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PubMed2000

Clinical correlates of 6-hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome.

Pursuant to the clinical suspicion that restless legs syndrome (RLS) may involve dopaminergic diencephalic spinal neurons (A11), we performed stereotaxic bilateral 6-hydroxydopamine (6-OHDA) lesions into the A11 nucleus to observe for any behavioral correlates similar to this clinical condition. Pathologic examination demonstrated a 54% reduction in A11 tyrosine hydroxylase staining cells in rats injected with 6-OHDA versus sham treatment. Multiple blindly rated 90-120-minute video epochs demonstrated an increased average number of standing episodes (14.4+/-11.7 versus 7.3+/-5.5 episodes/epoch) and increased total standing time (38.9+/-20.5 versus 25.3+/-12.2 minutes/epoch) but similar total sleep time in four lesioned rats when compared with two sham rats. Treatment of the lesioned rats with intramuscular pramipexole subsequently resulted in fewer standing episodes (4.4+/-3.3 versus 14.4+/-11.7 episodes/epoch) and less total standing time (20.9+/-12.3 versus 38.9+/-20.5 minutes/epoch) when compared with untreated lesioned rats. Despite a large number of observations, the small number of lesioned animals precluded formal statistical analysis. These behaviors are consistent, although not specific, with what would be expected in an animal model of RLS.

Adrenergic Agents↗

PubMed2003

Effects of low-frequency cranial electrostimulation on the rest-activity rhythm and salivary cortisol in Alzheimer's disease.

OBJECTIVE: In previous studies, cranial electrostimulation (CES) had positive effects on sleep in depressed patients and in patients with vascular dementia. The present study examined the effects of low-frequency CES on the rest-activity rhythm and cortisol levels of patients with probable Alzheimer's disease (AD). METHOD: It was hypothesised that a decreased level of cortisol would parallel a positive effect of low-frequency CES on nocturnal restlessness. Sixteen AD patients were randomly assigned to an experimental group (n = 8) or a control group (n = 8). The experimental group was treated with CES, whereas the control group received sham stimulation, for 30 minutes a day, during 6 weeks. The rest-activity rhythm was assessed by actigraphy. Cortisol was measured repeatedly in the saliva throughout the day by means of salivette tubes. RESULTS: Low-frequency CES did not improve the rest-activity rhythm in AD patients. Moreover, both groups showed an increase instead of a decrease in the level of cortisol. CONCLUSIONS: These preliminary results suggest that low-frequency CES has no positive effect on the rest-activity rhythm in AD patients. An alternative research design with high-frequency CES in AD is discussed.

Activity Cycles↗

PubMed1995

[Analgesia and sedation to supplement incomplete regional anesthesia].

Pharmacological praemedication. In patients receiving regional anaesthetics induction of deep sedation prior to the performance of the block should be avoided because during the installation of the nerve block it is an advantage to have a cooperative patient. Adequate anxiolytic effects are achieved by oral administration of chloracepate (0.3-0.5 mg/kg body weight). Intraoperative sedation. Once regional anaesthesia is established deep sedation or even a light sleep might be appropriate to improve the patient's comfort. Short acting i.v. substances are the agents of choice. Propofol (1.5-5 mg/kg per h) and midazolam (0.03-0.09 mg/kg per h) are recommended. Both substances should be titrated as needed. Since respiratory depression or loss of airway patency may occur, close observation and pulse oxymetric monitoring are mandatory. Intraoperative analgesia. Restlessness due to pain is not an indication for sedatives and/or hypnotics. Pain can be caused not only by incomplete regional anaesthesia, but also by a tourniquet or uncomfortable body positions, for example, and it should be treated in different ways according to its cause. In the case of an incomplete block, a catheter technique makes a top-up dose for augmentation possible; additional peripheral nerve blocks can also be used to complete the analgesia. If these attempts are unsuccessful, systemic analgesics (preferable narcotics) or even anaesthetics must be given. Opioids are recommended only in mild to moderate pain or discomfort. The risk of respiratory depression should be considered. The administration of oxygen by mask and pulse oxymetric monitoring are useful. Ketamine is a common drug with a potent analgesic effect, which possesses the advantages of good support for the cardiovascular system, because of its sympathomimetic action, and minimal depression of the ventilatory drive. However, with the exception of a few specific indications, Ketamine is not a drug that is initially an integral part of planned regional anaesthetic procedures. In case of incomplete regional blocks administration of ketamine is more frequently the "ultima ratio" following a number of previous, unsuccessful attempts-primarily with sedatives and/or opioids-to achieve a condition that will permit surgical procedures; as a result, the hypnotic and respiratory depressant effects of subsequently administered drugs are enhanced and potentiated. An important consequence of this complex pharmacodynamic interaction scenario is a potential loss of the advantages that would otherwise be gained by using "subanaesthetic" ketamine doses (< 0.5 mg/kg), namely: a cooperative patient who is breathing spontaneously and has an intact laryngopharyngeal reflex response and, therefore, an uncompromised airway competence. Pulse oxymetric monitoring of the potentially endangered respiratory function is obligatory. The individual transition to general anaesthesia is not easy to determine. Therefore, it is essential that, whenever the need arises, intubation and mechanical ventilation intervention procedures be carried out immediately.

Analgesics↗

PubMed2000

Synkinetic blepharoclonus.

OBJECTIVES: To analyze the clinical data and test results collected in a group of patients exhibiting eyelid-closure blepharoclonus (BLC) on clinical neurologic examination. MATERIALS AND METHODS: Thirty-five patients were referred for neurologic evaluation for reasons other than BLC. Clinical electrophysiologic evaluations, including cranial nerve testing and electromyograms, were done according to standards. All patients had neuroimaging studies, including brain magnetic resonance imaging and head computerized tomography, or both, and many had electroencephalograms. Additional tests were done based on the patient's symptoms or reasons for referral. RESULTS: Eight patients had reflex BLC. Two cases were precipitated by vertical gaze; one of these patients had hereditary palmoplantar keratoderma and cataplexy, and the other patient had Ehlers-Danlos syndrome and familial BLC. Other precipitants included speech in four cases, postural changes in two cases, and light stimulation in one case. Two patients had generalized myoclonus independent of their BLC, two patients had a history of sleep myoclonus, and several patients had BLC-associated facial myoclonus. One patient had BLC-associated myoclonus of the right shoulder. Synkinetic cranial movements were detected in 11 patients (four oculofacial, three oculopterygoid, one oculolingual, two dual cases, and one case of imitation synkinesis.) Three patients had familial BLC, seven patients had congenital developmental disorders, six patients had synkinetic tremors, and six patients had restless feet. Some indication of peripheral neuropathy was evident in eight patients. CONCLUSIONS: Eyelid-closure BLC is an underrecognized, sporadic or familial, mostly benign, chronic eyelid-movement disorder that may be associated with tremors, myoclonus, cranial synkinesis, and restless feet. Reflex mechanisms may be identified in some patients. Gaze-induced BLC seems to have the greatest clinical relevance. In the current series, there were no examples of posttraumatic BLC, multiple sclerosis, hydrocephalus, or blepharospasm conditions previously reported to be associated with BLC. No electroencephalographic abnormalities were recorded during BLC, ruling out eyelid-closure epilepsy.

Adolescent↗

PubMed2003

One-year treatment with standard and sustained-release levodopa: appropriate long-term treatment of restless legs syndrome?

To investigate the long-term efficacy and safety of sustained-release (SR) in combination with regular-release (RR) levodopa/benserazide in the treatment of restless legs syndrome (RLS), an open-label, prospective, extension study of a preceding double-blind crossover trial was performed for 12 months. Twenty-three severely disturbed RLS patients (7 men, 16 women) received a combination of RR and SR levodopa. Patients were treated on average for 10 months with a mean daily dose of 203 +/- 101 mg of RR and of 185 +/- 93 mg of SR levodopa. The mean daily total dose was 388 +/- 162 mg levodopa. Efficacy was documented using patient's rating scales, sleep diaries, and investigator's global ratings with the Clinical Global Impressions (CGI). Ten of 23 patients completed the 1-year extension. Between baseline of the crossover trial and endpoint of the extension study (last-observation-carried-forward method, intention-to-treat population), quality of sleep improved (+3.5 +/- 1.9, 7-point scale), sleep latency was shortened (-131 +/- 152 minutes), and total sleep time lengthened (+ 190 +/- 136 minutes). Severity of RLS at time of falling asleep (-6.5 +/- 3.4, 11-point scale) and during the night (-6.0 +/- 3.5) was markedly lower at the end of the extension but severity of RLS during the day (+1.9 +/- 5.0) slightly increased. Of 13 dropouts, 8 patients discontinued therapy because of worsening RLS during the day. This trial shows that long-term treatment with the combination of RR and SR levodopa/benserazide in RLS patients with late-night problems was efficacious and not limited by tolerability problems in 40% of patients, whereas in the majority of patients, aggravating daytime problems required termination of the levodopa therapy within the 1-year treatment period.

Adult↗

PubMed1999

Restless legs syndrome improved by pramipexole: a double-blind randomized trial.

BACKGROUND: Restless legs syndrome (RLS) is characterized by leg paresthesia associated with an irresistible urge to move. Currently used dopaminergic agents, such as levodopa, pergolide, and bromocriptine, offer incomplete control of sensory and motor symptoms and induce severe side effects. OBJECTIVE: To assess the safety and efficacy of pramipexole, a full D3-receptor agonist, in the treatment of RLS. METHODS: Ten RLS patients were studied before and after two 1-month treatments (placebo and pramipexole) administered in a double-blind crossover fashion. The severity of sensory and motor manifestations was assessed by 1 week of home questionnaires and 2 consecutive nights of sleep laboratory recordings. The indexes of periodic leg movement during sleep (PLMS) and during wakefulness (PLMW) were used as primary outcome variables. RESULTS: Pramipexole dramatically reduced the PLMS index to normal values (Wilcoxon, p = 0.005). The PLMW index was also significantly reduced (Wilcoxon, p = 0.007). Pramipexole also alleviated leg discomfort at bedtime and during the night as measured by the home questionnaires. CONCLUSIONS: Pramipexole is the most potent therapeutic agent ever tested for RLS. Measures of both sensory and motor functions returned to normal values after treatment. Moreover, these results further support the hypothesis that D3 receptors play a major role in the physiopathology of this condition.

Adult↗

PubMedDate not supplied

Self-disparagement as feature and forerunner of depression: findings from the Stirling County Study.

Sleep disturbance has attracted considerable attention as an early indicator of depression. However, three epidemiologic investigations have shown psychological symptoms, such as self-disparagement, to be stronger predictors. This report examines the depressive symptoms commonly assessed in modern epidemiologic surveys and estimates the generalizability of this information using data from the Stirling County Study, a long-term epidemiologic investigation of psychiatric disorders. The Diagnostic Interview Schedule (DIS) was used to gather information about depression, defined as major depressive episode (MDE) and/or dysthymic disorder (DysD). A sample of 1,396 adults representing Stirling County in 1992 served to assess the prevalence of the different types of depressive symptoms and to investigate the associations between symptoms and lifetime diagnoses of MDE/DysD. A cohort of 489 follow-up subjects who were interviewed twice in the early part of the 1990s was used to examine the associations between baseline symptoms and subsequent incidence of MDE/DysD. Both "symptom groups" (such as appetite or psychomotor disturbances) and "individual symptoms" (such as weight gain or restlessness) were investigated. About one third of the representative sample had experienced the diagnostically required symptoms of "sadness" or "loss of pleasure," but many lacked sufficient other symptomatology to be diagnosed as depressed. Several of the symptom groups bore a different relationship to diagnosis than did the individual symptoms. Among the latter, "feeling worthless" and "having trouble concentrating" exhibited the strongest associations to diagnosis in the representative sample. The symptoms of "wanting to die" and "feeling worthless" were the most predictive of future depression in the twice-interviewed cohort. Thus, this study supports evidence from other epidemiologic studies that psychological symptoms are important in the prodromal phase of depression. Sleep disturbance, especially insomnia, cannot be ignored since it is a prominent manifestation of depression but it appears not to have as high specificity as some of the other symptoms. An exclusive focus on the symptom groups, as used to count symptoms according to diagnostic criteria, may obscure useful information about associations between individual symptoms and diagnosis. Feelings of personal inadequacy deserve particular attention in the population at large because they are strongly associated with lifetime diagnoses and forecast the incidence of depression when people are followed over time.

Adult↗

PubMed2002

Periodic limb movement in a community population detected by a new actigraphy technique.

BACKGROUND: Periodic limb movements (PLMs) have been studied in both community and sleep clinic populations using polysomnography. An alternative detection method is actigraphy. Our aims were to determine the frequency of PLMs, measured by actigraphy in a community sample, and to assess the relationships of PLMs with age, gender, and reported sleep-related symptoms. METHODS: Volunteers had bilateral foot actigraphy (Cambridge Neurotechnology) at home and completed sleep questionnaires. Actigraphy was scored for PLMs per hour in bed (PLMI) and statistical analysis performed to assess possible associations. RESULTS: PLMI (mean of two nights) ranged from 0 to 60.3 and 37% of the sample had a PLMI> or =5. Men had significantly higher PLMIs than females (P=0.003) but PLMI was not correlated with age. There was a modest but significant correlation between subjectively reported restless leg severity and PLMI (r=0.238; P=0.003), but none with reported sleepiness. CONCLUSIONS: This actigraphy technique is a practical and reliable tool for community studies. A large proportion of this community sample, particularly men, had PLMs. PLMI was not correlated with age or Epworth Sleepiness Score.

Journal Article↗

PubMed2000

Defining the phenotype of the restless legs syndrome (RLS) using age-of-symptom-onset.

Objective: RLS varies considerably in both frequency of occurrence in a family and in age of onset of symptoms. Patients whose RLS symptoms start before or at age 45 have many more affected relatives than those whose symptoms start later, suggesting etiological differences. When etiology differs, factors affecting severity may differ. This study compares the effects of current age and serum ferritin on RLS severity for early- and late-onset (over 45) RLS.Design and methods: RLS severity was evaluated using a validated clinical severity scale and sleep efficiency on a standard polysomnogram. Data from 26 consecutive RLS patients (14 early- and 12 late-onset) who met study criteria were analyzed.Results: Age-of-onset groups showed no significant differences in age, gender and RLS symptom severity. Regression analyses showed significant (P<0.05) differences with RLS severity primarily affected by age for early-onset RLS and by serum ferritin for late-onset RLS.Conclusions: The age effect for early-onset RLS indicates a slowly progressive disorder. Thus early-onset RLS appears to occur commonly in families, slowly progress with age and have a limited relation to serum iron status. In contrast, late-onset RLS appears to occur less commonly in families, rapidly progress with age and have a strong relation to serum iron status. Age of symptom onset should be considered to better define the RLS phenotype in future studies.

Journal Article↗

PubMed1979

Neuropharmacology of sedatives and anxiolytics.

Sedative drugs are intended to cause various degrees of drowsiness. Animal experiments indicate that barbiturates induce these effects primarily by depression of the reticular activating system in the rostral brainstem. This in turn potentiates the thalamic recruiting system, thereby inducing 'barbiturate bursts' in the EEG. Anxiolytic drugs are intended to reduce anxiety or tension at doses which do not cause sedation or sleep. Propanediols may depress deactivating centers in the caudal brainstem, thereby releasing the activating centers in the rostral brainstem and depressing the thalamic recruiting response. These drugs may also act on the amygdala. Benzodiazepines have depressant effects on the amydala or hippocampus. These effects may release the reticular formation from inhibition. Enhanced activity of the activating and deactivating centers, to a different extent in different animals, would produce restlessness in some animals and sedation in others, accompanied by a mixture of fast and slow waves in the EEG. Sedative and anxiolytic agents also have central relaxant effects. The barbiturates act directly on the spinal cord, depressing both monosynaptic and polysynaptic reflexes. Propanediols and benzodiazepines act primarily on the descending facilitatory influence of the brainstem. Reduction of this influence depresses spinal polysynaptic but not monosynaptic reflexes. Biochemical studies suggest that barbiturates may act by antagonizing synaptic excitation induced by glutamate. Benzodiazepines may act by enhancing presynaptic inhibition mediated by GABA. The mechanism of action of propanediols is unknown.

Animals↗

PubMed2005

[Holiday dreams with a downside: uncommon tapeworm infection in an infant].

Eight weeks after his return from Mauritius, a 2.5-year-old boy started to show signs of gastrointestinal illness including diarrhoea with frequent ill-smelling stools as well as restlessness, insomnia and apathy. Proglottids excreted with the faeces were diagnosed as Raillietina madagascariensis (Davain, 1870), the tropical rat tapeworm. Treatment with praziquantel (10 mg/kg BW) proved to be efficient.

Animals↗

PubMed2004

Restless legs syndrome: an update on treatment options.

Restless legs syndrome (RLS) was first described in 1672 but it is only recently that this disorder has attracted attention in defining its phenotype, and identifying its aetiology, pathogenesis and pharmacological treatment. RLS can be divided into primary (idiopathic) and secondary forms. RLS is common, affecting 5-15% of the total population and manifesting at any age from childhood to late adulthood. Prevalence tends to increase with patient age and there may be geographic variation. There is a clear genetic contribution to primary RLS and evidence for dopaminergic dysfunction. Although not all patients with RLS require medication, there can be a substantial reduction in the patient's quality of life related to pain, poor sleep and excessive daytime sleepiness. A variety of medications are now available for the symptomatic treatment of RLS. Dopaminergic therapy is currently the treatment of choice, usually initiated with a long-acting dopamine agonist, thereby avoiding some of the complications associated with levodopa. Anticonvulsants may be used as second-line treatment. Levodopa should be reserved for those patients who fail to respond to alternative medications because of the high risk of inducing augmentation. Hypnosedatives also have a role in RLS management. Patients with intractable RLS may require combination treatment. Several systemic disorders can cause RLS, and these should be identified and treated appropriately.

Analgesics, Opioid↗

PubMed2005

New paradigms in the treatment of restless legs syndrome.

Restless legs syndrome (RLS) is a common neurologic disorder occurring in 3% to 15% of the general population, which contributes to poor quality of life. Many patients go undiagnosed for years after onset of symptoms, which delays or prevents effective treatment. Extensive research over the past decade has led to a better understanding of RLS and effective treatment options. This review encompasses the most recently published pathophysiology, epidemiology, criteria for diagnosis, and clinical drug efficacy trials to provide clinicians with the information to effectively manage RLS. A comprehensive review of the medical literature was conducted and original research articles pertaining to RLS were evaluated. The pathophysiology of primary RLS is associated with dopaminergic dysfunction and abnormal brain iron metabolism. Secondary RLS is most often a consequence of iron deficiency. The prevalence of primary RLS is twofold greater in women and increases with age in men and women, although onset of symptoms may occur in up to 45% of patients before age 20 years. Patients may present with a variety of complaints including sleep disruption. Several studies have demonstrated the efficacy of low-dose levodopa and dopamine agonists. Ropinirole is the most widely studied. Other drugs that may help control symptoms include gabapentin, opioids, and clonazepam. Clinicians must be aware of the high prevalence of RLS, the potential for onset before age 20, and the various clinical presentations. Dopamine agonists are first-line therapy and provide symptom relief in 70% to 100% of patients.

Brain↗

PubMedDate not supplied

A longitudinal comparison of irritable and nonirritable infants.

Infantile colic is characterized by persistent crying, diminished soothability, and excessive activity or restlessness. The purpose of this study was to explore the processes underlying the persistent, recurrent irritability by investigating behavioral and interactional differences in irritable and nonirritable infants. In this two-group longitudinal study, 40 infants and their mothers were followed over the first 4 months of life. Statistically significant differences between the two groups were found, with the irritable infants demonstrating an increase in the amount and intensity of crying, more disruption in sleep-wake states, and less synchrony in mother-infant interaction.

Adolescent↗

PubMed2002

Evidence for a genetic association between monoamine oxidase A and restless legs syndrome.

BACKGROUND: Impairment in the central dopaminergic system has been consistently suggested as an etiologic factor in restless legs syndrome (RLS). OBJECTIVE: To investigate a possible role for the MAOA and MAOB genes in RLS using a population-based association study. METHODS: In addition to a dinucleotide repeat located within the second intron of the MAOB gene, a functional variable number of tandem repeat (VNTR) polymorphism recently identified in the MAOA gene promoter region was examined, using 96 extensively characterized patients and 200 control subjects matched for ethnic background. The relationship between variation at these loci and several clinical features was also considered. RESULTS: Pertaining to the MAOA gene, females with the high activity allele had a greater risk (OR: 2.0; 95% CI: 1.06 to 3.77) of being affected with RLS than females carrying the low activity alleles. The authors did not observe this association among the male subjects (OR: 0.98; 95% CI: 0.31 to 3.14). Interestingly, females carrying the high transcription alleles showed a longer sleep onset latency (U = 163.5; p = 0.015) and exhibited a higher movement index during the Suggested Immobilization Test (Student's t-test = -2.02; p = 0.048). No differences were observed regarding the MAOB gene in our sample. CONCLUSIONS: The high activity allele of the MAOA gene may represent a modifying factor involved in the severity of RLS manifestations in females.

Adult↗

PubMed1984

Double-blind crossover comparison of triazolam and lorazepam in the posthypnotic state.

A double-blind crossover study compared the hypnotic effect, daytime carryover, and safety of triazolam 0.5 mg, lorazepam 2 mg, and placebo. The two active drugs were similar in hypnotic effect and superior to placebo. Patients reported more drowsiness upon awakening and more sleepiness in mid-morning and mid-afternoon after nights on lorazepam than nights on triazolam or placebo. The most common side effects--drowsiness, lightheadedness, restlessness, impaired coordination, dizziness, and nausea--were reported three times as often with lorazepam than with triazolam or placebo.

Adolescent↗

PubMed2001

Validation of the Johns Hopkins restless legs severity scale.

Determine reliability and validity of the Johns Hopkins restless legs severity scale (JHRLSS), an easily used clinical scale assessing severity of the restless legs syndrome (RLS). There is, prior to this study, no validated scale assessing the wide range of RLS severity. The JHRLSS has been used in prior studies to assess RLS severity, but has not previously been validated in relation to direct measures of the morbidity associated with RLS. A consecutive case series of 31 RLS patients was used in the study. The JHRLSS was validated by its correlation with objective measures by a polysomnogram of the sleep disturbances associated with RLS (periodic leg movements of sleep per hour (PLMS/h), and sleep efficiency). Reliability was determined from the independent ratings of two clinicians. Reliability measures for the JHRLSS based on inter-rater agreement were 0.91 (Spearman Rho) and 0.87 (Cramers V). The subjective JHRLSS correlated significantly with both objective measures of sleep: sleep efficiency (R=0.60, P<0.01) and PLMS/h (R=0.45, P=0.01). The JHRLSS provides a reliable, valid, easily used clinical assessment of RLS severity.

Journal Article↗

PubMed2002

Treatment of periodic limb movements in sleep with selegiline HCl.

Thirty-one patients undergoing treatment with selegiline HCl for periodic limb movements in sleep (PLMS) were examined with respect to specific sleep composition in a retrospective study. Pre- and post-treatment overnight polysomnographs revealed a highly significant decrease in the number of PLMS per hour of total sleep time (P < 0.0005). The alerting effect associated with selegiline was not found to have significant effect on patients' sleep efficiency or sleep-onset latency (P > 0.10). As controversy continues regarding the medicated treatment of PLMS, our findings with selegiline point to an alternative for clinicians to consider.

Adult↗