Richard P Allen

• Johns Hopkins University

Restless legs syndrome (RLS) is a neurological disorder that can have a profound effect on sleep and quality of life. Idiopathic RLS is associated with brain iron insufficiency despite normal peripheral iron stores. There is, however, a five‐ to six‐fold increase in prevalence of RLS in patients with iron deficiency anemia (IDA). Several open‐label...

Our understanding of the causes and natural course of restless legs syndrome (RLS) is incomplete. The lack of objective diagnostic biomarkers remains a challenge for clinical research and for the development of valid animal models. As a task force of preclinical and clinical scientists, we have previously defined face validity parameters for rodent...

Pregabalin is increasingly being used as a first-line treatment for symptomatic control of restless legs syndrome (RLS). This study aimed to evaluate the efficacy and safety of pregabalin as add-on therapy in RLS patients already taking dopamine agonists (DA) but still in need of further management. Patients with idiopathic RLS were enrolled, and a...

Background Iron supplementation is the most commonly considered treatment option for children with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD); however, there is a scarcity of evidence on the effectiveness of intravenous preparations. In this study, we evaluated the effectiveness and tolerability of intravenous ferric car...

Objective Intravenous ferric carboxymaltose (FCM) has been shown to be efficacious in treating restless legs syndrome (RLS) symptoms in non-anemic patients. The aim of this study was to evaluate the effectiveness of FCM in treating RLS symptoms in patients who also had an iron deficiency anemia (IDA). Methods This is a randomized, double-blinded,...

This systematic review and meta-analysis evaluated the diagnostic accuracy of screening instruments for restless legs syndrome (RLS) and reports sensitivity, specificity, positive (PPV) and negative predictive values (NPV). Searches for primary studies were conducted in electronic databases. Of the 1541 citations identified, 52 were included in the...

Objectives Nighttime agitation or “sundowning” is challenging for clinicians and caregivers to manage in older adults in the dementia stage of Alzheimer's disease (AD-D). Our research previously revealed that nighttime agitation might be a manifestation of restless legs syndrome (RLS). The current study aims to describe the characteristics of older...

This study reports on an epigenetic biomarker for restless leg syndrome (RLS) developed using whole genome DNA methylation data. Lymphocyte-derived DNA methylation was examined in 15 subjects with and without RLS (discovery cohort). T-tests and linear regressions were used followed by a principal component analysis (PCA). The principal component mo...

Background. Restless legs syndrome (RLS) is a chronic sensorimotor disorder diagnosed by clinical symptoms. It is challenging to translate the diagnostic self-reported features of RLS to animals. Objectives. To help researchers design their experiments, a task force was convened to develop consensus guidelines for experimental readouts in RLS anima...

Background Restless sleep is a frequent complaint in clinical practice and has been reported in the medical literature since the 1970s. Most often, it has been described in association with specific sleep or medical conditions. However, more recently, publications have emerged that describe a disorder characterized by restless sleep as the core fea...

In this study, we aim to automate the sleep stage scoring process of overnight polysomnography (PSG) data while adhering to expert-based rules. We developed a sleep stage scoring algorithm utilizing the generalized linear modelling (GLM) framework and extracted features from electroencephalogram (EEG), electromyography (EMG) and electrooculogram (E...

Background: Brain iron deficiency (BID), especially for the substantia nigra (SN), without peripheral iron deficiency (ID) has been well documented as a ubiquitous finding for restless legs syndrome (RLS) patients. This close association suggests the biology of RLS BID can produce RLS symptoms. Association, however, cannot establish such a direct...

Background: The primary symptoms of Restless Legs Syndrome (RLS) are circadian-dependent, leading to increased activity or decreased rest, especially at night. The primary pathology in RLS is brain iron insufficiency despite normal systemic iron stores. Natural variances in brain and peripheral iron concentrations across recombinant inbred (RI) mu...

Objectives: Resting-state brain connectivity has been shown to differ for Restless Legs Syndrome (RLS) compared to healthy control (CON) groups. This study evaluates the degree these RLS-CON differences are changed by concurrent treatment. Methods: Resting-state functional MRIs were obtained from 32 idiopathic RLS patients during the morning asy...

Introduction: Restless legs syndrome (RLS) patients have been found to have high rates of transitory increases in the activity of the sympathetic autonomic nervous system with increases in heart rate and blood pressure. These were identified by evaluating heart rate or blood pressure changes independent of any leg movement analyses. There has been...

Purpose Restless legs syndrome is a common condition affecting nearly 2% Indian population. Certain questionnaires for screening or diagnostic purpose have been developed in the West, and they were translated to Hindi. However, those questionnaires have been found to have limitations in Indian context considering the cultural effect on vocabulary f...

Study Objectives Determine abnormalities in levels of iron-management proteins in neuronal origin-enriched extracellular vesicles (nEVs) in Restless Legs Syndrome (RLS). Methods: We used immunoprecipitation for neuronal marker L1CAM to isolate nEVs from the serum of 20 RLS subjects from a study including MRI determinations of iron deposition in the...

Introduction: The International Restless Legs Study Group (IRLSSG) has developed the IRLS (International Restless Legs Syndrome Severity Scale) and validated it as a clinician/researcher administered scale to be used when both patient and examiner are present. The IRLSSG recognized the need for a self-completing scale that can be used economically...

Introduction The International Restless Legs Study Group (IRLSSG) has developed the IRLS (International Restless Legs Syndrome Severity Scale) and validated it as a clinician/researcher administered scale to be used when both patient and examiner are present. The IRLSSG recognized the need for a self-completing scale that can be used economically i...

Restless legs syndrome, also known as Willis-Ekbom disease, is a common neurological condition whose manifestation is affected by complex environmental and genetic interactions. Restless legs syndrome can occur on its own, mostly at a young age, or with comorbidities such as cardiovascular disease, diabetes, and arterial hypertension, making it a d...

Restless legs syndrome (RLS) is a common sensorimotor disorder, whose basic components include a sensory experience, akathisia, and a sleep-related motor sign, periodic leg movements during sleep (PLMS), both associated with an enhancement of the individual’s arousal state. The present review attempts to integrate the major clinical and experimenta...

Overnight polysomnography (PSG) is the gold standard tool used to characterize sleep and for diagnosing sleep disorders. PSG is a non-invasive procedure that collects various physiological data which is then scored by sleep specialists who assign a sleep stage to every 30-second window of the data according to predefined scoring rules. In this stud...

The objective of the current review was to update the previous evidence‐based medicine review of treatments for restless legs syndrome published in 2008. All randomized, controlled trials (level I) with a high quality score published between January 2007 and January 2017 were reviewed. Forty new studies qualified for efficacy review. Pregabalin, ga...

We assessed corticomotor excitability in the primary motor cortex (M1) of participants with moderate-to-severe restless legs syndrome (RLS) symptoms using transcranial magnetic stimulation (TMS) in relation to the clinical and sleep aspects of the disease. Thirty-five participants (20 F; mean age: 59.23 ± 1.66 years; range: 42-78 years) affected by...

Background Restless Legs Syndrome (RLS) is characterized by uncomfortable nocturnal sensations in the legs making sedentary activities and sleep difficult, and is thus linked with psychosocial distress. Due to the symptomatology and neurobiology of RLS (disrupting brain iron and dopamine) it is likely that RLS associates with poorer health-related...

Background Restless Legs Syndrome (RLS) is characterized by uncomfortable nocturnal sensations in the legs making sedentary activities and sleep difficult, and is thus linked with psychosocial distress. Due to the symptomatology and neurobiology of RLS (disrupting brain iron and dopamine) it is likely that RLS associates with poorer health-related...

Parkinson’s disease (PD) and restless legs syndrome (RLS) may be clinically and/or etiologically related, yet this association is under debate. Single-nucleotide polymorphisms (SNPs) in the TOX3 gene locus were implicated in both RLS and PD genome-wide association studies (GWASs), suggesting a potential pleiotropy. Two case-control cohorts includin...

The symptomatology of Restless Legs Syndrome (RLS) includes periodic leg movements during sleep (PLMS), dysesthesias, and hyperarousal. Alterations in the dopaminergic system, a presynaptic hyperdopaminergic state, seem to be involved in PLMS, while alterations in glutamatergic neurotransmission, a presynaptic hyperglutamatergic state, seem to be i...

Introduction: There have been four randomized, placebo-controlled, double-blinded studies of intravenous (IV) iron in Restless Legs Syndrome (RLS), all of which delivered a final total dose of 1000 mg of iron. The purpose of this study was to evaluate effects of a lesser total dose (500 mg of iron). Methods: Subjects with idiopathic RLS were enr...

Study objectives: To study the effect of altitude on subjective sleep quality in populations living at high and low altitudes after excluding cases of restless legs syndrome (RLS). Methods: This population-based study was conducted at three different altitudes (400 m, 1,900-2,000 m, and 3,200 m above sea level). All consenting subjects available...

Background: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets....

Objective: The first aim was to demonstrate a previously hypothesized increased sensitivity of corticostriatal glutamatergic terminals in the rodent with brain iron deficiency (BID), a pathogenetic model of Restless Legs Syndrome (RLS). The second aim was to determine if these putative hypersensitive terminals could constitute a significant target...

Background Brain iron deficiency has been implicated in the pathophysiology of RLS, and current RLS treatment guidelines recommend iron treatment when peripheral iron levels are low. In order to assess the evidence on the oral and intravenous (IV) iron treatment of RLS and periodic limb movement disorder (PLMD) in adults and children, the Internati...

BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. ME...

Objective Restless legs syndrome (RLS) patients compared to controls have been found to have abnormal patterns in the default mode network (DMN) in the morning when symptom threshold is highest and symptoms are least likely to occur. If these morning abnormalities in DMN are pertinent to disease expression, then similar or further detectable differ...

This chapter deals with motor functions and dysfunctions in sleep. A variety of motor disorders may appear during sleep interfering with sleep. After a brief summary of motor control in wakefulness the chapter addresses how this control changes during different stages of sleep and how its dyscontrol may arise and affect an individual. We classify m...

Individuals with mental health and/or neurodevelopmental conditions often display disruptive day- and night-time behaviours associated with abnormally increased muscular activity and/or presentations described as hyperkinesia, hypermotor-restlessness and hyper-/hypo-arousability (all summarized as H-behaviours). H-behaviours are used as a diagnosti...

Study objectives: To determine the depth and distribution of sensory discomfort in idiopathic restless legs syndrome/Willis-Ekbom disease (RLS) and RLS concurrent with other leg conditions, specifically peripheral neuropathy, sciatica, leg cramps, and arthritis. Methods: RLS subjects (n = 122) were divided into 71 idiopathic RLS and 51 RLS-C, or...

Objective: Current standard guidelines for scoring periodic leg movements (PLM) define the start and end of a movement but fail to explicitly specify the movement morphology necessary to classify an EMG event as a PLM, rather than some other muscle event. This is currently left to the expert visual scorer to determine. This study aimed to define t...

Objective: To make evidence-based recommendations regarding restless legs syndrome (RLS) management in adults. Methods: Articles were classified per the 2004 American Academy of Neurology evidence rating scheme. Recommendations were tied to evidence strength. Results and recommendations: In moderate to severe primary RLS, clinicians should con...

This report presents the results of the work by a joint task force of the International and European Restless Legs Syndrome Study Groups and World Association of Sleep Medicine that revised and updated the current standards for recording and scoring leg movements (LM) in polysomnographic recordings (PSG). First, the background of the decisions made...

In this article, we review the original findings from MRI and autopsy studies that demonstrated brain iron status is insufficient in individuals with restless legs syndrome (RLS). The concept of deficient brain iron status is supported by proteomic studies from cerebrospinal fluid (CSF) and from the clinical findings where intervention with iron, e...

Study objectives: Periodic limb movements of sleep (PLMS) occur within a subject as a series with a remarkably stable period defined by the inter-movement interval (IMI). Sometimes a non-PLMS movement occurs intervening between two PLMS. PLMS scoring rules specify totally ignoring these intervening leg movements (iLM). This implicitly assumes an i...

Deficits of sensorimotor integration with periodic limb movements during sleep (PLMS) and hyperarousal and sleep disturbances in Restless Legs Syndrome (RLS) constitute two pathophysiologically distinct but interrelated clinical phenomena, which seem to depend mostly on alterations in dopaminergic and glutamatergic neurotransmission, respectively....

Restless legs syndrome (RLS) is a complex disorder that involves sensory and motor systems. The major pathophysiology of RLS is low iron concentration in the substantia nigra containing the cell bodies of dopamine neurons that project to the striatum, an area that is crucial for modulating movement. People who have RLS often present with normal iro...

Objective: There have been three randomized, placebo-controlled, double-blind studies of intravenous iron in restless legs syndrome (RLS), with differing outcomes. The one positive study used ferric carboxymaltose (FCM) at a total dose of 1000 mg. The purpose of this study was to replicate and extend the findings from the prior FCM study. Methods...

Background: The unusual sensations of restless legs syndrome/Willis-Ekbom disease (RLS/WED) are induced by rest or a low arousal state with a circadian variation in the threshold for induction. It has been suggested that the emergence of RLS/WED symptoms relates to abnormal brain functions dealing with internally generated stimuli. The purpose of...

Objectives: Altered brain iron homeostasis with regional iron deficiency has been previously reported in several studies of restless legs syndrome (RLS) patients. Inconsistencies still exist, however, in the reported iron changes in different brain regions and different RLS phenotypes. The purpose of this study was to assess differences in brain i...

A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) in conjunction with the European Restless Legs Syndrome Study Group (EURLSSG) and the RLS Foundation (RLS-F) to develop evidence-based and consensus-based recommendations for the prevention and treatment of long-term pharmacologic treatment of dopaminergic...

Background: The exact genetic causes within each of the known restless legs syndrome (RLS) loci are still unknown. Recently, it was suggested that an intronic protein tyrosine phosphatase, receptor type δ (PTPRD) single-nucleotide polymorphism (SNP) (reference SNP no. rs2381970) is associated with its expression, which may lead to RLS and other re...

Aim: Periodic leg movements in sleep (PLMS) are generally evaluated by the number of events per hour during sleep, but this is an unstable measure with marked nightly variability and also fails to assess the basic periodicity that essentially characterizes these movements. The inter-movement interval (IMI) evaluates a putative biological process p...

Restless leg syndrome/Willis-Ekbom disease has brain iron deficiency that produces excessive dopamine and known genetic risks, some of which contribute to the brain iron deficiency. Dopamine treatments work temporarily but may eventually produce further postsynaptic down-regulation and worse restless leg syndrome. This article includes sections foc...

After being recognized as a syndrome, Willis–Ekbom disease (WED) had been essentially ignored for three centuries until the excellent work of Ekbom in the mid-twentieth-century, carefully describing his case series. Shortly thereafter, attention to disorders disturbing sleep increased with advent of the discipline of sleep medicine. The discovery o...

Purpose Magnetic resonance imaging relaxometry studies differed on the relaxometry methods and their approaches to determining the regions of interest (ROIs) in restless legs syndrome (RLS) patients. These differences could account for the variable and inconsistent results found across these studies. The aim of this study was to assess the relation...

In this study, we used the Pittsburgh Sleep Quality Index to divide the subjects into two groups, good sleepers and bad sleepers. We computed sleep behavioral (macro-sleep architectural) features and sleep spectral (micro-sleep architectural) features in order to observe if the annotated EEG data can be used to distinguish between good and bad slee...

HIV patients are often plagued by sleep disorders and suffer from sleep deprivation. However, there remains a wide gap in our understanding of the relationship between HIV status, poor sleep, overall function and future outcomes; particularly in the case of HIV patients otherwise well controlled on cART (combined anti-retroviral therapy). In this s...

Background: Restless Legs Syndrome (RLS) is a common, age- and gender-related disorder. Although several genetic risk factors were identified, the actual genetic causes are unclear. Methods: Whole exome sequencing (WES) was performed in seven families with RLS, focusing on potential genetic causes around six known genetic loci; MEIS1, BTBD9, PTPRD,...

Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common sensorimotor disorder that can generally be effectively managed in the primary care clinic. However, some treatment complications may arise. According to the recommendations of the International Restless Legs Syndrome Study Group, non-ergot dopamine-receptor agonist...

OBJECTIVE: To evaluate if periodic leg movements (PLMs) in painful restless legs (RLS) are higher than in non-painful RLS. BACKGROUND: Recent clinical studies using subjective measures have shown that painful RLS could be a more severe form of RLS. No studies have used objective measures to evaluate painful RLS and its severity. PLMs are present in...

A Matrix Laboratory (MATLAB) script (MATPLM1) was developed to rigorously apply World Associations of Sleep Medicine (WASM) scoring criteria for periodic limb movements in sleep (PLMS) from bilateral electromyographic (EMG) leg recordings. This study compares MATPLM1 with both standard technician and expert detailed visual PLMS scoring. Validation...

The complaint of pain has largely been ignored in the diagnostic criteria for restless legs syndrome (RLS). The purpose of this study was to investigate the prevalence of painful symptoms in RLS, and to compare sleep-related characteristics between the patients who experienced the painful symptoms and those who did not. The patients with RLS were r...

Over the last decade, research in restless legs syndrome (RLS; also known as Willis-Ekbom disease) has increased dramatically. The International Parkinson and Movement Disorder Society commissioned a task force to formally evaluate the available evidence on severity rating scales in RLS. A literature search retrieved instruments specific to RLS. Ea...

Objectives: Over the last decade therapeutic, pathogenetic, epidemiological and genetic research in restless legs syndrome/Willis-Ekbom Disease (RLS/WED) has required the development of specific quality of life scales and sleep scales. A Movement Disorder Society Task Force formally evaluated the quality of these scales. Methods: A literature se...

Study Objectives Lack of a valid diagnostic measure of restless legs syndrome (RLS) for persons with dementia, who do not have the cognitive ability to report complex symptoms, impedes RLS treatment and research in this population. The aim of this study was to determine the sensitivity and specificity of a combination of indicators for identifying...

Objectives Iron-deficit anemia (IDA) engenders restless legs syndrome (RLS, aka Willis Ekbom disease). Intravenous (IV) iron can rapidly reverse IDA and would be expected to similarly reverse RLS caused by IDA. This is the first consecutive case series evaluating effects of intravenous (IV) iron therapy on RLS occurring with IDA (RLS-IDA) Methods...

The purpose of this study was to demonstrate whether or not restless legs syndrome (RLS) is associated with any morphological change in gray matter. Forty-six RLS subjects and 46 controls were enrolled. We performed voxel-based morphometry analysis and compared the results of the two groups. The RLS subjects showed significant regional decreases of...

Background In 2003, following a workshop at the National Institutes of Health, the International Restless Legs Syndrome Study Group (IRLSSG) developed updated diagnostic criteria for restless legs syndrome/Willis–Ekbom disease (RLS/WED). These criteria were integral to major advances in research, notably in epidemiology, biology, and treatment of R...

Iron deficiency (ID) in rodents leads to decreased ventral midbrain (VMB) iron concentrations and to changes in the dopamine (DA) system that mimic many of the dopaminergic changes seen in RLS patient where low substantia nigra iron is a known pathology of the disease. The ID-rodent model, therefore, has been used to explore the effects that low VM...

Restless legs syndrome/Willis Ekbom disease (RLS/WED) has been recognized as a significant medical disorder since the 17th century. It was studied mostly in the last 50 years in relation to increasing interest in sleep medicine and health-related quality of life. This led to recognition that the disease is not well characterized as restless feeling...

RLS, also known as Willis-Ekbom disease, is a predominately nocturnal, rest-induced, distressing urge to move the legs. Anecdotally, it seems to occur in a number of patients with peripheral vascular disease, and clinically significant RLS effects ∼2% to 3% of the European and American populations (Allen RP et al, Sleep Med 2010;11:31-7). Short-act...

OBJECTIVE: Evaluate leg and hand Corticomotor excitability in relation to sleep in RLS patients.BACKGROUND: Increased cortical excitability using paired pulse transcranial magnetic stimulation (TMS) shown for the hand in RLS patients has not been evaluated for the leg nor have these changes been related to the polysomnography measures characteristi...

Study objectives: To compare pregabalin versus placebo and pramipexole for reducing restless legs syndrome (RLS)-related sleep disturbance. Design: Randomized, double-blinded, crossover trial. Setting: Twenty-three US sleep centers. Participants: Eighty-five individuals with moderate to severe idiopathic RLS and associated sleep disturbance....

Under normal and dietary iron deficiency conditions, the BXD recombinant inbred (RI) strains of mice show large variations in regional brain iron concentration, particularly in the ventral midbrain (VMB). In a study utilizing just one of the BXD strains, diurnal changes in subregional brain iron concentration were found, which were dependent on the...

During normal sleep several neuroplasticity changes occur, some of which are considered to be fundamental to strengthen memories. Given the evidence linking sleep to neuroplasticity, it is conceivable that individuals with chronic sleep disruption, such as patients with chronic insomnia (CI), would experience abnormalities in neuroplastic processes...

Dopaminergic medications relieve symptoms of the restless legs syndrome (RLS) but have the potential to cause iatrogenic worsening (augmentation) of RLS with long-term treatment. Pregabalin may be an effective alternative. In this 52-week, randomized, double-blind trial, we assessed efficacy and augmentation in patients with RLS who were treated wi...

Restless legs syndrome (RLS) is a common neurological sensory-motor condition. High prevalence of comorbid depression and anxiety has been reported, but the few available data on the impact of RLS on cognition have been conflicting. The authors compared 91 participants (No-RLS group: N=37; Untreated RLS group: N=23; Treated RLS group: N=31) on cogn...

Objectives: A prior diffusion tensor imaging (DTI) of restless legs syndrome (RLS) subjects found alterations in brain white matter (WM). The aim of this study was to explore the possible mechanism of altered integrity of brain WM in RLS patients. Methods: The DTI measurement was performed in 22 subjects with RLS and 22 age-matched control subje...

Recent genome-wide association studies (GWAS) for Caucasians identified several allelic variants associated with increased risk of developing restless legs syndrome (RLS), also known as Willis-Ekbom disease. Although the pathogenic mechanisms of RLS are not entirely understood, it is becoming increasingly evident that many diseases such as RLS can...

Background: Opioids are a potential new treatment for severe restless legs syndrome. We investigated the efficacy and safety of a fixed-dose combination of prolonged release oxycodone-naloxone for patients with severe restless legs syndrome inadequately controlled by previous, mainly dopaminergic, treatment. Methods: This multicentre study consi...

Introduction Patterns of transient EEG correlates of sleep, such as sleep spindles, can potentially serve as fingerprint of the underlying neurological disease. Our primary goal was to explore the feasibility of adopting complexity measures of sleep architecture as quantitative criteria for insomnia diagnostics and to assess its discriminative powe...

Introduction Dopaminergic treatments, the mainstay of restless legs syndrome (RLS) therapy, are often associated with augmentation (worsening of RLS symptom severity after initial significant response). This multinational European study investigated oxycodone/naloxone prolonged-release fixed-combination (OXNPR) in severely affected RLS patients and...

The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and...