Design and rationale of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation: a global registry program on long-term oral antithrombotic treatment in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 1% to 2% of the population and raising the risk of stroke 5-fold. Until recently, the only treatment choices for stroke prevention in patients with AF have been vitamin K antagonists (VKA) or antiplatelet drugs. With approval of novel oral anticoagulants (NOACs) antithrombotic treatment, patterns are changing. The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation is designed to investigate patient characteristics influencing choice of antithrombotic treatment of stroke prevention in patients with nonvalvular AF and to collect data on outcomes of antithrombotic therapy in clinical practice. METHODS: The GLORIA-AF is a large, international, observational registry involving patients with newly diagnosed nonvalvular AF at risk for stroke, enrolling up to 56,000 patients in nearly 50 countries. We will collect and analyze data from routine care using an inception cohort design. Phase I includes patients before approval of NOACs. Phase II, beginning early after approval of dabigatran, monitors dabigatran safety and addresses potential channeling across treatment options based on propensity scoring to assess comparability of baseline characteristics of patients treated with dabigatran or VKA. Phase III entails analysis of large treatment groups, adjusting for differences in propensity score, to provide information about the relative effectiveness and safety of NOACs and VKA in routine clinical care. CONCLUSIONS: Novel features of this registry program will add data from clinical practice to those from randomized trials to expand knowledge of antithrombotic treatment in patients with AF.

Secondary stroke prevention: patent foramen ovale, aortic plaque, and carotid stenosis.

Stroke is the most debilitating cardiovascular event. It has a variety of causes that may be present simultaneously. In young or otherwise healthy people, the search for a patent foramen ovale (PFO) has become standard. In stroke of the elderly, atherosclerosis and atrial fibrillation are in the foreground but the PFO should not be ignored. The risk of a PFO-related stroke over time is controversial and so is its prevention by device closure. The association of proximal aortic plaques in arteries subtending the brain and stroke is considered strong, ignoring that it is as putative as that of the PFO. Statins can prevent progression of such plaques. Antiplatelet agents in asymptomatic and surgical endarterectomy in symptomatic patients or highly ulcerated lesions are the treatment of choice. Stenting with protection devices was shown competitive in selected patients.

Cluster headache shows no association with rapid eye movement sleep.

BACKGROUND: The connection of cluster headache (CH) attacks with rapid eye movement (REM) sleep has been suggested by various studies, while other authors challenge this assumption. We performed serial polysomnography to determine the association of nocturnal CH attacks and sleep. METHODS: Five patients diagnosed with CH (two with the episodic and three with the chronic subtype) were included and studied over four consecutive nights to evaluate connections between attacks onset and sleep stage. RESULTS: Twenty typical CH attacks were reported. Thirteen of these attacks arose from sleep. Seven attacks were reported after waking in the morning or shortly before going to sleep. The beginnings of sleep-related attacks were distributed arbitrarily between different non-REM sleep stages. No association of CH attacks with REM or sleep disordered breathing was observed. Increased heart rate temporally associated with transition from one sleep state to another was observed before patients awoke with headache. Total sleep time, total wake time, arousal index and distribution of non-REM sleep stages were different between chronic and episodic CH. CONCLUSION: CH attacks are not associated with REM sleep. Brain regions involved in sleep stage transition might be involved in pathophysiology of CH. Differences in sleep characteristics between subgroups might indicate adaptation processes or underlying pathophysiology.

Evaluating integrated headache care: a one-year follow-up observational study in patients treated at the Essen headache centre.

BACKGROUND: Outpatient integrated headache care was established in 2005 at the Essen Headache Centre in Germany. This paper reports outcome data for this approach. METHODS: Patients were seen by a neurologist for headache diagnosis and recommendation for drug treatment. Depending on clinical needs, patients were seen by a psychologist and/or physical therapist. A 5-day headache-specific multidisciplinary treatment programme (MTP) was provided for patients with frequent or chronic migraine, tension type headache (TTH) and medication overuse headache (MOH). Subsequent outpatient treatment was provided by neurologists in private practice. RESULTS: Follow-up data on headache frequency and burden of disease were prospectively obtained in 841 patients (mean age 41.5 years) after 3, 6 and 12 months. At baseline mean headache frequency was 18.1 (SD = 1.6) days per month, compared to measurement at 1 year follow-up a mean reduction of 5.8 (SD = 11.9) headache days per month was observed in 486 patients (57.8%) after one year (TTH patients mean: -8.5 days per month; migraine mean: -3.2 days per month, patients with migraine and TTH mean: -5.9 days per month). A reduction in headache days ≥ 50% was observed in 306 patients (36.4%) independent of diagnosis, while headache frequency remains unchanged in 20.9% and increase in 21.3% of the patient. CONCLUSION: Multidisciplinary outpatient headache centres offer an effective way to establish a three-tier treatment offer for difficult headache patients depending on clinical needs.

Single nucleotide polymorphisms of the serotonin transporter gene in migraine--an association study.

We report a case-control study with 251 unrelated migraine patients and 192 unrelated healthy controls to evaluate an association between the polymorphisms of the 5-HT transporter (5-HTT) gene rs2066713 and rs1979572 and different migraine phenotypes. We found a genetic association for the A allele of rs1979572 for migraine with aura (MA) especially in women as well as a significant lower prevalence for MA for carrier of the A allele of rs2066713 in women. These findings support previous results suggesting that the 5-HTT gene is involved in the polygenic etiology of MA. These data further suggest that women are more likely to be clinically affected by mutations in the 5-HTT gene than men.

Predicting long-term outcome after acute ischemic stroke: a simple index works in patients from controlled clinical trials.

BACKGROUND AND PURPOSE: An early and reliable prognosis for recovery in stroke patients is important for initiation of individual treatment and for informing patients and relatives. We recently developed and validated models for predicting survival and functional independence within 3 months after acute stroke, based on age and the National Institutes of Health Stroke Scale score assessed within 6 hours after stroke. Herein we demonstrate the applicability of our models in an independent sample of patients from controlled clinical trials. METHODS: The prognostic models were used to predict survival and functional recovery in 5419 patients from the Virtual International Stroke Trials Archive (VISTA). Furthermore, we tried to improve the accuracy by adapting intercepts and estimating new model parameters. RESULTS: The original models were able to correctly classify 70.4% (survival) and 72.9% (functional recovery) of patients. Because the prediction was slightly pessimistic for patients in the controlled trials, adapting the intercept improved the accuracy to 74.8% (survival) and 74.0% (functional recovery). Novel estimation of parameters, however, yielded no relevant further improvement. CONCLUSIONS: For acute ischemic stroke patients included in controlled trials, our easy-to-apply prognostic models based on age and National Institutes of Health Stroke Scale score correctly predicted survival and functional recovery after 3 months. Furthermore, a simple adaptation helps to adjust for a different prognosis and is recommended if a large data set is available.

Small ischemic brain lesions after cardiac valve replacement detected by diffusion-weighted magnetic resonance imaging: relation to neurocognitive function.

OBJECTIVE: Following coronary artery bypass graft surgery, some studies using magnetic resonance imaging (MRI) have demonstrated new small ischemic brain lesions in patients without apparent neurological deficits. We aimed to prospectively evaluate brain injury after cardiac valve replacement using MRI and to determine the relationship to neurocognitive function. METHODS: Thirty patients with a mean age of 64.9+/-9.8 years (range, 32-82, 12 female) receiving cardiac valve replacement (aortic valve replacement [AVR], n = 24; mitral valve replacement [MVR], n = 2; AVR and MVR, n = 2; AVR and mitral valve repair, n = 2) were investigated. Study protocol included neurological examination, comprehensive neuropsychological assessment and diffusion-weighted (DW) MRI. The investigations were performed before surgery and 5 days and 4 months after surgery. RESULTS: Postoperative DW MRI detected new focal brain lesions in 14 patients (47%). No patient revealed a focal neurological deficit. Six patients (43%) had multiple (> or = 3) lesions (range, 1-7). Lesion volume ranged from 50-500 mm3 except 1 territorial infarct of 1900 mm3. Of a total of 41 lesions, 27 (66%) were located in the right hemisphere and 32 in a subcortical location. By 5 days postoperatively, significant neurocognitive decline was observed in 5 of 13 tests affecting memory, attention and rate of information processing. By 4 months, dysfunction had recovered in all cognitive areas. The presence of new ischemic lesions was not associated with neurocognitive decline at discharge. There was also no significant correlation between clinical and operative variables and the presence of new DW lesions or neuropsychological outcome. CONCLUSIONS: Following cardiac valve replacement, new small ischemic brain lesions were detected by diffusion-weighted MRI. Neurocognitive decline was present early after operation, but resolved within 4 months. A correlation of new ischemic lesions to postoperative cognitive dysfunction or clinical variables was not found.

AMPA antagonist ZK200775 in patients with acute ischemic stroke: possible glial cell toxicity detected by monitoring of S-100B serum levels.

BACKGROUND AND PURPOSE: S-100B and neuron-specific enolase (NSE) serum concentrations can be used as peripheral markers of glial cell and neuronal damage, respectively. We investigated these markers in a clinical trial with the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) antagonist ZK200775 in acute ischemic stroke patients. METHODS: In a multicenter, double-blind, randomized, placebo-controlled phase 2 trial, 61 ischemic stroke patients were treated with either placebo or active drug in a dose-finding design. Twenty-five patients received placebo, 12 patients received a total dose of 262.5 mg in 48 hours (dose group 1), and 13 patients received a total dose of 525 mg in 48 hours (dose group 2). Eleven patients received a total dose of 105 mg over a period of 6 hours (dose group 3; reduction of total dose and infusion time because of adverse events in group 2). Serum concentrations of S-100B and NSE were analyzed with the use of a monoclonal sandwich immunoluminometric assay. Neurological outcome was assessed with the National Institutes of Health Stroke Scale (NIHSS). RESULTS: In group 2 there was a significant transient worsening in the mean NIHSS score 48 hours after the start of treatment. The mean increase was 11 points. This was due to reduction of consciousness (stupor and coma) in 8 of 13 patients. Neurological deterioration in group 2 was associated with a higher increase of S-100B concentrations, but not of NSE concentrations, than in the placebo group. The trial was stopped prematurely for safety reasons. CONCLUSIONS: The AMPA antagonist ZK200775 transiently worsened the neurological condition in patients with acute ischemic stroke. Our results suggest that in addition to neuronal dysfunction, glial cell toxicity may have occurred. It may be useful to introduce monitoring of serum markers of brain damage in phase 2 trials with glutamate receptor antagonists.

[Predicted functional outcome 100 days after ischemic strokes: design of a prospective study about the external validation of a prognostic model]. / Vorhersage des Funktionsstatus 100 Tage nach einem ischämischen Schlaganfall: Design einer prospektiven Studie zur externen Validierung eines prognostischen Modells.

The purpose of this study is to externally validate previously developed prognostic models predicting functional outcome 100 days after acute ischaemic stroke. Data prospectively collected from 1,754 patients were used to develop two models predicting functional dependence (Barthel Index < 95) and mortality. Both models were internally validated and calibrated. A prospective multicentre study is being performed to validate the developed models with an independent data set. On admission to one of 15 participating hospitals, all patients with acute ischaemic stroke will be registered prospectively in the co-ordinating centre. Within 72 hours, potential predictive variables will be assessed. 1,975 patients will have to be recruited to achieve a power of 95% at the 5% significance level. The resulting prognostic models will be useful for adequately stratifying treatment groups in clinical trials and to accurately predicting the outcome variable.

Predicting recovery after intracerebral hemorrhage--an external validation in patients from controlled clinical trials.

BACKGROUND: An early and reliable prognostic indication in stroke patients is potentially useful for initiation of individual treatment and for informing patients and relatives. We recently developed a regression model as well as a simple 11-point predictive score (Essen ICH score) for functional recovery within three months after acute intracerebral hemorrhage (ICH) based on age and the National Institutes of Health Stroke Scale (NIH-SS). Here, we demonstrate the applicability of our models in an independent sample of ICH patients from controlled clinical trials. METHODS: The prognostic models were used to predict functional recovery in 564 patients from the Virtual International Stroke Trials Archive (VISTA). Furthermore, we tried to improve the accuracy by re-calibration and estimating new model parameters. FINDINGS: The logistic regression model and the Essen ICH score were able to correctly classify 77.5 % and 76.4 % of patients, respectively. Re-calibration and novel estimation of parameters yielded only a slight improvement of overall predictive accuracy. INTERPRETATION: For acute ICH patients included in controlled trials, our predictive models based on age and the NIH-SS correctly predict functional recovery after three months and could be useful for future trial design.

Cognitive outcomes three years after coronary artery bypass surgery: relation to diffusion-weighted magnetic resonance imaging.

BACKGROUND: Cognitive decline is well recognized early after coronary artery bypass graft surgery (CABG), but controversy exists regarding the degree and duration of these changes. We investigated the course of cognitive performance during 3 years after surgery and determined whether ischemic brain injury detected by diffusion-weighted magnetic resonance imaging was related to cognitive decline. METHODS: Thirty-nine patients undergoing on-pump CABG completed preoperative neuropsychologic examination and were followed up prospectively at discharge, 3 months, and 3 years after surgery. Cognitive performance was assessed with a battery of 11 standardized psychometric tests assessing 7 cognitive domains. Cognitive outcome was analyzed by determining (1) mean changes in within-patient scores over time (identifying cognitive functions with decline), and (2) the incidence of cognitive deficit for each individual (identifying patients with decline). Objective evidence of acute cerebral ischemia was obtained by diffusion-weighted magnetic resonance imaging. Prospectively collected data were used to identify predictors of cognitive deficits. RESULTS: From baseline to discharge, cognitive test scores significantly declined in 7 measures. Most tests improved by 3 months. Between 3 months and 3 years, late decline was observed in 2 measures with persistent deterioration in 1 measure (verbal memory) relative to baseline. Postoperative cognitive deficits (drop of > or = 1 SD in scores on > or = 3 tests) were observed in 56% of patients at discharge, 23% at 3 months and 31% at 3 years. On postoperative diffusion-weighted magnetic resonance imaging, there were new ischemic cerebral lesions in 51% of patients. The presence of cognitive deficit at discharge was a significant univariate predictor of late cognitive decline (p = 0.025). A relation between the presence of new diffusion-weighted magnetic resonance imaging detected lesions and cognitive decline, however, was not found. CONCLUSIONS: Longitudinal cognitive performance of patients with CABG showed a two-stage course with early improvement followed by later decline. Long-term cognitive deficit was predicted by early cognitive decline, but not by ischemic brain lesions on magnetic resonance imaging.

Visual cortex excitability in migraine evaluated by single and paired magnetic stimuli.

OBJECTIVE: To determine the excitability of the visual cortex by phosphene thresholds (PT) in patients with migraine using transcranial magnetic stimulation (TMS) with single- and paired-pulses. METHODS: Nineteen patients with migraine with aura (MWA), 19 patients with migraine without aura (MWoA), and 22 control subjects were included. Patients were free from preventive anti-migraine treatment and were investigated within 3 days before or after an acute migraine attack. In each subject, PT were assessed by single-pulse and paired-pulse TMS with an interstimulus interval of 50 ms. RESULTS: The main effect of diagnosis indicated that mean PT were significantly lower in migraine patients than in control subjects (P = .001). Using single-pulse TMS, mean PT tended to be lower in MWoA-patients (57.7 +/- 11.8%) compared with control subjects (64.4 +/- 10.5%) (P = .064). In MWA-patients, mean PT (53.1 +/- 5.7%) were significantly lower compared with controls (P < .001). Using TMS with paired pulses, mean PT were significantly reduced in MWoA-patients (40.3 +/- 4.9%, P = .017) as well as in MWA-patients (39.6 +/- 4.2%, P = .005) compared with controls (44.6 +/- 6.0%). The main effect of stimulation type indicated that mean PT were lower determined with paired-pulse stimulation than with single pulses (P < .001). CONCLUSIONS: PT are reduced in patients with migraine in the interictal state suggesting an increased excitability of visual cortical areas. Compared with single-pulse TMS, paired-pulse magnetic stimulation is more efficient to elicit phosphenes. This technique provides the opportunity to evaluate visual cortex excitability with lower stimulus intensities and less discomfort.

The AMPA antagonist ZK 200775 in patients with acute ischaemic stroke: a double-blind, multicentre, placebo-controlled safety and tolerability study.

BACKGROUND AND PURPOSE: ZK 200775 is a selective competitive AMPA receptor antagonist. It has demonstrated neuroprotective efficacy in experimental models of stroke and tolerability in healthy volunteers. We tested the safety and tolerability of ZK 200775 in patients with acute ischaemic stroke. METHODS: In a multicentre double-blind, randomised, placebo-controlled phase II trial, 61 ischaemic stroke patients were treated with either placebo or active drug in a dose finding design. Twenty-five patients received placebo, 12 patients received a total dose of 262.5 mg in 48 h (group 1) and 13 patients received a total dose of 525 mg in 48 h (group 2), and 11 patients received a total dose of 105 mg over a period of 6 h (group 3). We studied the pharmacokinetics of the compound and the effect of the infusion on the neurologic and haemodynamic parameters of the patients. The study was not powered to detect neuroprotective efficacy. RESULTS: In group 2 there was a significant transient worsening in the mean NIH stroke scale score 14- 18 h after the start of treatment. This was due to reduction of consciousness (stupor and coma) in 8 out of 13 patients. Level of consciousness improved approximately 6 h after cessation of infusion. No significant haemodynamic responses were observed. Even after reduction of the administered dose and duration of infusion to 6 h (group 3), 2 patients experienced a reduction in level of consciousness. The effect of ZK 200775 on level of consciousness gave cause for concern and the trial was stopped prematurely for safety reasons. CONCLUSIONS: The AMPA antagonist ZK 200775 reversibly worsened the neurological condition in patients with acute ischaemic stroke. Our results suggest that ZK 200775 exerts significant sedative effects in patients with acute stroke which preclude its further development as a neuroprotective agent in this indication.