Migraine with aura: which patients are most at risk of stroke?

The complex association between migraine (M) and ischemic stroke (IS) is discussed. Epidemiological studies and meta-analyses show that M with aura (MA) and not M without aura, doubles the risk of IS. The risk is higher for female gender, young age and higher headache attacks frequency. Smoking habit and oral contraceptives, especially if associated, increase stroke risk. The underlying pathogenetic mechanisms are not completely understood, but it is hypothesized that a particular brain susceptibility to cortical spread depression could explain the association between MA and IS. The absolute risk of IS in migraineurs is relatively low and an antithrombotic primary prevention is not indicated, but it is mandatory to investigate and treat associated risk factors for IS and, in young MA women, consider only progestinic oral contraceptives, if needed, and smoking cessation.     

Defining response in migraine: which endpoints are important?

The primary endpoint traditionally measured in clinical trials of triptans for acute migraine therapy has been 2-hour pain relief, a decrease in pain intensity from moderate/severe to mild/none. Although harder to achieve, endpoints such as 2-hour pain free and the composite measure sustained pain free are now preferred as they better reflect what patients desire from medication, namely rapid onset of action, and complete and lasting relief of pain. A comprehensive meta-analysis has shown that oral triptans differ in their ability to achieve these endpoints, with almotriptan 12.5 mg, eletriptan 80 mg and rizatriptan 10 mg providing the highest likelihood of success. Although all triptans have simple and consistent pharmacokinetic features, they also have specific differences that may play a part in their differing clinical attributes. Incorporating tolerability to generate a more stringent endpoint, sustained pain free with no adverse events (SNAE), may provide an even better representation of patients' expectations. Comparison of SNAE rates using data from the meta-analysis of oral triptans indicates that almotriptan 12.5 mg has the best balance of high efficacy and good tolerability.     

Placebo treatment in acute stroke trials : benefit or harm to patients?

BACKGROUND AND PURPOSE: Some stroke patients and their families express reservations about participating in trials of experimental therapies for acute stroke. Among many reasons given for this is the concern that by participating, patients may be deprived of some component of routine care. We sought to determine the effect on outcome of participating in a clinical stroke trial while being treated with placebo. METHODS: Prospective clinical information was collected for all patients admitted with acute ischemic stroke between July 1995 and July 1996. A subgroup of these patients was enrolled in a clinical trial of acute stroke therapy and had been randomly assigned to the placebo group. The control group was selected from concurrent stroke patients who were not enrolled in any clinical trial. The National Institutes of Health Stroke Scale (NIHSS) was performed on admission and on day 7 after admission. The Glasgow Outcome Scale (GOS) was also performed at discharge. Stroke severity was classified as "severe" if NIHSS was >/=9 or GOS >/=3. Group comparisons were performed with chi(2) tests. RESULTS: One hundred twenty-six patients were evaluated. Forty-seven were placebo patients, and 79 were selected as control subjects. There were no significant differences between the groups with respect to age, sex, hematocrit, blood glucose level, history of hypertension, diabetes, smoking, or initial NIHSS. In addition, there was no difference between groups in terms of the frequency of baseline stroke subtype. Among our controls, 55 patients (70%) were on antithrombotic treatment during hospitalization, whereas none of our placebo patients were on any antithrombotic treatment. For the GOS at follow-up, a good outcome was attained by 76% of the control subjects and 72% of placebo patients (not significant). A severe NIHSS (>9) at follow-up, however, was documented in 15% of controls and 59% of placebo patients (P<0.001). There was a trend toward a higher ("worse") mean follow-up NIHSS among placebo patients (mean NIHSS, 11) versus controls (mean NIHSS, 6) (P=0.09). CONCLUSIONS: Patients enrolled in the placebo arms of some acute clinical stroke trials have similar functional outcomes but more severe neurological deficits at 1 week than did a control group. These findings might be partially explained by the withholding of antithrombotic medication and the exclusion criteria inherent in most trials. Vigilance is required to ensure that all patients participating in stroke studies be guaranteed optimal known medical therapy.     

Treatment in a combined acute and rehabilitation stroke unit: which aspects are most important?

BACKGROUND AND PURPOSE: We have previously shown that treatment of acute stroke patients in our stroke unit (SU) compared with treatment in general ward (GWs) improves short- and long-term survival and functional outcome and increases the possibility of earlier discharge to home. The aim of the present study was to identify the differences in treatment between the SU and the GW and to assess which aspects of the SU care which were most responsible for the better outcome. METHODS: Of the 220 patients included in our trial, only 206 were actually treated (SU, 102 patients; GW, 104 patients). For these patients, we identified the differences in the treatment and the consequences of the treatment. We analyzed the factors that we were able to measure and their association with the outcome, discharge to home within 6 weeks. RESULTS: Characteristic features in our SU were teamwork, staff education, functional training, and integrated physiotherapy and nursing. Other treatment factors significantly different in the SU from the GW were shorter time to start of the systematic mobilization/training and increased use of oxygen, heparin, intravenous saline solutions, and antipyretics. Consequences of the treatment seem to be less variation in diastolic and systolic blood pressure (BP), avoiding the lowest diastolic BP, and lowering the levels of glucose and temperature in the SU group compared with the GW group. Univariate analyses showed that all these factors except the level of glucose were significantly associated with discharge to home within 6 weeks. In the final multivariate Cox regression model, shorter time to start of the mobilization/training and stabilized diastolic BP were independent factors significantly associated with discharge to home within 6 weeks. CONCLUSIONS: Shorter time to start of mobilization/training was the most important factor associated with discharge to home, followed by stabilized diastolic BP, indicating that these factors probably were important in the SU treatment. The effects of characteristic features of an SU, such as a specially trained staff, teamwork, and involvement of relatives, were not possible to measure. Such factors might be more important than those actually measured.     

Which targets are relevant for therapy of acute ischemic stroke?

BACKGROUND: The efficiency of various strategies of neuroprotection is well documented in animal experiments but is thus far disappointing in ischemic stroke, for which only early reperfusion induced by thrombolysis has improved clinical outcome. This discrepancy between expectation from experimental research and clinical reality may be related to differences in the pathogenetic factors contributing to infarction. SUMMARY OF COMMENT: Positron emission tomography cerebral blood flow studies within 3 hours of onset were used to identify the various compartments of the infarct outlined on MRI 2 to 3 weeks after a hemispheric stroke in 10 patients. Critical hypoperfusion below the viability threshold accounted for the largest proportion (mean, 70%) of the final infarct, whereas penumbral tissue (18%) and initially sufficiently perfused tissue (12%) were responsible for considerably smaller portions of the final infarct. CONCLUSIONS: These results indicate that early critical flow disturbance leading to rapid cell damage is the predominant cause of infarction, while secondary and delayed pathobiochemical processes in borderline or initially sufficiently perfused regions contribute only little to the final infarct. Therefore, emerging therapeutic strategies should be targeted to the initially critically perfused tissue subcompartments. Clinical drug trials might benefit from stratification of patients for target tissue compartments applying functional imaging.     

Assessment of additional endpoints for trials in acute stroke - what, when, where, in who?

Functional outcome in acute stroke trials among others is usually measured on the modified Rankin Scale. However, new onset of depression, cognitive decline, and communication deficits alone or in combination affect more than 25% of patients. This report summarizes the findings and conclusions of a workshop by the European Stroke Organization held in February 2011 We propose that assessment of mood disorders, cognitive impairment/dementia, language or communication dysfunction, and quality of life should supplement outcome measures after acute stroke.     

Randomised controlled monotherapy trials: which comparators to use?

As approximately 50% of patients with newly diagnosed epilepsy achieve seizure remission after initial monotherapy, the selection of the first-choice drug to be used as the gold standard in randomised clinical trials is critical. Several first and second generation drugs have been used in regulatory and pragmatic monotherapy trials with similar efficacy but differing pharmacokinetic, tolerability, and safety profiles. None of the available compounds has an ideal profile and second generation drugs do not appear to present unequivocal advantages in this regard. Compared to first generation drugs, some newer generation antiepileptic drugs may be preferred as they have similar efficacy but lower potential for idiosyncratic reactions and drug interactions. However, more recent antiepileptic drugs also have limitations, which include lack of superiority and, in some cases, unbearable adverse effects. In this light, there are no standard criteria as a reference for the selection of the best comparator for new monotherapy trials. However, according to the recommendations of evidence-based guidelines, carbamazepine still represents the first-choice drug for patients with partial epilepsy. Ethosuximide may be an option for absence epilepsy. In contrast, for the treatment of patients with other generalised epilepsies, there is no clear indication of preferred drug, as valproate, which has been found to prevail over other compounds, should be withheld in women of childbearing age due to its teratogenic potential, and there is insufficient evidence to choose an alternative drug.     

Use of antiplatelet agents to prevent stroke: What is the role for combinations of medications?

Antiplatelet agents are the medications of choice for preventing non-cardioembolic strokes. The diverse pathways involved in platelet function suggest the possibility of synergistic effects by combining various agents. In heart disease and in the setting of coronary artery stents, antiplatelet therapy with clopidogrel and aspirin has established benefits. Although it is tempting to extrapolate the benefits of this combination for stroke prevention, recent clinical trials have not borne this out. Unacceptable bleeding risks without additional efficacy weigh against the routine use of clopidogrel with aspirin for stroke prophylaxis. The combination of aspirin and extended-release dipyridamole has demonstrated superiority over aspirin in two large secondary stroke prevention trials.     

The affect-regulation function of nonsuicidal self-injury in eating-disordered patients: which affect states are regulated?

This study examines the affect regulation function of different types of nonsuicidal self-injury (NSSI) in 177 female eating-disordered inpatients. Almost 45% of the eating-disordered patients displayed at least 1 type of NSSI. Cutting and scratching were the most common forms of NSSI followed by bruising and burning oneself. For all types of NSSI except bruising, the affect regulation function was most strongly endorsed. Affect states reported to precede and follow NSSI were also examined to determine the particular affect states regulated by NSSI. In general, positively valenced low-arousal affect states increased and negatively valenced high-arousal affect states decreased from before to after NSSI. Finally, affective changes associated with NSSI were related to different NSSI characteristics, indicating that the increase in positive affect after NSSI is significantly related to the frequency of NSSI and the numbers of functions reported for NSSI. Theoretical and treatment implications are discussed.     

How representative of everyday clinical populations are schizophrenia patients enrolled in clinical trials?

INTRODUCTION: There has been considerable discussion whether clinical trials accurately depict everyday practice. Restrictive inclusion/exclusion criteria, ethical considerations, differences in the severity of psychopathology between clinical and trial patients, or safety issues may bias results, which in turn may rather represent outcome for the "ideal" than for the "average"patient. Therefore, translation into psychiatric practice may be difficult. METHODS: A retrospective case-control study was performed. Schizophrenia inpatients at the LMU Department of Psychiatry, Munich, Germany, who had participated in clinical trials were compared to regular patients serving as controls. Probands and controls were matched by DSM-IV diagnosis, gender and age. The AMDP module, CGI and GAF were used to compare psychopathology. In addition, charts were reviewed for medication dosages, concurrent medical and neurological illness, and clinical history such as age of onset or family history. RESULTS: A total of 200 probands (100/100) were enrolled in the study. With respect to psychopathology, formally thought disordered or suicidal patients were significantly less likely to be study participants (n = 3) than controls (n = 22; p < or = 0.05). Similarly, negative schizophrenia symptoms were significantly less often present in study participants (n = 17) than in controls (n = 38; p < or = 0.05). Study participants were also medically and neurologically healthier than controls. (p = 0.05 respectively). No differences in overall illness severity as depicted by CGI and GAF were observed. CONCLUSION: We found the patients included in our clinical trials representative of the patient encountered in routine clinical practice. Adherence to inclusion and exclusion criteria prevents inclusion of severely ill (e. g. suicidal) patients requiring a more intensive treatment setting. Illness severity was found to be similar in trial participants and controls, and indicates an overall comparably severe psychopathology. The more chronic, rather treatment refractory patients were also not reflected in the trial participant pool; this population may arguably not represent the average clinical patient either. A more careful administration of antipsychotic medication was found in trial participants and may effectively be considered "good clinical practice".     

Acute stroke trials: the problems of local investigators?

During stroke trials local investigators have to face many practical problems and time consuming procedures (filling in huge case report forms, performing repeat blood sample drawings for pharmacokinetic studies etc.) which, however, simply require organizational structures which is understood to be necessary to be able to conduct such kind of studies. Other, and most worrisome problems, are indeed to be solved when a sponsored research may rise potential ethical issues, or when academic research proposals clash with the interest of pharmaceutical companies or find difficulties in being funded by public institutions. It is just a greater involvement of these latter, possibly free from bureaucratic laces, which might help a balance to be struck between academic and industrial aims.