Case-Fatality and Functional Outcome after Subarachnoid Hemorrhage (SAH) in INternational STRoke oUtComes sTudy (INSTRUCT).

BACKGROUND: There are few large population-based studies of outcomes after subarachnoid hemorrhage (SAH) than other stroke types. METHODS: We pooled data from 13 population-based stroke incidence studies (10 studies from the INternational STRroke oUtComes sTudy (INSTRUCT) and 3 new studies; N=657). Primary outcomes were case-fatality and functional outcome (modified Rankin scale score 3-5 [poor] vs. 0-2 [good]). Harmonized patient-level factors included age, sex, health behaviours (e.g. current smoking at baseline), comorbidities (e.g.history of hypertension), baseline stroke severity (e.g. NIHSS >7) and year of stroke. We estimated predictors of case-fatality and functional outcome using Poisson regression and generalized estimating equations using log-binomial models respectively at multiple timepoints. RESULTS: Case-fatality rate was 33% at 1 month, 43% at 1 year, and 47% at 5 years. Poor functional outcome was present in 27% of survivors at 1 month and 15% at 1 year. In multivariable analysis, predictors of death at 1-month were age (per decade increase MRR 1.14 [1.07-1.22]) and SAH severity (MRR 1.87 [1.50-2.33]); at 1 year were age (MRR 1.53 [1.34-1.56]), current smoking (MRR 1.82 [1.20-2.72]) and SAH severity (MRR 3.00 [2.06-4.33]) and; at 5 years were age (MRR 1.63 [1.45-1.84]), current smoking (MRR 2.29 [1.54-3.46]) and severity of SAH (MRR 2.10 [1.44-3.05]). Predictors of poor functional outcome at 1 month were age (per decade increase RR 1.32 [1.11-1.56]) and SAH severity (RR 1.85 [1.06-3.23]), and SAH severity (RR 7.09 [3.17-15.85]) at 1 year. CONCLUSION: Although age is a non-modifiable risk factor for poor outcomes after SAH, however, severity of SAH and smoking are potential targets to improve the outcomes.

Thrombophilic alterations, migraine, and vascular disease: results from a case-control study.

BACKGROUND: The association between thrombophilic alterations, migraine, and vascular events has been broadly investigated but not been completely clarified. METHODS: In this cross-sectional, case-control study, we included consecutive outpatients diagnosed with migraine referring to a tertiary headache center. Migraine patients were matched to headache-free control subjects. All participants were evaluated for free protein S anticoagulant, functional protein C anticoagulant, homocysteine, and antiphospholipid antibodies (aPLs). History of ischemic stroke (IS) or transient ischemic attack (TIA), coronary heart disease, and peripheral venous thrombosis was also ascertained. RESULTS: We included 329 migraine patients and 329 control subjects (mean age 41 years, 77% women in both groups). Among migraine patients, 239 (72.6%) had migraine without aura and 90 (27.4%) had migraine with aura. Migraine patients had more frequently arterial hypertension, hypercholesterolemia, history of IS or TIA and, peripheral venous thrombosis compared to control subjects, whereas we found no differences in diabetes mellitus, BMI, and coronary heart disease between the two groups. At least one thrombophilic alteration was detected in 107 (32.5%) migraine patients and in 74 (22.5%) control subjects (OR = 1.66, 95% CI 1.17-2.35, p = 0.004). We identified an association of migraine with aPL positivity (OR = 2.6, 95% CI 1.5-4.7, p = 0.001) and with free protein S deficiency (OR = 4.7, 95% CI 1.6-14.0, p = 0.002), whereas we found no differences in protein C deficiency, APCR, and hyperhomocysteinemia between the two groups. Furthermore, aPL positivity and free protein S deficiency were more common in migraine patients with and without aura than in control subjects. We found that in migraine patients, aPL positivity was associated with both IS or TIA (OR = 5.6, 95% CI 1.5-20.4, p = 0.009) and with coronary heart disease (OR = 27.6, 95% CI 1.4-531.1, p = 0.028), whereas free protein S deficiency was associated with IS or TIA only (OR = 14.3, 95% CI 2.8-74.4, p = 0.002). CONCLUSIONS: Our research documented a significative higher prevalence of aPL positivity and protein S deficiency in migraineurs than in controls. Data also showed an association between these alterations and some vascular thrombotic events in migraine patients. We can argue that thrombophilic disorders associated with migraine may contribute to the occurrence of vascular events.

Functional connectivity studies in migraine: what have we learned?

BACKGROUND: Resting-state functional connectivity (FC) MRI has widely been used to understand migraine pathophysiology and to identify an imaging marker of the disorder. Here, we review what we have learned from FC studies. METHODS: We performed a literature search on the PubMed website for original articles reporting data obtained from conventional resting-state FC recording in migraine patients compared with healthy controls or during and outside of migraine attacks in the same patients. RESULTS: We found 219 articles and included 28 in this review after screening for inclusion and exclusion criteria. Twenty-five studies compared migraine patients with healthy controls, whereas three studies investigated migraine patients during and outside of attacks. In the studies of interictal migraine more alterations of more than 20 FC networks (including amygdala, caudate nucleus, central executive, cerebellum, cuneus, dorsal attention network, default mode, executive control, fronto-parietal, hypothalamus, insula, neostriatum, nucleus accumbens, occipital lobe, periaqueductal grey, prefrontal cortex, salience, somatosensory cortex I, thalamus and visual) were reported. We found a poor level of reproducibility and no migraine specific pattern across these studies. CONCLUSION: Based on the findings in the present review, it seems very difficult to extract knowledge of migraine pathophysiology or to identify a biomarker of migraine. There is an unmet need of guidelines for resting-state FC studies in migraine, which promote the use of homogenous terminology, public availability of protocol and the a priori hypothesis in line with for instance randomized clinical trial guidelines.

Distribution and Temporal Trends From 1993 to 2015 of Ischemic Stroke Subtypes: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Preventive strategies, together with demographic and socioeconomic changes, might have modified the worldwide distribution of ischemic stroke (IS) subtypes. We investigated those changes by means of a systematic review and meta-analysis. METHODS: We evaluated all population- and hospital-based studies reporting the distribution of IS etiologic subtypes according to the TOAST criteria (Trial of ORG 10172 in Acute Stroke Treatment). Studies were identified by searching articles indexed on PubMed and Scopus from January 1, 1993, to June 30, 2017. Two independent investigators extracted data and checked them for accuracy. Proportions of each etiologic subtype were pooled according to a random effect meta-analytic model weighted by study size; temporal trends were assessed using a mixed-effect meta-regression model. RESULTS: Sixty-five studies including patients from 1993 to 2015 were finally included. Overall, ISs were attributed to cardioembolism (22%; 95% confidence interval [CI], 20-23); large artery atherosclerosis (23%; 95% CI, 21-25); small artery occlusion (22%; 95% CI, 21-24); other determined cause (3%; 95% CI, 3-3); and undetermined cause (26%; 95% CI, 24-28). Cardioembolism was the leading IS etiologic subtype in whites (28%; 95% CI, 26-29) and large artery atherosclerosis in Asians (33%; 95% CI, 31-36). Meta-regression showed an increasing temporal trend for cardioembolism in whites (2.4% annually, P=0.008) and large artery atherosclerosis in Asians (5.7% annually, P<0.001), and a decrease for small artery occlusion in whites (-4.7% annually, P=0.001); there was considerable heterogeneity across all the analyses. CONCLUSIONS: According to our systematic review and meta-analysis, cardioembolism in whites and large artery atherosclerosis in Asians are the leading causes of IS. The heterogeneous distribution of etiologic subtypes of IS may depend on the demographic and socioeconomic characteristics of the different populations. More extensive protocols should be adopted to reduce the persistently relevant proportion of undetermined cause IS.

The Role of Inflammation in Neurological Disorders.

Traditionally neurological diseases have been classified, on the basis of their pathogenesis, into vascular, degenerative, inflammatory and traumatic diseases. Examples of the main inflammatory neurological diseases include multiple sclerosis, which is characterized by an immune-mediated response against myelin proteins, and meningoencephalitis, where the inflammatory response is triggered by infectious agents. However, recent evidence suggests a potential role of inflammatory mechanisms also in neurological conditions not usually categorized as inflammatory, such as Alzheimer's disease, Parkinson's disease, Huntington' disease, amyotrophic lateral sclerosis, stroke and traumatic brain injuries. The activation of glial cells and of complement-mediated pathways, the synthesis of inflammation mediators, and the recruitment of leukocytes are the key elements of secondary inflammatory injury following a wide spectrum of primary brain injuries. A better understanding of the role that inflammatory processes play in the natural history of diseases is essential in order to identify potential therapeutic targets and to develop integrated pharmacological approaches acting at different levels and stages of the diseases.

Acute motor axonal neuropathy and transverse myelitis overlap: the importance of history taking.

In young adults, acute motor axonal neuropathy and transverse myelitis rarely occur as associated conditions. Clinical reasoning, symptoms, laboratory and ancillary investigations (electroneurographic and radiological findings), should properly address the physician to the correct diagnosis.

Epidemiology of Transient Ischemic Attacks Using Time- or Tissue-Based Definitions: A Population-Based Study.

BACKGROUND AND PURPOSE: Transient ischemic attack (TIA) epidemiology may have changed in recent years as a consequence of improved identification and treatment of vascular risk factors. Our aim was to provide updated information about TIA epidemiology in Italy. METHODS: Cases of first-ever TIA were ascertained from January 1, 2011, until December 31, 2012, in a population-based prospective registry. All residents in the L'Aquila district with an incident TIA were included and followed up to 2 years after the event. Outcome events were recurrent TIA, nonfatal and fatal stroke, nonfatal and fatal myocardial infarction, and all-cause mortality. RESULTS: A total of 210 patients with a TIA according to the traditional time-based definition were included (51.4% women); 151 patients (71.9%) with transient symptoms and negative brain neuroimaging were broadly considered as tissue-based TIA, 29 patients (13.8%) had transient symptoms and evidence of a congruous acute ischemic lesion, and 30 patients (14.3%) had an acute neurovascular syndrome. The crude annual incidence rate for traditional time-based TIA was 35.2 per 100 000 (95% confidence interval, 30.6-40.3) and 28.6 per 100 000 (95% confidence interval, 24.1-33.5) when standardized to the 2011 European population. The incidence peaked in subjects aged ≥85 years, in both sexes. At 2 years, outcome events occurred in 50 patients (23.8%) including 15 patients (7.1%) with nonfatal or fatal strokes. CONCLUSIONS: Our population-based study found a low annual TIA incidence rate and a fair TIA prognosis confirming the effectiveness of preventive strategies for cardiovascular diseases. We also proved the nonfitting applicability of the tissue-based definition in our district.

Composite Scores and Other Outcome Measures in Stroke Trials.

BACKGROUND: Randomized controlled trials represent the most useful tool to evaluate the effectiveness of a treatment in medical research. When designing a clinical trial, the choice of end points, assessment tools, and scores is crucial as they represent the prerequisites for the evaluation of outcomes and for the critical appraisal of findings. SUMMARY: In stroke research, outcomes are mainly represented by composite end points focusing on the occurrence of cardiovascular and cerebrovascular events in trials on primary and secondary prevention and by measures of recovery and residual disability in acute stroke trials. Assessment tools which are more frequently used to evaluate recovery after acute stroke care include the National Institutes of Health Stroke Scale, the Modified Rankin Scale, the Barthel Index, the Glasgow Outcome Scale, and the Stroke Impact Scale. However, there is a wide heterogeneity of outcome measures across different trials, which makes it difficult to compare results and to draw definitive conclusions on the usefulness of the investigated strategies and treatments. Moreover, in some cases, details about outcomes are poorly reported with a tendency to focus on outcomes that are statistically significant while information about nonsignificant outcomes is frequently missed. KEY MESSAGES: There is an urgent need to improve the quality of designing, conducting, analyzing, and reporting data from randomized clinical trials in order to obtain complete, clear, and rigorous information on the effectiveness of management strategies in stroke care. Key properties of tools measuring outcome should include validity, reliability, and convenient statistical characteristics.

The Epidemiology of Atrial Fibrillation and Stroke.

The burden of stroke is increasing due to aging population and unhealthy lifestyle habits. The considerable rise in atrial fibrillation (AF) is due to greater diffusion of risk factors and screening programs. The link between AF and ischemic stroke is strong. The subtype most commonly associated with AF is cardioembolic stroke, which is particularly severe and shows the highest rates of mortality and permanent disability. A trend toward a higher prevalence of cardioembolic stroke in high-income countries is probably due to the greater diffusion of AF and the control of atherosclerotic of risk factors.

Hypertension and Stroke: Epidemiological Aspects and Clinical Evaluation.

The strong relationship between stroke and hypertension has been the object of several studies and trials. These studies addressed the epidemiology of stroke and hypertension, in order to estimate their worldwide distribution and time evolution, and investigated the effects of the management of hypertension on stroke outcomes. Evidences coming from these studies are essential to plan proper health services, optimise economic resources, and estimate the effectiveness of therapeutic strategies in primary and secondary prevention. Additional suggestions are needed to tailor the pharmacologic management of hypertension on the individual needs of patients and to select the most appropriate treatment to avoid stroke recurrences on the basis of the first-ever stroke subtype. Moreover, an increasing attention has been given, over the last years, to the relationship between the presence of hypertension and the development of an end-organ brain damage leading to early cognitive dysfunctions. A better understanding of this relationship is the prerequisite to promote successful aging and well-being.

Migraine in menopausal women: a systematic review.

Evidence suggests that migraine activity is influenced by hormonal factors, and particularly by estrogen levels, but relatively few studies have investigated the prevalence and characteristics of migraine according to the menopausal status. Overall, population-based studies have shown an improvement of migraine after menopause, with a possible increase in perimenopause. On the contrary, the studies performed on patients referring to headache centers have shown no improvement or even worsening of migraine. Menopause etiology may play a role in migraine evolution during the menopausal period, with migraine improvement more likely occurring after spontaneous rather than after surgical menopause. Postmenopausal hormone replacement therapy has been found to be associated with migraine worsening in observational population-based studies. The effects of several therapeutic regimens on migraine has also been investigated, leading to nonconclusive results. To date, no specific preventive measures are recommended for menopausal women with migraine. There is a need for further research in order to clarify the relationship between migraine and hormonal changes in women, and to quantify the real burden of migraine after the menopause. Hormonal manipulation for the treatment of refractory postmenopausal migraine is still a matter of debate.

Migraine and body mass index categories: a systematic review and meta-analysis of observational studies.

BACKGROUND: Several studies have assessed the associations between migraine and underweight, pre-obesity or obesity, with conflicting results. To assess the consistency of the data on the topic, we performed a systematic review and meta-analysis of the available observational studies. METHODS: Multiple electronic databases were systematically searched up to October 2014 for studies assessing the association between migraine and body mass index categories (underweight, pre-obesity, or obesity). RESULTS: Out of 2,022 records, we included 15 studies. When considering the 11 studies following the World Health Organization BMI cutoffs, we found an increased risk of having migraine in underweight subjects (pooled adjusted effect estimate [PAEE] 1.21; 95% CI, 1.07-1.37; P = 0.002) and in obese women (PAEE 1.44; 95% CI, 1.05-1.97; P = 0.023) as compared with normal weight subjects; additionally, pre-obese subjects had an increased risk of having chronic migraine (PAEE 1.39; 95% CI, 1.13-1.71; P = 0.002). When considering all the 15 studies, we additionally found an increased risk of having migraine in obese as compared with normal weight subjects (PAEE 1.14; 95% CI, 1.02-1.27; P = 0.017); additionally, obese subjects had an increased risk of having chronic migraine (PAEE 1.75; 95% CI, 1.33-2.29; P < 0.001). The pooled analysis did not indicate an increased risk of having migraine in pre-obese subjects. CONCLUSIONS: The meta-analysis of the available observational studies suggested an association between migraine and obesity likely mediated by gender and migraine frequency. Further studies taking into account gender, migraine type, frequency, activity, and duration could provide more robust evidence.

Conventional vascular risk factors: their role in the association between migraine and cardiovascular diseases.

INTRODUCTION: Migraine, in particular migraine with aura, has been found to be associated with cardiovascular disease. However, the role of conventional vascular risk factors in the association is still debated. The aim of the present review is to address the association between migraine and conventional cardiovascular risk factors as well as to address their possible role in the association between migraine and cardiovascular disease. METHODS: Data for this review were obtained through searches in multiple sources up to May 2014 using the terms "migraine" OR "headache" in combination with all the vascular risk factors of interest. RESULTS: Data about the possible association between migraine and high blood pressure values are heterogeneous, hindering any final conclusion. Data addressing the possible association between migraine and diabetes mellitus indicate the lack of any association or in some cases a negative association between the two conditions. The body of evidence on the role of dyslipidemia in migraineurs is relatively homogeneous and, with few exceptions, reports an association between migraine and an unfavorable lipid profile; however, the difference in lipid levels between migraineurs and non-migraineurs is small and its clinical implication unclear. Regarding obesity, a trend has been observed of increased risk of migraine with increasing obesity, especially in young patients, albeit in the midst of conflicting data. Evidence about the association between cigarette smoking and migraine mostly indicates that migraineurs are more commonly smokers than non-migraineurs. On the other hand, the majority of the available studies report less alcohol use in migraineurs than in non-migraineurs. Finally, many of the available studies suggest a more frequent family history of cardiovascular disease in migraineurs as compared to non-migraineurs. Since most of the studies that supported the association between migraine and cardiovascular disease adjusted the analyses for the presence of several vascular risk factors, they cannot entirely explain this association. CONCLUSIONS: Based on the available reported data, it seems unlikely that the higher risk of cardiovascular disease in migraineurs is mediated by any single vascular risk factor. For this reason the role of specific interactions among risk factors with the contribution of genetic, environmental, personality and psychological factors should be appropriately investigated.

Migraine in women: the role of hormones and their impact on vascular diseases.

Migraine is a predominantly female disorder. Menarche, menstruation, pregnancy, and menopause, and also the use of hormonal contraceptives and hormone replacement treatment may influence migraine occurrence. Migraine usually starts after menarche, occurs more frequently in the days just before or during menstruation, and ameliorates during pregnancy and menopause. Those variations are mediated by fluctuation of estrogen levels through their influence on cellular excitability or cerebral vasculature. Moreover, administration of exogenous hormones may cause worsening of migraine as may expose migrainous women to an increased risk of vascular disease. In fact, migraine with aura represents a risk factor for stroke, cardiac disease, and vascular mortality. Studies have shown that administration of combined oral contraceptives to migraineurs may further increase the risk for ischemic stroke. Consequently, in women suffering from migraine with aura caution should be deserved when prescribing combined oral contraceptives.