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PubMed2005

Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro.

Insomnia is the most frequently encountered sleep complaint worldwide. While many prescription drugs are used to treat insomnia, extracts of valerian (Valeriana officinalis L., Valerianaceae) are also used for the treatment of insomnia and restlessness. To determine novel mechanisms of action, radioligand binding studies were performed with valerian extracts (100% methanol, 50% methanol, dichloromethane [DCM], and petroleum ether [PE]) at the melatonin, glutamate, and GABA(A) receptors, and 8 serotonin receptor subtypes. Both DCM and PE extracts had strong binding affinity to the 5-HT(5a) receptor, but only weak binding affinity to the 5-HT(2b) and the serotonin transporter. Subsequent binding studies focused on the 5-HT(5a) receptor due to the distribution of this receptor in the suprachiasmatic nucleus of the brain, which is implicated in the sleep-wake cycle. The PE extract inhibited [(3)H]lysergic acid diethylamide (LSD) binding to the human 5-HT(5a) receptor (86% at 50 microg/ml) and the DCM extract inhibited LSD binding by 51%. Generation of an IC(50) curve for the PE extract produced a biphasic curve, thus GTP shift experiments were also performed. In the absence of GTP, the competition curve was biphasic (two affinity sites) with an IC(50) of 15.7 ng/ml for the high-affinity state and 27.7 microg/ml for the low-affinity state. The addition of GTP (100 microM) resulted in a right-hand shift of the binding curve with an IC(50) of 11.4 microg/ml. Valerenic acid, the active constituent of both extracts, had an IC(50) of 17.2 microM. These results indicate that valerian and valerenic acid are new partial agonists of the 5-HT(5a) receptor.

Animals↗

PubMed2001

[A patient with restless legs syndrome/periodic limb movement successfully treated by wearing a lumbar corset].

We report a 77-year-old woman with restless legs syndrome(RLS) and periodic limb movement(PLM). From 62 years of age, she was awakened by tingling and involuntary movement in her legs during sleep. There symptoms disappeared when she stood up and walked. She was treated with clonazepam (2.5 mg/day) and valproate (400 mg/day) at 77 years of age, and the symptoms clearly ameliorated. However, she developed mild truncal ataxia and was referred to our hospital. On admission, neurological examination revealed Babinski and Chaddock signs bilaterally with depressed tendon reflexes in the lower limbs, mild truncal ataxia and horizontal gaze nystagmus. She did not present with involuntary movement of the legs while taking the anti-epileptic drugs. Cessation of these drugs alleviated the truncal ataxia and nystagmus, but reexacerbated abnormal sensation with involuntary movement in her legs during sleep. The involuntary movements in her legs were slower than myoclonus and resembled a Babinski reflex (duration about 1 second), and they appeared periodically (around every 30 seconds) in I-II sleep stages. Neither brain MRI nor EEG detected any abnormality. Cervical MRI revealed focal compression of the spinal cord by osteophytes at C5-C6 (more severe on the left side). Motor evoked potentials with transcranial magnetic stimulation revealed a mild delay in the central conduction time (CCT), which was more prolonged on the left side. She was thus diagnosed as having RLS/PLM with involvement of the bilateral pyramidal tracts. Although nerve conduction studies did not detect any abnormality in the peripheral nerves, RLS/PLM of the left leg was induced by electric stimulation of the left tibial nerve. Because she did not want medication any more, we treated her with a lumbar corset, hoping that wearing a lumbar corset might induce contraction of the truncal muscles that would mimic standing and walking or might produce additional sensory input that would induce a 'sensory trick'. Consequently, her abnormal sensation and involuntary movement during sleep as well as the stimulation of the tibial nerve disappeared. Wearing a lumbar corset may inhibit the excitability of the spinal cord that generates RLS/PLM, though the level of sensory input by the corset was higher than the input level of abnormal sensation in her legs. A lumbar corset may be a useful alternative choice for patients with RLS/PLM, who cannot tolerate either anti-epileptic or dopaminergic drugs.

Aged↗

PubMed2006

Is ferroportin-hepcidin signaling altered in restless legs syndrome?

Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs. Sufferers of RLS often experience chronic sleep deprivation, due to the characteristic worsening of symptoms both when at rest and during the night. MRI data, autopsy studies, and a consistent decrease in CSF ferritin all suggest that early-onset RLS is associated with insufficient iron in the brain. In this study, we examined the relationship between the iron regulatory hormone hepcidin and RLS. Hepcidin serves as a hormone that signals iron release from cells by interacting with ferroportin. We measured the expression and concentration of pro-hepcidin in the brain and cerebrospinal fluid of both RLS patients and control individuals. In CSF, we found that pro-hepcidin levels were significantly decreased in early-onset RLS patient samples, but not in late-onset RLS patients, when compared to controls. Conversely, in neuromelanin cells, substantia nigra, and putamen, the concentration of pro-hepcidin in RLS samples is significantly increased compared to controls. Functionally, hepcidin binds to ferroportin to limit iron movement from cells. Therefore, we provide immunocytochemical evidence that ferroportin is expressed by the epithelial cells of the choroid plexus and the ependymal cells lining the ventricles. These data suggest that sites of action for hepcidin include signaling the ventricular system for movement between brain and CSF. At this time, it cannot be determined if the lower levels of pro-hepcidin in the CSF represent a compensatory response to the decreased levels of iron in the brain or a defective signaling mechanism in RLS. Nonetheless, these data support the mounting evidence that there is a biological basis for RLS and the underlying mechanism involves iron management.

Age of Onset↗

PubMed2002

Chronic ethanol intake and ageing effects on cortical and basal forebrain cholinergic parameters: morphometric and biochemical studies.

Abstract Twenty-eight Wistar rats treated orally with 20% ethanol solution, were divided into two groups: adult group (n = 19) and aged group (n = 9) consisting of animals aged 4 and 12 months, respectively, at the beginning of the treatment. Neurons from the basal nucleus region were counted and the percentage of choline acetyltransferase-immunoreactive cholinergic neurons was determined in adjacent sections. Acetylcholine release and choline-acetyltransferase activity in the cerebral cortex were assessed in the same animals. Nutritional parameters of the ethanol treated animals were monitored and found to be normal. Chronic exposure to ethanol did not result in global neuronal loss or loss of cholinergic neurons in the basal nucleus region. However, a greater expression of ChAT-immunoreactivity in the basal nucleus region and a tendency toward increased ChAT activity in the cerebral cortex of the control and treated aged animals, compared respectively to adult ones, were observed. These findings suggest adaptive changes of the aged rats in response to the possible cholinergic hypofunction, manifested as a decreased release of acetylcholine under stimulated conditions.

Acetylcholine↗

PubMed2007

Current guidelines and standards of practice for restless legs syndrome.

Algorithms for treatment of restless legs syndrome (RLS) include both nonpharmacologic and pharmacologic therapy. Patients with RLS are divided into 3 groups: (1) those with intermittent RLS symptoms; (2) those with daily RLS symptoms; and (3) those whose symptoms are refractory to standard treatments. Many patients do not require medication, and symptoms often can be relieved with good sleep hygiene and avoidance of medications and factors that provoke symptoms. Recent large-scale clinical trials have proved the efficacy of therapy for RLS when it is required. Several classes of medications are helpful, but dopaminergic therapy appears to be most effective and relieves symptoms rapidly. The first step in managing RLS is to ensure that there is an adequate diagnosis; this involves discriminating RLS from other conditions that may share a number of features. Finally, it is important to tailor treatment to the needs of each individual patient.

Algorithms↗

PubMedDate not supplied

[Periodic movements of the limbs during sleep in childhood].

INTRODUCTION: Periodic movements of the limbs (PML) whilst sleeping is a disorder included in the group of intrinsic dysomnias which cause problems of insomnia and somnolence during the day. It is usually associated with the restless legs syndrome (it occurs in 80% of the patients with this syndrome) although PML may occasionally be an isolated finding. The prevalence of the disease is of 11%. It usually occurs in patients aged over 50 years, and the frequency increase with age. It is uncommon in persons aged under 30 years. In children it is almost unknown. When it does occur in this age group it is usually associated with the restless legs syndrome. OBJECTIVE: To obtain data regarding this disorder in childhood, in view of the scarcity of information available in the literature and the importance of the neuropsychological problems and difficulty with learning that affected children have. CLINICAL CASES: We report two cases of PML occurring in girls of under 7 years of age. They had severe associated neuropsychological disorders (disorders of behavior and feeding, psychotic episodes, etc.). The effect on performance at school led to complete failure in one case. We describe the clinical course of the two girls, emphasizing the variability, and both diagnostic and therapeutic difficulties. CONCLUSIONS: Although this condition is uncommon in childhood, it should always be borne in mind in cases of children with sleep disorders, since early diagnosis will prevent major behavior and learning problems.

Anticonvulsants↗

PubMed2006

Correlation between putative indicators of primary restless legs syndrome severity.

BACKGROUND AND PURPOSE: Several methods of assessing disease severity in restless legs syndrome (RLS) have been suggested. The purpose of this study was to examine the relationship between the suggested immobilization test (SIT), the International RLS Study Group rating scale (IRLS), sleep efficiency, and periodic leg movements of sleep index (PLMI). PATIENTS AND METHODS: Forty primary RLS patients with periodic leg movements of sleep were included in this prospective study. Study procedures were all performed during the same night, beginning with IRLS administration and following with SIT and polysomnography (PSG) evaluations, in that order. SIT was composed of two parameters: SIT mean discomfort score (SIT-MDS) and SIT periodic leg movements of wakefulness index (SIT-PLMW). PSG target measures were PLMI and sleep efficiency. Pearson's correlation was used for analysis at a P<0.01 significance level. RESULTS: PSG-PLMI correlated with IRLS (r=0.462; P=0.003) and with SIT-PLMW (r=0.681; P=0.0004). A correlation was also found between IRLS and SIT-MDS (r=0.447; P=0.004), even though SIT-PLMW and IRLS did not correlate with each other (P=0.286). A negative correlation was found between PSG-PLMI and sleep efficiency (r=-0.435; P=0.005). Neither SIT nor IRLS correlated with sleep efficiency. Only SIT discomfort scores from the second half of SIT correlated with SIT-PLMW (r=0.457, P=0.004), and they had a stronger correlation with IRLS (P=0.003). CONCLUSIONS: This study attempted a much needed comprehensive evaluation of the relationship between various RLS severity indicators. Our findings support a strong role of motor dysfunction on sleep quality in RLS, as well as the potential use of SIT-PLMW as a sensitive indicator of RLS severity.

Adolescent↗

PubMed1984

Clinical complications of obesity.

The development of important respiratory disorders and significant hypertension in association with increasing body weight is not widely recognized. Altered respiratory function results from a combination of mechanical impedance to breathing exerted by thoracic and abdominal fat and a ventilation-perfusion mismatch. Sleep-disordered breathing with periods of hypoventilation, with or without apnoeic episodes, may commonly occur in patients with extreme obesity. Nocturnal hypercapnia and hypoxia in such patients may lead to a decrease in ventilatory drive, abnormal central respiratory control and possibly, in time, the development of the obese-hypoventilation syndrome. Respiratory abnormalities should be suspected in obese patients with a history of restlessness at night, loud snoring and daytime somnolence. Treatment is substantial weight reduction, but short-term measures include the use of compressed air via nasal cannulae for obstructive apnoea, and drugs which alter sleep pattern or stimulate respiration. The alterations in endocrine function, which accompany weight gain, may contribute to an increase in blood pressure and there appears to be a relationship between plasma insulin and catecholamine concentrations, fat cell size and the development of hypertension. The confirmation of a raised blood pressure requires that readings be taken with an adequately sized arm-cuff. In many instances endocrine function becomes normal with weight loss, and there is a corresponding decrease in blood pressure. The ideal management for an obese hypertensive patient is the combination of a suitable calorie-restricted diet with a programme of physical exercise.

Female↗

PubMed2004

The restless legs syndrome and periodic limb movement disorder: a review of management.

The restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) are distinguishable but overlapping disorders. Both feature nocturnal involuntary limb movements (periodic limb movements) that can cause sleep disruption, but each has distinct clinical features that are relevant to the diagnosis and management of the patient. The diagnosis of RLS is made by meeting established clinical criteria, not from discovery of periodic limb movements of sleep (PLMS) on a sleep study. PLMD, however, does require the presence of PLMS on polysomnography as well as an associated sleep complaint. Moreover, PLMS are themselves nonspecific, occurring both with RLS and with other sleep disorders as well as in normal individuals. The diagnosis of PLMD, then, requires not merely finding a significant number of PLMS but also excluding other potential causes for the associated sleep complaint. Treatment of RLS is based on consideration of the pattern and severity of the disorder, with dopaminergic drugs generally favored for initial treatment. Anticonvulsants, opioids, and sedative/hypnotics also have a role. A treatment algorithm is provided to assist with the management of RLS. Treatment of PLMD relies on many of the same medications, but is generally more straightforward and places a greater reliance on levodopa compounds and sedative-hypnotics.

Diagnosis, Differential↗

PubMed1978

The use of a kymograph in a comparative trial of flunitrazepam and meprobamate in elderly patients.

A double-blind crossover trial was carried out in 31 hospitalized elderly patients receiving night-time sedation to compare the effects of flunitrazepam (0.5 mg) and meprobamate (200 mg). After 1 week on placebo, patients received 1-week's treatment with each drug in random order. Quality of sleep was assessed by a nurse at hourly intervals over 8 hours each night. In 11 patients, the results were compared with those from kymographic recordings measuring patient restlessness (motility index). No statistically significant difference was found between the two active drug treatments, and there was a close correlation between the two methods of assessment. It is suggested that the kymograph may well be a useful and economic method of evaluating the effectiveness of hypnotics.

Aged↗

PubMed2004

Increased motor drive and sleep loss in mice lacking Kv3-type potassium channels.

The voltage-gated potassium channels Kv3.1 and Kv3.3 are widely expressed in the brain, including areas implicated in the control of motor activity and in areas thought to regulate arousal states. Although Kv3.1 and Kv3.3-single mutants show some physiological changes, previous studies revealed relatively subtle behavioral alterations suggesting that Kv3.1 and Kv3.3 channel subunits may be encoded by a pair of redundant genes. In agreement with this hypothesis, Kv3.1/Kv3.3-deficient mice display a 'strong' mutant phenotype that includes motor dysfunction (ataxia, myoclonus, tremor) and hyperactivity when exposed to a novel environment. In this paper we report that Kv3.1/Kv3.3-deficient mice are also constitutively hyperactive. Compared to wildtype mice, double mutants display 'restlessness' that is particularly prominent during the light period, when mice are normally at rest, characterized by more than a doubling of ambulatory and stereotypic activity, and accompanied by a 40% sleep reduction. When we reinvestigated both single mutants, we observed constitutive increases of ambulatory and stereotypic activity in conjunction with sleep loss in Kv3.1-single mutants but not in Kv3.3-single mutants. These findings indicate that the absence of Kv3.1-channel subunits is primarily responsible for the increased motor drive and the reduction in sleep time.

Animals↗

PubMed2006

Medication tolerance and augmentation in restless legs syndrome: the need for drug class rotation.

Restless legs syndrome (RLS) is a common condition characterized by an unpleasant urge to move the legs that usually occurs at night and may interfere with sleep. The medications used most commonly to treat RLS include dopaminergic drugs (levodopa, dopamine agonists), benzodiazepines, and narcotic analgesics. We report the cases of 2 patients with RLS who illustrate the problems of tolerance (declining response over time) and augmentation (a worsening of symptoms due to ongoing treatment) that can complicate the pharmacotherapy of RLS. We discuss the optimal management of RLS and propose strategies to overcome tolerance and augmentation such as a rotational approach among agents from different classes.

Aged↗

PubMed2001

Long-term follow-up on restless legs syndrome patients treated with opioids.

The medical records of 493 patients with restless legs syndrome (RLS) from three major centers were studied to determine the number and outcome of patients who had been treated with opioids as a monotherapy. At one time or another 113 patients (51 men, 62 women; age range, 37-88 years) had been on opioid therapy either alone (36 patients) or with opioids added secondarily to other medications used to treat RLS (77 patients). Twenty-three of the 36 opioid monotherapy patients had failed dopaminergic and other therapeutic agents prior to the initiation of opioid monotherapy. Twenty of the 36 opioid monotherapy patients continue on monotherapy for an average of 5 years 11 months (range, 1-23 years), despite their knowledge of the availability of other therapies. Of the 16 patients who discontinued opioids as a sole therapy, the medication was discontinued in only one case because of problems related to addiction and tolerance. Polysomnography on seven patients performed after an average of 7 years 1 month of opioid monotherapy (range, 1-15 years) showed a tendency toward an improvement in all leg parameters and associated arousals (decrease in PLMS index, PLMS arousal index, and PLM while awake index) as well as all sleep parameters (increase in stages 3 and 4 and REM sleep, total sleep time, sleep efficiency, and decrease in sleep latency). Two of these seven patients developed sleep apnea and a third patient had worsening of preexisting apnea. Opioids seem to have long-term effectiveness in the treatment of RLS and PLMS, but patients on long-term opioid therapy should be clinically or polysomnographically monitored periodically for the development of sleep apnea.

Aged↗

PubMed1997

Predictors of sleepiness in epilepsy patients.

Sleepiness, a common complaint of epilepsy patients, is frequently attributed to antiepileptic medications. To determine predictors of subjective sleepiness in epilepsy patients, we gave self-administered, validated surveys of sleepiness [Epworth sleepiness scale (our major outcome measure)] and sleep apnea [sleep apnea scale of the sleep disorders questionnaire (SA/SDQ)] to 158 epilepsy patients and 68 neurology patients without epilepsy (controls). An elevated Epworth score (>10) was more likely in epilepsy patients compared to controls after controlling for age and gender (p < 0.05). When Epworth scores were adjusted for SA/SDQ scores and restless legs symptoms (RLS), however, epilepsy patients showed only a nonsignificant trend toward elevated Epworth scores compared to controls (p = 0.08). SA/SDQ scores (p < 0.005) and RLS (p < 0.007) were significant predictors of elevated Epworth score in both epilepsy patients and controls. Among the epilepsy patients, the number or type of antiepileptic medication, seizure frequency, epilepsy syndrome (partial vs. generalized), and the presence of sleep-related seizures were not significant predictors (p > 0.10) of elevated Epworth score. Before attributing sleepiness in epilepsy patients to antiepileptic medications or uncontrolled seizures, clinicians should consider the possibility of a coexisting sleep disorder.

Adolescent↗

PubMed2005

Antidepressant medication use and restless legs syndrome in patients presenting with insomnia.

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a movement disorder that frequently results in significant complaints of insomnia. Based on published case reports, it is commonly believed that RLS can be caused or exacerbated by antidepressant agents, thus complicating the treatment of depressed patients who are already prone to sleep disturbances. However, there are no systematic studies demonstrating an association between the clinical diagnosis of RLS and the use of antidepressant medication. PATIENTS AND METHODS: Retrospective chart review of 200 consecutive patients presenting for evaluation of sleep initiation insomnia at an accredited freestanding sleep disorders center that is part of an integrated health care system. RESULTS: Mean age (+/-SD) of patients was 51.1+/-14.8 years; 60% were women. Fifty-six percent carried a diagnosis of depression, 38% were being treated with antidepressant medication at presentation and 45% met clinical diagnostic criteria for RLS. There were no statistical associations, either by chi(2) analysis or odds ratios, between RLS and antidepressant use or use of any specific class of antidepressant. Positive associations with RLS were found for patients receiving treatment for hypothyroidism and those taking estrogens; a significant negative association was found for patients receiving beta adrenergic antagonists. CONCLUSIONS: Although there are anecdotal reports of antidepressant use causing or exacerbating RLS, systematic study of this issue fails to corroborate an association.

Adult↗

PubMed1997

[Management of drug addict pregnant women and their children].

Children of substance abuse mothers have an increased risk of severe pathological disorders such as perinatal diseases (prematurity, intrauterine growth retardation, infections) with their neurological and respiratory complications and sequelae, and transmission of drug addiction related infections, ie human immunodeficiency virus, hepatitis B and C virus, syphilis. Many of these children present a drug withdrawal syndrome characterized by restlessness and jetteriness during the neonatal period. This is frequently followed by a post withdrawal period of several weeks duration with crying, excitement, sleep and feeding difficulties. Although these drug withdrawal manifestations have no incidence on the vital prognosis, it severely impairs the mother-infant interaction. Despite these disorders it appears that the outcome of these children is mainly related to their familial environment which is exposed to many risk factors: mother-child separation, violence, delinquency, precariousness, unhealthy housing, prostitution, drug dependency, parental death or imprisonment... Early medico-psycho-social intervention starting during pregnancy and a prolonged support for several years are the only way to improve their spontaneously poor outcome.

Female↗

PubMed1992

[Intra-individual variation of cerebral blood flow velocity in sleeping and awake children].

A considerable intraindividual variability of blood flow velocities in the middle and posterior cerebral artery was found in 74 children by continuous transcranial Doppler recording during EEG registration. The coefficient of variation of the mean flow velocities in the posterior cerebral artery was higher than in the middle cerebral artery, and higher in restless children than in calm children. During hyperventilation the mean flow velocities decreased to about 50 per cent of the baseline values. They increased to 130-140 per cent of the baseline values after hyperventilation. Repeated variations of the velocities of more than 30 per cent of the baseline values were observed during non-REM sleep in the majority of the children. They may be caused by a lower damping of the cerebral autoregulatory response. The intraindividual variability of cerebral blood flow velocities in children has to be kept in mind in pathological conditions and during Doppler monitoring.

Arousal↗

PubMed1984

Clonazepam and vibration in restless legs syndrome.

There have been no controlled therapeutic trials in Restless Legs Syndrome (RLS). In 6 patients with RLS, a randomized double-blind cross-over trial vs placebo showed a significant efficacy of clonazepam in improving subjective quality of sleep and leg dysaesthesia. Vibratory stimulation of the leg showed a less pronounced and non-significant effect. Clonazepam is a safe and effective drug for treatment of RLS; however its long-term efficacy needs confirmation.

Adult↗