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1.
Medicine (Baltimore). 2019 Dec;98(51):e18450. doi: 10.1097/MD.0000000000018450.

Risk factors for restless legs syndrome in hemodialysis patients in Taiwan: A case-control study.

Author information

1
Department of Nursing, Chang Gung University of Science and Technology, Taoyuan.
2
Department of Nephrology, Chang Gung Memorial Hospital at Linkou.
3
Department of Public Health, College of Medicine.
4
Biostatistics Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Taoyuan.
5
Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou.
6
Department of Nursing, Central Taiwan University of Science and Technology, Taichung, Taiwan.

Abstract

Restless legs syndrome (RLS) increases the risks of cardiovascular disease and death in hemodialysis (HD) patients. Previous studies of risk factors for RLS in HD patients have yielded varying results. We attempted to identify risk factors for RLS in HD patients in Taiwan.This case-control study recruited 59 HD patients with RLS and 353 HD patients without RLS from the largest HD center in Taiwan during the period from April 1, 2015 through August 31, 2015. Demographic and disease characteristics, information from the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic questionnaire, and IRLSSG Severity Scale scores were collected by interview. Clinical laboratory data were abstracted from medical records and then analyzed with logistic regression and Pearson correlation analysis. A P value of less than .05 was considered to indicate statistical significance.A dialysis duration of longer than 5 years (odds ratio [OR] = 2.32; 95% CI = 1.23-4.39; P = .002) and a low high-density lipoprotein cholesterol level (<40 mg/dL in men; <50 mg/dL in women) (OR = 2.73; 95% CI = 1.44-5.15; P = .009) were associated with increased risk of RLS. Among the 59 patients with RLS, 48 (81.3%) had moderate or severe symptoms (IRLSSG Severity Scale >10), and RLS severity was significantly correlated with dialysis duration (r = .26; P = .043).Among HD patients, RLS was more common among those receiving dialysis for longer than 5 years and those with a low serum high-density lipoprotein cholesterol (HDL-C) level.

PMID:
31861018
DOI:
10.1097/MD.0000000000018450
[Indexed for MEDLINE]
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2.
3.
Maturitas. 2019 Nov;129:30-39. doi: 10.1016/j.maturitas.2019.08.006. Epub 2019 Aug 15.

Italian Association of Sleep Medicine (AIMS) position statement and guideline on the treatment of menopausal sleep disorders.

Author information

1
Center of Sleep Medicine, UOSD of Neurophysiopathology and Disorders of Movement, AOU G Martino, Department of Clinical and Experimental Medicine, University of Messina, Italy. Electronic address: rsilvestri@unime.it.
2
Center of Sleep Medicine, UOSD of Neurophysiopathology and Disorders of Movement, AOU G Martino, Department of Clinical and Experimental Medicine, University of Messina, Italy.
3
Division of Neurology, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
4
Division of Pneumology, University Hospital AOUP "Paolo Giaccone" PROMISE Department, University of Palermo, Italy.
5
Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
6
Department of Clinical and Experimental Medicine, Psychiatric Clinic, University of Pisa, Italy.
7
Sleep Disorder Centre, Department of Medical Sciences and Public Health, University of Cagliari, Italy.
8
Istituto Auxologico Italiano, IRCCS, Sleep Disorders Center & Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan, Italy; Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
9
Department of Clinical and Experimental Medicine, University of Pisa, Italy.
10
IRCCS, Institute of Neurological Sciences, Bologna, Italy; Department of BioMedical and NeuroMotor Sciences, University of Bologna, Italy.
11
"FM Puca" Neurology Unit, University Hospital Consortium Corporation Polyclinic of Bari, Italy.
12
Neurological Day Care Unit - Local Health Authority (AUSL 4), Parma, Italy.

Abstract

Insomnia, vasomotor symptoms (VMS) and depression often co-occur after the menopause, with consequent health problems and reductions in quality of life. The aim of this position statement is to provide evidence-based advice on the management of postmenopausal sleep disorders derived from a systematic review of the literature. The latter yielded results on VMS, insomnia, circadian rhythm disorders, obstructive sleep apnea (OSA) and restless leg syndrome (RLS). Overall, the studies show that menopausal hormone therapy (MHT) improves VMS, insomnia, and mood. Several antidepressants can improve insomnia, either on their own or in association with MHT; these include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and mirtazapine. Long-term benefits for postmenopausal insomnia may also be achieved with non-drug strategies such as cognitive behavioral therapy (CBT) and aerobic exercise. Continuous positive airway pressure (CPAP) and mandibular advancement devices (MADs) both reduce blood pressure and cortisol levels in postmenopausal women suffering from OSA. However, the data regarding MHT on postmenopausal restless legs syndrome are conflicting.

KEYWORDS:

Cognitive behavioral therapy for insomnia (CBT-I); Hormone replacement therapy (HRT); Menopause; Position statement; Sleep disorders; Vasomotor symptoms (VMS)

PMID:
31547910
DOI:
10.1016/j.maturitas.2019.08.006
[Indexed for MEDLINE]
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4.
Postgrad Med. 2019 Sep;131(7):473-478. doi: 10.1080/00325481.2019.1658506. Epub 2019 Sep 15.

Restless legs syndrome - the under-recognised non-motor burden: a questionnaire-based cohort study.

Author information

1
Parkinson Foundation Centre of Excellence, King's College Hospital , London , UK.
2
Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London , London , UK.
3
Department of Neurology, Technical University Dresden , Dresden , Germany.
4
National Center of Epidemiology, Carlos III Institute of Health , Madrid , Spain.
5
Center for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Carlos III Institute of Health , Madrid , Spain.
6
Mid Essex Hospital Services NHS Trust, Broomfield Hospital , UK.
7
Department of Psychiatry, Ng Teng Fong General Hospital , Singapore.

Abstract

Objectives: Non-motor symptoms (NMS) range from neuropsychiatric to pain and are an important but underexplored feature of restless legs syndrome (RLS). There are currently no tools available which enable the holistic assessment of NMS in RLS in clinical practice. The primary aim of this study was to systematically assess NMS prevalence and burden in patients with RLS using the NMS Questionnaire (NMSQuest) validated for Parkinson's disease. Methods: Patients with idiopathic RLS according to the criteria of the international RLS study group (IRLSSG) were included. Patients underwent a physical examination and clinical interview as well as completed the NMS Questionnaire and the international restless legs syndrome study group (IRLSSG) rating scale. Results: Seventy-four patients with primary RLS were included (mean age 64.6 ± 14.4 years, 62.2% female, mean disease duration 23.5 ± 17.8 years, mean Levodopa equivalent daily dose 63.3 ± 67.4 mg). On average patients reported an IRLSSG rating scale score of 24.8 ± 8.2 (maximum 40) and NMSQuest score of 9.9 ± 5.0 (maximum 30). Patients reported a minimum of two NMS with the majority (39.2%) reporting a moderate NMS burden, followed by severe (28.4%) and very severe (17.6%) burden. The most frequent NMS were insomnia (89.2%) followed by nocturia (70.3%), feeling sad (59.5%), forgetfulness (54.1%), urgency (47.3%), feeling anxious (43.2%), unexplained pain (41.9%), difficulty concentrating (40.5%) and dizziness (40.5%). There were no significant differences in NMSQuest total scores according to disease duration and gender (p = 0.739, p = 0.849). Conclusion: In conclusion, this study is one of the first to address NMS in RLS systematically and the data underlines the need to holistically assess NMS in RLS in order to deliver true value-based healthcare for these patients.

KEYWORDS:

Restless legs syndrome; non-motor symptoms; non-motor symptoms questionnaire

PMID:
31522582
DOI:
10.1080/00325481.2019.1658506
[Indexed for MEDLINE]
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5.
Ideggyogy Sz. 2019 Jul 30;72(7-8):236-240. doi: 10.18071/isz.72.0236.

Restless leg syndrome frequency in health workers.

Author information

1
Baskent University Faculty of Medicine, Department of Neurology, Ankara, Turkey.
2
Baskent University Faculty of Medicine, 3. Class Student, Ankara, Turkey.

Abstract

Introduction - Restless Leg Syndrome (RLS) is a disease, primarily composed of sensational symptoms, caused by the urge to move lower extremities especially at night, and characterized by undesired feelings of the legs. Decreasing of the dopaminergic effect at night is thought to be responsible from these symptoms. RLS patients suffer from low quality of sleep affecting their daily life activities even causing socio-economic loss. Although RLS is a common and treatable disease, it can not be diagnosed easily due to the variability of symptoms. Aim - The purpose of this study is to determine the frequency of RLS among health workers and to define the disease causing factors. Method - A questionnaire was applied to 174 randomly selected health workers at Baskent University Medical Faculty (KA17/285). The demographic information, history of illnesses or usage of drugs, socioeconomic status, working hours and daytime sleepiness were questioned. Included in the questionnaire were diagnostic criteria for RLS, frequency assessment scale, and survey of sleep quality. We used "the diagnostic criteria of international RLS working group" for the diagnosis, and "Pittsburgh sleep quality index survey" to determine the quality of sleep. Reliability and validity studies were performed on both tests. Results - A significant relationship between socio-economic status and RLS was found (p<0.05) as an increase of RLS frequency in parallel with decreased socio-economic status. RLS was found to be common among health workers. We suggest that health workers should be checked regularly, and they should be informed about the disease in order to raise an awareness and hence increase their quality of life.

KEYWORDS:

health workers; restless leg syndrome; sleeping disorder

PMID:
31517455
DOI:
10.18071/isz.72.0236
[Indexed for MEDLINE]
6.
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2019 May 25;48(3):275-281.

[Restless legs syndrome in ischemic stroke patients: clinical features and significance].

[Article in Chinese]
Zhang L1,2, Sun Y2, Wang T3, Pan Y2, Yao Y2, Pan L2, Xu Q1,2, Zhang W1,2, Xu J1,2, Hu X1.

Author information

1
Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
2
Center for Sleep Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
3
Department of Pharmacy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.

Abstract

OBJECTIVE:

To investigate the clinical features and implication of restless legs syndrome (RLS) in ischemic stroke patients.

METHODS:

A total of 199 ischemic stroke patients were enrolled and assessed by polysomnography (PSG). RLS was identified according to criteria of International Restless Legs Syndrome Study Group. Epworth Sleepiness Scale (ESS), Mini-mental State Examination (MMSE) and Patient Health Questionnaire (PHQ-9) were used to evaluate the sleep quality, cognitive function and post-stroke depression, respectively. The National Institute of Health Stroke Scale (NIHSS) was used to evaluate the neurological function 3 months after stroke onset. Gender-and age-matched non-ischemic stroke patients with RLS (primary PLS) were selected as controls.

RESULTS:

Twenty-two cases of RLS were identified among 199 ischemic stroke patients (11.1%). Generalized linear model and logistic regression showed that low serum ferritin level (β=-133.3 mg/L, 95%CI:-200.4--0.1, P<0.01), subcortical infarction (OR=4.05, 95%CI:1.15-14.18, P<0.05) and female (OR=2.54, 95%CI:1.04-6.23, P<0.05) were identified as the risk factors of RLS in ischemic stroke patients. Compared with ischemic stroke patients without RLS, ESS increased by 4.37 (95%CI:2.33-6.41, P<0.01), PHQ-9 increased by 2.17 (95%CI:0.39--3.94, P<0.05), and reduced NIHSS from the baseline deceased by 0.97 (95%CI:-1.79--0.15, P<0.05) in ischemic stroke patients with RLS. In addition, the incidence of moderate-severe depression increased (OR=4.27, 95%CI:1.40-13.10, P<0.05) in ischemic stroke patients with RLS. The index of periodic leg movements of sleep (PLMS) with arousal in ischemic stroke patients with RLS was significantly higher than that in patients with primary RLS (β=12.85, 95%CI:2.04-23.67, P<0.05).

CONCLUSIONS:

RLS is common in ischemic stroke patients and has adverse influences on patients.

PMID:
31496159
[Indexed for MEDLINE]
7.
Int Heart J. 2019 Sep 27;60(5):1098-1105. doi: 10.1536/ihj.19-049. Epub 2019 Sep 4.

Prognostic Impact of Restless Legs Syndrome on Patients with Heart Failure.

Author information

1
Department of Cardiovascular Medicine, Fukushima Medical University.
2
Department of Advanced Cardiac Therapeutics, Fukushima Medical University.
3
Department of Pulmonary Hypertension, Fukushima Medical University.

Abstract

The restless legs syndrome (RLS) is a neurological disorder characterized by an irresistible urge to move the legs or arms for relief of uncomfortable or unpleasant sensations. Prevalence and prognostic impact of RLS on patients with heart failure (HF) remain unclear. We aimed to investigate the clinical characteristics and prognostic impact of RLS on HF patients.Consecutive 338 HF patients were evaluated for RLS and divided into two groups on the basis of presence of RLS: HF patients with RLS (RLS group, n = 29) and HF patients without RLS (non-RLS group, n = 309). We compared clinical characteristics, parameters of laboratory data and echocardiography, and rate of follow-up cardiac events including worsening HF and cardiac death between the two groups. Compared with the non-RLS group, the RLS group had higher prevalence of anemia (65.5% versus 40.8%, P = 0.010), higher usage of inotropic agents (31.0% versus 15.2%, P = 0.028), higher levels of B-type natriuretic peptide (570.8 versus 215.8 pg/mL, P = 0.018), and lower levels of left ventricular ejection fraction (40.4% versus 48.4%, P = 0.019). By contrast, age, gender, prevalence of other co-morbidities and medications were comparable between the groups. In the Kaplan-Meier analysis, the cardiac event rate was significantly higher in the RLS group than in the non-RLS group (log-rank P = 0.034). In the Cox proportional hazard analysis, RLS was a predictor for cardiac events in HF patients (hazard ratio: 1.783, 95% confidence interval: 1.038-3.063).RLS is associated with adverse prognosis in HF patients.

KEYWORDS:

Anemia; Cardiac function; Prognosis; Sleep; Sleep disturbance; Sleep quality

PMID:
31484875
DOI:
10.1536/ihj.19-049
[Indexed for MEDLINE]
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8.
Hypertension. 2019 Oct;74(4):726-732. doi: 10.1161/HYPERTENSIONAHA.119.13456. Epub 2019 Sep 3.

Neurological Sleep Disorders and Blood Pressure: Current Evidence.

Author information

1
From the Center for Sleep Medicine, Mayo Clinic, Rochester, MN (M.P.M.).
2
Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (N.C., V.K.S.).

Abstract

Hypertension is a major determinant of cardiovascular morbidity and mortality and is highly prevalent in the general population. While the relationship between sleep apnea and increased blood pressure has been well documented, less recognized is emerging evidence linking sleep-related movement disorders such as restless legs syndrome/periodic limb movements of sleep and sleep-related bruxism with blood pressure (BP) dysregulation and hypertension. There is also recent literature linking narcolepsy-cataplexy with elevated BP and altered pressor responses, and there are data suggesting abnormal BP control in rapid eye movement sleep behavior disorder. It is thought that neural circulatory mechanisms, sympathetic activation in particular, comprise the predominant mediator underlying elevated BP in these neurological sleep disorders. There is very limited evidence that treating these sleep disorders may be beneficial in lowering BP primarily because this question has received very little attention. In this review, we discuss the potential pathophysiologic mechanisms underlying elevated BP in restless legs syndrome/periodic limb movements of sleep, sleep-related bruxism, narcolepsy-cataplexy, and rapid eye movement sleep behavior disorder. We also examine the relationship between these sleep disorders and elevated BP and the impact of treatment of these conditions on BP control. Last, we discuss gaps in the literature evaluating the associations between these sleep disorders and elevated BP and identify areas for further research.

KEYWORDS:

attention; blood pressure; hypertension; restless legs syndrome sleep

PMID:
31476906
PMCID:
PMC6872192
[Available on 2020-10-01]
DOI:
10.1161/HYPERTENSIONAHA.119.13456
[Indexed for MEDLINE]
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9.
Presse Med. 2019 Oct;48(10):1051-1058. doi: 10.1016/j.lpm.2019.08.002. Epub 2019 Aug 28.

[Sleep disorders and their treatment in post-traumatic stress disorder].

[Article in French]

Author information

1
CHU de Lille, secteur des urgences psychiatriques, pôle de l'urgence, 59037 Lille, France. Electronic address: pauline.mascarel@chru-lille.fr.
2
CHU de Lille, service de psychiatrie adulte, médecine légale et médecine en milieu pénitentiaire, pôle de psychiatrie, 59037 Lille, France.
3
Centre hospitalier de Versailles, service de psychiatrie adulte, 78150 Le Chesnay, France.
4
CHU de Lille, service de psychiatrie adulte, médecine légale et médecine en milieu pénitentiaire, pôle de psychiatrie, 59037 Lille, France; Centre national de ressources et de résilience pour le psychotraumatisme (CN2R), 59000 Lille, France.

Abstract

Subjects suffering from post-traumatic stress disorder present sleeping disorders like a chronic insomnia, traumatic nightmares, but also less expected, sleep breathing disorders. Sleep problems are a factor of development and maintenance of PTSD, but also a factor of resistance to treatment. After a therapy focused on PTSD, they represent frequent residual symptoms. It is necessary to couple, with the usual management of PTSD, targeted approaches for sleep problems. These targeted approaches allow an improvement of the nocturnal properties but also diurnal specific symptoms of PTSD. Stakes around primary, secondary and tertiary prevention of PTSD emerge around these sleep disorders.

PMID:
31473024
DOI:
10.1016/j.lpm.2019.08.002
[Indexed for MEDLINE]
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10.
J Clin Neurosci. 2019 Nov;69:139-142. doi: 10.1016/j.jocn.2019.08.010. Epub 2019 Aug 19.

Non-length-dependent somatosensory small fiber pathology presenting with restless legs syndrome in pre-motor Parkinson's disease. Evidence from skin biopsy in four patients.

Author information

1
Unità Operativa di Neurologia, Azienda Ospedaliero Universitaria di Parma, via Gramsci 14, 43126 Parma, Italy. Electronic address: stefano.calzetti@unipr.it.
2
Laboratorio di Neuropatologia, Azienda Ospedaliero Universitaria di Parma, via Gramsci 14, 43126 Parma, Italy.
3
Unità Operativa di Neurologia, Azienda Ospedaliero Universitaria di Parma, via Gramsci 14, 43126 Parma, Italy.
4
Unità Operativa di Neurologia, Azienda Ospedaliero Universitaria di Parma, via Gramsci 14, 43126 Parma, Italy; Laboratorio di Neuropatologia, Azienda Ospedaliero Universitaria di Parma, via Gramsci 14, 43126 Parma, Italy.

Abstract

BACKGROUND:

The determinants of restless legs syndrome (RLS) occurring in co-morbid association with Parkinson's disease (PD) are currently unknown.

METHODS:

We performed a skin biopsy in proximal and distal sites of lower limbs in four PD patients, in which RLS had emerged in the pre-motor phase.

RESULTS:

A reduced somato-sensory intraepidermal nerve fiber (IENF) density mainly in the proximal sites, indicative of non-length-dependent small fiber pathology (SFP), was found in all patients, in absence of electroneurographic signs of large fiber neuropathy.

DISCUSSION:

The lack of known secondary causes of SFP is consistent with a process intrinsic to PD and, likewise, the absence of known disease conditions associated to RLS, would support the view of a link between the latter disorder and the distal axonopathy. The non-length-dependent pattern of SFP suggest an involvement of the somato-sensory dorsal root ganglia small neurons, consistent with a somato-sensory neuronopathy, which characterizes the RLS in these patients.

CONCLUSION:

If these findings will be confirmed in a larger cohort of patients, the RLS co-morbid with PD should be regarded as an heterogeneous condition, since the one emerging in the pre-motor phase might represent a prodromal feature of the neurodegenerative disease as an epiphenomenon of somato-sensory SFP. In contrast, for the RLS developing in clinically manifest PD, a possible association with the impairment of the DAergic diencephalo-spinal pathway and the induction by chronic DAergic treatment has been hypothesized.

KEYWORDS:

PD premotor phase; Parkinson’s disease; Restless legs syndrome; Sleep disorders; Small fiber pathology

PMID:
31439483
DOI:
10.1016/j.jocn.2019.08.010
[Indexed for MEDLINE]
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11.
Expert Opin Pharmacother. 2019 Nov;20(16):1971-1980. doi: 10.1080/14656566.2019.1654997. Epub 2019 Aug 19.

Advancing synthetic therapies for the treatment of restless legs syndrome.

Author information

1
Neurology Unit, Department of Neurosciences, University Hospital of Udine , Udine , Italy.
2
DMIF, University of Udine , Udine , Italy.
3
Department of Medicine, University of Udine Medical School , Udine , Italy.

Abstract

Introduction: Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) is a common sensory-motor neurological disorder that impairs nocturnal rest causing decreased alertness, depressed mood, reduced job performance and poor quality of life. In patients affected by moderate to severe RLS/WED, a pharmacological treatment is mandatory. Areas covered: The present review is based on an extensive Internet and PubMed search from 1996 to 2019. It is focused on drugs currently used and under development (phase III and beyond) for the treatment of RLS/WED. Expert opinion: The drugs currently available for the treatment of the disease do not always allow for obtaining the optimal control of symptoms, in particular in the long-term treatment. Although initially effective, long-term dopaminergic treatment tends to wane over time and augmentation can occur. Updated international guidelines now recommend α2δ calcium channel ligand medications as the initial drug of choice. Oxycodone-naloxone demonstrated a significant and sustained treatment effect for patients with severe RLS/WED insufficiently controlled with previous treatments. Head-to-head trials of different drugs, as well as more studies on nondopaminergic agents and combination therapy, are greatly needed. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of RLS/WED, sparing stronger dopaminergic agents for later stages of the disease.

KEYWORDS:

Augmentation; MAO-B inhibitors; dopamine; investigational drugs; iron; oxycodone-naloxone; restless legs syndrome; α2δ calcium channel ligand

PMID:
31424287
DOI:
10.1080/14656566.2019.1654997
[Indexed for MEDLINE]
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12.
Medicine (Baltimore). 2019 Aug;98(33):e16892. doi: 10.1097/MD.0000000000016892.

Leg restlessness preceding the onset of motor symptoms of Parkinson disease: A case series of 5 patients.

Abstract

Patients with Parkinson disease (PD) often show restless legs syndrome (RLS), leg motor restlessness (LMR) and other leg restlessness (OLR) related to sensorimotor symptoms.Here, we describe 5 patients who presented with leg restlessness as an early manifestation of PD.In case 1, the patient had leg restlessness that was not LMR or RLS and preceded the onset of motor symptoms by 1 year. In case 2, LMR preceded motor symptoms by 2 years. Case 3 had unilateral RLS symptoms on the left side of the body for 33 years. Two and a half years after the spread of RLS symptoms to the right leg with increased frequency of left-sided RLS symptoms, the patient developed PD at the age of 58 years. In cases 4 and 5, RLS symptoms preceded motor symptoms by 3 months and 1 month, respectively. All patients developed Parkinsonism within 3 years (median, 1.0 year; range 0.083-2.5 years) after initial onset or exacerbation of leg restlessness. All patients had frequent leg restlessness symptoms (6-7 days per week). In our series, the preceding leg restlessness was unilateral and confined to the dominant side of the subsequent Parkinsonism, or preceding leg restlessness was bilateral but dominant on the dominant side of the subsequent Parkinsonism.Clinicians should be aware that late-onset leg restlessness (>50 years of age) including RLS, LMR, and OLR, particularly if frequent and asymmetrical, can be an early nonmotor manifestation of PD.

PMID:
31415433
PMCID:
PMC6831196
DOI:
10.1097/MD.0000000000016892
[Indexed for MEDLINE]
Free PMC Article
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13.
Sleep Breath. 2019 Sep;23(3):909. doi: 10.1007/s11325-019-01878-4. Epub 2019 Jul 13.

Response to: The association between retinal thickness variations and restless leg syndrome (RLS).

Author information

1
Department of Neurology, Acibadem Private Hospital, Kayseri, Turkey. haticekse@hotmail.com.
2
Department of Neurology, Private Konak Hospital, Adapazarı, Sakarya, Turkey.
3
Medical Faculty Department of Eye Disease, Trakya University, Edirne, Turkey.
4
Department of Neurology, Adatıp Private Hospital, Adapazarı, Sakarya, Turkey.
PMID:
31302836
DOI:
10.1007/s11325-019-01878-4
[Indexed for MEDLINE]
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14.
Scand J Pain. 2019 Jul 26;19(3):429-431. doi: 10.1515/sjpain-2019-2013.

Painful Willis-Ekbom disease: unbearable and distinct form of restless legs?

Author information

1
Department of Neurology, The George Washington University School of Medicine and Health Sciences, 2150 Pennsylvania Ave, NW 9th Floor, Washington, DC 20037, USA.
PMID:
31256071
DOI:
10.1515/sjpain-2019-2013
[Indexed for MEDLINE]
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15.
Yale J Biol Med. 2019 Jun 27;92(2):201-204. eCollection 2019 Jun.

Refractory Insomnia in an Adolescent with Total Blindness.

Author information

1
Sleep and Health Research Program, Department of Psychiatry, University of Arizona, Tucson, AZ.
2
Department of Pediatrics, University of Arizona, Tucson, AZ.
3
Department of Medicine, University of Arizona, Tucson, AZ.

Abstract

We present a totally blind adolescent with refractory insomnia due to a combination of Non-24 hour sleep-wake disorder and restless leg syndrome that was successfully treated with tasimelteon, iron replacement, and gabapentin. To our knowledge, this is the first published report of treatment of N24 with tasimelteon in an adolescent. In addition, this case highlights the importance of recognizing and treating multifactorial causes of insomnia.

KEYWORDS:

adolescent; insomnia; non-24 hour sleep-wake disorder; tasimelteon

PMID:
31249480
PMCID:
PMC6585511
[Indexed for MEDLINE]
Free PMC Article
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16.
Adv Pharmacol. 2019;84:79-100. doi: 10.1016/bs.apha.2019.01.002. Epub 2019 Feb 18.

D3 and D1 receptors: The Yin and Yang in the treatment of restless legs syndrome with dopaminergics.

Author information

1
Brody School of Medicine, Department of Physiology, East Carolina University, Greenville, NC, United States. Electronic address: clemenss@ecu.edu.
2
Clinical Neurophysiology Department, Clinical Neurosciences Pole, Bordeaux Teaching Hospital, Bordeaux, France; Aquitaine Institute for Cognitive and Integrative Neuroscience, Bordeaux University, CNRS-UMR 5287, Bordeaux, France; CNRS, Aquitaine Institute of Cognitive and Integrative Neurosciences, UMR, Bordeaux, France.

Abstract

Dopaminergic treatments targeting the D3 receptor subtype to reduce the symptoms of RLS show substantial initial clinical benefits but fail to maintain their efficacy over time. Sensorimotor circuits in the spinal cord are the gateway for the sensory processing of the symptoms and critical for the associated leg movements that relieve the symptoms and the periodic limb movements that often develop during sleep. There is a high preponderance of the inhibitory D3 receptor in the sensory-processing areas of the spinal cord (dorsal horn), whereas the motor areas in the ventral horn more strongly express the excitatory D1 receptor subtype. D3 and D1 receptors can form functional heteromeric ensembles that influence each other. In the spinal cord, long-term treatment with D3 receptor agonists is associated with the upregulation of the D1 receptor subtype and block of D1 receptor function at this stage can restore the D3 receptor effect. Alternate scenarios for a role of dopamine involve a role for the D5 receptor in regulating motor excitability and for the D4 receptor subtype in controlling D3-like effects. A model emerges that proposes that the behavioral changes in RLS, while responsive to D3 receptor agonists, may be ultimately be the result of unmasked increased D1-like receptor activities.

KEYWORDS:

Augmentation model; Dopamine, receptor interactions; RLS; Receptor heteromers; Sensorimotor circuits; Spinal cord

PMID:
31229178
DOI:
10.1016/bs.apha.2019.01.002
[Indexed for MEDLINE]
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17.
Adv Pharmacol. 2019;84:37-78. doi: 10.1016/bs.apha.2019.01.001. Epub 2019 Feb 13.

The heterotetrameric structure of the adenosine A1-dopamine D1 receptor complex: Pharmacological implication for restless legs syndrome.

Author information

1
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain.
2
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain. Electronic address: vcasado@ub.edu.

Abstract

Dopaminergic and purinergic signaling play a pivotal role in neurological diseases associated with motor symptoms, including Parkinson's disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, Huntington disease, Restless Legs Syndrome (RLS), spinal cord injury (SCI), and ataxias. Extracellular dopamine and adenosine exert their functions interacting with specific dopamine (DR) or adenosine (AR) receptors, respectively, expressed on the surface of target cells. These receptors are members of the family A of G protein-coupled receptors (GPCRs), which is the largest protein superfamily in mammalian genomes. GPCRs are target of about 40% of all current marketed drugs, highlighting their importance in clinical medicine. The striatum receives the densest dopamine innervations and contains the highest density of dopamine receptors. The modulatory role of adenosine on dopaminergic transmission depends largely on the existence of antagonistic interactions mediated by specific subtypes of DRs and ARs, the so-called A2AR-D2R and A1R-D1R interactions. Due to the dopamine/adenosine antagonism in the CNS, it was proposed that ARs and DRs could form heteromers in the neuronal cell surface. Therefore, adenosine can affect dopaminergic signaling through receptor-receptor interactions and by modulations in their shared intracellular pathways in the striatum and spinal cord. In this work we describe the allosteric modulations between GPCR protomers, focusing in those of adenosine and dopamine within the A1R-D1R heteromeric complex, which is involved in RLS. We also propose that the knowledge about the intricate allosteric interactions within the A1R-D1R heterotetramer, may facilitate the treatment of motor alterations, not only when the dopamine pathway is hyperactivated (RLS, chorea, etc.) but also when motor function is decreased (SCI, aging, PD, etc.).

KEYWORDS:

Adenosine receptor; Allosteric interaction; Dopamine receptor; G protein-coupled receptor; RLS; Receptor heteromer

PMID:
31229177
DOI:
10.1016/bs.apha.2019.01.001
[Indexed for MEDLINE]
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18.
Adv Pharmacol. 2019;84:3-19. doi: 10.1016/bs.apha.2018.12.005. Epub 2019 Jan 18.

Adenosine mechanisms and hypersensitive corticostriatal terminals in restless legs syndrome. Rationale for the use of inhibitors of adenosine transport.

Author information

1
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, United States. Electronic address: sferre@intra.nida.nih.gov.
2
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, United States.
3
Sleep Research Institute, Madrid, Spain.

Abstract

Our working hypothesis is that a hypoadenosinergic state is a main pathogenetic factor that determines the sensory-motor symptoms and hyperarousal of restless legs syndrome (RLS). We have recently demonstrated that brain iron deficiency (BID) in rodents, a well-accepted animal model of RLS, is associated with a generalized downregulation of adenosine A1 receptors (A1R) in the brain and with hypersensitivity of corticostriatal glutamatergic terminals. Here, we first review the experimental evidence for a pivotal role of adenosine and A1R in the control of striatal glutamatergic transmission and the rationale for targeting putative downregulated striatal A1R in RLS patients, which is supported by recent clinical results obtained with dipyridamole, an inhibitor of the nucleoside transporters ENT1 and ENT2. Second, we perform optogenetic-microdialysis experiments in rats to demonstrate that A1R determine the sensitivity of corticostriatal glutamatergic terminals and the ability of dipyridamole to counteract optogenetically-induced corticostriatal glutamate release in both animals with BID and controls. Thus, a frequency of optogenetic stimulation that was ineffective at inducing cortico-striatal glutamate release in control rats became effective with the local perfusion of a selective A1R antagonist. Furthermore, in animals with and without BID, the striatal application of dipyridamole blocked the optogenetic-induced glutamate release and decreased basal levels of glutamate, which was counteracted by the A1R antagonist. The results support the clinical application of ENT1 inhibitors in RLS.

KEYWORDS:

Adenosine; Adenosine A(1) receptor; Dipyridamole; Equilibrative nucleoside transporter; Glutamate; Restless legs syndrome; Striatum

PMID:
31229176
DOI:
10.1016/bs.apha.2018.12.005
[Indexed for MEDLINE]
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19.
Adv Pharmacol. 2019;84:255-265. doi: 10.1016/bs.apha.2019.02.002. Epub 2019 Mar 20.

Pharmacological treatments of augmentation in restless legs syndrome patients.

Author information

1
Department of Neurosurgery, University Medical Center, Göttingen, Germany; Paracelsus-Elena Hospital, Center of Parkinsonism and Movement Disorders, Kassel, Germany. Electronic address: claudia.trenkwalder@med.uni-goettingen.de.
2
Department of Clinical Neurophysiology, University Medical Center Göttingen, Georg August University, Göttingen, Germany.

Abstract

Augmentation, a treatment-induced paradoxical worsening of the symptoms of restless legs syndrome (RLS) that is caused by long-term dopaminergic therapy, in particular with higher doses, remains the major challenge of RLS treatment. The mainstay of treatment continues to be preventing augmentation, either by starting RLS therapy with alternative drugs or by sensitizing physicians about the absolute necessity of respecting approved dosages of dopaminergic drugs when treating RLS and never exceeding the maximum recommended dosages. In the case of a positive diagnosis of augmentation, treatment consists of reducing or eliminating dopaminergic therapy, ensuring that serum ferritin is clearly higher than the level assumed to be necessary from a hematological point of view and/or switching treatment to alternative drugs such as α2δ ligands, opiates, or to combination therapy.

KEYWORDS:

Augmentation; Dopamine; Opiate; RLS; Restless legs syndrome; α2δ ligands

PMID:
31229175
DOI:
10.1016/bs.apha.2019.02.002
[Indexed for MEDLINE]
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20.
Adv Pharmacol. 2019;84:237-253. doi: 10.1016/bs.apha.2018.11.001. Epub 2018 Dec 18.

Treatment of pediatric restless legs syndrome.

Author information

1
University of Washington and Seattle Children's Hospital, Seattle, WA, United States.
2
Pediatric Sleep Center, Department of Developmental and Social Psychology, Sapienza University, Rome, Italy. Electronic address: oliviero.bruni@uniroma1.it.

Abstract

Restless legs syndrome (RLS) is not uncommon in children with an estimated prevalence of 2%. There is clear evidence that RLS affects quality of life, sleep, cognition and behavior in children and adults. Although the diagnosis of RLS can be challenging in young children, the International Restless Legs Study Group (IRLSSG) has published guidelines for diagnosis which include description of symptoms in the child's own words. Once the diagnosis is made, treatment options must be explored. It is commonly accepted that non-pharmacological interventions be recommended to all affected families. These include maintaining a consistent bedtime routine, establishing healthy eating habits and exercise, avoiding caffeine and other substances that can exacerbate RLS, and stretching before bedtime. Pharmacological interventions in children are challenged by the lack of solid data supporting effectiveness and long-term safety. Historically and based on pathophysiology, iron supplementation is the first line therapy in children. Recently intravenous iron supplementation has shown promising results, following studies in adults. Most studies in children on various pharmacological options follow a robust body of data previously published in adult patient with RLS, yet data in children remain scarce. This chapter will discuss both non-pharmacologic and pharmacologic treatment options for children with RLS.

KEYWORDS:

Ferritin; Pediatric RLS; RLS treatment; Restless legs syndrome

PMID:
31229174
DOI:
10.1016/bs.apha.2018.11.001
[Indexed for MEDLINE]
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