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.

Risk of stroke with different levels of leisure-time physical activity: a systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: Leisure-time physical activity (LTPA) protects against vascular diseases. Whether and to what extent different levels of LTPA, including lower ones, benefit stroke prevention is still unclear. METHODS: We searched prospective cohort studies, indexed on PubMed and Scopus, published in English up to 22 April 2023, that investigated, in a general healthy population, the relationship between different predefined LTPA levels, compared with inactivity, and the risk of any type of stroke. We applied random effect modelling for meta-analyses and meta-regression to control for the impact of age and sex. RESULTS: Out of 3064 screened articles, 15 articles on 16 cohorts of subjects were included in meta-analyses, with a total of 752 050 followed-up subjects. Mean follow-up was 125.7±77.5 months. Included studies identified three (none, below target and ideal) to five (none, insufficient, low, moderate and intense) levels of LTPA. In the five studies identifying three levels of LTPA, compared with no LTPA, below target (risk ratio (RR)=0.82, 95% CI=0.75 to 0.88) and ideal LTPA significantly reduced stroke risk (RR=0.71, 95% CI=0.58 to 0.86).Lower levels of LTPA also mitigated stroke risk in studies reporting on four (n=6; RR=0.73, 95% CI=0.62 to 0.87 favouring moderate LTPA over no LTPA) and five levels (n=2; RR=0.71, 95% CI=0.58 to 0.88 favouring moderate LTPA over no LTPA). The benefits of LTPA were independent of age and sex. CONCLUSIONS: According to our results, all levels of LTPA can be beneficial for stroke prevention, including levels currently regarded as low or insufficient. People should be encouraged to be physically active even at the lowest levels. PROSPERO REGISTRATION NUMBER: CRD42023425302.

Redefining migraine prevention: early treatment with anti-CGRP monoclonal antibodies enhances response in the real world.

BACKGROUND: Anti-CGRP monoclonal antibodies (anti-CGRP MAbs) are approved and available treatments for migraine prevention. Patients do not respond alike and many countries have reimbursement policies, which hinder treatments to those who might respond. This study aimed to investigate clinical factors associated with good and excellent response to anti-CGRP MAbs at 6 months. METHODS: European multicentre, prospective, real-world study, including high-frequency episodic or chronic migraine (CM) patients treated since March 2018 with anti-CGRP MAbs. We defined good and excellent responses as ≥50% and ≥75% reduction in monthly headache days (MHD) at 6 months, respectively. Generalised mixed-effect regression models (GLMMs) were used to identify variables independently associated with treatment response. RESULTS: Of the 5818 included patients, 82.3% were females and the median age was 48.0 (40.0-55.0) years. At baseline, the median of MHD was 20.0 (14.0-28.0) days/months and 72.2% had a diagnosis of CM. At 6 months (n=4963), 56.5% (2804/4963) were good responders and 26.7% (1324/4963) were excellent responders. In the GLMM model, older age (1.08 (95% CI 1.02 to 1.15), p=0.016), the presence of unilateral pain (1.39 (95% CI 1.21 to 1.60), p<0.001), the absence of depression (0.840 (95% CI 0.731 to 0.966), p=0.014), less monthly migraine days (0.923 (95% CI 0.862 to 0.989), p=0.023) and lower Migraine Disability Assessment at baseline (0.874 (95% CI 0.819 to 0.932), p<0.001) were predictors of good response (AUC of 0.648 (95% CI 0.616 to 0.680)). These variables were also significant predictors of excellent response (AUC of 0.691 (95% CI 0.651 to 0.731)). Sex was not significant in the GLMM models. CONCLUSIONS: This is the largest real-world study of migraine patients treated with anti-CGRP MAbs. It provides evidence that higher migraine frequency and greater disability at baseline reduce the likelihood of responding to anti-CGRP MAbs, informing physicians and policy-makers on the need for an earlier treatment in order to offer the best chance of treatment success.

Outcomes of mechanical thrombectomy in acute stroke patients with atrial fibrillation detected after stroke versus known atrial fibrillation.

We aim to compare the outcomes in patients with atrial fibrillation detected after stroke (AFDAS) and their counterparts with known AF (KAF) presenting with large vessel occlusion (LVO) treated with mechanical thrombectomy (MT). This observational, prospective study included consecutive patients with acute LVO ischemic stroke of the anterior circulation with AFDAS, KAF and without AF. The primary study outcome was functional independence at 90 days after stroke. The secondary study outcomes were variation of the NIHSS score at 24 h, rate of successful reperfusion, death at 90 days and rate of immediate complications post-procedure. Overall, our cohort included 518 patients with acute ischemic stroke and LVO treated with MT, with 289 (56.8%) without a diagnosis of AF; 107 (21%) with AFDAS; 122 (22.2%) with KAF. There was no significant difference in terms of functional independence at 90 days after stroke between the three groups. Regarding the secondary study outcome, the rate of symptomatic intracranial haemorrhage (sICH) and/or parenchymal hematoma (PH) were significantly higher in the group of patients without AF (respectively, P = 0.030 and < 0.010). Logistic regression analysis showed that the subtypes of AF were not statistically significantly associated with functional independence at 90 days after stroke and with the likelihood of any ICH. Our results suggest that the subtypes of AF are not associated with clinical and safety outcomes of MT in patients with acute stroke and LVO. Further studies are needed to confirm our findings.

Acute treatment of migraine: quantifying the unmet need through real-world data in Italy.

OBJECTIVE: This study is describing subjects with migraine interrupting or not receiving triptans for acute treatment and providing a national-level estimate of people who might benefit from different therapeutic approaches. METHODS: This is a retrospective analysis using IQVIA Longitudinal Patient Database. Starting from 18 + years old individuals with migraine, we selected two cohorts: subjects with triptans prescriptions before and no triptans prescriptions after Index Date (triptan withdraw) and subjects without triptans prescriptions both before and after Index Date (no triptan prescriptions). Index Date was the first record of a health encounter for migraine in 2019. Individuals with cardiovascular disease (CVD) within no triptan prescriptions group were also quantified. RESULTS: Triptan withdraw and no triptan prescriptions cohorts numbered 605 and 3270, respectively, 5% and 29% of subjects with migraine. Mean age was 47 and 51 years respectively; women were more represented (~ 80%). Hypertension and thyroid disease were most frequent comorbidities; non-steroidal anti-inflammatory drugs were among most frequently recorded treatments. Subjects with CVD within no triptan prescriptions cohort were 621 and with triptan withdraw cohort subjects represented the basis to estimate those who might benefit from alternative options for the acute treatment of migraine, who were around 60,000 and accounted for 11% of subjects seeking primary care due to migraine. CONCLUSIONS: This analysis provides a real-word estimate of Italian people that might benefit from different therapeutic approaches as an alternative to triptans, which sometimes might be not effective and/or poorly tolerated. Such estimate should be intended as the lower limit of a wider range due to strict criteria adopted.

Monoclonal antibodies targeting the calcitonin gene-related peptide pathway improve the effectiveness of acute medication-a real-world study.

BACKGROUND: One of the aims of migraine prevention is to improve response to acute migraine treatments. The aim of the present study was to assess whether monoclonal antibodies targeting the CGRP pathway (CGRP-mAbs) can improve the perceived efficacy of acute treatments. METHODS: We included and followed up patients with chronic or episodic migraine from the Headache Centers of Avezzano-L'Aquila and Naples treated with CGRP-mAbs from March 2021 to December 2022. All patients filled out the Migraine Treatment Optimization Questionnaire (MTOQ), the Headache Impact Test (HIT-6), and the Migraine Impact and Disability Assessment Scale (MIDAS) at baseline and 3-6 months after the start of treatment with CGRP-mAbs. RESULTS: Sixty-five patients (81.3%) completed the 6-month follow-up. Most patients were female (55, 84.6%), with a median age of 46 years (IQR 39-56). Median MTOQ score increased from 8 (interquartile range [IQR] 4-13) at baseline to 15 (IQR 11-17) at 3 months (p < 0.001) and 16 (IQR 13-17) at the 6-month follow-up (p < 0.001). Median migraine days over 90-day periods decreased from 40 (IQR 24-60) to 24 (IQR 15-30) at 3 months (p < 0.001) and to 20 (IQR 12-24) at 6 months (p < 0.001). Median monthly intake of acute medication decreased from 55 doses (IQR 29-80.5) to 24 doses (IQR 15-40) at 3 months and 18 doses (IQR 11-30) at 6 months (p < 0.001). CONCLUSIONS: We showed that 6 months of preventive treatment with CGRP-mAbs led to a significantly better effectiveness of acute treatments, paralleled by decreased monthly migraine days and acute treatment intake.

MicroRNA profiling in women with migraine: effects of CGRP-targeting treatment.

BACKGROUND: Migraine lacks biomarkers that can trace the biological pathways of the disease and predict the effectiveness of treatments. Monoclonal antibodies targeting calcitonin gene-related peptide pathway - including erenumab - offer the opportunity of investigating potential migraine biomarkers due to their specific mechanism of action in preventing both episodic (EM) and chronic (CM) migraine. Our study aims at evaluating the expression levels of circulating microRNAs (miRNAs) according to migraine type, before and after treatment with erenumab and based on treatment response, in order to identify miRNAs with potential role as epigenetic biomarkers. METHODS: The study included women aged 25-50 years with EM or CM treated with erenumab according to clinical indications. MiRNAs expression levels were assessed before (baseline) and after a 16-week treatment with erenumab, 140 mg every four weeks (post-treatment). An extensive miRNAs profiling was performed by qRT-PCR in small, pooled groups of ≤ 8 women each, classified according to migraine frequency (EM and CM) and the degree of response to erenumab. The expression levels of selected miRNAs were also validated using single miRNA assays in each woman with EM and CM. RESULTS: During the study, 36 women with migraine (19 with EM and 17 with CM) out of 40 who were initially screened, performed the assessment of miRNA expression at baseline and post-treatment, Erenumab treatment significantly improved migraine burden in both EM and CM. MiRNA profiling revealed differential expression levels of a wide set of miRNAs (hsa-let-7d-3p, hsa-miR-106b-3p, hsa-miR-122-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-16-5p, hsa-miR-181a-5p, hsa-miR-221-3p, hsa-miR-25-3p, hsa-miR-29b-2-5p, hsa-miR-326, miR-363-3p, hsa-miR-424-5p, hsa-miR-485-3p, hsa-miR-532-5p, hsa-miR-543, hsa-miR-629-5p, hsa-miR-660-5p, hsa-miR-92a-3p) depending on treatment response. Among them, single miRNA assays confirmed the progressive decrease of hsa-miR-143-3p expression levels in relation to increasing response to erenumab in women with EM (7 with low, 6 with medium, and 6 with high response; p = 0.02). Additionally, single assays showed higher hsa-miR-34a-5p and hsa-miR-382-5p expression levels at baseline in women with CM compared with those with EM (p = 0.0002 and p = 0.0007, respectively), as well as their expression level decrease in women with CM from baseline to follow-up (p = 0.04 and p = 0.02, respectively). CONCLUSIONS: Our study suggests that targeting the CGRP pathway in migraine changes the expression levels of certain miRNAs. These miRNA levels are linked to the levels of response to CGRP receptor blockage. Future research challenges include assigning specific functions to the modulated miRNAs to unravel pathways modulated by the disease and the treatment. TRIAL REGISTRATION: The study was registered in clinicaltrials.gov with code NCT04659226 and in the Novartis database with code CAMG334AIT05T.

Divergence Between Clinical Trial Evidence and Actual Practice in Use of Dual Antiplatelet Therapy After Transient Ischemic Attack and Minor Stroke.

BACKGROUND: Randomized controlled trials (RCTs) proved that short-term (21-90 days) dual antiplatelet therapy (DAPT) reduces the risk of early ischemic recurrences after a noncardioembolic minor stroke or high-risk transient ischemic attack (TIA) without substantially increasing the hemorrhagic risk. We aimed at understanding whether and how real-world use of DAPT differs from RCTs. METHODS: READAPT (Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or TIA) is a prospective cohort study including >18-year-old patients treated with DAPT after a noncardioembolic minor ischemic stroke or high-risk TIA from 51 Italian centers. The study comprises a 90-day follow-up from symptom onset. In the present work, we reported descriptive statistics of baseline data of patients recruited up to July 31, 2022, and proportions of patients who would have been excluded from RCTs. We compared categorical data through the χ² test. RESULTS: We evaluated 1070 patients, who had 72 (interquartile range, 62-79) years median age, were mostly Caucasian (1045; 97.7%), and were men (711; 66.4%). Among the 726 (67.9%) patients with ischemic stroke, 226 (31.1%) did not meet the RCT inclusion criteria because of National Institutes of Health Stroke Scale score >3 and 50 (6.9%) because of National Institutes of Health Stroke Scale score >5. Among the 344 (32.1%) patients with TIA, 69 (19.7%) did not meet the RCT criteria because of age, blood pressure, clinical features, duration of TIA, presence of diabetes score <4 and 252 (74.7%) because of age, blood pressure, clinical features, duration of TIA, presence of diabetes score <6 and no symptomatic arterial stenosis. Additionally, 144 (13.5%) patients would have been excluded because of revascularization procedures. Three hundred forty-five patients (32.2%) did not follow the RCT procedures because of late (>24 hours) DAPT initiation; 776 (72.5%) and 676 (63.2%) patients did not take loading doses of aspirin and clopidogrel, respectively. Overall, 84 (7.8%) patients met the RCT inclusion/exclusion criteria. CONCLUSIONS: The real-world use of DAPT is broader than RCTs. Most patients did not meet the RCT criteria because of the severity of ischemic stroke, lower risk of TIA, late DAPT start, or lack of antiplatelet loading dose. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05476081.

Placebo and nocebo in the treatment of migraine: How much does real world effectiveness depend on contextual effects?

PURPOSE: Treatments in medicine impact individuals beyond their intended effects, due to phenomena such as the placebo and nocebo effects. The placebo effect arises from the positive expectation of a treatment being beneficial, while the nocebo effect stems from the negative expectation of a treatment causing harm. Both in real-world practice and clinical trials, treatments can lead to outcomes unrelated to their intended mechanism of action, which we categorize as placebo and nocebo responses. These responses, combined with the inherent fluctuation in a condition's natural progression, regression to the mean, and random comorbidities, make up a significant part of the therapeutic experience. Particularly in pain management, placebo and nocebo effects play a substantial role. By addressing modifiable contextual factors such as patient expectations, lifestyle choices, and the therapeutic relationship, healthcare providers can enhance the effectiveness of migraine treatments, paving the way for a more comprehensive, individualized approach to patient care. We must also consider non-modifiable factors like personal experiences, beliefs, and information from social media and the internet. CONCLUSION: This review offers a summary of our current understanding of the placebo and nocebo effects in migraine management.

White matter hyperintensities in migraine are not mediated by a dysfunction of the glymphatic system-A diffusion tensor imaging magnetic resonance imaging study.

OBJECTIVE: We assessed whether brain magnetic resonance imaging (MRI) markers of glymphatic function are altered in patients with migraine and brain white matter hyperintensities (WMHs). BACKGROUND: The glymphatic system is responsible for the outflow of waste products from the brain. An impaired glymphatic system has been associated with WMH; however, this impairment has not been shown in patients with migraine. METHODS: The present cross-sectional study included consecutive patients with migraine from a single tertiary headache center. Glymphatic function was assessed by measuring the diffusion tensor imaging along the perivascular space (DTI-ALPS) technique, resulting in an index value. WMHs were assessed and quantified by using the Scheltens semi-quantitative score. RESULTS: We included 147 patients (120 women [81.6%]) with a median (interquartile range [IQR]) age of 45 (36-50) years. In all, 74 (50.3%) patients had WMHs. The median (IQR) ALPS index was similar in patients with WMHs compared with those without, at 2.658 (2.332-3.199) versus 2.563 (2.222-3.050) (p = 0.344). The Scheltens score did not correlate with ALPS index (rho = 0.112, p = 0.268). CONCLUSIONS: Our results suggest that the presence of WMHs is not associated with an impairment in the glymphatic system in patients with migraine. Although negative and worthy of further confirmation, our finding has implications for the understanding of the nature of WMH in patients with migraine.

Reduction of in-hospital non-COVID-19 pneumonia in stroke patients during the COVID-19 pandemic.

BACKGROUND: Measures adopted to contain the spread of SARS-CoV-2 could have led to a reduction in the rate of non-COVID-19 infections. We assessed whether a similar reduction was present in patients with stroke. METHODS: We performed a hospital-based study nested in a prospective population-based registry. We compared prevalence of infections and in-hospital mortality in subjects admitted for acute stroke between the first pandemic year (study period, from March 2020 to February 2021) and the pre-pandemic year (control period, from March 2019 to February 2020). Infections were reported as pneumonia (PNA), urinary tract infections (UTI), and any infection (INF). RESULTS: From the control (n = 677) to the study period (n = 520), the prevalence of INF decreased from 11.5 to 4.6% (p < 0.001) and that of PNA decreased from 6.9 to 2.5% (p = 0.001). No changes in in-hospital mortality and length of hospital stay were observed between the two periods. CONCLUSIONS: The observed reduction of in-hospital pneumonias in patients with stroke was likely attributable to the use of protective measures and limitation of hospital visits. Maintaining some of those measures in the long term may contribute to control infections in hospitalized patients with stroke.

Validation of the Italian version of the Cluster Headache Impact Questionnaire (CHIQ).

BACKGROUND: The Cluster Headache Impact Questionnaire (CHIQ) is a specific and easy-to-use questionnaire to assess the current impact of cluster headache (CH). The aim of this study was to validate the Italian version of the CHIQ. METHODS: We included patients diagnosed with episodic CH (eCH) or chronic CH (cCH) according to the ICHD-3 criteria and included in the "Italian Headache Registry" (RICe). The questionnaire was administered to patients through an electronic form in two sessions: at first visit for validation, and after 7 days for test-retest reliability. For internal consistency, Cronbach's alpha was calculated. Convergent validity of the CHIQ with CH features and the results of questionnaires assessing anxiety, depression, stress, and quality of life was evaluated using Spearman's correlation coefficient. RESULTS: We included 181 patients subdivided in 96 patients with active eCH, 14 with cCH, and 71 with eCH in remission. The 110 patients with either active eCH or cCH were included in the validation cohort; only 24 patients with CH were characterized by a stable attack frequency after 7 days, and were included in the test-retest cohort. Internal consistency of the CHIQ was good with a Cronbach alpha value of 0.891. The CHIQ score showed a significant positive correlation with anxiety, depression, and stress scores, while showing a significant negative correlation with quality-of-life scale scores. CONCLUSION: Our data show the validity of the Italian version of the CHIQ, which represents a suitable tool for evaluating the social and psychological impact of CH in clinical practice and research.

Immunological Profile of Vasospasm after Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) carries high mortality and disability rates, which are substantially driven by complications. Early brain injury and vasospasm can happen after SAH and are crucial events to prevent and treat to improve prognosis. In recent decades, immunological mechanisms have been implicated in SAH complications, with both innate and adaptive immunity involved in mechanisms of damage after SAH. The purpose of this review is to summarize the immunological profile of vasospasm, highlighting the potential implementation of biomarkers for its prediction and management. Overall, the kinetics of central nervous system (CNS) immune invasion and soluble factors' production critically differs between patients developing vasospasm compared to those not experiencing this complication. In particular, in people developing vasospasm, a neutrophil increase develops in the first minutes to days and pairs with a mild depletion of CD45+ lymphocytes. Cytokine production is boosted early on after SAH, and a steep increase in interleukin-6, metalloproteinase-9 and vascular endothelial growth factor (VEGF) anticipates the development of vasospasm after SAH. We also highlight the role of microglia and the potential influence of genetic polymorphism in the development of vasospasm and SAH-related complications.

Health equity, care access and quality in headache - part 2.

BACKGROUND: Headache disorders are a global public health concern affecting diverse populations. This review examines headache service organizations in low-, middle-, and high-income countries. It addresses global challenges in pharmacological headache treatment, with a focus on safety, tolerability, reproductive and child health, and outlines disparities in accessing innovative treatments worldwide. MAIN BODY: Organized headache services are essential due to the wide prevalence and varying severity of headache disorders. The tiered headache service model is globally recognized, although its implementation varies based on financial and workforce considerations. Headache burden affects well-being, causing disability, economic challenges, and work limitations, irrespective of location or income. All nations still require improved diagnosis and treatment, and the majority of countries face obstacles including limited access, awareness, economic barriers, and inadequate health policies. Provided adequate internet availability, telemedicine could help improve health equity by expanding access to headache care, since it can offer patients access to services without lengthy waiting times or extensive travel and can provide healthcare unavailable in underserved areas due to staff shortages. Numerous health disparities restrict global access to many headache medications, especially impacting individuals historically excluded from randomized controlled trials, such as those with cardiovascular and cerebrovascular conditions, as well as pregnant women. Furthermore, despite advancements in researching migraine treatments for young patients, the options for treatment remain limited. Access to headache treatment relies on factors like medication availability, approval, financial coverage, and healthcare provider expertise. Inadequate public awareness leads to neglect by policymakers and undertreatment by patients and healthcare providers. Global access discrepancies are exacerbated by the introduction of novel disease-specific medications, particularly impacting Asian, African, and Latin American nations excluded from clinical trials. While North America and Europe experience broad availability of migraine treatments, the majority of countries worldwide lack access to these therapies. CONCLUSIONS: Healthcare disparities, treatment access, and medication availability are concerning issues in headache medicine. Variations in national healthcare systems impact headache management, and costly innovative drugs are widening these gaps. Healthcare practitioners and experts should acknowledge these challenges and work towards minimizing access barriers for equitable global headache care in the future.

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 2: flunarizine.

OBJECTIVE: Novel disease-specific and mechanism-based treatments sharing good evidence of efficacy for migraine have been recently marketed. However, reimbursement by insurers depends on treatment failure with classic anti-migraine drugs. In this systematic review and meta-analysis, we aimed to identify and rate the evidence for efficacy of flunarizine, a repurposed, first- or second-line treatment for migraine prophylaxis. METHODS: A systematic search in MEDLINE, Cochrane CENTRAL, and ClinicalTrials.gov was performed for trials of pharmacological treatment in migraine prophylaxis, following the Preferred Reporting Items for Systematic Reviews (PRISMA). Eligible trials for meta-analysis were randomized, placebo-controlled studies comparing flunarizine with placebo. Outcomes of interest according to the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) were the proportion of patients reaching a 50% or more reduction in monthly migraine days, the change in monthly migraine days (MMDs), and Adverse Events (AEs) leading to discontinuation. RESULTS: Five trials were eligible for narrative description and three for data synthesis and analysis. No studies reported the predefined outcomes, but one study assessed the 50% reduction in monthly migraine attacks with flunarizine as compared to placebo showing a benefit from flunarizine with a low or probably low risk of bias. We found that flunarizine may increase the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.02; 95% CI -0.03 to 0.06). CONCLUSIONS: Published flunarizine trials predate the recommended endpoints for evaluating migraine prophylaxis drugs, hence the lack of an adequate assessment for these endpoints. Further, modern-day, large-scale studies would be valuable in re-evaluating the efficacy of flunarizine for the treatment of migraines, offering additional insights into its potential benefits.

Primary headache epidemiology in children and adolescents: a systematic review and meta-analysis.

INTRODUCTION: Headache is the most prevalent neurological manifestation in adults and one of the leading causes of disability worldwide. In children and adolescents, headaches are arguably responsible for a remarkable impact on physical and psychological issues, yet high-quality evidence is scarce. MATERIAL AND METHODS: We searched cross-sectional and cohort studies in Embase, Medline, Web of Science, and Cochrane databases from January 1988 to June 2022 to identify the prevalence of headaches in 8-18 years old individuals. The risk of bias was examined with the Joanna Briggs Institute (JBI) scale. A random-effects model was used to estimate the pooled prevalence of pediatric headache. Subgroup analyses based on headache subtypes were also conducted. RESULTS: Out of 5,486 papers retrieved electronically, we identified 48 studies that fulfilled our inclusion criteria. The pooled prevalence of primary headaches was 11% for migraine overall [95%CI: 9-14%], 8% for migraine without aura (MwoA) [95%CI: 5-12%], 3% for migraine with aura (MwA) [95%CI:2-4%] and 17% for tension-type headache (TTH) [95% CI: 12-23%]. The pooled prevalence of overall primary headache in children and adolescents was 62% [95% CI: 53-70%], with prevalence in females and males of 38% [95% CI: 16-66%] and 27% [95% CI: 11-53%] respectively. After the removal of studies ranked as low-quality according to the JBI scale, prevalence rates were not substantially different. Epidemiological data on less common primary headaches, such as trigeminal autonomic cephalalgias, were lacking. CONCLUSION: We found an overall remarkably high prevalence of primary headaches in children and adolescents, even if flawed by a high degree of heterogeneity. Further up-to-date studies are warranted to complete the picture of pediatric headache-related burden to enhance specific public interventions.

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 1: amitriptyline.

OBJECTIVE: The aim of this paper is to critically re-appraise the published trials assessing amitriptyline for migraine prophylaxis. METHODS: We report our methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared amitriptyline with placebo for migraine prophylaxis in adults. Our outcomes of interest were informed by the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in migraine days per month, migraine days per month, and adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB 2.0 tool and the certainty of evidence by using the GRADE approach. RESULTS: Our search yielded 10.826 unique records, of which three trials (n = 622) were eligible for data synthesis and analysis. We found moderate certainty evidence that amitriptyline increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo (relative risk: 1.60 (95% CI 1.17 to 2.19); absolute risk difference: 165 more per 1,000 (95% CI 47 more to 327 more). We found moderate certainty evidence that amitriptyline increases the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.05 (95% CI 0.01 to 0.10); absolute risk difference: 50 more per 1,000 (95% CI 10 more to 100 more). CONCLUSIONS: Our meta-analysis showed that amitriptyline may have a prophylactic role in migraine patients, however these results are far from robust. This warrants further large-scale research to evaluate the role of amitriptyline in migraine prevention.

The COVID-19 Pandemic as an Opportunity to Improve Health Care Through a Nurse-Coordinated Multidisciplinary Model in a Headache Specialist Center: The Implementation of a Telemedicine Protocol.

Background: Due to coronavirus disease-19 (COVID-19) pandemic, Italian outpatient clinics were suspended in March-April 2020 and subsequently slowed down. Telemedicine was shown to be useful in headache clinics, despite absence of a detailed protocol for its development. Objective: To describe the implementation of a structured telemedicine protocol during COVID-19 pandemic. Materials and Methods: Since May 2020, we performed a quality improvement study in a Headache Specialist Center in central Italy. We involved patients who had in-person follow-up visits scheduled during suspension and initial reopening of clinics. Patients had two appointments with a nurse specialized in headache care and a headache physician, respectively, using Microsoft Teams®. The service is still active. We collected sociodemographic and clinical characteristics of patients, technical details of telemedicine visits, patient feedback, medical judgment about complexity of clinical decisions, and need for in-person re-evaluation. We also performed a Strengths-Weaknesses-Opportunities-Threats analysis to provide a realistic picture of the service. Results: We performed 207 telemedicine visits involving 100 patients with a median age of 44 (interquartile range [IQR]: 35-56) years; 76.0% were women and lived at a median of 68 (IQR: 24-109) km from the Center. Thirty-nine (39.0%) were visited for migraine without aura. Patients mostly used a computer (68.1% visits) with high audio-video quality in 93.2% of visits. First and second appointments lasted in median 20 (IQR: 14-25) minutes and 9 (IQR: 7-13) minutes, respectively. Interacting with patients was very easy in 66.7% of visits. Patients reported no difficulty in sharing documents and high satisfaction in 78.6% and 93.5% of visits, respectively. Perceived complexity of clinical decisions was generally low (86.5%), whereas 8.2% of cases required in-person re-evaluation. Conclusions: Telemedicine facilitated follow-ups, ensuring multidisciplinary care and high patient satisfaction, justifying its wider adoption in headache care.

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.

Behavioral and psychological factors in individuals with migraine without psychiatric comorbidities.

BACKGROUND: It is well known that the course of migraine is influenced by comorbidities and that individual psychological characteristics may impact on the disease. Proper identification of psychological factors that are relevant to migraine is important to improve non-pharmacological management. This study aimed at investigating the relationship between psychological factors and migraine in subjects free of psychiatric comorbidities. METHODS: A sample of women with episodic (EM) and chronic migraine (CM) without history of psychiatric comorbidities were included in this cross-sectional study. The study also included female healthy controls (HC) without migraine or other primary headaches. We evaluated sleep, anxiety, depression, intolerance of uncertainty, decision making style and tendence to pain catastrophizing by validated self-report questionnaires or scales. Comparisons among groups were performed using ANOVA and Bonferroni post-hoc tests. Statistical significance was set at p < 0.05. RESULTS: A total of 65 women with EM (mean age ± SD, 43.9 ± 7.2), 65 women with CM (47.7 ± 8.5), and 65 HC (43.5 ± 9.0) were evaluated. In sleep domains, CM patients reported poorer overall sleep quality, more severe sleep disturbances, greater sleep medication use, higher daytime dysfunction, and more severe insomnia symptoms than HC. EM group showed better sleep quality, lower sleep disturbances and sleep medication use than CM. On the other hand, the analysis highlighted more severe daytime dysfunction and insomnia symptoms in EM patients compared to HC. In anxiety and mood domains, CM showed greater trait anxiety and a higher level of general anxiety sensitivity than HC. Specifically, CM participants were more afraid of somatic and cognitive anxiety symptoms than HC. No difference in depression severity emerged. Finally, CM reported a higher pain catastrophizing tendency, more severe feeling of helplessness, and more substantial ruminative thinking than EM and HC, whilst EM participants reported higher scores in the three above-mentioned dimensions than HC. The three groups showed similar decision-making styles, intolerance of uncertainty, and strategies for coping with uncertainty. CONCLUSIONS: Even in individuals without psychiatric comorbidities, specific behavioral and psychological factors are associated with migraine, especially in its chronic form. Proper identification of those factors is important to improve management of migraine through non-pharmacological strategies.