Characteristics and outcomes of intracerebral hemorrhage in a population-based stroke registry

Background. Intracerebral hemorrhage (ICH) is the most severe stroke type. Understanding the epidemiology and pathogenesis of ICH is key to design adequate prevention and treatment strategies to improve the dismal prognosis of ICH. Methods. We performed a prospective population-based study in the district of L’Aquila covering the years 2011-2019. ICH incidence, 30-day and 1-year and case-fatality rates (CFRs) were computed in patients residing in the district and suffering a first-ever ICH over the 2011-2017 period (incidence dataset). All the other assessments were performed in residents of the district reporting either a first-ever ICH or an ICH after a stroke during the 2011-2019 period (full dataset). Cases were actively monitored from multiple sources. We classified ICH according to the SMASH-U system. ICH volumes were calculated using the ABC/2 method. The presence of radiological Edinburgh criteria, including associated subarachnoid hemorrhage (aSAH) and finger-like projections (FLPs) was assessed on the first available brain CT of patients with lobar ICH. Crude incidence rates were calculated assuming a Poisson distribution. Incidence rates were also standardized to the European population using the direct method. Univariate comparisons were performed using the chi-square test, t test, ANOVA, Mann-Whitney or Kruskal-Wallis tests, as appropriate. Logistic regression or Cox regression models were used to perform multivariate analyses. Results. We identified 645 patients with ICH (full dataset; 58.6% men; mean age 75.3±13.4 years). The incidence dataset included 514 patients. The crude ICH incidence rate was 24.6 per 100,000 person-years (95% confidence interval [CI] 22.5-26.8); the corresponding rate was 19.4 per 100,000 person-years (95% CI 17.9-20.9) after standardization to the European population. Case-fatality rates were 36.0% at 30 days and 44.6% at 1-year. Compared with the 567 patients with a first-ever ICH, the 78 patients with ICH after a stroke had a higher pre-stroke disability (median modified Rankin Scale score 2, interquartile range [IQR] 1-3, vs 1, IQR 0-2; P<0.001) and higher ICH volume at onset (median 20 cm3, IQR 3-53, vs 8, IQR 2-25; P=0.004), but not higher case-fatality rate. The 34 patients with ICH after hemorrhagic stroke had a higher proportion of lobar location compared with the 44 patients with ICH after ischemic stroke (79.4% vs 40.9%; P=0.009). According to the SMASH-U classification, 39 patients (6.0%) had an ICH attributable to structural lesions, 74 (11.5%) to medication, 41 (6.4%) to systemic or other disease, 217 (33.6%) to amyloid angiopathy, 235 (36.4%) to hypertensive angiopathy, and 39 (6.0%) to undetermined cause. ICH attributable to medication was the only category which independently predicted 30-day (hazard ratio 1.78, 95% CI 1.18-2.67; P=0.006) and 1-year case-fatality (hazard ratio 1.50, 95% CI 1.02-2.19; P=0.038). We included 259 patients with lobar ICH; 87 (33.6%) had both the Edinburgh CT criteria for the classification of probable amyloid angiopathy, i.e. aSAH+FLPs, while 77 (29.7%) had only one and 95 (25.6%) none of the criteria. Patients with aSAH+FLPs also had more severe ICH at onset, higher 30-day (log rank test P=0.009) and 1-year case-fatality (log rank test P=0.003), and higher mRS scores at discharge (P<0.001) as compared to those fulfilling one or none of the Edinburgh criteria. However, the Edinburgh criteria were not independent predictors of case-fatality. Conclusions. In our population-based study, the incidence and outcomes of first-ever ICH were comparable to those reported in similar studies. Applying a classification tool to patients with ICH identified patient categories with different prognosis; however, only ICH attributable to anticoagulant medication was an independent predictor of ICH case-fatality. Besides, the available classification tools are limited by the coexistence of several etiologic factors in the same patient

Male and female sex hormones in primary headaches

Background: The three primary headaches, tension-type headache, migraine and cluster headache, occur in both genders, but all seem to have a sex-specific prevalence. These gender differences suggest that both male and female sex hormones could have an influence on the course of primary headaches. This review aims to summarise the most relevant and recent literature on this topic. Methods: Two independent reviewers searched PUBMED in a systematic manner. Search strings were composed using the terms LH, FSH, progesteron, estrogen, DHEA, prolactin, testosterone, androgen, headach, migrain, "tension type" or cluster. A timeframe was set limiting the search to articles published in the last 20 years, after January 1st 1997. Results: Migraine tends to follow a classic temporal pattern throughout a woman's life corresponding to the fluctuation of estrogen in the different reproductive stages. The estrogen withdrawal hypothesis forms the basis for most of the assumptions made on this behalf. The role of other hormones as well as the importance of sex hormones in other primary headaches is far less studied. Conclusion: The available literature mainly covers the role of sex hormones in migraine in women. Detailed studies especially in the elderly of both sexes and in cluster headache and tension-type headache are warranted to fully elucidate the role of these hormones in all primary headaches

Patterns of Migraine in Postmenopausal Women: A Systematic Review

Introduction: Migraine prevalence is higher in fertile than in postmenopausal women. However, few literature data are available on the prevalence and characteristics of migraine after the menopause and on the effect of hormones in postmenopausal women with migraine.Methods: We performed a systematic literature review of studies available on Scopus and Web of Science from the beginning off indexing until October 18th, 2020. We included both randomized trials and observational studies.Results: We included 12 papers, six of which assessed the prevalence and characteristics of migraine in postmenopausal women, while the other six assessed the effect of hormones on migraine after the menopause. One of the studies was a randomized trial, while the remaining 11 were observational studies. Ten studies were clinic-based, while the remaining two were population-based. Studies assessing the prevalence and characteristics of migraine after the menopause reported inconsistent findings; in studies performed in headache clinics, likely affected by selection bias towards the most severe cases, a relevant proportion of women reported migraine worsening after the menopause. Studies assessing the effect of hormones on migraine after the menopause showed that postmenopausal hormone replacement therapy was invariably associated with migraine worsening, if containing estrogen.Conclusion: Our systematic review showed that migraine could be a relevant health problem in postmenopausal women, mostly in headache clinics. However, the available studies allow a limited assessment of the prevalence and characteristics of postmenopausal migraine. Further large studies are needed to better determine the burden of migraine after the menopause according to migraine characteristics and the impact of hormonal treatments

Development and validation of the ID-EC - The ITALIAN version of the identify chronic migraine

Background: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting. Methods: The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (self-diagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version. Results: We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity. Conclusions: Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid case-finding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings

Prevention and treatment of ischaemic and haemorrhagic stroke in people with diabetes mellitus: a focus on glucose control and comorbidities

Diabetes mellitus is a significant risk factor for both ischaemic and haemorrhagic stroke, affecting up to a third of individuals with cerebrovascular diseases. Beyond being a risk factor for stroke, diabetes and hyperglycaemia have a negative impact on outcomes after ischaemic and haemorrhagic stroke. Hyperglycaemia during the acute ischaemic stroke phase is associated with a higher risk of haemorrhagic transformation and poor functional outcome, with evidence in favour of early intervention to limit and manage severe hyperglycaemia. Similarly, intensive glucose control nested in a broader bundle of care, including blood pressure, coagulation and temperature control, can provide substantial benefit for clinical outcomes after haemorrhagic stroke. As micro- and macrovascular complications are frequent in people with diabetes, cardiovascular prevention strategies also need to consider tailored treatment. In this regard, the broader availability of sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists can allow tailored treatments, particularly for those with heart failure and chronic kidney disease as comorbidities. Here, we review the main concepts of hyperacute stroke management and CVD prevention among people with diabetes, capitalising on results from large studies and RCTs to inform clinicians on preferred treatments. Graphical Abstract

Effectiveness of Transcranial Direct Current Stimulation and Monoclonal Antibodies Acting on the CGRP as a Combined Treatment for Migraine (TACTIC): Protocol for a Randomized, Double-Blind, Sham-Controlled Trial

BACKGROUND: Migraine is a recurrent headache disorder that has a still unclear pathophysiology, involving several circuits of both the central and peripheral nervous system. Monoclonal antibodies acting on the calcitonin gene-related (CGRP) pathway (CGRP-MAbs) are the first drugs specifically designed for migraine; those drugs act peripherally on the trigeminal ganglion without entering the blood-brain barrier. Conversely, neuromodulation techniques such as transcranial direct current stimulation (tDCS) act centrally by increasing or decreasing the neuronal firing rate of brain cortical areas. The aim of the study will be to evaluate whether tDCS, in addition to CGRP-MAbs, is an effective add-on treatment in reducing headache frequency, intensity and acute medication use in patients with migraine. To demonstrate the biological effects of tDCS, the electroencephalographic (EEG) power changes after tDCS will be assessed. METHODS: We will include patients with migraine on treatment with CGRP-MAbs and reporting ≥8 monthly migraine days. During a prospective 28-day baseline period, patients will fill in a headache diary and questionnaires to evaluate migraine-related disability, anxiety and depressive symptoms, sleep quality, and health-related quality of life. Subjects will be randomly assigned in a 1:1 ratio to active or sham tDCS. The stimulation protocol will consist in five daily sessions, the cathodes will be applied bilaterally above the occipital areas, with the reference anode electrodes positioned above the primary motor areas. Before the first, and immediately after the last stimulation session, patients will perform a 10-min resting EEG recording. During a 28-day follow-up period following tDCS, patients will have to fill in a headache diary and questionnaires identical to those of the baseline period. DISCUSSION: This trial will evaluate the efficacy of an add-on treatment acting on the brain in patients with migraine, who are already treated with peripherally acting drugs, showing how tDCS acts in restoring the dysfunctional brain networks typical of the migraine patient. CLINICAL TRIAL REGISTRATION: NCT05161871

A call for academic pragmatic clinical trials to address open questions in migraine prevention

: The migraine treatment landscape has seen significant advancements in recent years, including the introduction of novel preventive agents specifically targeting the disease. These new treatments offer improved efficacy and tolerability, potentially addressing the issue of poor treatment adherence commonly observed with conventional preventatives. In this context, pragmatic trials emerge as a critical tool for advancing migraine care, offering a real-world approach to evaluating open clinical questions at the same time as avoiding the biases of real-world observational evidence. By prioritizing external validity and patient-centered outcomes, pragmatic trials provide valuable insights into the advantages of new treatments in improving migraine care. Possible applications of pragmatic trials in migraine research include head-to-head comparisons, evaluation of combination therapies, assessment of treatment sequences and switch, testing the added value of patient-reported outcomes, investigation of long-term effectiveness and on optimal treatment duration, understanding the role of preventive treatments in altering the course of migraine and preventing progression, and cost-effectiveness analyses. Pragmatic trials allow for the assessment of interventions in diverse patient populations and healthcare settings, enhancing the generalizability of findings and informing evidence-based clinical practice. As such, pragmatic trials represent an excellent tool to bridge the gap between placebo-controlled trials and real-world practice and should receive consideration for funding, especially by public institutions such as universities, national health services, and charities

Applying a biopsychosocial model to migraine: rationale and clinical implications

Migraine is a complex condition in which genetic predisposition interacts with other biological and environmental factors determining its course. A hyperresponsive brain cortex, peripheral and central alterations in pain processing, and comorbidities play a role from an individual biological standpoint. Besides, dysfunctional psychological mechanisms, social and lifestyle factors may intervene and impact on the clinical phenotype of the disease, promote its transformation from episodic into chronic migraine and may increase migraine-related disability.Thus, given the multifactorial origin of the condition, the application of a biopsychosocial approach in the management of migraine could favor therapeutic success. While in chronic pain conditions the biopsychosocial approach is already a mainstay of treatment, in migraine the biomedical approach is still dominant. It is instead advisable to carefully consider the individual with migraine as a whole, in order to plan a tailored treatment. In this review, we first reported an analytical and critical discussion of the biological, psychological, and social factors involved in migraine. Then, we addressed the management implications of the application of a biopsychosocial model discussing how the integration between non-pharmacological management and conventional biomedical treatment may provide advantages to migraine care

Acute Medication Use in Patients With Migraine Treated With Monoclonal Antibodies Acting on the CGRP Pathway: Results From a Multicenter Study and Proposal of a New Index

Introduction: Assessing the impact of migraine preventive treatments on acute medication consumption is important in clinical evaluation. The number of acute medication intakes per each monthly migraine day (MMD) could provide insights on migraine burden and represent a new proxy of treatment effectiveness in clinical trials and real-life studies. We evaluated the effect of monoclonal antibodies acting on calcitonin gene-related peptide (CGRP) pathway on the consumption of migraine acute medication in real-life. Methods: In two headache centers in Prague (CZ), we included and followed up to 6 months consecutive patients treated with MoAbs acting on CGRP (erenumab or fremanezumab). For each month of treatment, we reported monthly drug intake (MDI) in doses of any medication, migraine-specific (MS), and non-migraine-specific (non-MS) medications, and computed a ratio between MMDs and MDI, i.e., Migraine Medication Index (MMI) for MS and non-MS medications. Results: We included 90 patients (91.1% women) with a median age of 47 [interquartile range (IQR) 42-51] years; 81 (90.0%) treated with erenumab and 9 (10.0%) with fremanezumab. Median MMDs decreased from 11 (IQR 8-14) at baseline to 4 (IQR 2-5) at Month 3 (p &lt; 0.001 vs. baseline) and 3 (IQR 2-6) at Month 6 (p &lt; 0.001 vs. baseline). Median MDI decreased from 15 drug intakes (IQR 11-20) at baseline to four drug intakes (IQR 2-7) at Month 3 (p &lt; 0.001) and four drug intakes (IQR 2-7) at Month 6 (p &lt; 0.001).The corresponding MDIs for MS medications were 10 (IQR 6-14) at baseline, 3 (IQR 1-5, p &lt; 0.001) at Month 3, and 2 (IQR 0-4, p &lt; 0.001) at Month 6. Monthly drug intakes for non-MS medications were 4 (IQR 0-9) at baseline, 1 (IQR 0-3, p &lt; 0.001) at Month 3 and at Month 6.Median MMI decreased from 1.32 (IQR 1.11-1.68) at baseline to 1.00 (IQR 1.00-1.50, p &lt; 0.001) at Month 3 and 1.00 (IQR 1.00-1.34, p &lt; 0.001) at Month 6. Conclusions: We confirmed that MoAbs acting on CGRP pathway decrease acute migraine medication consumption. We proposed a new index that can be easily applied in clinical practice to quantify migraine burden and its response to acute medication. Our index could help optimizing migraine acute treatment in clinical practice