EFNS guidelines on management of restless legs syndrome and periodic limb movement disorder in sleep.

In 2003, the EFNS Task Force was set up for putting forth guidelines for the management of the Restless Legs Syndrome (RLS) and the Periodic Limb Movement Disorder (PLMD). After determining the objectives for management and the search strategy for primary and secondary RLS and for PLMD, a review of the scientific literature up to 2004 was performed for the drug classes and interventions employed in treatment (drugs acting on the adrenoreceptor, antiepileptic drugs, benzodiazepines/hypnotics, dopaminergic agents, opioids, other treatments). Previous guidelines were consulted. All trials were analysed according to class of evidence, and recommendations formed according to the 2004 EFNS criteria for rating. Dopaminergic agents came out as having the best evidence for efficacy in primary RLS. Reported adverse events were usually mild and reversible; augmentation was a feature with dopaminergic agents. No controlled trials were available for RLS in children and for RLS during pregnancy. The following level A recommendations can be offered: for primary RLS, cabergoline, gabapentin, pergolide, ropinirole, levodopa and rotigotine by transdermal delivery (the latter two for short-term use) are effective in relieving the symptoms. Transdermal oestradiol is ineffective for PLMD.

[Restless legs syndrome and periodic limb movements in sleep]. / Restless-legs-Syndrom und "periodic limb movements in sleep".

Restless legs syndrome is one of the most common neurological disorders, with a prevalence of 2% to 9% in the elderly population. Sensory and motor symptoms of the legs and an urge to move that occur at rest may lead to severe sleep disturbances and are part of the syndrome. Typical history and normal neurological examination lead to the clinical diagnosis. Additional laboratory and neurophysiological investigations are necessary to rule out associated diseases. The indication for polysomnography to record periodic limb movements in sleep must be discussed in individual cases. Treatment strategies will be recommended individually according to the disease severity. In this article we present an overview of the clinical symptomatology and include recommendations on diagnosis and treatment of RLS and differentiation of RLS from periodic limb movement disorder. To this purpose, the Motor System and Sleep Work Group of the German Society of Sleep Medicine presents modified guidelines for diagnosis and treatment of RLS according to recent recommendations of the American Sleep Disorder Association.

Sleep and stroke.

Although the incidence of strokes is not maximal during sleeping hours, several lines of evidence make it probable that sleep in combination with breathing disorders like snoring and obstructive apneas are risk factors for ischemic strokes: the natural history of snoring and obstructive sleep apnea shows a higher incidence of strokes than in undisturbed sleep, the prevalence of snoring and sleep apneas in stroke patients is by far higher than in non-stroke patients; odds-ratios of stroke are higher in snorers and apneic patients than in normals, although the correction for confounders seems never perfect. The analysis of potential pathomechanisms linking sleep disordered breathing to strokes is another approach to the main topic: snoring and sleep apnea induce hypertension and arrhythmia, the carotid intima-media-thickness is increased, carotid atheromas are more common among apneics than among normals, the flow in the A. cerebri media is as well altered as the reaction to angiotensine II, noradrensine, isoproterenol and bradykinin. Homocysteine is increased, plasminogen activator inhibitor type 1 is inhibited and platelets are activated leading to an increased risk of thrombosis. There are no studies showing the effectiveness of treatment with nasal continuous positive airway pressure (nCPAP) on the rehabilitation of apneic stroke patients, but the outcome of non-apneic stroke patients is better than that of apneic stroke patients.

[Isolated reversible unilateral paresis of hypoglossal nerve in tonsillitis--case report]. / Transitorische isolierte und unilaterale periphere Hypoglossusparese bei Tonsillitis--Falldarstellung.

We report on a 30-year-old patient with isolated, left-sided hypoglossal nerve palsy after uncomplicated, presumably streptococci-induced tonsillitis. Needle electromyography (EMG) of the tongue showed denervation changes in the muscles supplied by the left hypoglossal nerve. Cranial CT and MRI, CSF examination, Doppler sonography, visual evoked potential (VEP), and auditory evoked potential (AEP) showed no abnormalities and, in particular, no signs of the carotid artery dissection or brainstem lesion. The symptoms and signs resolved within a few weeks after penicillin V treatment. We suppose that the hypoglossal affection of the uncomplicated tonsillitis in this case was due to an aberrant position of the nerve.

Parkinson's disease and sleep.

There are many reasons for patients with idiopathic Parkinson's disease to develop sleep disorders and subsequent daytime sleepiness. Important causes are reduction of total sleep duration and sleep efficiency, and an increase in respiratory and motor arousals. This daytime sleepiness at first glance seems different from the "sleep attacks" which caused motot vehicle mishaps reported recently in persons taking pramipexole and ropinirole. There is, however, only little evidence that we deal with a new phenomenon in a new clinical situation, i. e. cataplexy-like attacks after high doses of new non-ergot dopamine-agonists. Until now there is no single case of a proven cataplexy on one hand, and older dopamine agonists like pergolide as well as L-Dopa + carbidopa have been reported to induce sudden onsets of sleep, too.

Workshop I: Parkinson's disease and sleep--results of the group discussion.

The group agreed on the facts that unwanted sleep onset has been observed after non-ergot as well as ergot dopamine agonists, that patients on these drugs need to be warned, that patients who have experienced sleepiness already must not drive a car unless the dosage is lowered and sleepiness has vanished, that a genetic predisposition for narcoleptic cataplexy has to be ruled out, that predictors of so-called sleep attacks need to be explored individually with the help of sleepiness scales and collectively in a careful study, respectively.

Rebound insomnia after hypnotic withdrawal in insomniac outpatients.

The effect of abrupt medication withdrawal (no-pill discontinuation) was investigated in 1507 insomniacs using the patients' self-ratings on visual analogue scales. Drug discontinuation followed a 28-day treatment period with either 7.5 mg zopiclone, 0.25 mg triazolam, 1.0 mg flunitrazepam, or placebo in a randomized, double-blind, parallel group, multicenter study in private practice. Deterioration below individual pretreatment values (no-pill baseline) in at least one of three subjective parameters of sleep quality (sleep latency, total sleep time, nocturnal awakenings) and three parameters of daytime well-being (morning freshness, daytime tiredness, anxiety) were defined as rebound. The number of patients with rebound (rebound rate) was analyzed for every day of a 2-week posttreatment period. The overall rebound rate was higher in the placebo group (p < or = 0.001) than in each group treated with active drugs. Rebound rates affecting sleep quality were higher for placebo than for zopiclone (p < or = 0.001) and for flunitrazepam (p < or = 0.05). Rebound rates were smaller for zopiclone (p < or = 0.001) and flunitrazepam (p < or = 0.01) than for triazolam. Rebound in at least one item per day appeared in 21.5% (sleep quality) and 25.5% (daytime well-being) of the patients. Rebound decreased with increasing numbers of items of sleep quality or daytime well-being. Patients who did not respond to treatment showed higher rebound rates than those who were treatment responders (p < or = 0.001). Concerning treatment nonresponders, highest rebound was seen in the placebo group, whereas rebound was lowest in placebo responders. These results show that pill discontinuation itself may worsen sleep and daytime well-being in the sense of a rebound phenomenon. Furthermore, the number of patients with rebound remained at a high and varying level during the whole posttreatment period. This result indicates that a deterioration of sleep after drug withdrawal is not apparent during a few days but may last for longer periods in some patients and is modified by marked night-to-night variations.

[Recommendations for the diagnosis and therapy of insomnia. German Society of Sleep Research and Sleep Medicine DGSM]. / Empfehlungen zu Diagnostik und Therapie der Insomnie. Deutsche Gesellschaft für Schlafforschung und Schlafmedizin DGSM.

There exist a variety of American and European recommendations regarding treatment with hypnotics, especially the duration of treatment. The German Sleep Society now publishes its own view to help physicians to cope with these different recommendations, some of which are contradictory. Therapy with hypnotics must include substantial information on the type of drug, dose, timing and duration as well as information about the possibility of interval treatment. Agonists at the benzodiazepine receptor, like the conventional benzodiazepines and zopiclone or zolpideme, are indicated in short-lasting adjustment insomnia as well as in long-lasting psychophysiological insomnia. Regarding the duration of prescription the German Sleep Society recommends a period of 14 days in de novo patients, which can be repeated once only. In persisting insomnias further approaches should disregard benzodiazepine receptor agonists, but rely on other classes of substances such as tricyclic antidepressants instead. If such approaches are ineffective, the intake of benzodiazepine receptor agonists may be extended to 6 months, when a sleep log and objective observations have documented a true sleep deficit, when daytime impairment arises, when daytime impairment arises, when rebound insomnia, organic or mental insomnias and dependencies have been excluded, and when the indication is monitored at 14-day intervals. If the insomnia persists, during and in spite of therapy a specialist in sleep medicine should be consulted. If therapy is still ineffective after 3 months of daily treatment, a sleep laboratory should be consulted.

[Interaction of epileptic seizures and biological rhythms]. / Wechselwirkung von epileptischen Anfällen und biologischen Rhythmen.

Circadian modulation of seizure threshold is subjected to a multitude of periodical, aperiodical and stochastical influences. Epilepsies on the other hand influence the biological rhythms themselves. Epileptic seizures are activated during transient sleep stages. Nocturnal seizures lead to severe sleep disorders and therefore to hypersomnia. Partial and generalized epilepsies have a different sleep profil even without seizure manifestation. Finally antiepileptic drugs may interfere with circadian rhythms. Knowing the chronobiological context a differentiation of epileptic seizures from nonepileptic parasomnias may succeed more easily. To ensure the appropriate diagnostical proceeding multichannel EEG should be used in every polysomnography with neurological topics.

Effects of hypnotics on sleep quality and daytime well-being. Data from a comparative multicentre study in outpatients with insomnia.

The effect of treatment (28 days) with zopiclone, triazolam, flunitrazepam and placebo on sleep quality and daytime well-being was proven in a randomised, double-blind, parallel group, multicentre study in private practice. Results of an exploratory statistic of treatment efficacy in a subgroup of 1,291 patients suffering from insomnia are presented. Patients met the following criteria: insomnia lasting at least four weeks and the presence of at least two of the following: 1) sleep latency >/= 45 minutes, 2) total sleep time /=3 times. Treatment efficacy was assessed according to the following factors: either a shortening of sleep latency by at least 15 minutes, or prolongation of total sleep time by at least 20%, or reduction of the number of nocturnal awakenings to three or less and a refreshed feeling in the morning as well as no impairment in daytime well-being due to tiredness or anxiety. The total response rate was markedly higher with zopiclone (42.3%; p = 0.0003) than with placebo (29.0%). Triazolam (36.6%; p = 0.0905) and flunitrazepam (33.1%; p = 0.3401) were also more effective than the placebo, but they both tended to have a lower response rate than with zopiclone (p = 0.1199 and 0.0151, respectively). Total response was found to be essentially a reflection of the response of the socially important parameter of daytime well-being. These results suggest that zopiclone is more effective in the treatment of insomnia than either triazolam or flunitrazepam. Since the response of daytime well-being to therapy was generally poor, this parameter embodies the next main therapeutic challenge in the treatment of patients with insomnia.

Zopiclone improves sleep quality and daytime well-being in insomniac patients: comparison with triazolam, flunitrazepam and placebo.

In a randomized, double-blind, parallel group study in private practice, zopiclone given for 28 days was compared with flunitrazepam, triazolam and placebo in its effect on quality of sleep and daytime well-being in 1507 patients suffering from insomnia. For quantitative assessment, patients were defined as responders according to either a shortening of sleep latency by at least 15 min, or prolongation of total sleep time by at least 20%, or reduction of the number of nocturnal awakenings to three or less and a fresh feeling in the morning, as well as lack of impairment in daytime well-being as a result of tiredness or anxiety. The responder rate tended to be higher with zopiclone (37.4%) than with flunitrazepam (30%) and triazolam (32.2%) and was significantly greater (p = 0.0017) than with placebo (26.8%). Daytime well-being was particularly responsive to zopiclone and most responsive in severe insomniacs. With the exception of those to triazolam, rates of response were most pronounced in patients with insomnia of a short duration (< or = 1 year) than in those with insomnia of a longer duration (> or = 1 year). Following discontinuation of treatment, all groups showed a moderate reduction in therapeutic effect, but no rebound insomnia occurred.

Problems in performing a double-blind multicenter study using a hypnotic in private practice.

1. The procedure described--the immediate data transfer and entry system (ITES)--is suitable to improve the quality of data collected in multicentre studies in private practice. 2. The results of the study show that regarding influence on sleep quality and daytime well-being the non-benzodiazepine Z is significantly superior to placebo and slightly superior to the benzodiazepines F and T. 3. The advantage of Z treatment is the better daytime well-being after taking the hypnotic for sleep induction the night before. 4. This study shows that a quality standard equal to that in clinical practice may be achieved in private practice.

Early signs of cognitive deficits among human immunodeficiency virus-positive hemophiliacs.

A total of 181 human immunodeficiency virus (HIV)-seropositive hemophiliacs and 28 hemophilic controls were evaluated by psychometric tests and by electroencephalogram (EEG). Patients were classified from stages 1-6 according to the immunological criteria of the Walter Reed staging system. Statistical analysis of psychometric data showed an effect of the stage of the disease on test performances, indicating a decline in attention, accumulation of perceptual interferences, decline in visuoperceptual speed and visuomotor response speed and reduced verbal memory performance, especially in stage 6 patients. Comparison of performance levels with normative test data already revealed cognitive deficits in about 20-30% of the patients in stages 2-5. As regards verbal memory, especially learning and recognition of new verbal information were impaired. In contrast, there was no significant deficit for nonverbal memory processing. Compared with the controls, patients exhibited an increasing number of abnormal EEG findings in stages 2-6. As a conclusion, in the stages before acquired immunodeficiency syndrome (AIDS) develops, EEG findings as well as psychometric findings indicate central nervous system involvement of AIDS in about 20-30% of cases, whereas in full-blown AIDS there is a marked increase to 80%. Besides a more general deficit of attention and psychomotor speed as is seen in subcortical dementia, there is evidence for a particular verbal learning disorder, suggesting additional selective impairment of the brain.

Cerebral sarcoidosis presenting as supranuclear gaze palsy with hypokinetic rigid syndrome.

A 31-year-old man with histologically documented pulmonary sarcoidosis developed a severe hypokinetic rigid syndrome with a supranuclear gaze palsy following recurrent lymphocytic meningitis and occlusive hydrocephalus. Magnetic resonance imaging (MRI) showed multiple hyperintense foci in the CNS, not detectable by computed tomography (CT). Long-term steroid therapy led to clinical complete remission.

EEG discharges in WR 1-5 HIV-seropositive hemophiliacs.

Human immunodeficiency virus (HIV)-seropositive patients show involvement of the central and/or peripheral nervous system. We present here the results of electroencephalographic (EEG) findings in stage WR 1-5 HIV-seropositive hemophiliacs from a total of 184 who attended our clinic prior to October 1987.

Gabapentin augments whole blood serotonin in healthy young men.

It has been previously demonstrated that gabapentin, a gamma-amino butyric acid analogue, inhibits monoaminergic neurotransmitter release from rabbit caudate nucleus slices and from rat cortex. In humans this drug has been shown to have anti-epileptogenic activity. Serotonin may act as an inhibitory neurotransmitter and its interaction with blood platelets is thought to reflect its central actions. We investigated sleep stages, whole blood serotonin levels, and serum melatonin in healthy men after the administration of gabapentin. With increasing serum gabapentin levels six healthy subjects showed an increase in sleep stages 3 and 4 and in whole blood serotonin (P less than 0.05) Serum melatonin levels were not influenced. On account of these results we speculate that gabapentin modulates the release of serotonin from blood platelets. The increase in peripheral serotonin points paradigmatically to an increase in the bioavailability of serotonin which may account for the increase in sleep stages 3 and 4.