Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, ß-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is ß-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

Evaluation of sleep medicine fellowship program websites.

STUDY OBJECTIVES: Sleep fellowship program websites likely serve as a preliminary source of information for prospective fellows. Arguably, applicants have likely become even more reliant on program websites during the COVID-19 pandemic due to travel restrictions and social-distancing measures limiting in-person interviews. In this study, we evaluated the content and comprehensiveness of sleep medicine fellowship websites to identify areas of improvement. METHODS: A list of sleep medicine fellowship programs in the United States participating in the 2021 match cycle was compiled using the Electronic Residency Application Service (ERAS) and Fellowship and Residency Electronic Interactive database (FREIDA) websites. Twenty-two prespecified content criteria related to education, recruitment, and compensation were used to evaluate each program website. Sleep programs' website comprehensiveness were compared based on US location, type, matching status, core specialty, and size of programs. RESULTS: Seventy-eight US sleep fellowship program websites were evaluated. Most program websites had a working hyperlink on ERAS or FREIDA. There was considerable variability in content reported across program websites, with a mean of 56.8% of content items reported per program. There was a greater educational website content comprehensiveness for internal medicine compared with other specialty-based sleep programs. There was no difference in sleep programs' website comprehensiveness based on US location, type, matching status, or size of programs. CONCLUSIONS: Website content comprehensiveness among sleep fellowship programs is variable. There is opportunity for all sleep fellowship programs to improve their websites to better inform prospective trainees. CITATION: Shenoy S, Akberzie W, Landeo-Gutierrez JS, Leon Guerrero CR, Karroum EG. Evaluation of sleep medicine fellowship program websites. J Clin Sleep Med. 2023;19(6):1083-1088.

Validation of an Arabic version of the Cambridge-Hopkins diagnostic questionnaire for restless legs syndrome.

PURPOSE: To validate an Arabic version of the short form of the Cambridge-Hopkins diagnostic questionnaire for restless legs syndrome (CH-RLSq13). METHODS: The Arabic version was created using a standard forward-backward translation method. A pre-final Arabic version was administered with the original English version to a group of bilingual subjects as a pretest. The inter-rater agreement between these two versions was measured. A finalized Arabic version was obtained. For the validation, the Arabic version of the CH-RLSq13 was administered to Lebanese subjects, above 18 years old, selected upon a clinical interview. The diagnosis provided by the Arabic version of the CH-RLSq13 was compared to the clinical diagnosis made by a neurologist at Hotel-Dieu de France hospital. Inter-rater agreement was assessed using Cohen's kappa coefficient. Sensitivity, specificity, and positive and negative predictive values of the translated questionnaire were calculated. RESULTS: Inter-rater agreement, between the 2 versions, for the entire questionnaire, was excellent (κ = 0.950). All items showed a substantial level of agreement between the two versions. In the validation process, 91 participants were included (17 patients diagnosed with RLS and 74 control subjects). The mean age was 40 years, with female predominance. The final Arabic version of the CH-RLSq13 had a sensitivity of 71%, a specificity of 100%, and with negative and positive predictive values of 94% and 100% respectively. CONCLUSION: The Arabic version of the CH-RLSq13 is a reliable tool for the screening and diagnosis of RLS in Lebanese and Arabic-speaking populations.

Exploring the role of the endogenous opiate system in the pathogenesis of anemia in an opiate receptor knock-out model of Restless Legs Syndrome.

Restless Legs Syndrome (RLS) is characterized by bothersome leg discomfort accompanied by an urge to move to obtain relief and symptoms are worse at night and on lying down. There is at least partial and temporary relief with activity. It is also an opioid responsive disorder, often accompanied by iron deficiency with or without anemia, and inflammation may be a precipitating factor in some cases. We created two in-vivo opiate receptor knock out mouse models of RLS - a triple opiate receptor knock-out mouse and a mu opiate receptor knock-out mouse. Both sets of animals were restless during the sleep period as is also true of RLS. Both of our knockout models showed statistically significantly decreased Hemoglobin and Hematocrit indicating anemia and both models showed statistically significant decreases in serum iron suggestive of either iron deficiency anemia or inflammatory anemia. The rest of the hematologic studies were not consistent enough to determine which of these two types of anemia was present in either model. An additional experiment in normal wild type mice showed a statistically significant decrease in serum iron when an opiate receptor blocker was used. To our knowledge this is the first demonstration that deficiency of endogenous opioids might play a role in the production of anemia. Our hypothesis is that an intact endogenous opiate system is necessary for red cell homeostasis. The presence of opioid receptors both on red blood cells and on various immunologically based white blood cells suggest mechanisms by which deficiency in the endogenous opiate system could cause anemia of either the iron deficiency or inflammatory types. The administration of opioid agonists or antagonists to iron deficient cultures of red blood cell precursors is a next step in determining the role of the endogenous opiate system in the maintenance of red cell homeostasis and in the possible prevention of iron deficiency or inflammatory anemia where iron dysregulation is key.

Restless Legs Symptoms and Periodic Leg Movements in Sleep Among Patients with Parkinson's Disease.

BACKGROUND: The association between restless legs syndrome (RLS) and Parkinson's disease (PD) remains controversial, with epidemiologic and descriptive evidence suggesting some potential overlap while mechanistic/genetic studies suggesting relative independence of the conditions. OBJECTIVE: To examine a known, objectively measured endophenotype for RLS, periodic leg movements (PLMS) in sleep, in patients with PD and relate that objective finding to restless legs symptoms. METHODS: We performed polysomnography for one (n = 8) or two (n = 67) consecutive nights in 75 PD patients and examined the association of PLMS with restless legs symptoms. RESULTS: We found no association between restless legs symptoms and PLMS in PD. Prevalence of both was similar to data reported previously in other PD samples. CONCLUSION: We interpret these results as suggesting that restless legs symptoms in PD patients may represent a different phenomenon and pathophysiology than RLS in the non-PD population.

Women are underrepresented in major US sleep societies recognition awards.

STUDY OBJECTIVES: To investigate gender distribution of US sleep professionals who received major recognition awards over a 40-year period from the 2 national sleep societies: the American Academy of Sleep Medicine and the Sleep Research Society. METHODS: We reviewed and analyzed the publicly available lists of sleep recognition awards recipients from the American Academy of Sleep Medicine and the Sleep Research Society websites. The primary outcome measures were the overall proportion of individual sleep recognition awards given to US men and women sleep professionals and the trend over time (1981-2020) analyzed by decade using the Cochran-Armitage test. RESULTS: Seven major sleep recognition awards (4 by the American Academy of Sleep Medicine and 3 by the Sleep Research Society) were identified over 40 years. There were overall 164 individual sleep recognition awards presented by the 2 sleep societies to US sleep professionals, including 136 (82.9%) awarded for men and only 28 (17.1%) awarded for women. The analysis of the sleep recognition awards over time by decade revealed a significant increasing trend (P < .0001) in the proportion of awards recognizing women relative to men, with a progression from 0.0% in the 1980s to 3.4% in the 1990s to 13.1% in the 2000s and to 31.7% in the 2010s. CONCLUSIONS: US women sleep professionals were historically underrepresented in major sleep recognition awards, with a reduction in the gender gap in the last 10 years. The reasons behind gender inequality in sleep recognition awards remain unclear and deserve further investigation. CITATION: Naime S, Karroum EG. Women are underrepresented in major US sleep societies recognition awards. J Clin Sleep Med. 2021;17(8):1665-1673.

Evaluation of Adult Neurology Residency Program Websites.

OBJECTIVE: Neurology residency program websites often serve as the initial face of a program for prospective residents early in the application process. We evaluated adult neurology residency program websites to determine their comprehensiveness to identify areas for improvement. METHODS: A list of adult neurology residency programs in the United States was compiled using information on the Electronic Residency Application Service (ERAS) and Fellowship and Residency Electronic Interactive Database (FREIDA) websites. A total of 24 website criteria covering educational, recruitment, and compensation content were assessed for comprehensiveness. Programs' website comprehensiveness was compared based on geographic location, program affiliation (community and/or academic), program size, and program/hospital Doximity and U.S. News & World Report rankings. RESULTS: A total of 153 US adult neurology residency program websites were evaluated. Fewer than one-half of program websites were accessible with a direct link from either FREIDA or ERAS. The number of residency program websites reporting each content criterion varied greatly. Mean percentage of overall website comprehensiveness among neurology residency programs was 65.9%. Northeast location, academic affiliation, larger programs, and top-ranked programs on Doximity were associated with greater program website comprehensiveness. INTERPRETATION: There is opportunity for all neurology residency programs to improve their websites to provide prospective applicants with a more informed and comprehensive perspective of programs during the application process. ANN NEUROL 2021;89:637-642.

TOX3 gene variant could be associated with painful restless legs.

BACKGROUND/OBJECTIVE: Restless legs syndrome (RLS) is a neurological disorder with a strong genetic susceptibility. A painful RLS sub-phenotype has been described previously but the neurobiological basis for this phenotypic variant remains unknown. This study investigated whether any of the six initially discovered genomic loci associating with RLS (BTBD9, MEIS1, PTPRD, MAP2K5/SKOR1, TOX3, and an intergenic region on chromosome 2), were more strongly associated with complaints of painful versus non-painful RLS. METHODS: RLS patients (N = 199; Age = 53.1 ± 16.8; 100% Caucasians; 57% women) diagnosed clinically were genotyped for known variants associating with RLS. Definition of painful RLS required that subjects selected "painful" from a list of 14 adjectives to describe their RLS sensory experience and answered positively to a separate question that queried specifically as to whether they perceived their RLS sensations as painful. Genotype association tests employed logistic regression analyses with assumption of an additive genetic model. Analyses were performed using PLINK software v1.07. RESULTS: We identified two RLS patient subgroups: a painful (n = 41) and non-painful (n = 158). Among 10 tested SNPs, only rs3104767 (related to the TOX3 gene locus) was more associated with painful RLS. The minor allele T of SNP rs3104767 was associated with an increased risk of RLS being perceived as painful with an OR of 1.67 [CI = (1.01-2.74); p = 0.049]. Notably, this minor T allele associated with pain sensation in RLS patients in this study was the non-risk allele for RLS in the original RLS genome wide association study, but a similar trend was observed in a recent Parkinson disease sample study. CONCLUSION: This study might suggest the TOX3 gene variant as a potential genetic substrate for the painful RLS sub-phenotype. This was an exploratory small study and correction for multiple comparisons would have rendered the results not significant. Therefore, the above findings require replication in larger clinical as well as population-based samples of RLS subjects.

Entanglement between thermoregulation and nociception in the rat: the case of morphine.

In thermoneutral conditions, rats display cyclic variations of the vasomotion of the tail and paws, the most widely used target organs in current acute or chronic animal models of pain. Systemic morphine elicits their vasoconstriction followed by hyperthermia in a naloxone-reversible and dose-dependent fashion. The dose-response curves were steep with ED50 in the 0.5-1 mg/kg range. Given the pivotal functional role of the rostral ventromedial medulla (RVM) in nociception and the rostral medullary raphe (rMR) in thermoregulation, two largely overlapping brain regions, the RVM/rMR was blocked by muscimol: it suppressed the effects of morphine. "On-" and "off-" neurons recorded in the RVM/rMR are activated and inhibited by thermal nociceptive stimuli, respectively. They are also implicated in regulating the cyclic variations of the vasomotion of the tail and paws seen in thermoneutral conditions. Morphine elicited abrupt inhibition and activation of the firing of on- and off-cells recorded in the RVM/rMR. By using a model that takes into account the power of the radiant heat source, initial skin temperature, core body temperature, and peripheral nerve conduction distance, one can argue that the morphine-induced increase of reaction time is mainly related to the morphine-induced vasoconstriction. This statement was confirmed by analyzing in psychophysical terms the tail-flick response to random variations of noxious radiant heat. Although the increase of a reaction time to radiant heat is generally interpreted in terms of analgesia, the present data question the validity of using such an approach to build a pain index.

Melatonin for Sleep Disorders in Patients with Neurodegenerative Diseases.

In patients with neurodegenerative diseases, sleep disorders are common; they impair the quality of life for patients and caregivers and are associated with poorer clinical outcomes. Melatonin has circadian, hypnotic, and free radical-scavenging effects, and preclinical data suggest benefits of melatonin on neurodegeneration. However, randomized, controlled trials of melatonin in patients with neurodegenerative diseases have not shown strong effects. Trials in Alzheimer's patients demonstrate a lack of benefit on sleep quantity. Subjective measures of sleep quality are mixed, with possible symptomatic improvements seen only on some measures or at some time points. Benefits on cognition have not been observed across several studies. In Parkinson's patients, there may be minimal benefit on objective sleep measures, but a suggestion of subjective benefit in few, small studies. Effective treatments for the sleep disorders associated with neurodegenerative diseases are urgently needed, but current data are insufficient to establish melatonin as such a treatment.

Painful restless legs syndrome: a severe, burning form of the disease.

OBJECTIVES: Limb sensations in restless legs syndrome (RLS) include an urge to move, a discomfort, or even a frank pain. However, no large studies compared painful to nonpainful RLS as specific phenotypes. We investigated the painful form of RLS in a clinical series of primary RLS patients and a large sample of members of the French RLS association (AFE). MATERIALS AND METHODS: Fifty-six patients with primary RLS (face-to-face interviewed) and 734 AFE members (received by ground mail an self-report questionnaire) responded to the presence/absence of painful RLS sensations and were included. They completed a French reconstruction of the McGill Pain Questionnaire (Questionnaire Douleur de Saint-Antoine [QDSA]) to assess their RLS sensations as well as questions about demographics and clinical RLS features. RESULTS: Sixty-one percent of interviewed patients and 55% of AFE members had painful RLS sensations. The patients with painful RLS were more sleepy and tired than those with nonpainful sensations. The RLS severity and need for current, dopaminergic treatment were higher in AFE members with painful than with nonpainful RLS. In both the groups, the QDSA qualifier "burning" was the most frequent (37% to 44%) sensory discriminator of painful RLS. In the AFE sample, QDSA scores, and the distribution of words in all QDSA subclasses was skewed toward a more severe connotation with more than one third of patients selecting affective discriminating words like "exasperating," "exhausting," and "unbearable." DISCUSSION: Painful RLS appears to be a severe, "burning" subtype of RLS, and could be a distinct disease or a clinical variant in a sensations continuum.

Thermoregulatory vasomotor tone of the rat tail and paws in thermoneutral conditions and its impact on a behavioral model of acute pain.

The tail and paws in rodents are heat exchangers involved in the maintenance of core body temperature (T(core)). They are also the most widely used target organs to study acute or chronic "models" of pain. We describe the fluctuations of vasomotor tone in the tail and paws in conditions of thermal neutrality and the constraints of these physiological processes on the responses to thermal nociceptive stimuli, commonly used as an index of pain. Skin temperatures were recorded with a calibrated thermal camera to monitor changes of vasomotor tone in the tail and paws of awake and anesthetized rats. In thermoneutral conditions, the sympathetic tone fluctuated at a rate of two to seven cycles/h. Increased mean arterial blood pressure (MAP; ∼46 mmHg) was followed by increased heart rate (HR; ∼45 beats/min) within 30 s, vasoconstriction of extremities (3.5-7°C range) within 3-5 min, and increased T(core) (∼0.7°C) within 6 min. Decreased MAP was followed by opposite events. There was a high correlation between HR and T(core) recorded 5-6 min later. The reaction time of the animal's response to a radiant thermal stimulus-heat ramp (6°C/s, 20 mm(2) spot) generated by a CO2 laser-directed to the tail depends on these variations. Consequently, the fluctuations in tail and paw temperature thus represent a serious confound for thermal nociceptive tests, particularly when they are conducted at thermal neutrality.

Topography of the sensations in primary restless legs syndrome.

OBJECTIVES: To evaluate the topography of restless legs syndrome (RLS) sensations and to compare subgroups of patients based on RLS topography. METHODS: Forty-four treated patients with primary RLS were interviewed and reported the localization of RLS sensations on body diagrams. RESULTS: RLS sensations were felt deep inside the muscles of mainly the middle portions of the lower limbs in 86% of patients. Superposition of patients' drawings showed a predominant involvement of the upper calves (75%). RLS sensations were diffuse, affecting on average 21% of the body. They occurred bilaterally, but also unilaterally (41%). During symptomatic periods, 66% of the patients experienced sensations spreading, frequently from the legs to other limbs segments. Clinical features were similar in patients with sensations: superficial versus strictly deep; limited or not to the lower limbs; unilateral versus strictly bilateral; and spreading or not. The percentage of affected surface did not correlate with patient age, age at RLS onset, RLS duration and severity. The percentage of affected area in the lower limbs correlated with the one in the upper limbs (r=0.53; p=0.0003). CONCLUSION: RLS sensations affect large body areas (predominantly the upper calves). Body diagrams could be used to explore the evolution of RLS topography and treatment effects.

Sensations in restless legs syndrome.

OBJECTIVE: To characterize the verbal descriptors of the sensations in restless legs syndrome (RLS) in depth. METHODS: Fifty-six patients with primary RLS (interviewed in person) and 738 members of the French RLS Association (sent a postal questionnaire) were included in the study. Patients in the clinical series were asked to report their RLS sensations in detail. The two groups completed a French reconstruction of the McGill Pain Questionnaire (QDSA) to assess their RLS sensations. RESULTS: All patients in both groups had abnormal sensations associated with the urge to move the legs. Most patients in the clinical series reported spontaneous "electrical," "prickling," "burning," "tingling," and "itching" sensations. In the QDSA, more than two-thirds of subjects in both groups selected the sensory subclasses "temporal" and "paresthesias," and the affective subclasses "evaluative," "nervous tension," "asthenia, fatigue," and "punishment." More than one-third of subjects chose the sensory words "electric shocks," "irradiating," and "tingling," and the affective words "exhausting," "distressing," "unbearable," "irritating," and "depressing." The subjects used more heat than cold descriptors to express their sensations. CONCLUSION: RLS is a primary sensory disorder without any pure motor form. The sensory descriptors in RLS could be similar to those of neuropathic pain, except for rare cold and numbness sensations.

Restless legs syndrome, rapid eye movement sleep behavior disorder, and hypersomnia in patients with two parkin mutations.

Parkin gene mutations cause a juvenile parkinsonism. Patients with these mutations may commonly exhibit REM sleep behaviour disorders, but other sleep problems (insomnia, sleepiness, restless legs syndrome) have not been studied. The aim of this study was to evaluate the sleep-wake phenotype in patients with two parkin mutations, compared with patients with idiopathic Parkinson's disease (iPD). Sleep interview and overnight video-polysomnography, followed by multiple sleep latency tests, were assessed in 11 consecutive patients with two parkin mutations (aged 35-60 years, from seven families) and 11 sex-matched patients with iPD (aged 51-65 years). Sleep complaints in the parkin group included insomnia (73% patients versus 45% in the iPD group), restless legs syndrome (45%, versus none in the iPD group, P = 0.04), and daytime sleepiness (45%, versus 54% in the iPD group). Of the parkin patients, 45% had REM sleep without atonia, but only 9% had a definite REM sleep behavior disorder. All sleep measures were similar in the parkin and iPD groups. Two parkin siblings had a central hypersomnia, characterized by mean daytime sleep latencies of 3 min, no sleep onset REM periods, and normal nighttime sleep. Although the patients with two parkin mutations were young, their sleep phenotype paralleled the clinical and polygraphic sleep recording abnormalities reported in iPD, except that restless legs syndrome was more prevalent and secondary narcolepsy was absent.