatment options albeit providing sustained relief to many patients are limited in number. Additionally, the development of augmentation with dopamine agonists represents a major treatment problem. A better understanding of RLS pathomechanisms can bring to light novel treatment possibilities. With emerging new avenues of research in pharmacology, imaging, genetics, and animal models of RLS, this is an interesting and constantly growing field of research ¹⁾.

Restless legs syndrome epidemiology.

In most cases, doctors do not know the cause of restless legs syndrome; however, they suspect that genes play a role. Nearly half of people with RLS also have a family member with the condition.

At the outset of genetic studies in restless legs syndrome (RLS), the disorder was assumed to be a classical monogenic disorder that runs in families. However, years of family studies did not reveal any causally-related genes or genetic variants. The advent of high-throughput genotyping technology led to a change; genome-wide association studies in large case-control samples became feasible, which led to the identification of first genetic risk variants for RLS. Variants detected by this approach are common ones, which that individually confer only a minor increase in risk of disease. Overall, the currently known risk variants in six genomic loci account for only a small proportion of the genetically determined susceptibility to RLS. Additional risk loci and individual variants remain to be discovered. First studies indicate that rare genetic variants are also important contributors in RLS. These are expected to have a larger impact on the phenotype and may thus prove to be excellent candidates for functional studies and, in the long-term, targets for developing therapeutics or preventive measures. To enable their discovery, large-scale studies including tens of thousands of affected individuals may be needed. Next-generation sequencing technologies such as whole exome or whole genome sequencing will be essential for this endeavor. Even though the number of known risk variants is still limited, they have been indispensable in terms of deciphering the underlying pathophysiology of RLS, providing the molecular starting points for animal models and in vitro studies to understand disease mechanisms. In addition, genetic risk variants can be valuable tools for disentangling the phenotypic complexity observed in RLS. Testing RLS risk variants for associations with periodic limb movements (PLMs) identified a significant role of some of the variants and suggested PLMs as an endophenotype in RLS. Further advances in genetics research in RLS will be driven by large-scale sequencing projects and the identification of additional common, but also rarer risk variants with larger effects on disease risk. Another uncharted territory in RLS research epigenetic effect on gene activity. Overall, genetic studies continue to hold great potential for understanding biology of the disease ²⁾.

Other factors associated with the development or worsening of restless legs syndrome include:

Chronic diseases. Certain chronic diseases and medical conditions, including iron deficiency, Parkinson’s disease, kidney failure, diabetes, and peripheral neuropathy often include symptoms of RLS. Treating these conditions often gives some relief from RLS symptoms. Medications. Some types of medications, including antinausea drugs, antipsychotic drugs, some antidepressants, and cold and allergy medications containing sedating antihistamines, may worsen symptoms. Pregnancy. Some women experience RLS during pregnancy, especially in the last trimester. Symptoms usually go away within a month after delivery.

Other factors, including alcohol use and sleep deprivation, may trigger symptoms or make them worse. Improving sleep or eliminating alcohol use in these cases may relieve symptoms.

Restless legs syndrome pathophysiology.

People with restless legs syndrome have uncomfortable sensations in their legs (and sometimes arms or other parts of the body) and an irresistible urge to move their legs to relieve the sensations. The condition causes an uncomfortable, “itchy,” “pins and needles,” or “creepy crawly” feeling in the legs. The sensations are usually worse at rest, especially when lying or sitting.

The severity of RLS symptoms ranges from mild to intolerable. Symptoms can come and go and severity can also vary. The symptoms are generally worse in the evening and at night. For some people, symptoms may cause severe nightly sleep disruption that can significantly impair their quality of life.

Findings showed that neuro-cognitive co-morbidities such as parkinsonism, peripheral neuropathy, SCI, acting out dreams and hyposmia as well as cardio-metabolic risk factors and diseases were independent determinants of RLS. It is recommended to screen individuals with either these comorbid conditions for RLS or the ones with RLS for the accompanying diseases ³⁾.

Increased neutrophil-to-lymphocyte ratio: is it really diagnostic of restless legs syndrome? ⁴⁾.

see Uremic neuropathy

see Restless legs syndrome treatment.

Fifteen drug-naive, idiopathic RLS patients (13 female and 2 male) and 15 female healthy controls participated in this study. Nineteen-channel electroencephalograms were obtained during polysomnographic (PSG) recordings. An automated sleep spindle and SO detection algorithm were used to detect sleep spindle (12-16 Hz) and SO (<1 Hz) activity. The quantitative characteristics of sleep spindle and SO activity were investigated.

Compared with the healthy controls, in RLS patients, we observed density and power reduction in sleep spindles. In SOs, density reduction and duration increment were shown in RLS patients. In addition, SO-spindle coordination was deficient in RLS as revealed by reduced SO locked spindle power, dispersed and delayed spindle phase, and decreased SO-spindle coupling. Although sleep spindle power was negatively correlated with wake after sleep onset (WASO) time, SO duration was positively correlated with the arousal index in Restless legs syndrome.

This study suggests that sleep disturbances may be mediated by a combined deficit in spindle and SO activity and SO-spindle coordination. The abnormal SO and spindle activity observed in RLS support the notion that thalamocortical abnormalities underlie this condition and may promote disturbed sleep integrity ⁵⁾.

A patient with advanced pancreatic cancer was referred to an acute palliative care unit for the treatment of cancer-related pain. Yet, in thorough exploration of her symptom burden, the patient reported that she felt her quality of life had been predominantly limited by symptoms other than cancer pain. Her medical history and neurological examination revealed that these symptoms were most obviously caused by severe RLS. In the years before, pharmacological therapies with dopamine-agonists and delta-2-alpha calcium channel ligands were initiated, but failed to relieve the RLS. In the palliative care ward, intravenous morphine was successfully titrated to treat her cancer pain. Concurrently, the patient also experienced almost complete relief from her RLS-symptoms and an increase in quality of life. The amelioration of her RLS-symptoms continued after morphine therapy was switched from intravenous to oral administration. Even after the patient was dismissed to home care and opioid rotation to transdermal fentanyl, symptom control of RLS remained excellent. To our knowledge, this is the first report of successfully treating RLS with intravenous and oral morphine. Since morphine is more easily available worldwide and the cost of morphine therapy is substantially lower compared to oxycodone/naloxone, comparisons to morphine may be an intriguing option for future RCTs ⁶⁾.