Absence of cardiovascular disease risk factors in restless legs syndrome.

OBJECTIVE: Restless legs syndrome (RLS) might represent a condition at risk of cardiovascular (and cerebrovascular) disease; the role of sleep periodic leg movements, sleep deprivation, and presence of common risk factors for heart disease in these patients remains to be determined. The aim of this study was to evaluate the eventual presence of risk factors for cerebrovascular disease in RLS. MATERIALS & METHODS: Eighty-seven consecutive patients affected by idiopathic RLS were included in this study together with 81 controls. Blood count, chemistry, and kidney function tests were obtained. We detected subjects suffering from diabetes mellitus, kidney diseases, heart diseases, disk herniation, neuropathy, blood diseases, liver diseases, artery diseases, dyslipidemia, or hypertension. Polysomnography was recorded in 66 patients, and cerebral neuroimaging was obtained in 59 patients with RLS. RESULTS: None of the differences in blood test parameters was statistically significant; however, hypertension was found to be more frequent in controls and dyslipidemia was more frequent in patients with RLS, but this was explained by its higher frequency in patients also affected by obstructive sleep apnea. A diagnosis of cerebrovascular disease was posed for 14 patients with RLS (16.1%), but no predictive factor for its presence was found at the binomial logistic regression. CONCLUSION: Our findings argue against the presence of an altered lipid metabolism as a risk factor for the development of cerebrovascular disease in patients with RLS, even if they do support the idea that cerebrovascular disease might be frequent in this condition.

Bruxism and nocturnal groaning.

Sleep bruxism (SB) is a sleep-related movement disorder, characterized by tooth grinding and/or clenching. The causes of SB range from psychosocial factors to an excessive sleep arousal response. Some studies showed that SB episodes during sleep are under the influences of transient activity of the brainstem arousal. Nocturnal groaning (NG) is a parasomnia characterized by an expiratory monotonous vocalization occurring during sleep, especially in REM sleep and during the second half of the night. The pathogenesis of NG remains still unclear and many hypotheses arose, ranging from the persistence of a vestigial ventilatory pattern rather than an expiratory upper airways' obstruction. Sleep microstructure fluctuation might modulate the NG, since the end of the NG episode usually is synchronized with a cortical arousal and an autonomic activation. Further studies should clarify the pathophysiology of SB and NG, especially when the two phenomena are associated.

Periodic leg movements in Cheyne-Stokes respiration.

Periodic leg movements during sleep (PLMS) are repetitive jerks of the lower limbs. Their occurrence can be isolated or part of various sleep disorders, such as restless legs syndrome (RLS), narcolepsy and obstructive sleep apnoea. Dopamine agonists are very effective in suppressing PLMS in RLS from the first night of administration. PLMS are often associated with cortical and autonomic arousals and may contribute to sleep disruption. Herein, a case of association between PLMS, Cheyne-Stokes respiration (CSR) and severe insomnia is described. Repeated polysomnographic studies demonstrated a clear synchronisation between PLMS and hyperventilation episodes, and the complete recovery of CSR, sleep quality and PLMS during nocturnal ventilation. In the same patient, pharmacological treatment with a dopamine agonist was ineffective on both PLMS and CSR. These results suggest that periodic leg movements during sleep coupled with central breathing events, similar to those observed in conjunction with obstructive events, may have a different origin in terms of neurotransmitter and pathway implicated, compared with periodic leg movements during sleep in restless legs syndrome, and are resolved by treatment of the respiratory abnormalities.

A single question for the rapid screening of restless legs syndrome in the neurological clinical practice.

The purposes of this study were to validate the use of a single standard question for the rapid screening of restless legs syndrome (RLS) and to analyze the eventual effects of the presence of RLS on self-assessed daytime sleepiness, global clinical severity and cognitive functioning. We evaluated a group of 521 consecutive patients who accessed our neurology clinic for different reasons. Beside the answer to the single question and age, sex, and clinical diagnosis, the following items were collected from all patients and normal controls: the four criteria for RLS, the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Severity (CGI-S), and the Mini-Mental State evaluation. RLS was found in 112 patients (70 idiopathic). The single question had 100% sensitivity and 96.8% specificity for the diagnosis of RLS. ESS and CGI-S were significantly higher in both RLS patient groups than in normal controls. RLS severity was significantly higher in idiopathic than in associated/symptomatic RLS patients. RLS can be screened with high sensitivity and good reliability in large patient groups by means of the single question; however, the final diagnosis should always be confirmed by the diagnostic features of RLS and accompanied by a careful search for comorbid conditions.

Aetiopathogenesis of restless legs syndrome.

The pathogenesis of restless legs syndrome (RLS) is not yet completely understood. However, recent research addressed the hypothesis that dopaminergic pathways are involved in the mechanisms responsible for the syndrome both for sensory and motor symptoms. Different aspects of RLS physiopathogenesis are discussed: the genetic components indicating different chromosomes are responsible for the heterogeneity in the phenotypic expression of the familial forms of RLS; the neurophysiologic data showing the hyperexcitability of the cortico-motor efferents at supraspinal level, with spinal cord involvement leading to a definition of RLS as a syndrome of somatosensory misperception, disturbed gain regulation and/or a shifted threshold; the paucity of neuroimaging data, which do not definitively clarify the eventual dopaminergic dysfunction in RLS patients, at least at the basal ganglia level; an illustration of the iposideremic hypothesis starting from the therapeutic effect of iron, although not for all patients, and based on some neurophysiologic and neuropathologic results both in humans and animal models; and finally the role of the opioid system, suggesting an imbalance of dopamine-opiate system inputs to brain regions involved in motor responses and pain perception, and representing an aberrant behavioural response to sensory inputs. All these theories may have a final common pathway in the dopaminergic system, reinforcing the empirical results of benefit with dopamine or dopamine-agonist treatments in RLS.

On the pathway of an animal model for restless legs syndrome...

Restless legs syndrome (RLS) is a chronic sleep motor disorder that affects up to 10% of the general population. Except for periodic leg movements (PLM), which can be found in the great majority of RLS patients, no objective hematochimic or neurophysiological markers are available to prove the diagnosis, which is based on clinical standard criteria. Nowadays, the aetiopathogenesis of the syndrome is unknown. In a consistent sample of patients affected by the idiopathic form, the disease is inherited as an autosomal dominant trait related to an unidentified locus, while each symptomatic form is probably linked to a specific cause. Although of possible different origins, both the primary and secondary forms may share the same pathogenetic mechanism, which, even if unclear, could be characterised by a neurological dysfunction of the dopaminergic system. Several issues, including strong efficacy of dopamine-agonist treatments, support this theory, which is currently considered the main pathogenetic hypothesis. Most of the past studies tried to clarify the RLS mechanism using the neurophysiological, biochemical and neuroimaging techniques applied to the field of human research. Now the time has come to accept the challenge in creating an animal model of RLS, which may emerge as a decisive step in understanding RLS pathogenesis, and to develop and test new therapies. Even though there have been a few significant efforts, a valid animal model of RLS still does not exist. In past pioneering studies, the authors attempted to induce restless motor behaviour in animals by different strategies: antidopaminergic pharmacological interventions, spinal or cerebral lesions of specific regions involved in the motor control and in dopamine regulation, and selective deletion of genes coding for dopamine receptors. Rodents (mice and rats) were always chosen by the authors as the animals for their experiments. The current tendency in achieving an RLS model is generally represented by simulation of a symptomatic condition of RLS or by a direct interference of the dopaminergic system. In this regard, the pharmacological method had the intention to reproduce the neuroleptic-induced acathisia, the spinal lesional model was based on the hypothesis of myelopathic- related PLM, and the hypothalamic lesion tested the motor consequence of A11 dopaminergic neurons. Preliminary studies are underway to replicate the pregnancy-related form of RLS by using a hormonal intervention, and the iron-deficiency secondary form by using specific iron-free diets. Today, modern technologies are available to easily replicate in animals most of the symptomatic RLS conditions. In addition, more than a few well validated animal models of different diseases known to be related to RLS or PLM, for instance, Parkinson's disease, rheumatoid arthritis and renal failure, could also be exploited in addressing this topic. The real obstacle in achieving an RLS model is the absence of a certain diagnostic marker to recognise if the animal that underwent the different experimental procedures has developed the RLS condition or not. Concerning this issue, possible specific endpoints are represented by the increase in locomotor activity, which are ascertainable by different techniques, such as openfield or run-wheel activity, or by sleep fragmentation, in which the circadian shift can be verified by applying polysomnography on the animal. PLM are probably the only specific and reliable markers available to recognise and quantify experimentally induced RLS. Despite a few authors who reported the presence of limb-phasic, pseudoperiodic activity during sleep in old or in lesioned rats, the existence of spontaneous or provoked PLM in animals is still debated. Eventually, the PLM features in an animal could be markedly different compared to human ones. To recognise and characterise PLM in animals, three more essential steps are required: a method to record directly, as in humans, the activity of the tibialis anterior (TA) muscles, a consistent amount of normative control data on the TA activity in healthy animals, and reliable analysis to distinguish the generic phasic muscular activity to a possible unambiguous PLM pattern. This review includes a summary and a critical discussion of the previous tentative RLS models, proposals for other possible animal models, and firstly the preliminary normative data on TA activity during sleep in normal rodents.

World Association of Sleep Medicine (WASM) 2016 standards for recording and scoring leg movements in polysomnograms developed by a joint task force from the International and the European Restless Legs Syndrome Study Groups (IRLSSG and EURLSSG).

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 and the explanations of the new rules are reported and then specific standard rules are presented for recording, detecting, scoring and reporting LM activity in PSG. Each standard rule has been classified with a level of evidence. At the end of the paper, Appendix 1 provides algorithms to aid implementation of these new standards in software tools. There are two main changes introduced by these new rules: 1) Candidate LM (CLM), are any monolateral LM 0.5-10 s long or bilateral LM 0.5-15 s long; 2) periodic LM (PLM) are now defined by runs of at least four consecutive CLM with an intermovement interval ≥10 and ≤ 90 s without any CLM preceded by an interval <10 s interrupting the PLM series. There are also new options defining CLM associated with respiratory events. The PLM rate may now first be determined for all CLM not excluding any related to respiration (providing a consistent number across studies regardless of the rules used to define association with respiration) and, subsequently, the PLM rate should also be calculated without considering the respiratory related events. Finally, special considerations for pediatric studies are provided. The expert visual scoringof LM has only been altered by the new standards to require accepting all LM > 0.5 s regardless of duration, otherwise the technician scores the LM as for the old standards. There is a new criterion for the morphology of LM that applies only to computerized LM detection to better match expert visual detection. Available automatic scoring programs will incorporate all the new rules so that the new standards should reduce technician burden for scoring PLMS.

Hemifacial spasm in sleep.

We conducted polygraphic studies during wakefulness and all-night sleep in 13 patients with cryptogenic and 3 with postparalytic hemifacial spasm. The movements decreased progressively with deepening sleep stages, reaching lowest values in REM sleep. The reduction was inversely related to the severity of movements during wakefulness. There was no relation between hemifacial spasm and mimic activity on the unaffected side. Central inhibitory processes may account for the partial decline in intensity of the movements in sleep.

Magnetization transfer and diffusion-weighted imaging in nocturnal frontal lobe epilepsy.

The authors assessed the presence of brain abnormalities in 21 patients with nocturnal frontal lobe epilepsy (NFLE), using magnetization transfer ratio (MTR) and mean diffusivity (;D) histograms. Compared with healthy volunteers and patients with idiopathic generalized epilepsy, patients with NFLE had lower MTR (p = 0.002 and 0.01) and;D (p = 0.03 and 0.04) histogram peak heights. Subtle and widespread abnormalities related to intra- and extracellular distribution and motion of water are detectable in the brains of patients with NFLE.

Sleep arousal response to experimental thermal stimulation during sleep in human subjects free of pain and sleep problems.

Although the interaction between sleep and pain is generating considerable interest (NIH Technology Assessment Panel, 1996), it is still unknown if chronic pain is the cause or effect of poor sleep. To further this understanding, subjects free of pain and sleep problems need to be studied in order to assess their response to pain during sleep, defined as a behavioral and a physiological state in which sensory processing is altered. (For example, while auditory perception remains active, other sensory inputs are facilitated, attenuated, or suppressed (Velluti, 199746 degrees C) was statistically greater in the lighter sleep stage 2 (48.3%) than in the deeper stages 3&4 (27.9%). A nocifensive behavioral-motor response was associated with only 2.5% of the 351 heat pain stimuli. Two other markers of sleep quality-sleep stage shift and awakening-were not influenced by the thermal stimuli. None of the subjects demonstrated any burns in the morning following the thermal stimulations applied during sleep. We conclude that the processing of nociceptive inputs is attenuated across sleep stages.

Cerebral anoxic attacks in sleep apnea syndrome.

In a 52-year-old man who presented with an obstructive sleep apnea (OSAS) syndrome, we observed cerebral anoxic attacks during rapid eye movement (REM) sleep. Polysomnography showed that the attacks were due to severe hypoxia provoked by apneas lasting up to 220 s. Electroencephalogram (EEG) and clinical features clearly differentiate cerebral anoxic attacks from epileptic seizures. The length of apneas in our patient is very unusual, indicating an impairment of the mechanism terminating apneas. The cause of this impairment is unknown. However, this case report documents a possible pathogenetic mechanism other than heart arrhythmias responsible for sudden death or coma arising during sleep.

Cardiac autonomic activity during wakefulness and sleep in REM sleep behavior disorder.

In REM sleep behavior disorder (RBD) it has been reported that tachycardia may not accompany the impressive movements associated with dream mentation. Up to now there are no data concerning the cardiac autonomic activity during wakefulness as well as during sleep out of nocturnal dream-enacting behaviors, in RBD. We evaluated 14 RBD patients. Our study shows that only 36% of patients had normal results in all traditional autonomic tests during wakefulness. Moreover, RBD patients had a reduced tonic and phasic heart rate variability during sleep. Autonomic evaluation during sleep may show impairment earlier than the traditional tests during wakefulness. No difference was found between idiopathic RBD patients and symptomatic ones.

Effect of melatonin on sleep microstructure: preliminary results in healthy subjects.

The ability of melatonin (MLT) to potentiate the effects of gamma-aminobutyric acid and the benzodiazepines has been demonstrated repeatedly in animal models, and recent experimental data favored the hypothesis that MLT, given together with threshold doses of benzodiazepines, could significantly improve the quality of sleep. This preliminary study was designed to compare the effects of MLT (100 mg) with those of a benzodiazepine hypnotic [triazolam (TRI) 0.125 mg] and to explore the effects of a combination of MLT and TRI at a low dose in healthy volunteers. No significant changes in the classical polysomnographic variables were observed following MLT, TRI and MLT + TRI, whereas MLT and especially MLT + TRI resulted in significant modulation of some microstructural parameters. These changes were paralleled by ameliorated subjective sleep quality. A combination of MLT and low benzodiazepine doses could avoid the residual, dose-related benzodiazepine effects.

Slow wave sleep and cyclic alternating pattern (CAP) in HIV-infected asymptomatic men.

Alterations of sleep structure have been reported in asymptomatic human immunodeficiency virus (HIV)-infected subjects. In these patients some authors have found an increased percentage of slow wave sleep (SWS) and a SWS preponderance in the second half of the night, as well as subjective sleep complaints. Other authors have found an increased stage 1 non-rapid eye movement (NREM) and reduced stage 2 NREM percentages in asymptomatic subjects. We evaluated the macrostructure and the microstructure (cyclic alternating pattern, CAP) of sleep in nine HIV-infected asymptomatic men without sleep complaints or psychiatric illness, in comparison with nine age-matched controls. Our study showed a decreased amount of SWS and a significantly higher CAP rate in HIV-subjects, suggesting an altered organization of the sleep process in these patients.

Cardiac autonomic nervous activity in sleep-related painful erections.

Sleep-related painful erections (SRPE) are characterized by penile pain that occurs during erections, typically during REM sleep. Afflicted individuals usually have normal erections during wakefulness. The disorder could be related to an altered autonomic function only during sleep. The aim of this study was to evaluate tonic and phasic heart rate (HR) modifications during sleep in 10 SRPE patients compared to 25 age-matched controls. A reduced cardiac vagal activity during sleep, as well as a trend towards a higher HR acceleration in relation to spontaneous body movements, have been found in SRPE patients. The possible beta-adrenergic hyperactivity during sleep in these patients could explain the reported efficacy of a beta-blocker, such as propranolol, in this disorder.

Atrial natriuretic peptide and catecholamines in obstructive sleep apnea syndrome.

Nocturnal polyuria with repeated micturitions during the night is a clinically evident feature of obstructive sleep apnea syndrome (OSAS). These effects are reversed by continuous positive airway pressure (CPAP). There is some evidence that atrial natriuretic peptide (ANP) and catecholaminergic activity may be implicated in the pathogenesis of these symptoms. We studied these biochemical parameters in six patients with severe OSAS during two nights: the first (basal) in their normal conditions and the second during CPAP treatment. CPAP treatment reversed apnea episodes in all our patients. A significant (p less than 0.035) reduction of nocturnal urine volume (from 902 +/- 297 to 447 +/- 130 ml; mean +/- SD), sodium excretion (from 150 +/- 33 to 89 +/- 35 mEq/12 h), noradrenaline excretion (from 95 +/- 101 to 52 +/- 16 micrograms/g creatinine), noradrenaline plasma concentrations (from 325 +/- 96 to 259 +/- 75 pg/ml), ANP plasma concentrations (from 35 +/- 20 to 19 +/- 5 pg/ml) was observed during the night under CPAP application. These data suggest that in OSAS patients the high ANP plasma concentration is responsible for the observed elevated diuresis and sodium excretion. These effects are rapidly reversible, as they are reversed during the first CPAP treated night.

Snoring & sleep apnea: a population study in Italian women.

The aim of this cross-sectional study was to evaluate the prevalence of sleep-disordered breathing by means of a validated portable instrument (MESAM IV) and to investigate the relationship between snoring and sleep apnea in a sample of Italian middle-aged female population. We randomly chose 750 subjects aged 40 to 65 years and 365 agreed to participate to the study. In this group, 19.7% of subjects were every-night snorers according to the questionnaire; when recorded, 54.2% snored for more than 10% of the night, and 7.1% for more than 50% of the night. Sleep apnea was also common: 10.7% of subjects had a respiratory disturbances per hour (RDI) between 5 and 9, 7.7% an RDI between 10 and 19, and 2.2% had an RDI > or =20. Snoring percentage and RDI were significantly correlated. However, 50% of subjects who snored for more than half the night had no evidence of sleep apnea. Snoring amount >50% resulted influenced by body mass index, while RDI>10 was influenced by neck diameter. We concluded that in middle-aged women, both snoring and sleep apnea are very common. A high percentage of snoring is not essential for the occurrence of sleep apnea, nor it necessarily indicates the presence of sleep apnea.

SER252PHE and 776INS3 mutations in the CHRNA4 gene are rare in the Italian ADNFLE population.

41 patients (19 sporadic and 22 familial) affected by autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) were analyzed for the presence of two mutations (Ser252Phe, 776ins3) in the CHRNA4 gene, reported to be associated with this disease. Electroclinical findings of sporadic forms were indistinguishable from familial ones. In none of the patients, these mutations were found by dot blot analysis with allele specific oligonucleotides. These data, obtained on the largest group so far studied, suggest the rarity of the reported mutations.

Structured psychiatric interview and ambulatory sleep monitoring in young psychophysiological insomniacs.

BACKGROUND: The presence of psychiatric disorders (according to DSM-III-R), the discriminating power of a psychiatric structured interview, and sleep monitoring were investigated in psychophysiological insomnia. METHOD: Forty young (20-40 years old) patients, selected for putative psychophysiological insomnia, underwent a psychiatric structured interview and home ambulatory sleep monitoring for 2 nights. The results were compared with those of a group of nine young normal sleepers. RESULTS: 48% of the insomniacs showed some psychiatric disorders, while 52% did not meet DSM-III-R criteria for a psychiatric diagnosis. Both groups, but not the controls, showed a slight first-night effect in the sleep analysis. The sleep structure of all insomniacs was found to be disturbed, mainly in sleep continuity, but essentially the two groups showed no significant differences. When we used a stepwise logistic regression analysis, the number of sleep stage shifts (indicating sleep instability) was the best variable in discriminating the insomniacs from controls, but not the patients with psychiatric disturbances from those without psychopathologies. CONCLUSION: The evaluation of young insomniacs with a structured psychiatric interview rather than with ambulatory sleep monitoring seems to be most useful in discriminating between patients with only psychophysiological insomnia and patients with both insomnia and an associated diagnosis of another mental disorder.

Heart rate variability during sleep in snorers with and without obstructive sleep apnea.

Changes in sympathetic and vagal tone may be the substrate for the development of cardiac arrhythmias in patients with obstructive sleep apnea (OSA). The cardiovascular responses in the traditional autonomic tests show great interindividual and intraindividual variations. During sleep there are repetitive modifications of heart rate (HR) that are not influenced by psychologic factors or the patient's cooperation. For this reason, we evaluated HR modifications in relation to spontaneous body movements (BM) and sleep apneas during nonrapid eye movement (NREM) and rapid eye movement (REM) sleep in habitual snorers with normal and pathologic respiratory disturbance index (RDI). From 132 consecutive patients referred to our sleep center for habitual snoring and/or daytime somnolence, we selected 35 male patients younger than 60 years without clinical evidence of autonomic dysfunction. They were divided into three groups: group A (RDI < 10); group B (RDI > 10 and < 20); and group C (RDI > 20). No significant difference was found among the three groups in the HR variability related to BM. In the evaluation of bradytachyarrhythmias related to apneic events of 20 to 30 s, we found a significant difference between group A and the other two groups. In patients with RDI > 10, a reduced HR variability related to a reduced sympathetic tone in the post-apnea phase was observed. Some authors suggested that an HR increase during the post-apnea period can be used as an index of "brainstem arousal." Our results seem to indicate a reduced apnea-related "arousability" in patients with RDI > 10. This finding might be one of the factors contributing to the worsening of OSA.