Intravenous levetiracetam in clinical practice--Results from an independent registry.

PURPOSE: Most common clinical studies with antiepileptic drugs do not reflect medical everyday practice due to their strict in- and exclusion criteria and specifications of treatment regimens. Here we present a large non-interventional registry with the intention to evaluate the spectrum of applications in daily use and the efficacy and tolerability of intravenously given levetiracetam (LEV-iv). METHODS: In a prospective approach of 17 neurological and neuropediatric centres in Germany LEV-iv treated patients of all ages were included over a period of 10 months. The observational period was 10 days with daily documentation of LEV-iv administration, type and frequency of seizures, currently used drugs and doses, and adverse events (AEs). In addition, treatment efficacy and tolerability were assessed by patients and physicians at study end as well as practicability of LEV-iv using a five-step scale. RESULTS: In 95 patients LEV-iv was administered, 93 were included into the analysis. The median LEV-iv dose was 1500 mg (range 110-6000 mg) per day. Median age was 66 years (range 0.7-90.3 years). The majority of patients (n=70, 75%) suffered from status epilepticus (SE, n=55, 59%) and acute seizure clusters (n=15, 16%). Of those with SE, 41 patients (75%) had SE for the first time. Acute seizure clusters and SE terminated in 83% after LEV-iv administration. A total of 29 adverse events were reported in 17 of the 95 patients from the safety set. Ten of these were at least possibly related to LEV-iv treatment. Slight decrease of blood pressure during the infusion (3 patients each) was captured most frequently. No serious side effect was observed. Physicians rated the efficacy and tolerability of LEV-iv treatment as good or very good in 78% and 82% of the cases, respectively. CONCLUSION: In this large observational study of everyday practise the use of LEV-iv exhibited a remarkable good response and tolerability in patients with acute onset seizures (mostly SE). Further randomized controlled studies, like the established status epilepticus trial (ESET) are needed to confirm these findings.

[Sleep medicine differential diagnostics in psychiatry and psychotherapy]. / Schlafmedizinische Differenzialdiagnostik in Psychiatrie und Psychotherapie.

Complaints about disturbed sleep or increased daytime sleepiness are among the most frequent symptoms reported to psychiatrists by patients. Such complaints can be symptoms of an underlying psychiatric disorder or indicative of a separate or comorbid sleep disorder. Hence, basic knowledge in the differential diagnosis of sleep medicine pathologies is pivotal for psychiatrists and psychotherapists. In the present overview following a description of the diagnostic methods, the diagnostic work-up according to the major symptomatic clusters, namely disturbances in initiating and maintaining sleep, abnormal nocturnal movements and excessive daytime sleepiness will be presented.

Effects of frontal transcranial direct current stimulation on emotional state and processing in healthy humans.

The prefrontal cortex is involved in mood and emotional processing. In patients suffering from depression, the left dorsolateral prefrontal cortex (DLPFC) is hypoactive, while activity of the right DLPFC is enhanced. Counterbalancing these pathological excitability alterations by repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) improves mood in these patients. In healthy subjects, however, rTMS of the same areas has no major effect, and the effects of tDCS are mixed. We aimed to evaluate the effects of prefrontal tDCS on emotion and emotion-related cognitive processing in healthy humans. In a first study, we administered excitability-enhancing anodal, excitability-diminishing cathodal, and placebo tDCS to the left DLPFC, combined with antagonistic stimulation of the right frontopolar cortex, and tested acute emotional changes by an adjective checklist. Subjective emotions were not influenced by tDCS. Emotional face identification, however, which was explored in a second experiment, was subtly improved by a tDCS-driven excitability modulation of the prefrontal cortex, markedly by anodal tDCS of the left DLPFC for positive emotional content. We conclude that tDCS of the prefrontal cortex improves emotion processing in healthy subjects, but does not influence subjective emotional state.

[Sleep and its disorders in the elderly]. / Schlaf und seine Störungen im Alter.

Restorative sleep is an important factor for preservation of health and quality of life. Sleep quality is associated with age, i.e., sleep disorders occur more frequently particularly after the age of 75 years. Furthermore, sleep shows an association with female gender, inactivity, dissatisfaction with social life, depressive symptoms, pain, intake of sedatives, genetic predisposition, and increased morbidity and mortality in the elderly. Strategies for improving sleep should include (1) effective treatment of organic diseases and mental disorders, (2) elimination of social life factors that impair sleep quality, (3) light therapy and other nonpharmacological treatment options for longer periods, and (4) short-term use of sleep medication as required. For the latter, it should be kept in mind that lower doses are needed in the elderly.

[Restless legs syndrome and nocturnal leg pain : Differential diagnosis and treatment]. / Restless-Legs-Syndrom und nächtliche Beinschmerzen. Differenzialdiagnose und Therapie.

Pain in the legs belongs to the five most frequent regional pain symptoms. Restless legs syndrome (RLS) presents a particular differential diagnosis for pain in the legs, which is characterized by a nocturnal urge to move the legs often associated with painful sensations in the legs. It is one of the most common neurological disorders and probably the leading cause of nocturnal pain in the legs. In this overview, the diagnosis and therapy of RLS as well as aspects of pain therapy of the disorder are presented. In addition, the differential diagnoses for exclusion of other specific causes of nocturnal pain in the legs are discussed.

Diurnal time course of heat pain perception in healthy humans.

Rapid skin heating by infrared lasers can be used to investigate the integrity of the nociceptive system by activating A-delta and C fibers. The aim of our study was to analyze if healthy humans exhibit any clinically relevant diurnal variations in their heat pain sensitivity. Circadian A-delta fiber function was analyzed by studying N2 and P2 components of laser-evoked potentials (LEP) and pain thresholds evoked by laser stimulation of the foot every 2h from 8a.m. to 10p.m. in 15 healthy subjects. Heat stimuli were generated by an infrared Tm-YAG laser and were delivered to an area of 4 cm × 4.5 cm on the dorsum of the right or left foot in 3 runs of incremental and decremental intensities. After each stimulus subjects were asked to classify the intensity of pain with a numeric rating scale (NRS). LEPs were recorded with fixed stimulus intensities that were 1.5× of the pain threshold. Data were collected with the SynAmps System (Neuroscan, El Paso, USA) and averaged across 35-40 trials. Laser-induced heat pain thresholds and circadian latencies of LEP did not significantly vary during the day. Our results correspond with previous studies that did not detect any consistent significant diurnal variations in perception of heat pain perception using contact thermodes. The intensity of pain perception did not demonstrate any correlation with mood or sleep parameters as measured with the Beck Depression Inventory (BDI), the subjective sleep scales Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS).

Intravenous levetiracetam: a new treatment alternative for refractory status epilepticus.

The purpose of this study was to investigate the safety and efficacy of intravenous levetiracetam (LEV-iv) in refractory status epilepticus (SE). A retrospective chart review was performed on patients who received LEV-iv for treatment of SE (n = 36) and had failed at least one other antiepileptic drug. LEV-iv (median 3000 mg/day; range 1000-9000) was administered as a bolus loading (500-2000 mg per 30-60 min, n = 30) or as a continuous pump infusion (n = 6). SE was terminated in 69% ("responders"); 31% ("non-responders") remained in SE. Factors associated with failure were: dose escalation over 3000 mg/day, lack of bolus loading, treatment latency over 48 h, age over 80 years, non-convulsive SE with coma ("subtle SE"), periodic lateralised epileptiform discharges (PLEDs) on EEG, acute cerebral lesion and intubation narcosis. SE was terminated in all eight patients without brain lesion (p = 0.033), and in all seven patients with complex partial SE (p = 0.051). Outcome was favourable (ambulatory patients) in 48% (responders) compared with 0% (non-responders), and "adverse" (death or continuing coma/stupor) in 24% (responders) compared with 100% (non-responders). Mortality was 17% (responders 4%, non-responders 45%). No patient had cardiocirculatory side effects or worsening of SE. Two patients experienced nausea and vomiting during LEV-iv loading, leading to aspiration pneumonia in one. This study suggests that LEV-iv may be a safe and efficacious treatment of SE. Prospective and controlled trials are imperative to confirm these preliminary findings.

Comorbidity of restless legs syndrome and HIV infection.

BACKGROUND: The lifetime prevalence of restless legs syndrome (RLS) is about 10 % in the general population. The association of RLS with HIV infection is unknown. We aimed to investigate the prevalence of RLS in HIV positive patients and to define predictors. METHODS: A standardized questionnaire was presented to 228 HIV infected patients of the HIV outpatient clinic at the Department of Neurology,University of Münster, Germany. 129 patients (57% recall; 15% female, 44 +/- 9 years; mean CD4(+) cell count 333 +/- 274/microl, 82% under highly active antiretroviral treatment) were included in the statistical analysis. 100 age- and sex-matched controls (20 % female, 42 +/- 13 years) were recruited from waiting relatives of surgical patients. Beside demographic and disease-specific data, the questionnaire included the diagnostic questions for RLS and the RLS severity scale by the International RLS Study Group. Diagnosis of RLS was confirmed by experienced neurologists. RESULTS: 33.3% of the HIV infected patients and 7% of the controls (p <0.001) fulfilled the diagnostic criteria for RLS. The mean RLS severity score was higher in HIV infected patients (19.5 +/- 7.2) than in controls (7.3 +/- 1.5; p <0.001) and correlated inversely with the CD4(+) cell count (r = -0.381; p = 0.024) and the BMI (r = -0.548; p <0.001) but not with other disease-specific factors. CONCLUSIONS: HIV infected patients show a significantly higher prevalence rate for RLS than the general population. The HIV infection itself with its immunological changes and involvement of the central nervous system may predispose for a risk of RLS in HIV infected patients.

Comorbidity of migraine and restless legs syndrome--a case-control study.

In order to evaluate a possible association between migraine and restless legs syndrome (RLS), we performed a case-control study on the comorbidity of RLS and migraine. Patients with migraine (n = 411) and 411 sex- and age-matched control subjects were included. Migraine was diagnosed according to International Headache Society criteria, RLS according to the criteria of the International Restless Legs Syndrome Study Group. Furthermore, all patients had to fill out a self-assessment test performance on depression [Beck's Depression Inventory (BDI)]. RLS frequency was significantly higher in migraine patients than in control subjects (17.3% vs. 5.6%, P < 0.001; odds ratio 3.5, confidence interval 2.2, 5.8). In our sample, there was no significant association between migraine and depression as defined by the BDI score (9.6% in migraine vs. 4.0% in control subjects, P = 0.190). Depression was, however, not significantly more frequent in migraine patients with RLS (13.6%) than in migraine patients without RLS (8.7%). In addition, migraine patients with RLS had a significantly higher BDI score. RLS features did not differ significantly between migraine patients with RLS and control subjects with RLS. There is an association between RLS and migraine and, in addition, a co-association with depression. The underlying mechanism, however, remains undetermined and might be related to a dysfunction of dopaminergic metabolism in migraine.

[Expert opinions regarding daytime sleepiness in neurological diseases and obstructive sleep apnea syndrome]. / Begutachtung der Tagesschläfrigkeit bei neurologischen Erkrankungen und dem obstruktiven Schlafapnoesyndrom (OSAS).

Patients with increased daytime sleepiness are impaired in all areas of their social environment. Expert opinions are recommended for pension proceedings, regarding driving licenses as well as for restrictions at the workplace. All possibilities should be considered in the differential diagnosis of sleep disorders, which have to be treated before an expert opinion is submitted. Statutory regulations on evaluation of sleepiness are contained in the guidelines for assessing a patient's fitness to drive. The importance of daytime sleepiness in other occupations should be assessed according to the respective workplace. The patient should be informed of the appraisal with regard to career choice and workplace design. The expert thus has the responsible task of carrying out interdisciplinary differential diagnosis of pathological sleepiness and monitoring treatment success with appropriate test methods. In the present paper the legal guidelines in Germany and available test methods are presented.

Growth hormone response in low-dose apomorphine test correlates with nigrostriatal dopamine transporter binding in patients with Parkinson's disease.

Challenge with low-dose apomorphine causes a rise in growth hormone (GH) in patients with Parkinson's disease (PD). We studied 18 patients with early PD, who showed an increase of GH in the low-dose apomorphine test, by means of [(123)I] FP-CIT-SPECT. The mean specific dopamine transporter binding of the 18 patients was 1.50 +/- 0.56 in the striatum, 1.20 +/- 0.59 in the putamen, and 1.76 +/- 0.59 in the caudate nucleus. The increase of GH (1.05 +/- 1.01 ng/ml at baseline to 9.46 +/- 6.36 ng/ml 45 min after apomorphine injection; p < 0.001) was significant. There was a significant negative correlation of the increase of GH with the mean specific dopamine transporter binding in all three regions (r between -0.490 and -0.587; p between 0.04 and 0.01). Challenge with low-dose apomorphine may therefore be used as an indirect tool to measure the extent of nigrostriatal neurodegeneration in early PD.

[Sleep in neurodegenerative disorders]. / Schlaf bei neurodegenerativen Erkrankungen.

Neurodegenerative disorders are a group of heterogeneous, progressive disorders of varying etiology that affect one or more systems. They occur predominantly at older age, during which the structure and amount of sleep undergo changes. Neurodegenerative processes cause structural changes of the sleep/wake generators in the brainstem which result in disorders such as daytime sleepiness, insomnia, sleep-related movement and breathing disturbances, and disorders of the circadian rhythms. Some sleep disorders manifest years before the onset of neurodegenerative disorders and may serve as predictors. Polysomnography shows sleep fragmentation, tonic or phasic movements of the extremities, alteration of respiratory muscles, reduced slow wave sleep, REM sleep absence or without muscle atonia, increased arousal or wake activity, epileptiform EEG activity, and changes in sleep-related breathing. Very frequently, REM sleep behaviour disorder is associated with neurodegenerative disorders. In this overview we present symptoms, pathophysiology, and polysomnographic findings of sleep disorders in prevalent neurodegenerative disorders.

Efficacy of cabergoline in restless legs syndrome: a placebo-controlled study with polysomnography (CATOR).

OBJECTIVE: To assess the efficacy and safety of the dopamine agonist cabergoline in the treatment of patients with idiopathic restless legs syndrome (CATOR study). METHODS: Patients with moderate to severe restless legs syndrome (RLS) were randomly assigned to cabergoline (single evening dose: 2 mg) or placebo and treated for 5 weeks in a double-blind, multicenter polysomnography (PSG) trial. The primary efficacy measures were the periodic leg movements during sleep arousal index (PLMS-AI) and sleep efficiency. These and further PSG variables were monitored by centrally evaluated PSG. Severity of RLS was assessed using the International RLS Study Group Severity Scale (IRLS), the RLS-6 scales, the Sleep Questionnaire Form A (SF-A; quality of sleep), and the Quality of Life for RLS questionnaire. RESULTS: Forty-three patients were treated and 40 patients were evaluated with PSG (age 56 +/- 10 years, 73% women). Cabergoline was superior to placebo in terms of the PLMS-AI (-17.7 +/- 16.4 vs -4.5 +/- 20.0 placebo; p = 0.0024), sleep efficiency (+6.2 +/- 13.9% vs +3.3 +/- 11.7%; p = 0.0443), PLMS index (p = 0.0014), PLM index (p = 0.0012), and total sleep time (p = 0.0443). Improvements in IRLS total score (-23.7 +/- 11.2 vs -7.9 +/- 11.0 placebo; p = 0.0002), RLS-6 severity scales during the night (p = 0.0010) and during the day (p = 0.0018), Clinical Global Impressions severity item (p = 0.0003), sleep quality (p = 0.0180), SF-A sleep quality (p = 0.0371), and QoL-RLS (p = 0.0247) were larger in patients treated with cabergoline compared with the placebo group. Adverse events were only mild and well-known side effects of dopamine agonists. CONCLUSION: Single-evening cabergoline is an efficacious and well-tolerated short-term therapy for sensorimotor symptoms of restless legs syndrome and associated sleep disturbances.

[Neurophysiological and neuroimaging studies for restless legs syndrome and periodic leg movement disorder]. / Neurophysiologische und Bildgebungsstudien beim Restless-legs-Syndrom und bei periodischen Beinbewegungen.

The restless legs syndrome (RLS) is a clinical diagnosis based on the four essential criteria defined by the International Restless Legs Syndrome Study Group (IRLSSG). An idiopathic form can be separated from a symptomatic form. Neurophysiological studies have investigated the pathophysiology of the idiopathic RLS or have been used to exclude a symptomatic cause, in particular polyneuropathy. So far cortical excitability changes, corticomotor, somatosensory and auditory pathways, spinal cord excitability, B-wave rhythm and cycling alternating pattern, as well as reflex mechanisms have been investigated by electroencephalography, evoked potentials, Bereitschaftspotentials, nerve conduction and thermal threshold measurements, electromyography, transcranial Doppler sonography, measurements of the spinal flexor reflex as well as neuroimaging techniques. The etiology of the RLS cannot be revealed by these methods, neurophysiological studies in RLS are, however, useful for a better understanding of the pathophysiology and for exclusion of a polyneuropathy or other symptomatic causes. In addition to neurophysiological investigations, small fiber neuropathy, which seems to be a more common finding in RLS patients than expected to date, may need biopsy for confirmation. This review will focus on investigations of the different systems involved with diverse neurophysiological methods.

Restless legs syndrome and sleep problems in children and adolescents with insulin-dependent diabetes mellitus type 1.

The restless legs syndrome (RLS) occurs in adulthood with a prevalence of 5 to 10% and can be associated with diabetes mellitus. The prevalence in childhood, however, is unknown. We asked consecutive children with type 1 (insulin-dependent) diabetes mellitus as well as their parents and siblings about RLS according to a standardised questionnaire. Altogether, 46 patients (25 female, 12.0 +/- 3.7 years), 50 siblings (29 female, 12.3 +/- 5.5 years) and 75 parents (41 mothers, 40.4 +/- 5.1 years; 34 fathers, 42.5 +/- 5.3 years; 1.3 % with diabetes mellitus) were included. One patient (2.2%), one sibling (2.0%), and 14 parents (18.7%) were diagnosed as having RLS. Disturbances of sleep initiating, sleep maintenance and daytime tiredness were similar in patients and siblings. There was a significant association of higher HbA1c values (mean 7.7 +/- 2.2%) with sleep initiating problems. The mean dose of international units of insulin/kg body weight/day (0.79 +/- 0.26 IU) was not associated with the presence of RLS or sleep problems. To conclude, there seems to be no association of diabetes mellitus type 1 with RLS in children and adolescents. However, there is a relationship between diabetes and sleep disturbances and an optimally controlled diabetes mellitus might be an important factor for an improved sleep initiation.

Normal striatal D2 receptor binding in idiopathic restless legs syndrome with periodic leg movements in sleep.

Dopaminergic treatment is very effective in restless legs syndrome (RLS) and periodic leg movements in sleep (PLMS). However, neuroreceptor imaging studies that addressed altered striatal dopaminergic function have given controversial results. In this present study, 14 patients with idiopathic RLS (iRLS) and PLMS with a good response to dopaminergic and non-dopaminergic treatment and ten healthy sex- and age-matched controls were investigated off-medication by using 123I-IBZM and SPECT. RLS symptoms and sleep disturbances were evaluated using three nights of polysomnography, the Pittsburgh Sleep Quality Index, and the International RLS Study Group (IRLSSG) rating scale. The patients presented with sleep disturbances, a high PLMS index (56.2 +/- 33.1 per h), and severe RLS symptoms during SPECT (IRLSSG rating scale 23.1 +/- 8.0), and showed no significant differences in striatal to frontal IBZM binding to D2 receptors compared to controls (ratio striatum/frontal cortex, right side 1.60 +/- 0.10 vs 1.63 +/- 0.08, P = 0.35, NS; left side 1.61 +/- 0.11 vs 1.63 +/- 0.08, P = 0.51, NS). These findings show normal function of striatal D2 receptors in successfully treated patients with iRLS and PLMS. Dopaminergic and non-dopaminergic pretreatment does not appear to change striatal D2 receptor binding as compared to healthy controls. Structures other than striatal D2 receptors are discussed as possible causes of the treatment effects in RLS.

[Restless legs syndrome in childhood]. / Das Restless-legs-Syndrom im Kindesalter.

The diagnostic criteria of restless legs syndrome were defined in 1995 by the International Restless Legs Syndrome Study Group (IRLSSG). In light of the latest scientific evidence and increasing clinical experience, the diagnostic criteria were revised in a consensus workshop. Participants of the workshop considered the development of new diagnostic criteria especially important for the following subgroups: (1) for children and (2) for the cognitively impaired elderly. The common characteristic of both groups lies in their difficulty in expressing subjective symptoms adequately. This considerably impedes the diagnosis of restless legs syndrome. In 2002, a proposal for diagnostic criteria of restless legs syndrome in childhood was formulated by members of the study groups "Movement Disorders and Sleep" and "Paediatrics" of the German Sleep Society. The proposal was partially incorporated into the diagnostic criteria for restless legs syndrome in childhood suggested by the IRLSSG. The current criteria are recommendations to enhance further research and must be validated by clinical studies. The following article gives an overview of published studies on restless legs syndrome in childhood, reviews the proposals for diagnostic criteria, and summarizes the peculiarities to be considered in diagnosing restless legs syndrome in children.