Reduced Admissions for Cerebrovascular Events during COVID-19 Outbreak in Italy

Background and Purpose: We aimed to investigate the rate of hospital admissions for cerebrovascular events and of revascularization treatments for acute ischemic stroke in Italy during the coronavirus disease 2019 (COVID-19) outbreak. Methods: The Italian Stroke Organization performed a multicenter study involving 93 Italian Stroke Units. We collected information on hospital admissions for cerebrovascular events from March 1 to March 31, 2020 (study period), and from March 1 to March 31, 2019 (control period). Results: Ischemic strokes decreased from 2399 in 2019 to 1810 in 2020, with a corresponding hospitalization rate ratio (RR) of 0.75 ([95% CI, 0.71-0.80] P<0.001); intracerebral hemorrhages decreased from 400 to 322 (hospitalization RR, 0.81 [95% CI, 0.69-0.93]; P=0.004), and transient ischemic attacks decreased from 322 to 196 (hospitalization RR, 0.61 [95% CI, 0.51-0.73]; P<0.001). Hospitalizations decreased in Northern, Central, and Southern Italy. Intravenous thrombolyses decreased from 531 (22.1%) in 2019 to 345 in 2020 (19.1%; RR, 0.86 [95% CI, 0.75-0.99]; P=0.032), while primary endovascular procedures increased in Northern Italy (RR, 1.61 [95% CI, 1.13-2.32]; P=0.008). We found no correlation (P=0.517) between the hospitalization RRs for all strokes or transient ischemic attack and COVID-19 incidence in the different areas. Conclusions: Hospitalizations for stroke or transient ischemic attacks across Italy were reduced during the worst period of the COVID-19 outbreak. Intravenous thrombolytic treatments also decreased, while endovascular treatments remained unchanged and even increased in the area of maximum expression of the outbreak. Limited hospitalization of the less severe patients and delays in hospital admission, due to overcharge of the emergency system by COVID-19 patients, may explain these data

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

OnabotulinumtoxinA: Still the Present for Chronic Migraine

OnabotulinumtoxinA (BT-A) is one of the few drugs approved for the preventive treatment of chronic migraine (CM). Despite this, some aspects of its mechanism of action are still a matter of debate, and the precise magnitude of BT-A effects needs to be completely elucidated. BT-A acts primarily upon trigeminal and cervical nerve endings, by inhibiting the release of inflammatory mediators such as calcitonin gene-related peptide, as well as reducing the insertion of ionotropic and metabotropic receptors into the neuronal membrane. These actions increase the depolarization threshold of trigeminal and cervical nerve fibers, thus reducing their activation. The central actions of BT-A are still a matter of debate: a retrograde axonal transport has been postulated, but not clearly assessed in humans. Clinically, the efficacy of BT-A in CM has been assessed by large, randomized placebo-controlled trials, such as the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials. Those results were also confirmed in a wide range of open-label studies, even for long-term periods. Recently, novel findings have led to a better understanding of its pharmacological actions and clinical usefulness in migraine prevention. This narrative review summarizes, updates and critically revises the available data on BT-A and its possible implementation in chronic migraine. Moreover, the current role of BT-A in CM treatment has been discussed

Headache and pregnancy. a systematic review

This systematic review summarizes the existing data on headache and pregnancy with a scope on clinical headache phenotypes, treatment of headaches in pregnancy and effects of headache medications on the child during pregnancy and breastfeeding, headache related complications, and diagnostics of headache in pregnancy. Headache during pregnancy can be both primary and secondary, and in the last case can be a symptom of a life-threatening condition. The most common secondary headaches are stroke, cerebral venous thrombosis, subarachnoid hemorrhage, pituitary tumor, choriocarcinoma, eclampsia, preeclampsia, idiopathic intracranial hypertension, and reversible cerebral vasoconstriction syndrome. Migraine is a risk factor for pregnancy complications, particularly vascular events. Data regarding other primary headache conditions are still scarce. Early diagnostics of the disease manifested by headache is important for mother and fetus life. It is especially important to identify "red flag symptoms" suggesting that headache is a symptom of a serious disease. In order to exclude a secondary headache additional studies can be necessary: electroencephalography, ultrasound of the vessels of the head and neck, brain MRI and MR angiography with contrast ophthalmoscopy and lumbar puncture. During pregnancy and breastfeeding the preferred therapeutic strategy for the treatment of primary headaches should always be a non-pharmacological one. Treatment should not be postponed as an undermanaged headache can lead to stress, sleep deprivation, depression and poor nutritional intake that in turn can have negative consequences for both mother and baby. Therefore, if non-pharmacological interventions seem inadequate, a well-considered choice should be made concerning the use of medication, taking into account all the benefits and possible risks

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

Is There a Gender Difference in the Response to onabotulinumtoxinA in Chronic Migraine? Insights from a Real-Life European Multicenter Study on 2879 Patients

Migranya crònica; Diferència de gènere; OnabotulinumtoxinAMigraña crónica; Diferencia de género, OnabotulinumtoxinAChronic migraine; Gender difference; OnabotulinumtoxinAIntroduction Migraine is mostly a female disorder because of its lower prevalence in men. Less than 20% of patients included in the available studies on migraine treatments are men; hence, the evidence on migraine treatments might not apply to men. The aims of the present study were to provide reliable information on the effectiveness of onabotulinumtoxinA (BT-A) for chronic migraine in men and to compare clinical benefits between men and women. Methods We performed a pooled patient-level gender-specific analysis of real-life data on BT-A for chronic migraine of patients followed-up to 9 months. We reported the 50% responder rates during each BT-A cycle, defined as percentage of reduction in monthly headache days (MHDs) compared to baseline, along with 75% and 30% responder rates. We also reported the mean decrease in MHDs and in days of acute medication use (DAMs) during each BT-A cycle as compared to baseline. We also evaluated the reasons for stopping the treatment within the third cycle. Results We included an overall cohort of 2879 patients, 522 of whom (18.1%) were men. In men, 50% responder rates were 27.7% during the first BT-A cycle, 29.2% during the second, and 35.6% during the third cycle; in women, the corresponding rates were 26.6%, 33.5%, and 41.0%. In the overall cohort, responder rates did not differ between men and women during the first two cycles; during the third cycle, the distribution was different (P < 0.001) mostly because of higher rates of treatment stopping and non-responders in men. In the propensity score matched cohort, the trend was maintained but lost its statistical significance. Both men and women had a significant decrease in MHDs and in DAMs with BT-A treatment (P < 0.001). There were no gender differences in those changes with the only exception of MHD decrease which, during the third cycle, was lower in men than in women (7.4 vs 8.2 days, P = 0.016 in the overall cohort and 9.1 vs 12.5 days, P = 0.009 in the propensity score matched cohort). At the end of follow-up, 152 men and 485 women stopped BT-A treatment (29.1% vs 20.6%; P < 0.001). The relative proportion of patients stopping treatment because of inadequate response (less than 30% decrease in MHDs from baseline) was higher in men than in women (42.8% vs 39.6%), while the proportion of patients stopping because of adverse events was higher in women than in men (5.6% vs 0%; P = 0.031). Conclusions Our pooled analysis suggests that the response to BT-A is significant in both men and women with a small gender difference in favor of women. Men tended to stop the treatment more frequently than women. We emphasize the need for more gender-specific data on migraine treatments from randomized controlled trials and observational studies.No funding or sponsorship was received for this study or publication of this article

Excellent Response to OnabotulinumtoxinA: Different Definitions, Different Predictors

Chronic migraine; OnabotulinumtoxinA; Predictors of responseMigraña crónica; OnabotulinumtoxinA; Predictores de respuestaMigranya crònica; OnabotulinumtoxinA; Predictors de respostaThe identification of patients who can benefit the most from the available preventive treatments is important in chronic migraine. We explored the rate of excellent responders to onabotulinumtoxinA in a multicenter European study and explored the predictors of such response, according to different definitions. A pooled analysis on chronic migraineurs treated with onabotulinumtoxinA and followed-up for, at least, 9 months was performed. Excellent responders were defined either as patients with a ≥75% decrease in monthly headache days (percent-based excellent responders) or as patients with <4 monthly headache days (frequency-based excellent responders). The characteristics of excellent responders at the baseline were compared with the ones of patients with a <30% decrease in monthly headache days. Percent-based excellent responders represented about 10% of the sample, whilst frequency-based excellent responders were about 5% of the sample. Compared with non-responders, percent-based excellent responders had a higher prevalence of medication overuse and a higher excellent response rate even after the 1st and the 2nd injection. Females were less like to be frequency-based excellent responders. Chronic migraine sufferers without medication overuse and of female sex may find fewer benefits with onabotulinumtoxinA. Additionally, the excellent response status is identifiable after the first cycle

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

Multi-Center Randomized Phase II Clinical Trial on Remote Ischemic Conditioning in Acute Ischemic Stroke Within 9 Hours of Onset in Patients Ineligible to Recanalization Therapies (TRICS-9): Study Design and Protocol

Aim: To assess the efficacy of remote ischemic conditioning (RIC) in patients with ischemic stroke within 9 h of onset, that are not candidates for recanalization therapies.Sample Size Estimates: A sample size of 80 patients (40 in each arm) should yield 80% power to detect a 20% difference in early neurological improvement at 72 h at p = 0.05, two sided.Methods and Design: TRICS-9 is a phase II, multicenter, controlled, block randomized, open-label, interventional clinical trial. Patients recruited in Italian academic hospitals will be randomized 1:1 to either RIC plus standard medical therapy or standard medical therapy alone. After randomization, RIC will be applied manually by four alternating cycles of inflation/deflation 5 min each, using a blood pressure cuff around the non-paretic arm.Study Outcomes: The primary efficacy outcome is early neurological improvement, defined as the percent change in the National Institute of Health Stroke Scale (NIHSS) at 72 h in each arm. Secondary outcomes include early neurologic improvement at 24 and 48 h, disability at 3 months, rate of symptomatic intracerebral hemorrhage, feasibility (proportion of patients completing RIC), tolerability after RIC and at 72 h, blood levels of HIF-1 alpha, and HSP27 at 24 h and 72 h.Discussion/Conclusion: RIC in combination with recanalization therapies appears to add no clinical benefit to patients, but whether it is beneficial to those that are not candidates for recanalization therapies is still to be demonstrated. TRICS-9 has been developed to elucidate this issue